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 NINTH EDITION

Skeel’s Handbook of
Cancer Therapy
Samir N. Khleif, MD
Director
Georgia Cancer Center
Immuno-Oncology Therapeutics Program
Professor of Medicine
Professor of Biochemistry and Molecular Biology
Medical College of Georgia
Professor of Graduate Studies
Augusta University
Augusta, Georgia

Olivier Rixe, MD, PhD

Professor
Division of Hematology-Oncology
The Dana Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research
University of New Mexico Comprehensive Cancer Center
Albuquerque, New Mexico

Roland T. Skeel, MD
Professor and Interim Chair
Department of Medicine
Division of Hematology-Oncology
University of Toledo College of Medicine and Life Sciences
Attending Physician
University of Toledo Medical Center
Toledo, Ohio
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Ninth Edition

Copyright © 2016 Wolters Kluwer.

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Library of Congress Cataloging-in-Publication Data

Names: Khleif, Samir N., editor. | Rixe, Olivier, editor. | Skeel, Roland T., editor.
Title: Skeel’s handbook of cancer therapy/[edited by] Samir N. Khleif, Olivier Rixe, Roland T. Skeel.
Other titles: Handbook of cancer chemotherapy.
Description: Ninth edition. | Philadelphia: Wolters Kluwer Health, 2016. |
Preceded by Handbook of cancer chemotherapy/edited by Roland T. Skeel, Samir N. Khleif. Eighth edition. 2011. | Includes
bibliographical references and index.
Identifiers: LCCN 2015051073 | 9781496305558 | 9781496353399
Subjects: | MESH: Neoplasms—therapy | Antineoplastic Agents—administration & dosage | Handbooks
Classification: LCC RC271.C5 | NLM QZ 39 | DDC 616.99/4061—dc23 LC record available at http://lccn.loc.gov/2015051073

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 To May, Zein, Noor, and Farah (SK)
To Sophie, Lea, Jeanne, Martin, and Eliott (OR)
and
Kristie, Joy, Kristi, Erika, Brian, Josh, Ali, and Jessica (RS)
and to all our patients.
CONTRIBUTORS

Olivia Bally, MD
Associate Professor
Department of Medical Oncology
Centre Léon Bérard
Université Claude Bernard Lyon I
Lyon, France

Rachid Baz, MD
Associate Member
Department of Malignant Hematology
H. Lee Moffitt Cancer Center and Research Institute
Associate Professor
Department of Oncologic Sciences
University of South Florida
Tampa, Florida

Al B. Benson III, MD
Professor of Medicine
Division of Hematology-Oncology
Associate Director for Cooperative Groups
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois

Michael J. Birrer, MD, PhD

Professor
Department of Medicine
Harvard Medical School
Physician
Division of Hematology-Oncology
Massachusetts General Hospital
Boston, Massachusetts

Jean-Yves Blay, MD, PhD

Professor of Medicine
Department of Medical Oncology
Centre Léon Bérard
Université Claude Bernard Lyon 1
Lyon, France

Jad Chahoud, MD
Resident Physician
Department of Internal Medicine
The University of Texas Health Science Center at Houston
McGovern Medical School
Houston, Texas

Shruti Chaturvedi, MBBS

Clinical Fellow
Vanderbilt University
Nashville, Tennessee

Bruce D. Cheson, MD, FACP, FAAAS, FASCO

Professor of Medicine and Deputy Chief
Division of Hematology-Oncology
Head of Hematology
Georgetown University Hospital
Lombardi Comprehensive Cancer Center
Washington, District of Columbia

Muhammad O. Chohan, MD
Director
Neurosurgical Oncology
Department of Neurosurgery
Co-leader
Neuro-Oncology
Multidisciplinary Program
University of New Mexico Comprehensive Cancer Center
Albuquerque, New Mexico

Jean-Michel Coindre, MD
Professor
Department of Pathology
Institut Bergonié
Bordeaux, France
Marcela G. del Carmen, MD, MPH
Professor
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

Jaydira del Rivero, MD

Medical Oncology Fellow
Adult Clinical Endocrinology
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

Don S. Dizon, MD, FACP

Associate Professor of Medicine
Harvard Medical School
Clinical Co-Director
Gynecologic Oncology
Director
The Oncology Sexual Health Clinica
Massachusetts General Hospital Cancer Center
Boston, Massachusetts

Robert Dreicer, MD, MS, FACP, FASCO

Section Head
Medical Oncology
Deputy Director
University of Virginia Cancer Center
Associate Director for Clinical Research
Professor of Medicine and Urology
University of Virginia School of Medicine
Charlottesville, Virginia

Robert A. Figlin, MD, FACP

Professor of Medicine and Biomedical Sciences
Steven Spielberg Family Chair in Hematology Oncology
Director
Division of Hematology-Oncology
Deputy Director, Samuel Oschin Comprehensive Cancer Institute
Cedars-Sinai Medical Center
Los Angeles, California

Antonio Tito Fojo, MD, PhD

Medical Oncology Branch and Affiliates
Head
Experimental Therapeutics Section
Senior Investigator
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland

Olga Frankfurt, MD
Associate Professor in Medicine
Division of Hematology-Oncology
Northwestern University Feinberg School of Medicine
Chicago, Illinois

Gregory N. Gan, MD, PhD

Assistant Professor
Director of Basic Research in Radiation Oncology
Division of Medical Oncology
Section of Radiation Oncology
University of New Mexico Comprehensive Cancer Center
Albuquerque, New Mexico

Guillermo Garcia-Manero, MD
Professor
Chief Section of MDS
Deputy Chair
Translational Research
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas

David E. Gerber, MD
Associate Professor
Division of Hematology-Oncology
Department of Internal Medicine
Harold C. Simmons Comprehensive Cancer Center
University of Texas Southwestern Medical Center
Dallas, Texas

David M.J. Hoffman, MD, FACP

Associate Clinical Professor of Medicine
University of California
Clinical Associate Professor of Medicine
Cedars Sinai Medical Center
Los Angeles, California

Clifford A. Hudis, MD, FACP

Chief
Breast Medicine Service
Department of Medicine
Vice President for Government Relations and Chief Advocacy Officer
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, New York

Mohamad A. Hussein, MD, MB, BCh

Professor of Medicine and Oncology
University of South Florida
Morsani College of Medicine
Tampa, Florida

Elias Jabbour, MD
Associate Professor
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas

John E. Janik, MD
Director
Immune Therapy Clinical Trials Program Leader
Melanoma Multi-Disciplinary Clinic
Professor of Medicine
Georgia Cancer Center
Augusta University
Augusta, Georgia

Hagop M. Kantarjian, MD
Professor
Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas

Timothy J. Kennedy, MD, MBA

Associate Professor
Department of Surgery
Rutgers Cancer Institute of New Jersey
Chief of Gastrointestinal Surgical Oncology
Rutgers Cancer Institute of New Jersey
Robert Wood Johnson Hospital
New Brunswick, New Jersey

Samir N. Khleif, MD
Director
Georgia Cancer Center
Immuno-Oncology Therapeutics Program
Professor of Medicine
Professor of Biochemistry and Molecular Biology
Medical College of Georgia
Professor of Graduate Studies
Augusta University
Augusta, Georgia

Sheetal M. Kircher, MD
Assistant Professor in Medicine
Division of Hematology-Oncology
Northwestern University Feinberg School of Medicine
Chicago, Illinois

Ashwin Kishtagari, MD
Resident
Department of Internal Medicine
Mount Sinai St. Luke’s–Roosevelt Hospital
New York, New York
Ragini Kudchadkar, MD
Assistant Professor
Division of Hematology-Oncology
Winship Cancer Institute
Emory University
Atlanta, Georgia

Rekha A. Kumbla, MD
Hematology-Oncology Fellow
Division of Hematology-Oncology
Samuel Oschin Comprehensive Cancer
Cedars Sinai Medical Center
Los Angeles, California

Paul R. Kunk, MD
Hematology Oncology Fellow
Division of Hematology Oncology
Department of Medicine
University of Virginia Health System
Charlottesville, Virginia

Catherine Lai, MD, MPH

Faculty
Lymphoid Malignancies Branch
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland

Steven K. Libutti, MD, FACS

Director
Montefiore Einstein Center for Cancer Care
Vice-Chairman
Department of Surgery
The Marvin L. Gliedman, MD Distinguished Surgeon
Professor of Surgery and Genetics
Montefiore Medical Center and Albert Einstein College of Medicine
Bronx, New York

Christophe Massard, MD, PhD

Medical Oncologist
Senior Consultant
Department of Medical Oncology and Drug Development Department (DITEP)
Head of Inpatient Unit (SITEP)
Chairman of Early Drug Development Tumor Board
Gustave Roussy Cancer Campus
Villejuif, France

David S. Morgan, MD
Associate Professor of Medicine
Division of Hematology-Oncology
Vanderbilt University Medical Center
Nashville, Tennessee

Frank E. Mott, MD, FACP

Professor of Medicine
Division of Hematology-Oncology
Georgia Cancer Center
Augusta University
Augusta, Georgia

Lorraine C. Pelosof, MD, PhD

Assistant Professor
Attending Physician
Division of Hematology-Oncology
University of Texas Southwestern Medical Center
Dallas, Texas

Osama E. Rahma, MD
Assistant Professor of Medicine
Division of Hematology-Oncology
Department of Medicine
University of Virginia Health System
Charlottesville, Virginia

J. Alejandro Rauh-Hain, MD
Instructor
Division of Gynecologic Oncology
Vincent Obstetrics and Gynecology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

Olivier Rixe, MD, PhD

Professor
Division of Hematology-Oncology
The Dana Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research
University of New Mexico Comprehensive Cancer Center
Albuquerque, New Mexico

Mark Roschewski, MD
Staff Clinician
Lymphoid Malignancies Branch
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland

Ibrahim Ebada Sadek, MD

Second Year Fellow
Division of Hematology-Oncology
Augusta University
Augusta, Georgia

Joan H. Schiller, MD
Professor and Chief
Division of Hematology-Oncology
Harold C. Simmons Comprehensive Cancer Center
University of Texas Southwestern Medical Center
Dallas, Texas

Josh David Simmons, MD

Hematology/Oncology Fellow
Department of Internal Medicine
Division of Hematology-Oncology
Medical College of Georgia
Georgia Regents University
Augusta, Georgia

Roland T. Skeel, MD
Professor and Interim Chair
Department of Medicine
Division of Hematology-Oncology
University of Toledo College of Medicine and Life Sciences
Attending Physician
University of Toledo Medical Center
Toledo, Ohio

Lillian M. Smyth, MD
Advanced Medical Oncology Fellow
Breast Medicine Service
Memorial Sloan Kettering Cancer Center
New York, New York

Mario Sznol, MD
Professor
Section of Medical Oncology
Department of Internal Medicine
Yale University
Yale–New Haven Hospital
New Haven, Connecticut

Martin S. Tallman, MD
Chief of Leukemia Service
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, New York

Janelle M. Tipton, MSN, RN, AOCN

Oncology Clinical Nurse Specialist
Infusion Center Director
Eleanor N. Dana Cancer Center
University of Toledo Medical Center
Volunteer Faculty
Colleges of Medicine and Nursing
University of Toledo
Toledo, Ohio

Anis Toumeh, MD
Medical Oncologist
Central Care Cancer Center
Attending Physician
Southwest Medial Center
Liberal, Kansas

Chaitra Ujjani, MD
Assistant Professor
Division of Hematology-Oncology
Department of Medicine
Lombardi Comprehensive Cancer Center
Medstar Georgetown University Hospital
Washington, District of Columbia

Srdan Verstovsek, MD, PhD

Professor of Medicine
Director
Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas

Jeffrey S. Weber, MD, PhD

Deputy Director
Laura and Isaac Perlmutter Cancer Center
Professor of Medicine
New York University Langone Medical Center
New York, New York

Wyndham H. Wilson, MD, PhD

Senior Investigator
Lymphoid Malignancies Branch
Head
Lymphoma Therapeutics Section
National Institutes of Health
National Cancer Institute
Bethesda, Maryland

Jessica Yarber, MD
Hematology and Oncology Fellow
Division of Hematology-Oncology
McGaw Medical Center of Northwestern University
Chicago, Illinois
 PREFACE

Since the last edition of this book, many new significant advances have occurred in the
systemic treatment of cancer, and they have occurred at a pace that has never been seen since
1982, when this Handbook was first published. This has led to major additions to the book and
some changes to the way information is being presented. The recent immunotherapy revolution
and the advances in oncology genomics and in molecular targeted therapy are reflected in this
current edition in both the general sections and the disease-specific chapters. The rapid
expansion of these new agents has resulted from the explosion of biologic insights into the
etiology and behavior of cancer that have taken place over the last quarter century. These drugs
have clearly changed the face of cancer treatment and are rapidly becoming integrated into
cancer therapeutics and treatment strategies for many cancers. Because of the importance of
this new class of agents, we have added a new chapter entitled “Biologic Basis of Molecular
Targeted Therapy.” In this chapter, we give a brief overview of the molecular basis for the
activity of these agents and the relevant pathways they target in order to provide the reader
with the basic knowledge and understanding of the rationale for the use of such agents in the
treatment of cancer. These major developments in the field of oncology, as reflected in the
book, led us to change the name from Handbook of Cancer Chemotherapy to Handbook of
Cancer Therapy.
This book has been one of the leading handbooks in cancer treatment for more than three
decades and has been one of the best-selling books in its category. It has been translated into
several languages and is used by all levels of physicians, nurses, and allied health
professionals who provide care to cancer patients. The champion behind this great effort has
been Dr. Roland T. Skeel. For over five decades, Roland has been one of the best and most
skillful clinicians who have ever existed and, most importantly, is an amazingly compassionate
human being. Dr. Skeel is a true professor and an incredible educator. The Handbook is an
example of his commitment to disseminating the knowledge of oncology and the skills of
healing art. In recognition of Dr. Skeel’s contributions, we decided to name this book, starting
with its 9th edition, Skeel’s Handbook of Cancer Therapy.
As with previous editions, several new authors have been added to keep the information
fresh and timely. As done previously, primary indications, usual dosage and schedule, special
precautions, and expected toxici-ties have been added for the new drugs and biologic agents
that oncologists have begun to use in the past five years, and new data have been added to the
information for many of the older agents. To facilitate easy access to this practical information,
we have kept the section containing an alphabetical listing for all drugs used in practice at the
end of the Handbook. In addition, each of the chapters dealing with specific cancer sites has
been revised to reflect current best medical practice, including the use of molecular targeted
therapy, and to point the way toward future advances.
 Cure of cancer with less toxic systemic treatment has been a long-term aspiration for many
people: those engaged in basic cancer research, physicians who are daily faced with anxious
patients who have cancer, and others in the health profession. It has also been a fervent hope
for patients and their families. Although cure is possible for some common tumors, particularly
when there is only micrometastasis, and for some more advanced tumors such as lymphomas,
for most patients chemotherapy remains palliative, at best. When curing and minimizing the
cancer can no longer be achieved, then expert, compassionate supportive care becomes the
essential and appropriate focus of the oncology team. The section on supportive care has been
updated to highlight those issues and pharmacologic agents that are most essential to the daily
care of patients with cancer.
The Handbook continues to be a practical pocket or desk reference, with a wide range of
information for oncology specialists, non oncology physicians, house officers, oncology
nurses, pharmacists, and medical and pharmacy students. It can even be read and understood by
many patients and their families who want to be able to find practical information about their
cancer and its treatment. Unlike many other books, Skeel’s Handbook combines in one place
the most current rationale and the specific details necessary to safely administer
pharmacologic therapy for most adult cancer patients.
Progress is always slower than patients, physicians, and basic scientists would like.
Current research that joins the expertise and discoveries of the basic scientist, systematic
investigation through clinical trials by the clinician, and their interaction in “translational”
research continues to offer a realistic expectation of accelerated progress in the control of
cancer in the decades ahead.

Samir N. Khleif, MD
Olivier Rixe, MD
 CONTENTS

Contributors
Preface

SECTION I: BASIC PRINCIPLES AND CONSIDERATIONS OF RATIONAL

CHEMOTHERAPY AND MOLECULAR TARGETED THERAPY

Biologic and Pharmacologic Basis of Cancer Chemotherapy

1 Roland T. Skeel

Biologic Basis of Molecular Targeted Therapy

2 Osama E. Rahma, Paul R. Kunk, and Samir N. Khleif

Principles of Cancer Immunotherapy

3 Mario Sznol

Systematic Assessment of the Patient With Cancer and Consequences of Treatment

4 Roland T. Skeel

Selection of Treatment for the Patient With Cancer

5 Roland T. Skeel

SECTION II: MEDICAL THERAPIES OF HUMAN CANCER

Carcinomas of the Head and Neck

6 Frank E. Mott, Ibrahim Ebada Sadek, and Josh David Simmons

Carcinoma of the Lung

7 Lorraine C. Pelosof, David E. Gerber, and Joan H. Schiller

Carcinomas of the Gastrointestinal Tract

8 Jessica Yarber, Sheetal M. Kircher, and Al B. Benson III

Carcinomas of the Pancreas, Liver, Gallbladder, and Bile Ducts

9 Timothy J. Kennedy and Steven K. Libutti

Carcinoma of the Breast

10 Lillian M. Smyth and Clifford A. Hudis

Gynecologic Cancer
11 J. Alejandro Rauh-Hain, Marcela G. del Carmen, Don S. Dizon, and Michael J. Birrer

Urologic and Male Genital Cancers

Robert Dreicer
12

Kidney Cancer
13 David M.J. Hoffman, Rekha A. Kumbla, and Robert A. Figlin

Endocrine Cancers
14 Jaydira del Rivero and Antonio Tito Fojo

Melanomas and Other Cutaneous Malignancies

15 Ragini Kudchadkar and Jeffrey S. Weber

Primary and Metastatic Brain Tumors

16 Muhammad O. Chohan, Gregory N. Gan, and Olivier Rixe

Soft-Tissue Sarcomas
17 Jean-Yves Blay, Olivia Bally, and Jean-Michel Coindre

Bone Sarcomas
18 Jean-Yves Blay and Olivia Bally

Acute Leukemias
19 Ashwin Kishtagari, Olga Frankfurt, and Martin S. Tallman

Chronic Leukemias
20 Chaitra Ujjani and Bruce D. Cheson

Myeloproliferative Neoplasms and Myelodysplastic Syndromes

21 Jad Chahoud, Srdan Verstovsek, Guillermo Garcia-Manero, Hagop M. Kantarjian, and Elias Jabbour

Hodgkin Lymphoma
22 Shruti Chaturvedi and David S. Morgan

Non-Hodgkin Lymphoma
23 Catherine Lai, Mark Roschewski, and Wyndham H. Wilson

Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis

24 Rachid Baz and Mohamad A. Hussein

Metastatic Cancer of Unknown Origin

25 Christophe Massard

SECTION III: SUPPORTIVE CARE OF PATIENTS WITH CANCER

Side Effects of Chemotherapy

26 Janelle M. Tipton

Side Effects of Immune Therapy

27 John E. Janik

SECTION IV: CHEMOTHERAPEUTIC AND MOLECULAR TARGETED AGENTS

AND THEIR USE

Classification, Use, and Toxicity of Clinically Useful Chemotherapy and Molecular

28 Targeted Therapy
Anis Toumeh and Roland T. Skeel

Index
 SECTION I: BASIC PRINCIPLES AND
CONSIDERATIONS OF RATIONAL
CHEMOTHERAPY AND MOLECULAR
TARGETED THERAPY

I. GENERAL MECHANISMS BY WHICH CHEMOTHERAPEUTIC AGENTS

CONTROL CANCER
The purpose of treating cancer with chemotherapeutic agents, whether traditional or
targeted, is to prevent cancer cells from multiplying, invading, metastasizing, and
ultimately killing the patient. Most traditional chemotherapeutic agents appear to exert their
effect primarily on cell proliferation. Because cell multiplication is a characteristic of
many normal cells as well as cancer cells, most nontargeted cancer chemotherapeutic
agents also have toxic effects on many normal cells, particularly those with a rapid rate of
turnover, such as bone marrow and mucous membrane cells. The goal in selecting an
effective drug in this category, therefore, is to find an agent that has a marked growth-
inhibitory or controlling effect on the cancer cell and a minimal toxic effect on the host. In
the most effective chemotherapeutic regimens, the drugs are capable not only of inhibiting
but also of completely eradicating all neoplastic cells while sufficiently preserving normal
marrow and other target organs to permit the patient to return to normal, or at least
satisfactory, function, duration, and quality of life.
Inhibition of cell multiplication and tumor growth can take place at several levels
within the cell and its environment:
■ Macromolecular synthesis and function
■ Cytoplasmic organization and signal transduction
■ Cell membrane and associated cell surface receptor synthesis, expression, and function
■ Environment of cancer cell growth
A. Classic chemotherapy agents
Most traditional chemotherapy agents (not including immunotherapeutic agents, other
biologic response modifiers, and molecular targeted therapies) appear to have their
 primary effect on either macromolecular synthesis or its function.1 This effect means
that they interfere with the synthesis of DNA, RNA, or proteins or with the appropriate
functioning of the preformed molecule. When interference in macromolecular synthesis
or function in the neoplastic cell population is sufficiently great, a proportion of the
cells die. Some cells die because of the direct effect of the chemotherapeutic agent. In
other instances, the chemotherapy may trigger differentiation, senescence, or apoptosis,
the cell’s own mechanism of programmed death.
Cell death may or may not take place at the time of exposure to the drug. Often, a
cell must undergo several divisions before the lethal event that took place earlier finally
results in the death of the cell. Clinical responses may thus be delayed even when the
treatment has effectively put the tumor cells into a death spiral. Because only a
proportion of the cells die as a result of a given treatment, repeated doses of
chemotherapy must be used to continue to reduce the cell number (Fig. 1.1). In an ideal
system, each time the dose is repeated, the same proportion of cells—not the same
absolute number—is killed. In the example shown in Figure 1.1, 99.9% (3 logs) of the
cancer cells are killed with each treatment, and there is a 10-fold (1-log) growth
between treatments, for a net reduction of 2 logs with each treatment. Starting at 1010
cells (about 10 g or 10 cm3 leukemia cells), it would take five treatments to reach fewer
than 100, or 1, cell. Such a model makes certain assumptions that rarely are strictly true
in clinical practice2,3:
■ All cells in a tumor population are equally sensitive to a drug.
■ Drug accessibility and cell sensitivity are independent of the location of the cells
within the host and of local host factors such as blood supply and surrounding
fibrosis.
■ Cell sensitivity does not change during the course of therapy.
The lack of curability of most initially sensitive tumors is probably a reflection of
the degree to which these assumptions do not hold true.
FIGURE 1.1 The effect of chemotherapy on cancer cell numbers. In an ideal system,
chemotherapy kills a constant proportion of the remaining cancer cells with each dose.
Between doses, cell regrowth occurs. When therapy is successful, cell killing is greater than
cell growth.

B. Biologic response modifiers and molecular targeted therapy

There are intricate interrelated mechanisms within individual cells and cell populations
that promote or suppress cell proliferation, facilitate invasion or metastasis when the
cell is malignant, lead to cell differentiation, promote (relative) cell immortality, or set
the cell on the path to inevitable death (apoptosis). These activities are controlled in
large part by normal genes and, in the case of cancer by mutated constitutive genes,
cancer promoter genes, tumor suppressor genes, and their products. Included in these
products are a host of cell growth factors that control the machinery of the cell. Some of
these factors that affect normal cell growth have been biosynthesized and are now used
to enhance the production of normal cells (e.g., epoetin- α and filgrastim) and to treat
cancer (e.g., interferon).
The recent expansion of our understanding of the biologic control of normal cells
and tumor growth at the molecular level has begun to offer improved therapy for many
 types of cancer, such as melanoma and kidney cancer that formerly were quite resistant
to traditional chemotherapy, and has helped to explain differences in response among
cancers, formerly thought to be similar such as diffuse large cell lymphoma. New
discoveries in cancer cell biology have provided insights into apoptosis, cell cycling
control, angiogenesis, metastasis, cell signal transduction, cell surface receptors,
differentiation, and growth factor modulation. New drugs in clinical trials have been
designed to block growth factor receptors, prevent oncogene activity, block the cell
cycle, restore apoptosis, inhibit blockade of immune recognition and control, inhibit
angiogenesis, restore lost function of tumor suppressor genes, and selectively kill
tumors containing abnormal genes. Further understanding of each of these holds a great
potential for providing powerful and more selective means to control neoplastic cell
growth and have already led to more effective cancer treatments in the past decade.4
The fundamental principles related to this group of antineoplastic agents are discussed
in Chapter 2.

II. TUMOR CELL KINETICS AND CHEMOTHERAPY5

Cancer cells, unlike other body cells, are characterized by a growth process whereby their
sensitivity to normal controlling factors has been partially or completely lost. As a result of
this uncontrolled growth, it was once thought that all cancer cells grew or multiplied faster
than normal cells and that this growth rate was primarily responsible for the sensitivity of
cancer cells to chemotherapy. Now it is known that most cancer cells grow less rapidly
than the more active normal cells such as bone marrow. Thus, although the growth rate of
many cancers may be faster than that of normal surrounding tissues, growth rate alone
cannot explain the greater sensitivity of cancer cells to chemotherapy.
A. Tumor growth. The growth of a tumor depends on several interrelated factors.6
1. Cell cycle time or the average time for a cell that has just completed mitosis to
grow, redivide, and again pass through mitosis determines the maximum growth rate
of a tumor, but probably does not determine drug sensitivity. The relative proportion
of cell cycle time taken up by the DNA synthesis phase may relate to the drug
sensitivity of some types (synthesis phase–specific) of chemotherapeutic agents.
2. Growth fraction or the fraction of cells undergoing cell division contains the
portion of cells that are sensitive to drugs whose major effect is exerted on cells that
are dividing actively. If the growth fraction approaches 1 and the cell death rate is
low, the tumor-doubling time approximates the cell cycle time.
3. Total number of cells in the population (determined at some arbitrary time at which
the growth measurement is started) is clinically important because it is an index of
how advanced the cancer is; it frequently correlates with normal organ dysfunction.
As the total number of cells increases, so does the number of resistant cells, which
in turn leads to decreased curability. Large tumors may also have greater
compromise of blood supply and oxygenation, which can impair drug delivery to the
tumor cells as well as impair sensitivity to both chemotherapy and radiotherapy.
 4. Intrinsic cell death rate of tumors is difficult to measure in patients, but probably
makes a major and positive contribution by slowing the growth rate of many solid
tumors.
B. Cell cycle
The cell cycle7 of cancer cells is qualitatively the same as that of normal cells (Fig.
1.2). Each cell begins its growth during a postmitotic period, a phase called G1, during
which enzymes necessary for DNA production, other proteins, and RNA are produced.
G1 is followed by a period of DNA synthesis (S phase), in which essentially all DNA
synthesis for a given cycle takes place. When DNA synthesis is complete, the cell enters
a premitotic period (G2), during which further protein and RNA synthesis occurs. This
gap is followed immediately by mitosis, at the end of which actual physical division
takes place, two daughter cells are formed, and each cell again enters G1. G1 phase is in
equilibrium with a resting state called G0. Cells in G0 are relatively inactive with
respect to macromolecular synthesis and are consequently insensitive to many
traditional chemotherapeutic agents, particularly those that affect macromolecular
synthesis.

FIGURE 1.2 Cell cycle time for human tissues has a wide range (16 to 260 hours), with
marked differences among normal and tumor tissues. Normal marrow and gastrointestinal
lining cells have cell cycle times of 24 to 48 hours. Representative durations and the kinetic or
synthetic activity are indicated for each phase.

C. Phase and cell cycle specificity

Most classic chemotherapeutic agents can be grouped according to whether they depend
on cells being in cycle (i.e., not in G0) or, if they depend on the cell being in cycle,
whether their activity is greater when the cell is in a specific phase of the cycle. Most
agents cannot be assigned to one category exclusively. Nonetheless, these
classifications can be helpful for understanding drug activity.
1. Phase-specific drugs. (see) Table 1.1.
a. Implications of phase-specific drugs
1) Limitation to single-exposure cell kill. With a phase-specific agent, there is
 a limit to the number of cells that can be killed with a single instantaneous (or
very short) drug exposure because only those cells in the sensitive phase are
killed. A higher dose kills no more cells.
2) Increasing cell kill by prolonged exposure. To kill more cells requires
either prolonged exposure to, or repeated doses of, the drug to allow more
cells to enter the sensitive phase of the cycle. Theoretically, all cells could
be killed if the blood level or, more importantly, the intracellular
concentration of the drug remained sufficiently high while all cells in the
target population passed through one complete cell cycle. This theory
assumes that the drug does not prevent the passage of cells from one
(insensitive) phase to another (sensitive) phase.

TABLE
Examples of Cell Cycle Phase–Specific Chemotherapeutic Agents
1.1

3) Recruitment. A higher number of cells could be killed by a phase-specific

drug if the proportion of cells in the sensitive phase could be increased
(recruited).
 b. Cytarabine. One of the best examples of a phase-specific agent is cytarabine
(ara-C), which is an inhibitor of DNA synthesis and thus is active only in the
synthesis phase (at standard doses). When used in doses of 100 to 200 mg/m2
daily (i.e., not “high-dose ara-C”), ara-C is rapidly deaminated in vivo to an
inactive compound, ara-U, and rapid injections result in very short effective
levels of ara-C. As a result, single doses of ara-C are nontoxic to the normal
hematopoietic system and are generally ineffective for treating leukemia. If the
drug is given as a daily rapid injection, some patients with leukemia respond
well but not nearly as well as when ara-C is given every 12 hours (or by
continuous infusion). The apparent reason for the greater effectiveness of the 12-
hour schedule is that the synthesis phase (DNA synthesis) of human acute
myelogenous leukemia cells lasts about 18 to 20 hours. If the drug is given every
24 hours, some cells that have not entered the synthesis phase when the drug is
first administered will not be sensitive to its effect. Therefore, these cells can
pass all the way through the synthesis phase before the next dose is administered
and will completely escape any cytotoxic effect. However, when the drug is
given every 12 hours, no cell that is “in cycle” will be able to escape exposure
to ara-C because none will be able to get through one complete synthesis phase
without the drug being present.8
If all cells were in active cycle, that is, if none were resting in a prolonged
G1 or G0 phase, it would be theoretically possible to kill any cells in a
population by a continuous or scheduled exposure equivalent to one complete
cell cycle. Experiments with patients who have acute leukemia have shown that
if tritiated thymidine is used to label cells as they enter DNA synthesis, it may be
7 to 10 days before the maximum number of leukemia cells have passed through
the synthesis phase. This means that, barring permutations caused by ara-C or
other drugs, for ara-C to have a maximum effect on the leukemia, the repeated
exposure must be continued for a 7- to 10-day period. Clinically, continuous
infusion or administration of ara-C every 12 hours for 7 days appears to be most
effective for treating patients with newly diagnosed acute myelogenous
leukemia. However, even with such prolonged exposure, it appears that a few of
the cells do not pass through the synthesis phase and escape total cell kill, thus
evading cure of the patient.
2. Cell cycle–specific drugs. Agents that are effective while cells are actively in cycle
but that are not dependent on the cell being in a particular phase are called cell
cycle–specific (or phase-nonspecific) drugs. This group includes most of the
alkylating agents, the antitumor antibiotics, and some miscellaneous agents,
examples of which are shown in Table 1.2. Some agents in this group are not totally
phase-nonspecific; they may have greater activity in one phase than in another, but
not to the degree of the phase-specific agents. Many agents also appear to have some
activity in cells that are not in cycle, although not as much as when the cells are
 rapidly dividing.

TABLE
Examples of Cell Cycle–Specific and Cell Cycle–Nonspecific Chemotherapeutic
Agents
1.2
Class Type Characteristic Agents
Cell Cycle–Specific
Chlorambucil, cyclophosphamide-
Alkylating agent Nitrogen mustard
melphalan
Alkyl sulfonate Busulfan
Triazene Dacarbazine
Metal salt Cisplatin, carboplatin
Dactinomycin, daunorubicin, doxorubicin,
Natural product Antibiotic
idarubicin
Cell Cycle–Nonspecific
Alkylating agent Nitrogen mustard Mechlorethamine
Nitrosourea Carmustine, lomustine

3. Cell cycle–nonspecific drugs. A third group of drugs appears to be effective

whether cancer cells are in cycle or are resting. In this respect, these agents are
similar to photon irradiation; that is, both types of therapy are effective irrespective
of whether or not the cancer cell is in cycle. Drugs in this category are called cell
cycle–nonspecific drugs and include mechlorethamine (nitrogen mustard) and the
nitrosoureas (see Table 1.2).
D. Changes in tumor cell kinetics and therapy implications
As cancer cells grow from a few cells to a lethal tumor burden, certain changes occur in
the growth rate of the population and affect the strategies of chemotherapy. These
changes have been determined by observing the characteristics of experimental tumors
in animals and neoplastic cells growing in tissue culture. Such model systems readily
permit accurate cell number determinations to be made and growth rates to be
determined. (Because tumor cells cannot be injected or implanted into humans and
permitted to grow, studies of growth rates of intact tumors in humans must be limited
largely to observing the growth rate of macroscopic tumors.)
1. Stages of tumor growth. Immediately after inoculation of a tissue culture or an
experimental animal with tumor cells, there is a lag phase, during which there is
little tumor growth; presumably, the cells in this phase are becoming accustomed to
the new environment and are preparing to enter into cycle. The lag phase is followed
by a period of rapid growth called the log phase, during which there are repeated
doublings of the cell number. In populations in which the growth fraction approaches
100% and the cell death rate is low, the population doubles within a period
 approximating the cell cycle time. As the cell number or tumor size becomes
macroscopic, the doubling time of the tumor cell population becomes prolonged and
levels off (plateau phase). Most clinically measurable human cancers are probably
in the plateau phase, which may account, in part, for the slow doubling time
observed in many human cancers (30 to 300 days). Because the rate of change in the
slope of the growth curve during the premeasurable period is unknown for most
human cancers, extrapolation from two points when the mass is measurable to
estimate the onset of the growth of the malignancy is subject to considerable error.
The prolongation in tumor-doubling time in the plateau phase may be due to a
smaller growth fraction, a change in the cell cycle time, an increased intrinsic death
rate (predominantly apoptosis, which is a programmed and highly orchestrated cell
death that occurs both naturally and under the influence of many types of
chemotherapy), or a combination of these factors. Factors responsible for these
changes include decreased nutrients or growth promotion factors, increased
inhibitory metabolites or inhibitory growth factors, and inhibition of growth by other
cell-cell interactions. In the intact host, new blood vessel formation is a critical
determinant of these factors.
2. Growth rate and effectiveness of chemotherapy. Traditional chemotherapeutic
agents are most effective during the period of logarithmic growth. As might be
expected, this result is particularly true for the antimetabolites, which are largely
synthetic phase–specific. As a result, when human tumors become macroscopic, the
effectiveness of many chemotherapeutic agents is reduced because only part of the
cell population is dividing actively. Theoretically, if the cell population could be
reduced sufficiently by other means such as surgery or radiotherapy, chemotherapy
would be more effective because a higher fraction of the remaining cells would be
in logarithmic growth. The validity of this theoretical premise is supported by the
varying degrees of success of surgery plus chemotherapy or radiotherapy plus
chemotherapy in the treatment of breast cancer, colon cancer, Wilms tumor, ovarian
cancer, small-cell anaplastic cell carcinoma of the lung, non–small-cell carcinoma
of the lung, head and neck cancers, and osteosarcomas.

III. COMBINATION CHEMOTHERAPY

Combinations of drugs are frequently more effective in producing responses and
prolonging life than are the same drugs used sequentially. Combinations are likely to be
more effective than single agents for several reasons.9
A. Reasons for effectiveness of combinations
1. Prevention of resistant clones. If 1 in 105 cells is resistant to drug A and 1 in 105
cells is resistant to drug B, it is likely that treating a macroscopic tumor (which
generally would have more than 109 cells) with either agent alone would result in
several clones of cells that are resistant to that drug. If, after treatment with drug A, a
resistant clone has grown to macroscopic size (if the same mutant frequency persists
 for drug B), resistance to that agent will also emerge. If both drugs are used at the
outset of therapy or in close sequence, however, the likelihood of a cell being
resistant to both drugs (excluding, for a moment, the situation of pleiotropic drug
resistance) is only 1 in 1010. Thus, the combination confers considerable advantage
against the emergence of resistant clones. Compounding the problem of preexisting
resistant clones is the resistance that develops through spontaneous mutation in the
absence of drug exposure. The use of multiple drugs with independent mechanisms
of action or alternating non–cross-resistant combinations (as well as the use of
surgery or radiotherapy to eliminate macroscopic tumor) theoretically minimizes the
chances for outgrowth of resistant clones and increases the likelihood of remission
or cure.
2. Cytotoxicity to resting and dividing cells. The combination of a drug that is cell
cycle–specific (phase-nonspecific) or cell cycle–nonspecific with a drug that is cell
cycle phase–specific can kill cells that are dividing slowly as well as those that are
dividing actively. The use of cell cycle–nonspecific drugs can also help recruit cells
into a more actively dividing state, which results in their being more sensitive to the
cell cycle phase–specific agents.
3. Biochemical enhancement of effect
a. Combinations of individually effective drugs that affect different biochemical
pathways or steps in a single pathway can enhance each other. This may apply to
some newer agents whereby blocking more than one molecular target in the
interacting signal transduction pathways may magnify the interference of cell
proliferation compared with that seen with either agent alone. While this
principle may apply equally well to targeted agents as traditional agents, in
either circumstance toxicity may be enhanced as well.
b. Combinations of an active agent with an inactive agent can potentially result
in beneficial effects by several mechanisms, but with the exception of
cooperative inhibition described in what follows, have limited clinical utility.
1) An intracellular increase in the drug or its active metabolites, by either
increasing influx or decreasing efflux (e.g., calcium channel inhibitors with
multiple agents affected by multidrug resistance [MDR] due to P-
glycoprotein overexpression)
2) Reduced metabolic inactivation of the drug (e.g., inhibition of cytidine
deaminase inactivation of ara-C with tetrahydrouridine)
3) Cooperative inhibition of a single enzyme or reaction (e.g., leucovorin
enhancement of fluorouracil inhibition of thymidylate synthetase)
4) Enhancement of drug action by inhibition of competing metabolites (e.g., N-
phosphonacetyl-L-aspartic acid inhibition of de novo pyrimidine synthesis
with resultant increased incorporation of 5-fluorouridine triphosphate into
RNA)
4. Sanctuary access. Combinations can be used to provide access to sanctuary sites
 for reasons such as drug solubility or affinity of specific tissues for a particular drug
type.
5. Rescue. Combinations can be used in which one agent rescues the host from the
toxic effects of another drug (e.g., “leucovorin rescue” or glucarpidase
(carboxypeptidase g2) administration after high-dose methotrexate).
B. Principles of agent selection
When selecting appropriate agents for use in a combination, the following principles
should be observed.
1. Choose individually active drugs. Do not use a combination in which one agent is
inactive when used alone unless there is a clear, specific biochemical or
pharmacologic reason to do so (e.g., high-dose methotrexate followed by leucovorin
rescue or leucovorin followed by fluorouracil). This principle may not be
applicable to the combined use of chemotherapeutic agents with biologic response
modifiers or molecular targeted agents because the cooperativity of chemotherapy
and these drugs may not depend on the independent cytotoxic effect of these
nonclassic agents.
2. When possible, choose drugs in which the dose-limiting toxicities differ
qualitatively or in time of occurrence. Often, however, two or more agents that have
marrow toxicity must be used, and the selection of a safe dose of each is critical. As
a starting point, two cytotoxic drugs in combination can usually be given at two-
thirds of the dose used when the drugs are given alone. Whenever a new drug
combination is tried, a careful evaluation of both expected and unanticipated
toxicities must be carried out. Unexpected results such as the increased
cardiotoxicity of the combination of trastuzumab with doxorubicin may occur, and
this latter case has precluded the use of these agents together.
3. Select agents for a combination for which there is a biochemical or
pharmacologic rationale. Preferably, this rationale has been tested in an animal
tumor system or other appropriate model system, and the combination has been
found to be better than either agent alone.
4. Be cautious when attempting to improve on a successful two-drug combination
by adding a third, fourth, or fifth drug simultaneously. Although this approach may be
beneficial, two undesirable results may be seen, as follows:
■ An intolerable level of toxicity that leads to excessive morbidity and mortality.
■ Unchanged or reduced antitumor effect because of the necessity to reduce the
dose of the most effective drugs to a level below which antitumor responses are
not seen, despite the theoretical advantages of the combination. Therefore, the
addition of each new agent to a combination must be considered carefully, the
principles of combination therapy closely followed, and controlled clinical
trials carried out to compare the efficacy and toxicity of any new regimen with a
more established (standard) treatment program.
C. Clinical effectiveness of combinations
 Combinations of drugs have been clearly demonstrated to be better than single agents
for treating many, but not all, human cancers. The survival benefit of combinations of
drugs compared with that of the same drugs used sequentially has been marked in
diseases such as acute lymphocytic and acute nonlymphocytic leukemia, Hodgkin
lymphoma, non-Hodgkin lymphomas with more aggressive behavior (intermediate- and
high-grade), breast carcinoma, anaplastic small-cell carcinoma of the lung, colorectal
carcinoma, ovarian carcinoma, and testicular carcinoma. The benefit is less marked in
cancers such as non–small-cell carcinoma of the lung, non-Hodgkin lymphomas with
favorable prognoses, head and neck carcinomas, carcinoma of the pancreas, and
melanoma, although reports exist for each of these tumors in which combinations are
better in one respect or another than single agents. It is critical to evaluate the evidence
for each cancer type, stage, prior therapy, and patient status prior to making a decision
what if any therapy to propose.

IV. RESISTANCE TO ANTINEOPLASTIC AGENTS

Resistance to antineoplastic chemotherapy is a combined characteristic of a specific drug,
a specific tumor, and a specific host whereby the drug is ineffective in controlling the
tumor without excessive toxicity. Resistance of a tumor to a drug is the reciprocal of
selectivity of that drug for that tumor. The problem for the medical oncologist is not simply
to find an agent that is cytotoxic but to find one that selectively kills neoplastic cells while
preserving the essential host cells and their function. Were it not for the problem of
resistance of human cancer to antineoplastic agents or, conversely, the lack of selectivity of
those agents, cancer chemotherapy would be similar to antibacterial chemotherapy in
which complete eradication of infection is regularly observed. Such a utopian state of
cancer chemotherapy has not yet been achieved for most human cancers. The problem of
resistance, including ways to overcome or even exploit it, remains an area of major interest
for the oncologist, pharmacologist, and cell biologist. This reductionist description glosses
over the fact that each of these factors is a consequence of the complex genetic
characteristics and changes of the cancer cell as it evolves.
Resistance to antineoplastic chemotherapeutic agents may be either natural or
acquired. Natural resistance refers to the initial unresponsiveness of a tumor to a given
drug, and acquired resistance refers to the unresponsiveness that emerges after initially
successful treatment. There are three basic categories of resistance to chemotherapy:
kinetic, biochemical, and pharmacologic.
A. Cell kinetics and resistance
Resistance based on cell population kinetics relates to cycle and phase specificity,
growth fractions and the implications of these factors for responsiveness to specific
agents, and schedules of drug administration. A particular problem with many human
tumors is that they are in a plateau growth phase with a small growth fraction. This
factor renders many of the cells insensitive to the antimetabolites and relatively
unresponsive to many of the other chemotherapeutic agents. Strategies to overcome
 resistance due to cell kinetics include the following:
■ Reducing tumor bulk with surgery or radiotherapy
■ Using combinations to include drugs that affect resting populations (with many G0
cells)
■ Scheduling of drugs to prevent phase escape or to synchronize cell populations and
increase cell kill
B. Biochemical causes of resistance
Resistance can occur for biochemical reasons including the inability of a tumor to
convert a drug to its active form, the ability of a tumor to inactivate a drug, or the
location of a tumor at a site where substrates are present that bypass an otherwise lethal
blockade. How cells become resistant is only partially understood. There can be
decreased drug uptake by the cell, increased efflux, changes in the levels or structure of
the intracellular target, reduced intracellular activation or increased inactivation of the
drug, or increased rate of repair of damaged DNA. In one pre–B-cell leukemia cell
line, bcl-2 overexpression or decreased expression of the homolog bax renders cells
resistant to several chemotherapeutic agents. Because bcl-2 blocks apoptosis, it has
been proposed that its overexpression blocks chemotherapy-induced apoptosis. The
interrelationship between mutations of p53, overexpression of HER2, and similar
changes in a host of other oncogenes and tumor suppressor genes and resistance to the
cytotoxic effects of radiotherapy and chemotherapeutic, hormonal, and biologic agents,
when better understood, may further our understanding of resistance and provide new
therapeutic strategies.
MDR,10 also called pleiotropic drug resistance, is a phenomenon whereby treatment
with one agent confers resistance not only to that drug and others of its class but also to
several other unrelated agents. MDR is commonly mediated by an enhanced energy-
dependent drug efflux mechanism that results in lower intracellular drug concentrations.
With this type of MDR, overexpression of a membrane transport protein called P-
glycoprotein (“P” meaning pleiotropic or permeability) is observed commonly.11 Other
MDR proteins are the MDR protein found in human lung cancer lines and the lung
resistance protein. These proteins appear to have differing expression in different sets
of neoplasms. Drugs that are effective in reversing resistance to P-glycoprotein do not
reverse these latter MDR proteins. Combination chemotherapy can overcome
biochemical resistance by increasing the amount of active drug intracellularly as a
result of biochemical interactions or effects on drug transport across the cell membrane.
Calcium channel blockers, antiarrhythmics, cyclosporine A analogs (e.g., PSC-833, a
nonimmunosuppressive derivative of cyclosporine D), and other agents have been found
to modulate the P-glycoprotein MDR effect in vitro, but limited beneficial effects have
been observed clinically.
The use of a second agent to rescue normal cells may also permit the use of high
doses of the first agent, which can overcome the resistance caused by a low rate of
conversion to the active metabolite or a high rate of inactivation. Another way to
 overcome resistance is to follow marrow-lethal doses of chemotherapy by posttherapy
infusion of stem cells obtained from the peripheral blood or bone marrow. This
technique is effective for the treatment of some patients with lymphoma, leukemia,
multiple myeloma, and a few other cancers. A more widely applicable technique is to
combine higher or more frequent doses of chemotherapy with granulocyte colony-
stimulating factor or granulocyte-macrophage colony-stimulating factor. These and other
marrow-protective and marrow-stimulating agents are being used increasingly and may
enhance the effectiveness of chemotherapy in the treatment of several types of cancer.
C. Pharmacologic causes of resistance
Dosing of drugs based on body surface area has been used traditionally to account for
drug distribution and glomerular filtration rate differences among individuals of
different height and weight. This does not take into account potential differences in
absorption, distribution, metabolism, and excretion that may occur depending on the
route of administration, body composition, pharmacogenomics (relating to the cancer
cell), and pharmacogenetics (relating to host genetic differences, including single
nucleotide polymorphisms). Apparent resistance to cancer chemotherapy can result
from poor tumor blood supply, poor or erratic absorption, increased excretion or
catabolism, and drug interactions, all leading to inadequate blood levels of the drug.
Strictly speaking, this result is not true tumor cell resistance; but to the degree that the
clinician does not appreciate the insufficient blood levels, resistance appears to be
present. The variation from patient to patient at the highest tolerated dose has led to
dose modification schemes that permit dose escalation when the toxicities of the
chemotherapy regimen are minimal or nonexistent, as well as dose reduction when
toxicities are great. This regulation is particularly important for some chemotherapeutic
agents for which the dose-response curve is steep or for patients who have genetically
altered drug metabolism, such as can occur with irinotecan. Selection of the appropriate
dose on the basis of predicted pharmacologic behavior is essential for some agents not
only to avoid serious toxicity but also to optimize effectiveness. This has been applied
successfully to dose selection of carboplatin by predicting the time × concentration
product (area under the curve [AUC]) on the basis of the individual patient’s creatinine
clearance.
True pharmacologic resistance is caused by the poor transport of agents into certain
body tissues and tumor cells. For example, the central nervous system (CNS) is a site
that many drugs do not reach well. Several drug characteristics favor transport into the
CNS, including high lipid solubility and low molecular weight. For tumors that
originate in the CNS or metastasize there, the drugs of choice should be those that
achieve effective antitumor concentration in the brain tissue and that are also effective
against the tumor cell type being treated.
D. Nonselectivity and resistance
Nonselectivity is not a mechanism for resistance but rather an acknowledgment that for
most cancers and most drugs, the reasons for resistance and selectivity are only
 partially understood. Given a limited understanding of the biochemical differences
between normal and malignant cells prior to the last 10 years, it is gratifying that
chemotherapy has been as successful as frequently as it has. With the burgeoning of
knowledge about the cancer cell, there is reason to hope that in 20 years, we will view
current chemotherapy regimens as a fledgling—if not crude—beginning and will have
found many more tumor molecular target–directed agents that have a high potential for
curing the human cancers that now resist effective treatment.

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I. INTRODUCTION
Molecular targeted therapy (MTT) is a new approach to cancer treatment that resulted from
the plethora of molecular and biologic discoveries into the etiology of cancer over the last
quarter of a century. Several agents have been approved by the U.S. Food and Drug
Administration (FDA) for clinical use and have replaced traditional chemotherapy in the
treatment of some cancers. Many more are currently being tested in clinical trials, and their
widespread integration into the mainstream for cancer treatment is expected to increase at
an accelerated pace during the next decade.
Agents in this type of therapy are vastly different from the traditional
chemotherapeutic agents that constitute the majority of therapy described throughout the
chapters of this book. These drugs are designed with the intention to specifically target
molecules that are uniquely or abnormally expressed within cancer cells while sparing
normal cells. In this chapter, we discuss drugs that are already available for clinical use
and provide a brief description of the mechanism of action of these agents, the pathways
they target, and some of their clinical uses. This chapter also addresses promising agents
currently in clinical trials that may be available soon in the clinic.
A. Characteristics of MTT
The ideal molecule for targeted therapy should have the following characteristics:
■ Uniquely expressed in cancer cells but not in normal cells.
■ Important for the maintenance of the malignant phenotype; therefore, once the
targeted molecule has been effectively disabled, the cancer cell will not be able to
develop resistance against the therapeutic agent by suppressing its function or
expelling the targeted molecule from the cell.
The degree to which target molecules do not embody these characteristics coupled
with nonspecificity of the therapeutic agent determines the limitations of the current
targets and agents.
B. Classification and type of MTT
The classification of MTT is a moving target. In this chapter, we classify MTT based on
the targeting strategy of each molecule. There are two targeting strategies for MTT.
1. Function-directed therapy
This therapeutic strategy is intended to restore the normal function or abrogate the
abnormal function of the defective molecule or a pathway in the tumor cell. This is
 accomplished by the following:
■ Reconstituting the normal molecule
■ Inhibiting the production of a defective molecule
■ Aborting, altering, or reversing a newly acquired function by targeting the
defective molecule, its function, and its downstream effect
Agents under this category are classified based on the mechanism of action and
subclassified based on the known affected targeted pathway.
2. Phenotype-directed therapy
This is a therapeutic strategy that is intended to target the unique phenotype of the
cancer cell where killing the cell is more dependent on nonspecific mechanisms
rather than targeting a specific pathway. Accordingly, agents under this category are
classified based on the type of therapy and subclassified based on the targeted
pathway or molecule.
Table 2.1 summarizes the classification and FDA-approved indications of
molecular-targeted agents.

II. FUNCTION-DIRECTED THERAPY

Agents under this category target specific cellular pathways (e.g., signal transduction
pathways, angiogenesis, protein degradation, etc.).
A. Cell signaling–targeted therapy
Signal transduction pathways are crucial for delivering messages from the extracellular
environment into the nucleus and enabling the cell to carry on cellular processes
including survival, proliferation, and differentiation. These signals are initiated from
the cell surface by the interaction of molecules (ligands) such as hormones, cytokines,
and growth factors with cell receptors. Cell receptors, in turn, transfer the signal
through a network of molecules to the nucleus, which leads to the transcription of new
molecules responsible for engineering the desired outcome.
In cancer cells, these pathways are found to be altered through the mutation of some
of their components. This leads to the functional dysregulation of the affected pathways
resulting in uncontrolled proliferation and inhibition of apoptosis. Accordingly,
targeting the components of these pathways is a prime goal for the development of
MTT. The components of these pathways include the following:
■ The ligand
■ The receptors for these ligands, the majority of which are receptor kinases
■ The cascade of proteins that form these pathways, the majority of which are protein
kinases

TABLE
Classification and FDA-Approved Indications of Molecular-Targeted Agents
2.1
 Accordingly, strategies targeting signal transduction pathways include the following:
■ Blocking the ligand-receptor interaction. This leads to the prevention of the
initiation of the signal and can be accomplished by either blocking circulating
ligands or blocking ligand binding to the extracellular domain of the receptor.
■ Inhibition of receptor kinases. This leads to the prevention of phosphorylation of
the intracellular kinase domain of the receptor, resulting in the abortion of protein
cascade in the cell signaling pathways.
■ Inhibition of intracellular signaling proteins.
1. Blocking of the ligand-receptor binding
Blocking receptors and ligand-receptor interaction is currently achieved by utilizing
specific monoclonal antibodies (MoAbs) directed against the ligand or the receptor.
 MoAbs are biologic agents designed with the intention to specifically target soluble
proteins or membrane proteins with an extracellular domain. The MoAbs can exert
their antitumor effect through multiple potential mechanisms including blocking the
targeted receptor or ligand and preventing its function in transmitting signals to the
nucleus, activating antibody-dependent cellular cytotoxicity, or helping to internalize
the receptor and hence deliver toxic agents into the cells. The MoAb technology has
considerably improved in the last decade by humanizing these agents partially in
chimeric or fully humanized constructs. Substituting the murine Fc portion of the
MoAb with a human equivalent leads to a significant decrease in the generation of a
human anti-mouse antibody (HAMA) immune reaction. Although generation of
human anti-chimeric antibodies (HACAs) may still occur for those MoAbs, it does
not occur with fully humanized MoAbs. This technology to humanize MoAbs has
made these molecules more usable in the treatment of cancer, particularly when
repetitive dosing is required.
2. Epidermal growth factor receptor family
Epidermal growth factor receptors (EGFRs) are a small family of proteins belonging
to the larger receptor tyrosine kinase (RTK) family. The EGFR family includes at
least four described receptors: EGFR1, HER-2-neu (erbB2), HER3 (erbB3), and
HER4 (erbB4). These receptors are glycoproteins consisting of three domains: an
extracellular ligand-binding domain, a transmembrane domain, and an intracellular
domain with a tyrosine kinase activity. Binding of the ligands to the receptor leads to
the activation of the intracellular tyrosine kinase and the phosphorylation of the
receptor, which, in turn, leads to activation of the downstream signal transduction
pathway. The activation of this pathway promotes cell activation, proliferation, and
enhanced survival. Agents have been developed against the receptors EGFR1 and
HER-2-neu.
3. EGFR1-targeted therapy
EGFR1 was the first member of the EGFR family to be identified. It is activated by
binding to epidermal growth factor (EGF) and to transforming growth factor-α
(TGF-α). EGFR1 is found to be overexpressed in many cancers, including 50% to
70% of colon, lung, and breast cancers. Several antibodies targeting EGFR have
been approved by the FDA.
a. Cetuximab (Erbitux) is a humanized immunoglobulin-G1 (IgG1) chimeric MoAb
that binds to the external ligand-binding domain of EGFR1. It also binds with
much lower affinity to EGF and TGF-α. The combination of cetuximab and
irinotecan was found to improve disease response rate (RR) and progression-free
survival (PFS) over the use of cetuximab alone in patients with metastatic
colorectal carcinoma (CRC) who have previously failed irinotecan therapy.
Recent studies have shown an improved PFS by 1.4 months and median overall
survival (OS) by 4 months in patients with KRAS wild-type (WT) metastatic
CRC with the addition of cetuximab to either FOLFIRI (folinic acid, fluorouracil
 [5-FU], and irinotecan) or FOLFOX (folinic acid, 5-FU, and oxaliplatin). An
increased RR was also observed in this patient population (46% vs. 38% in all
patients, 57% vs. 39% in patients with KRAS-WT). Additionally, cetuximab has
been studied in patients with metastatic CRC previously treated with irinotecan,
with an improved OS of 1.5 months in all patients and 3.6 months in patients with
KRAS-WT. These studies have led to its approval in the first-line setting for
patients with KRAS-WT metastatic CRC in combination with FOLFIRI, patients
who failed both irinotecan- and oxaliplatin-based chemotherapy regimens as a
single agent, and patients who are refractory or intolerant to irinotecan-based
chemotherapy in combination with irinotecan. Recently, the combination of
cetuximab and FOLFIRI in patients with untreated KRAS-WT metastatic CRC
was compared to FOLFIRI plus bevacizumab and showed an improved rate of
carcinoembryonic antigen (CEA) decline, which correlated with an improved
OS, favoring the cetuximab arm. Cetuximab is also approved for the treatment of
squamous cell carcinoma of head and neck (SCCHN). It has been shown to
improve local-regional control by 9.5 months and OS by 19.7 months in patients
with stage III or IV previously untreated SCCHN when combined with radiation
therapy (RT) compared to RT alone. It was also shown to improve RR (35.6%
vs. 19.5%), PFS by 2.2 months, and OS by 2.7 months in patients with stage III or
IV SCCHN when combined with 5-FU and either carboplatin or cisplatin.
Additionally, cetuximab alone showed a RR of 13% with duration of response of
5.8 months in patients with recurrent or metastatic SCCHN who progressed
within 30 days of a platinum agent. These studies have led to its approval as a
first line in combination with either radiation or platinum-based therapy and 5-FU
in patients with recurrent, locally advanced, or metastatic SCCHN and as a
second line in SCCHN patients who progressed on a platinum agent. Common
adverse effects include rash and diarrhea. Although very uncommon, cardiac
arrest and myocardial infarction (MI) were reported among the serious side
effects.
b. Panitumumab (Vectibix) is a fully humanized MoAb that binds to EGFR1 with
higher affinity than cetuximab. A randomized phase III study demonstrated that
patients with refractory EGFR-expressing metastatic CRC treated with
panitumumab plus best supportive care (BSC) had a better PFS compared to
patients who received BSC alone. The patients who benefited from the treatment
were those with tumors that did not express KRAS mutations. Therefore,
panitumumab was approved by the FDA as a monotherapy for chemotherapy-
refractory KRAS-WT metastatic CRC. It was also shown to improve PFS by 1.6
months and OS by 4.4 months in combination with FOLFOX in patients with
untreated KRAS-WT metastatic CRC compared to FOLFOX alone. Importantly, it
was found to be noninferior to cetuximab in patients with metastatic CRC
previously treated with FOLFOX or FOLFIRI. It was also studied in patients with
 metastatic SCCHN in combination with cisplatin and 5-FU compared to
chemotherapy alone and had a nonsignificant trend toward improved OS and
modest, but significant, improvement in PFS of 1.2 months. Other diseases with
promising results using panitumumab include non–small-cell lung cancer
(NSCLC) and renal cancer. Common adverse effects include rash, peripheral
edema, fatigue, and diarrhea. Serious toxicity, including bronchospasm, has been
reported only rarely.
4. HER-2-neu (HER2, erbB2)-targeted therapy
HER2 is the second member of the EGFR family. This receptor has the same basic
structure as the other family members; however, no conjugate ligand has been
identified for HER2. There have been no mutations identified in the HER2 gene in
human cancers, yet it is overexpressed in many epithelial cancers, including colon,
pancreas, genitourinary, and breast cancers. HER2 signals through the
phosphoinositide-3 kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase
pathways, and HER2 overexpression leads to inhibition of apoptosis and increase in
cell proliferation.
a. Trastuzumab (Herceptin) was one of the first MTTs to be introduced in the clinic.
It is a humanized (chimeric) MoAb that binds to HER2. Although the mechanism
of action of trastuzumab is not entirely clear, it is believed to act through one or
more of the following mechanisms: inhibiting the tyrosine kinase signaling of the
receptor, activating antibody-dependent cellular cytotoxicity, inducing apoptosis,
inducing G1 arrest by modulating the cyclin-dependent kinases, inhibiting
angiogenesis, and enhancing chemotherapy-induced cytotoxicity. The FDA
approved trastuzumab in 1998 for use in patients with metastatic breast cancer
overexpressing HER2 protein. In a large, multicenter phase III study in patients
with metastatic breast cancer overexpressing HER2, it was demonstrated that
trastuzumab, when used as a first-line therapy in combination with chemotherapy
(with either the combination of anthracyclines and cyclophosphamide or
paclitaxel as a single agent), can significantly increase both the duration of
response and OS.1 Trastuzumab is currently used in three settings for patients with
breast cancer overexpressing HER2: as a first-line therapy in combination with
paclitaxel; as a second-line monotherapy in patients who have received at least
one prior chemotherapy regimen; or in an adjuvant setting in combination with
doxorubicin, cyclophosphamide, and paclitaxel. It is also approved for patients
with metastatic HER2+ gastric or gastroesophageal junction (GEJ)
adenocarcinoma. This is based on an improved OS of 4.8 months when used in
combination with cisplatin and either capecitabine or 5-FU compared to
chemotherapy alone. Patients with HER2− disease showed no benefit when
treated with trastuzumab. Common adverse effects are asthenia, rash, and
diarrhea. Serious side effects are ventricular dysrhythmia, decreased left
ventricular ejection fraction (LVEF), and thromboembolism.
 b. Pertuzumab (Perjeta) is a fully humanized MoAb directed against the
extracellular domain of HER2. It prevents dimerization of the HER2 receptor that
is necessary for its activity and is a potential mechanism of resistance to
trastuzumab. When combined with trastuzumab and docetaxel in patients with
untreated metastatic HER2+ breast cancer, pertuzumab improved RR from 12.5%
to 20.2%, median PFS by 6.3 months, and median OS by 15.7 months.2 This led
to its FDA-approval for untreated HER2+ breast cancer in combination with
trastuzumab and docetaxel. It has also been studied in the neoadjuvant setting and
showed an improved pathologic complete response (pCR) rate of 46% when
combined with docetaxel and trastuzumab (compared to 29% for docetaxel and
trastuzumab). Common side effects include diarrhea, nausea, rash, and peripheral
neuropathy. Serious effects include febrile neutropenia, severe diarrhea, and left
ventricular dysfunction. Importantly, the combination of pertuzumab and
trastuzumab does not seem to increase cardiotoxicity compared to trastuzumab
alone.
5. Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF) family of proteins is one of the specific
positive regulators of angiogenesis. It is composed of five different growth factors:
VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor. Of these,
VEGF-A exerts the most influence on the angiogenesis process. The VEGF proteins
bind to three tyrosine kinase receptors: VEGF receptor 1 (VEGFR-1/FLT-1),
VEGFR-2 (kinase insert domain receptor/fetal liver kinase 1, FLK-1), and VEGFR-
3 (FLT-1). VEGFR-2, through its interaction with VEGF, is thought to be the main
mediator of tumor-associated angiogenesis and metastatic processes, whereas
VEGFR-1 plays a role in hematopoiesis. The VEGF-A is expressed or
overexpressed in many tumors, including lung, breast, and ovarian cancer tumors, as
well as gastrointestinal stromal tumors (GISTs) and renal cell carcinoma (RCC).
Accordingly, targeting these molecules to block tumor-associated angiogenesis
constitutes a logical therapeutic strategy to control cancer. Both antibodies and small
molecules have been developed as targeted therapies utilizing this pathway. Here,
we discuss the antibodies. The small molecules are discussed later in the chapter.
a. Bevacizumab (Avastin) is a humanized murine anti-VEGF MoAb. It functions by
blocking VEGF-A binding to its receptors (VEGFR), thereby inhibiting the tumor-
induced angiogenesis process. Given the ubiquitous nature of angiogenesis in
cancer, bevacizumab is used in many cancers, including colon, lung,
glioblastoma, RCC, ovarian, and uterine cancers. Bevacizumab was found to
improve RR, PFS, and OS when combined with first-line chemotherapy of
FOLFOX or FOLFIRI in patients with metastatic CRC. Even in patients with
metastatic CRC who received bevacizumab in the first-line setting, its addition to
second-line chemotherapy showed an improved PFS of 1.7 months compared to
second-line chemotherapy alone. However, bevacizumab use in the adjuvant
 setting did not improve OS. These studies have led to its approval for metastatic
CRC as a first-line treatment in combination with FOLFOX or FOLFIRI and as a
second-line treatment with similar regimens, but not in the adjuvant setting. In
previously untreated patients with metastatic, recurrent, or locally advanced
nonsquamous NSCLC, bevacizumab plus paclitaxel and carboplatin (PC) was
shown to improve OS by 2 months compared to PC alone.3 A similar study
combining bevacizumab with gemcitabine and cisplatin failed to show an
improvement in PFS or OS. This led to its approval for patients with previously
untreated metastatic, recurrent, or locally advanced nonsquamous NSCLC in
combination with PC. Squamous-type histology was excluded from these studies
given an unacceptably high risk of massive hemoptysis with bevacizumab use.
Bevacizumab is also approved for the use in patients with glioblastoma
previously treated with either temozolomide or irinotecan with radiation. This
was based on an improvement of RR of 26% and 20%, respectively, on two
separate studies but with no survival advantage. Bevacizumab is also approved
for the use in patients with previously untreated metastatic RCC in combination
with interferon (IFN)-α2a, based on improvement of 18% in RR and 4.8 months
in PFS with no difference in OS. Recently, bevacizumab was also studied in both
cervical and ovarian cancer patients. Patients with refractory metastatic cervical
cancer following initial chemotherapy received bevacizumab in combination with
paclitaxel and cisplatin or paclitaxel and topotecan. Bevacizumab with either
chemotherapy doublet improved RR by 11% and OS by 3.9 months. Patients with
platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary
peritoneal cancer had an improved PFS of 6.8 months when received
bevacizumab in combination with paclitaxel, doxorubicin, or topotecan,
compared to 3.4 months with chemotherapeutic agent alone. Accordingly,
bevacizumab was approved in combination with chemotherapy in patients with
persistent, recurrent or metastatic cervical cancer and patients with platinum-
resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal
cancer. Bevacizumab was approved by the FDA in 2008 for use as a first-line
therapy in combination with paclitaxel in patients with metastatic HER2− breast
cancer, based on an improvement in PFS of 5.9 months in patients receiving the
combination compared to those receiving paclitaxel alone. However, the FDA
Oncology Drugs Advisory Committee recommended that approval be withdrawn
based on the new trials that did not show any improvement in OS and minimal
improvement in PFS. Serious adverse effects include arterial and venous
thrombosis, hypertension (HTN), gastrointestinal perforation, and delayed wound
healing following surgery. Up to 31% of patients with squamous cell lung cancer
(SCLC) were found to have serious or fatal pulmonary hemorrhage, restricting its
use in this patient population.
b. Ramucirumab (Cyramza) is a recombinant human IgG1 MoAb against VEGFR-2
 that is approved in multiple settings. In patients with locally advanced or
metastatic gastric or GEJ adenocarcinoma previously treated with either
platinum-based or 5-FU-based regimen, ramucirumab showed an improvement of
PFS by 0.8 months and OS by 1.4 months compared to placebo. In the same
patient population, ramucirumab was combined with paclitaxel and compared to
placebo in combination with paclitaxel. This study showed that ramucirumab
improved RR by 12%, PFS by 1.5 months, and OS by 2.2 months. These studies
had led to its approval in these disease settings. In addition, ramucirumab is
approved for patients with locally advanced or metastatic NSCLC after
progression on a platinum-based regimen. This was based on a phase III study
comparing it in combination with docetaxel to docetaxel in combination with
placebo showing an improvement of PFS by 1.5 months, with a nonsignificant
trend toward improved OS. Recently, ramucirumab was approved in patients with
metastatic colorectal cancer after 5-FU-, oxaliplatin-, bevacizumab-based
chemotherapy failure, based on improved OS by 1.6 months and PFS by 1.2
months compared to placebo. Common adverse effects include HTN and diarrhea
when used as a single agent. When used in combination with a taxane, adverse
effects include neutropenia, neuropathy, and fatigue. Serious effects are similar to
those of bevacizumab.
c. Axitinib (Inlyta) is a small-molecule tyrosine kinase inhibitor (TKI) that inhibits
VEGFR-1–3 in addition to platelet-derived growth factor receptor (PDGFR) and
c-KIT. It is approved for patients with metastatic RCC after progression on at
least one prior therapy (including sunitinib, temsirolimus, bevacizumab, or
cytokines). In this patient population, it was shown to improve PFS by 2 months
compared to sorafenib with added OS benefit. It has also been studied in the first-
line setting compared to sorafenib in patients with untreated metastatic RCC and
showed a nonsignificant trend toward improved PFS and RR. Common adverse
effects include diarrhea, HTN, fatigue, hand-foot syndrome, constipation, and
weight loss. Serious effects are similar to those of bevacizumab.
d. Ziv-aflibercept (Zaltrap) is a recombinant fusion protein composed of VEGF-
binding portions from the extracellular domains of human VEGFR-1 and -2 fused
with the Fc portion of the human IgG1. It has been shown to effectively bind to
VEGF-A and VEGF-B. This binding inhibits the proliferation of endothelial cells
and in turn angiogenesis. It is approved in combination with FOLFIRI for patients
with metastatic CRC that is resistant or refractory to an oxaliplatin-containing
regimen. This is based on a large phase III clinical trial that showed an improved
RR of 20% when combined with FOLFIRI (vs. 11% for FOLFIRI plus placebo),
PFS of 6.9 months (vs. 4.6 months), and OS of 13.5 months (vs. 12 months).4
Common adverse effects include leukopenia, diarrhea, stomatitis, fatigue, and
HTN. Serious effects include arterial thrombosis, severe HTN, and
gastrointestinal fistula formation.
 e. Lenvatinib (Lenvima) is an oral TKI of VEGFR-1–3, and also has activity against
PDGFR, c-KIT, RET, and fibroblast growth factor (FGF). It is approved for
patients with locally recurrent or metastatic, progressive, radioactive iodine–
refractory differentiated thyroid cancer, based on improved RR by 63% and PFS
by 14.7 months compared to placebo. Common adverse effects include fatigue,
diarrhea, weight loss, nausea, and hand-foot syndrome. Serious adverse effects
include HTN, decreased LVEF, arterial thrombosis, hepatotoxicity, QT
prolongation, rare gastrointestinal perforation, kidney injury, hypocalcemia, and
hemorrhage.
f. Nintedanib (Ofev) is an orally available multiple kinase inhibitor of VEGFR,
PDGFR, and FGF receptor (FGFR). It is currently approved in the United States
for treatment of patients with idiopathic pulmonary fibrosis and used in Europe
for patients with locally advanced or metastatic lung adenocarcinoma previously
treated with chemotherapy. This is based on an improved OS by 2.3 months when
combined with docetaxel compared to docetaxel alone.
g. Brivanib is a humanized MoAb against VEGFR-2 that also has activity against
PDGFR and FGF. It was compared to sorafenib in patients with untreated
advanced hepatocellular carcinoma (HCC) in a recent phase III trial, but did not
show a survival benefit. In another phase III trial, brivanib was shown to have an
improved RR of 10% versus 2% for BSC in HCC patients who failed sorafenib.
h. Telatinib is an oral TKI that targets VEGFR-2 and -3 in addition to PDGFR and
KIT. In a phase II trial treating patients with advanced gastric adenocarcinoma, it
had an RR of 66% when combined with capecitabine in the first-line setting. It
was reportedly well tolerated, and additional studies are ongoing.
i. Cediranib is an inhibitor of VEGFR that showed clinical response in NSCLC,
RCC, and CRC in early phase I trials. In a recent phase II trial, it showed an
improved PFS by 8.5 months when combined with olaparib (a poly(ADP-ribose)
polymerase [PARP] inhibitor discussed later) versus olaparib alone in patients
with recurrent platinum-sensitive high-grade serous ovarian cancer. It was also
studied in a phase II trial in patients with NSCLC, but did not show an
improvement in PFS or OS. It is currently being investigated in patients with
glioblastoma.
j. Dovitnib is an oral TKI of VEGFR and FGFR. It has been studied in the third-line
setting for patients with metastatic RCC and found to be noninferior to sorafenib
in terms of PFS. In patients with advanced GIST who were intolerant or resistant
to imatinib, dovitinib showed a disease control rate at 12 weeks of 53%, with no
difference in PFS compared to historical control patients treated with sunitinib.
6. Insulin-like growth factor type I receptor
Insulin-like growth factor type I receptor (IGF-1R) is an RTK belonging to the
insulin-like growth factor (IGF) receptor family, which is composed of three
transmembrane proteins and binds to IGF-1 and -2. It is overexpressed in many
 tumors, including melanoma, colon, pancreas, prostate, and kidney tumors. IGF-1R
overexpression in cancer cells is an important factor for their proliferation,
transformation, and metastasis. Therefore, IGF-1R became an attractive target for
cancer therapy, although no IGF-1R-targeted agents are currently approved for use.
a. Cixutumumab is a fully humanized MoAb IgG1 against IGF-1R that has shown to
be safe and active in multiple phase II trials in a variety of cancers, including
adrenocortical carcinoma, thymoma, and bone and soft-tissue sarcomas.
Cixutumumab is currently being investigated in several phase III trials.
b. Linsitinib is an oral small molecule that inhibits IGF-1R. In a recent phase III
study in patients with locally advanced or metastatic adrenocortical carcinoma, it
did not show any improvement in PFS or OS compared to placebo. Additional
studies are ongoing.
c. Ganitumab is a fully human MoAb that targets IGF-1R. Ganitumab was found to
be promising in initial trials, but a recent phase III trial in patients with metastatic
pancreatic cancer showed no benefit compared to gemcitabine alone. It is now
being investigated in patients with metastatic Ewing sarcoma.
7. Inhibition of receptor tyrosine kinases
Kinases are enzymes that have the ability of attaching a phosphate moiety to another
protein. This occurs on a side chain of a serine, threonine, or tyrosine moiety, and
the side chain that becomes phosphorylated is used to classify these kinases. The
phosphorylation of proteins regulates the behavior of the molecules, including
protein-binding activity, enzymatic activity, trafficking within the cell, or
degradation. As a consequence, the phosphorylation process is a crucial
biochemical reaction involved with controlling the behavior of a cell. Their critical
role in cancer is shown by the observation that mutations in these kinases may lead
to drastic outcomes, including uncontrolled proliferation. Receptor serine/threonine
kinases are discussed later in this chapter; here, we discuss RTKs. RTKs are a
family of proteins sharing several structural and functional features. These kinases
are glycoprotein receptors with extracellular, transmembrane, and intracellular
domains. While the transmembrane domain acts as an anchor for the receptor within
the membrane of the cell, the extracellular domain contains a binding site for a
specific multipeptide ligand. On receptor-ligand binding, signaling events specific
to the receptor are initiated. The cytoplasmic domain contains a catalytic tyrosine
kinase region and a regulatory region, which are integral to the transmission of
downstream signals to the nucleus. Autophosphorylation of the receptor’s kinase
region initiates a signal transduction cascade leading to cell proliferation,
survival/apoptosis, migration, adhesion, and promotion of angiogenesis. Some of the
subfamilies in this group of RTKs include PDGFR, EGFR, VEGFR, and FGFR.
These RTKs are overexpressed or mutated in many human cancers. Therefore,
targeting the activity of RTKs is an attractive strategy for cancer therapy and is
currently achieved by small molecules. A few small molecules have already been
 introduced into the clinical practice, and many more are currently in clinical trials.
Here, we discuss some of these molecules.
8. EGFR, VEGFR, PDGFR, and/or FGF
a. Erlotinib (Tarceva) is an oral small molecule that is a reversible kinase inhibitor
of EGFR and acts by competing with ATP in binding the intracellular domain of
the tyrosine kinase region. It blocks the signal transduction of the EGFR, leading
to the inhibition of the downstream effect of the pathway, including cell
propagation and survival, as well as angiogenesis. Erlotinib is a highly selective
inhibitor of the EGFR tyrosine kinase region, as concentrations of more than
1,000-fold are required for the inhibition of other tyrosine kinases. Erlotinib has
been studied in a variety of settings for patients with NSCLC and pancreatic
cancer. In previously untreated patients with metastatic NSCLC with exon 19
deletions or exon 21 substitution mutations (L858R), it was superior to standard
chemotherapy with improved RR (65% vs. 16%) and PFS (10.4 vs. 5.2 months).5
In patients with metastatic NSCLC who responded to first-line platinum-based
chemotherapy, erlotinib maintenance until progression improved OS by 1 month
compared to placebo, although the benefit was greater if tumor samples were
positive for EGFR by immunohistochemistry (IHC) and had adenocarcinoma
histology. Erlotinib has also been shown to be effective in patients with locally
advanced or metastatic NSCLC who failed at least one chemotherapy regimen,
showing an improved RR of 9% (vs. 1% with placebo) and OS by 2 months
compared to placebo. However, studies combining erlotinib with platinum-based
chemotherapy in similar patient population did not show a clinical benefit.
Accordingly, these studies have led to its approval as a first line for patients with
metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution
mutations (L858R), as a second line after progressing on a platinum doublet, and
as a maintenance following first-line platinum-based chemotherapy. In pancreatic
cancer, the addition of erlotinib to gemcitabine was found to improve median
survival by 13.8 days over gemcitabine alone, with an increase in 1-year survival
from 19% to 24%. Despite this limited improvement in OS, erlotinib is FDA-
approved for patients with locally advanced or metastatic pancreatic cancer in
combination with gemcitabine. The most common toxicities include skin rash and
diarrhea. MI and interstitial lung disease are reported among the serious side
effects.
b. Gefitinib (Iressa) is an oral small molecule designed to effectively inhibit the
tyrosine kinase activity of EGFR. This compound initially showed an effect in
randomized phase II trials with symptomatic improvement in advanced NSCLC
(with RR around 15%). However, further placebo-controlled phase III studies
showed no survival benefit as a frontline. Therefore, the FDA changed the
labeling to limit its use to patients with locally advanced or metastatic NSCLC
who have previously benefited from the drug or to patients who are already
 receiving the agent and have demonstrated benefit. As a first-line therapy in
NSCLC, gefitinib in combination with platinum-based chemotherapy showed no
benefit. Gefitinib can cause rash and diarrhea. Serious adverse effects include
interstitial lung disease and hemorrhage.
c. Afatinib (Gilotrif) is an oral small molecule that competitively inhibits ATP at the
kinase domain of EGFR, HER2, and HER4, as well as irreversibly blocks its
autophosphorylation. It has been found to be particularly active in NSCLC
patients with EGFR exon 19 deletions and exon 21 substitution mutations
(L858R). Afatinib is approved for patients with untreated metastatic NSCLC
whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations
(L858R). This is based on a large phase III trial comparing afatinib to pemetrexed
and cisplatin in NSCLC patients with EGFR mutation. Afatinib improved RR by
31% and PFS by 4.2 months, but no benefit in OS was demonstrated. The main
benefit was observed in patients with exon 19 deletions or exon 21 (L858R)
substitution mutations. The 11% of patients with other EGFR mutations did not
achieve a benefit with afatinib. Adverse effects include diarrhea, rash, stomatitis,
pruritus, and dry skin. Serious effects include interstitial lung disease, severe
diarrhea leading to dehydration, and hepatotoxicity.
d. Sunitinib (Sutent) is a competitive inhibitor of ATP that leads to the inhibition of
the phosphorylation of the kinase and inhibition of further downstream signal
transduction in multiple RTKs. It functions as an inhibitor to a closely related
family of RTKs, including PDGFR-α and -β, VEGFR, stem cell factor receptor
KIT, FMS-like tyrosine kinase-3 receptor, and the RET oncoprotein. Accordingly,
the sunitinib antitumor effect is multifactorial. It inhibits cell proliferation and has
an antiangiogenesis effect. The antiangiogenesis effect of sunitinib is through the
inhibition of both VEGFR and PDGFR, which is important for the recruitment of
pericytes. By inhibiting both VEGFR and PDGFR, sunitinib possesses a stronger
inhibiting effect on angiogenesis cells than those agents targeting VEGF alone.
Since angiogenesis is the hallmark of RCC and RCC has been demonstrated to
overexpress VEGF and PDGF, it is not surprising that sunitinib plays a major
therapeutic role in this disease. A multinational phase III clinical trial comparing
sunitinib to IFN-α as a first-line treatment in advanced RCC showed a major
advantage in OS of 11 months versus 5 months,6 which had led to its approval as
a first-line therapy for this indication. KIT and PDGFR play an important role in
the development of GIST. More than 85% of GISTs possess activating mutations
of the KIT kinase, and another 5% are associated with mutation in the PDGFR. In
patients with GIST who progressed through imatinib, sunitinib showed PFS of
24.1 weeks (vs. 6 weeks with placebo) and time to progression (TTP) of 27.3
weeks (vs. 6.4 weeks with placebo). As a result, sunitinib is approved for
patients with GIST whose disease has progressed on or unable to tolerate
treatment with imatinib. Sunitinib is also approved for patients with locally
 advanced or metastatic pancreatic neuroendocrine tumors, based on an increased
PFS of 11.4 months compared to 5.5 months with placebo. Common side effects
are rash, neutropenia, lymphopenia, thrombocytopenia, and increased
transaminases. Serious side effects are HTN, left ventricular dysfunction,
prolonged QT, and severe hypothyroidism.
e. Lapatinib ditosylate (Tykerb) is an HER2 RTK inhibitor. It is FDA-approved in
combination with capecitabine for patients with advanced, refractory HER2+
breast cancer who failed prior therapy including anthracycline, taxane, and
trastuzumab and in combination with letrozole as a first-line therapy in patients
with hormone receptor–positive metastatic breast cancer. When lapatinib was
combined with capecitabine in a phase III, open-label, randomized trial, patients
with HER2+, refractory, locally advanced or metastatic breast cancer had a
longer time to disease progression compared with capecitabine alone (27.1 vs.
18.6 weeks) and a nonsignificant trend toward longer OS.7 Similar outcomes
were found combining lapatinib with letrozole in patients with hormone receptor–
positive metastatic breast cancer who had not received prior therapy for
metastatic disease, showing PFS of 35.4 months with the combination versus 13
months with letrozole and placebo. Importantly, these outcomes were not found in
patients with HER2− disease. Common adverse effects are diarrhea, anemia, and
rash. Severe side effects are hand-foot syndrome and severe hepatotoxicity.
f. Pazopanib (Votrient) is a TKI of VEGFR, PDGFR, and c-KIT. Pazopanib is FDA-
approved for patients with advanced RCC. Pazopanib provided objective RRs of
30% and PFS of 9.2 months in patients with advanced RCC who were previously
untreated or who received only cytokine therapy, compared to 3% and 4.2
months, respectively, for placebo. It has also been compared to sunitinib in this
patient population and showed an improved RR (31% vs. 25%), but no
differences in PFS or OS. It is also approved for patients with metastatic soft-
tissue sarcomas after chemotherapy or who are unfit for chemotherapy, based on
improved PFS of 3 months compared to placebo. This improvement was greater
in patients with synovial sarcoma. Pazopanib is better tolerated than sunitinib in
patients with metastatic RCC. Adverse effects include diarrhea, HTN, and
nausea. Noted serious side effects are hepatotoxicity, hemorrhage, MI, and QT
prolongation.
g. Vandetanib (Zactima) is a multi-TKI of EGFR, VEGFR-2, and RET gene, which
is associated with hereditary and sporadic medullary thyroid cancer. Vandetanib
demonstrated an improvement in median PFS compared to placebo in
unresectable locally advanced or metastatic medullary thyroid cancer with no
survival benefit, which had led to its FDA-approval in this disease setting. In
patients with advanced NSCLC, the addition of vandetanib to docetaxel resulted
in a statistically significant improvement in PFS; however, in a more recent large
multicenter study no benefit was found. Common side effects are fatigue,
 headache, anorexia, nausea, vomiting, diarrhea, and myelosuppression. HTN and
QT interval prolongation are occasional.
h. Cabozantinib (Cometriq) is an oral small molecule that inhibits the tyrosine
kinase activity of multiple kinases, including RET, MET, VEGFR-1–3, KIT, LFT-
3, and TIE-2. It is approved for patients with metastatic medullary thyroid cancer
based on an improved PFS of 7.2 months compared to placebo and a RR of 27%
(none with placebo). In this study, 25% of patients had received prior therapies,
and 48% were reported to have a known RET mutation. Common adverse effects
include diarrhea, stomatitis, hand-foot syndrome, elevated liver enzymes,
neutropenia, and thrombocytopenia. Serious adverse effects include intestinal
perforations, rare but fatal hemorrhage, arterial thrombosis, osteonecrosis, and
HTN.
i. Dacomitinib is an oral TKI that irreversibly inhibits EGFR and has shown activity
in patients who developed resistance to other EGFR inhibitors. In a recent phase
III trial in unselected patients with advanced or metastatic NSCLC treated with at
least one chemotherapy regimen, dacomitinib was found not to be superior to
erlotinib. In a more recent phase III trial in patients with untreated exon 19 or
exon 21 mutated metastatic NSCLC, PFS at 4 months was 77%. Additional
studies are ongoing. Adverse effects include diarrhea, rash, mucositis, dry skin,
and nausea.
j. Matuzumab is an EGFR inhibitor that was shown to have a RR of 5% and 24%
rate of stable disease in patients with NSCLC previously treated with
chemotherapy. In a recent phase II study, it was not shown to be effective in
combination with chemotherapy in patients with advanced gastroesophageal
carcinoma.
k. Masitinib (Kinavet) is an orally available small molecule that has activity toward
c-KIT and PDGFR. It is used for systemic mastocytosis in canines and now being
investigated for the same disease in humans. In a phase II trial with symptomatic
systemic or cutaneous mastocytosis, masitinib showed an RR of 56% with most
responses lasting over 60 weeks. It is also being studied in patients with GIST.
l. Midostaurin is a multitargeted kinase inhibitor with specific activity in D816V
KIT mutation. In patients with aggressive systemic mastocytosis (ASM), it
showed a RR of 73%. In a separate Italian study, it was used through
compassionate use to treat seven patients with systemic mastocytosis. One patient
had major response, but the remaining six had a partial response (PR).
9. Bruton tyrosine kinase
Bruton tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor,
and its inhibition results in decreased B-cell chemotaxis, adherence, and trafficking.
Mutations in the gene causes the primary immunodeficiency disease X-linked
agammaglobulinemia (also known as Bruton agammaglobulinemia), which results
from decreased mature, circulating B-cells and subsequent decreased amount of
 immunoglobulins.
a. Ibrutinib (Imbruvica) is an oral small molecule that can inhibit BTK, which is an
essential tyrosine kinase for B-cell maturation. It is approved for patients with
mantle cell lymphoma (MCL) previously treated, including following stem cell
transplant, based on an overall RR of 68%, 21% being complete responses
(CRs). It has also been studied in patients with relapsed or refractory chronic
lymphocytic leukemia (CLL), with an overall RR of 71%, 26-month PFS rate of
75%, and OS rate of 83%. This response was not seen in patients with a mutated
immunoglobulin variable-region heavy chain gene, but was maintained in patients
with 11q or 17p mutations. Ibrutinib was compared to ofatumumab (discussed
further later) in patients with previously treated CLL and demonstrated an
improvement of PFS and OS. This led to its approval in patients with relapsed or
refractory CLL.8 These outcomes were again preserved in patients with 17p
deletions. More recently, it was studied in patients with previously treated
Waldenstrom macroglobulinemia. This study showed an overall RR of 90.5%,
with 73% being major responses, mainly in patients with MYD88 and CXCR4
mutations.9 Ibrutinib significantly decreased IgM levels while increasing
hemoglobin and decreasing bone marrow involvement, resulting in a 2-year OS
rate of 95.2%. Common adverse effects include neutropenia, diarrhea,
thrombocytopenia, and fatigue. Serious adverse effects include rare cases of
hemorrhage, severe myelosuppression, non-melanoma skin cancer, and renal
failure.
10. Anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is found to be
mutated in a variety of cancers. ALK typically becomes activated by formation of a
fusion gene with a constitutively active gene, gene amplification, or point mutations
within the gene itself. The ALK gene, found on chromosome 2, is fused with the
nucleophosmin (NPM) gene found on chromosome 5 to form a NPM-ALK fusion
protein that is found in 60% of anaplastic large-cell lymphomas. Similarly, ALK
may fuse with EML-4 to form an ELM-4-ALK fusion protein that is found in 3% to
5% of NSCLC (most of which are adenocarcinoma), and in 2% of colon, breast, and
renal cancers. ALK amplification is found in 40% of neuroblastomas and 87% of
inflammatory breast cancers. Overactivation of ALK can contribute to increased cell
growth and survival, leading to malignant transformation. Accordingly, a class of
inhibitors was created to target ALK.
a. Crizotinib (Xalkori) is an oral TKI against ALK, c-MET, and ROS1. It was
granted accelerated approval for patients with ALK+ locally advanced or
metastatic NSCLC based on an overall RR of 50% to 61% with median duration
of response of 42 to 48 months. There were 2 patients who achieved CRs and 69
patients with PRs. On the basis of two separate follow-up studies in patients
with ALK+ metastatic NSCLC, it was subsequently granted regular approval.
 The first study showed an improved PFS of 7.7 months (vs. 3 months for
pemetrexed or docetaxel) in patients who previously received a platinum-based
chemotherapy regimen. The second study showed a similar improvement in PFS
compared to chemotherapy (11 vs. 7 months) in previously untreated patients.10
Common adverse effects include vision changes, nausea, diarrhea, peripheral
edema, and constipation. Serious adverse effects include pneumonitis, increased
alanine transaminase (ALT) and bilirubin, and QT prolongation.
b. Ceritinib (Zykadia) is an oral ALK TKI against IGF-1R, insulin receptor, and
ROS1. It inhibits ALK autophosphorylation and downstream activation of signal
transduction and activator of transcription 3 (STAT3) and is roughly 20 times
more potent than crizotinib. It is approved in patients with ALK+ metastatic
NSCLC who have progressed through or are intolerant to crizotinib, based on a
RR of 43% to 55% and median duration of response of 7 months.11 In this study,
1% to 2% of patients had CRs while 40% to 50% of patients had PRs. Common
adverse effects include diarrhea, increased aspartate transaminase AST, fatigue,
and constipation. Serious adverse effects include pneumonitis, severe nausea and
vomiting, hepatotoxicity, QT prolongation, bradycardia, and hyperglycemia.
c. Alectinib is an ALK inhibitor that is still under investigation. It has been studied
in patients with metastatic NSCLC previously untreated with an ALK inhibitor as
well as those previously treated with crizotinib. In two separate studies, it
showed a RR of 93% in patients without previous ALK inhibitor exposure and
55% in patients who were previously treated with crizotinib. Additional studies
are ongoing.
11. Inhibition of intracellular signaling proteins and protein kinases
This therapeutic strategy is directed against a group of proteins that function in a
network of communicating cascades to transfer the signal from receptors into the
nucleus to produce the intended biologic effect such as cell proliferation, apoptosis,
and angiogenesis. When these proteins mutate, the pathways become unregulated,
contributing to the malignant transformation of the cell. These proteins are either
non-RTKs or serine/threonine kinases. The non-RTKs are cytoplasmic kinases.
Many of these are attached to and closely linked to membrane receptors. They are
usually activated by the binding of ligand to their associated receptors. Some of
these kinases include Src, Abl, and Janus kinase (JAK). The serine/threonine
kinases are intracellular kinases, and some play crucial roles in carcinogenesis.
These kinases include Raf, kinases from the PI3K/Akt/mammalian target of
rapamycin (mTOR) pathway, and MAP kinases. Small molecules have been
designed to block or reverse the effect of these pathways. In general, these
molecules can target multiple proteins, including receptor kinases. They can,
therefore, be classified as receptor kinase inhibitors. For simplicity, this chapter
classifies these kinases based on their primary kinase or pathway effect and alludes
to their other roles within the description of the drug.
 12. BCR-ABL fusion protein
The BCR-ABL fusion protein is the resultant product of the translocation between
the BCR and ABL-1 genes. The ABL-1 gene encodes a non-RTK, while the BCR
encodes a serine/threonine kinase. The product of the translocation encodes for a
phosphorylated fusion protein that activates many pathways, including the RAS,
PI3K, and STAT pathways, and results in malignant transformation. A few drugs are
designed to target this molecule.
a. Imatinib mesylate (Gleevec) is one of the first targeted therapy small molecules
to enter into clinical practice. It is primarily a protein kinase inhibitor that is
designed to inhibit BCR-ABL fusion tyrosine kinase. By inhibiting the BCR-ABL
fusion tyrosine kinase, imatinib mesylate induces apoptosis in BCR-ABL–
positive cells through binding to ABL-1 and competing with ATP, leading to
inhibition of the active tyrosine kinase of the fusion protein. Imatinib has seven
FDA-approved indications in both solid and hematologic cancers. Given its
mechanism of action, it is active in any cancer with the BCR-ABL fusion tyrosine
kinase (also known as the Philadelphia chromosome [Ph]), particularly BCR-
ABL–positive chronic myelogenous leukemia (CML) and BCR-ABL–positive
acute lymphocytic leukemia (ALL). Imatinib mesylate produces hematologic,
cytogenetic, and molecular remissions that are often long-term and sustainable
and have now been shown to be beneficial for up to 5 years of use. In patients
with newly diagnosed chronic-phase CML, imatinib has an improved
hematologic RR of 96.6% compared to 56.6% for IFN in combination with
cytarabine (IFN + Ara).12 Of these responses, 85.2% of the imatinib responses
were major (vs. 16.8% with IFN + Ara) and 73.1% were complete (vs. 6.3%
with IFN + Ara). Similar RRs were found when studied in patients with
accelerated phase and blast crisis, with 20% and 18%, respectively, returning to
chronic phase and 16% and 2%, respectively, having a complete cytogenetic
response with imatinib alone. In two separate studies, similar RRs were
observed in untreated pediatrics patients (up to 20 years old) and patients
resistant to IFN. Patients with chronic-phase Ph+ ALL have also been found to
have a benefit from imatinib. Patients with previously untreated or
relapsed/refractory Ph+ ALL have shown RRs similar to patients with CML. The
current FDA-approved indications for imatinib include CML that is Ph+ whether
newly diagnosed, in chronic phase, in accelerated phase or blast crisis, after
failure of IFN-α therapy, or recurrence after stem cell transplant. It is also
approved in Ph+ ALL that has recurred or is refractory (in adults) and as the first
treatment (in children). Imatinib is also approved in patients with
myelodysplastic/myeloproliferative syndromes (MDS/MPS) with PDGFR gene
rearrangements. In a small phase II study of seven patients with MDS, 45%
developed a complete hematologic response with 39% being a major cytogenetic
response. In addition, imatinib mesylate inhibits the receptor kinases PDGF and
 c-KIT, which are found to be mutated in a variety of cancers. Thus, imatinib was
approved for patients with untreated ASM, having a complete hematologic RR of
100% in patients with a FIP1L1-PDGFR fusion kinase or CHIC2 deletion. This
benefit was not seen in patients with the D816V c-KIT mutation, and these
patients should not receive imatinib. Imatinib is not approved for the less
aggressive forms of mastocytosis such as cutaneous, smoldering, or isolated
bone marrow mastocytosis. Another cancer associated with c-KIT and PDGFR
mutations is hypereosinophilic syndrome/chronic eosinophilic leukemia. In this
patient population, imatinib has a 61% complete hematologic RR and a 13%
partial RR. In patients with a FIP1L1-PDGFR fusion kinase, 100% had a CR.
Imatinib is also approved for patients with dermatofibrosarcoma protuberans,
which is characterized by a translocation involving the PDGFR and collagen
type 1 genes. In patients with metastatic, locally recurrent, or locally advanced
disease, 83% of patients responded to imatinib, with 39% CR and 44% PR. As
c-KIT is mutated in 85% of GISTs, imatinib has been studied in patients with c-
KIT-positive GISTs. In patients with metastatic or unresectable c-KIT-positive
GIST, PFS was found to be 20 months, OS was 50 months, and overall RR was
around 50% with 5% of the responses being CRs. In the adjuvant setting,
imatinib has also shown a survival benefit compared to placebo following
resection of GIST with a 1-year relapse-free survival (RFS) rate of 98% versus
83% with placebo. This benefit extended to a 5-year RFS rate of 66% if imatinib
is taken for 36 months (vs. 48% if taken for 12 months). Common adverse effects
are edema, rash, diarrhea, vomiting, and night sweats. Serious side effects are
congestive heart failure (CHF), cardiogenic shock and tamponade, severe
anemia, thrombocytopenia, and febrile neutropenia. Clinically significant
resistance to imatinib mesylate has been found to occur in patients who develop
mutations within the kinase domain of the BCR-ABL proteins. Therefore,
alternative BCR-ABL inhibitors have been developed.
b. Dasatinib (Sprycel) is an oral inhibitor of multiple tyrosine kinases, including
BCR-ABL, c-KIT, and PDGFR. In patients with chronic-phase CML who are
resistant or intolerant to imatinib, 92% achieved complete hematologic
responses with dasatinib, with 63% being major cytogenetic and 50% being
complete cytogenetic responses. Similar RRs were found in patients with
accelerated, myeloid blast or lymphoid blast CML as well as Ph+ ALL.
Therefore, dasatinib was initially approved for patients with chronic,
accelerated, or blast phase of CML who are intolerant or resistant to prior
therapy with imatinib. Subsequently, dasatinib was also approved as a first-line
therapy in CML based on a study that showed a superiority of dasatinib over
imatinib in major molecular RR and complete cytogenetic RR at 12 months (46%
vs. 28% and 77% vs. 66%, respectively).13 Dasatinib is also indicated in
patients with Ph+ ALL who failed or are intolerant to prior therapy. Dasatinib
 can cause edema, pleural effusions, ascites, and rash. Serious side effects
include CHF, prolonged QT, anemia, thrombocytopenia, and neutropenia.
c. Nilotinib (Tasigna) is another ABL kinase inhibitor. Similar to imatinib, it acts
by competing with the ATP-binding site of BCR-ABL. Nilotinib differs from
imatinib by having a higher binding activity to the ABL kinase site with higher
inhibitory activity in imatinib-sensitive cell lines. Similar to dasatinib, nilotinib
was found to induce both hematologic and cytogenetic responses in patients with
Ph+ CML in chronic or accelerated phase who are resistant or intolerant to
imatinib. Nilotinib was initially approved by the FDA in chronic- or
accelerated-phase CML that is resistant or intolerant to imatinib. Also similar to
dasatinib, nilotinib was subsequently approved as a first-line therapy in CML
based on data demonstrating superiority over imatinib in complete cytogenetic
RR at 12 months (80% vs. 65%) and major molecular RR (from 22% to 44%)
and the time of progression to accelerated phase or blast crisis.14 Edema, rash,
nausea, diarrhea, thrombocytopenia, and anemia are among the common side
effects. Prolonged QT, torsade de pointes, and sudden death are among the
serious side effects.
d. Ponatinib (Iclusig) is a highly potent ABL kinase inhibitor with inhibitory effects
on VEGFR, PDGFR, FGFR, KIT, and FLT3. It is specifically effective in
patients with a T315I-mutated BCR-ABL kinase. It is approved for patients with
all phases (chronic, accelerated, or blast) of CML as well as Ph+ ALL that
relapsed or refractory to other TKIs. This is based on a large study showing a
major cytogenetic RR of 54% (with 44% CRs) in patients in all phases of CML.
This RR was improved to 49% (37% complete) in patients who were refractory
or intolerant to prior TKIs and further increased to 70% (with 66% CRs) in
patients with the T315I substitution mutation.15 In patients with Ph+ ALL who
were resistant or intolerant to prior TKIs, major hematologic RR was 41%, with
34% having complete hematologic responses. Common adverse effects include
HTN, rash, fatigue, fever, and pancytopenia. Serious adverse effects include
decreased LVEF, pancreatitis, fatal hemorrhage, QT prolongation, arterial
thrombosis, and hepatotoxicity.
e. Bosutinib (Bosulif) is also a BCR-ABL kinase inhibitor and has activity against
the Scr-family of kinases. Bosutinib was designed to inhibit imatinib-resistant
forms of BCR-ABL that is expressed in murine myeloid cell lines and has been
shown to block 16 of the 18 resistant forms. It is approved for patients with all
phases of CML who are resistant or intolerant to imatinib and have failed
combination TKIs (particularly imatinib followed by dasatinib and/or nilotinib).
This is based on a major cytogenetic RR of 34% in patients with chronic-phase
CML previously treated with imatinib alone and 29% in patients treated with
combination TKIs. In patients with accelerated or blast phase, complete
hematologic RRs were 30% and 15%, respectively. Bosutinib is not active in
 patients with the highly resistant T315I mutation. Common adverse effects
include diarrhea, nausea, thrombocytopenia, rash, and fever. Serious adverse
effects include severe myelosuppression, hepatotoxicity, and peripheral edema.
f. Navitoclax (ABT-263) is a BCL-2 inhibitor that has been studied in patients with
SCLC that progressed after at least one prior chemotherapy regimen with 1 out of
29 patients achieving a PR for over 2 years. In a more recent phase II trial in
similar patient population, single-agent navitoclax showed a PFS of 1.5 months
and OS of 3.2 months, with 41% of patients developing grade 3 or 4
thrombocytopenia.
g. ABT-199 (Venetoclax) is a BCL-2 inhibitor that was designed to reduce the
degree of severe thrombocytopenia seen in earlier inhibitors in its class. It
demonstrated significant anti-leukemia activity in early studies, with a RR of
77% in patients with relapsed or refractory CLL (23% with CRs). ABT-199
resulted in significant tumor lysis after a single dose in three patients with
refractory CLL. Additional studies are ongoing. It is generally well tolerated
with neutropenia, diarrhea, nausea, and fatigue but without severe
thrombocytopenia.
h. Quizartinib is an oral potent FLT3 kinase inhibitor that has shown activity in
patients with FLT3-mutated acute myeloid leukemia (AML), which typically
conveys an aggressive leukemia and is less likely to respond to standard
chemotherapy. In a recent phase II trial, it had a 46% RR in patients with FLT3-
mutated AML, allowing 37% to proceed to stem cell transplant. Additional
studies are ongoing.
13. Signal transduction and activator of transcription
STAT proteins are a family of seven transcription factors that are active by a variety
of extracellular ligand-receptor interactions and are involved in cell proliferation,
differentiation, and apoptosis. Studies have suggested that STAT proteins, and
STAT5 in particular, are involved in controlling cell cycle, cell survival, and
angiogenesis. Several other mutated oncogenic proteins have been shown to lead to
constitutive activation of STAT proteins, including BCR-ABL, FLT-3, ABL, and
JAK2. This has made STAT inhibition a novel therapeutic strategy, with several
investigational drugs currently under investigation.
a. OBP-31121 is a novel STAT3 inhibitor that has been shown to have a significant
antitumor effect against leukemia and lymphoma cell lines. Phase I clinical trials
are ongoing in patients with both solid tumor and hematologic malignancies.
b. ISIS-481464 (AZD-9150) is an antisense oligonucleotide targeting STAT3. It
was recently studied in patients with variety of solid tumors and both Hodgkin
lymphoma (HL) and non-Hodgkin lymphoma (NHL), resulting in PRs in two
patients with diffuse large B-cell lymphoma (DLBCL). Multiple studies are
ongoing in patients with HCC, DLBCL, and other advanced lymphomas.
14. Janus kinase
 The cytoplasmic Janus protein tyrosine kinases (JAK) are a family of signal
transduction kinases that are essential for cellular survival, proliferation, and
apoptosis. Activation of JAK has been shown to result in downstream activation of
other pathways such as STAT, Raf, and the PI3K/Akt pathways. Thus, the JAK
pathway has been targeted in a variety of malignancies.
a. Ruxolitinib (Jakafi) is an oral small molecule that inhibits JAK1 and JAK2 and
is FDA-approved for patients with untreated intermediate or high-risk
myelofibrosis (MF). This is based on two separate phase III trials in patients
with MF, mostly untreated but some had previously received hydroxyurea or
steroids. In the first study, single-agent ruxolitinib resulted in a 42% reduction in
spleen size compared to 1% with placebo. The second study showed similar
splenic reduction (41% vs. 0% with placebo).16 Ruxolitinib has also been shown
to improve patient’s symptoms. It is also approved for patients with
polycythemia vera refractory or intolerant to hydroxyurea, based on an improved
RR (spleen size and phlebotomy dependence) of 21% compared to 1% with
placebo. Ruxolitinib has also been studied in patients with previously treated
metastatic pancreatic cancer demonstrating an improved OS and PFS compared
to placebo. Common adverse effects include mild thrombocytopenia, anemia,
dizziness, and headache. Serious effects include thrombocytopenia and
neutropenia.
b. Pacritinib is an oral TKI with potent activity against JAK2 and Flt-3. It was
granted Fast Track Designation by the FDA for patients with intermediate or
high-risk MF. This was based on its use in this patient population showing a
reduced spleen size by over 50% (31% by MRI, 42% by physical exam) and
improved symptoms in over 50% of patients. Phase III trials are ongoing.
15. The RAF/MAP pathway
The RAF is a family of serine/threonine kinases that includes ARAF, BRAF, and
CRAF and is part of the RAS pathway. RAF is activated when RAS, in response to
the activation of a RTK, recruits and phosphorylates RAF kinase at the membrane
site. RAF, in turn, phosphorylates MEK that activates and phosphorylates ERK.
Activated ERK enters the nucleus to activate other transcription factors, leading to
cellular proliferation. Aberration in this pathway leads to deregulation of
proliferation, resulting in transformation of the cell. BRAF has been found to be
mutated in many tumors such as melanoma, thyroid, and colorectal cancers.
Therefore, inhibition of this kinase is a desirable target in cancer treatment.
a. Sorafenib (Nexavar) is a small molecular inhibitor of CRAF kinase that leads to
the inhibition of the RAF/MEK/ERK signaling pathway. Sorafenib has also been
found to be a strong inhibitor of both VEGFR-2 and PDGF kinase. In patients
with metastatic or advanced RCC untreated or treated previously with IL-2 or
IFN, sorafenib showed an improved PFS compared to placebo leading to its
FDA-approval in advanced RCC. However, with only 2% radiologic RR, the
 benefit reflected stable disease. Sorafenib is also approved for the treatment of
patients with unresectable HCC after it was found to prolong the median survival
by 2.8 months and the time to radiologic progression by 2.7 months compared to
placebo.17 The majority of these patients had well-compensated, early cirrhosis,
with 95% Child-Pugh class A cirrhosis. Sorafenib was also recently approved
for patients with recurrent or metastatic, progressive, differentiated thyroid
cancer after radioactive iodine, based on an improved RR of 12% (1% with
placebo) and PFS of 10.8 months (5.8 months with placebo). Other clinical trials
are ongoing to test the efficacy of sorafenib in other cancers. Common side
effects are HTN, alopecia, hypophosphatemia, and diarrhea. Severe side effects
are hand-foot syndrome, chronic heart failure, and MI.
b. Trametinib (Mekinist) is an inhibitor of MAP kinase (MEK/MAPK/ERK kinase).
MEK-1 and -2 are upregulated in different cancers, and they are involved in the
activation of the RAS/RAF/MEK/ERK signaling pathway. Trametinib
specifically inhibits MEK-1 and -2, resulting in an inhibition of growth factor–
mediated cell signaling and proliferation. It is approved for patients with
metastatic or unresectable melanoma with BRAFV600E or BRAFV600K point
mutations based on improved PFS (by 3.3 months) and RR (by 14%) compared
to chemotherapy of paclitaxel or dacarbazine.18 In a second trial, trametinib was
combined with dabrafenib in patients with BRAFV600E- or BRAFV600K-mutated
unresectable or metastatic melanoma who had received one prior chemotherapy
regimen.19 This combination demonstrated an RR of 76% compared to 54% in
patients who received dabrafenib alone, leading to its approval in this patient
population. Common adverse effects include rash, diarrhea, and lymphedema.
When combined with dabrafenib, additional adverse effects include fever,
nausea, fatigue, and myalgia. Serious effects include decreased LVEF, venous
thromboembolism (VTE), increased rate of basal cell carcinoma, and
hemorrhage.
c. Dabrafenib (Tafinlar) is a selective inhibitor of RAF kinases. It has more
potency toward BRAF than CRAF and inhibits BRAF kinase activity 100-fold
more than sorafenib. Thus, it may be promising in overcoming the resistance to
BRAF inhibitors. It is approved for patients with untreated BRAFV600E- or
BRAFV600K-mutated unresectable or metastatic melanoma. Compared to
dacarbazine, dabrafenib improved RR by 35% (3% CR vs. none with
dacarbazine) and PFS by 2.4 months. Dabrafenib is also approved for use with
trametinib as described earlier. Common adverse effects are similar to those of
trametinib in addition to alopecia and hand-foot syndrome.
d. Vemurafenib (Zelboraf) is a selective inhibitor of the oncogenic V600E-mutant
BRAF kinase. It is approved for patients with untreated BRAFV600E-mutated
unresectable or metastatic melanoma based on an improved PFS of 3.7 months
 and RR of 43% compared to dacarbazine.20 Common adverse effects include
arthralgia, rash, alopecia, and fatigue. Serious adverse effects are QT
prolongation, photosensitivity, rash, and increased incidence of cutaneous
squamous cell carcinoma.
e. Binimetinib (MEK-162) is an oral potent inhibitor of MEK-1 and -2. It is
currently being studied in patients with NRAS-mutant unresectable or metastatic
melanoma that have previously received immunotherapy.
f. Regorafenib (Stivarga) is an oral multikinase inhibitor, including RET, VEGFR-
1–3, KIT, PDGFR, FGFR-1 and -2, RAF, BRAF, and TIE-2. It was recently
approved for heavily pretreated patients with metastatic CRC. This is based on a
study of patients with metastatic colorectal cancer previously treated with 5-FU-,
oxaliplatin-, and irinotecan-based chemotherapies as well as bevacizumab. Most
patients were also KRAS-WT and previously received panitumumab or
cetuximab. In this patient population, regorafenib demonstrated an RR of 5%, an
improved PFS by 0.3 months, and OS by 1.4 months compared to placebo. It is
also approved for patients with advanced GIST who are refractory or intolerant
to imatinib, based on an improved PFS of 4.8 months (compared to 0.9 months
with placebo). Common adverse effects include fatigue, hand-foot syndrome,
diarrhea, mucositis, and HTN. Serious effects include hepatotoxicity and rare but
fatal hemorrhage.
g. Tivantinib is a MET inhibitor that has shown activity in a variety of cancers
including NSCLC, HCC, and gastric adenocarcinoma. In a recent phase II trial,
patients with metastatic gastric cancer showed a PFS of 1.4 months and stable
disease in 37% patients when used as a second or third line after chemotherapy.
h. Pimasertib is a selective MEK-1 and MEK-2 inhibitor that has shown
preclinical activity in lung and colorectal cancers. It is currently being studied in
phase II trials in melanoma, lung, and colorectal cancers.
i. Foretinib is a multikinase inhibitor of MET, VEGFR-2, and ROS1. ROS1 has
been found to be overexpressed in a variety of tumors including lung
adenocarcinoma, cholangiocarcinoma, gastric adenocarcinoma, and
glioblastoma. Foretinib is currently being studied in patients with lung
adenocarcinoma.
j. Linifanib is an oral tyrosine kinase with activity against VEGFR and PDGFR. It
showed an improved PFS of 2.9 months compared to placebo in patients with
advanced nonsquamous NSCLC. It was also studied in patients with advanced
HCC, but did not show a survival benefit compared to sorafenib. Common
adverse effects include diarrhea, anemia, and HTN. Serious adverse effects
include severe thrombocytopenia.
k. Refametinib is a potent inhibitor of MEK-1 and MEK-2. In a recent phase II trial
in patients with previously treated metastatic pancreatic cancer, the combination
of refametinib and gemcitabine demonstrated a trend toward improved response,
 PFS, and OS in the KRAS-WT subset of patients.
16. Aurora kinase
Aurora kinases are a network of kinases involved in mitosis. Aurora kinase A, in
particular, is essential for centrosome function and maturation, spindle assembly,
chromosome alignment, and entry into mitosis. Inhibition of these kinases disrupts
spindle formation and prevents entry into mitosis, leading to cell cycle arrest and
apoptosis. Overexpression of these kinases has been found in gastric, breast, lung,
and head and neck squamous cancers.
a. Alisertib is an orally available selective aurora kinase A inhibitor that
demonstrated a significant activity in preclinical studies. In a recent phase II trial
in patients with previously treated malignancies, it is was found to have an RR of
18% in breast cancer, 21% in SCLC, 4% in NSCLC, 9% in SCCHN, and 9% in
gastric cancer. Adverse effects include severe neutropenia, fatigue, alopecia, and
diarrhea. Additional studies are ongoing in patients with breast, lung, and
peripheral T-cell lymphomas.
17. PI3K, Akt, and mTOR pathway
The PI3Ks are a family of lipid kinases divided into three classes based on their
protein structure. Class I PI3K has been studied more closely due to the role it plays
as a regulator of cell survival, proliferation, and differentiation. Class IA PI3Ks,
composed of four subunits (p110α, β, γ, and δ), is recruited to the membrane upon
the activation of RTKs. This leads to a signaling cascade that activates multiple
downstream signaling pathways, including the Akt pathway. The mTOR pathway is
downstream of the PI3K/Akt pathway and plays an important role in cell growth
regulation and proliferation. The mTOR pathway is regulated by the PTEN tumor-
suppressor gene, which encodes for a phosphatase that works as an on/off switch.
The switch moves to “on” position when PI3K deposits a phosphate group on the D3
position of the inositol ring; when PTEN removes this same phosphate group, the
switch moves to the “off” position. It has been found that genetic alterations in the
PI3K pathways play an important role in different cancers, including breast, colon,
and ovarian cancers. Therefore, a plethora of novel agents targeting the
PI3K/Akt/mTOR pathways have recently been developed for treatment of cancer.
Three of these agents are already approved by the FDA, and the rest are still under
clinical trials and expected to reach the clinic in the next decade.
a. Everolimus (Afinitor) is a kinase mTOR inhibitor. It is approved for patients
with metastatic RCC previously treated with sunitinib, sorafenib, or both, based
on an improvement of PFS by 3 months compared to placebo. Everolimus, in
combination with exemestane, is also approved in postmenopausal women with
hormone receptor–positive metastatic breast cancer after letrozole or anatrozole.
This is based on an improved PFS of 7 months (vs. 3 months with placebo) and
improved RR of 9.5% (vs. 0.4%), but no difference in OS. Everolimus has also
been studied in combination with tamoxifen in postmenopausal women who have
 previously been treated with an aromatase inhibitor and showed an improved
TTP of 9 months compared to 5 months with placebo.21 Everolimus is also
approved for patients with locally advanced, unresectable or metastatic
pancreatic neuroendocrine tumors, based on an improved PFS of 11 months
versus 4.6 months with placebo. It has also been studied in patients with
advanced carcinoid tumors and, when combined with long-acting octreotide, it
improved PFS to 16.4 months compared to 11.3 months with long-acting
octreotide and placebo. Everolimus is also approved for patients with tuberous
sclerosis complicated by unresectable subependymal giant cell astrocytoma
based on reduction in tumor size by at least 30% in 75% of patients at 3 months
compared to placebo. Everolimus showed a decreased seizure frequency and
improved quality of life in these patients compared to placebo. Common side
effects include rash, edema, and diarrhea. Serious side effects include
pneumonitis, anemia, leukopenia, and neutropenia.
b. Temsirolimus (Torisel) is a competitive inhibitor of the mTOR kinase. It is
approved for patients with untreated advanced RCC, both clear cell and non–
clear cell histology. In a phase III trial, patients with a poor prognosis and/or
poor performance status were treated with either temsirolimus or IFN-α. Both
PFS and OS were improved by 2.4 and 3.6 months, respectively, favoring
temsirolimus.22 Common side effects include anemia and hyperlipidemia.
Serious anaphylaxis was also reported.
c. Idelalisib (Zydelig) is a potent inhibitor of PI3K-δ. Inhibiting PI3K-δ
subsequently blocks cellular proliferation and induces apoptosis. It is currently
approved for patients with relapsed CLL in combination with rituximab as well
as relapsed follicular lymphoma and relapsed small lymphocytic lymphoma
(SLL). In patients with relapsed CLL who were unable to tolerate additional
chemotherapy after an average of three prior regimens, idelalisib plus rituximab
improved PFS compared to placebo.23 In patients with relapsed follicular
lymphoma after two previous therapies, idelalisib showed a RR of 54% with 8%
having a CR, and median time to response of 1.9 months. Similar RRs were
found in patients with relapsed SLL, although no CRs were observed. Common
adverse effects include diarrhea, fever, fatigue, nausea, and rash. Serious
adverse effects include anaphylaxis, colitis (with rare cases of perforation),
pneumonitis, and neutropenia.
d. Pilaralisib (XL147) is an orally available selective inhibitor of class I PI3K
isoform. It was studied in a phase I trial in patients with solid tumors, primarily
NSCLC, and found to be safe with some patients having stable disease. It was
shown to have an overall RR of 6% in patients with advanced or recurrent
endometrial cancer after at least one prior chemotherapy regimen. It is also being
evaluated in combination with trastuzumab or paclitaxel and trastuzumab in
patients with metastatic breast cancer who have progressed on a previous
 trastuzumab-based regimen. The most common side effects are rash, diarrhea,
and fatigue.
e. XL765 is a selective inhibitor of mTOR and class I PI3K isoform. A phase II
trial is ongoing to evaluate the safety and clinical efficacy of either XL147 or
XL765 in combination with letrozole in patients with breast cancer that is
ER+/PR+ and HER2− and refractory to a nonsteroidal aromatase inhibitor. It is
also currently being studied in glioblastomas and NHL.
f. Buparlisib is an inhibitor of PI3K and found to be safe and active in early studies
treating breast cancer and glioblastomas. In a recent phase II trial, it provided
stable disease without a survival benefit in patients with resectable and
unresectable glioblastomas. Additional studies are ongoing. Adverse effects
include asymptomatic lipase elevation, rash, hyperglycemia, and fatigue.
g. MK2206 is an orally available inhibitor of Akt through a non-ATP–competitive
inhibition mechanism leading to apoptosis. It has shown activity against
nasopharyngeal carcinoma cell lines, and clinical trials are ongoing.
18. Hedgehog signaling pathway
The hedgehog signaling pathway is essential for embryonic and limb development. It
has been found to be important in cell signaling and migration during brain and limb
development, in addition to stem cell migration. Its role in these processes is thought
to convey the cancer cells ability to metastasize to distant organs. It has been found
to be over-activated in multiple cancers such as lung, brain, prostate, and skin
cancers. Inhibition of this pathway has been shown to inhibit proper formation of the
brain, gastrointestinal system, and limbs in mouse models and represents a novel
antineoplastic mechanism.
a. Vismodegib (Erivedge) is an orally available hedgehog pathway inhibitor that is
approved for patients with locally advanced or metastatic basal cell carcinoma.
This is based on a RR of 10% in patients with metastatic disease and 27% in
patients with locally advanced disease (13% of these patients had CR) and a
median duration of response of 7.6 months in both groups.24 Vismodegib has also
shown activity in combination with chemotherapy in a small set of 59 patients
with untreated metastatic pancreatic cancer demonstrating 2% CR, 41% PR, and
43% stable disease. Common adverse effects include muscle spasms, alopecia,
weight loss, diarrhea, and nausea. Patients who are treated with vismodegib
should not donate blood or blood products due to the teratogenicity of this drug.
b. Erismodegib (Sonidegib) is a hedgehog signaling pathway inhibitor being
studied in a variety of cancers, including basal cell carcinoma.
c. IPI-926 (Saridegib) is also a hedgehog signaling pathway inhibitor being studied
in chondrosarcoma treatment.
19. Poly(ADP-ribose) polymerase (PARPS)
PARPs are a family of proteins involved in DNA repair. Found in the nucleus, it
surveys DNA for single-strand breaks and, once found, initiates a cascade of
 proteins to repair the break. If unable to repair the damage, it can induce
programmed cell death through a caspase-independent mechanism. Inhibition of
PARP is thought to disrupt cellular homeostasis and lead to cell death. This
mechanism is thought to be essential for the BRCA1/2 oncogenesis and thus multiple
agents have been developed to target PARP.
a. Olaparib (Lynparza) is an oral PARP inhibitor that showed initial activity in
BRCA1/2 related cancers, including ovarian, breast, and prostate related
cancers. It is currently approved for patients with BRCA-mutated advanced
ovarian cancer previously treated with at least three chemotherapy regimens.
This is based on an RR of 34% in this patient population, with 2% complete RR.
Common adverse effects include anemia, nausea, fatigue, diarrhea, and
headache. Serious adverse effects include an increased incidence of MDS and
AML and rare but fatal pneumonitis.
b. Iniparib is an irreversible PARP-1 inhibitor (although recent data suggest
alternative mechanisms). It has been studied in combination with gemcitabine
and carboplatin (GC) in patients with metastatic triple-negative breast cancer,
showing an improved RR of 52% (vs. 32% with GC alone), PFS of 5.9 months
(vs. 3.6 months), and OS of 12.3 months (vs. 7.7 months). These findings,
however, were not replicated in a later phase III trial. Additional studies are
ongoing.
c. Niraparib is an orally available PARP-1 and PARP-2 inhibitor that showed
promising preclinical activity. It is currently being studied in a phase III trial in
patients with platinum-sensitive recurrent ovarian cancer.
20. Histone deacetylase
Histone deacetylases (HDACs) are a family of proteins that catalyze the removal of
acetyl groups from lysine groups on histones and non-histone proteins. The removal
of the lysine group is necessary for DNA to properly coil around histone groups and
condense chromatin. If blocked, chromatin relaxes and cannot proceed through the
cell cycle and results in apoptosis.
a. Panobinostat (Farydak) is a small molecule that is highly specific and sensitive
for the HDAC. In preclinical studies, it was shown to be more cytotoxic to tumor
cells than normal cells, likely a result of tumor cells reliance on frequent
chromatin condensing for proliferation. It is approved in combination with
bortezomib (Velcade) and dexamethasone (VD), in patients with multiple
myeloma (MM) who have progressed through two prior therapies. The
combination of panobinostat with VD improved RR from 41% to 55% and PFS
by 4.8 months compared to placebo. It is also being studied in MDS, breast, and
prostate cancers. Common adverse effects include diarrhea, fatigue, nausea, and
pancytopenia. Serious adverse effects include rare but fatal hemorrhage, severe
thrombocytopenia, and hepatotoxicity.
b. Vorinostat (Zolinza) is an orally available small molecule that inhibits HDAC1–
 3 and HDAC6. It is approved for patients with cutaneous T-cell lymphoma
(CTCL) after at least two prior therapies. This is based on two separate trials in
patients with CTCL refractory to two previous therapies, both showing a RR of
around 30% with a median duration of response of around 3.5 months. Common
adverse effects include diarrhea, fatigue, nausea, and thrombocytopenia. Serious
effects include pulmonary emboli and anemia.
c. Romidepsin (Istodax) is an infusional HDAC inhibitor with activity in patients
with CTCL. It is approved for patients who have received at least one prior
treatment, based on two studies showing a 35% RR and duration of response of
11 to 15 months. Common adverse effects include fatigue, nausea, decreased
appetite, and weight loss. Serious effects include QT prolongation, leukopenia,
and thrombocytopenia.
d. Mocetinostat is an oral small molecule that selectively inhibits HDAC1–3 and
HDAC11. In preclinical studies, it was shown to be active in AML, HL, and
NHL. In a recent phase II trial, it was combined with azathioprine in mostly
untreated patients with MDS and showed a RR of 80% with a complete bone
marrow RR of 50%, even in patients with baseline marrow blast count over
10%. In another phase II trial in patients with relapsed or refractory HL,
mocetinostat showed a RR of 35%. Additional trials are ongoing in MDS, AML,
HL, and urothelial cancer.
B. Angiogenesis-targeted therapy
Angiogenesis is a biologic process that is crucial for the development of tumors. The
process of angiogenesis starts by the release of VEGF. VEGF binds to receptors on the
blood vessels’ endothelial cells, leading to their proliferation and immigration toward
the source of the angiogenic signal. Tumors have exploited this physiologic process to
provide the milieu to permit the growth of both primary and metastatic cancers.
Although the antineoplastic effect of antiangiogenesis therapy is mediated through the
effect on the environment for the cancer cell growth, the initial mechanism of current
therapies is based on molecular targeting, which was previously described.
1. Trebananib is a potent inhibitor of angiopoetin-1 and -2, as well as TIE-2R, which
has been shown to be important in cancer-related angiogenesis. In patients with
recurrent epithelial ovarian cancer treated with at least three previous chemotherapy
regimens, trebananib showed an improved PFS of 1.8 months but no improvement in
OS. In this study, 17% of patients discontinued trebananib because of adverse
effects, including edema, ascites, and neutropenia.
C. Protein degradation–targeted therapy
Protein degradation is one of the mechanisms by which cell function is regulated. The
ubiquitin-proteasome pathway plays a very important role in this regard. The
proteasome is a large complex of proteins that degrades other ubiquitinated proteins. It
exerts its degradation capability through coordinated catalytic activities of its three
proteolytic sites that leads to chymotryptic, tryptic, and postglutamyl peptide hydrolytic-
 like activities. Many key proteins in the cell cycle, apoptotic, and angiogenesis
pathways are regulated by degradation, including the p53, p21, and p27 (cell cycle
regulatory) proteins; NF-κB, a key transcription factor that is activated by the
proteasomes; and intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion
molecule (VCAM), and E-selectin (cell adhesion molecules). Drugs targeting
degradation machinery in the cell include the following.
1. Bortezomib (Velcade) is a dipeptidyl boronic acid derivative that inhibits the 26S
proteasome, which is the principal regulator of the intracellular protein degradation.
Bortezomib is the first of its class to be approved for clinical use. Bortezomib can
selectively inhibit the chymotryptic site of the proteasome. This leads to a selective
inhibition of the degradation of proteins involved in cell proliferation and survival
regulation; as a consequence, apoptosis is induced. Bortezomib has been found to be
particularly effective in MM where it is approved as a first-line therapy. The
addition of bortezomib to melphalan and prednisone (MP) improved RR to 71%
(35% with MP alone), PFS to 18.3 months (14 months with MP), and OS (median
not reached in 16.3 months in either group).25 It has also been shown to be effective
in combination with several other agents in patients with untreated and pretreated
MM, in addition to patients who had stem cell transplant. Bortezomib is also FDA-
approved for patients with MCL who failed at least one prior therapy, based on an
RR of 33% (8% complete) with median duration of response of 9.3 months (15.4
months for those with a CR). Bortezomib has also been studied in patients with
relapsed or refractory peripheral T-cell lymphoma with an RR of 67% when used
alone and a CR rate of 62% when combined with Cytoxan, hydroxydaunorubicin,
Oncovin, and prednisone (CHOP). Additional studies in this patient population are
ongoing. Common adverse effects include asthenia, HTN, rash, and diarrhea.
Serious side effects include CHF, anemia, neutropenia, and thrombocytopenia.
2. Carfilzomib (Kyprolis) is the next generation of proteasome inhibitor with higher
selectivity and specificity than bortezomib. It binds selectively to the N-terminal
threonine active sites within the proteasome and is approved for patients with MM
who have failed two prior therapies, including bortezomib and an immunomodulator.
This is based on its overall RR of 23% and OS of 15.6 months (compared to 9
months for historical controls). In patients with MM previously treated with one to
three previous regimens, carfilzomib with lenalidomide and dexamethasone (Rd)
showed an impressive PFS of 26.3 months compared to 17.6 months with Rd alone.
Common adverse effects include fatigue, anemia, thrombocytopenia, dyspnea, and
diarrhea.
D. Nonspecific immunomodulators
Nonspecific immunomodulators are a family of medications that are derivatives of
thalidomide by minor structural modifications. These modifications lead to the
enhancement of drug efficacy and the improvement in the side effect profile, including
the neurologic toxicity and prothrombotic effects of thalidomide. The mechanism of
 action for this group of compounds is not clearly defined, but many pathways have been
shown to be triggered by these medications, including caspase-8, proteasome, NF-κB,
and the antiangiogenesis pathways.
1. Lenalidomide (Revlimid) is one of the new generations of nonspecific
immunomodulators. In a randomized phase III study, when combined with
dexamethasone, lenalidomide was found to be superior in CR, PFS, and OS to
dexamethasone alone in patients with relapsed or refractory MM. When
lenalidomide was combined with dexamethasone in patients with newly diagnosed
MM in two separate studies, combined results showed 91% of patients achieved an
objective response, including 11% with CR.26,27 Lenalidomide has also been studied
in various combination with other active agents in myeloma in this patient
population demonstrating improvement in RRs and PFS. A lower dose of
lenalidomide is approved for patients with MDS with 5q deletion who are
transfusion dependent, with 67% achieving transfusion independence (90% within 3
months). It is also approved for patients with relapsed MCL after two prior
therapies including bortezomib, based on an RR of 28%, PFS of 4 months, and OS
of 19 months. Common adverse effects include somnolence, constipation,
neuropathy, edema, and rash. Serious side effects include atrial fibrillation, Stevens-
Johnson syndrome, neutropenia, anemia, and thrombocytopenia.
2. Pomalidomide (Pomalyst) is an oral thalidomide analog that is an
immunomodulatory agent with antineoplastic activity. It has shown to induce
apoptosis in lenalidomide-resistant MM cell lines and provide synergy with
dexamethasone. It is approved for patients with MM that has been refractory to at
least two prior therapies, including lenalidomide and bortezomib. This is based on
an overall RR of 33% and duration of response of 7.4 months when combined with
low-dose dexamethasone. More recently, a higher dose of dexamethasone in
combination with pomalidomide showed an improved PFS of 4 months compared to
1.9 months with low-dose dexamethasone. Common adverse effects include fatigue,
neutropenia, anemia, diarrhea, nausea, neuropathy, and fever. Serious effects include
VTE, leading to a recommendation to consider prophylactic anticoagulation when
using this medication, and severe neutropenia.

I. PHENOTYPE-TARGETED THERAPY
As outlined previously, this is a therapeutic strategy that is intended to target the unique
phenotype of the cancer cell where killing the cell is more dependent on direct induction of
a cytotoxic effect rather than targeting a specific pathway, as discussed subsequently. These
MoAbs may be used alone (unconjugated) or as a delivery system for cellular toxins,
radionuclides, or chemotherapy (conjugated). Agents under this category are classified
based on the type of therapy and subclassified based on the target pathway or molecule, if
applicable.
A. Unconjugated antibodies
 1. Rituximab (Rituxan) is an IgG1-κ murine-human chimeric MoAb that is generated
against the CD20 antigen. CD20 is expressed on the cell surface of B-cells and
hence on the surface of B-cell lymphoma. Rituximab is used in a variety of clinical
setting and FDA-approved in NHL and CLL. Several studies have shown improved
RRs with rituximab (around 50%) in patients with a variety of NHL, in addition to
improve survival in follicular lymphoma and DLBCL. In combination with
cyclophosphamide, vincristine, and prednisone (CVP), PFS was improved by 12
months in patients with follicular lymphoma, and 2-year OS was improved by 10%
to 20% when combined with CHOP in patients with DLBCL.28 Rituximab is also
approved in combination with fludarabine and cyclophosphamide in previously
untreated patients with CD20+ CLL, based on improved PFS of 5 to 8 months.
Rituximab is also used for CD20+ HL and a variety of autoimmune diseases such as
thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura,
granulomatosis with polyangiitis, posttransplant lymphoproliferative disease
(PTLD), and chronic graft-versus-host disease (GVHD). Rituximab can cause HTN,
nausea, vomiting, fever, chills, and lymphopenia. Cardiac arrhythmia, cardiogenic
shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, and tumor lysis
syndrome are reported as serious side effects. As with any chimeric antibody,
severe infusion reactions and anaphylaxis can occur. Reactivation of hepatitis B and
progressive multifocal leukoencephalopathy (PML) are also rare but serious
adverse effects.
2. Alemtuzumab (Campath) is a humanized IgG1-κ chimeric MoAb that is directed
against CD52 cell surface glycoprotein. CD52 is expressed on the surface of normal
and malignant B- and T-cells, natural killer cells, monocytes, and macrophages.
Alemtuzumab is approved for untreated patients with B-cell CLL, based on
improved PFS of 14.6 months versus 11.7 months with chlorambucil. In patients
with B-cell CLL previously treated with fludarabine, alemtuzumab showed a 2% CR
and 31% PR. Similar to rituximab, alemtuzumab is used in a variety of off-label
settings, including T-cell prolymphocytic leukemia, CLL-related autoimmune
cytopenias, GVHD, and relapsing multiple sclerosis. Common side effects are
anemia, neutropenia, thrombocytopenia, rash, and diarrhea. Serious side effects are
cardiac arrhythmia and cardiomyopathy. Patients who have recently been treated
with this MoAb should not receive any live viral vaccines because of the severe
immune suppression effect of the medication.
3. Ofatumumab (Arzerra) is a humanized IgG1-κ MoAb that binds to the CD20
molecule on B-lymphocytes, which leads to B-cell lysis. It is FDA-approved in
combination with chlorambucil in patients with untreated CLL and in patients with
refractory CLL. In patients with untreated CLL, ofatumumab in combination with
chlorambucil showed an improved PFS of 22.4 months compared to 13.1 months
with chlorambucil alone. In patients with CLL refractory to fludarabine and
alemtuzumab, it was shown to have an RR of 50% as a single agent. Ofatumumab
 can cause rash, neutropenia, anemia, diarrhea, and sepsis.
4. Blinatumomab (Blincyto) is a bispecific humanized antibody directed against CD19
B-cells and CD3 T-cells. It activates T-cells by connecting the CD3 receptors of T-
cells to the CD19 receptor on benign and malignant B-cells, enhancing the T-cell
recognition of malignant B-cells. This mechanism leads to increased production of
cytokines resulting in malignant B-cell lysis. It is approved for patients with
relapsed Ph− ALL or refractory B-precursor ALL, based on a minimal residual
disease rate of 80% and a duration of response of 6.7 months.29 It is currently being
studied in gastrointestinal and lung cancers. Common adverse effects include fever,
headache, peripheral edema, hypokalemia, and constipation. Serious effects include
febrile neutropenia, encephalopathy, and headache.
5. Epratuzumab is a humanized MoAb that binds to CD22 glycoprotein. CD22 is
expressed on the cell surface of mature B-cells in follicular NHL. An overall RR of
88% (with a 42% CR rate) was achieved when epratuzumab was combined with
rituximab in patients with untreated follicular lymphoma. It is also being studied in
patients with lupus and ALL.
6. Elotuzumab is a humanized IgG1 MoAb targeting signaling lymphocytic activation
molecule (SLAM7), which is found primarily on natural killer cells and myeloma
cells but not on other normal cells. For this reason, it has been studied in MM,
showing an RR of 92% and PFS of 33 months when used in combination with
lenalidomide and dexamethasone in previously treated patients. On the basis of these
data, it received a Breakthrough Therapy Designation by the FDA. It is currently
being studied in the first-line setting for smoldering myeloma and relapsed or
refractory MM.
B. Conjugated antibodies
1. Cellular toxin-conjugated antibodies
a. Gemtuzumab ozogamicin (Mylotarg) is a humanized IgG4-κ antibody directed
against the CD33 antigen and conjugated with calicheamicin. Calicheamicin is a
cytotoxic agent isolated from fermentation of the bacterium Micromonospora
echinospora ssp. calichensis. The CD33 antigen is a sialic acid–dependent
adhesion protein expressed on the surface of immature myelomonocytic cells and
on the surface of leukemic blast cells but not on the surface of normal pluripotent
hematopoietic stem cells. When this fusion antibody binds to the CD33
receptors, it is internalized into the cell, and the calicheamicin is cleaved and
released. Calicheamicin binds to the minor grooves of the DNA, leading to DNA
breaks and apoptosis. Gemtuzumab is indicated for the treatment of patients over
60 years old after the first relapse of myeloid leukemia expressing CD33 who
are not candidates for chemotherapy. Gemtuzumab as a single agent may lead to
16% CR and 30% overall response with a median time to remission of 2 months.
Follow-up trials, however, failed to show a clinical benefit, and it was
subsequently removed from the US market. Gemtuzumab can cause fever,
 shivering, and nausea. Side effects can also be severe, including
myelosuppression, hemorrhage, disseminated intravascular coagulation, and
hepatotoxicity.
b. Ado-trastuzumab emtansine (T-DM1 or Kadcyla) is a humanized MoAb against
HER2 that is conjugated to DM1, a maytansine derivative and microtubule
inhibitor. Upon binding to the HER2 receptor, it undergoes internalization and
lysosomal degradation releasing DM1, which disrupts microtubule networks
resulting in cell cycle arrest and apoptosis. In a phase III trial, it was shown to
increase PFS by 3.2 months when combined with lapatinib and capecitabine in
patients with HER2+ metastatic breast cancer. It was also shown to have a
partial RR of 39% in patients with metastatic breast cancer who previously
received trastuzumab. This led to its approval in patients with previously treated
HER2+ metastatic breast cancer. Common adverse effects include fatigue,
nausea, thrombocytopenia, increased liver enzymes, and headache. Serious
effects include pulmonary toxicity, severe thrombocytopenia, and neuropathy.
c. Brentuximab vedotin (Adcetris) is a chimeric IgG1 antibody against CD30 that is
conjugate to monomethyl auristatin E (MMAE), an antimicrotubule agent. Upon
binding to the CD30 receptor, the drug is internalized and the antineoplastic
agent MMAE is released to disrupt the microtubule network, which results in
cell cycle arrest and apoptosis. It is approved for patients with relapsed HL
following autologous stem cell transplant, based on an overall RR of 73%, with
32% being CRs.30 Further study has shown that in patients with relapsed CD30+
HL or anaplastic large-cell lymphoma, including 73% who had undergone
autologous stem cell transplantation, 50% had a response, lasting an average of
9.7 months (with a 38% CR rate). It is also approved for patients with relapsed
systemic anaplastic large-cell lymphoma, based on an overall RR of 86%, with
57% being CRs. Common adverse effects are neutropenia, peripheral
neuropathy, fatigue, anemia, diarrhea, cough, and fever. Peripheral neuropathy
and neutropenia may be severe in rare cases.
d. Inotuzumab ozogamicin is a humanized MoAb directed against CD22 that is
conjugated to an ozogamicin, a cytotoxic agent from the calicheamicin class.
Since CD22 is expressed in 90% of B-cell malignancies, inotuzumab has been
studied in patients with ALL with promising results. In a recent interim analysis
of an ongoing phase III study in patients with relapsed or refractory CD22+ ALL,
it was found to have a complete hematologic RR of 58%, with 19% being CRs,
allowing 40% to undergo allogeneic stem cell transplant. It has also been
studied in patients with relapsed or refractory NHL, but was unable to show a
survival benefit and stopped early. Common adverse effects include bilirubin
elevations, fever, and asymptomatic hypotension (all reversible after therapy).
Serious effects are an increased rate of venoocclusive disease in 17% after stem
cell transplantation.
 2. Radioimmunoconjugate antibodies
a. Ibritumomab tiuxetan (Zevalin, IDEC-Y2B8) is a murine anti-CD20 MoAb
conjugated to tiuxetan that chelates to pure β-emitting yttrium-90. The mechanism
of action includes antibody-mediated cytotoxicity and cellular-targeted
radiotherapy (radioimmunotherapy [RIT]). It is approved for patients with
CD20+ refractory follicular lymphoma, based on an RR of 83%, with 37%
achieving a CR. Ibritumomab tiuxetan is also being used in patients with
relapsed B-cell NHL following high-dose chemotherapy and autologous stem
cell transplantation with promising results. It should be used with caution in
patients with 25% or greater marrow involvement with lymphoma, prior external
beam radiotherapy to 25% or greater of the bone marrow, or a history of
HAMAs or HACAs. Neutropenia and thrombocytopenia are common and are
related to the radionuclide dose. Low-grade nausea and vomiting are common.
Infusion-related fever, chills, dizziness, asthenia, headache, back pain,
arthralgia, and hypotension are occasional side effects.
b. Iodine-131 (131I)-tositumomab (Bexxar) is a murine IgG2a anti-CD20 MoAb
radiolabeled with 131I, an emitter of both β and γ radiation. The mechanism of
action includes antibody-mediated cytotoxicity and cellular-targeted RIT. It is
indicated as a monotherapy in patients with rituximab-refractory NHL that is
chemotherapy refractory, CD20+, low grade, or transformed low grade.
Furthermore, it was found that the combination of high-dose 131I-tositumomab
and autologous hematopoietic stem cell transplantation is effective for relapsed
B-cell NHL. 131I-tositumomab can cause HTN, shivering, and diarrhea. It must
be used with caution in patients with 25% marrow involvement with lymphoma,
prior external beam radiotherapy to 25% of the bone marrow, or a history of
HAMAs or HACAs.
3. Immunotoxins
These are recombinant proteins that are conjugated to cellular toxins and are
designed to bind to specific proteins on the surface of cancer cells, internalized, and
induce direct cytotoxic effect by releasing conjugated toxins intracellularly.
a. Denileukin diftitox (Ontak) is a recombinant construct that includes a fragment of
the IL-2 protein (Ala1–Thr133) linked to a fragment of the diphtheria toxin
fragments A and B (Met1–Thr387). This construct is designed to bind to the CD25
component of the IL-2 receptor (IL-2R) on the surface of the targeted cells
expressing the receptor. The complex becomes internalized into the cytoplasm
and releases the toxin to exhibit its damaging effect. The high-affinity IL-2R is
normally present on the activated T- and B-lymphocytes and activated
macrophages. CTCL expresses high-affinity IL-2R and forms an appropriate
target. A phase III randomized trial in patients with refractory CTCL compared
denileukin diftitox to placebo and showed a median PFS over 2 years, 10% CR,
 and 34% PR in patients who received denileukin diftitox, which is significantly
better than placebo (median PFS of 4 months and overall response of 15.9%).
This led to its approval for patients with persistent or recurrent CTCL
expressing CD25. Denileukin diftitox can cause elevated liver transaminases,
fever, nausea, edema, rash, and diarrhea. It can also cause serious capillary leak
syndrome.

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4. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil,
leucovorin, and irinotecan improves survival in a phase III randomized trial in patients
with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J
Clin Oncol. 2012;30:3499–3506.
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line treatment for European patients with advanced EGFR mutation-positive non-small-
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Oncol. 2012;13:239–246.
6. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for
sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J
Clin Oncol. 2009;27:3584–3590.
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advanced breast cancer. N Engl J Med. 2006;355:2733–2743.
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melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516.
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2012;30:2183–2189.
I. INTRODUCTION
Agents that produce anticancer activity through one or more components of the immune
system play an important and, in some cases, a predominant role in the treatment of several
malignancies. The broad relevance of antitumor immunity to cancer therapeutics is likely
underappreciated. For example, components of the immune system may contribute to the
overall activity of certain cytotoxic and molecular targeted agents, and also to the activity
of therapeutic antibodies against cell surface receptors with oncogenic function.1–6 The
graft-versus-tumor effect in allogeneic bone marrow transplant can be considered a form of
cancer immunotherapy. This chapter reviews the principles of cancer treatment with agents
whose principal activity is mediated by the cells of the immune system.

II. ANTICANCER IMMUNE RESPONSES

The majority of effective immunotherapies produce tumor regression through induction,
expansion, or activation of T-lymphocytes (T-cells) that recognize tumor antigens. Through
their T-cell receptors (TCR), T-cells recognize peptide fragments of proteins that are
processed intracellularly, bound to major histocompatibility complex (MHC) molecules,
and then brought to the cell surface. Studies in patients have shown that T-cell responses
against peptides from mutated proteins (neoantigens), tissue differentiation proteins such as
MART-1 in melanoma, or developmental proteins re-expressed during malignant
transformation (e.g., NY-ESO-1) can mediate tumor regression.7–9
Naïve T-cells are first activated by interactions with professional antigen-presenting
cells (APCs, also called dendritic cells) in lymph nodes. Once activated, T-cells
differentiate into effector cells and long-lived memory cells. In addition to the signal
received by the TCR, T-cell activation, differentiation, and function are controlled by
multiple soluble cytokines (hormone-like substances) or cell surface ligands on other cells
(including APC and tumor cells) interacting with receptors on the T-cell surface.10 Because
the immune system must have the capacity to eliminate foreign invaders while limiting
autoimmunity and tissue damage, multiple mechanisms exist not only to provide activation
signals but also to delete, inhibit, or terminate immune responses. Multiple types of T-cells
with multiple functions can be involved in the generation of an immune response, including
regulatory T-cells (Tregs) that are capable of suppressing the function of effector cells. For
T-cells to produce an antitumor response, they must migrate back to the tumor site where
they produce cytokines or kill tumor cells directly following TCR binding to the tumor
 peptide–MHC complexes.11
Anticancer T-cell responses can be enhanced by several types of interventions. The
interventions can include providing the putative tumor antigen in the form of an optimized
“vaccine”; providing signals that enhance APC function; providing cytokines that support
T-cell expansion and function; administering antibodies that directly activate costimulatory
receptors or block inhibitory receptors on T-cells; administering agents that inhibit other T-
cell–suppressive mechanisms within the tumor microenvironment; infusing T-cells with
natural or engineered recognition of tumor cells; or combining one or more of the possible
immunomodulating strategies. The type of intervention necessary to produce effective
antitumor immune responses is highly dependent on the nature of the tumor-host
relationship in the individual patient, which can be influenced by many factors, including
host genetic variations in immune response, the number and type of tumor mutations, prior
exposures to foreign antigens, and possibly even by the microbiome. In a substantial
number of patients, the immune system is able to mount a T-cell response against tumor
antigens during the course of time in which the malignancy is evolving in the host. In fact,
inflammation may promote tumor growth at the early stages of tumor development, and
likely controls the developing cancer for a period of time until the tumor develops escape
mechanisms.12 Consistent with the latter observations, multiple factors that are capable of
suppressing effector tumor antigen-specific T-cells within the tumor microenvironment
have been identified. One of the most important is induced by tumor-infiltrating T-cells
mounting the anticancer response. Activated T-cells produce cytokines, particularly
interferon-γ (IFN-γ), which induce PD-L1 expression by tumor cells, stromal cells, or
other immune infiltrating cells. PD-L1 then binds to the inhibitory receptor PD-1 on the
activated T-cells, suppressing their function.13
Chronic exposure of tumor-specific T-cells to tumor antigens either within the tumor
or in draining lymph nodes produces further “exhaustion” of the T-cells, with diminished
capacity to produce cytokines or to proliferate.14 The exhausted T-cells are characterized
by expression of multiple other coinhibitory receptors. Other factors that could inhibit
effector T-cells include Tregs, myeloid-derived suppressor cells, a subset of macrophages,
or possibly other stromal cells such as vascular endothelium. Inhibition may require direct
cell-cell contact or production of inhibitory substances (e.g., enzymes that deplete essential
amino acids and/or produce inhibitory metabolites, or cytokines that inhibit or deviate T-
cell function or contribute to formation of Tregs). While not yet proven, a subset of tumors
containing minimal to no T-cell infiltrate may actively “exclude” T-cells from the
microenvironment by mechanisms which remain to be defined.
The targets for agents that modulate T-cell responses can be found on multiple types of
immune cells that may have opposing functions, and the outcome of any specific
intervention may be context dependent and thus vary on the basis of unknown factors. For
example, interleukin-2 (IL-2) administered to enhance the function of effector T-cells can
also expand a population of Tregs.15 Moreover, activating interventions (e.g., vaccines,
cytokines, or agonist T-cell costimulatory antibodies) can induce counterregulatory
 mechanisms that limit effector T-cell expansion and function, and the tumor-specific T-cells
must still overcome induced and constitutive immunosuppressive mechanisms in the tumor
microenvironment. The latter factors likely explain the relative lack of efficacy for multiple
cytokines and cancer vaccines developed since the early 1980s. In contrast, antibody
antagonists of PD-1 or one of its ligands PD-L1 are capable of producing substantial and
durable tumor regression in a subset of patients across many different malignancies.16–20
The remarkable activity of PD-1/PD-L1 antagonists confirms that many patients have
ongoing T-cell responses against their cancers at the time of presentation with advanced
disease, and highlights the importance of blocking negative regulation of T-cell responses
to enable their antitumor function, particularly within the tumor microenvironment.
Currently, there are relatively few examples of effective anticancer immunotherapies
that are T-cell independent or rely primarily on other components of the immune system.
Natural killer (NK) cells, whose cytotoxic activity is controlled by activating and
inhibitory receptors, may contribute to the graft-versus-leukemia effect when the recipient
is lacking ligands for the donor killer–inhibitory receptors.21 Induced or passively
transferred antibodies can produce antitumor activity by mediating antibody-dependent
cellular cytotoxicity (ADCC) or complement-dependent cytolysis (CDC). ADCC is
triggered by binding of the Fc portion of the antibody with the Fc receptor on NK cells or
myeloid-derived cells. The ability to induce ADCC depends on the IgG isotype and also on
the type of Fc receptor, which may be either activating or inhibitory.22 Preclinical studies
and some clinical correlative data suggest that ADCC may play a role in the antitumor
activity of antibodies such as trastuzumab and rituximab. Currently only one antibody,
targeted to the ganglioside GD-2 (ch14.18), is presumed to produce its anticancer effect
primarily by ADCC. It was effective when used in combination with IL-2 and granulocyte-
macrophage colony-stimulating factor (GM-CSF) in neuroblastoma patients following
autologous marrow transplant, suggesting that the antitumor activity mediated by ADCC
would produce the greatest benefit in a minimal residual disease setting.23

III. TOXICITY AND MANAGEMENT OF TOXICITY

Excluding hypersensitivity reactions or antibody infusion-related events, the toxicities of
immunotherapies can be classified as follows: cytokine-induced, for example, after
administration of IFN or IL-2 or after T-cell expansion and activation in adoptive cellular
therapy; autoimmune-type reactions, usually observed after administration of immune
checkpoint inhibitors; and on-target effects, by recognition of passively transferred
antibodies or cells of their intended targets on normal tissues. In addition to the indicated
supportive care for symptoms, management of toxicity depends on the cause and expected
time course for reversibility, and will often involve steroids.
Because of the broad applicability of immune checkpoint inhibitors, most physicians
treating cancer patients will be required to manage the autoimmune-like reactions
associated with their use. Currently, only anti-CTLA-4 and anti-PD-1 have been approved
for cancer treatment indications around the world. Unlike cytokines, immune checkpoint
 inhibitors rarely produce acute adverse events following the infusion. When adverse events
occur, almost any organ system can be affected, but most common are skin, gastrointestinal
tract, liver, and endocrine glands.16,24–26 In a subset of patients, adverse events can occur in
multiple organ systems, either concurrently or serially. Adverse events induced by anti-
CTLA-4 are more frequent and can be more severe than by PD-1/PD-L1 antagonists.
Within the dose range of 1 to 10 mg/kg, the toxicity of anti-CTLA-4 is dose-related; in
contrast, for anti-PD-1 doses in the 0.3- to 10-mg/kg range, no clear dose-response
relationship for toxicity is apparent.16,27 Preliminary data suggest that patients developing
high-grade immune-related adverse events (irAEs) from anti-CTLA-4 can be treated safely
with PD-1/PD-L1 antagonists once toxicities resolve to baseline.28 Because of the long
half-life of the antibodies, combined effects could be observed if administered within a
short interval of each other. Concurrent administration of 3 mg/kg of anti-CTLA-4 with 1
mg/kg of nivolumab produced a higher rate of grade III to IV irAEs compared to either
agent alone, which in incidence and severity resembled the toxicity profile of ipilimumab
administered alone at 10 mg/kg.29–31
Careful observation of patients, frequent communication between patients and medical
staff, and prompt administration of steroids when indicated are necessary to prevent severe
outcomes from irAEs. A few toxicities associated with immune checkpoint inhibitors may
be life-threatening if not treated promptly (e.g., bowel perforation that results from ongoing
colitis, or progressive pneumonitis). After the development of an irAE, an initial workup is
required to exclude other potential causes, and supportive care measures should be
initiated. Physicians must subsequently determine if and when to start steroids, the dose of
steroids, route of administration, inpatient or outpatient management, and length of steroid
therapy. In steroid-refractory toxicity, a second immunosuppressive agent may be required,
such as anti–tumor necrosis factor (TNF) or mycophenolate mofetil. Algorithms have been
developed and published for management of each of the most common irAEs.
For severe toxicities, including grade III to IV colitis or diarrhea, high-dose steroids
equivalent to 2 mg/kg of IV solumedrol are administered for approximately a week, and
then tapered slowly over approximately 30 days. Although the management algorithms are
useful, clinical judgment is still required, for example, in assessing the rate of improvement
and deciding if escalation of measures is required. If symptoms worsen or the rate of
improvement is too slow on the starting dose of steroids, options include administering
even higher doses of steroids, in some cases up to a gram of solumedrol IV daily, or
initiating treatment with a second immunosuppressive agent. Recurrence of symptoms
during the steroid taper can be managed by re-escalation of the steroid dose until resolution
of the irAE, followed by another period of steroid dose taper, or administration of a
second immunosuppressive agent. Because of the potential liver toxicity of anti-TNF
agents, mycophenolate is used as the second-line immunosuppressive for liver irAEs.
For prolonged immunosuppression exceeding 4 to 6 weeks, administration of
prophylactic antibiotics to prevent opportunistic infection should be considered. With few
exceptions such as the endocrinopathies, irAEs fully reverse over time. Administration of
 steroids or other immunosuppressive agents to prevent onset of toxicity would be expected
to counteract the antitumor effect of immune checkpoint inhibitors. However, current data
suggest that use of steroids or other immunosuppressive agents to manage an adverse event
does not substantially affect tumor response or duration of response.
In contrast to the immune checkpoint inhibitors, toxicities induced by cytokines or
cytokines combined with cell therapies are generally managed with intensive supportive
care, and steroids are administered only if the complications are immediately life-
threatening.32 The toxicities are almost always rapidly reversible over hours to days.
Administration of T-cells modified with a chimeric antigen receptor targeting CD19 on B-
cells produced severe toxicity during the period of T-cell activation and expansion. Studies
correlated the severe toxicity to induced cytokines and particularly to high circulating
levels of IL-6. Toxicity was reversed rapidly by administration of an anti-cytokine against
IL-6 without affecting antitumor response.33

IV. RESPONSE KINETICS

Studies of cytokines such as IL-2 provided strong proof of concept that immunotherapies
could produce regression of advanced and large-volume metastatic disease.34–36
Moreover, in a subset of patients, complete regressions persisted for years without relapse,
indicating that responses were durable and possibly curative. For cytokines such as IL-2,
which is given weeks 1 and 3 in cycles of 8 to 12 weeks, tumor regression was usually
observed at the 8- to 12-week staging scans. Most patients with evidence of tumor
regression received a second “cycle” of treatment, and rarely a third. Regression could
continue beyond the end of treatment, but near-maximal tumor regression was often
observed on staging scans obtained 5 to 9 weeks after the second cycle. Most patients with
stable disease at the end of the first cycle did not go on to achieve complete responses with
additional cycles of treatment. The majority of partial responses were short-lived, and
occasional mixed responses were observed, but there are no comprehensive data on
outcome for treatment continued beyond mixed response. The benefit, if any, of cytokine-
induced mixed or partial responses or stable disease cannot be determined. However, a
small subset of patients experienced long-term disease-free survival after surgical removal
of a residual, recurrent, or discordant progressing lesion following substantial regression
of multiple other sites of disease.
Cell therapies (e.g., melanoma tumor-infiltrating lymphocytes administered with
systemic IL-2) are usually given for one cycle.37,38 Regression of disease is often observed
at 4 weeks after treatment and can continue over time. The kinetics of tumor regression for
immune checkpoint inhibitors depends on the individual agents and other factors that
currently remained undefined. Treatment with anti-CTLA-4 is given every 3 weeks for a
total of 4 doses, and tumor response is assessed at 12 weeks. A large fraction, possibly
50%, of objective responses to anti-CTLA-4 are achieved beyond the 12-week
assessment.26 In contrast, anti-PD-1 as a single agent is administered every 2 to 3 weeks
for at least 1 year and in some trials until disease progression. Most objective responses to
 anti-PD-1 are evident at the first staging study at 8 to 12 weeks, although responses may
improve over time.39–41 The optimal duration of therapy for single-agent anti-PD-1 has not
been defined. For both anti-CTLA-4 and anti-PD-1, partial responses may persist for
prolonged periods, despite discontinuation of treatment. Similar to IL-2, the durable
responses observed with checkpoint inhibitors may result in cures. For example, 10-year
follow-up data for patients with metastatic melanoma treated with anti-CTLA-4 show flat
survival curves beyond year 3 for up to 10 years.42 Preliminary data suggest that certain
combinations, such as anti-CTLA-4 with anti-PD-1, may accelerate the kinetics of
response and also the extent of tumor regression.29
Unconventional response patterns are reported infrequently with cytokines or
adoptive cell therapies. In contrast, unconventional tumor responses appear to occur more
frequently following treatment with immune checkpoint inhibitors such as anti-CTLA-4 and
anti-PD-1, and possibly confer clinical benefit similar to patients achieving objective
responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.43
Recognition of the unconventional response patterns is important for optimal patient
management and also to avoid underestimation of potential treatment effect in single-arm
phase II trials. The most common, and most difficult to manage in the clinic, manifests as
initial progression of existing lesions or new lesions, possibly concurrent with reduction or
stability of other lesions, followed subsequently by overall tumor burden reduction or
stability. Late overall tumor burden reduction will often be associated with stabilization or
regression of the previously noted new or progressing lesions. In addition to systemic sites
of disease, we and others have observed apparent disease progression in brain while other
sites of disease were regressing, followed subsequently by regression of the new brain
lesions, without the addition of radiation. Therefore, patients whose initial scans at 8 to 12
weeks show traditional disease progression by RECIST criteria, but do not experience
deterioration in performance status, should not change treatment until a second scan 4 to 8
weeks later confirms continued increase in overall tumor burden.
Other unconventional response patterns were observed during trials of the immune
checkpoint inhibitors, including long periods of stable disease, long periods of stable
disease followed by late regression, slow prolonged tumor regression, or regression of
multiple sites of disease concurrent with one or a few discordant continuously progressive
lesions. For a subset of patients with a small number of discordant progressing lesions,
local surgery or radiation for the growing lesions produced long disease-free intervals.
The rate of unconventional response patterns likely varies between diseases and agents,
and is higher with anti-CTLA-4 compared to anti-PD-1. Overall 10% to 15% of all
patients with metastatic melanoma treated with anti-CTLA-4 will develop an
unconventional response. A special set of immunotherapy response criteria (iRC) were
developed to capture data on unconventional antitumor responses in clinical trials.43
In general, most immunotherapies are administered for a defined period and then
discontinued. The role of maintenance therapy with any of the current agents is unknown.
Even for treatments currently given for long periods, such as anti-PD-1, treatment will be
 discontinued in a subset including complete responders, patients with maximal response
after a period of additional therapy, and in those with severe toxicity. Although many
responses will persist possibly without relapse, a subset of responding patients who are
off treatment will eventually develop progression of disease. In clinical studies, selected
patients with relapse after clinical response to the various immunotherapies were offered
re-treatment with the same agent. In melanoma or renal cell carcinoma patients treated with
IL-2, re-treatment at relapse with high-dose IL-2 rarely produced a second objective
response.44 In contrast, a relatively high rate of clinical activity was observed in relapsed
patients who were re-treated with anti-CTLA-4 after achieving at least stable disease for
24 weeks, or a response by standard RECIST or iRC criteria.45 In the patients re-induced
with anti-CTLA-4, clinical activity included prolonged stable disease or a second
objective response, both of which could be equal to or more durable than the initial
response. Although reported only as anecdotes, second responses were also observed
among a small number of patients re-treated at relapse with anti-PD-1 or with the
combination of anti-CTLA-4 and anti-PD-1.46

V. PREDICTIVE BIOMARKERS AND PATIENT SELECTION

Multiple candidates for predictive biomarkers to immunotherapy have been explored in
clinical trials.18,47–49 In peripheral blood, potential candidates included cell counts such as
absolute lymphocyte counts; number or percentage of various immune cell subsets
including Tregs and myeloid-derived suppressor cells; functional capacity of various
lymphocyte populations; circulating markers of disease or inflammation such as lactate
dehydrogenase (LDH) and C-reactive protein; panels of circulating growth factors,
cytokines, and chemokines; and gene expression studies in peripheral blood mononuclear
cells (PBMCs) or subsets of PBMC. Several prior studies also included assays for
preexisting serologic or T-cell responses to tumor antigens.50
Assays for predictive biomarkers in tumor tissue are generally performed on fresh or
archived biopsy samples.48,51 In clinical trials, investigators have measured the immune
cell infiltrate, including phenotype, function (as assessed by proliferative markers,
cytotoxic molecules, or cytokine production), and TCR diversity and clonality. Studies on
the cellular infiltrates are performed by flow cytometry of dissociated specimens, or by
immunohistochemistry, which can provide the spatial relationships between the immune
cell infiltrate and tumor cells. In some studies, gene expression analyses of tumor biopsies
and patterns of antigen neoepitopes derived from mutations (as detected by whole exome
sequencing) were correlated with response and overall survival.52,53
Despite the substantial efforts, no predictive biomarker assays are currently approved
for any immunotherapy, including cytokines, anti-CTLA-4, the prostate cancer vaccine
sipuleucel-T, and the two anti-PD-1 antibodies, nivolumab and pembrolizumab. In clinical
trials for the immune checkpoint inhibitors, selected assays appeared to enrich for response
or better outcome in the biomarker-positive group, but tumor responses to therapy were
consistently observed in a fraction of the biomarker-negative groups.18,30,54–56 The failure
 to find highly sensitive and specific biomarkers reflects the complexity of the events
required to produce tumor regression after an immune intervention, and also inherent
problems with assay methodologies, particularly in tumor biopsies. Assays in tumor tissue
can be confounded by the heterogeneity of tumors and the immune cell infiltrates, the
dynamic nature of the assessed biomarkers, sampling errors related to use of core biopsies
or fine-needle aspirates, and difficulties in determining appropriate positive and negative
cutoffs for biomarkers with a broad range of expression.
Although the clinical utility of the assessed predictive biomarkers remains unclear,
studies conducted to date provide insight into factors required for response to immune
interventions. As a general rule, tumors with inflammatory infiltrates or inflammatory gene
signatures are more likely to respond to current immunotherapies.47,48,56,57 A preexisting T-
cell infiltrate in tumor tissue may be most critical for agents that block immune checkpoints
active within the tumor microenvironment (e.g., anti-PD-1 or anti-PD-L1). As expected, for
PD-1/PD-L1 antagonists, most trials showed higher response rates in patients with tumors
expressing PD-L1, and survival differences between PD-1/PD-L1 antagonists and control
arms in randomized trials were greatest in the PD-L1-positive group.54,58 In contrast,
addition of anti-CTLA-4 to anti-PD-1 produced the greatest effect in the PD-L1-“negative”
group, possibly because anti-CTLA-4 promotes T-cell infiltration into the tumor
microenvironment.30
Certain clinical features also provide insight into the biologic conditions required for
response to immune interventions. Although exceptions are clearly seen, response to PD-
1/PD-L1 antagonists appears to be higher in diseases with a larger number of genetic
mutations, which presumably lead to formation of either more or a unique set of
neoantigens that can induce broad tumor-specific T-cell responses. Melanoma and lung
cancer are among the tumor types that carry the highest rate of genetic mutations. In lung
cancer, response rates to PD-1/PD-L1 antagonists were higher in prior smokers versus
nonsmokers, consistent with expected higher rates of tumor genetic mutations in prior
smokers.53
Other clinical features less consistently predict response to immunotherapies. In
metastatic melanoma studies, high baseline LDH has been associated with lower response
rates to high-dose IL-2, and possibly also predicts for lower response rates to immune
checkpoint inhibitors.59 Higher tumor burdens (e.g., above the mean for the population of
patients) may also be associated with lower response rates, but the lower response rates in
the “high” tumor burden group are likely to remain clinically meaningful. Overall, high
tumor burden should not preclude treatment with the most effective immunotherapies,
including cytokines and the immune checkpoint inhibitors. In contrast, certain types of
immunotherapies, for example, cancer vaccines used alone or antibodies that primarily act
through ADCC, may be effective only in patients with low tumor burdens or
micrometastatic disease. For example, in the analysis of a trial comparing talimogene
laherparepvec, an oncolytic herpesvirus that is administered by intratumoral injection, to
GM-CSF in metastatic melanoma, a survival advantage was observed in advanced stage III
 and stage IV M1a patients (limited to lymph node and soft tissue disease), but not in
patients with visceral metastases.60
With the most active immunotherapies, all sites of disease appear capable of
responding, including brain metastases.61 Depending on the agent and disease type, lower
response rates may be observed for patients with disease involvement of certain organs
(e.g., the liver). Similar to tumor burden, site of disease should not preclude offering an
immunotherapy. However, caution is warranted for patients in whom the occasional
induced inflammatory response and surrounding edema in tumor may create local
complications, such as in untreated brain metastases in potentially symptomatic locations
or near the spinal cord.
At this time, the impact of prior cytotoxic or targeted therapies, or abnormal organ
function, on the activity or safety of immunotherapies remains unknown. We administered
anti-PD-1 to a metastatic melanoma patient on renal hemodialysis and observed a clinical
response without complications. On the basis of limited animal model data, patients on
immunosuppressive agents have been excluded from treatment with immunotherapies. The
activity and safety of immunotherapies, and particularly immune checkpoint inhibitors or
cytokines, in patients with prior autoimmunity has not been studied in prospective trials. Of
particular concern are patients with prior inflammatory bowel disease, and the potential
for marked exacerbation of symptoms leading to gastrointestinal bleeding or perforation.
Nevertheless, prior autoimmunity not requiring current immunosuppressive agents should
be considered only a relative contraindication to immunotherapy, and therefore the
risk/benefit ratio of treatment must be weighed in each individual patient. There are a few
anecdotal reports of patients with renal or marrow allografts treated safely with IL-2, anti-
CTLA-4, or anti-PD-1.62,63

VI. CLINICAL ACTIVITY AND APPLICATION

Prior to the development of the immune checkpoint PD-1/PD-L1 antagonists, there were
relatively few approved indications for use of traditional immunotherapies. The most
common indications for immunotherapy agents were high-dose IL-2 in the treatment of
metastatic melanoma and renal cell carcinoma, high-dose IFN-α for the adjuvant treatment
of resected primary and regional melanoma at high risk for systemic recurrence, anti-
CTLA-4 for the treatment of metastatic melanoma, sipuleucel-T for the treatment of
metastatic hormone-resistant prostate cancer, and anti-GD-2 in combination with GM-CSF
and IL-2 for neuroblastoma following autologous bone marrow transplant.
In randomized studies, anti-PD-1 improved survival compared to ipilimumab in
melanoma, and improved survival in both adenocarcinoma and squamous cell carcinoma of
the lung compared to second-line treatment with docetaxel.64,65 Anti-PD-1 is currently
approved for treatment of metastatic melanoma and metastatic non–small-cell lung cancer.
Current phase II trials demonstrate activity of anti-PD-1 or anti-PD-L1 in a subset of
patients with multiple malignancies, and phase III trials are ongoing. Regulatory approvals
are expected for the PD-1/PD-L1 antagonists in multiple types of malignancies. The
 remarkable activity of chimeric antigen receptor–modified T-cells against CD20 in B-cell
malignancies will also change the standard of care for those diseases.
The optimal sequencing and integration of immunotherapy with chemotherapy,
radiation, or targeted therapies remain unclear. The pattern of use for an individual disease
will depend on the immunotherapy agent, its expected activity, comorbid conditions,
presentation of the disease, the activity and toxicity of other available therapeutics, and
potential agonist and antagonist drug interactions, many of which remain undefined. For
certain agents, such as vaccines and antibodies that act primarily through ADCC, the
immunotherapies will be directed primarily at small-volume or minimal residual disease
settings. The substantial activity of immune checkpoint inhibitors in advanced disease
raises more difficult questions on sequencing and integration with other therapies. It
appears likely that in certain settings, the superior activity, potential for durable response,
and better toxicity profile of the immunotherapy will justify first-line use in metastatic
disease. Although not proven in human settings, expansion of tumor-specific immune
responses would likely enhance the activity of subsequent nonimmunotherapies. However,
the reverse sequence could also be effective; nonimmunotherapies may reduce tumor bulk,
release antigen, and reduce tumor immunosuppressive mechanisms and thus enhance the
activity of concurrent or subsequently administered immunotherapy. For melanoma tumor-
infiltrating lymphocytes (TIL), lymphodepletion with chemotherapy prior to cell transfer
appears necessary to demonstrate optimal clinical activity, possibly due to removal of
tumor immunosuppressive mechanisms and to the rise of circulating cytokines that support
persistence of the transferred cells.38
Combinations of immunotherapies with each other or with other treatment modalities
will play an increasingly important role in the treatment of malignancies. The combination
of anti-CTLA-4 and anti-PD-1 improved response rate and progression-free survival
compared to either agent alone in metastatic melanoma, but with higher rates of grade III to
IV irAEs.30 Effects of the combination on lymphocyte and monocyte gene expression
differed markedly from either agent alone.66 Multiple combinations are in clinical
development. Although combinations of immunotherapy with chemotherapy or radiation
therapy appear safe, the benefit of such combinations remains to be proven. Unexpected
adverse interactions can also occur with specific combinations, for example, elevated liver
function tests with vemurafenib and anti-CTLA-4.67 Adverse interactions may be specific
to individual agents and may not extend to other agents in the same class.
Although agents such as IL-2, anti-CTLA-4, and anti-PD-1 cause regression of
advanced disease, which is easily assessed on imaging studies, other types of potentially
beneficial clinical activity for these and other types of immunotherapies are not readily
captured with standard clinical endpoints (e.g., RECIST criteria and progression-free
survival). Progression-free survival may underestimate activity for agents producing a
substantial number of unconventional responses. The studies of sipuleucel-T also
demonstrated that survival could be increased for a patient population with metastatic
disease, but without an effect on progression-free survival or traditional measures of tumor
 clinical response.68,69
Optimal use of immunotherapies in the surgical adjuvant setting or after substantial
tumor debulking with other agents also remains undefined. Multiple large randomized
studies of cancer vaccines in the surgical adjuvant setting for melanoma were negative,
although the results do not preclude success of newer vaccination approaches.70
Immunologic responses that cause cancer regression in advanced disease may not be
sufficient or optimal in the surgical adjuvant setting; for example, induction of antibody
responses against cell surface targets, which may have little activity in advanced disease,
could play an important role in eliminating micrometastases. Anti-CTLA-4 improved
survival in metastatic melanoma, and early analysis of a large adjuvant study shows a 25%
reduction in the risk of progression at 3 years; the studies will not address if the treatment
effect is larger in the adjuvant setting compared to advanced disease.71 Studies of PD-
1/PD-L1 antagonists in the adjuvant setting have only recently been initiated.

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I. ESTABLISHING THE DIAGNOSIS
A. Pathologic diagnosis is critical
Although it might seem obvious that the diagnosis of cancer must be firmly established
before chemotherapy or any other treatment is administered, the critical nature of an
accurate diagnosis warrants a reminder. As a rule, there must be cytologic or histologic
evidence of neoplastic cells together with a clinical picture consistent with the
diagnosis of the cancer under consideration. It is rarely acceptable to initiate treatment
based solely on clinical examination, radiologic evidence, and nontissue laboratory
evidence, such as tumor markers. Commonly, patients present to their physicians with a
complaint such as a cough, bleeding, pain, or a lump; through a logical sequence of
evaluation, the presence of cancer is revealed on a cytologic or histologic specimen.
Less frequently, lesions are discovered fortuitously during routine examination,
evaluation of an unrelated disorder, or systematic screening for cancer. With some types
of cancer, pathologists can establish the diagnosis based on small amounts of material
obtained from needle biopsies, aspirations, or tissue scrapings. Other cancers require
larger pieces of tissue for special staining, immunohistologic evaluation, flow
cytometry, examination by electron microscopy, or more sophisticated studies such as
evaluation for genetic deletions, amplifications, or other mutations.
It is often helpful to confer with the pathologist before obtaining a specimen to
determine what kind and size of specimen is adequate to establish the complete
diagnosis. When a tissue diagnosis of cancer is made by the pathologist, it is incumbent
on the clinician to review the material with the pathologist. This practice is good
medicine. It also allows the clinician to tell the patient that he or she has actually seen
the cancer and to avoid administering chemotherapy without a firm pathologic
diagnosis. In addition, the pathologist often gives a better consultation—not just a tissue
diagnosis—when the clinician shows a personal interest.
B. Pathologic and clinical diagnosis must be consistent
Once the tissue diagnosis is established, the clinician must be certain that the pathologic
diagnosis is consistent with the clinical findings. If the two are not consistent, a search
must be made for additional information, clinical or pathologic that allows the clinician
to make a unified diagnosis. A pathologic diagnosis, like a clinical diagnosis, is also an
opinion with varying levels of certainty. The first part of the pathologic diagnosis—and
 usually the easier part—is an opinion about whether the tissue examined is neoplastic.
Because most pathologists rarely render a diagnosis of cancer unless the degree of
certainty is high, a positive diagnosis of cancer is generally reliable. The clinician must
be more cautious if the diagnosis rendered states that the tissue is “highly suggestive of”
or “consistent with the diagnosis of” cancer. Absence of definitively diagnosed cancer
in a specimen does not mean that cancer is not present, however; it means only that it
could not be diagnosed on the tissue obtained, and clinical circumstances must establish
if additional tissue sampling is necessary. A second part of the pathologist’s diagnosis
is an opinion about the type of cancer and the tissue of origin. This determination is not
necessary in all circumstances but is usually helpful and may be critical in selecting the
most appropriate therapy and making a determination of prognosis, and will become
more relevant with precision (personalized) cancer treatment.
C. Treatment without a pathologic diagnosis
There are rare circumstances in which treatment is undertaken before a pathologic
diagnosis is established. Such circumstances are clearly exceptions, however, and
involve less than 1% of all patients with cancer. Therapy is begun without a pathologic
diagnosis only when the following conditions are met:
■ The clinical features strongly suggest the diagnosis of cancer, and the likelihood of
a benign diagnosis is remote.
■ Withholding prompt treatment or carrying out the procedures required to establish
the diagnosis would greatly increase a patient’s morbidity or risk of mortality.
Two examples of such circumstances are (1) a primary tumor of the midbrain and
(2) superior vena cava syndrome from a large mediastinal mass with no accessible
supraclavicular nodes and no endobronchial disease found on bronchoscopy in the
occasional patient in whom the risk of bleeding from mediastinoscopic biopsy is
deemed greater than the risk of administering radiotherapy for a disease of uncertain
nature.

II. STAGING
Once the diagnosis of cancer is firmly established, it is important to determine the anatomic
extent or stage of the disease. The steps taken for staging vary considerably among cancers
because of the differing natural histories of the tumors.
A. Staging system criteria
For most cancers, a system of staging has been established on the basis of the following
factors:
■ Natural history and mode of spread of the cancer
■ Prognostic import of the staging parameters used
■ Value of the criteria used for decisions about therapy
B. Staging and therapy decisions
In the past, surgery and radiotherapy were used to treat patients with cancer in early
stages, and chemotherapy was used when surgery and radiotherapy were no longer
 effective or when the disease was in an advanced stage at presentation. In such
circumstances, chemotherapy was only palliative (except for gestational
choriocarcinoma), and in the absence of exquisitely sensitive tumors or strikingly potent
drugs, the likelihood of increasing the survival was low. As knowledge has increased
about the genetic determinants of cancer growth, tumor cell kinetics, and the
development of resistance, the value of early intervention with chemotherapy has been
transposed from animal models to human cancers. To plan this intervention and evaluate
its effectiveness, careful staging has become increasingly important. Only when the
exact extent of disease has been established can the most rational plan of treatment for
the individual patient be devised, whether it is surgery, radiotherapy, chemotherapy, or
molecular targeted therapy alone or in combination.
Although no single staging system is universally used for all cancers, the system
developed jointly by the American Joint Committee on Cancer and the TNM Committee
of the International Union Against Cancer is most widely used for staging solid tumors.1
It is based on the status of the primary tumor (T), regional lymph nodes (N), and distant
metastasis (M). For some cancers, tumor grade (G) is also taken into account. The stage
of the tumor is based on a condensation of the total possible TNM and G categories to
create stage groupings, usually stages 0, I, II, III, and IV, which are relatively
homogeneous with respect to prognosis.

III. PERFORMANCE STATUS

The performance status refers to the level of activity of which a patient is capable. It is a
measure independent from the anatomic extent or histologic characteristics of the cancer
and of how much the cancer or comorbid conditions have affected the patient, and a
prognostic indicator of how well the patient is likely to respond to treatment.
A. Types of performance status scales
Two performance status scales are in wide use:
■ The Karnofsky Performance Status Scale (Table 4.1) has 10 levels of activity. It has
the advantage of allowing discrimination over a wide scale, but the disadvantages
of being difficult to remember and perhaps of making discriminations that are not
clinically useful.
■ The Eastern Cooperative Oncology Group (ECOG)/World Health Organization
(WHO)/Zubrod Performance Status Scale (Table 4.2) has the advantages of being
easy to remember and making discriminations that are clinically useful.
According to the criteria of each scale, patients who are fully active or have mild
symptoms respond more frequently to treatment and survive longer than patients who
are less active or have severe symptoms. A clear designation of the performance status
distribution of patients in therapeutic clinical trials is thus critical in determining the
comparability and generalizability of trials and the effectiveness of the treatments used.
 TABLE
Karnofsky Performance Status Scale
4.1
Functional Capability Level of Activity
100%—Normal; no complaints, no evidence of disease
90%—Able to carry on normal activity; minor signs or symptoms of
Able to carry on normal activity; no special care needed
disease
80%—Normal activity with effort; some signs or symptoms of disease
70%—Cares for self; unable to carry on normal activity or to do active
work
Unable to work; able to live at home; cares for most personal
60%—Requires occasional assistance but is able to care for most of
needs; needs varying amount of assistance
own needs
50%—Requires considerable assistance and frequent medical care
40%—Disabled; requires special medical care and assistance
30%—Severely disabled; hospitalization indicated, although death not
imminent
Unable to care for self; requires equivalent of institutional or
20%—Very sick; hospitalization necessary; active supportive treatment
hospital care
necessary
10%—Moribund; fatal processes progressing rapidly
0%—Dead

B. Use of performance status for choosing treatment

In the individualization of therapy, the performance status is often a useful parameter to
help the clinician decide whether the patient will benefit from treatment or will be
made worse. For example, unless there is some reason to expect a dramatic response of
a cancer to chemotherapy, treatment may be withheld from many patients with an ECOG
Performance Status Scale score of 3 or 4, particularly those with solid tumors, because
responses to therapy are infrequent and toxic effects of the treatment are likely to be
great.

TABLE
ECOG/WHO/Zubrod Performance Status Scale
4.2
Grade Level of Activity
0 Fully active; able to carry on all predisease performance without restriction (Karnofsky 90%–100%)
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature such
1
as light housework or office work (Karnofsky 70%–80%)
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours
2
(Karnofsky 50%–60%)
3 Capable of only limited self-care; confined to bed or chair >50% of waking hours (Karnofsky 30%–40%)
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair (Karnofsky 10%–20%)
 C. Quality of life
A related but partially independent measure of performance status can be determined on
the basis of patients’ own perceptions of their quality of life (QOL). QOL evaluations
have been shown to be independent predictors of tumor response and survival in some
cancers, and they are important components in a comprehensive assessment of response
to therapy. For some cancers, improvement in QOL measures early in the course of
treatment is the most reliable predictor of survival time.

IV. RESPONSE TO THERAPY

Response to therapy may be measured by survival (with or without disease), objective
change in tumor size or in tumor product (e.g., immunoglobulin in myeloma), and
subjective change.2
A. Survival
One goal of cancer therapy is to allow patients to live as long and with the same QOL
as they would have if they did not have the cancer. If this goal is achieved, it can be
said that the patient is cured of the cancer (though biologically, the cancer may still be
present). From a practical standpoint, we do not wait to see if patients live a normal
lifespan before saying that a given treatment is capable of achieving a cure, but we
follow a cohort of patients to see if their survival within a given timespan is different
from that in a comparable cohort without the cancer. For the evaluation of response to
adjuvant therapy (additional treatment after surgery or radiotherapy that is given to
treat potential nonmeasurable, micrometastatic disease), survival analysis (rather than
tumor response) must be used as the definitive objective measure of antineoplastic
effect. With neoadjuvant therapy (chemotherapy or biologic therapy given as initial
treatment before surgery or radiotherapy), tumor response and resectability are also
partial determinants of effectiveness.
B. Definitions
The overall survival rate is used to describe the percentage of people in a cohort who
are alive for a specified period of time after diagnosis or initiation of a given treatment.
The median survival time is the time after either diagnosis or treatment at which half of
the patients with a given disease are still alive. Disease-free survival, the length of time
after treatment for a specific disease during which a patient survives with no sign of the
disease, is often a useful comparator in clinical studies of adjuvant therapy, as return of
disease most often represents loss of curability. Progression-free survival (PFS) is the
length of time during and after treatment in which a patient is living with a disease that
does not get worse. It is used primarily in studies of metastatic or unresectable disease.
C. Other considerations
It is, of course, possible that a patient may be cured of the cancer that was treated but
dies early owing to complications associated with the treatment, including second
cancers. Even with complications (unless they are acute ones such as bleeding or
infection), survival of patients who have been cured of the cancer is likely to be longer
 than if the treatment had not been given, though shorter than if the patient had never had
the cancer.
If cure is not possible, the reduced goal is to allow the patient to live longer than if
the therapy under consideration were not given. It is important for physicians to know
if, and with what likelihood, any given treatment will result in a longer life. Such
information helps physicians to choose whether to recommend treatment and the patient
to decide whether to undertake the recommended treatment program.
It is important to learn from the patient what his or her goals of therapy are and to
have a frank discussion about whether those goals are realistic. This can avoid
unnecessary surprises and anger at some later time, which can occur when the patient
has set a goal that is not realistic and the physician has not discussed what may or may
not reasonably be expected as a consequence of therapy.
D. Objective response
Although survival is important to the individual patient, it is determined not only by the
initial treatment undertaken but also by biologic determinants of the patient’s individual
cancer and subsequent treatment; thus, survival does not give an early measurement of a
given treatment effectiveness. Tumor regression, on the other hand, when measurable,
frequently occurs early in the course of effective treatment and is therefore a readily
used determinant of treatment benefit. Tumor regression can be determined by a
decrease in size of a tumor or the reduction of tumor products.
1. Tumor size. When tumor size is measured, responses are usually classified by the
Response Evaluation Criteria in Solid Tumors (RECIST) methodology first
published in 2000 and revised in 2008 (RECIST 1.1), reported by Eisenhauer et al.3
in the European Journal of Cancer in 2009, and available online at
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf, and for the iPad from
the APP Store (RECIST 1.1)
a. Baseline lesions are characterized as “measurable” or “nonmeasurable.” To be
measurable, non–lymph node lesions must be 20 mm or more in longest diameter
and measurable by calipers using conventional techniques, or 10 mm or more in
longest diameter using computed tomography (CT). On CT scan, lymph nodes
must be more than or equal to 15 mm for target lesions or 10 to 15 mm in short
axis for nontarget lesions. Smaller lesions and truly nonmeasurable lesions are
designated nonmeasurable. To assess response, all measurable lesions up to a
maximum of two per organ and five in total are designated as “target” lesions
and measured at baseline. Except for lymph nodes, only the longest diameter of
each lesion is measured. The sum of the longest diameters of all target lesions is
designated the “baseline sum longest diameter.”
There are a variety of lesions in cancer that cannot be measured. These
include blastic and sclerotic metastatic lesions to the bone, effusions,
lymphangitic disease of the lung or skin, and lesions that have necrotic or cystic
centers. Bone lesions are measurable only if they include an identifiable soft-
 tissue component, which constitutes the measureable lesion.
b. Response categories are based on measurement of target lesions.
1) Complete response (CR) is the disappearance of all target lesions. If lymph
nodes are included in target lesions, each node must achieve a short axis of
less than 10 mm.
2) Partial response (PR) is a decrease of at least 30% in sum of the longest
diameters of target lesions, using as reference the baseline sum of the longest
diameters.
3) Stable disease (SD) is when there is neither sufficient shrinkage to qualify
for PR nor sufficient increase to qualify for progressive disease (PD).
4) Progressive disease is an increase of 20% or more in the sum of the longest
diameters of target lesions, taking as reference the smallest sum’s longest
diameter recorded since the treatment started or the appearance of one or
more new lesions. The sum must also demonstrate an absolute increase of at
least 5 mm. While the fluorodeoxyglucose (FDG)-positron emission
tomography (PET) scan cannot be used to determine measureable disease, if
there is negative FDG-PET at baseline with a positive FDG-PET at follow-
up, this is a sign of PD, based on a new lesion.
5) Inevaluable for response is a category used where there is early death by
reason of malignancy or toxicity, tumor assessments were not repeated, and
so on.
c. Time to progression based on response criteria is an additional indicator that is
often used, similar to PFS. It takes into account the fact that from the patient’s
perspective, CR, PR, and SD may be meaningless distinctions so long as the
tumor is not causing symptoms or impairment of function. It also takes into
account that some agents result in disease stability for a substantial period,
despite failure to produce measurable disease shrinkage. This is particularly true
for biologic targeted agents where it has been shown that time to progression for
some cancers is substantially prolonged, despite no measurable reduction in
tumor size; in other cases, such as with ipilimumab, responses may be delayed
for months.
Time to progression can also be used as an indicator of disease status Time
to progression can also be used as an indicator of disease status when there was
no measurable disease at the outset of therapy or when the therapeutic modalities
were not comparable. For example, if one wanted to compare the results of
surgery alone with those of chemotherapy alone, time to progression from the
onset of treatment would allow a valid comparison of the effectiveness of the
treatments, whereas the traditional tumor response criteria would not. Time to
progression thus places each of the agents or modalities on an even basis.
d. Survival curves. If survival curves of patient populations having different
categories of response are compared, those patients with a CR frequently
 survive longer than those with a lesser response. If a sizable number of CRs
occur with a treatment regimen, the survival rate of patients treated with that
regimen is likely to be significantly greater than that of patients who are
untreated. When the number of complete responders in a population rises to
about 50%, the possibility of cure for a small number of patients begins to
appear. With increasing percentages of complete responders, the frequency of
cures is likely to increase correspondingly.
Although patients who have PR to a treatment usually survive longer than
those who have SD or PD, it is often not easy to demonstrate that the overall
survival of the treated population is better than that of a comparable untreated
group. In part, this difficulty may be due to a phenomenon of small numbers. If
only 15% to 20% of a population respond to therapy, the median survival rate
may not change at all, and the numbers may not be high enough to demonstrate a
significant difference in survival duration of the longest surviving 5% to 10% of
patients (the “tail” of the curves) of the treated and untreated populations. It is
also possible that the patients who achieve a PR to therapy are those who have
less aggressive disease at the outset of treatment and thus will survive longer
than the nonresponders, regardless of therapy. These caveats notwithstanding,
most clinicians and patients welcome even a PR as a sign that offers hope for
longer survival and improved QOL.
2. Tumor products. For many cancers, objective tumor size changes are difficult or
impossible to document. For some of these neoplasms, tumor products (hormones,
antigens, antibodies) may be measurable and may provide a good, objective way to
evaluate tumor response. Two examples of such markers that closely reflect tumor
cell mass are the abnormal immunoglobulins (M proteins) produced in multiple
myeloma and the human chorionic gonadotropin produced in choriocarcinoma and
testicular cancer. Other markers such as prostate-specific antigen or
carcinoembryonic antigen are not quite as reliable, but are nonetheless helpful
measures of response of the tumor to therapy. In some cancers, reduction in the
number of circulating tumor cells is also an indicator of response to therapy.
3. Evaluable disease. Other objective changes may occur, but are not easily
quantifiable. When these changes are not easily measurable, they may be termed
evaluable. For example, neurologic changes secondary to primary brain tumors
cannot be measured with a caliper, but they can be evaluated using neurologic
testing. An arbitrary system of grading the degree of severity of neurologic deficit
can be devised to permit surrogate evaluation of tumor response. Evaluable disease
is not a category of the RECIST criteria.
4. Performance status changes may also be used as a measure of objective change;
although in some respects, the performance status is as representative of subjective
aspects as it is of the objective status of the disease.
E. Subjective change and QOL considerations
 A subjective change is one that is perceived by the patient but not necessarily by the
physician or others around the patient. Subjective improvement and an acceptable QOL
are often of far greater importance to the patient than objective improvement: If the
cancer shrinks, but the patient feels worse than before treatment, he or she is not likely
to believe that the treatment was worthwhile. It is not valid to look at subjective change
in isolation, however, because temporary worsening in the perceived state of well-
being may be necessary to achieve subsequent long-term improvement.4
This point is particularly well illustrated by the combined modality treatment in
which chemotherapy is used to treat micrometastases after surgical removal of the
macroscopic tumor. In such a circumstance, the patient is likely to feel entirely well
after the primary surgical procedure, but the side effects of chemotherapy increase the
symptoms and make the patient feel subjectively worse for the period of treatment. The
patient should be encouraged to continue treatment, however, because if the
chemotherapy treatment of the micrometastases is successful, he or she will be cured of
the cancer and can be expected to have a normal or near-normal life expectancy rather
than dying from recurrent disease. Most patients agree that the temporary subjective
worsening is not only tolerable but well worth the price if cure of the cancer is a
distinct possibility. This judgment depends on the severity and duration of symptoms,
functional impairment, and perceptions of illness during the acute phase of the
treatment; the expected benefit (increased likelihood of survival) anticipated as a result
of the treatment; and the potential long-term adverse consequences of the treatment.
In contrast, when chemotherapy is given with a palliative intent, patients (and less
often physicians) may be unwilling to tolerate significant side effects or subjective
worsening from treatment. Fortunately, subjective improvement often accompanies
objective improvement, so those patients in whom there is measurable improvement of
the cancer also feel better. The degree of subjective worsening that each patient is
willing to tolerate varies, and the patient and physician together must discuss and
evaluate whether the chemotherapy treatment program is worth continuing. Such
discussions should include a clear presentation of the scientific facts that include
objective survival and tumor response data together with whatever QOL information
has been documented for the treatment proposed. Moreover, the expressed goals and
desires and the social, economic, psychological, and spiritual situations of the patient
and his or her family must be sensitively considered.
A word of caution about discussions of response and survival is important. Patients
can more easily understand the notion of response rates than survival probabilities. For
example, a 50:50 chance of the cancer shrinking helps them to understand the goals and
expectations of therapy and does not lead to undue anxiety over time. On the other hand,
understanding and dealing with median or expected survival estimates is more
problematic intellectually and even more difficult emotionally. It is therefore usually
best to give the patient a range of expected survival rather than a discrete number. For
example, the physician can say, “Some patients may have progression of their disease
 and possibly die within 6 months, but others may go on feeling fairly well and
functioning well for 2 or more years.” This helps the patient and family not to focus on a
single number (“They said I had only 13 months to live”) and to avoid some of the
feeling of impending doom.

I. TOXICITY
A. Factors affecting toxicity
One of the characteristics that distinguishes cancer chemotherapeutic agents from most
other drugs is the frequency and severity of anticipated side effects at usual therapeutic
doses. Because of the severity of the side effects, it is critical to monitor the patient
carefully for adverse reactions so that therapy can be modified before the toxicity
becomes life-threatening. Most toxicity varies according to the following factors:
■ Specific agent
■ Dose
■ Schedule of administration, including infusion rate and frequency of dose and prior
therapy with the same or other agents.
■ Route of administration
■ Predisposing factors in the patient, including genetic variants,* that may be known
and predictive for toxicity or unknown and resulting in unexpected toxic effects
B. Clinical testing of new drugs for toxicity
Before the introduction of any agent into wide clinical use, the agent must undergo
testing in carefully controlled clinical trials. The first set of clinical trials are called
phase I trials. They are carried out with the express purpose of determining toxicity in
humans and establishing the maximum tolerated dose; although with antineoplastic
agents, they are done only in patients who might benefit from the drug. Such trials are
undertaken only after extensive tests in animals have been completed. Much human
toxicity is predicted by animal studies, but because of significant species differences,
initial doses used in human studies are several times lower than doses at which toxicity
is first seen in animals. Phase I trials are carried out using several schedules, and the
dose is escalated in successive groups of patients once the toxicity of the prior dose has
been established.
At the completion of phase I trials, there is usually a great deal of information about
the spectrum and anticipated severity of acute drug effects (toxicity). However, because
patients in phase I trials often do not live long enough to undergo many months of
treatment, chronic or cumulative effects may not be discovered. Discovery of these
toxicities may occur only after widespread use of the drug in phase II trials (to establish
the spectrum of effectiveness of the drug), in phase III trials (to compare the new drug
or combination with standard therapy), or from postmarketing reports (when even larger
numbers and less rigorously selected patients are treated).
C. Common acute toxicities
Some toxicities are relatively common among traditional cancer chemotherapeutic
 agents. Common acute toxicities include the following:
■ Myelosuppression with leukopenia, thrombocytopenia, and anemia
■ Nausea, vomiting, and other gastrointestinal effects
■ Mucous membrane ulceration and cutaneous effects, including alopecia
■ Infusion reactions
Some of these toxicities occur because of the cytotoxic effects of chemotherapy on
rapidly dividing normal cells of the bone marrow and epithelium (e.g., mucous
membranes, skin, and hair follicles) incidental to the mechanism of action of the drugs;
others such as nausea and vomiting or infusion reactions are not related to the
antineoplastic mechanism of action.
D. Selective toxicities
Other toxicities are less common and are specific to individual drugs or classes of
drugs. Examples of drugs and their related toxicities include the following:
■ Anthracyclines and anthracenediones: irreversible cardiomyopathy
■ Asparaginase: anaphylaxis (allergic reaction), pancreatitis
■ Bleomycin: pulmonary fibrosis
■ Cisplatin: renal toxicity, neurotoxicity
■ Epidermal growth factor receptor inhibitors: acneiform rash
■ Fludarabine, cladribine, pentostatin, and temozolomide: prolonged suppression of
cellular immunity with heightened risk of opportunistic infection
■ Ifosfamide and cyclophosphamide: hemorrhagic cystitis
■ Ifosfamide: central nervous system toxicity
■ Immune modulators, such as ipilimumab: a host of severe immune-mediated
adverse reactions due to T-cell activation and proliferation. They may involve any
organ system, but most common are the gastrointestinal tract, liver, skin, nervous
system, and endocrine system
■ Mitomycin: hemolytic-uremic syndrome and other endothelial cell injury
phenomena
■ Monoclonal antibodies (e.g., rituximab, trastuzumab): hypersensitivity reactions
■ Paclitaxel: neurotoxicity, acute hypersensitivity reactions (primarily from the
vehicle)
■ Procarbazine: food and drug interactions
■ Trastuzumab: reversible cardiomyopathy
■ Vascular endothelial growth factor inhibitors: gastrointestinal perforation, impaired
wound healing
■ Vinca alkaloids: neurotoxicity
E. Recognition and evaluation of toxicity
Anyone who administers chemotherapeutic agents must be familiar with the expected
and the unusual toxicities of the agent the patient is receiving, be prepared to avert
severe toxicity when possible, and be able to manage toxic complications when they
cannot be avoided. The specific toxicities of commonly used individual
 chemotherapeutic agents are detailed in Chapter 28.
For the purpose of reporting toxicity in a uniform manner, criteria are often
established to grade the severity of the toxicity. For many years, a simplified set of
criteria was used by several National Cancer Institute (NCI)–supported clinical trial
groups for the most common toxic manifestations. Although this document was helpful,
it was, in many respects, incomplete. To address this issue, a new set of more
comprehensive toxicity criteria, the Common Toxicity Criteria, was developed in 1999.
A revised version of these criteria (Common Terminology Criteria for Adverse Events
v3.0 [CTCAE]) was published in 2003 and updated again in 2009 (CTCAE v4.0) and
is available online5 at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm or the
latest version can be downloaded from http://evs.nci.nih.gov/ftp1/CTCAE/About.html.
A host of other helpful information can be obtained online at http://ctep.cancer.gov/.
All new clinical trials approved by the NCI Cancer Therapy Evaluation Program use
these new toxicity criteria. Such standardization is important in the evaluation of the
toxicity of cancer treatment.
F. Acute toxicity management
Prevention and treatment of bone marrow suppression can be partially achieved using
filgrastim, sargramostim, epoetin-α, and oprelvekin. Management of nausea and
vomiting, mucositis, and alopecia as well as diarrhea, nutrition problems, and drug
extravasation are discussed in Chapter 26. Other acute toxicities are discussed with the
individual drugs in Chapter 28. Long-term medical problems are a special issue and are
highlighted in the subsequent section.

VI. LATE PHYSICAL EFFECTS OF CANCER TREATMENT

A. Late organ toxicities
Late organ toxicities may be minimized by limiting doses when thresholds are known. In
most instances, however, individual patient effects cannot be predicted.6–9 Treatment is
primarily symptomatic.
1. Cardiac toxicity (e.g., congestive cardiomyopathy) is most commonly associated
with high total doses of the anthracyclines (doxorubicin, daunorubicin, epirubicin).
In addition, high-dose cyclophosphamide as used in transplantation regimens may
contribute to congestive cardiomyopathy. When mediastinal irradiation is combined
with these chemotherapeutic agents, cardiac toxicity may occur at lower doses.
Although evaluation of ventricular ejection fraction with echocardiography or
nuclear radiography studies has been useful for acutely monitoring the effects of
these agents on the cardiac ejection fraction, studies have reported late onset of
congestive heart failure during pregnancy or after the initiation of vigorous exercise
programs in adults who were previously treated for cancer as children or young
adults. The cardiac reserve in these previously treated cancer patients may be
marginal. It is probable that there are some changes that take place even at low
 doses, and it is only because of the great reserve in cardiac function that effects are
not measurable until higher doses have been used. Mediastinal irradiation also
accelerates atherogenesis and may lead to premature symptomatic coronary artery
disease.
Because of the large number of women with breast cancer who are treated with
doxorubicin as part of an adjuvant chemotherapy regimen, this group is of special
concern and warrants ongoing clinical follow-up.
Many targeted agents, such as trastuzumab, are also associated with cardiac
toxicity, but the mechanism of toxicity is different from that of the anthracyclines and
often is at least partially reversible.10 Nonetheless, the adverse effect may limit the
use and thus the efficacy of these agents.
2. Pulmonary toxicity has been classically associated with high doses of bleomycin
(>400 U). However, a number of other agents have been associated with pulmonary
fibrosis (e.g., alkylating agents, methotrexate, nitrosoureas). Premature respiratory
insufficiency, especially with exertion, may become evident with aging.
3. Nephrotoxicity is a potential toxicity of several agents (e.g., cisplatin, methotrexate,
nitrosoureas). These agents can be associated with both acute and chronic toxicities.
Other nephrotoxic agents such as amphotericin or aminoglycosides may exacerbate
the problem. Even usually benign agents such as the bisphosphonates or allopurinol
may be a problem. Rarely, some patients may require hemodialysis as a result of
chronic toxicity.
4. Neurotoxicity has been particularly associated with the vinca alkaloids, cisplatin,
oxaliplatin, epipodophyllotoxins, taxanes, bortezomib, and ixabepilone. Peripheral
neuropathy can cause considerable sensory and motor disability. Autonomic
dysfunction may produce debilitating postural hypotension. Whole-brain irradiation,
with or without chemotherapy, can be a cause of progressive dementia and
dysfunction in some long-term survivors. This is particularly a problem for patients
with primary brain tumors and for some patients with small-cell lung cancer who
have received prophylactic therapy. Survivors of childhood leukemia have
developed a variety of neuropsychological abnormalities related to central nervous
system prophylaxis that included whole-brain irradiation.11
It has become evident over the years that some patients (up to one in five) who
have received adjuvant chemotherapy for carcinoma of the breast also have
measurable cognitive deficits such as difficulties with memory or concentration.12
This appears to be greater for women who have received high-dose chemotherapy
than for those women who have received standard-dose chemotherapy; in both
groups, the incidence is higher than in control groups. It is not uncommon for patients
to refer to the effects of chemotherapy with complaints about memory being worse
than it was, not being able to calculate numbers in their head, or just having “chemo-
brain.” Rarely patients may have severe, debilitating, idiosyncratic cognitive
impairment or even fatal central nervous system damage subsequent to
 chemotherapy.
5. Hematologic and immunologic impairment is usually acute and temporally related
to the cancer treatment (e.g., chemotherapy or radiation therapy). In some instances,
however, there can be persistent cytopenias, as with alkylating agents. Immunologic
impairment is a long-term problem for patients with Hodgkin lymphoma, which may
be due to the underlying disease as well as to the treatments that are used.
Fludarabine, cladribine, and pentostatin, with or without rituximab, cause profound
suppression of cluster of differentiation 4 (CD4) and CD8 lymphocytes and render
treated patients susceptible to opportunistic infections for many months after
treatment has been discontinued. Temozolomide causes CD4 lymphopenia and also
carries a risk of opportunistic infection. Complete immunologic reconstitution may
take 2 years after these therapies or marrow-ablative therapy requiring stem cell
reconstitution. In some circumstances such as after stem cell transplant,
revaccination is indicated. Patients who have undergone splenectomy are also at risk
of overwhelming bacterial infections and must be given vaccination for both
pneumococcal and haemophilus influenza infections prior to the spleen being
removed.
B. Second malignancies13
1. Acute myelogenous leukemia and myelodysplasia may occur secondary to
combined modality treatment (e.g., radiation therapy and chemotherapy in Hodgkin
lymphoma), prolonged therapy with alkylating agents or nitrosoureas, or other
chemotherapy.14–18 In general, this form of treatment-related acute leukemia arises in
the setting of myelodysplasia and is refractory even to intensive treatment. Treatment
with the epipodophyllotoxins also has been associated with the development of
acute nonlymphocytic leukemia. This may be the result of a specific gene
rearrangement between chromosome 9 and chromosome 11 that creates a new
cancer-causing oncogene: ALL-1/AF-9. The peak time of occurrence of secondary
acute leukemia in patients with Hodgkin lymphoma is 5 to 7 years after treatment,
with an actuarial risk of 6% to 12% by 15 years. Thus, a slowly developing anemia
in a survivor of Hodgkin lymphoma should alert the clinician to the possibility of a
secondary myelodysplasia or leukemia.
Fortunately, the risk of secondary leukemias in women treated with standard
adjuvant therapy for breast cancer (e.g., cyclophosphamide and doxorubicin) is only
modestly higher (excess absolute risk of 2 to 5 per 100,000 person years) than that
in the general population.
2. Solid tumors and other malignancies are seen with increased frequency in
survivors who have been treated with chemotherapy or radiation therapy.19 Non-
Hodgkin lymphomas have been reported as a late complication in patients treated for
Hodgkin lymphoma or multiple myeloma. Patients treated with long-term
cyclophosphamide are at risk of bladder cancer. Patients who have received mantle
irradiation for Hodgkin lymphoma have an increased risk of breast cancer, thyroid
 cancer, osteosarcoma, bronchogenic carcinoma, colon cancer, and mesothelioma. In
these cases, the second neoplasm is usually in the irradiated field. In general, the
risk of solid tumors begins to increase during the second decade of survival after
Hodgkin lymphoma. As a result, young women who have received mantle irradiation
for Hodgkin lymphoma should be screened more carefully for breast cancer, starting
at an age earlier than what is advised in standard screening recommendations.
Patients treated with molecular targeted agents such as dabrafenib may develop
squamous cell carcinomas of the skin as well as noncutaneous malignancies.
C. Other sequelae
1. Endocrine problems may result from cancer treatment. Patients receiving radiation
therapy to the head and neck region may develop subclinical or clinical
hypothyroidism. This is a particular risk in patients receiving mantle irradiation for
Hodgkin lymphoma. Biennial assessment of thyroid-stimulating hormone should be
undertaken in these patients. Thyroid replacement therapy should be given if the
thyroid-stimulating hormone level rises in order to decrease the risk of thyroid
cancer. Short stature may be a result of pituitary irradiation and growth hormone
deficiency.
2. Premature menopause may occur in women who have received certain
chemotherapeutic agents (e.g., alkylating agents, procarbazine) or abdominal and
pelvic irradiation. The risk is age-related, with women older than 30 years at the
time of treatment having the greatest risk of treatment-induced amenorrhea and
menopause. Early hormone replacement therapy should be considered in such
women, if not otherwise contraindicated, to reduce the risk of accelerated
osteoporosis and premature heart disease from estrogen deficiency.
3. Gonadal failure or dysfunction can lead to infertility in both male and female
cancer survivors during their peak reproductive years.20 Azoospermia is common,
but the condition may improve over time after the completion of therapy.
Retroperitoneal lymph node dissection in testicular cancer may produce infertility
due to retrograde ejaculation. Psychological counseling should be provided to these
patients to help them adjust to these long-term sequelae of therapy. Cryopreservation
of sperm before treatment should be considered in men. For women, there are
limited means available to preserve ova or protect against ovarian failure
associated with treatment. Abdominal irradiation in young girls can lead to future
pregnancy loss due to decreased uterine capacity.
4. The musculoskeletal system can be affected by radiation therapy, especially in
children and young adults. Radiation may injure the growth plates of long bones and
lead to muscle atrophy. Short stature may be a result of direct injury to bone.
Aromatase inhibitors increase bone loss and can contribute to pathologic
osteoporotic fractures.
5. Psychological and social concerns can be severe as patients who have had cancer
often carry an ongoing sense of vulnerability and frequent worry of the cancer
 returning. Changes in body image and sexual function can lead to difficulty with
marriage and other relationships. Survivors may also suffer from discrimination on
the job and find it difficult or impossible to get insurance, despite having been cured
from their cancer.

Acknowledgments
The author is indebted to Dr. Patricia A. Ganz, who contributed to previous editions of this
chapter. Most of the section on the late consequences of cancer treatment in this revision of the
handbook represents Dr. Ganz’s work.

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*An example is homozygosity for the UGT1A1*28 allele, a variation of a uridine diphosphate

glucuronosyltransferase gene and its corresponding enzyme (UGT1A1), which is responsible

for glucuronidation of bilirubin and involved in deactivation of Sn-38, a toxic active
metabolite of irinotecan.
I. SETTING TREATMENT GOALS
A. Patient perspective
Although patients most often come to the physician looking for medical perspective on
what can be done about their cancer, it is critical that physicians and other health-care
professionals remember that unless we know what the patient’s goals are, our ideas and
our plans of therapy may not address the patient’s needs. As a consequence, it is critical
for the physician to ask the patient to share in setting treatment goals because it is the
patient who must undergo the rigors of treatment and be willing to abide by its
consequences. Whereas the physician’s medical recommendations most commonly are
accepted, some patients reject them as inappropriate for a variety of reasons. Some ask
the physician for another recommendation, and others seek the opinion of a second
physician. The physician must clearly present the reasons for the treatment
recommendations and why those recommendations seem to be the best ways to achieve
the treatment objective. The physician has the obligation to make a treatment
recommendation, but the patient always has the right to reject that advice without fear
that the physician will be upset, dislike the patient, or refuse to continue to give the
patient care.
B. Medical perspective
Before a physician decides on a course of treatment to recommend for a patient with
cancer, an achievable medical goal of treatment must be clearly defined. If the goal is to
cure the patient of cancer, the strategy of therapy is likely to be different from the
strategy chosen if the purpose is to prolong life or to relieve symptoms. To propose the
goal of therapy, the physician must be:
■ Familiar with the natural history and behavior of the cancer to be treated.
■ Knowledgeable about the principles and practice of therapy for each of the
treatment modalities that may be effective in that cancer.
■ Well-grounded in the ethical principles of the treatment of patients with cancer.
■ Familiar with the theory and use of antineoplastic agents.
■ Informed about the particular therapy for the cancer in question.
■ Aware of the patient’s individual circumstances, including stage of disease,
performance status, social situation, psychological status, and concurrent illnesses.
Armed with this information and with the treatment goals in mind, the physician can
develop a course of treatment and make a recommendation to the patient.
 Components of the treatment plan include the following:
■ Should the cancer be treated at all? If so, is the treatment to be designed for cure,
prolongation of life, or palliation of symptoms?
■ How aggressive should the therapy be to achieve the defined objective?
■ Which modalities of therapy will be used and in what sequence?
■ How will the treatment efficacy be determined?
■ What are the criteria for deciding the duration of therapy?

II. CHOICE OF CANCER TREATMENT MODALITY

A. Surgery
The oldest, most established, and still most effective way to cure most cancers is
surgery. Surgery is selected as the treatment if the cancer is limited to one area and if it
is anticipated that all cancer cells can be removed without unduly compromising vital
structures. If it is believed that the patient can survive the operation and return to a
worthwhile life, surgery is recommended. Surgery is not recommended if the risk of
surgery is greater than the risk of the cancer; if metastasis always occurs despite
complete removal of the primary tumor; or if the patient will be left so debilitated,
disfigured, or otherwise impaired that although cured of cancer he or she feels that life
is not worthwhile. If metastasis regularly (or always) occurs despite complete removal
of the primary tumor, the benefits of removal of the gross tumor should be clearly
defined before surgery is undertaken.
Most commonly, surgery is reserved for treatment of the primary neoplasm; at times
it may be used effectively to remove isolated metastases (e.g., in lung, brain, or liver)
with curative intent. Surgery is also used palliatively, such as for decompression of the
brain in patients with glioma or biliary bypass in patients with carcinoma of the
pancreas. In nearly all nonhematologic cancers, a surgeon should be consulted to
determine the role of surgery in the optimal treatment of the patient.
B. Radiotherapy
Radiotherapy is used for the treatment of local or regional disease when surgery cannot
completely remove the cancer or when it would unduly disrupt normal structures or
functions. In the treatment of some cancers, radiotherapy is as effective as surgery for
eradicating the tumor. In this circumstance, factors such as the anticipated side effects of
the treatment, the expertise and experience of local oncologists, and the preference of
the patient may influence the choice of treatment.
One determinant of the appropriateness of radiotherapy is the inherent sensitivity of
the cancer to ionizing radiation. Some kinds of cancer (e.g., lymphomas and seminomas)
are highly sensitive to radiotherapy. Other kinds (e.g., melanomas and sarcomas) tend to
be less sensitive. Such considerations do not preclude the use of radiotherapy, however,
and it is helpful to obtain the evaluation of the radiation oncologist before initiating
treatment so that treatment planning can take into consideration the possible contribution
of this modality.
 Although radiotherapy is frequently used as the primary or curative mode of therapy,
it is also well suited to palliative management of problems such as bone metastases,
superior vena cava syndrome, and local nodal metastases.
C. Chemotherapy
As its primary role, chemotherapy treats disease that is no longer confined to anatomic
one site or region and has spread systemically. In the earliest days of chemotherapy, this
interpretation directed its use to diseases that regularly presented in a disseminated
form (e.g., leukemia) or after disease recurred following primary management with
surgery or radiotherapy. It is now understood that widespread systemic micrometastases
commonly occur early in cancer. These metastases are associated with certain
predictive factors such as the axillary node metastases of carcinoma of the breast and
the large tumor size and poorly differentiated histologic features of sarcomas or the
genetic profile of the cancer. Therefore, chemotherapy is now applied earlier to treat
systemic disease. When this treatment is used for micrometastases, the response of an
individual patient cannot be measured unless the chemotherapy is used as a
neoadjuvant, that is, before surgery or radiotherapy. In that case, tumor response may
predict more important endpoints such as time to treatment failure and survival. More
commonly, when the chemotherapy is used as an adjuvant after removal of visible
disease, the effectiveness of therapy must be determined by comparing the survival (or
disease-free survival) of patients who receive therapy with that of similar (control)
patients who do not receive therapy for the micrometastases. Chemotherapy also has a
role in the treatment of localized or regional disease.
D. Biologic response modifiers and molecular targeted therapy
It has long intrigued cancer biologists that cancer does not occur randomly but
preferentially selects specific populations: the young, the elderly, the
immunosuppressed (predominantly certain types of cancer), and those with a strong
family history of cancer. These observations have led cancer biologists to postulate that
some kind of biologic control over or proclivity toward the emergence of cancer exists,
which some people have and others do not, at least at the time the cancer becomes
established. One prime candidate for the mechanism of biologic control of cancer has
been immunity. That immunity plays some role in controlling the development of cancer
has been clearly demonstrated in animal models and a few, though not most, human
neoplasms. Other biologic factors, including those controlled by oncogenes and tumor
suppressor genes and their protein products that affect the cancer cell directly or its
environment, are becoming better defined and are even more important than classic
immunity in the development of cancer.
In an attempt to exploit and enhance the biologic control that is presumed to exist to
some degree in everyone, or to counteract cancer-promoting factors that facilitate
cancer growth, invasion, and metastases, a variety of agents called biologic response
modifiers and molecular targeted therapy have been used in the treatment of cancer.
Two classes of biologic response modifiers, the interferons and lymphokines (of which
 interleukin-2 is an example), have been studied for many years, and there is evidence of
their modest activity in some types of cancer. Related, but separate, are the molecular
targeted agents discussed in Chapter 2 that inhibit the activity of abnormally expressed
protein products such as the constitutively activated Bcr-Abl tyrosine kinase in chronic
myelogenous leukemia or other unique features, such as the interaction between immune
mechanisms and the cancer cell. This area of intensive research (as well as Wall Street
interest) has begun to reach fruition, including those previously refractory to
conventional chemotherapy such as renal cell carcinoma, and is expected to provide an
increasingly important, though expensive, contribution to effective cancer therapy.
E. Combined-modality therapy
Alone, surgery, radiotherapy, biotherapy, and chemotherapy are not appropriate for the
treatment of all cancers. Frequently, patients present with cancer in which there is a
bulky primary lesion, macroscopically evident regional disease, and presumed
microscopic or submicroscopic systemic disease. For this reason, oncologists have
turned to a multidisciplinary approach to the treatment of cancer, selecting two or more
modalities of therapy for sequential or simultaneous use. This approach requires close
cooperation among the surgical oncologist, radiation oncologist, and medical oncologist
to provide the patient with the best overall treatment plan. Although combined-modality
therapy is neither effective nor desirable for all kinds or stages of cancers, the regular
practice of a multidisciplinary approach provides the best opportunity to exploit the
advantages of each mode of treatment. “Tumor Boards” often serve as the format for
ensuring that patients will regularly have the benefit of various treatment perspectives.

III. PALLIATIVE CARE

The medical oncologist, who is also an internist, is often seen as the coordinator of cancer
treatment. In this role, although the focus is on the cancer, the broader perspective of the
oncologist as a coordinator of the patient’s care—in partnership with the patient—should
not become obscured. Decisions about what therapy to use and how aggressively to treat
the cancer are critically important to medically sound patient care. Decisions about when
to stop active cancer treatment are also vitally important and may be among the most
difficult responsibilities for the oncologist.1 It is critical that oncologists, who provide and
profit from therapy, recognize the inherent conflict of interest in their dual role as
caregivers and drug salespersons.
Quality of life is often enhanced in patients responding to chemotherapy and other
cancer treatments; it just as surely deteriorates more rapidly when the tumor does not
respond to therapy and the patient experiences the toxicity of treatment along with the pain,
fatigue, cachexia, and other symptoms of the cancer. For the 50% of patients with cancer
who are not cured, the decision to stop antineoplastic therapy is just as important as the
selection of chemotherapy regimens earlier in the disease. There comes a time when the
best advice a physician can give is for the patient to forgo additional chemotherapy or any
other active cancer treatment.2
 The introduction and rapid acceptance of hospice programs throughout the United
States during the last 35 years reflect the need for this kind of care.3,4 Hospice programs
have effectively addressed the special physical, psychological, social, and spiritual needs
of patients approaching the end of life and have provided the unique skills required to
maintain the best possible quality of life as long as possible. More recently, acute care
hospitals have recognized that they, too, have patients who are at the end of life and need a
special focus on the palliative aspects of their care. Yet too often, physicians are reluctant
to “give up” and are unable to recognize or to accept when the patient will be helped more
by an acknowledgment that active cancer therapy will not improve survival or enhance
quality of life.
Oncologists and others caring for patients with cancer who have been trained as acute
care physicians can learn specific techniques to enhance the quality of life from those who
are expert in palliative care. There is some evidence that early palliative care integrated
with standard oncologic care improves quality of life and mood and is associated with a
longer survival, compared with giving standard care alone.5 Comfort at the end of life is
also improved when there is a focus on palliative care. For example, consider the quality
of death in hospitalized patients given “maintenance” intravenous hydration with that of
hospice home care patients offered oral fluids and mouth care to assuage thirst. The former
method may result in an overhydrated, edematous patient who dies with an uncomfortable-
sounding “death rattle” that is disconcerting to family and staff; the latter usually results in
a visibly more comfortable patient who is more likely to die with less edema and without
as much apparent respiratory distress.
Legitimate questions also can be raised about medical costs toward the end of life that
are incurred when physicians give “futile” and “marginal” care.6,7 Development of
guidelines by physicians and hospitals that define futile care, along with thoughtful
consideration of when the therapy offered patients has marginal value, may enable
physicians to improve the quality of life for patients and at the same time hold down one
component of the rising spiral of health-care costs.8,9

References
1. Brody H, Campbell ML, Faber-Langendoen K, et al. Withdrawing intensive life-
sustaining treatment—recommendations for compassionate clinical management. N Engl
J Med. 1997;336:652–657.
2. Skeel RT. Measurement of quality of life outcomes. In: Berger AM, Portnoy JL,
Weissman DE, eds. Principles and practice of palliative care and supportive oncology.
2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1107–1122.
3. Byock I. Palliative care and oncology: growing better together. J Clin Oncol.
2009;27:170–171.
4. Ferris FD, Bruera E, Cherny N, et al. Palliative cancer care a decade later:
accomplishments, the need, next steps—from the American Society of Clinical Oncology.
 J Clin Oncol. 2009;27:3052–3058.
5. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with
metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733–742.
6. Hillner BE, Smith TJ. Efficacy does not necessarily translate to cost effectiveness: a case
study in the challenges associated with 21st-century cancer drug pricing. J Clin Oncol.
2009;27:2111–2113.
7. Meropol NJ, Schulman KA. Cost of cancer care: issues and implications. J Clin Oncol.
2007;25:180–186.
8. Jacobson M, O’Malley AJ, Earle CC, et al. Does reimbursement influence chemotherapy
treatment for cancer patients? Health Aff. 2006;25:437–443.
9. Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum
Pretium—the just price. J Clin Oncol. 2013;31:3600–3604.
 SECTION II: MEDICAL THERAPIES OF HUMAN
CANCER

I. INTRODUCTION
Data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End
Results) program estimate more than 1.6 million new cancer cases in 2014. Cancers of the
head and neck (HNCs) account for 55,000 or 3.3% of those. The majority of HNCs are in
the oral cavity and pharynx (oropharyngeal cancers [OPCs]) accounting for 42,000, with
cancers of the larynx the next most common with 12,600.1 The common anatomic sites of
HNCs include the oral cavity, nasal cavity, and pharyngeal cavity with subsites defined for
nasopharynx, oropharynx, and hypopharynx, and the laryngeal-epiglottic region (considered
part of the hypopharynx) (Fig. 6.1). Brain tumors and other cancers of the central nervous
system, head and neck lymphomas, and thyroid cancers are considered separately.
The commonly associated causes of squamous cell carcinoma of the head and neck
(HNSCC) have been tobacco use in all forms and excessive alcohol consumption. In
addition, some viral etiologies have been defined including the Epstein-Barr virus (EBV)
and its association with nasopharyngeal carcinomas (NPCs)2; and, in recent years, the
human papillomavirus (HPV) and its correlation with OPCs, especially the base of tongue
and tonsillar regions.3,4 Eighty to ninety percent are squamous cell histology, with the
remainder composed of adenocarcinoma, mucoepidermoid, and adenoid cystic histologies;
these latter types are seen mostly in salivary glands.
A. Presenting symptoms
Presenting symptoms in HNC vary depending on the primary site and can be sometimes
vague and confused with benign etiologies such as sinusitis or infectious pharyngitis. A
heightened level of suspicion, especially in a patient with obvious risk factors such as
smoking, is warranted. Vocal hoarseness is a common complaint in patients with
laryngeal cancer. Ear pain or persistent nasal congestion could indicate a
nasopharyngeal tumor. Other suspicious symptoms include oral pain, nonhealing
ulcerative lesions, dysphagia, odynophagia, hemoptysis, epistaxis, headaches,
 nonhealing dental infections, and a nonpainful neck mass. More advanced disease may
also be associated with systemic symptoms such as anorexia and weight loss, fatigue,
and even neurocognitive changes.

FIGURE 6.1 Anatomic divisions of the head and neck. Percentages indicate the relative
frequencies of carcinoma in these regions.

B. Evaluation
Patients who are ultimately diagnosed with HNC will often present initially to a
primary care physician, a dentist, or directly to an otolaryngologist, so an awareness of
the possibility of cancer is important on the part of these providers. A careful history
may help point to the primary site and suggest involved structures. A thorough head and
neck evaluation will include an assessment of the primary site and the extent of nodal
disease. Neck masses need careful assessment and often will require either fine-needle
aspiration (FNA) or a core-needle biopsy to determine cancer and to provide adequate
tissue for additional studies such as immunohistochemistry for HPV. An endoscopic
examination is usually performed on initial evaluation by an otolaryngologist to identify
and/or confirm the primary site. Most patients with laryngeal or pharyngeal tumors will
undergo direct laryngoscopy with biopsy to determine the extent of disease and to rule
out a second primary tumor. Imaging studies are considered a standard component of the
workup in patients with locally advanced disease. The purpose of radiographic studies
is to clearly define the extent of local disease, to identify nodal spread, and to rule out
metastatic disease or a second primary tumor. Computed tomography (CT) scans,
magnetic resonance imaging (MRI), and positron emission tomography (PET) scans
may each contribute unique clinical information; it is therefore important to discuss the
appropriate radiographic evaluation with the radiologist in order to optimize the staging
workup and to provide clinicians with the information needed for treatment planning. A
 cohesive multidisciplinary team is essential to the proper evaluation and treatment
planning for these patients.
The HNC team consists of members representing all facets of the patient’s care and
needs. This includes otolaryngologists with extensive training and expertise in HNC
surgery, medical oncologists, radiation oncologists with expertise in complex
radiotherapy protocols, pathologists, radiologists and nuclear medicine radiologists,
dieticians, speech pathologists, oral surgeons and oral medicine specialists, psycho-
oncologists and social workers, nurse navigators, and research coordinators. It is
essential that all members of this complex team work seamlessly; this is often best
accomplished in a multidisciplinary clinic setting with patient case discussion at tumor
board conferences attended by all of the aforementioned members.
C. Pathology
Over 80% of HNCs are squamous cell carcinomas, typically showing areas of
keratinization; however, basaloid (“jigsaw pattern”) features are more characteristic of
HPV-associated squamous cell cancers. The remainder is composed of
adenocarcinoma, mucoepidermoid, and adenoid cystic histologies; these latter types are
seen mostly in salivary glands.
D. Staging
Treatment of HNC is based on primary tumor location and stage. Once a tissue
diagnosis of HNC is obtained, a workup is undertaken to determine the clinical and/or
pathologic stage of the tumor. This includes endoscopic evaluation of the throat,
hypopharynx and larynx, and possibly the bronchial and esophageal areas;
CT/MRI/PET imaging modalities; and biochemical assessment with complete blood
counts, liver and kidney functions, and thyroid status. Tissue sampling of suspect areas
is critical not only for histology and immunohistochemical (IHC) analysis but also for
staging. Staging is based on the tumor, node, and metastasis (TNM) system defined in
the American Joint Committee on Cancer (AJCC) staging system.5
Approximately one-third of patients present with localized disease (stages I and II);
half present with locoregional disease (stages III and IV with nodal metastases); only
about 10% present with distant metastatic disease. Early-stage or localized disease is
often treated with a single modality, surgery or radiation therapy with an 80% to 90%
long-term (5 years) survival. Locoregional disease (stages III, IVA, and IVB) is treated
with multimodality therapy including various combinations and sequences of surgery,
radiation therapy, and chemotherapy. Long-term survival for this group of patients is
approximately 40%. Patients with recurrent disease can occasionally be “salvaged”
with surgery (approximately 15% of patients); however, many of these patients as well
as those with distant metastases are incurable and are usually managed with either
palliative chemotherapy or supportive care.
E. Treatment
1. Pretreatment assessment
Even though HNC is usually confined to the head and neck area, a complete history
 and physical examination is critical as these patients often have comorbidities that
affect their treatment. Tobacco, alcohol, and other substance abuse need to be
identified and discussed. Patients who continue to smoke during radiation therapy do
poorly and have increased mucositis; therefore, a robust smoking cessation program
is important. Other comorbidities such as cerebrovascular disease, cardiovascular
disease, renal insufficiency, chronic obstructive pulmonary disease (COPD), and
alcohol-related disorders are frequently present and need to be managed. An
accurate medication history is important; antihypertensives, diuretics, and
antihyperglycemic agents may need adjustment or even discontinuation during
treatment. Nephrotoxic agents (drugs and contrast for imaging studies) can be
harmful in the midst of dehydration. Depression and suicide are not uncommon in
HNC patients, thus initial and ongoing screening for mood disorders is appropriate,
and psychosocial oncology support is important. Social workers are helpful in
dealing with patients who have poor support systems and lower socioeconomic
status. It is also recommended that all patients undergo an upfront evaluation by oral
health specialists to assess for any necessary dental extractions prior to radiotherapy
as well as recommendations for oral health care during treatment, such as fluoride
trays, rinses, and other preventive measures. Speech pathology assessment and
evaluation before treatment can identify potential dysphagia risks and provide
advice for swallowing mechanics to minimize aspiration risks and reduce long-term
gastrostomy tube dependence. Dietary assessment and determination of nutritional
support requirements such as gastrostomy tube placements are important. All
chemotherapy agents may impair fertility either temporarily or permanently, so
fertility preservation methods should be addressed where appropriate. Baseline
assessment of bone marrow, liver, and renal function as well as audiograms may be
indicated due to potential toxicities with chemotherapy agents, including cisplatin,
5-flourouracil, taxanes, and other drugs.
2. Localized disease
Node-negative HNC can be managed with surgery alone in most cases, especially
for small (T1–T2) tumors that are easily accessible. Radiation therapy is an
acceptable alternative for patients who are poor surgical candidates. Chemotherapy
has little role in this setting.
Surgery is performed with curative intent with the aim to remove all disease
with clear surgical margins. Neck dissections, either ipsilaterally or bilaterally, are
determined on the basis of the primary tumor size and/or location, but are not routine
in T1–T2, N0 tumors. Transoral robotic surgery (TORS) is an emerging technique
that can be utilized in certain situations. Reconstructive measures are rarely needed
for these early-stage tumors, but microvascular tissue “flaps” are occasionally
needed to rebuild structural defects depending on site of the primary tumor and
extent of surgery necessary.
Radiation therapy as a single modality has evolved over the past four decades
 with the development of intensity-modulated radiation therapy (IMRT), which has
been shown to be useful in reducing long-term toxicity in oropharyngeal cancer,
paranasal sinus cancer, and NPC. The use of altered fractionation schema and the
incorporation of brachytherapy implants and stereotactic body radiation therapy
(SBRT) have also been developed. Three-dimensional planning and improved
understanding of tissue tolerance and physics of radiation have improved the
delivery of higher doses, as much as 70 to 74 Gy in many cases. Careful treatment
planning with pretreatment CT or PET imaging in the treatment position improves
tumor delivery and takes into account moving structures affected by swallowing,
breathing, and postural changes).6,7 Dental extractions, prior to treatment, to remove
any teeth in the treatment field reduce the risk of mandibular osteonecrosis, but can
delay the start of radiation by 2 to 4 weeks. Hyperfractionated or accelerated
radiation protocols have shown a 10% to 15% improved locoregional control in
phase II trials and a trend toward improved disease-free survival and overall
survival in phase III trials. Acute toxicity (mucositis) was worse, but, at 2 years
follow-up, late toxicity (xerostomia) was no different. A simultaneous integrated
boost (SIB) technique, which utilizes “dose painting” with higher doses to the gross
sites of tumor and lower doses to subclinical disease, is commonly used with
conventional (five fractions/week) and accelerated (six fractions/week)
schedules.8,9
3. Locoregional disease
Locoregionally advanced (LRA) disease is defined as stages III to IVB disease of
the head and neck. This includes newly diagnosed patients with a T3–T4 primary
tumor, advanced or unresectable nodal disease, patients with recurrent/persistent
disease, and/or patients with advanced disease who are unfit for surgery. Despite the
disease being advanced, these patients can still be treated with curative intent. An
exception would be if the patient has previously received radiotherapy and is
deemed surgically unresectable, treatment would then be directed toward palliation.
As mentioned previously, treatment usually involves input from a specialized
multidisciplinary team and can involve options such as surgery, chemotherapy,
and/or radiotherapy. The majority of patients with LRA disease are treated with
definitive concurrent chemoradiotherapy in efforts to preserve the function of
involved organs. Functional organ preservation approaches may not be appropriate
in all situations, and surgical resection may be preferred if the tumor has already
destroyed organ function, especially with laryngeal cancer. Other treatment options
can include upfront surgery with postoperative radiotherapy or chemoradiotherapy,
induction chemotherapy followed by chemoradiation, or salvage surgery after
chemoradiotherapy. The decision on which combination would be optimal is made
keeping multiple factors in mind, specifically, the patient’s age, performance status,
comorbidities, size/location of primary tumor, organ function, nodal status, and
patient preferences. Other factors should be considered as well especially those
 affecting adherence, including patient motivation, psychosocial issues, family
support, and travel distance.
Select patients will undergo primary therapy with surgical resection depending
on the size, location, and extent of local invasion. This depends on the experience
and technology available at the specific treating institution. Areas that are more
approachable, such as the oral cavity, are more amenable to surgical resection.
Technological advances, such as TORS and TOLM (transoral laser microsurgery),
now allow for increasing accessibility to the oropharynx, hypopharynx, and larynx
permitting organ-preserving surgery. Postoperative radiation is often incorpora ted
after surgery to eliminate residual disease in cases with pathology showing high-risk
disease (e.g., close margins, perineural invasion, lymphovascular invasion, or
multiple positive nodes/nodal sites). Consideration of chemoradiotherapy should be
discussed with an experienced multidisciplinary team for patients with high-risk
features. Studies show that chemoradiotherapy is warranted for evidence of
extracapsular extension or positive margins after surgery showing improved
locoregional control and disease-free survival compared to radiotherapy alone.10,11
HNCs commonly metastasize to the cervical lymph nodes. Metastases can be
clinically occult, but once locoregionally advanced, the prognosis is markedly
affected. If a surgical strategy is employed upfront, after resection of the primary
tumor, the surgeon will consider either a selective or a comprehensive neck
dissection depending on the amount of clinically evident disease in the neck. For
patients with no, or limited, evidence of cervical lymph node extension, a selective
neck dissection will be considered. This method depends on the location of the
primary tumor as to which levels of lymph nodes will be removed. Oftentimes for
tumors of the oral cavity, a selective lymph node dissection will involve the lymph
nodes above the omohyoid in levels I to III and occasionally the superior region of
level IV. For tumors arising in the pharynx/larynx, dissections will often involve
lymph node levels II to IV and occasionally VI when deemed appropriate. When
disease in the neck is extensive, including bulky disease, multiple nodal regions, or
bilateral neck disease, a comprehensive neck dissection is usually employed. This is
a more extensive surgery involving the removal of lymph nodes in levels I to V, and
the term encompasses either the removal or the sparing of nonnodal structures such
as the sternocleidomastoid muscle, spinal accessory nerve, and jugular vein.
In the majority of patients with LRA disease, surgery is not indicated. This
decision is based on the location of the primary tumor, extent of local invasion,
and/or nodal involvement. These patients will be treated with either concurrent
chemoradiotherapy or induction chemotherapy followed by chemoradiotherapy with
efforts to preserve organ function. Combined modality treatment with chemotherapy
and radiation is based on results of multiple randomized trials and meta-analyses.12–
16 This approach came into favor with the results of the Veterans Affairs Laryngeal

Study Group proving that combined modality treatment with sequential

 chemotherapy and radiation was equivalent in overall survival as compared to
surgical resection with postoperative radiation.12 The long-term follow-up of the
pivotal RTOG 91-11 trial proved that concomitant high-dose cisplatin with
radiotherapy was similar in efficacy for laryngeal-free survival as compared to
sequential chemotherapy followed by radiation. In this case, concurrent
chemoradiation did show an improvement in locoregional control and larynx
preservation, making this the new standard of care for LRA disease.13–15
Carboplatin is not as directly cytotoxic to tumor cells as cisplatin, but its
effectiveness as a radiosensitizer is still in question. One trial suggests that
carboplatin is not as effective as high-dose cisplatin with radiotherapy, but others
argue that weekly carboplatin with radiation may be a reasonable option for patients
with underlying renal dysfunction.17,18 Carboplatin has also been studied in
combination with other agents such as 5-fluorouracil and paclitaxel. Some patients
may not be able to tolerate platinum-based chemotherapy in general due to multiple
factors. This group of patients may benefit from the addition of cetuximab, a
monoclonal antibody (MoAb) inhibiting the epidermal growth factor receptor, in
combination with radiotherapy as compared to radiation alone.19 Elderly or poorly
functioning patients may consider radiation alone for palliation of symptoms.
Induction chemotherapy is still quite controversial as to its efficacy when
compared to concurrent chemoradiotherapy. The TAX 323, TAX 324, and GORTEC
trials established TPF (docetaxel (Taxotere), cisplatin, 5-flourouracil) as a more
active regimen when compared to PF (cisplatin, 5-fluorouracil) as induction therapy
prior to concurrent chemoradiotherapy; significantly improving survival, local
control, and laryngeal preservation.18,20,21 However, these trials did not compare
induction chemotherapy followed by chemoradiation versus chemoradiation alone.
Trials that have evaluated this have shown mixed results.16,21–27 A recent phase II
Italian study favored sequential therapy with higher complete response rate and
better progression-free survival, but still no difference in overall survival.25 This
led to a phase III trial with a 2 × 2 design comparing induction therapy with TPF
versus no induction therapy followed by concurrent chemoradiation with either
cisplatin-fluorouracil or cetuximab. At a follow-up of 33 months, the induction
regimen showed statistically better progression-free survival and overall survival.28
This is a significant result as this is the first randomized trial to show improvement
in overall survival; however, the 2 × 2 design of the trial makes extrapolation to
clinical practice controversial at present and further follow-up as well as additional
phase III trials will be needed to confirm. Induction therapy is still useful in a select
group of healthy individuals at high risk of both locoregional recurrence and distant
metastatic disease, specifically the subgroup of patients with bulky tumors/lymph
nodes and low level nodal disease. Induction chemotherapy does come with the risk
of increased toxicity leaving up to 25% of patients unable to finish full sequential
therapy with combined chemoradiation, significantly increasing the risk of local
 relapse. Therefore, this question still remains unanswered and requires further
evaluation for a definitive solution.
Close follow-up with clinical examination and endoscopy is important after
initial therapy with nonsurgical treatment. Post treatment imaging can be helpful in
guiding further care if necessary. CT, MRI, or PET imaging modalities can be used
in this situation. If PET imaging is selected, it should be done at least 12 weeks after
the completion of therapy to reduce the rate of false-positive findings. If imaging
shows no further evidence of malignancy, typically these patients are monitored
closely. If imaging shows residual disease, salvage surgery is indicated. Oftentimes
imaging may not be clear-cut and further close observation is indicated to evaluate
for progressive nodal disease.
4. Metastatic and/or recurrent disease
About 15% of HNC patients who develop local recurrence can be managed
surgically; however, most patients will not be candidates for surgery due to prior
treatment considerations (surgery and/or radiation effects), location/extent of the
tumor, comorbidities (which may have eliminated surgery as an option with the
initial diagnosis), or declining health and functional status. These patients are often
managed palliative, either with a chemotherapy regimen or with supportive care
alone.
For many years, dogma has held that once radiated, further radiation was not
possible. But studies in which re-irradiation is given to twice the expected tissue
tolerance with minimal toxicity, resulting in disease control and good outcomes,
have challenged the previous perceptions.29,30 Selection is important: tissue health,
prior response to radiation, and durable radiation responses of a year or more have
been shown to be good criteria for re-irradiation. For patients with recurrent HNC
who meet these criteria, 50% to 75% may be able to receive more radiation
therapy.8
Most patients with metastatic disease will not be candidates for local therapies
such as surgery or radiation other than for palliative intent to relieve pain, and so on.
Systemic therapy with chemotherapy will be the mainstay of treatment. The decision
of whether or not to recommend chemotherapy requires assessment of the patient’s
performance status, comorbidities, prior treatment(s) response and duration of
response, and potential toxicities of the regimen being considered. If patients have
poor performance status (Eastern Cooperative Oncology Group [ECOG], 3 to 4),
are cachectic, and had less than 3 to 6 months of durable response from their prior
treatment, they are unlikely to benefit from cytotoxic chemotherapy of any kind and
should have serious discussion about supportive care and hospice referral. For those
who are candidates for systemic therapy, options include monotherapy or
combination regimens, with the decision based on potential toxicities and ability to
tolerate.
The specific chemotherapy agents are discussed later in this chapter, but
 several points can be made here. Although response rates may be higher for
combination regimens, in most cases the survival is not significantly different.
Single-agent regimens such as cetuximab, weekly docetaxel or methotrexate, and
oral capecitabine are all options to consider. Cost and convenience are factors as
well. Monotherapy with cetuximab produces response rates of 13%.31 Combination
chemotherapy for fit patients is usually platinum-based. The EXTREME trial
demonstrated a survival advantage (Hazard ratio [HR], 0.797) for the addition of
cetuximab to the combination of either cisplatin or carboplatin with infusional 5-
fluorouracil.32
5. Nasopharyngeal carcinoma
NPC has a high prevalence in China, Southeast Asia, and North Africa, but is
uncommon in other parts of the world. In low-risk areas such as the United States,
NPC has a bimodal age distribution with peak incidence occurring between the ages
of 15 and 25 years, and again between the ages of 56 and 79 years. Risk factors for
the development of NPC include infection with EBV, environmental factors, and
genetic predisposition. In the low-risk areas, the early peak in incidence is thought
to be due to genetic susceptibility in conjunction with exposure to EBV and/or other
environmental contacts; however, more traditional risk factors such as tobacco and
alcohol use may play a role. Not all people with EBV infection develop NPC, thus
other factors are implicated. NPC is commonly classified using the World Health
Organization system. The first is a World Health Organization classification. This
classifies NPC as keratinizing, nonkeratinizing well-differentiated, and
nonkeratinizing undifferentiated. The keratinizing subtype is most common in the
low-risk and older patients, whereas undifferentiated histologies are more common
in the high-risk areas.
6. HPV-associated oropharyngeal carcinoma
The incidence of OPCs, especially the base of tongue and tonsillar regions, has been
increasing, and a causal relationship between the HPV and OPCs has been known
for some time.3 The vast majority of cases within the United States are associated
with serotype 16. The HPV-associated cancers present with a different clinical
phenotype compared with the non-HPV counterparts. Patients are minimal or non-
smokers, non–alcohol abusing, and typically present at a younger age, and, while
men are still more likely to be affected, the number of women with HPV-associated
cancer is increasing more than that of HPV-negative counterparts. Histologically,
these tumors are more likely to show basaloid squamous features (“jigsaw puzzle”
appearance) with minimal to no keratinization; it is important to distinguish tonsillar
cancers with a basaloid appearance from “basaloid squamous cancers,” which are
an aggressive subtype thought to have a poor outcome. HPV can be demonstrated
with IHC techniques for the p16 protein expression or by the more sensitive reverse
transcriptase–polymerase chain reaction (RT-PCR) for the HPV-16/18 DNA. The
use of p16 as a surrogate marker is supported by the fact that OPCs have a higher
 likelihood of being HPV-positive compared to other anatomic sites of the head and
neck; thus, it is considered a reliable diagnostic option.33 HPV-positive patients tend
to have better prognosis than non-HPV patients; however, smoking appears to
mitigate this advantage. Because of the better prognosis, studies of “de-intensified”
regimens with shorter or fewer cycles of chemotherapy and altered fractionations of
radiotherapy have been conducted and seem to support equivalent outcomes for less
intense treatment.34 Randomized trials are stratifying patients into risk groups based
on tumor size, surgical margins, number of lymph nodes involved, and presence of
nodal extracapsular spread (ECS).
7. Organ preservation
The concept of organ preservation is often applied to cancers of the larynx and the
base of tongue in which nonsurgical approaches are initially recommended in an
effort to preserve the function of these sites. In most cases, treatment consists of
concurrent chemotherapy and radiation (discussed in the section on definitive
concurrent chemoradiotherapy). Studies have demonstrated acceptable organ
preservation and survival rates. Patients who fail can be salvaged with surgery;
however, newer treatment modalities and re-irradiation principles have enabled
patients to still be treated nonsurgically in the recurrent setting with potential
success and continued delay of organ removal.
F. Chemotherapy agents
Chemotherapy for HNC consists of either single-agent therapy, usually cisplatin and
often in combination with radiotherapy, or combination therapies, often cisplatin-based
and usually for advanced or recurrent disease. Chemotherapy response, as in most
cancers, is predicted by tumor stage, prior treatments, and the patient’s performance
status and comorbidities.
1. Cisplatin
cis-Diammino platinum or cisplatin is one of the most commonly used agents in HNC
therapy, either as a single agent concurrent with radiation therapy or in combination
with other chemotherapy agents. It intercalates with tumor DNA, creating DNA
adducts that disrupt normal helical function. It can be a very toxic drug, particularly
causing acute and delayed nausea and vomiting, and renal and ototoxicities;
however, with careful supportive care, many of these toxicities can be ameliorated.
Regimens giving cisplatin at a lower dose weekly during radiation are better
tolerated and managed with outcomes similar to the higher dose regimens given
every 3 weeks. Acute and delayed nausea and vomiting can be managed with 5-HT3
receptor antagonists and neurokinin-1 receptor antagonists as well as vigorous
hydration with adequate potassium and magnesium replacement, which can protect
against renal toxicities. The use of mannitol, a common practice for many years, may
not be necessary with adequate hydration protocols and, in fact, may even be
associated with a higher incidence of renal toxicity.35
2. Carboplatin
 Carboplatin differs from cisplatin in that it contains a bidentate dicarboxylate
(CBDCA) ligand in place of the two-chloride ligand. Its mechanism of action is
similar to cisplatin; however, it is easier to administer than cisplatin because there
is no requirement for forced hydration and less nausea and vomiting, renal toxicity,
ototoxicity, and neuropathy. Response rates comparable to single-agent cisplatin are
reported, but myelosuppression, in particular thrombocytopenia, can be dose-
limiting. Allergic reactions may occur in patients, particularly after multiple cycles.
3. Paclitaxel
Paclitaxel as a single agent given either every 3 weeks (175 to 250 mg/m2) or
weekly (50 to 120 mg/m2) is another option with comparable response rates.
Toxicities include alopecia, neutropenia, neuropathy, and allergic reactions. The
latter can be mitigated by premedicating with steroids, H1 and H2 blockers.
4. Docetaxel
Docetaxel can also be dosed every 3 weeks (75 to 100 mg/m2) or weekly (15 to 40
mg/m2). Neuropathy may be lower than with paclitaxel, but asthenia may be greater
with the high-dose regimen. Tissue edema may occur with higher doses; thus, steroid
prophylaxis is indicated.
5. Methotrexate
Methotrexate is an older antimetabolite and antifolate drug that has largely been
replaced by platinum- and/or taxane-based regimens; however, it still has single-
agent activity and is reasonably well tolerated, making it an option in the palliative
setting.
6. Cetuximab
Epidermal growth factor receptors are overexpressed in 90% of HNCs. Cetuximab
is a MoAb that binds to epidermal growth factor receptors, thus blocking the
proliferative signal. Cetuximab has been approved by the U.S. Food and Drug
Administration (FDA) for the treatment of metastatic disease and unresectable
disease that failed prior platinum-based therapy and as a radiation-sensitizing agent.
The standard regimen begins with a loading dose of cetuximab 400 mg/m2 IV given
over 2 hours followed by weekly doses of 250 mg/m2 IV over 1 hour. Responses of
up to 10% have been observed among patients with metastatic or recurrent disease.
Skin rash, hypomagnesemia, and diarrhea are the common side effects. Anaphylactic
reactions, although uncommon, may be severe, especially with hypokalemia or
hypomagnesemia. Of note, anaphylactic reactions are more common in areas of the
southeastern United States, where rates are as high as 20%.
7. Fluorouracil
Fluorouracil is well tolerated and has comparable activity to cisplatin and other
single agents. It is most often given as a 4- or 5-day continuous infusion. The drug is
a vascular irritant at high concentrations and therefore, for prolonged infusions, a
central venous catheter or access device is customary. Although suitable for use as a
single agent, it is most often used in combination with other drugs. Common
 toxicities are mucositis, palmar-plantar erythrodysesthesia (“hand-foot syndrome”),
diarrhea, and rarely cardiotoxicity. Administration requires a port and an ambulatory
pump.
8. Capecitabine
Capecitabine is a prodrug that is converted enzymatically to fluorouracil. It is
administered orally, which is more convenient. It has similar toxicity as infusional
fluorouracil, but is usually reserved for palliative settings.
Other chemotherapeutic agents that are less frequently used include ifosfamide,
bleomycin, gemcitabine, and anthracyclines such as doxorubicin and mitoxantrone.
As single agents, these all have minimal response rates and have, for the most part,
been replaced by newer agents.
G. New agents
The discovery of the presence of epidermal growth factor receptors led to targeted
therapies and cetuximab is one such agent (discussed previously). The EXTREME trial,
which combined cetuximab with cisplatin and infusional fluorouracil, demonstrated
improved response and survival compared to cisplatin and infusional fluorouracil
alone.32 Panitumumab is another MoAb targeting the epidermal growth factor receptor.
In the SPECTRUM trial, panitumumab combined with cisplatin and infusional
fluorouracil demonstrated similar results with significantly prolonged progression-free
survival compared to cisplatin and infusional fluorouracil alone with similar toxicity
profile as the EXTREME trial.36
Another emerging approach in many cancers including HNC is to target the immune
system, specifically the program death (PD) ligands 1 and 2 (PD-L1 and PD-L2).
MoAbs formed from highly selective, humanized MoAbs designed to block PD-1
interaction with its ligands PD-L1 and PD-L2, reactivate the immune system to target
the tumor. Phase I and II trials have demonstrated activity of these compounds in both
HPV-associated and non-HPV–associated HNC. Results showed a best overall
response rate of 20% in previously treated patients.37
1. Radiosensitizing chemotherapy
The concurrent administration of chemotherapy and radiation has improved
outcomes in locally advanced NPCs, advanced unresectable cancers, organ
preservation in locally advanced larynx and base of tongue cancers, and in high-risk
postoperative patients (positive margins and/or ECS nodal disease). Concurrent
chemoradiotherapy results in a 4% to 8% absolute improvement in survival or a
12% to 19% reduction in the risk of death. Thus, concurrent chemoradiation is
accepted as a standard option for these patients. High-dose cisplatin (100 mg/m2 on
days 1, 22, and 43 concurrent with radiation) has been the most studied regimen and
remains the reference standard. Other single-agent regimens such as weekly low-
dose cisplatin, weekly cetuximab, and taxanes have been studied as well as
combination regimens with cisplatin or carboplatin plus a second agent such as
fluorouracil or a taxane.38 No comparative data to date have been done to show
 combination regimens better than single-agent cisplatin; however, phase III
cooperative group trials through RTOG are underway. Concurrent therapy does
enhance toxicities, and careful pretreatment evaluation of the patient is critical.
2. Combination chemotherapy
Combination chemotherapy regimens as the sole treatment modality are mainly used
in the recurrent or metastatic setting in cases where surgery or radiation therapy is
not possible. Median survival of metastatic or recurrent HNC is short (6 to 9
months), and treatment in this setting is palliative at best. The results of the
EXTREME trial are discussed elsewhere. Common combination regimens are
shown in Table 6.1.
3. Second-line therapy
For patients who are a candidate for second-line cytotoxic chemotherapy, the choice
of agent is based on prior treatment history and the overall condition of the patient.
Cetuximab is approved by the FDA for second-line therapy in patients with recurrent
or metastatic HNC with response rate of 11%. Similar targeted agents including
gefitinib, sunitinib, erlotinib, and lapatinib have been tested in patients with
advanced HNC, but have no clinically significant activity.39–43 Current trials are
investigating immune targeted therapies with anti-PD-L1 and anti-PD-L2 agents in
the second- and even third-line treatment of these patients.
H. Palliative/supportive care
Palliative care has been defined by various organizations and the definition has evolved
over recent years. The Center to Advance Palliative Care defines palliative care as
specialized medical care for people with serious illnesses, focusing on providing
patients with relief from the symptoms, pain, and stress of a serious illness—whatever
the diagnosis with a goal to improve quality of life for both the patient and the family.44
The National Cancer Institute defines palliative care as care given to improve the
quality of life of patients who have a serious or life-threatening disease, where the goal
is to prevent or treat as early as possible the symptoms of a disease, side effects caused
by treatment of a disease, and psychological, social, and spiritual problems related to a
disease or its treatment.45 Data have shown that integrating palliative care early along
with the standard-of-care treatment results in better quality of life, better survival, and
less cost than standard of care alone.46,47 A truly multidisciplinary team is necessary for
the care of these patients.
Treatment of HNC is time-intensive, complex, and fraught with complications. It
requires a compliant and willing patient as well as a dedicated support system. The
support system is composed of the patient’s caregivers, usually defined as a network of
family and friends, and the health-care team. Prior to initiating therapy, it is important to
inform the patient and caregivers about anticipated treatment toxicities and their
potential impact on the patient’s ability to conduct routine activities of daily living.
Working with the health-care team, the patient must identify the individuals who will
provide support if and when it becomes necessary. Specific issues that should be
 discussed include the following: (1) insurance coverage (including dental and
pharmacy); (2) living situation (homeless, living alone, or living with others); (3) social
supports (ability and willingness of caregivers to provide physical and emotional
support); (4) financial issues (with specific discussion of ability to pay for household
expenses during treatment); and (5) work issues (impact of cancer on work status of
patient and caregivers). It is important to identify patients with critically limited
resources in order to plan adequately for their ongoing care and to guide treatment
decisions. Use of a validated psychosocial distress screening tool can be very helpful
in this area. The health-care team should be composed of physicians, nursing staff,
nutritionists, speech and swallowing therapists, physical therapists, psycho-oncologists
and palliative care experts, and social workers who are trained to deal with the unique
challenges faced by HNC patients and their caregivers. Because patient support needs
change dramatically over time, frequent and ongoing assessment is required.

TABLE
Response Rate for Combination Chemotherapy Agents in Recurrent HNC
6.1
Agent Approximate Response Rate
Cisplatin/fluorouracil 25%–40%
Carboplatin/fluorouracil 26%
Cisplatin/paclitaxel 28%–35%
Cisplatin/docetaxel 42%
Cisplatin/cetuximab 26%
Methotrexate/bleomycin/cisplatin 48%
In NPC
Gemcitabine/paclitaxel 41%

HNC, head and neck cancer; NPC, nasopharyngeal carcinoma.

1. Nutrition
Due to the anatomic proximity to structures critical for normal alimentation, HNC
and its treatment may have a dramatic impact on oral intake. Malnutrition is
associated with impaired healing, increased toxicity of treatment, and decreased
survival. Therefore, it is important to identify and treat nutritional deficiencies in a
proactive and aggressive manner. At the time of diagnosis and periodically
thereafter, patients should undergo a nutritional assessment by a dietician who is
familiar with the issues facing HNC patients. A nutritional assessment should
include a weight loss history, assessment of nutrient intake, and identification of
barriers to adequate nutritional intake. Treatable causes of decreased caloric intake
should be identified and appropriate interventions instituted.
Ongoing monitoring and education is critical and should include routine
 measurement of weight, assessment of hydration, and counseling by a certified
dietician. Dieticians also ensure adequate nutrition as patients transition from an
enteral to oral diet. Chronic xerostomia, which alters a patient’s ability to take in dry
foods such as breads, requires management and education. Patients who are
edentulous may have difficulty with intake of adequate protein. Dietary adaptations
may predispose to long-term nutrient deficiencies that may impair overall health.
2. Mucositis
Radiation therapy and select chemotherapy agents cause mucositis, a pan-tissue
inflammation of the mucosa and underlying soft tissue. The classic mucosal
manifestations are erythema, ulcer, and pseudomembrane formation. Mucositis
associated with systemic chemotherapy is cyclic in nature. With chemotherapy
regimens administered on a 3-week cycle, mucositis usually develops 7 to 10 days
after administration and resolves 5 to 7 days later. Chemotherapy regimens
administered weekly tend to have a slow escalation of mucosal symptoms over time,
with resolution when chemotherapy is dose-reduced or held. Radiation-associated
mucositis begins to develop 2 to 4 weeks after the initiation of therapy. Symptoms
usually peak at 5 to 7 weeks, although occasionally patients will note worsening
mucositis after the completion of therapy. Radiation-induced mucositis may take 4 to
12 weeks to resolve. Some patients have persistent symptomatic ulceration for
protracted periods of time. It should be noted that the incidence of grade 3 to 4
mucositis increases from 25% to 35% with radiation alone to 40% to 100% with
concurrent chemotherapy. Management of mucositis includes oral medicine experts
and pain management. Early preventive measures with salt and soda rinses, viscous
lidocaine-based solutions, and analgesics can reduce and ameliorate the severity of
mucositis.
3. Dysphagia and aspiration
Swallowing is a complex function that requires intact musculature, dentition,
vasculature, and nervous system. Damage to any of these components may result in
altered swallowing function. Thus, swallowing dysfunction is one of the common
and devastating acute and late effects of therapy. Surgery-induced dysphagia is
secondary to structural changes due to tissue extirpation and altered sensation from
transected nerves. Acutely, radiation therapy–induced dysphagia is secondary to
edema and painful mucositis. Over the long term, radiation therapy results in
noncompliant fibrotic or contracted tissues that are unable to function normally. Of
particular note, radiation may cause upper esophageal stricture formation. Stricture-
induced dysphagia may be successfully treated with balloon dilation procedures.
In order to maximize swallow function, it is important to involve speech and
language pathologists (SLPs) at an early point in a patient’s treatment course.
Health-care providers should also be aware of signs and symptoms that may indicate
aspiration, which requires rapid referral and evaluation. These include coughing or
throat clearing during or after swallow. Other indications for an SLP evaluation
 include nasal regurgitation, drooling, pocketing food in the cheek, and food sticking
in the throat. The role of the SLP includes (1) identifying swallowing abnormalities,
(2) recommending further testing, (3) developing a treatment plan (including
education and swallow therapy), (4) helping dieticians develop an adequate yet safe
diet, and (5) ruling out significant aspiration. Common instrumental methods to
assess swallow function include the modified barium swallow and the flexible
endoscopic evaluation of swallowing safety.
As noted previously, dysphagia may result in dietary adaptations and/or weight
loss due to inadequate caloric intake. In addition, dysphagia may result in aspiration.
Aspiration puts patients at risk for acute and long-term pulmonary toxicity. Acutely,
aspiration may lead to pneumonia; in patients actively undergoing myelosuppressive
chemotherapy, aspiration pneumonia is associated with a high rate of morbidity and
mortality. Over the long term, aspiration may lead to pulmonary fibrosis and
respiratory compromise. Of note, microaspiration can simulate pulmonary
metastasis.
4. Xerostomia and oral care
Poor oral health outcomes are one of the major late effects of HNC therapy. This is
largely related to radiation-induced xerostomia. Initial dental evaluation is important
for all patients undergoing therapy for HNC, particularly for those who will receive
radiation therapy. Patients require extensive education regarding oral hygiene and
preventive strategies to avoid radiation-induced dental caries. Oral hygiene should
include the use of prescription-strength fluoride treatments because this agent has
consistently demonstrated the ability to significantly reduce adverse late dental
effects. In addition, patients undergoing radiation therapy should have extraction of
nonviable teeth at least 10 to 14 days prior to initiation of therapy. This will allow
adequate time for healing. As health-care providers, our role is to assess
compliance with dental hygiene regimens and to refer to oral health specialists if
problems are identified.
5. Lymphedema and fibrosis
Surgery and radiation therapy can damage the soft tissues within the head and neck
region with resulting lymphedema (swelling with lymphatic fluid) and fibrosis. In
contemporary grading systems, lymphedema and fibrosis exist on a continuum with
fibrosis, considered the end stage of tissue damage. Chronic inflammation may
accompany lymphedema and fibrosis; damage may be ongoing and self-perpetuating,
thus resulting in late toxicity. Generally, lymphedema and fibrosis may be
characterized as involving external (neck and shoulders) or internal (pharynx and
tongue) structures. Associated function loss may be severe. Early identification and
treatment by certified physical therapists experienced in lymphedema and scar
management is critical. Trismus is one of the most common and problematic
manifestations of fibrosis. It is caused by surgery or radiation therapy involving the
mandibular joint and muscles of mastication. It is characterized by a decrease in the
 movement of the jaw, thus limiting the opening of the oral cavity. When trismus is
severe, patients have difficulty with eating solid foods, dental hygiene, and
procedures such as intubation. Trismus usually begins to develop within 1 year of
the completion of therapy and is progressive in nature. Aggressive physical therapy
may halt progression of symptoms; however, reversal of existing symptoms is
limited.
6. Metabolic abnormalities
HNC patients are subject to a number of metabolic abnormalities. First, radiation
therapy to the thyroid gland can result in gradual loss of function. Estimated to occur
in 25% to 50% of patients who receive doses above 6,000 cGy to the thyroid gland,
hypothyroidism may develop years after the completion of therapy. Routine testing of
thyroid function is recommended, particularly in patients with symptoms indicative
of hypothyroidism.
Patients with late-stage HNC may develop humoral hypercalcemia of
malignancy. Although estimates vary widely, up to 23% of patients with advanced
recurrent HNCs will manifest hypercalcemia before death. Standard treatment with
hydration, saline diuresis, and bisphosphonate therapy are used.
7. Secondary cancer prevention and survivorship
Some HNC patients are long-term survivors. HNC survivors with the traditional risk
factors of smoking and drinking are at risk for the development of second primary
cancers. The majority of second primary tumors involve the upper aerodigestive
tract. It is hypothesized that this is related in part to a field cancerization effect of
tobacco and alcohol exposure. Thus, smoking cessation and abstinence from alcohol
are important adjuncts to the care of these patients. Although data are lacking, the
widespread use of vaccination against HPV infections may lead to decreases in
tumors associated with this virus. Chronic hypothyroidism and even thyroid cancer
can occur and should be assessed in regular follow-up evaluations. Many of these
issues can be managed in a survivorship program where attention to surveillance,
second malignancies, chronic toxicities, and healthy lifestyle choices can be
implemented.

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27. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by
concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent
chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a
randomised phase 3 trial. Lancet Oncol. 2013;14(3):257–264.
28. Ghi MG, Paccagnella A, Ferrari D, et al. Concomitant chemoradiation (CRT) or
cetuximab/RT (CET/RT) versus induction docetaxel/cisplatin/5-fluorouracil (TPF)
followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell
Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study
(NCT01086826). J Clin Oncol. 2014;32(15, suppl):Abstract 6004. Special issue on
ASCO Annual Meeting.
29. Stevens KR, Britsch A, Moss WT. High-dose reirradiation of head and neck cancer with
curative intent. Int J Radiat Oncol Biol Phys. 1994;29:687–698.
30. Weppelmann B, Wheeler RH, Peters GE, et al. Treatment of recurrent head and neck
cancer with 5-fluorouracil, hydroxyurea, and reirradiation. Int J Radiat Oncol Biol
Phys. 1992;22:1051–1056.
31. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study
to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with
recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to
 respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–2177.
32. Rivera F, García-Castaño A, Vega N, et al. Cetuximab in metastatic or recurrent head and
neck cancer: the EXTREME trial. Expert Rev Anticancer Ther. 2009;9(10):1421–1428.
33. Chung CH, Zhang Q, Kong CS, et al. P16 protein expression and human papillomavirus
status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell
carcinomas. J Clin Oncol. 2014;32(35):3930–3938.
34. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with
oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.
35. Santoso JT, Lucci JA, Coleman RL, et al. Saline, mannitol, and furosemide hydration in
acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol.
2003;52(1):13–18.
36. Vermorken JB, Stöhlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil
with or without panitumumab in patients with recurrent or metastatic squamous-cell
carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
Lancet Oncol. 2013;14(8):697–710.
37. Mahoney KM, Atkins MB. Prognostic and predictive markers for the new
immunotherapies. Oncology (Williston Park). 2014;28(suppl 3):39–48.
38. Jacobs C, Lyman G, Velez-García E, et al. A phase III randomized study comparing
cisplatin and fluorouracil as single agents and in combination for advanced squamous
cell carcinoma of the head and neck. J Clin Oncol. 1992;10(2):257–263.
39. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or
metastatic squamous cell carcinoma of the head and neck. J Clin Oncol.
2003;21(10):1980–1987.
40. Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250 mg daily in patients
with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin
Cancer Res. 2005;11(23):8418–8424.
41. Kirby AM, A’Hern RP, D’Ambrosio C, et al. Gefitinib (ZD1839, Iressa) as palliative
treatment in recurrent or metastatic head and neck cancer. Br J Cancer. 2006; 94(5):631–
636.
42. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with
intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck
[corrected]. J Clin Oncol. 2009;27(11):1864–1871.
43. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral
epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or
metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22(1):77–85.
44. Center to Advance Palliative Care. What is palliative care? Retrieved from
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45. National Cancer Institute. What is palliative care? Retrieved from
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sheet#q1. Published 2014.
46. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with
 metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–742.
47. Zimmerman C, Swami N, Krzyzanowska M, et al. Early palliative care for patients with
advanced cancer: a cluster-randomized controlled trial. Lancet. 2014;383:1721–1730.
I. INTRODUCTION
Carcinoma of the lung is responsible for roughly 160,000 deaths each year in the United
States. This represents one-fourth of all deaths due to cancer and more than the number of
deaths due to breast, colon, and prostate cancers combined.1 Because early-stage lung
tumors are often asymptomatic and, until recently, there has been no proven approach to
radiographic screening, most patients are diagnosed with advanced-stage disease.
Approximately 85% of cases are histologically classified as non–small-cell lung cancer
(NSCLC), of which adenocarcinoma, squamous cell carcinoma, and large cell carcinoma
are the primary subtypes. Small-cell lung cancer (SCLC) accounts for the remaining 15%
of cases. The biology, staging, and treatment of SCLC differ substantially from NSCLC.
Thus, these two groups are addressed in two separate sections.

II. ETIOLOGY
Lung cancer is predominantly a disease of smokers, although some studies suggest the rate
of NSCLC is increasing in never smokers.2 Eighty-five percent of lung cancer occurs in
active or former smokers, and an additional 5% of cases are estimated to occur as a
consequence of passive exposure to tobacco smoke. Tobacco smoke causes an increased
incidence of all four histologic types of lung cancer, although adenocarcinoma (particularly
the adenocarcinoma in situ (AIS) variant) is also found in nonsmokers. Other risk factors
for lung cancer include exposure to asbestos or radon. Familial factors such as
polymorphisms in carcinogen-metabolizing hepatic enzyme systems may also play a role in
determining an individual’s propensity to develop lung cancer.3

III. MOLECULAR BIOLOGY

Numerous genetic changes have been associated with lung tumors. Most common among
these include activation or overexpression of the myc family of oncogenes in SCLC and
NSCLC and of the KRAS oncogene in NSCLC, particularly adenocarcinoma. Inactivation
or deletion of the p53 and retinoblastoma tumor suppressor genes and a tumor suppressor
gene on chromosome 3p (the FHIT gene) have been found in 50% to 90% of patients with
SCLC. Abnormalities of p53 and 3p have been associated with 50% to 70% of cases of
NSCLC. The KRAS mutation is more frequently found in smokers, those with
adenocarcinoma, and those with poorly differentiated tumors. It is also associated with
poor prognosis.4–6
 Epidermal growth factor receptor (EGFR) is expressed or overexpressed in the
majority of NSCLC tumors. Binding of ligand to the extracellular domain of EGFR causes
receptor dimerization, which in turn activates an intracellular tyrosine kinase domain.7
Autophosphorylation of the receptor induces a cascade of signal transduction events
leading to cell proliferation, inhibition of apoptosis, angiogenesis, and invasion, all
resulting in tumor growth and spread. Tumors harboring activating EGFR gene mutations
render the cancer highly dependent on EGFR for proliferation and survival. The most
common activating mutations are found in exons 19 and 21, which result in in-frame
deletions of amino acids 747 to 750 and L858R substitutions, respectively. Agents
targeting mutated EGFR include tyrosine kinase inhibitors (TKIs), such as gefitinib,8
erlotinib,9 and afatinib.10 In NSCLC harboring EGFR gene mutation, these treatments often
result in dramatic and sustained responses, with response rates exceeding 60% and median
survival exceeding 2 years for stage IV cases. However, most patients often progress in
about 9 months, and studies have shown that in about 50% of cases, this is due to a
secondary mutation in exon 20, the T790M mutation.11 Drugs that target this mutation are
currently being developed and one has recently gained FDA approval.12 KRAS and EGFR
mutations are rarely found in the same tumor.13
Abnormalities in the anaplastic lymphoma kinase (ALK) gene have been identified in
a subset of lung cancers. These gene rearrangements, which appear mutually exclusive with
both EGFR and KRAS gene mutations, render cancers highly responsive to ALK inhibitors
including crizotinib14 and ceritinib.15
Additional mutations found in smaller subsets (<2% to 3%) of NSCLC patients
predict for variable sensitivity to targeted agents including BRAF V600E mutations
(vemurafenib), MET amplification (crizotinib), ROS1 rearrangements (crizotinib), RET
rearrangements (cabozantinib), and HER2 mutations (trastuzumab and afatinib).16–21

IV. SCREENING
Three US randomized screening studies in the 1980s failed to detect an impact on mortality
of screening high-risk patients with chest radiography or sputum cytology, although earlier-
stage cancers were detected in the screened groups. Since then, however, low-dose spiral
computed tomography (CT) has emerged as a new tool for lung cancer screening. Spiral
CT is CT imaging in which only the pulmonary parenchyma is scanned, thus negating the
use of intravenous contrast medium and the necessity of a physician having to be present.
This type of scan can usually be done quickly (within one breath) and involves low doses
of radiation. A large randomized controlled trial conducted by the National Cancer Institute
(the National Lung Screening Trial [NLST]) involving over 50,000 participants
demonstrated a 20% reduction in lung cancer mortality with screening by low-dose CT
compared to chest radiograph in high-risk individuals. The high-risk population that
benefitted has been defined as being 55 to 74 years old, current or former smoker (if quit
less than 15 years prior) with 30 or more pack-year smoking history.22 Disadvantages of
screening, which need to be discussed with the patient, include the very high rate of false-
 positive scans (24%), with the need for frequent follow-up scans and/or invasive
procedures. Other factors to be discussed include costs, risks of radiation exposure, impact
on smoking cessation efforts, and the psychosocial ramifications of identifying
radiographic abnormalities.

V. NON–SMALL-CELL LUNG CANCER

A. Histology
Until recently, the histologic subtype of NSCLC, while thought to influence the
presentation and natural history of disease, did not affect patient management. Due to
differences in both efficacy and safety, histologic designation now represents a primary
consideration in treatment selection. For instance, some adenocarcinoma variants, such
as AIS, which was formerly classified as bronchioloalveolar carcinoma,23 have a
predilection for younger, never-smoking women, and are frequently associated with
EGFR gene mutations and a high likelihood of response to EGFR inhibitors.
Pemetrexed, a multitargeted antifolate, has greater efficacy for the treatment of
nonsquamous tumors, presumably due to higher thymidylate synthase levels in squamous
cell cancers. Bevacizumab, a monoclonal antibody (MoAb) directed against vascular
endothelial growth factor (VEGF), is contraindicated in patients with squamous cell
tumors due to unacceptably high rates of life-threatening hemoptysis in early-phase
clinical trials. (However, the anti-VEGF receptor MoAb ramucirumab is indicated for
all NSCLC subtypes.) These histology-dependent safety and efficacy distinctions have
highlighted the importance of accurate pathologic classification.
B. Staging
The prognosis and treatment of NSCLCs are dependent primarily on stage of disease at
the time of diagnosis. Major changes in the staging of lung cancer were adopted in
2009. These changes are based on an analysis of 68,463 patients with NSCLC
worldwide; by contrast, the previous (1997 and 2002) editions of the TNM
classification of lung cancer were based on data from 5,319 patients in North America.
The 2010 TNM staging classification is outlined in the AJCC Cancer Staging Manual,
7th edition.24 Major changes include subclassification of T1 and T2 by tumor size,
reclassification of additional nodule(s) in the same lobe or another ipsilateral lobe, and
reclassification of malignant effusions as M1a. This reflects the similar prognosis and
treatment (typically chemotherapy alone) of patients with malignant effusions and
patients with distant disease. As before, a pleural or pericardial effusion is generally
considered malignant if it has any of the following characteristics: positive cytology,
exudative, or hemorrhagic. Survival based on the 2010 staging classification ranges
from 47% to 50% for stage I patients, 26% to 36% for stage II patients, 19% for stage
IIIA patients, 7% for stage IIIB patients to 2% for stage IV patients.25
C. Pretreatment evaluation
The diagnosis of lung cancer is usually made by bronchial biopsy or percutaneous
needle biopsy. A CT scan of the chest is necessary to evaluate the extent of the primary
 disease, mediastinal extension or lymphadenopathy, and the presence or absence of
other parenchymal nodules in patients in whom surgical resection is a consideration.
The upper abdomen is included to evaluate for hepatic or adrenal metastases. Nuclear
bone scans should be obtained for the patient with bone pain or an elevated calcium or
alkaline phosphatase level. Because the presence of mediastinal nodal metastases is a
key factor in determining tumor resectability, lymph node sampling by mediastinoscopy,
Chamberlain procedure (anterior mediastinotomy, which samples station 5 and 6 nodes
not accessible by mediastinoscopy), and/or endobronchial ultrasound is recommended
in most instances when there is not clear evidence of distant disease.
Positron emission tomography (PET), a metabolic imaging scan using
fluorodeoxyglucose (FDG), is a useful staging modality. PET scans are more sensitive
and specific than CT scans and could thus potentially save patients with advanced
disease, either within or outside of the chest, from unnecessary invasive procedures.
However, it is generally recommended that PET-positive mediastinal findings be
confirmed pathologically since the scan can be falsely positive in inflammatory
processes and falsely negative in lung tumors with low metabolic activity such as
bronchioloalveolar carcinoma or carcinoid tumors. Furthermore, due to high
background FDG uptake in the brain, PET-CT scans are generally not sufficient to
evaluate for brain metastases, and a head magnetic resonance imaging (MRI) should be
performed. PET scans are frequently performed in conjunction with CT imaging (PET-
CT scans) to assess for metastatic disease, or guide the surgeon toward particular
lymph nodes during mediastinoscopy. Randomized clinical trials have demonstrated that
use of PET-CT scans decreases the total number of thoracotomies and number of futile
thoracotomies performed. Population-based studies suggest that increasing use of PET-
CT scans may have resulted in stage shifting.26,27
Pulmonary function testing is generally recommended before surgery and, if severe
pulmonary disease is clinically apparent, before radiation therapy. Increased
postoperative morbidity is associated with a predicted postoperative 1-second forced
expiratory volume (FEV1) of less than 800 to 1,000 mL, a preoperative maximum
voluntary ventilation less than 35% of predicted, a carbon monoxide diffusing capacity
(DLCO) less than 60% of predicted, and an arterial oxygen pressure of less than 60 mm
Hg or a carbon dioxide pressure of more than 45 mm Hg.
D. Management of early-stage NSCLC
1. Stage I disease
Surgical resection is the mainstay of treatment for stage I NSCLC, with cure rates of
60% to 80%. Anatomic resection such as lobectomy is considered superior to
smaller procedures such as wedge resection. Exceptions may include smaller
peripheral AIS nodules that spread by lepidic (airway) growth rather than
hematogenous or lymphatic spread and may be adequately treated with more focal
excision.28 If not performed preoperatively, it is recommended that mediastinal
lymph nodes be sampled at the time of resection to complete staging.
 In patients with medical contraindications to surgery but with adequate
pulmonary function, conventional fractionated radiotherapy (e.g., 6,000 cGy in 30
fractions of 200 cGy each) results in cure in about 20% of patients. Advances in
imaging and radiation delivery have led to the use of stereotactic body radiation
therapy (SBRT) for lung tumors. With this technology, radiation delivery to
surrounding normal lung parenchyma is substantially less than that occurring with
conventional radiation. Thus, it is possible to give much higher, “ablative” radiation
doses over a small number of fractions (e.g., 20 Gy per fraction for three fractions).
To date, SBRT in early-stage NSCLC can achieve 5-year local control rates of 85%
to 90%.29–33 Clinical trials of stereotactic radiation for early-stage lung cancer in
both medically operable and inoperable patients are ongoing.
The rationale for adjuvant chemotherapy in patients with early-stage lung
cancer is based on the observation that distant metastases are the most common site
of failure following potentially curative surgery. Interest in this treatment strategy
grew after a 1995 meta-analysis of over 4,300 patients, in which those who received
cisplatin-based regimens had a survival benefit nearing statistical significance (p =
0.07).34 Since then, a number of randomized clinical trials have evaluated the role of
adjuvant chemotherapy following resection of early-stage NSCLC (see Table 7.1).
In a pooled analysis of five of these trials, the hazard ratio (HR) for death was 0.89
(95% confidence interval [CI], 0.82 to 0.96; p = 0.005), corresponding to a 5-year
absolute benefit of 5.4% from chemotherapy. Importantly, the benefit of
chemotherapy varied considerably by stage. For stage IA NSCLC, adjuvant
chemotherapy resulted in a trend toward worse survival (HR for death 1.40; 95%
CI, 0.95 to 2.06). For stage IB disease, the HR was 0.93 (95% CI, 0.78 to 1.10),
whereas the HR rate was 0.83 (95% CI, 0.73 to 0.95) for stage II disease.35
Similarly, in the CALGB 9633 trial of patients with stage IB disease randomized to
surgery alone or surgery followed by carboplatin-paclitaxel, only those patients with
tumors of more than or equal to 4 cm demonstrated a significant survival difference
in favor of adjuvant chemotherapy (HR, 0.69; 95% CI, 0.48 to 0.99; p = 0.04).36
Given these data, it seems reasonable to discuss the option of adjuvant platinum-
based doublet chemotherapy with good performance status (PS) patients with
completely resected stage IB disease, particularly those with tumors of more than or
equal to 4 cm. Additional studies are needed for stage IA disease before adjuvant
therapy can be routinely recommended for this group of patients. Recently, a meta-
analysis of individual patient data for more than 11,000 patients across 47 different
trials found a survival benefit (approximately 4% at 5 years) for adjuvant
chemotherapy regardless of whether this was in the context of radiation or not.37
Patients with resected stage I NSCLC are also at high risk for the development
of second lung cancers (about 2% to 3% per year). To date, however, secondary
prevention efforts have proven unsuccessful. Neither vitamin A nor its derivatives,
β-carotene or cis-retinoic acid, have been found to have any benefit in
 chemoprevention, and contrary to predictions, they may even be deleterious.38 A
recent phase III trial of selenium for secondary prevention was closed early when an
interim analysis showed no benefit.39

TABLE
Randomized Studies of Adjuvant Chemotherapy for Resected NSCLC
7.1

2. Stage II disease
Surgical resection is a standard component of the treatment of stage II NSCLC.
Patients with peripheral chest wall invasion (T3N0) should undergo resection of the
 involved ribs and underlying lung. Chest wall defects are then repaired with chest
wall musculature or surgical mesh and methylmethacrylate. Postoperative
radiotherapy is often given. Five-year survival rates as high as 50% have been
reported.
The role of adjuvant chemotherapy for resected stage II NSCLC is clearer than
for stage I disease. In the Adjuvant Navelbine International Trialist Association
(ANITA) trial,40 patients with stages IB to IIIA NSCLC were randomized to surgery
alone versus surgery followed by four cycles of cisplatin plus vinorelbine. Overall
survival (OS) was significantly improved at 5 years (51% vs. 43%), although the
survival benefit was restricted to patients with stages II and IIIA disease. In the
pooled analysis of cisplatin-based adjuvant chemotherapy trials, patients with stage
II NSCLC had a significant survival benefit (HR 0.83; 95% CI, 0.73 to 0.95).
Accordingly, adjuvant chemotherapy is generally recommended following complete
resection of stage II NSCLC.
Issues in the use of adjuvant therapy have also included identification of the
most appropriate drugs. Given the toxicity and tolerability of cisplatin, there was an
interest in substituting carboplatin for adjuvant treatment of NSCLC. On the basis of
available data, it is generally accepted that carboplatin should not routinely be used
in lieu of cisplatin, but can be considered in patients who would be considered high
risk for cisplatin-associated toxicities.
The International Adjuvant Lung Cancer, BR10, and ANITA trials all used
vinca alkaloids in combination with cisplatin.40–42 Given that there is no major
difference in chemotherapy doublets in advanced disease, many clinicians have
extrapolated that data in advanced disease to earlier-stage disease and are using
other “third-generation” drugs in combination with cisplatin (such as pemetrexed,
docetaxel, and gemcitabine), albeit without level I data.
Neoadjuvant (preoperative) chemotherapy has also been studied for resectable
NSCLC. Compared to adjuvant chemotherapy, it offers the potential advantages of
reducing tumor volume before surgery (which might simplify resection),
demonstrating in vivo chemosensitivity, addressing micrometastatic disease earlier,
and possibly being better tolerated. Although phase III trials comparing neoadjuvant
platinum-based regimens with surgery alone have demonstrated the feasibility of this
approach, there is no level I data showing a benefit for neoadjuvant compared to
adjuvant therapy. In addition, patients who undergo a pneumonectomy following
induction chemoradiation have a higher incidence of treatment-related deaths.43
a. Pancoast tumors
Pancoast tumors are upper lobe tumors that adjoin the brachial plexus and are
frequently associated with Horner syndrome or shoulder and arm pain; the latter
is due to rib destruction, involvement of the C8 or T1 nerve roots, or both. These
tumors are often treated with preoperative chemoradiation, surgery, and then
additional postoperative chemotherapy. With this approach, the preoperative
 chemoradiation facilitates resection in an area where neural structures might
otherwise limit surgical options. Five-year survival rates range from 25% to
50%.44
3. Locally advanced (stages IIIA and IIIB) disease
Treatment of locally advanced NSCLC is one of the most controversial issues in the
management of lung cancer. Interpretation of the results of clinical trials involving
patients with locally advanced disease has been clouded by a number of issues
including changing diagnostic techniques, different staging systems, and
heterogeneous patient populations that may have disease that ranges from “nonbulky”
stage IIIA (clinical N1 nodes, with microscopic N2 nodes discovered only at the
time of surgery or mediastinoscopy) to “bulky” N2 nodes (enlarged adenopathy
clearly visible on chest radiographs or multiple nodal level involvement) to clearly
inoperable stage IIIB disease.
a. Nonbulky stage IIIA disease
The optimal treatment for nonbulky stage IIIA generally consists of a local
approach (surgery or radiation therapy) plus a systemic treatment
(chemotherapy). Current investigational efforts are directed at identifying the
optimal combined-modality approach. Possibilities include surgery followed by
adjuvant chemotherapy, preoperative (neoadjuvant) chemotherapy followed by
surgery, chemotherapy plus radiation therapy (either concurrent or sequential),
or a trimodality approach.
The potential benefit of adding surgery to combined chemoradiation for
stage IIIA NSCLC has been evaluated in a 2009 randomized phase III intergroup
trial.43 In this study, 396 patients with stage T1–3N2M0 NSCLC were
randomized to concurrent chemoradiation (45 Gy) with cisplatin-etoposide
followed by either surgical resection or continuation of radiation therapy to 61
Gy total, followed by additional cycles of chemotherapy. Although progression-
free survival (PFS) was significantly longer in the surgery arm (12.8 vs. 10.5
months; p = 0.02), there was no significant difference in OS (23.6 vs. 22.2
months; p = 0.24). There were greater treatment-related mortalities in the
surgery arm as compared to the chemoradiation alone arm (8% vs. 2%),
particularly for patients undergoing a pneumonectomy.
Several studies have shown, in subset analyses, that those patients receiving
neoadjuvant therapy who subsequently have their N2 nodes “cleared” with
preoperative therapy do better than those who do not. As of this writing, there is
no level I evidence to recommend neoadjuvant chemotherapy over adjuvant
chemotherapy, although several theoretical reasons for doing so include the fact
that patients are more likely to tolerate preoperative chemotherapy over
postoperative chemotherapy.
Occasionally, despite preoperative staging, patients thought to have stage I
or II disease are found to have N2 nodal involvement at the time of surgery. For
 these stage III patients, postoperative radiation therapy (PORT; 50 to 54 Gy) may
be considered for fit patients, preferably after completion of adjuvant
chemotherapy, based on retrospective and nonrandomized studies demonstrating
benefit. Currently, PORT is not recommended for patients with less than N2
nodal involvement.45
b. Bulky stage IIIA (N2) and stage IIIB
Bulky stages IIIA and IIIB tumors are generally considered unresectable, with
treatment consisting of combined chemoradiation in medically fit patients.
1) Chemotherapy plus radiation therapy. Chemotherapy plus radiotherapy is
the treatment of choice for patients with bulky or inoperable stage IIIA or IIIB
disease. Numerous randomized studies have demonstrated an improvement in
median and long-term survival with chemotherapy plus radiation therapy
versus radiation therapy alone. Active areas of investigation include choice
of chemotherapy, fractionation, and treatment fields.
A phase III Japanese trial reported a 3-month survival advantage with
concurrent chemoradiation over a sequential approach.46 A randomized
Radiation Therapy Oncology Group trial demonstrated an OS benefit for
concurrent cisplatin and vinblastine with daily radiation over sequential
chemoradiation, albeit with more acute toxicities, making concurrent
chemoradiation therapy the treatment of choice for good PS patients.47
Chemotherapy can be given in full “systemic” doses with radiotherapy, in
weekly “radiosensitizing” doses, or a combination of both. One of the most
commonly used chemotherapy regimens for stage III NSCLC is carboplatin in
combination with paclitaxel (Table 7.2). Although single-agent weekly
carboplatin alone has not resulted in a survival benefit when given with
radiotherapy, weekly doses of paclitaxel at 50 mg/m2 and carboplatin area
under the curve (AUC) 2 with concurrent radiation confer a similar benefit to
concurrent radiation with cisplatin and vinblastine in randomized phase II
studies.48,49 Generally, concurrent therapy is followed by two cycles of full-
dose carboplatin AUC 6 plus paclitaxel at 200 mg/m2 every 21 days to treat
micrometastatic disease. By contrast, with concurrent radiation therapy and
commonly used cisplatin-etoposide chemotherapy regimens, drug doses
during radiation therapy are considered “systemic” and may not require
additional chemotherapy after radiation therapy is completed. No survival
benefit has been shown for “consolidation” therapy, maintenance therapy
with EGFR inhibitors, or radiotherapy doses higher than 6,000 cGy.50–52
 TABLE
Chemotherapy Regimens for Concurrent Chemoradiation for Stage III NSCLC
7.2

4. Stage IV disease
Chemotherapy improves survival in patients with metastatic NSCLC (about 10% 1-
year survival rate in untreated patients vs. 30% to 35% 1-year survival rate with
treatment). The principal factors predicting response to chemotherapy and survival
are PS and extent of disease. Patients with a poor PS (Eastern Cooperative
Oncology Group [ECOG] PS of 2 to 4) are less likely to respond to treatment and
will tolerate the therapy poorly, although recent retrospective subset analysis has
suggested that PS2 patients may also enjoy a modest benefit in survival with
treatment. Favorable prognostic factors include female sex, absence of bone or liver
metastases, and absence of weight loss.53 Total radiographic burden of disease has
also been associated with survival.54
a. First-line chemotherapy
Systemic treatment for patients with metastatic NSCLC and adequate PS (ECOG,
0 to 1) generally includes platinum-based doublet chemotherapy. A meta-
analysis of large randomized trials indicated that there is a small but significant
survival advantage with platinum-based therapy compared with best supportive
care.34 Whereas best supportive care resulted in median survival rates of 4 to 5
months and 1-year survival rates of 5% to 10%, current third-generation
regimens of platinums combined with paclitaxel (and albumin-bound paclitaxel)
and docetaxel, gemcitabine, vinorelbine, and pemetrexed have yielded median
survivals of 8 to 9 months and 1-year survivals of 35% to 40%. In addition,
randomized studies have shown an improvement in symptoms and quality of life
 compared with patients treated with best supportive care.55–58
b. Choice of chemotherapy
The common chemotherapy regimens for advanced NSCLC are shown in Table
7.3. Historically, randomized studies have failed to show a major advantage of
one new doublet regimen over another.55,57,59 More recently, however, certain
agents have been restricted to specific histologies. For instance, pemetrexed, a
multitargeted antifolate, has greater efficacy for the treatment of nonsquamous
tumors,56 presumably due to higher thymidylate synthase levels in squamous cell
cancers; pemetrexed is approved only for nonsquamous NSCLC in all settings
(first-line, maintenance, and second-line). Bevacizumab, a MoAb directed
against VEGF, is contraindicated in patients with squamous cell tumors due to
unacceptably high rates of life-threatening hemoptysis in early-phase clinical
trials.60
Although a direct comparison of cisplatin- and carboplatin-based therapies
is limited, meta-analyses have suggested that cisplatin may have a small benefit
in terms of survival over carboplatin,61 albeit with a different toxicity profile. A
more recent Cochrane database meta-analysis demonstrates increased response
rate with cisplatin, depending on the second agent in the doublet, but no
difference in OS.62 Any small difference may be of limited clinical consequence
for patients with metastatic disease, it may be more important in the adjuvant
setting, where cure is the goal.

TABLE
Common Frontline Regimens for Metastatic NSCLC
7.3
Non-Squamous Histology Only
Carboplatin-paclitaxel plus bevacizumab
Carboplatin AUC 6 on day 1
Paclitaxel* 200 mg/m2 IV on day 1 over 3 hours
Repeat cycle every 3 weeks
Bevacizumab 15 mg/kg IV every 3 weeks until progression
Cisplatin/carboplatin plus pemetrexed
Cisplatin 75 mg/m2 IV on day 1
Pemetrexed † 500 mg/m2 on day 1
Repeat each cycle every 3 weeks
or
Carboplatin AUC 6 on day 1
Pemetrexed † 500 mg/m2 on day 1
Repeat each cycle every 3 weeks
Squamous or Non-Squamous Histology
Cisplatin/carboplatin plus gemcitabine
Cisplatin 100 mg/m2 IV on day 1
Gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15
Repeat each cycle every 4 weeks
or
Cisplatin 80 mg/m2 IV on day 1
Gemcitabine 1,250 mg/m2 IV on days 1 and 8
Repeat each cycle every 3 weeks
or
Carboplatin AUC 5 on day 1
Gemcitabine 1,000 mg/m2 IV on days 1 and 8
Repeat each cycle every 3 weeks
Cisplatin/carboplatin plus docetaxel
Cisplatin 75 mg/m2 IV on day 1
Docetaxel 75 mg/m2 IV on day 1
Repeat each cycle every 3 weeks
or
Carboplatin AUC 6 on day 1
Docetaxel 75 mg/m2 IV on day 1
Repeat each cycle every 3 weeks
EGFR and ALK tyrosine kinase inhibitors
150 mg by mouth daily: is only used as frontline therapy for patients
Erlotinib
with sensitive EGFR mutations
Afatinib 40 mg by mouth daily: only in patients with sensitive EGFR mutations
250 mg by mouth twice daily: only in patients with ALK or ROS1
Crizotinib
rearrangements

*Albumin-bound paclitaxel (nab-paclitaxel) may be used in place of paclitaxel or docetaxel.

†To reduce toxicity rates, patients treated with pemetrexed should receive (1) vitamin B 1,000 μg intramuscularly every 9
12
weeks during treatment starting 1 week before first pemetrexed dose and (2) folic acid 400–1,000 μg by mouth daily starting 1
week before first pemetrexed dose and continuing until 21 days after the last pemetrexed dose.
AUC, area under the curve; IV, intravenously; NSCLC, non–small-cell lung cancer.

c. Duration of therapy/maintenance therapy

Randomized studies failed to show a survival difference with “prolonged” (more
than six) cycles of chemotherapy compared with a fewer (four to six) number of
cycles and so chemotherapy was typically stopped after four to six cycles. In
recent years, however, maintenance therapy has demonstrated PFS and OS
benefits. Continuation maintenance therapy refers to continuation of a component
of initial therapy (as with the ongoing administration of pemetrexed,
bevacizumab, or cetuximab following completion of a maximum of six cycles of
combination chemotherapy). Switch maintenance therapy refers to the immediate
introduction of another agent on completion of first-line chemotherapy.
Continuation of pemetrexed in patients with stable disease after four cycles
of a platinum doublet with pemetrexed has demonstrated OS benefits.63 Other
 maintenance strategies include bevacizumab, bevacizumab plus pemetrexed,
cetuximab, and gemcitabine, although these approaches have not demonstrated
benefits beyond PFS.64–69 Switch maintenance therapy options include
pemetrexed (OS and PFS benefit),70 erlotinib71 (OS and PFS benefit), and
docetaxel (PFS benefit).72
Although a substantial proportion of thoracic oncologists have adopted
maintenance chemotherapy, a number of questions remain. First, how
maintenance therapy fits into the increasingly complex overall treatment
paradigm for advanced NSCLC is not clear, as some first-line regimens (such as
those incorporating bevacizumab or cetuximab) continue treatment until
progression. Second, it is not clear whether these studies demonstrate a benefit
from early use of docetaxel or pemetrexed, or rather a benefit from exposure—
regardless of timing—to these drugs.
d. Nonplatinum-based regimens
Given the toxicities associated with platinum-based chemotherapy, particularly
cisplatin, there is considerable interest in combining two nonplatinum drugs. The
majority of recent randomized trials have failed to show a significant difference
in survival with platinum regimens compared with nonplatinum-based regimens,
although the toxicity profile is different.
e. Patients with poor performance status
Patients with ECOG PS2 may be treated with single-agent cytotoxic
chemotherapy. The most commonly studied agents include vinorelbine and the
taxanes. Patients with ECOG PS3–4 are generally not offered chemotherapy. An
exception is a patient with a tumor harboring an activating EGFR mutation or
another actionable molecular alteration that may respond rapidly and
dramatically to well-tolerated molecularly targeted treatments (see subsequent
discussion). For such a patient, an EGFR TKI could result in a dramatic
response without conveying substantial toxicity.
f. Oligometastatic disease
In certain circumstances, definitive local therapy of both thoracic disease and a
metastatic site may be considered. In patients with controlled disease outside of
the brain who have an isolated cerebral metastasis in a resectable area,
resection followed by whole brain radiation is superior to whole brain
radiotherapy alone. This oligometastatic approach appears most beneficial in
patients with stage I thoracic disease, where survival approximates that of stage
I patients without brain metastases. In patients with locally advanced thoracic
disease, the benefit of metastasectomy is less clear. Stereotactic radiosurgery is
another option for stage IV patients with limited disease burden overall and
prolongs PFS and OS in carefully selected patients.73 Adrenalectomy for an
isolated adrenal metastasis may be associated with up to 25% 5-year survival.
Outcomes appear to be superior for patients with a metachronous rather than a
 synchronous metastasis.74
g. Second-line cytotoxic chemotherapy
Docetaxel and pemetrexed (nonsquamous tumors) are currently approved by the
U.S. Food and Drug Administration (FDA) for second-line monotherapy for
patients with metastatic NSCLC.
1) Docetaxel
There have been two randomized trials evaluating second-line docetaxel
versus best supportive care in patients who have failed first-line therapy.
Docetaxel at a dose of 75 mg/m2 every 3 weeks significantly prolongs
survival in comparison with best supportive care and, in comparison with
either vinorelbine or ifosfamide, improves time to progression and 1-year
survival. Moreover, it also improves quality of life. It was noted that
previous paclitaxel exposure did not affect patients’ response to docetaxel,
suggesting no cross-resistance between the two taxane agents.72,745
2) Pemetrexed
Pemetrexed has similar antitumor activity as docetaxel in the second-line
setting but with less toxicity. In a randomized trial, patients were treated with
pemetrexed at 500 mg/m2 or docetaxel at 75 mg/m2 every 3 weeks. Overall
response rates were similar (9.1% vs. 8.8% for pemetrexed and docetaxel,
respectively) with no differences in median survival (8.3 vs. 7.9 months for
pemetrexed and docetaxel, respectively). Docetaxel was associated with
higher rates of neutropenia, neutropenic fever, and hospitalization due to
neutropenic events or other drug-related adverse events as compared to
pemetrexed. A post hoc analysis by histology demonstrated a selective
benefit for pemetrexed in nonsquamous histology.75
5. Other approaches
a. Inhibitors of angiogenesis
Inhibition of angiogenesis is based on the observations that neovascularization
occurs in tumor tissues and rarely in other physiologic processes except wound
healing. Although many antiangiogenesis agents have been studied in lung cancer,
including several multitargeted kinase inhibitors, only the anti-VEGF MoAb
bevacizumab and the anti-VEGFR MoAb ramucirumab have been shown to have
survival benefit in NSCLC.
Bevacizumab has been evaluated in a randomized ECOG trial in
combination with standard cytotoxic chemotherapy for advanced NSCLC, in
which 878 chemonaïve patients with advanced NSCLC were randomized to
receive carboplatin and paclitaxel with or without bevacizumab (15 mg/kg)
every 3 weeks for six cycles. Bevacizumab was continued for up to 1 year in
patients with nonprogressing disease. Patients with squamous cell histology
were excluded on the basis of phase II data showing increased hemorrhagic
events as a complication with bevacizumab therapy. The study demonstrated an
 improvement in median survival (12.3 vs. 10.3 months; p < 0.001), overall
response rates (35% vs. 15%; p < 0.001), and PFS (6.2 vs. 4.5 months; p <
0.001), favoring the bevacizumab arm.60,76 A European study showed a small
improvement in PFS with 7.5 mg/kg or 15 mg/kg of bevacizumab plus
gemcitabine and cisplatin, compared to gemcitabine plus cisplatin alone but OS
was not improved.77
Ramucirumab is an anti-VEGFR2 MoAb recently approved in
combination with docetaxel for stage IV NSCLC following platinum-based
therapy. The phase III REVEL trial demonstrated an OS benefit (10.5 vs. 9.1
months; p = 0.023) from adding ramucirumab to docetaxel in the second-line for
stage IV NSCLC.78 Trials are underway examining ramucirumab with
chemotherapy in the first-line setting. Unlike bevacizumab, it is approved for use
in squamous cell NSCLC. As with bevacizumab, risks include severe
hemorrhage and gastrointestinal fistulas and perforation, as well as hypertension.
b. Immunotherapy
Immune “checkpoints” are proteins that block the immune response by inhibiting
T-cell activation, thus helping control the balance of costimulatory and
coinhibitory signals that have essential roles in maintaining self-tolerance. The
immune checkpoint inhibitors intensify the antitumor immune response by
disrupting these negative feedback signals, thus releasing the breaks on the
immune system, allowing the T-cells to “attack” the cancer. For example, binding
of the protein called programmed death ligand 1 (PD-L1), which is expressed on
cancer cells, to its receptor on T-cells (PD-1) results in dampening of the
immune response, whereas disrupting it through the use of MoAbs activates T-
cells. Similarly, binding of a MoAb to cytotoxic T lymphocyte antigen (CTLA-4)
on the surface of T-cells also “releases the brakes” on T-cells, freeing the
immune system to recognize and attack cancer cells.79
Melanoma research has been at the forefront of immune checkpoint
inhibitors, and the FDA approved ipilimumab, an anti–cytotoxic T-lymphocyte–
associated protein 4 (CTLA-4) antibody, in 2011 and nivolumab, an anti–
programmed death 1 (PD-1) antibody, in 2014 for the treatment of metastatic
melanoma. These agents have been intensely studied in other tumor types
including in NSCLC. A phase II, multisite, single-arm trial (CheckMate 063) of
nivolumab, a PD-1 inhibitor, at 3 mg/kg IV every 2 weeks demonstrated an
objective response in 14.5% of patients and stable disease in 30% of the
patients. Grade III to IV adverse events included fatigue, diarrhea, and
pneumonitis.80 The CheckMate 017 study indicates improved OS (9.2 vs. 6.0
months; p = 0.00025) for nivolumab compared to docetaxel in metastatic
squamous NSCLC following prior platinum-based treatment.81 In March 2015,
nivolumab was approved for use in metastatic squamous NSCLC after
progression on platinum-based therapy. It has since been approved for use in
 nonsquamous NSCLC as well based on the CheckMate 057 trial.82 It is not yet
clear which biomarker, if any, can be used to predict whether a patient is likely
to respond to these drugs, although a preliminary study involving
pembrolizumab, a PD-L1 antibody that has also been recently approved for use
in NSCLC, observed a correlation between PD-L1 expression on the tumor with
response and survival.83 Because they activate the immune system,
immunotherapy drugs are generally contraindicated in patients with active
autoimmune disease. Additionally, patients on these agents need to be monitored
for the development of immune-mediated events such as pneumonitis,
hypothyroidism, and hypophysitis. Management of these complications includes
steroids for inflammatory events and hormone replacement for the endocrine
events.
c. Drugs aimed at targeting specific mutations
1) Inhibitors of EGFR
EGFR, also known as human epidermal growth factor receptor 1 (HER1) or
ErbB1, is a transmembrane receptor tyrosine kinase. On ligand binding,
receptor subunits dimerize, resulting in autophosphorylation of intracellular
tyrosine residues and initiation of a signal transduction cascade resulting in
cellular proliferation, resistance to apoptosis, cellular invasion, metastasis,
and angiogenesis.7,84
The primary toxicities of EGFR TKIs are acneiform rash and diarrhea,
reflecting the expression of EGFR in normal tissues.
Earlier clinical trials failed to demonstrate a survival benefit with the
EGFR TKIs erlotinib or gefitinib. However, in the first-line Iressa Pan-Asia
Study (IPASS),85 in which over 1,200 previously untreated nonsmokers or
former light smokers in East Asia who had advanced adenocarcinoma
NSCLC were randomized to gefitinib at 250 mg orally daily or carboplatin-
paclitaxel, PFS was superior in the gefitinib arm (HR 0.74; p < 0.001), with
12-month PFS rates 25% for gefitinib and 7% for carboplatin-paclitaxel.
Among those patients whose tumors harbored EGFR mutations, PFS was
significantly longer with gefitinib (HR 0.48; p < 0.001); by contrast, in the
mutation-negative group, gefitinib resulted in significantly shorter PFS
compared with carboplatin-paclitaxel (HR 2.85; p < 0.001). There was no
difference in OS, presumably due to receipt of EGFR TKIs after disease
progression among patients with EGFR mutant cancers.86 Studies in
populations selected for tumors containing EGFR mutations have
demonstrated that patients harboring certain EGFR mutations do benefit from
erlotinib or gefitinib.87
2) EGFR TKIs
a) Gefitinib was granted FDA-approval for previously treated advanced
NSCLC based on the outcomes of phase II studies. However, the
 subsequent phase III Iressa Survival Evaluation in Lung Cancer (ISEL)
failed to demonstrate a significant survival benefit compared to
placebo.88 Following the negative survival result, gefitinib was relabeled
for use restricted to patients already receiving and benefiting from the
drug or patients participating in clinical trials. This essentially removed
the drug from the American and European markets, although it remained
approved and widely used in Asia. In July 2015, it again gained FDA
approval for first-line use in metastatic NSCLC.
b) Erlotinib is a similar orally available EGFR/TKI. Single-agent treatment
with erlotinib for previously treated advanced NSCLC was evaluated in
the National Cancer Institute of Canada BR21 trial. This study
randomized 731 patients with stage IIIB or IV NSCLC who had failed
one or two prior treatment regimens in a 2:1 ratio to receive erlotinib at
150 mg orally daily versus placebo. The overall response rate for
erlotinib was 9% versus <1% for placebo (p < 0.001). Stable disease
was observed in 35% of patients on the erlotinib arm as compared to
27% of patients on placebo. In contrast to the results with gefitinib, there
was a significant improvement in PFS (2.2 vs. 1.8 months; p < 0.001) and
OS (6.7 vs. 4.7 months; p < 0.001), in favor of erlotinib. While all
patient subtypes in BR21 derived a survival benefit, the HR of 0.4 for
never smokers was statistically significantly different from the HR of 0.9
for smokers (p < 0.001).89 The OPTIMAL randomized phase III trial
compared erlotinib to standard chemotherapy in stage IIIB or IV NSCLC
harboring either the exon 19 deletion or exon 21 L858R point mutation.
This multicenter Chinese trial demonstrated a median PFS benefit of
approximately 8 months in the erlotinib arm (p < 0. 0001).90
The EURTAC trial was a randomized, multicenter, European, phase
III trial of 173 patients to examine erlotinib versus standard
chemotherapy for first-line treatment of advanced NSCLC with activating
mutations (exon 19 deletion or L858R mutation in exon 21). The results
demonstrated a 4- to 5-month PFS benefit in the erlotinib arm and
objective response rates were 65% in the erlotinib arm compared with
16% in the chemotherapy arm.91,92 On the basis of these trials, erlotinib
is approved in the first line for advanced, recurrent, or metastatic
NSCLC containing activating EGFR mutations and in second line and
beyond for advanced or metastatic unselected NSCLC.
c) Afatinib is a small-molecule TKI that irreversibly blocks ErbB family
members including EGFR, HER2, and ErbB4 and that gained FDA-
approval in 2013. The LUX-Lung-3 trial was a randomized phase III
study comparing first-line afatinib to cisplatin/pemetrexed in patient with
stage IIIB/IV NSCLC with EGFR-activating mutations. PFS was the
 primary endpoint and among patients with either the EGFR exon 19
deletion or L858R EGFR mutation, the median PFS was 13.6 months
with afatinib compared to 6.9 months for the cisplatin/pemetrexed arm (p
= 0.001).10 It is currently approved in the first-line setting for patients
with metastatic NSCLC that harbor EGFR-activating mutations and is
also used in patients in the second-line setting, similar to erlotinib.
3) EGFR monoclonal antibodies
A phase III clinical trial of cisplatin-vinorelbine with or without the anti-
EGFR antibody cetuximab in patients with EGFR-expressing NSCLC (80%
to 90% of cases) demonstrated a modest but statistically significant increase
in survival (11.3 vs. 10.1 months; p = 0.04).69 Whether the discrepant results
with EGFR TKIs or an anti-EGFR antibody combined with chemotherapy
reflect differences in drug efficacy, study design, or other factors is not clear.
Cetuximab is not widely used for this indication in the United States.
Clinical parameters that appear to predict response to EGFR TKIs
include never-smoking history, East Asian ethnicity, adenocarcinoma
histology (particularly tumors with bronchioloalveolar features), and female
gender. Molecular analysis of tumor specimens from individuals with these
characteristics has revealed high rates of activating mutations in the EGFR
tyrosine kinase domain. These mutations hyperactivate the EGFR tyrosine
kinase, rendering cancer cells highly dependent on EGFR oncogenic
pathways and thus exquisitely sensitive to EGFR inhibition. Among patients
with “classic” EGFR mutations (exon 19 in-frame deletions of amino acids
747 to 750 and exon 21 L858R substitutions that account for more than 90%
of EGFR mutations),11 response rates to EGFR TKIs exceed 60% and median
survival exceeds 2 years. EGFR amplification and gene copy number
(determined by fluorescence in situ hybridization) and EGFR protein
expression, determined by immunohistochemistry, are not as strongly
correlated with outcomes. Additionally, development of acneiform rash has
been associated with improved survival for both EGFR TKIs and anti-EGFR
MoAbs in multiple disease settings, including colorectal cancer, pancreatic
cancer, and NSCLC.
Because of its impact on PFS and OS in the setting of EGFR TKIs,
EGFR mutation testing is recommended in stage IV patients with
nonsquamous NSCLC or NSCLC, not otherwise specified (NOS).
Additionally, EGFR testing should be considered in never-smoking patients
with squamous histology or in patients with squamous histology based on a
small biopsy specimen only. The prevalence of activating EGFR mutations in
NSCLC adenocarcinoma is estimated to be 50% in the Asian population93
and 10% to 15% in Western populations.94,95
With the increasing use of EGFR TKIs in clinical practice, data on tumor
 resistance to these agents are accumulating. Median tumor response to these
agents averages 6 to 12 months before resistance develops. The T790M
mutation in exon 20 is found in about half of patients with acquired EGFR
TKI resistance.11 The T790M mutation has rarely been identified in
pretreatment samples and, interestingly, T790M germ line mutations have
been identified in hereditary NSCLC.11,96 Clinical trials of “third-generation”
TKIs active on T790M-containing tumors are underway and have started to
be FDA-approved.12 Another main mechanism of acquired resistance to the
EGFR TKIs is through MET pathway amplification in approximately 22% of
cases,11,97 and small-molecule MET inhibitors are being explored in trials
with this context in mind. Other mechanisms include mutations and
amplifications in the PI3K/AKT/mTOR pathway, another downstream
pathway of EGFR, and SCLC phenotypic transformation.97
4) Inhibitors of ALK
About 3% to 5% of NSCLC tumors have rearrangements in the ALK gene
with some overlap in the demographics with NSCLC patients with EGFR
mutations (younger, never smokers). Crizotinib is an oral small-molecule
TKI, active against ALK, ROS1, and MET, which is approved for the
treatment of advanced NSCLC harboring ALK rearrangements. Clinical
studies have demonstrated response rates of 60% to 75%, and the recent
phase III trial comparing first-line crizotinib to cisplatin (or carboplatin) plus
pemetrexed in advanced, ALK-positive NSCLC demonstrated a PFS of 10.9
months with crizotinib compared to 7.0 months with chemotherapy (p <
0.001).98,99 Toxicities of ALK inhibitors include visual disturbances,
neuropathy, edema, and increased serum transaminases. There is also a rare
(<1%) incidence of fatal hepatotoxicity associated with ALK inhibitors. As
with other targeted therapies, resistance typically develops within the first
year of treatment. The central nervous system (CNS) is a frequent site of
disease recurrence during ALK inhibitor therapy and may be due to lower
levels of crizotinib in the CSF.100 Molecular mechanisms of resistance
include amplification of the ALK fusion gene and also secondary mutations in
the ALK kinase domain. Additionally, alterations (mutations, amplification,
or phosphorylation) that activate other oncogenic drivers such as K-RAS, c-
KIT, and EGFR also lead to resistance to ALK inhibition. Ceritinib is a
second-generation ALK inhibitor that has recently been approved in ALK-
positive patients who have either progressed on crizotinib or are intolerant to
it. This approval is based on a phase I study demonstrating response rates of
greater than 50% even in patients who had been previously treated with
crizotinib.14Additionally, more recently, alectinib was granted FDA
accelerated approval for patients with advanced ALK-positive NSCLC
 whose disease has progressed on crizotinib.101,102

VI. SMALL-CELL LUNG CANCER

SCLC differs from NSCLC in a number of important ways. First, it has a more rapid
clinical course and natural history, with the rapid development of metastases, symptoms,
and death. Untreated, the median survival time for patients with local disease is typically
12 to 15 weeks and for those with advanced disease 6 to 9 weeks. Second, it exhibits
features of neuroendocrine differentiation in many patients (which may be distinguishable
histopathologically) and is more commonly associated with paraneoplastic syndromes.
Third, unlike NSCLC, SCLC is exquisitely sensitive to both chemotherapy and
radiotherapy, although resistant disease often develops.103 Because of the rapid
development of distant disease and its extreme sensitivity to the cytotoxic effects of
chemotherapy, this mode of therapy forms the backbone of treatment for this disease,
irrespective of stage.
A. Staging
Although SCLC has a propensity to metastasize quickly and micrometastatic disease is
presumed to be present in all patients at the time of diagnosis, this disease is usually
classified into either a local or an extensive stage. Limited-stage disease is typically
defined as stage I, II, or III disease (based on TNM staging) that can be encompassed
within one radiation port, usually considered limited to the hemithorax and to regional
nodes, including mediastinal and ipsilateral supraclavicular nodes. Extensive-stage
disease is usually defined as disease that has spread outside those areas (stage IV by
TNM staging).
B. Pretreatment evaluation
Common sites of metastases for SCLC include the brain, liver, bone marrow, bone, and
CNS. For this reason, a complete staging workup has traditionally consisted of a
complete blood cell count; liver function tests; CT or MRI of the brain; CT of the chest
and abdomen; bone scan; and bone marrow aspiration and biopsy. As for NSCLC, PET-
CT scans are now routinely employed in the initial staging of SCLC and may be
considered in place of the CT chest/abdomen and bone scan. However, this complete
staging workup need not be undertaken unless the patient is a candidate for combined-
modality treatment with chest radiation and chemotherapy, the patient is being evaluated
for a clinical study, or the information is helpful for prognostic reasons. If the patient is
not a candidate for combined-modality treatment or a clinical study, stopping the staging
at the first evidence of extensive-stage disease is usually appropriate. Given that
isolated bone marrow metastases are rare, bone marrow biopsies and aspirates are not
usually done.
C. Prognostic factors
As in NSCLC, the major pretreatment prognostic factors are stage, PS, and bulky
disease. Hepatic metastases also confer a poorer prognosis. Due to the chemosensitivity
of SCLC, if a patient’s initial poor PS is due to the underlying malignancy, these
 symptoms often disappear quickly with treatment, resulting in a net improvement in
quality of life. However, major organ dysfunction from nonmalignant causes often
results in an inability of the patient to tolerate chemotherapy.
D. Therapy
1. Combination chemotherapeutic regimens
A number of combination chemotherapeutic regimens are available for SCLC (Table
7.4). No clear survival advantage has been consistently demonstrated for any one
regimen over another. With these chemotherapy regimens, overall response rates of
75% to 90% and complete response rates of 50% for localized disease can be
anticipated. For extensive-stage disease, overall response rates of about 75% and
complete response rates of 25% are common. Despite these high response rates,
however, the median survival time remains about 14 to 20 months for limited- stage
disease and 8 to 9 months for extensive-stage disease. Less than 5% of patients with
extensive-stage disease survive more than 2 years.103–105
At present, either cisplatin or carboplatin together with etoposide are the
standard of care in North America for the treatment of SCLC. Generally, cisplatin is
preferred if given with thoracic radiation for limited-stage disease. For extensive-
stage disease, both cisplatin and carboplatin are widely used.

TABLE
Chemotherapy Regimens for SCLC
7.4
Cisplatin-Based
Cisplatin 60 mg/m2 IV on day 1
Etoposide 120 mg/m2 IV on days 1–3 or
120 mg/m2 by mouth twice a day on days 1–3
or
Cisplatin 25 mg/m2 IV on days 1–3
Etoposide 100 mg/m2 IV on days 1–3
Repeat cycle every 3 weeks
Carboplatin-Based
Carboplatin AUC 5–6 on day 1

Etoposide 100 mg/m2 IV on days 1–3

IV, intravenously; SCLC, small-cell lung cancer.

2. Dose intensity
A dose intensity meta-analysis of chemotherapy in SCLC, which evaluated doses not
requiring bone marrow transplantation support, showed no consistent correlation
between dose intensity and outcome. There have been several phase I and II clinical
trials evaluating the role of marrow-ablative doses of chemotherapy with subsequent
 progenitor cell replacement (e.g., autologous bone marrow transplantation) with
disappointing survival results. In a randomized phase III study, when compared with
conventional-dose chemotherapy, a high-dose regimen with stem cell support
prolonged relapse-free survival but not OS.106–108
3. Duration of therapy
Most randomized studies do not show a survival benefit for prolonged
administration of chemotherapy. Several studies have demonstrated no survival
benefit of prolonged first-line treatment over treatment on relapse. The optimal
duration of treatment for extensive-stage SCLC (ES-SCLC) is four to six cycles and
for limited-stage SCLC (LS-SCLC), four cycles is considered optimal.103
4. Second-line therapy
No curative regimens for patients with recurrent disease have been identified. The
only drug approved for second-line therapy of SCLC is topotecan, which has a 20%
to 40% response rate in patients with sensitive SCLC (those patients who relapsed 2
to 3 or more months after their first-line therapy), with a median survival of 22 to 27
weeks. Other possible options for patients with sensitive disease include oral
etoposide, irinotecan, taxanes, vinorelbine, gemcitabine, ifosfamide, temozolomide,
the combination of cyclophosphamide, doxorubicin, and vincristine, or a return to
the first treatment regimen. For patients with refractory disease (progressed through
or within 3 months of completion of first-line therapy), the response rate in phase II
studies is only between 3% and 11%, and median survival is about 20 weeks.109–111
5. Chemotherapy plus chest irradiation. Numerous studies combining chemotherapy
and thoracic radiation therapy have been performed in patients with LS-SCLC.
Conflicting results have been attributed to differences in chemotherapy regimens and
different schedules integrating chemotherapy and thoracic radiation (concurrent,
sequential, and “sandwich” approach). Two meta-analyses concluded that thoracic
irradiation does result in a small but significant improvement in survival and major
control of the disease in the chest, although no conclusions could be made regarding
the optimal sequencing of chemotherapy and thoracic radiation.112,113 In one
randomized study, twice-daily hyperfractionated radiation was compared with a
once-daily schedule; both were given concurrently with four cycles of cisplatin and
etoposide. Survival was significantly higher with the twice-daily regimen (median
survival of 23 vs. 19 months, 5-year survival of 26% vs. 16%), albeit at the expense
of more grade III esophagitis.114 In another randomized trial, early administration of
thoracic irradiation in the combined-modality therapy of limited-stage SCLC was
superior to late or consolidative thoracic irradiation.115 These data suggest that
patients with good PS and with limited disease should receive concurrent
chemoradiation. A cooperative group study is ongoing to comparing higher doses of
radiation with the twice-daily fractionation schedule.
For patients with extensive-stage disease who have complete response to
chemotherapy at extrathoracic disease sites, consolidative chest radiation therapy
 may be considered. In a randomized study, patients who had a complete
extrathoracic response and a partial or complete thoracic response after three cycles
of cisplatin-etoposide were randomized to either (1) 54 Gy thoracic radiation
followed by two additional cycles of cisplatin-etoposide or (2) four additional
cycles of cisplatin-etoposide. Patients who received radiation had a significantly
longer OS (17 vs. 11 months; p = 0.04).116 A single-arm trial examined 32 ES-SCLC
patients who had achieved an objective response to chemotherapy and who went on
to receive both prophylactic cranial irradiation (PCI) and consolidation chest
radiotherapy. Of the 32 treated patients, 16 had disease recurrence in the chest, 5 of
which were symptomatic. OS was 8.3 months.117 More recently, the results of a
randomized phase III trial demonstrated a 2-year OS benefit (13% vs. 3%; p =
0.004) for thoracic radiation for persistent thoracic disease following chemotherapy
and PCI.118
6. Prophylactic cranial irradiation
Given the propensity of SCLC to metastasize to the brain and the resultant morbidity
of this event, prophylactic cranial irradiation has been offered to patients with
limited-stage disease who have an excellent response to chemoradiation. In a meta-
analysis of seven trials, prophylactic cranial irradiation decreased the risk of brain
metastasis, prolonged disease-free survival, and significantly increased 3-year OS,
with a net gain of 5.4%.119 A randomized trial of patients with ES-SCLC who had
had a response to chemotherapy were randomized to prophylactic cranial irradiation
or observation. The trial met its primary endpoint with a reduced rate of
symptomatic brain metastasis (HR 0.27; p < 0.001). Furthermore, prophylactic
cranial irradiation significantly extended disease-free survival and OS; the 1-year
survival rate was 27% in the irradiation group and 13% in the control group.120 A
total PCI dose of 25 Gy is the recommended dose to minimize the risk of
neurotoxicity.121 Regardless, in patients with a poor PS or impaired neurocognition,
PCI is not recommended. Additionally, a recent study comparing PCI or observation
in patients with confirmed absence of brain metastases based on preenrollment
MRIs, did not demonstrate an OS benefit with PCI.122
E. Palliation
1. Radiotherapy
Palliative radiotherapy is often helpful in controlling the pain of bone metastases or
neurologic function in patients with brain metastases. Chest radiotherapy may help
control hemoptysis, superior vena cava syndrome, airway obstruction, laryngeal
nerve compression, and other local complications.123 For patients with bronchial
obstruction who have received maximum external-beam radiotherapy, the use of
high-dose endobronchial irradiation may be of temporary benefit.
2. Endobronchial stents
Endobronchial stents, typically inserted by interventional pulmonologists, can help
alleviate airway obstruction due to compression by tumor. Additionally, these stents
 have been used to reopen and tamponade airways obstructed by hemoptysis.124,125
3. Pleural effusions
For pleurodesis, common sclerosing agents include doxycycline, talc, and
bleomycin. The disadvantage of bleomycin is its cost; talc, although effective, has
the disadvantage of requiring a thoracoscopy and general anesthesia for insufflation.
Alternatively, an indwelling pleural drainage catheter may be placed.
4. Colony-stimulating factors
Filgrastim (granulocyte colony-stimulating factor) decreases the incidence of
neutropenic fevers, the median duration of neutropenia, days of hospitalization, and
days of antibiotic treatment in patients. However, the clinical benefit of maintaining
a dose-intense approach in the treatment of patients with lung cancer has not been
established. In addition, caution must be exercised when using colony-stimulating
factors in patients receiving combined-modality treatment with both chemotherapy
and thoracic irradiation. A randomized study by the Southwest Oncology Group
found that LS-SCLC patients receiving sargramostim (granulocyte-macrophage
colony-stimulating factor) and chemotherapy with concurrent thoracic irradiation
had a significant increase in thrombocytopenia over patients receiving concurrent
chemotherapy and radiation therapy without growth factor.126

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 complete remission. N Engl J Med. 1999;341(7):476–484.
120. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive
small-cell lung cancer. N Engl J Med. 2007;357(7):664–672.
121. Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial
Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and
schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life
for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys.
2011;81(1):77–84.
122. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a
detrimental effect on the overall survival (OS) of patients (pts) with extensive disease
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Clin Oncol. 1995;13(7):1632–1641.
I. INTRODUCTION
Cancers of the gastrointestinal (GI) tract (esophagus, stomach, small and large intestines,
and anus) account for nearly 12% of all cases of cancer in the United States and 20% of
cancer deaths. Colon cancer is by far the most common of these malignancies, with cancer
of the rectum, stomach, esophagus, small intestine, and anus occurring with decreasing
frequency. Surgery continues to be the principal curative modality, but radiation and
chemotherapy have increasingly important roles and, in certain adjuvant settings, improve
the cure rate produced by surgery. Select patients with isolated, resectable metastatic
colorectal cancer lesions also may be cured with surgical resection. Chemotherapy alone
is not curative in patients with overt metastatic disease. Recent combination drug regimens
have produced objective responses in up to 60% of patients, with increasing numbers of
individuals obtaining stabilization of their disease. There is little question that meaningful
palliation and an increase in survival can be achieved in patients who respond to
chemotherapy or achieve disease stabilization. Clinical trials, often by cooperative groups,
have been useful in defining the natural history and therapeutic benefit of various treatment
modalities. Participation in such clinical trials is encouraged because not only could
participation provide benefit for the patient but also could reveal future therapeutic options
for others. Staging of all GI neoplasms using the American Joint Committee on Cancer
Staging Manual is essential to determine appropriate treatment for all tumor sites.1

II. CARCINOMA OF THE ESOPHAGUS

A. Epidemiology
In the United States, an estimated 16,980 new cases and 15,590 deaths due to
esophageal cancer were expected in 2014.2 Incidence rates vary internationally with the
highest rates seen in Southern and Eastern Africa and Eastern Asia. The lowest rates
are found in Western and Middle Africa and Central America in both males and
females.3 Esophageal cancers are either esophageal adenocarcinoma (EAC) or
esophageal squamous cell carcinoma (ESCC). Historically, ESCC has predominated. In
the 1960s, ESCC accounted for more than 90% of all esophageal tumors in the United
States, and adenocarcinomas were considered uncommon. For the past two decades,
however, the incidence of EAC has increased dramatically in Western countries, and
EAC now accounts for more than 60% of all esophageal cancers in the United States. In
 contrast, worldwide, ESCC still predominates.4
ESCC and EAC differ in a number of features, including tumor location and risk
factors. EAC tends to involve the lower third of the esophagus, whereas the middle
third is the most common site for ESCC. Smoking and regular alcohol use are strong
risk factors for ESCC and only moderate risk factors for EAC. A unique risk factor for
ESCC is other aerodigestive tract malignancies, such as head and neck or lung cancer.
Risk factors associated with EAC appear to be gastroesophageal reflux disease
(GERD), smoking, obesity, and Barrett esophagitis.5
Because ESCC and EAC appear to have distinct pathogenesis, epidemiology,
biology, and outcomes, the most recent 2010 tumor-node-metastasis (TNM) staging
system provides separate stage groupings.6 This change was based on an analysis of
worldwide data on 4,627 patients with esophageal or gastroesophageal junction (GEJ)
cancer who underwent surgery alone, and this showed that among patients with lymph
node–negative tumors, prognosis was dependent on T-stage as well as histology, grade,
and tumor location.7
B. Clinical manifestations and pretreatment evaluation
Carcinoma of the esophagus is usually associated with progressive and persistent
dysphagia. Pain, hoarseness, weight loss, and chronic cough are unfavorable
manifestations that indicate spread to regional structures (e.g., mediastinal nodes),
recurrent laryngeal nerves, or fistula formation between the esophagus and the airway.
The most common sites of metastasis are regional lymph nodes (which may include
cervical, supraclavicular, intrathoracic, diaphragmatic, celiac axis, or periaortic lymph
nodes), the liver, and lungs.
Diagnosis is usually made by barium swallow or endoscopy with a biopsy or
lavage cytology. Staging should be assessed with a computed tomography (CT) scan of
the abdomen and chest, careful physical examination of the cervical and supraclavicular
nodes, and positron emission tomography (PET). PET/CT appears to be most sensitive
for identifying occult metastatic disease and less effective at accurately identifying
regional nodal metastases. In patients without metastatic disease identified, endoscopic
esophageal ultrasound (EUS)8 may be useful in assessing the depth of tumor invasion,
given the difference in management of T1 to T2 lesions versus T3 to T4 lesions and
regional nodal metastases. Laparoscopy to detect occult intraperitoneal metastases in
distant esophageal and esophagogastric junction (EGJ) tumors has the advantage of
changing management in approximately 17% of patients who have otherwise been fully
staged with CT, PET/CT, and EUS.9 Bronchoscopy should be considered for upper- and
middle-third tumors to rule out a bronchoesophageal fistula. A bone scan is useful in
patients with bone pain or tenderness. Survival is related to pathologic stage, which can
be defined only surgically.
C. Treatment and prognosis
The management of locoregional esophageal cancer has undergone significant changes
over the last 15 years and the majority of these patients are now treated with combined-
 modality therapy rather than local therapy alone. However, the optimal management of
these patients remains unclear. Complete surgical resection results in a median survival
of approximately 18 months with 15% to 20% of patients surviving 5 years. Patients
with metastatic disease are best treated with systemic therapy. Palliative feeding
procedures such as with a jejunostomy or gastrostomy tube may be useful if subsequent
surgical resection is not to be done. For metastatic disease, the overall median survival
time is less than 1 year, and the overall 5-year survival rate is 5% to 10%. The
prognosis is related to the size of the lesion, the depth of penetration of the esophagus,
and nodal involvement.
1. Surgery alone
Only approximately 30% to 40% of patients diagnosed with esophageal cancer have
potentially resectable disease at presentation; however, surgery has historically been
included in standard treatment approaches. The utility of surgery alone, however,
has been challenged owing to the poor prognosis with 5-year survival rates 15% to
20% with surgery alone.10–14 In an analysis of 4,627 patients with esophageal cancer
treated with surgery alone, those with T1N0 disease had 5-year survivals more than
50%, and therefore, surgery alone is still the standard care with those with T1N0
disease.15
2. Combined-modality treatment for potentially curable patients
The poor results with immediate surgery, due in part to inadequate staging
techniques, have focused attention for some years on preoperative combined-
modality treatment with radiation therapy, chemotherapy, or both, followed by
surgery. When this approach is used, aggressive staging including EUS, CT
scanning, PET/CT, and laparoscopy is needed and is often combined with
jejunostomy feeding tube placement for nutritional support. Despite conflicting
results from randomized trials, patients with stages II and III disease are often
treated in this fashion.
a. Preoperative chemotherapy alone
The National Cancer Institute (NCI) Gastrointestinal Intergroup has reported a
randomized trial of 440 patients with either EAC or ESCC that compared
preoperative chemotherapy (cisplatin and fluorouracil [CF] for three cycles)
versus surgery alone. After a median follow-up of 55.4 months, there were no
median, 1-year, or 2-year survival differences between the two groups. These
results differ compared with data from the Medical Research Council Clinical
Trials Unit in the United Kingdom, which included 802 patients randomized to
receive either two cycles of preoperative CF followed by surgery or surgery
alone. Approximately 66% of patients had adenocarcinoma. Long-term follow-
up at 6 years revealed a significant difference in 5-year overall survival (OS)
(chemotherapy vs. surgery alone, 23% vs. 17.1%; hazard ratio [HR], 0.84; 95%
confidence interval [CI], 0.72 to 0.98; p = 0.03) regardless of histologic
subtype.16 Different proportions of the two different histologies contribute to the
 difficulties in interpretation of these trials.
b. Preoperative chemoradiation
Radiation therapy alone, as either a preoperative or a postoperative adjunct to
surgery, has not improved OS in most series, with 5-year survival rates ranging
from 0% to 10%. Combined-modality treatment of radiotherapy with
chemotherapy has been superior. In addition, concurrent chemotherapy and
radiotherapy is superior to sequentially administered treatment.11,17,18 In a
randomized trial, Radiation Therapy Oncology Group (RTOG) 85-01,
comparing radiotherapy alone with radiotherapy plus chemotherapy in 121
patients, 88% of whom had squamous cell cancer, the RTOG reported a 5-year
survival rate of 27% for the combined-modality group and 0% for the radiation
therapy alone group, with median survival times of 14.1 and 9.3 months,
respectively. Most patients had stage T2 disease and were node-negative by CT
scanning.19 There have been five completed trials that compared preoperative
concurrent chemoradiation versus surgery alone, with two showing statistically
significant survival benefits of chemoradiation.20 The first trial, CALGB 9781,
closed prematurely because of poor accrual and randomized only 56 patients to
either esophagectomy with node dissection alone or cisplatin 100 mg/m2 and
fluorouracil 1,000 mg/m2/day for 4 days on weeks 1 and 5 concurrent with
radiation therapy followed by esophagectomy with node dissection. An intent-to-
treat analysis showed a median survival of 4.48 versus 1.79 years in favor of
trimodality therapy (exact stratified log-rank, p = 0.002).21 The CROSS trial
randomly assigned 363 patients with potentially resectable esophageal or EGJ
cancer to preoperative chemoradiation using weekly paclitaxel 50 mg/m2 plus
carboplatin area under the curve (AUC) 2 plus concurrent radiotherapy (41.4 Gy
over 5 weeks) versus surgery alone.22 The complete (R0) resection rate was
higher with chemoradiotherapy (92% vs. 69%), and 29% of those treated with
chemoradiotherapy had a pathologic complete response. At a median follow-up
of 32 months, OS was significantly better with preoperative chemoradiotherapy
(HR, 0.657; 95% CI, 0.495 to 0.871; 3-year survival rate, 58% vs. 44%).
c. Radiation plus chemotherapy options
■ Paclitaxel 50 mg/m2 plus carboplatin AUC 2 together weekly plus radiation
for a total of 41.4 Gy over 5 weeks.
■ Cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2 daily for 4 days on
weeks 1 and 5 plus radiation therapy for a total of 50.4 Gy.
■ Cisplatin 15 mg/m2 IV daily on days 1 to 5 and fluorouracil 800 mg/m2
continuous infusion over 24 hours daily on days 1 to 5 every 21 days for
two cycles plus radiation therapy.
■ Oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 and fluorouracil 400
mg/m2 IV on day 1 then fluorouracil 800 mg/m2 IV continuous infusion over
 24 hours on days 1 and 2 every 14 days for three cycles plus concurrent
radiation. An additional three cycles are completed after radiation.
■ Oxaliplatin 85 mg/m2 IV on days 1, 15, and 29 for three doses and
fluorouracil 180 mg/m2 IV as a continuous infusion over 24 hours on days 1
to 33 plus radiation therapy.
3. Treatment of advanced (metastatic) disease. Similar systemic chemotherapy
regimens are used for both EAC and ESCC. Various agents with modest activity
when used alone are available. These include cisplatin, carboplatin, fluorouracil,
bleomycin, paclitaxel, docetaxel, irinotecan, gemcitabine, methotrexate, mitomycin,
vinorelbine, and doxorubicin. Response rates range from 15% to 30% and are
usually brief. Most data are for ESCC, the exception being paclitaxel, which
appears equally effective in both histologic types. The most active drugs appear to
be platinum analogs, paclitaxel, and fluorouracil. Single agents are less helpful than
doublet combination chemotherapy because of their lower response rates and brief
duration of response. Approximately 7% to 22% of esophagogastric
adenocarcinomas overexpress the type II epidermal growth factor receptor (EGFR)
(HER2) and may benefit from trastuzumab, an anti-HER2 monoclonal antibody. The
benefit of trastuzumab in advanced HER2-positive adenocarcinoma was studied in
the phase III ToGA trial, which compared standard chemotherapy (six courses of
cisplatin plus either infusional 5-fluorouracil [5-FU] or capecitabine) with and
without trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks until
disease progression). The objective response rate was significantly higher with
trastuzumab (47% vs. 35%) and at a median follow-up of 17.1 to 18.6 months, OS
was significantly better with trastuzumab (13.8 vs. 11.1 months).23
a. Regimens for first-line therapy
1) CF
■ Cisplatin 75 to 100 mg/m2 IV on day 1.
■ Fluorouracil 1,000 mg/m2/day as a continuous IV infusion on days 1 to 5.
Repeat every 28 days.
2) Paclitaxel plus cisplatin
■ Paclitaxel 175 mg/m2 IV on day 1.
■ Cisplatin 75 mg/m2 IV on day 1.
Repeat every 21 days.
3) Carboplatin plus paclitaxel
■ Carboplatin AUC 5 IV on day 1.
■ Paclitaxel 200 mg/m2 IV on day 1.
Repeat every 21 days.
4) Paclitaxel plus cisplatin plus fluorouracil
■ Paclitaxel 175 mg/m2 IV over 3 hours on day 1.
■ Cisplatin 20 mg/m2/day IV on days 1 to 5.
 ■ Fluorouracil 750 mg/m2/day continuous IV on days 1 to 5.
Repeat every 28 days.
5) Cisplatin plus irinotecan
■ Irinotecan 65 mg/m2 IV on days 1, 8, 15, and 22.
■ Cisplatin 30 mg/m2 IV on days 1, 8, 15, and 22.
Repeat every 6 weeks.
6) Irinotecan plus fluorouracil plus leucovorin
■ Irinotecan 180 mg/m2 IV over 30 minutes followed by a 30-minute
break.
■ Leucovorin 125 mg/m2 IV over 15 minutes.
■ Fluorouracil 400 mg/m2 IV over 3 to 4 minutes.
Repeat every 2 weeks.
7) Fluorouracil
■ 1,200 mg/m2/day continuous IV for 2 days.
Repeat every 2 weeks.
8) EOX
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by oxaliplatin and
capecitabine.
■ Oxaliplatin 130 mg/m2 IV over 2 hours on day 1.
■ Capecitabine 625 mg/m2 twice daily on days 1 to 21.
Repeat every 21 days.
9) Oxaliplatin plus fluorouracil
■ Oxaliplatin 85 mg/m2 IV over 2 hours on day 1.
■ Leucovorin 400 mg/m2 IV over 2 hours followed by
■ Fluorouracil 400 mg/m2 IV by rapid infusion then fluorouracil 2,400
mg/m2 IV continuously over 46 hours.
Repeat every 2 weeks.
4. Second-line therapy
This may be chosen from the list of alternative combination therapies or the single
agents, including single-agent docetaxel, paclitaxel, ramucirumab, or irinotecan. In
the phase III REGARD trial, 355 patients with previously treated advanced or
metastatic gastric or EGJ adenocarcinoma were randomly assigned to best
supportive care plus either ramucirumab or placebo, and although the benefit was
small, it was shown that patients who received ramucirumab had better median
progression-free survival (PFS) (2.1 vs. 1.3 months) and OS (5.2 vs. 3.8 months;
HR, 0.78; 95% CI, 0.60 to 0.998).24 In the phase III RAINBOW trial, patients were
randomized to either weekly paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day
cycle plus ramucirumab (8 mg/kg IV every 2 weeks) or placebo who had disease
progression on or within 4 months after first-line platinum and fluoropyrimidine-
based combination therapy, and median OS was significantly better with
 ramucirumab (9.6 vs. 7.4 months, HR 0.807, 95% CI, 0.678 to 0.962) as was PFS
(4.4 vs. 2.9 months).25 Combination therapy can be used depending on prior therapy
and performance status.
D. Supportive care
Esophagitis during a combined-modality treatment program is nearly universal, and
nutritional support frequently is required, preferably using alimentation by feeding tube
placed by enterostomy. Peripheral alimentation is difficult with the continuous
chemotherapy administration. Gastrostomy tubes are to be avoided in patients with
potentially resectable lesions because of the usual requirement for a gastric pull-up
after resection of the esophageal tumor.
E. Follow-up studies
The optimal surveillance strategy after local therapy of esophageal cancer remains
unclear with little prospective data. For asymptomatic patients who have had
potentially curative therapy, history and physical examination may be done every 3 to 6
months for years 1 to 3, every 6 months for years 3 to 5, and then annually. CT scans,
endoscopy, chemistries, and complete blood count should be evaluated as clinically
indicated.

III. GASTRIC CARCINOMA

A. Epidemiology
The incidence of stomach cancer has decreased dramatically in the United States since
the beginning of the century, although it has stabilized in the last 20 years. The incidence
of gastric cancer varies geographically with the highest rates in Eastern Asia, Eastern
Europe, and South America and lowest rates in North America and Africa.3 No
improvement has been seen over the last two decades though, with 5-year survival rates
ranging from 45% to 71% in node-negative disease to 5% to 30% in node-positive or
metastatic disease. The male-to-female ratio is nearly 2:1. A high rate of chronic
gastritis and intestinal metaplasia of the stomach is associated with a high incidence of
gastric cancer. Helicobacter pylori has been implicated in such changes and in gastric
cancer, particularly the more distal “intestinal” type, as well as in peptic ulcer disease.
Other environmental factors such as a high-salt diet and consumption of nitrates have
been associated with a higher risk of gastric cancer.26 Although the incidence in the
United States has decreased, the location of gastric cancers has migrated proximally.
Nearly half the stomach cancers occurring in white men are located proximally (GEJ,
cardia, and proximal lesser curvature).
B. Clinical manifestations and evaluation
The most common symptoms are weight loss, abdominal pain, nausea, vomiting,
changes in bowel habits, fatigue, anorexia, and dyspepsia. The diagnosis generally is
made by endoscopy and biopsy, although barium swallow is frequently helpful. Staging
of a suspected gastric cancer should initially include CT scans of the chest, abdomen,
and pelvis. Endoscopic ultrasonography is increasingly used; it is more accurate in
 gauging the depth of the cancer in the gastric wall than in determining nodal
involvement.27 PET scans are more sensitive than CT scans for detection of distant
metastases, and in one prospective study, integrated PET/CT identified otherwise
radiographically occult metastatic lesions in 10% of patients with locally advanced
tumors (larger than T3 lesions and N1 nodal involvement).28 Laparoscopy can also
improve clinical staging as it can more accurately identify peritoneal metastases and
further evaluate the liver. Tumor markers such as carcinoembryonic antigen (CEA),
cancer antigen (CA) 19-9, and CA 72-4 may be useful for subsequent assessment of the
response to therapy. Prognosis is reflected by accurate staging. The revised staging
method classifies patients according to the number of pathologically involved regional
lymph nodes. The groupings are one to two (N1), three to six (N2), and seven or more
involved lymph nodes (N3).
C. Treatment and prognosis
Most stomach cancers are adenocarcinomas. Important prognostic factors include tumor
grade and gross appearance. Diffusely infiltrating lesions are less likely to be cured
than sharply circumscribed, nonulcerating lesions. The presence of regional lymph node
involvement or involvement of contiguous organs in the surgical specimen indicates an
increased likelihood of recurrence, as does the presence of dysphagia at the time of
diagnosis. Patients with proximal lesions or lesions requiring total, rather than distal
subtotal, gastrectomy are also at greater risk.
There has been controversy as to the contribution of extensive lymphadenectomy
(D1 vs. D2 dissection) to survival benefit. Japanese surgeons have widely promoted the
D2 dissection; however, initial data from the randomized clinical trials including the
Dutch Gastric Cancer Group29 and the Medical Research Council trials30 did not show
a survival benefit of D2 over D1 lymphadenectomy and that there was increased
morbidity and mortality for the patients who had D2 dissection. More recently, long-
term data from the Dutch Gastric Cancer Group has now shown a survival benefit of D2
dissection (15-year OS rate of 21% vs. 29%; p = 0.34) and that it is associated with
lower rates of locoregional recurrence.31 Additionally, two other studies from Austria
and Spain demonstrated better outcomes with D2 versus D1 dissections.32,33
1. Adjuvant and perioperative chemotherapy
Meta-analyses comparing adjuvant chemotherapy versus surgery alone have shown
benefit to postoperative chemotherapy.34 The optimal choice of adjuvant
chemotherapy has not been established and acceptable options include epirubicin,
cisplatin, and 5-FU (ECF) as used in the MAGIC trial35 described later, or
capecitabine and oxaliplatin as used in the CLASSIC trial.36 In Asian patients, S-137
has been shown to improve both OS and relapse-free survival in patients with stage
II or III gastric cancer who underwent a D2 gastrectomy.
Neoadjuvant and perioperative chemotherapy has also been used as a means to
attempt downstaging of a locally advanced tumor prior to surgery. In 2006, the
 European MAGIC trial35 was published which studied 503 patients with gastric
cancer randomized to surgery alone versus three preoperative and three
postoperative cycles of the ECF regimen. The patients who received chemotherapy
demonstrated significant downstaging of their tumors with improved PFS (19 vs. 13
months; p = 0.0001), median survival (24 vs. 20 months; p = 0.02), and 5-year
survival (36% vs. 23%; p = 0.009). Because only 55% of patients were able to
begin postoperative therapy, it is postulated that the preoperative chemotherapy
provided the most significant benefit. Other neoadjuvant regimens, including
combinations with radiation, are undergoing study.
2. Adjuvant chemoradiation
There have been three randomized trials of postoperative chemoradiation that have
shown survival benefit when compared to surgery alone.35,38–40 The largest of these
trials is the U.S. Gastrointestinal Intergroup38 that has reported the results of a 556-
patient randomized trial comparing surgery with or without postoperative
chemotherapy (fluorouracil and leucovorin) and combined chemotherapy and
radiation followed by two additional cycles of chemotherapy. Patients had resected
stages IB through stage IV M0 adenocarcinoma of the stomach or GEJ. Postoperative
combined therapy produced a statistically significant median survival benefit (36 vs.
27 months, respectively; p = 0.005). Although the study did not show any significant
difference in relapse-free survival or OS according to the extent of lymph node
dissection, 54% of patients had a D0 lymphadenectomy (surgery that did not remove
all of the N1 nodes), 36% had a D1 dissection, and only 10% underwent a D2
dissection (includes perigastric, celiac, splenic, hepatic artery, and cardial lymph
nodes). Major toxic effects (grade 3 or higher) in the chemoradiotherapy group were
predominantly hematologic (54%) and GI (33%).
3. Chemotherapy versus chemoradiation
Adjuvant chemoradiation has been directly compared to adjuvant chemotherapy in a
number of trials, only one of which showed a significant OS benefit to
chemoradiation. The largest of these trials, the ARTIST trial, randomized 458
patients with complete resected gastric cancer, D2 lymph node dissection to six
courses of postoperative capecitabine plus cisplatin, or two courses of the same
chemotherapy followed by chemoradiotherapy (45 Gy radiotherapy with concurrent
daily capecitabine [825 mg/m2 twice daily]) and two additional courses of
chemotherapy).41 At a median follow-up of 84 months, 3-year disease-free survival
(DFS) was not significantly better in patients who received chemoradiation (HR,
0.74; 95% CI, 0.52 to 1.05), although unplanned subset analysis did indicate a
significantly better outcome with chemoradiotherapy in those with node-positive
disease (3-year DFS, 76% vs. 72%; p = 0.004). OS, a secondary endpoint, was also
not significantly different (HR, 1.13; 95% CI, 0.775 to 1.647).42 A meta-analysis of
six trials concluded that while chemoradiotherapy was associated with significantly
higher rates of 5-year DFS (odds ratio [OR], 1.56; 95% CI, 1.09 to 2.24) and
 significantly lower rates of locoregional recurrence (OR, 0.46; 95% CI, 0.32 to
0.67), there was only a trend toward a survival benefit for chemoradiotherapy that
was not statistically significant (OR for OS, 1.32; 95% CI, 0.92 to 1.99).43
4. Recommended perioperative and combined-modality regimens
a. Perioperative chemotherapy (please see ECF modifications later under
metastatic regimens)
1) ECF
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by CF.
■ Cisplatin 60 mg/m2 IV over 2 hours on day 1.
■ Fluorouracil 200 mg/m2 daily as a continuous infusion IV on days 1 to
21.
The regimen is repeated every 21 days for three cycles preoperatively
and three cycles postoperatively (if possible).
2) Fluorouracil and cisplatin
■ Leucovorin 20 mg/m2 IV bolus on days 1 to 5.
■ Fluorouracil 425 mg/m2 IV bolus on days 1 to 5.
■ Cisplatin 100 mg/m2 IV over 2 hours on day 1.
The regimen is repeated every 21 days.
b. Radiotherapy and chemotherapy
1) Radiation therapy plus fluorouracil and leucovorin
■ 45 Gy at 180 cGy/day to the tumor (or tumor bed) and nodal chains daily
for 5 days weekly for 5 weeks. Chemotherapy is started on the first day
of radiotherapy and repeated during the last 3 days of radiation.
■ Leucovorin 20 mg/m2 IV bolus followed by fluorouracil 400 mg/m2 IV
bolus on the first 4 days and last 3 days of radiation therapy.
2) Radiation therapy plus paclitaxel and carboplatin
■ Radiation therapy 41.4 Gy over 5 weeks, and
■ Paclitaxel 50 mg/m2 plus carboplatin AUC 2 weekly.
5. Treatment of advanced (metastatic, locally unresectable, or recurrent) disease
In metastatic disease, there are data to support the OS, PFS, and response rate (RR)
of cytotoxic chemotherapy when compared with best supportive care.
a. Single agents
Agents with activity include epirubicin, mitomycin, doxorubicin, cisplatin,
etoposide, fluorouracil, irinotecan, hydroxyurea, the taxanes, and the
nitrosoureas. Single agents have low response rates (15% to 30%), brief
durations of response, few complete responses, and little impact on survival.
b. Combination chemotherapy
Two drug regimens are more widely used than single agents, largely because of
higher response rates, more frequent complete responses, and the potential of
longer survival. Many combination therapies have benefits, including cisplatin
 plus 5-FU44 or capecitabine,45 anthracycline-containing regimens (ECF, EOX),
taxane-based combinations (paclitaxel, docetaxel, DCF, or docetaxel plus
capecitabine), oxaliplatin combinations (FOLFOX, CAPOX, EOF), and
irinotecan-containing regimens (FOLFIRI).
The REAL trial was a landmark, large, randomized trial that compared four
different chemotherapy regiments in over 1,000 patients with advanced gastric
cancer. ECF, EC plus capecitabine, and epirubicin plus oxaliplatin and either
infusional 5-FU (EOF) or capecitabine (EOX) were compared.46 This trial
showed that capecitabine can be substituted for infusional 5-FU. It also showed
that outcomes are comparable when oxaliplatin is substituted for cisplatin in the
ECF regimen. When the four groups were considered separately, median
survival in patients treated with EOX was modestly longer when compared with
ECF (median, 11.2 vs. 9.9 months; HR, 0.80; 95% CI, 0.66 to 0.97).
c. Targeted agents to treat metastatic disease
Approximately 7% to 22% of EGJ adenocarcinomas overexpress the type II
EGFR (HER2). Trastuzumab is an anti-HER2 monoclonal antibody that has been
U.S. Food and Drug Administration (FDA)-approved, in combination with
cisplatin and a fluoropyrimidine, for the treatment of metastatic gastric or EGJ
adenocarcinomas. The ToGA study was the first randomized, prospective,
multicenter phase III study to evaluate the efficacy and safety of trastuzumab in
patients with HER2-neu-positive gastric and GEJ adenocarcinoma in
combination with cisplatin and a fluoropyrimidine.23 This study of 594 patients
with HER2-neu-positive (3+ on immunohistochemistry [IHC] or fluorescence in
situ hybridization [FISH]-positive) locally advanced, recurrent, or metastatic
gastric and EGJ adenocarcinoma were randomized to trastuzumab plus
chemotherapy versus chemotherapy alone. The majority of the patients in this
trial had gastric cancer. There was a significant improvement in the median OS
(13.8 vs. 11 months, respectively; p = 0.46) with the addition of trastuzumab to
chemotherapy.
d. Angiogenesis inhibitors
Angiogenesis inhibitor has been explored in metastatic gastric cancer. The
Avastin in Gastric Cancer (AVAGAST)47 was a multinational, randomized,
placebo-controlled trial that evaluated the efficacy of adding bevacizumab, a
vascular endothelial growth factor (VEGF) inhibitor, to capecitabine and
cisplatin in the first-line treatment of advanced gastric cancer. This trial of 774
patients did not meet its primary OS endpoint, but the progression free survival
and overall response rate did favor bevacizumab. There was suggestion that
there may be variation in OS benefit based on geographic location, with little
benefit in Asian patients (also seen in China study) but there was a benefit in
Pan-American population; however, this was just an exploratory analysis.
Bevacizumab is not FDA-approved for metastatic gastric cancer, and its use is
 not endorsed by guidelines such as National Comprehensive Cancer Network
(NCCN) guidelines.
Ramucirumab37 is a fully humanized VEGF receptor 2 (VEGFR-2)
antibody. In the first-line setting, the efficacy of ramucirumab in esophagus, GEJ,
and gastric in combination with FOLFOX has been evaluated.48 This study did
not meet its OS endpoint in all patients, but there was suggestion of improvement
in the gastric/GEJ subset and there will be an ongoing trial exploring this further.
The REGARD trial randomized 355 patients with advanced gastric of EGJ
adenocarcinoma after progression on first-line therapy to RAM versus
placebo.49 Median OS was 5.2 months in the patients treated with RAM
compared to 3.8 months in the placebo group (p = 0.47). RAM was associated
with higher rates of hypertension than in the placebo group (16% vs. 8%), but
other adverse events were similar in the two groups. The RAINBOW trial
evaluated paclitaxel with or without RAM in patients with metastatic gastric or
EGJ adenocarcinoma progressing on first-line chemotherapy.50 In this study of
665 patients, the median OS was significantly longer for the RAM plus
paclitaxel group compared to the paclitaxel alone (9.63 vs. 7.36 months; p <
0.0001). The ORR favored RAM plus paclitaxel versus paclitaxel alone (28%
vs. 16%; p = 0.0001). RAM was well tolerated with increased rate of bleeding,
neutropenia, and hypertension in the combination group. This study led to FDA-
approval of RAM with paclitaxel, and this can be considered in patients after
progression in addition to other second-line therapies. Apatinib (anti-VEGFR-2
tyrosine kinase inhibitor [TKI]) has been studied in Chinese patients with
advanced third-line gastric cancer and randomized to apatinib versus placebo,
and preliminary results showed modest improvement in OS and is currently
approved in China.51
e. Other targeted and immune-checkpoint therapies
A variety of investigational agents including MET inhibitors, PD-1 inhibitor, and
other immune-checkpoint inhibitors have early-phase data that may be
encouraging; however, definitive results of ongoing studies are needed.
6. Regimens for advanced gastric cancer
a. DCF
■ Docetaxel 75 mg/m2 as a 1-hour infusion IV.
■ Cisplatin 75 mg/m2 as a 2-hour infusion IV.
■ Fluorouracil 750 mg/m2 daily as a continuous infusion IV on days 1 to 5.
■ Dexamethasone 8 mg is given by mouth twice a day 1 day prior to
chemotherapy, on the day of treatment, and the day after.
The regimen is repeated every 21 days.
b. CF
■ Cisplatin 100 mg/m2 IV over 2 hours on day 1.
 ■ Fluorouracil 1,000 mg/m2 daily as a continuous infusion IV on days 1 to 5.
The regimen is repeated every 21 days.
c. ECF1
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by CF.
■ Cisplatin 60 mg/m2 IV over 2 hours on day 1.
■ Fluorouracil 200 mg/m2 daily as a continuous infusion IV on days 1 to 21.
Repeat every 21 days.
A UK study randomized 274 patients to receive either epirubicin, cisplatin, and
protracted infusional fluorouracil (ECF) or fluorouracil, doxorubicin, and methotrexate,
which was the standard at the time. The results favored ECF with improved response
rate (45% vs. 20%), a 2-month improvement in median survival, and an improved 2-
year OS (14% vs. 5%).
The REAL 2 study enrolled 1,002 patients with mostly metastatic gastric and
gastroesophageal cancer and randomized patients in a two-by-two design to receive one
of four anthracycline-containing regimens: epirubicin and fluorouracil with either
cisplatin (ECF) or oxaliplatin (EOF) as well as epirubicin and capecitabine with either
cisplatin (ECX) or oxaliplatin (EOX). They concluded that capecitabine was
noninferior to fluorouracil and that oxaliplatin was noninferior to cisplatin. Of note,
oxaliplatin-containing regimens appeared to be better tolerated than cisplatin-containing
regimens. In a secondary subset analysis, there was suggestion of a survival benefit of
EOX compared with ECF.
d. EOF
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by oxaliplatin and
fluorouracil.
■ Oxaliplatin 130 mg/m2 IV over 2 hours on day 1.
■ Fluorouracil 200 mg/m2 daily as a continuous infusion IV on days 1 to 21.
Repeat every 21 days.
e. EOX
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by oxaliplatin and
capecitabine.
■ Oxaliplatin 130 mg/m2 IV over 2 hours on day 1.
■ Capecitabine 625 mg/m2 twice daily on days 1 to 21.
Repeat every 21 days.
f. ECX
■ Epirubicin 50 mg/m2 IV bolus on day 1 followed by cisplatin and
capecitabine.
■ Cisplatin 60 mg/m2 IV over 2 hours on day 1.
■ Capecitabine 625 mg/m2 twice daily on days 1 to 21.
Repeat every 21 days.
More recently, the ToGA trial enrolled 584 patients with HER2-positive (IHC 3+
 and/or FISH-positive) gastric cancer to receive fluorouracil or capecitabine with
cisplatin and randomized to either receive trastuzumab or placebo. They found
improved response rate (47.3% vs. 34.5%), improved PFS, and improved median OS
(13.8 vs. 11.1 months). This is the first biologic agent to demonstrate a convincing
survival advantage in gastric cancer.
g. CF or cisplatin and capecitabine with trastuzumab
Please note that this regimen is appropriate only in HER2-positive patients, as
defined by IHC 3+ or FISH-positive.
■ Fluorouracil 800 mg/m2/day as a continuous infusion IV on days 1 to 5 or
capecitabine 1,000 mg/m2 orally twice daily on days 1 to 14.
■ Cisplatin 80 mg/m2 IV over 2 hours on day 1.
■ Trastuzumab 8 mg/kg IV loading dose over 90 minutes on day 1. If tolerated,
then the following cycle dose is 6 mg/kg IV over 30 to 90 minutes.
The regimen is repeated every 21 days. After six cycles, if there is stable disease,
then continue only trastuzumab maintenance until progression.
Baseline echocardiogram every 3 months is recommended to assess for
asymptomatic decline in ejection fraction seen with trastuzumab.
Currently, the NCCN supports the use of DCF and ECF in advanced gastric cancer
with a category 1 level of evidence, but other regimens including irinotecan plus
cisplatin, oxaliplatin plus a fluoropyrimidine, DCF modifications, irinotecan plus a
fluoropyrimidine, and paclitaxel-based regimens are supported with a category 2B
level of evidence.
h. Irinotecan and fluorouracil
■ Irinotecan 80 mg/m2 over 30 minutes IV days 1, 8, 15, 22, 29, and 36
followed by leucovorin and fluorouracil.
■ Leucovorin 500 mg/m2 over 2 hours IV on days 1, 8, 15, 22, 29, and 36
followed immediately by fluorouracil.
■ Fluorouracil 2,000 mg/m2 continuously over 22 hours IV on days 1, 8, 15,
22, 29, and 36.
The regimen is repeated every 7 weeks (6 weeks on, followed by 1 week
off).
i. Irinotecan plus cisplatin
■ Irinotecan 65 mg/m2 IV over 30 minutes on days 1, 8, 15, and 22.
■ Cisplatin 30 mg/m2 IV over 2 hours on days 1, 8, 15, and 22.
The cycle is repeated every 6 weeks.
j. Oxaliplatin plus fluorouracil
■ Oxaliplatin 85 mg/m2 IV over 2 hours on day 1.
■ Leucovorin 400 mg/m2 IV over 2 hours followed by fluorouracil 400
mg/m2.
■ Fluorouracil 2,400 mg/m2 IV continuously over 46 hours.
 Repeat every 2 weeks.
k. Paclitaxel plus cisplatin
■ Paclitaxel 100 mg/m2 IV over 1 hour on days 1 and 8 followed by cisplatin.
■ Cisplatin 30 mg/m2 IV over 30 minutes (with 2 L of normal saline) on days
1 and 8.
Repeat every 21 days.
l. Fluorouracil, leucovorin, and oxaliplatin (FLO)
■ Oxaliplatin 85 mg/m2 IV over 1 to 2 hours on day 1.
■ Leucovorin 200 mg/m2 IV over 1 to 2 hours on day 1, followed by
fluorouracil.
■ Fluorouracil 2,600 mg/m2 continuous IV over 24 hours.
Repeat every 2 weeks.
m. FLO plus docetaxel
■ Oxaliplatin, leucovorin, and fluorouracil as discussed previously.
■ Docetaxel 50 mg/m2 IV over 1 to 2 hours on day 1.
This regimen is repeated every 2 weeks.
This “modified” DCF regimen was shown to have a more acceptable
adverse event profile than the DCF regimen from V325 (complicated
neutropenia, 3.8% vs. 29%).
n. Capecitabine plus cisplatin
■ Capecitabine 1,000 mg/m2 orally twice daily on days 1 to 14.
■ Cisplatin 80 mg/m2 IV on day 1.
Repeat every 21 days.
o. Ramucirumab
■ Ramucirumab 8 mg/kg IV on day 1.
Repeat every 14 days.
p. Ramucirumab plus paclitaxel
■ Ramucirumab 8 mg/kg IV on days 1 and 15
■ Paclitaxel 80 mg/m2 IV on days 1, 8, and 15.
Repeat every 28 days.
D. Follow-up studies
Reasonable follow-up studies for patients in remission after surgery consist of history
and physical examination every 3 to 6 months for years 1 to 2, every 6 to 12 months for
years 3 to 5, and then annually. Complete blood cell count, chemistries, endoscopy, and
radiologic imaging should be evaluated as clinically indicated. Monitoring for
nutritional deficiency (such as vitamin B12 and iron) is indicated who have had
proximal resections or total gastrectomy.

IV. CANCER OF THE SMALL INTESTINE

A. Neuroendocrine tumors
 Carcinoid tumors are the most common neuroendocrine tumors (NETs) of the small
intestine, often found in the appendix and ileum. They may develop in other parts of the
GI tract but much less frequently. NETs tend to be less aggressive than
adenocarcinomas of the small intestine. Negative prognostic findings generally include
nodal metastases, high Ki67 index (>5%), high mitotic rate, presence of clinical
symptoms, tumor size (>2 cm), and elevated chromogranin A or other hormonally active
tumor byproducts. Five-year OS approaches about 60%. Ileal NETs tend to be more
invasive than appendiceal NETs. The most common sites of metastases include lymph
nodes (89.8%), liver (44.1%), lung (13.6%), peritoneum (13.6%), and pancreas
(6.8%), with adjacent organs being involved due to extensive fibrosis that is
characteristic of this type of tumor.
B. Carcinoid syndrome
About 10% of patients with NETs have carcinoid syndrome, which includes diarrhea,
abdominal cramps, malabsorption, flushing, bronchoconstriction, and cardiac valvular
disease (late sequela). Carcinoid syndrome is largely associated with metastatic NETs
from the midgut (jejunum, ileum, and cecum) and is rarely associated with metastatic
disease from the hindgut (distal colon and rectum). Bronchial carcinoids can produce a
carcinoid syndrome in approximately 10% of cases. Ninety percent of patients
presenting with carcinoid syndrome have metastatic disease to the liver, which may be
under the level of detection of imaging. Serotonin is thought to be responsible for the
abdominal symptoms, and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), can be
measured in the plasma or urine as it is excreted in large quantities and can be used as a
marker of disease activity when measured over a 24-hour period. Other markers may be
elevated, including chromogranin A, which is the most frequently elevated carcinoid
marker and several other proteins such as histamine, kallikrein, prostaglandins, and
tachykinins are thought to contribute to the syndrome. Symptoms of carcinoid can be
managed by simple measures such as antidiarrheal agents, but often this is not sufficient.
The best treatment is the synthetic long-acting somatostatin analog octreotide acetate
(Sandostatin). This agent, injected at a usual initial dose of 150 μg subcutaneously (SC)
every 8 hours or as the long-acting formulation (octreotide LAR depot) 20 to 30 mg
intramuscularly (IM) every month, effectively decreases the secretion of serotonin and
other gastroenteropancreatic peptides such as insulin or gastrin. It has been helpful in
ameliorating the symptoms of carcinoid tumors (e.g., flushing and diarrhea). A common
issue with octreotide treatment is steatorrhea, and therefore the addition of pancreatic
enzyme replacement may be warranted.
C. Treatment of advanced NETs
1. Effective agents
A large double-blind, randomized, phase IIIB German study (PROMID) treated
patients with midgut NET either with octreotide LAR 30 mg IM every 4 weeks or
placebo as first-line therapy. Median time to tumor progression was improved with
octreotide treatment (14.3 vs. 6 months; HR, 0.34; p = 0.00007). This effect
 persisted whether or not the tumor was active (i.e., presence of carcinoid
syndrome). Of note, 95% of these patients had Ki67 indexes of less than 2% and the
majority had liver tumor burden of less than or equal to 10%, which appeared to be
an important prognostic factor in subset analyses. The median OS was
approximately 73.7 months in the placebo group and had not been reached in the
octreotide LAR group; conclusions could not be drawn given the limited number of
deaths observed during the study.52,53 This agent can be continued despite
progression with additional second-line agents. Recently, the CLARINET trial was
completed, which evaluated the somatostatin analog lanreotide versus placebo, and
it was found that lenreotide significantly prolonged PFS (median not reached vs.
median of 18.0 months; p < 0.001).54
The chemotherapy agents doxorubicin, fluorouracil, dacarbazine, and
streptozocin have been shown to have limited activity in this disease. ECOG E1281
randomized 249 patients with advanced carcinoid to either fluorouracil plus
doxorubicin or fluorouracil plus streptozocin and found comparable response rates
(16%) and PFS (approximately 5 months), but they reported a significant
improvement in median OS for the streptozocin group (24.3 vs. 15.7 months; p =
0.02). Of note, crossover to dacarbazine yielded an 8% response rate and median
OS of 11.9 months.55
There are some studies that indicate metastatic GI NETs can have responses
with interferon-α (IFN-α) in combination with octreotide. A small prospective
randomized trial randomized 68 patients with metastatic midgut carcinoid tumors to
octreotide alone versus octreotide plus IFN-α and showed no survival difference but
significant difference in tumor progression.56
2. Targeted therapy for advanced disease
Several TKIs including sunitinib, sorafenib, and pazopanib have been evaluated and
show some promise with disease stabilization and PFS.57 Other active agents,
including bevacizumab 15 mg/kg IV every 3 weeks, showed improved PFS over
pegylated IFN-α-2b 0.5 µg/kg SC every week in combination with depot octreotide
in a phase II Southwest Oncology Group (SWOG) study.58 Initial reports from a
recent phase III SWOG trial comparing bevacizumab to IFN shows that
bevacizumab is not superior, but final data are still pending. Everolimus, an
inhibitor of the mammalian target of rapamycin (mTOR), has been studied in
combination with somatostatin analogs. In the RADIANT 2 trial, 429 patients with
advanced GI NETs and a history of carcinoid syndrome were randomized to
octreotide with or without everolimus (10 mg daily), and combination therapy
demonstrated clinically meaningful prolongation in median PFS, but it was only of
borderline statistical significance (16.4 vs. 11.3 months; HR for tumor progression,
0.77; 95% CI, 0.59 to 1.0).59
3. Localized treatment of liver metastases
When the disease is confined to the liver, it is sometimes possible to achieve good
 palliation with hepatic artery embolization, chemoembolization, or yttrium-90
microspheres. Of note, poorly differentiated NETs or small-cell/atypical lung
carcinoids lack sufficient data to direct their management, but are typically treated
with a small-cell lung cancer regimen. A current NCI trial is evaluating the role of
temozolomide plus capecitabine for poorly differentiated NETs.
4. Regimens
a. Octreotide monotherapy. Octreotide LAR is dosed as 20 to 30 mg IM every 14
to 28 days. Consider run-in and overlap of approximately 2 weeks with
octreotide acetate 150 μg SC three times a day to assess tolerability with a
short-acting agent and then to allow the LAR to reach steady state.
b. Lanreotide monotherapy. Lanreotide 120 mg every 28 days.
c. Streptozocin plus fluorouracil
■ Streptozocin 500 mg/m2/day by rapid push IV on days 1 to 5.
■ Fluorouracil 400 mg/m2/day IV on days 1 to 5 and 36 to 40.
This regimen is repeated every 10 weeks.
d. Dacarbazine. Dacarbazine 250 mg/m2/day by rapid push IV on days 1 to 5. This
regimen was repeated every 4 weeks.
e. IFN-α 3 to 6 × 106 U/day or 10 × 106 U three times per week.
Treatment of carcinoid tumors may precipitate or exacerbate the carcinoid
syndrome during the first days of treatment, and the serotonin antagonists
cyproheptadine, methysergide, and octreotide should be available.
D. Adenocarcinomas
Adenocarcinomas of the small intestine are so uncommon that there is not sufficient data
to guide therapy. These cancers have been historically treated with chemotherapy
regimens employed for advanced colorectal cancer (e.g., oxaliplatin, irinotecan,
fluorouracil, and leucovorin). Survival of patients with small intestinal cancer is a
function of stage. Radiation and infusional fluorouracil may be considered for patients
with local recurrence or unresectable disease.

V. CANCER OF THE LARGE INTESTINE

Taken together, cancers of the colon and rectum are by far the most frequent malignancies
of the GI tract and account for the most deaths. It is estimated that approximately 132,700
new cases of large-bowel cancer are diagnosed annually in the United States which
includes approximately 93,090 cases of colon cancer and 39,610 cases of rectal cancer.2
The rates of colon cancer in the United States have steadily declined approximately 2% to
3% over the last 15 years in the older patient population. However, the rates in younger
patients are increasing. Overall, it is the third most common cause of cancer death in the
United States.3 Approximately half of patients found to have large-bowel cancers are cured
by surgery, which remains the only curative modality, and 20% are found to have metastatic
disease at presentation.2 Rectal cancer is predominately treated using all three modalities
of radiation, chemotherapy, and surgical resection. Surgical resection alone is reserved for
 very early stage disease. Colorectal cancer will often recur distally in the liver, and rectal
cancer can recur distally or locally (often only in nonirradiated patients).
A. Staging
The TNM staging system of the American Joint Committee on Cancer/Union for
International Cancer Control1 is currently the recommended staging system for
colorectal cancer. The seventh edition of the American Joint Committee on Cancer
Staging Manual modified the stage II, stage III, and stage IV disease groups by
expanding the definitions of T4, N status, and M status to more accurately reflect the
wide variations in survival. For example, using the Surveillance, Epidemiology, and
End Results database, 5-year observed survival for T4N0 patients varies by over 10%
when there is a distinction made between penetrating to the visceral peritoneum (T4a)
versus invading or adhering to adjacent structures (T4b). The same is true when N1 and
N2 staging is further subclassified as one involved lymph node (N1a), one to three
involved lymph nodes (N1b), four to six involved lymph nodes (N2a), and finally seven
or more involved lymph nodes (N2b). In addition, tumor deposits separate but adjacent
to the primary tumor without evidence of lymph node involvement is classified as N1c
stage. Metastatic disease has been divided into two groups: M1a with a solitary
metastasis or M1b with more than one metastasis, given data indicating approximately
20% of patients who undergo liver resection for their metastatic colorectal cancer are
disease-free at 5 years. This pathologic staging method is helpful for selecting patients
who are at sufficiently high risk to justify adjuvant therapy such as chemotherapy or
irradiation (rectal cancer) as well as those with metastatic disease that could derive
long-term benefit from surgical or interventional procedures. Abdominal, chest, and
pelvic CT are helpful for preoperative assessment of extra-bowel involvement, but the
findings may be falsely negative when small peritoneal implants are present.60 Bone
scans are seldom needed, except for assessment of bone pain, because bone metastases
occur rather late in the course of the disease. PET scans are helpful for identifying
occult metastatic disease in patients who are being considered for surgical resection of
the primary tumor and an isolated metastatic site (i.e., liver, lung) disease.
B. Serum carcinoembryonic antigen
CEA level may parallel disease activity, although it is not increased in all patients with
colon cancer. Its overall sensitivity for diagnosis of colorectal cancer is approximately
46% (95% CI, 0.45 to 0.47) based on a recent meta-analysis. The specificity is much
higher at approximately 89% (95% CI, 0.88 to 0.92).61 It is worth measuring
preoperatively because failure of an elevated value to return to normal may signify
incomplete resection or presence of metastatic disease. Likewise, a serial rise in CEA
values after an initial normalization could indicate recurrence. A rising CEA level is an
indication for careful reevaluation with CT, PET, and possibly laparoscopy because
some patients may have isolated, resectable, and thus potentially curable metastases,
particularly involving the liver.
C. Adjuvant chemotherapy for colon cancer
 For patients with node-positive (stage III) resectable colon cancer, the combination of
fluorouracil plus leucovorin given either by the 5-day or by the weekly schedule for 6
months improves the DFS as well as the OS of patients. The update of the MOSAIC
trial, which evaluated FOLFOX4 versus leucovorin/5-FU for stage II/III colon cancer
patients, found significant improvement in DFS and OS, but there was no significant
difference in the subgroup of stage II colorectal cancer. In addition, the National
Surgical Adjuvant Breast and Bowel Project (NSABP) trial evaluating a bolus regimen
of FLO compared to weekly fluorouracil and leucovorin alone produced comparable 3-
year DFS statistics as seen with MOSAIC for stages II and III patients, favoring the
FLO regimen. Of note, increased GI toxicity has somewhat limited the use of this
regimen. QUASAR has been the only large study to measure a difference in survival
with adjuvant treatment for stage II colon cancer with an absolute improvement of
3.6%. Current NCCN and American Society of Clinical Oncology guidelines for high-
risk stage II patients (based on clinical and histopathologic data) suggest a detailed
discussion between the oncologist and patient as to the risk versus the benefit of
receiving adjuvant chemotherapy for stage II disease. A current GI intergroup trial will
define risk for stage II patients based on molecular markers including 18q allele
deletion and microsatellite instability.
Two large adjuvant trials for patients with stage III colon cancer comparing
irinotecan with either infusional fluorouracil or bolus fluorouracil versus fluorouracil
and leucovorin failed to show a DFS advantage for the combination; therefore,
irinotecan cannot be recommended as an adjuvant therapy strategy at this time.
Additional trials comparing capecitabine versus fluorouracil/leucovorin and infusional
fluorouracil versus bolus fluorouracil and leucovorin have demonstrated that each of
these approaches produce comparable results. For patients who are candidates for
combination therapy, the FOLFOX regimen has become a standard for stage III colon
cancer patients. The addition of bevacizumab has shown only transient benefit in DFS
in a NSABP trial and did not reach its primary endpoint of DFS in the AVANT study.
Although historic data support the use of postoperative radiotherapy for locally
advanced colon cancer (Dukes B3 or C3 or any T4 lesion), a small intergroup trial did
not confirm its efficacy. Combination chemotherapy should probably be incorporated
into the regimen and a total of 6 months of therapy be given.
The recommended colon cancer adjuvant regimens for node-positive patients (stage
III) are as follows with the preferred regimens being capecitabine plus oxaliplatin and
mFOLFOX6 (see Section V.D.4. for doses of each regimen).
1. Fluorouracil plus high-dose leucovorin (weekly Roswell Park regimen)
■ This is given for four cycles.
2. sLV5FU2
■ Twelve cycles are administered.
3. Capecitabine
■ Eight cycles are administered.
 4. mFOLFOX6
■ Twelve cycles are administered.
5. FOLFOX4
■ Twelve cycles are administered.
6. FLO
■ Oxaliplatin 85 mg/m2 as a 120-minute infusion IV on weeks 1, 2, and 5 of each
8-week cycle.
■ Fluorouracil 500 mg/m2 IV bolus weekly for 6 weeks.
■ Leucovorin 500 mg/m2 IV bolus weekly for 6 weeks.
There are three 8-week cycles administered (total of 6 months).
D. Treatment of advanced colon cancer
1. Effective agents and combinations
For more than 40 years, fluorouracil has been the backbone of chemotherapy
treatment for advanced colorectal disease not amenable to surgical or
radiotherapeutic control. Chemotherapy combinations with fluorouracil, including
leucovorin, irinotecan, and oxaliplatin, have demonstrated equal efficacy in both
first- and second-line settings.62 The addition of the anti-VEGF monoclonal antibody
bevacizumab to chemotherapy as well as the use of anti-EGFR monoclonal
antibodies cetuximab and panitumumab in patients who are RAS wild-type alone or
with chemotherapy has further improved response rates and survival even further to
beyond 2 years. Irinotecan can be used in combination with fluorouracil or alone
with or without a monoclonal antibody added. Oxaliplatin does not have efficacy in
colorectal cancer without fluorouracil. Capecitabine has been shown to be
noninferior to fluorouracil and therefore can be used on its own or in combination,
although it should be noted that folinic acid, fluorouracil, and irinotecan (FOLFIRI)
regimen has been shown to be superior and less toxic to capecitabine and irinotecan
in a large phase III study (BICC-C trial), so this combination is not recommended.63
The fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) regimen as a
first-line regimen may improve response rates and survival (compared to FOLFIRI)
at the cost of increased toxicity, but only one or two studies confirmed these efficacy
results.64 In the recent phase III TRIBE trial, patients were randomized to first-line
treatment with either FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab and it
was found that the FOLFIRINOX/bevacizumab significantly increased PFS (median,
9.7 vs. 12.2 months; HR, 0.73 [0.60 to 0.88]; p = 0.0012) and response rate (53%
vs. 65%; p = 0.006).65 The combination of bevacizumab with cetuximab or
panitumumab in addition to chemotherapy in first-line therapy (CAIRO2 and PACCE
studies, respectively) showed significant worsening of PFS as well as increased
toxicity; therefore, this combination is not currently recommended.66,67
2. EGFR and bevacizumab
The FIRE-3 study randomized patients with KRAS exon 2 wild-type tumors to first-
line treatment with FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab and
 found that patients had similar response rates, but patients who received FOLFIRI
plus cetuximab had an OS benefit (28.7 vs. 25.0 months; HR, 0.77; 95% CI, 0.62 to
0.96; p = 0.017).68 The more recent CALGB/SWOG 80405 trial included unselected
patients with metastatic colorectal cancer who received treatment according to
physician-selected chemotherapy (FOLFIRI or mFOLFOX6) and were randomized
to cetuximab, bevacizumab, or both (the third arm was subsequently closed). In this
study, expanded RAS was tested in all wild-type RAS exon 2 including KRAS exons 3
and 4 and NRAS exons 2 and 3, and it was found in the expanded RAS wild-type
population, the median OS was pushed beyond 30 months. There was no significant
difference between the cetuximab and bevacizumab in combination with
chemotherapy (32 vs. 31.2 months) and no difference in the PFS. However, there
was higher response achieved in the cetuximab arm in the expanded RAS population
(68.6% vs. 53.6%; p < 0.01).69 Extended RAS testing was also performed on the
KRAS exon 2 wild-type patients of the FIRE-3 trial and an independent radiologic
review was performed to evaluate tumor response according to RECIST 1.1, and it
was found that patients with extended RAS wild-type tumors, the ORR was 72% in
the cetuximab arm versus 56.1% in the bevacizumab arm (p = 0.003). In addition,
OS favored the cetuximab arm at 33.1 versus 25.0 months in the bevacizumab arm
(HR, 0.697; p = 0.0059).70 Lastly, the BRiTE study, which was a large
observational cohort design, indicated a potential improved OS with continuation of
bevacizumab beyond progression of first-line therapy (19.9 vs. 31.8 months; p <
0.001).71 A survival benefit was further confirmed in the TML study, a prospective
phase III study investigating the impact of continuing bevacizumab treatment in
second-line therapy for patients who progressed after receiving a bevacizumab-
containing regimen in first-line treatment.72 Treatment now represents a continuum
whereby patients who are exposed to all active agents, including fluorouracil,
irinotecan, oxaliplatin, bevacizumab, and anti-EGFR monoclonal antibodies (RAS
wild-type only), over the course of their illness will achieve the maximum survival
advantage, now estimated as a median survival of over 30 months. The FDA
approved the use of panitumumab, an anti-EGFR monoclonal antibody, for use as a
monotherapy in refractory patients with response rates of 10%, stable disease in
27%, and a 4-month improvement in PFS compared to best supportive care.73 Please
note that only patients with RAS wild-type mutational status derive benefit from
these anti-EGFR monoclonal antibodies. It is also important to note that patients can
get an acneiform rash that should be managed aggressively to prevent delays in
therapy.
3. Other VEGF inhibitors
Regorafenib is an oral TKI of several receptors including VEGF1–3, KIT, and
PDGFR-α that has been approved for treatment of metastatic colorectal cancer. Its
effectiveness was demonstrated in the CORRECT trial where 760 patients who had
progressed on several prior therapies were randomized to placebo versus
 regorafenib. Patients treated with regorafenib had a small but significant
improvement in OS (6.4 vs. 5 months; HR, 0.77; 95% CI, 0.64 to 0.94).74 In a
preliminary report at the 2014 European Society for Medical Oncology, another trial
titled CONCUR confirmed the modest OS benefit for regorafenib; however, this
study was done only in Asian patients.75
Aflibercept, a recombinant fusion protein, consisting of VEGF-binding
portions from key domains of human VEGFR-1 and -2, was approved based on the
placebo-controlled VELOUR trial, in which 1,226 patients with oxaliplatin-
refractory metastatic colorectal cancer were randomly assigned to aflibercept (4
mg/kg IV) or placebo, plus FOLFIRI, every 2 weeks until progression. This trial
showed that median OS was significantly longer in patients treated with aflibercept
(13.5 vs. 12.1 months). Side effect profile is similar to bevacizumab.76
The most recently approved angiogenesis inhibitor for the treatment of
metastatic colorectal cancer is ramucirumab, which received FDA-approval in
April 2015. Ramucirumab is a recombinant human monoclonal antibody that binds to
the human VEGFR-2, preventing the interaction of VEGFR-2 to its ligands. This
approval is based on the results of a randomized, double-blind, multinational trial of
1,072 patients with advanced colorectal cancer that progressed during or within 6
months of discontinuation of bevacizumab-, oxaliplatin- and fluoropyrimidine-based
combination chemotherapy. Patients were randomly assigned to receive FOLFIRI
plus placebo or FOLFIRI plus ramucirumab at a dose of 8 mg/kg by intravenous
infusion every 2 weeks. The primary efficacy endpoint was OS. A statistically
significant OS improvement was observed in patients receiving FOLFIRI plus
ramucirumab compared to those receiving FOLFIRI plus placebo (HR, 0.85; 95%
CI, 0.73 to 0.98; p = 0.02). Median OS was 13.3 and 11.7 months for patients on the
FOLFIRI plus ramucirumab and FOLFIRI plus placebo arms, respectively. PFS was
also significantly improved in patients who received ramucirumab in combination
with FOLFIRI (HR, 0.79; 95% CI, 0.70 to 0.90; p < 0.001). Median PFS was 5.7
and 4.5 months, respectively.77 The optimal sequencing VEGF inhibitors in
advanced colorectal cancer remain unclear.
4. Other agents and potential new approaches in refractory disease
Trifluridine-tipiracil (TAS-102) is an oral cytotoxic agent that consists of the
nucleoside analog trifluridine and tipiracil, a potent thymidine phosphorylase
inhibitor.78 This agent was initially approved in Japan for the treatment of refractory
mCRC based on a randomized placebo-controlled phase II trial of 172 patients with
refractory mCRC in whom trifluridine-tipiracil significantly prolonged median
overall survival (9 vs. 6.6 months).79 The U.S. FDA approval was based on a
subsequent phase III trial (RECOURSE) in which 800 patients who were refractory
to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and an
anti-EGFR agents (if wild-type KRAS) were randomly assigned trifluridine-
tipiracil (35 mg/m2 orally twice daily on days 1 through 5, and 8 to 12 of each 28-
 day cycle) or placebo.80 Trifluridine-tipiracil was associated with a significant
prolongation in median overall survival, the primary endpoint (7.1 vs. 5.3 months;
HR 0.68; 95% CI, 0.58 to 0.81). The most frequently observed toxicities were
gastrointestinal and hematologic. Serious adverse events were observed in 30% of
patients receiving trifluridine-tipiracil compared with 34% of the placebo group,
and there was one treatment-related death with trifluridine-tipiracil. Importantly,
gastrointestinal toxicities with trifluridine-tipiracil were almost all grade 1 and 2,
with few grade ≥3 events recorded.
Although experimental at this time, immunotherapeutic approaches to cancer
treatment have been attempted in CRC. Mutations in one of several DNA mismatch
repair (MMR) genes are found in Lynch syndrome and in 15% to 20% of sporadic
colon cancers. The characteristic genetic signature of tumors with deficient MMR is
a high number of DNA replication errors and high levels of DNA microsatellite
instability, which are thought to produce a high number of neoantigens. In the
nonmalignant host, several immune checkpoints exist to dampen the immune
response in order to protect against detrimental inflammation and autoimmunity.
However, in the setting of malignancy, such immune checkpoints can lead to immune
tolerance of the tumor and subsequent progression of malignancy. One well-
characterized checkpoint being targeted in several tumor types is the programmed
death receptor 1 (PD-1). PD-1 is upregulated on activated T cells, and upon
recognition of tumor via the T-cell receptor, PD-1 engagement by programmed death
ligand 1 (PD-L1) can lead to T-cell inactivation. A phase II study in CRC
investigated pembrolizumab, an IgG4 monoclonal antagonist antibody to PD-1. In the
latest analysis of this small study, presented at the 2015 meeting of the American
Society of Clinical Oncology, patients with MMR-deficient mCRC had a 62%
objective response rate and a 92% disease control rate.81 Confirmation in a larger
study is needed.
5. Therapy options
a. Fluorouracil plus high-dose leucovorin (weekly Roswell Park regimen)
■ Leucovorin 500 mg/m2 IV given over 2 hours.
■ Fluorouracil 500 mg/m2 IV bolus injected 1 hour after beginning the
leucovorin infusion.
■ The combination is administered weekly for 6 weeks followed by a 2-week
rest. This regimen is now widely favored as the preferred fluorouracil plus
leucovorin combination.
b. Fluorouracil bolus weekly regimen
■ Leucovorin 20 mg/m2 IV over 2 hours followed by fluorouracil 500 mg/m2
IV bolus injection 1 hour after leucovorin is started. Repeat weekly.
c. Fluorouracil by 24-hour continuous infusion
■ Fluorouracil 2,600 mg/m2 is given by 24-hour continuous infusion IV
weekly plus leucovorin at 500 mg/m2.
 d. Simplified biweekly infusional 5-FU/leucovorin (sLV5FU2)
■ Leucovorin 400 mg/m2 as a 2-hour IV infusion, followed by fluorouracil.
■ Fluorouracil 400 mg/m2 IV bolus on day 1 only, then followed by
fluorouracil 2.4 g/m2 as a continuous IV infusion over 46 to 48 hours.
This regimen is repeated every 2 weeks.
e. FOLFIRI plus ramucirumab
■ Irinotecan 180 mg/m2 IV over 30 to 90 minutes on day 1.
■ Fluorouracil 400 mg/m2 IV bolus on day 1.
■ Leucovorin 400 mg/m2 IV over 30 to 90 minutes on day 1, followed by
■ Fluorouracil 2.4 g/m2 as a continuous infusion over 46 to 48 hours.
■ Ramucirumab 8 mg/kg IV over 60 minutes on day 1.
The cycle is repeated every 2 weeks.
f. Irinotecan
■ Irinotecan 125 mg/m2 as a 90-minute infusion IV is given weekly for 2
weeks with a 1-week rest or 180 mg/m2 every 2 weeks or 300 to 350
mg/m2 every 3 weeks.
g. FOLFIRI
■ Irinotecan 180 mg/m2 IV over 30 to 90 minutes on day 1.
■ Fluorouracil 400 mg/m2 IV bolus on day 1.
■ Leucovorin 400 mg/m2 IV over 30 to 90 minutes on day 1, followed by
■ Fluorouracil 2.4 g/m2 as a continuous infusion over 46 to 48 hours.
The cycle is repeated every 2 weeks
h. Modified FOLFOX6 (mFOLFOX6)
■ Oxaliplatin 85 mg/m2 as a 120-minute infusion IV in 500 mL of 5% dextrose
in water (D5W) on day 1.
■ Leucovorin 400 mg/m2 as a 120-minute infusion IV, followed by
■ Fluorouracil 400 mg/m2 IV bolus on day 1 followed by fluorouracil 2.4
g/m2 as a continuous infusion IV over 46 to 48 hours.
The cycle is repeated every 14 days. Day 1 leucovorin may be given during
the same 2-hour period as the oxaliplatin, but because of the incompatibility of
oxaliplatin with saline, both drugs must be in D5W.
i. FOLFOX4
■ Oxaliplatin 85 mg/m2 as a 2-hour infusion IV in 250 to 500 mL of D5W on
day 1 only simultaneously with leucovorin.
■ Leucovorin 200 mg/m2 as a 2-hour infusion IV on days 1 and 2, followed by
■ Fluorouracil 400 mg/m2 IV bolus on day 1 then fluorouracil 600 mg/m2 as a
22-hour infusion given on days 1 and 2 every 14 days.
mFOLFOX6 is the preferred oxaliplatin-containing regimen.
j. Capecitabine
 ■ Capecitabine is dosed at 800 to 1,250 mg/m2 administered twice daily
orally on days 1 to 14 every 3 weeks (2,000 to 2,500 mg/m2/day). In areas
of the world, including the United States, where food is heavily fortified
with folates, the lower dose of capecitabine has been better tolerated.
k. Capecitabine plus oxaliplatin (XELOX)
■ Oxaliplatin 130 mg/m2 IV day 1.
■ Capecitabine 850 to 1,000 mg/m2 by mouth twice a day for 14 days every
21 days.
Again, the capecitabine dose of 1,000 mg/m2 is considered standard in
Europe, but North American patients, likely due to higher dietary folate intake,
have experienced greater toxicity with this starting dose and therefore are
recommended to start with the lower 850 mg/m2 dosing.
l. FOLFOXIRI
■ Irinotecan 165 mg/m2 IV on day 1.
■ Oxaliplatin 85 mg/m2 IV on day 1.
■ Leucovorin 400 mg/m2 IV on day 1.
■ Fluorouracil 3,200 mg/m2 over 48-hour continuous infusion starting on day
1.
Repeat this regimen every 2 weeks.
m. Bevacizumab
■ Bevacizumab 5 mg/kg IV over 90 minutes (first cycle), 60 minutes (second
cycle), then up to 0.5 mg/kg/minute for each subsequent cycle every other
week given with FOLFOX, FOLFIRI, or sLV5FU2. Bevacizumab can be
used with XELOX, but the dose of 7.5 mg/kg IV every 3 weeks is
recommended.
Please note that the practitioner should exercise extreme caution in patients
with severe bleeding or clotting issues, active coronary artery disease, or
severely uncontrolled hypertension.
n. Cetuximab
■ 400 mg/m2 IV first infusion given over 2 hours, then 250 mg/m2 weekly or
500 mg/m2 IV every 2 weeks.
This can be used alone or in combination with the listed chemotherapy
regimens.
o. Panitumumab
■ 6 mg/kg IV over 60 minutes every 2 weeks.
p. Ramucirumab
■ Ramucirumab 8 mg/kg IV over 60 minutes on day 1.
The cycle is repeated every 2 weeks.
6. Resected hepatic metastases
Recent data have demonstrated that 5-year survival of patients with completely
 resected hepatic metastases secondary to colorectal cancer range from 24% to 58%,
averaging 40%.82–85 The goal of systemic chemotherapy in patients with liver-only
metastatic disease that is deemed initially unresectable is to convert them to a
resectable status, called “conversion therapy.” Chemotherapy can cause liver
damage, so the goal is to balance optimal response with avoiding toxicity.
Generally, patients receive 2 to 4 months of chemotherapy neoadjuvantly followed
by 2 to 4 months of postoperative chemotherapy for a total of 6 months of therapy.
Bevacizumab can interfere with wound healing and therefore requires
discontinuation 4 to 8 weeks prior to surgery.
E. Rectal cancer therapy
1. Preoperative chemoradiation is the standard of care for patients with stages II and
III rectal cancer. The NSABP R-03 showed prospectively, even though it was
underpowered, that preoperative chemoradiation improved DFS with a trend toward
OS compared to postoperative chemoradiation.86 In addition, a German group
showed improved locoregional control (without survival advantage) with
preoperative compared to postoperative chemoradiation, and showed significant
worse acute and long-term toxic effects with postoperative chemoradiation.87
Currently, preoperative chemoradiation employing any of the following regimens is
acceptable, and several trials evaluating the addition of oxaliplatin including SAR-
01 trial, ACCORD 12/0405 PRODIGE 1 trial and the PETACC-6 trial, showed that
this combination added toxicity and did not improve pathologic complete response
at the time of surgery.88–90
a. Fluorouracil 225 mg/m2 daily as a continuous infusion on the days of radiation.
This regimen has become a standard in the United States and Europe.
b. Capecitabine 825 mg/m2 by mouth twice daily on the days of radiation. This
regimen is being compared to fluorouracil in the neoadjuvant setting in a large
ECOG study, but given the noninferiority in the metastatic setting, this is
acceptable.
c. Fluorouracil 400 mg/m2 IV bolus plus leucovorin 20 mg/m2 IV bolus for 4 days
during weeks 1 and 5.
2. Postoperative chemotherapy
The European Organization for Research and Treatment of Cancer 22921 trial
showed nonsignificant trends with adjuvant chemotherapy toward improved PFS and
OS (p = 0.15 and p = 0.12, respectively).91 In a later subset analysis of patients who
were downstaged from neoadjuvant therapy (cT3-T4 to pT0-T2), adjuvant
chemotherapy was shown to improve OS and DFS.92 Based on the MOSAIC trial,
the addition of oxaliplatin to fluorouracil and leucovorin may be a reasonable
strategy for adjuvant chemotherapy in rectal cancer. The recommended
postoperative adjuvant regimen for stage II or III rectal cancers is as follows (see
Section V.D.4. for doses).
 a. sLV5FU2
1) Fluorouracil bolus weekly regimen
If the patient did not receive neoadjuvant therapy, then the following regimens
are recommended for adjuvant therapy:
a) Fluorouracil plus high-dose leucovorin (weekly Roswell Park
regimen). This regimen is given for one cycle prior to chemoradiation
and then two cycles after completion of chemoradiation.
b) mFOLFOX6
c) Capecitabine
3. Follow-up
A pooled analysis of clinical trials suggests that 85% of colorectal cancer
recurrences will occur within 3 years. In the asymptomatic patient, follow-up after
treatment includes history and physical examination, and CEA every 3 to 6 months
for 2 years, then every 6 months for 5 years. Colonoscopy often is performed 1 year
after surgery and then every 3 years if no polyps are found. CT scans of the chest,
abdomen, and pelvis may be considered every 6 months to yearly for 3 years for
patients at high risk for recurrence (i.e., lymphovascular invasion or poorly
differentiated tumors).
F. Complications of therapy or disease
The complications of chemotherapy are those attributable to the individual drugs.
Myelosuppression, nausea, vomiting, and diarrhea are common and may require dose
modification and symptomatic treatment. Radiation complications are similar and also
include dysuria, tenesmus, and rectal discharge of blood or mucus. Phenazopyridine is
useful in treating dysuria, and loperamide or diphenoxylate is recommended for
diarrhea. If toxicity is substantial (grade 3 or 4) during radiotherapy, a treatment delay
of at least 1 week is warranted. During chemotherapy with fluorouracil-based regimens,
mild diarrhea (grade 1) may be treated symptomatically. Moderate diarrhea (grade 2 or
3) is an indication for dose reduction by 50%, and severe diarrhea (grade 3 or 4) is an
indication for stopping chemotherapy for 1 week or longer. Dehydration is a real risk
with grade 3 or 4 diarrhea, and intravenous hydration may be necessary. Tincture of
opium or octreotide 150 μg three times a day may help to alleviate severe diarrhea.
Recent recommendations for management of irinotecan toxicity include evaluation
for a GI syndrome, which can encompass diarrhea, nausea, vomiting, anorexia,
abdominal cramping, dehydration, neutropenia, fever, and electrolyte abnormalities.
Patients receiving irinotecan should undergo weekly assessment, at least during the first
cycle, to evaluate for toxicities. In addition to treating the diarrhea with loperamide,
tincture of opium, or octreotide, oral fluoroquinolone should be initiated in any
neutropenic patient even in the absence of fever or in any patient experiencing fever and
diarrhea even in the absence of neutropenia. Antibiotics should be initiated in any
hospitalized patient with prolonged diarrhea regardless of granulocyte count and should
be continued until resolution of diarrhea. Any patient who experiences significant
 treatment-related diarrhea should not receive irinotecan until diarrhea-free or at
baseline bowel function for at least 24 hours without the use of antidiarrheal agents or
antibiotics. In addition, abdominal cramping should be considered equivalent to
diarrhea.
Oral mucositis can often be prevented on subsequent courses without dose reduction
by holding ice in the mouth for 20 minutes before, during, and after the IV bolus of
fluorouracil. Nausea is usually not severe with fluorouracil regimens and usually
responds to prochlorperazine or dexamethasone. Hematopoietic growth factors are
seldom warranted for the mild neutropenia that is observed with bolus fluorouracil
therapy.
Oxaliplatin causes an acute cold sensitivity associated with distal dysesthesias or
paresthesias and a chronic sensory neuropathy.
Potential bevacizumab toxicities include hypertension, bleeding, delayed wound
healing, arterial thrombosis, proteinuria, and GI perforation. There is also a vascular
syndrome, which can include myocardial infarction, pulmonary embolus, or cerebral
vascular accident.
Cetuximab and panitumumab are associated with acneiform rash, hypersensitivity,
interstitial lung disease, and infusion reactions.

VI. CANCER OF THE ANAL CANAL

Anal cancers, constituting only 2.5% of all cases of large-bowel cancer, were historically
treated by abdominoperineal resection with approximately 50% cure rate.2,93 Major
associations include a human papillomavirus infection; past receptive anal intercourse or
sexually transmitted infection; past cervical, vulvar, or vaginal cancer; immunosuppression
after solid organ transplantation; a human immunodeficiency virus infection; and smoking.94
A. Local disease
It has been found that combined-modality treatment with chemotherapy and radiation is
curative in 75% to 80% of patients and thus allows avoidance of abdominoperineal
resection with retention of anal function. The regimen of 5-FU at 1,000 mg/m2/day for
days 1 to 4 and 29 to 32 and mitomycin 10 mg/m2 on days 1 and 29 with concurrent
radiation was established in the RTOG 98-11 trial.95,96 A large US Gastrointestinal
Intergroup trial compared the standard regimen of mitomycin and fluorouracil versus
preradiation chemotherapy followed by chemoradiotherapy using the regimen of CF.
Five-year DFS and OS were not statistically different (DFS, mitomycin-based 54% vs.
cisplatin-based 60%; p = 0.17; OS, mitomycin-based 75% vs. cisplatin-based 70%; p =
0.10), but the cumulative colostomy rate was decreased with mitomycin-based therapy
(10% vs. 19%; p = 0.02).97 The ACT II trial in the United Kingdom randomized
patients to one of four groups, to receive either mitomycin (12 mg/m2 on day 1) or
cisplatin (60 mg/m2 on days 1 and 29), with fluorouracil (1,000 mg/m2/day on days 1 to
4 and 29 to 32) and radiotherapy (50.4 Gy in 28 daily fractions); with or without two
courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14).
 The complete response rate was similar in the mitomycin and cisplatin groups (90.5%
vs. 89.6%; difference −0.9%; 95% CI, −4.9 to 3.1; p = 0.64) in addition to the 3-year
PFS in the maintenance versus no maintenance groups (74% [95% CI, 69 to 77] vs.
73% [95% CI, 68 to 77]; HR, 0.95; 95% CI, 0.75 to 1.21; p = 0.70).98 It is
recommended that a posttreatment reevaluation with digital rectal examination be done
at 8 to 12 weeks after chemoradiotherapy. Clinical suspicion for persisting disease after
completion of combined-modality therapy should prompt a biopsy, with abdominal
perineal resection for those with biopsy-proven disease persistence/recurrence.
B. Metastatic disease
Metastatic disease is very uncommon in anal cancer, and liver is the most common site
of metastases. In the UKCCCR and EORTC trials, distant metastases developed
following combined-modality therapy in 10% and 17%, respectively.99,100 The most
widely used chemotherapy regimen used for metastatic disease is fluorouracil 1,000
mg/m2/day IV continuously on days 1 to 5 plus cisplatin 100 mg/m2 on day 1 of every
28-day cycle.101
1. Fluorouracil and mitomycin
■ Radiotherapy 4,500 cGy in 25 fractions (5 weeks), concurrent with
fluorouracil and mitomycin.
■ Fluorouracil 1,000 mg/m2 by continuous infusion IV daily for 4 days (days 1
to 4 and 29 to 32).
■ Mitomycin 10 mg/m2 IV on days 1 and 29.
2. Fluorouracil and cisplatin
■ Cisplatin 75 mg/m2 IV on days 1, 29, 57, and 85.
■ Fluorouracil 1,000 mg/m2 by continuous infusion IV on days 1 to 4, 29 to
32, 57 to 60, and 85 to 88.
■ Radiation 45 to 59 Gy, starting on day 57.
3. Metastatic disease
■ Fluorouracil 1,000 mg/m2/day IV continuously on days 1 to 5.
■ Cisplatin 100 mg/m2 IV on day 2. Repeat this regimen every 4 weeks.
■ Cetuximab is currently under investigation in this disease.

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I. ADENOCARCINOMA OF THE PANCREAS
A. Epidemiology
Pancreatic cancer accounts for only 3% of all cancer cases in the United States but it is
the fourth leading cause of cancer death and is responsible for approximately 7% of
cancer-related deaths. The American Cancer Society estimates that about 48,960 people
will be diagnosed with pancreatic cancer and about 40,560 people will die from
pancreatic cancer in the United States in 2015. The overall 5-year survival rate of all
patients diagnosed with pancreatic adenocarcinoma is approximately 6%. For the
majority of patients, the disease is either locally advanced and unresectable or
metastatic at the time of diagnosis, and the median survival in these patients is 3 to 12
months. Approximately 15% of patients present with localized disease that is amenable
to surgical resection; even in the most selective patient subgroups, however, median
survival is only 2 years and anticipated 5-year survival rates are only 12% to 20%.
B. Etiology
Risk factors for pancreatic cancer include age, sex, and race. The disease is more
common in the elderly, with the median age at diagnosis for pancreatic cancer being 71
years of age. Men and African Americans have a higher risk than others. Cigarette
smoking, obesity, diabetes, chronic pancreatitis, liver cirrhosis, Helicobacter pylori
infection, and exposure to chemicals such as β-naphthylamine and benzidine are also
associated with an increased risk. The link between diet and alcohol use and the
development of pancreatic cancer is unclear and currently being studied. The risk of
pancreatic cancer is also increased in patients with certain familial cancer syndromes,
but hereditary pancreatic cancer makes up less than 10% of cases. Hereditary
pancreatic cancer has been observed in hereditary breast and ovarian cancer syndrome
(BRCA2 mutation), familial melanoma (p16/CDKN2A mutation), familial pancreatitis
(PRSS1 mutation), Puetz-Jeghers syndrome (STK11 mutation), von Hippel-Landau
syndrome (VHL mutation) and hereditary nonpolyposis colorectal cancer (most often
MLH1 and MSH2 mutations). Greater than 80% of resected pancreatic cancers harbor
either activating point mutations in KRAS or inactivating mutations of the tumor
suppressor genes p16, p53, BRAF, and DPC4 (SMAD4).
C. Presenting signs and symptoms
Pancreatic cancer–associated symptoms are not specific and usually occur when the
 disease is already incurable. Pain is the most common presenting symptom. It occurs in
three-fourths of patients with carcinoma of the head of the pancreas and in virtually all
patients with carcinoma of the body or tail. Usually, the pain is a dull ache in the
epigastrium that radiates to the right upper quadrant when the tumor is in the head of the
pancreas or to the left upper quadrant when the tumor is in the body or tail; the pain may
radiate to the lumbar region of the back. Weight loss can be significant and is associated
with anorexia, steatorrhea, nausea, diarrhea, and early satiety, which are other
symptoms related to cancer of the pancreas. The nonspecific, vague nature of these
complaints may delay diagnosis for several months. Seventy percent of patients with
carcinoma of the head of the pancreas have jaundice, whereas fewer than 15% of
patients with carcinoma of the pancreatic body have jaundice. Depression and diabetes
commonly precede pancreatic cancer and can be early symptoms. Of patients aged 50
years and older with recent onset of diabetes, about 1% are diagnosed with pancreatic
cancer within 3 years. Physical findings are generally associated with advanced
carcinomas and include weight loss, hepatomegaly, and an abdominal mass. A palpable
gallbladder in the absence of cholecystitis or cholangitis suggests malignant obstruction
of the common bile duct (Courvoisier sign) and it is present in about 25% of all patients
with pancreatic cancer. Other physical findings, which can be indicative of distant
metastases, include Trousseau syndrome (migratory superficial phlebitis), ascites,
Virchow node (left supraclavicular lymph node), a periumbilical mass (Sister Mary
Joseph node), or a palpable pelvic shelf on rectal examination (Blumer shelf).
D. Diagnostic evaluation
Accurate diagnostic imaging is used to determine whether a patient with pancreatic
cancer is a candidate for surgical resection or has an incurable disease. Computed
tomography (CT) is the most commonly used study and is very effective when
performed according to a standard pancreatic protocol with thin slices and triphasic
cross-sectional imaging. CT scans can demonstrate masses in the pancreas or dilatation
of the pancreatic duct or the common bile duct. Sensitivity and specificity of CT are
about 90%, but CT can miss very small tumors. Endoscopic ultrasound may be useful
for staging (i.e., nodal status), determination of major vessel invasion, and for fine
needle aspiration (FNA) for the pathologic determination of tumor. To determine
vascular invasion, there are three options: helical CT, magnetic resonance
arteriography, or endoscopic ultrasound. Percutaneous FNA of suspicious abnormalities
identified on CT scan can confirm the diagnosis of pancreatic cancer with 80% to 90%
sensitivity and 100% specificity. A common histologic hallmark of pancreatic
adenocarcinoma is an associated desmoplastic reaction that, in a given tumor mass, can
vastly overestimate the malignant cell mass. Furthermore, pancreatic cancer may be
associated with varying degrees of acute or chronic pancreatitis or cyst formation,
which may make it difficult to make a diagnosis with FNA and may lead to false-
negative results.
E. Laboratory tests
 The majority of tumor markers have not proven to be specific or sensitive enough for
pancreatic cancer. Cancer antigen 19-9 is a cell surface glycoprotein that is associated
with pancreatic cancer and has been shown to be elevated in 90% of patients with
pancreatic cancer. A 20% or greater fall in the serum marker following treatment is a
good prognostic indicator and is associated with improved survival. Rising serum
levels may be a useful early indicator of recurrent or progressive disease once a
diagnosis has been established, but because of low specificity it is not used as a
screening method. However, there are data to support the obtaining of a CA19-9 level
in all patients in whom pancreatic cancer is suspected.
F. Staging and preoperative evaluation
1. Staging
The primary tumor, regional lymph nodes, and potential sites of metastatic disease
must be carefully assessed. The staging system has been modified to better take into
account “resectability” of disease. Resectable disease is loosely defined as disease
confined to the pancreas without involvement of the celiac axis or major vessels. A
surgeon experienced in pancreatic surgery should evaluate each case individually
when determining resectability as there are numerous clinical caveats.
2. Preoperative evaluation
Preoperative evaluation should be performed stepwise from least invasive to most
invasive as indicated by the clinical situation. Preoperative evaluation can be
stopped when metastatic disease or definite evidence for unresectable locoregional
spread is identified. All patients should undergo triphasic helical CT of the abdomen
for detection of pancreatic masses and evaluation of vessel encasement. If there is
no evidence of metastatic disease and no major blood vessel involvement is
identified, then laparoscopy can be used to identify small metastases in the liver or
peritoneum. The use of positron emission tomography with 2-[18F]fluoro-2-deoxy-
D-glucose in the preoperative evaluation of patients with pancreatic cancer is still
controversial and not routinely used.
G. Primary therapy
1. Surgery
Three-fourths of patients with pancreatic cancer are operative candidates, but only
15% to 20% have resectable tumors. Patients without evident metastatic cancer or
major blood vessel involvement and whose performance status permits operative
intervention are candidates for curative surgery.
2. Combined modality therapy
a. Resected carcinomas
1) Local and distant recurrence continues to be a common problem after
complete resection of pancreatic cancer. Options for the adjuvant treatment of
pancreatic cancer continue to be in evolution. One of the first prospective
randomized studies to explore the role of adjuvant therapy in pancreas
adenocarcinoma was the Gastrointestinal Tumor Study Group (GITSG) trial,
 originally published in 1985.1 This study randomized 43 patients (1974 to
1982) with surgically resected pancreas adenocarcinoma to observation
versus concurrent chemoradiation with bolus fluorouracil (5-FU), followed
by maintenance 5-FU for 2 years. The study showed an overall survival
benefit (median survival: 20 vs. 11 months, p = 0.03) and a 2-year survival
benefit (42% vs. 15%), but this study is criticized for small patient numbers,
low radiation doses (40 Gy), long accrual time, and early termination. The
European Organization for Research and Treatment of Cancer performed a
similar trial (EORTC 40891) that randomized 218 patients with resected
periampullary malignancy (1987 to 1995) to observation versus concurrent
chemoradiation with bolus 5-FU but no maintenance chemotherapy.2 Of these
patients, 114 had a diagnosis of pancreatic adenocarcinoma. On first analysis
with median follow-up of 7.3 years, results in the pancreatic cancer subgroup
showed a trend toward improved outcome in the treatment group (median
survival: 17.1 vs. 12.6 months, p = 0.099); however, long-term follow-up
analysis at median follow-up of 11.7 years showed no significance difference
in survival. This study has also been criticized for low radiation doses and
underpowering of the study.
2) A complicated trial in a 2 × 2 design was completed by the European Group
for Pancreatic Cancer (ESPAC-1) and randomized 289 patients (1994 to
2000) with resected pancreatic adenocarcinoma to one of four treatment arms
—chemoradiation, chemotherapy, combined chemoradiation followed by
chemotherapy, and observation.3 With a median follow-up time of 47 months,
5-year survival of patients treated with chemotherapy was 21% versus 8%
among patients not treated with chemotherapy (median survival: 20.1 vs. 15.5
months, p = 0.009); in addition, the estimated 5-year survival was 10% for
patients treated with chemoradiation compared with 20% for patients who
did not receive chemoradiation (p = 0.05). However, this trial has been
criticized as results are difficult to interpret given several trial design
concerns including selection bias and treatment variability.
3) The Charite Onkologie (CONKO-001) trial enrolled 368 patients (1998 to
2004) with surgically resected pancreatic adenocarcinoma to either six
cycles of gemcitabine or observation.4 This was the first trial showing that
gemcitabine alone in the adjuvant setting can prolong disease-free and
overall survival without significant toxicities compared with observation
alone (median survival 22.8 vs. 20.2 months, p = 0.005, and 5-year survival
of 21% vs. 10%).
4) At the same time as the CONKO-001 trial in Europe, the Radiation Therapy
Oncology Group in North America conducted the RTOG 97-04 randomized
phase III trial.5 This trial randomized 451 patients (1998 to 2002) with
resected pancreatic adenocarcinomas to either gemcitabine or 5-FU for 3
 weeks prior to chemoradiation therapy and 12 weeks following
chemoradiation. This study had the benefit of modern radiation doses and the
addition of gemcitabine to the chemotherapy regimen but did not evaluate the
benefit of radiation to adjuvant chemotherapy. A survival benefit of
gemcitabine over 5-FU (18.8 vs. 16.7 months, p = 0.047) was seen only in
pancreatic head adenocarcinomas.
5) Subsequently, the ESPAC 3 trial initially randomized patients with surgically
resected pancreatic adenocarcinoma to bolus 5-FU/leucovorin versus
gemcitabine versus observation; however, following ESPAC 1 results, the
observation arm was removed.6 This study accrued 1,088 patients from 2000
to 2007 and patients received 6 months of adjuvant therapy. After median
follow-up time of 34 months, there was equivalency between the two
regimens (median survival 23 months with 5-FU/leucovorin and 23.6 months
with gemcitabine). The study also reported that 14% of patients treated with
5-FU developed serious adverse advents (>grade 3) versus 7.5% of patients
treated with gemcitabine.
6) More recently, the preliminary results of the CONKO-005 trial were
presented at the 2015 ASCO meeting. This study randomized 436 patients
from 2008 through 2013 to 6 months of gemcitabine versus combination of
gemcitabine and erlotinib following surgical resection of pancreatic
adenocarcinoma. At a median follow-up of 41 months, there was no
difference in disease-free survival (GemErlo 11.6 months, Gem 11.6 months;
hazard ratio [HR] 0.89) or overall survival (median: GemErlo 24.6 months,
Gem 26.5 months; HR 0.90). Similarly, there was no correlation between
grade of rash and an improved disease-free survival in the GemErlo group.
However, the overall survival curves do show a late divergence in favor of
GemErlo (5-year survival, 28% vs. 19%) which will be followed further.
7) All of these trials show that in an acceptable candidate, chemotherapy
improves survival and therefore adjuvant chemotherapy with 6 months of
gemcitabine or 5-FU/leucovorin represents the standard of care. However,
the addition of radiotherapy is still controversial. Additional retrospective
data, phase II studies, and meta-analysis continue to provide evidence for and
against chemoradiation in the adjuvant setting. At this time, no standardized
regimen has been established for the adjuvant treatment of resected
pancreatic cancer. 5-FU–based chemoradiation with additional gemcitabine
chemotherapy as well as chemotherapy alone with gemcitabine, 5-FU, or
capecitabine are listed in the guidelines for the adjuvant treatment of
pancreatic cancer.
8) Currently, studies are underway looking at different approaches to improve
outcomes in the adjuvant treatment of pancreatic cancer. These include
combination of cytotoxic chemotherapeutic agents, the addition of targeted
 agents, and immunotherapeutic approaches. ESPAC 4 is a large randomized
phase III trial comparing the addition of capecitabine plus gemcitabine with
gemcitabine alone. The trial is powered for an end point of overall survival
with a target of 1,080 patients and will take several more years before results
are available. RTOG 0848 is enrolling 952 patients randomized to
gemcitabine alone compared with erlotinib and gemcitabine for 6 months;
this will be followed by restaging and if no evidence of recurrence, patients
will undergo second randomization with addition of chemoradiation versus
no added therapy.
9) Given the significant survival advantage seen in metastatic pancreatic cancer
with both FOLFIRINOX and the combination of gemcitabine and nab-
paclitaxel compared with single-agent gemcitabine, both of these treatments
are now being studied in the adjuvant setting. PRODIGE 24/ACCORD 24 is
a phase III trial comparing adjuvant chemotherapy with gemcitabine versus
modified FOLFIRINOX (omission of bolus 5-FU) to treat resected
pancreatic adenocarcinoma. Estimated enrollment is 490 patients with
primary outcome of disease-free survival at 3 years and began to accrue in
January 2012. The APACT study is a phase III multicenter randomized study
of nab-paclitaxel plus gemcitabine versus gemcitabine alone as adjuvant
therapy in patients with surgically resected pancreatic adenocarcinoma.
Estimated enrollment is 800 patients with primary outcome measure of
disease-free survival and trial began accrual in March 2014.
10) Up to this point, no vaccine or immunotherapy has demonstrated significant
improvement in overall survival in phase III clinical trials of resected
pancreatic adenocarcinoma patients. However, using the concept of
hyperacute rejection, a vaccine (algenpantucel-L) was recently studied with
promising results in a phase II study. Therefore, a phase III trial was recently
conducted, which randomized 722 patients with surgically resected
pancreatic adenocarcinoma to standard of care treatment of gemcitabine with
or without 5-FU–based chemoradiation and +/− HyperAcute pancreas
immunotherapy (algenpantucel-L). This study has completed enrollment and
results should be available in near future.
11) Currently, alternative adjuvant chemotherapy regimens (with or without
radiotherapy) include the following
a) Gemcitabine alone (1,000 mg/m2 on days 1, 8, and 15 with a 1-week
break) or
b) 5-FU 225 mg/m2 by continuous intravenous (IV) infusion throughout
radiation therapy followed by four to six courses of bolus 5-FU weekly,
or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 with a 1-week break)
or
c) 5-FU 425 mg/m2 by IV push 1 hour after leucovorin 20 mg/m2 by IV push
 daily for 4 days during the first week of radiation therapy and for 3 days
during the fifth week of radiation therapy followed by four to six courses
of bolus 5-FU weekly or gemcitabine (1,000 mg/m2 on days 1, 8, and 15
with a 1-week break) or
d) Capecitabine 1,500 mg/m2 daily in divided doses with radiation therapy
followed by four to six courses of bolus 5-FU weekly or gemcitabine
(1,000 mg/m2 on days 1, 8, and 15 with a 1-week break). Capecitabine
can be used in the chemotherapy-only part of the regimen as well, but
there are no phase III data to confirm capecitabine in this setting.
b. Neoadjuvant chemotherapy for resectable pancreatic adenocar-cinoma
On the basis of the results of the many large phase III trials above, adjuvant
chemotherapy provides a proven survival benefit compared with pancreatic
resection alone. However, because of the significant morbidity associated with
pancreatic surgery, many patients are not able to receive adjuvant therapy within
the therapeutic window provided after surgery. Therefore, a neoadjuvant
sequence of therapy provides a strong theoretical rationale to increase
percentage of patients who see systemic treatment. To date there are no
completed phase III trials studying role of neoadjuvant chemotherapy compared
with adjuvant therapy. A small phase II prospective trial, evaluating neoadjuvant
gemcitabine and cisplatin for resectable pancreatic cancer, demonstrated
feasibility with favorable overall survival. However, results from meta-analysis
have not shown benefit of neoadjuvant therapy over adjuvant therapy in terms of
resectability or survival benefit. Recently, a multicenter U.S. phase II trial
evaluating neoadjuvant and adjuvant gemcitabine and erlotinib (ACOSOG
Z5041) completed recruitment of 123 patients but results are not yet available.
Two phase III trials are currently underway in Europe that are studying the roles
of neoadjuvant chemotherapy and neoadjuvant chemoradiation. The NEOPAC
trial is a randomized multicenter phase III trial comparing adjuvant gemcitabine
with neoadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in patients
with resectable pancreatic cancer. This study completed enrollment of 310
patients and results should be available in near future. The NEOPA trial is a
randomized multicenter phase III trial comparing neoadjuvant chemoradiation
followed by surgery and adjuvant chemotherapy with upfront surgery and
adjuvant chemotherapy in patients with resectable pancreatic cancer. This study
is looking to enroll 410 patients and recently began recruiting patients.
c. Borderline resectable pancreatic cancer
Management of borderline resectable pancreatic cancer remains a challenging
field without a defined approach and requires a multidisciplinary effort. This
subgroup of patients with pancreatic cancer is potentially resectable if they have
a good response with preoperative chemotherapy or combined chemotherapy
with radiation. There are a number of phase II studies looking at gemcitabine-
 based chemotherapy regimens and chemoradiation regimens for the neoadjuvant
treatment of borderline resectable pancreatic cancer. However, there have been
no phase III studies and there is no consensus among groups as to the preferred
chemotherapeutic regimen or whether radiation should be utilized in the
neoadjuvant setting.
d. Localized unresectable carcinoma
1) Over two decades ago, a series of randomized trials conducted by the GITSG
demonstrated superior survival of patients with localized but unresectable
pancreatic cancer when treated with combined modality therapy compared
with patients treated with radiation therapy or chemotherapy alone.7 Around
the same time, the Eastern Cooperative Oncology Group (ECOG) randomly
assigned patients with locally advanced gastric and pancreas cancers to
receive 5-FU alone or in combination with radiation therapy; the study
showed no improvement in progression-free or overall survival. The 2000 to
2001 FFCD/SFRO French study was a phase III trial comparing intensive
induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent
cisplatin) followed by maintenance gemcitabine with gemcitabine alone for
locally advanced pancreatic cancer. This trial demonstrated worse outcome
with chemoradiotherapy (8.6 vs. 13 months; p = 0.03).
2) Subsequently, an ECOG trial compared gemcitabine alone with gemcitabine
and radiotherapy in patients with locally advanced pancreatic cancer.
Although this trial closed prematurely because of poor accrual, it was able to
randomize 71 patients and found an improved survival with the addition of
radiotherapy to gemcitabine (11.1 vs. 9.2 months; p = 0.017). The therapeutic
strategy used by Group Cooperateur Multidisciplinaire en Oncologie
(GERCOR) was to utilize systemic chemotherapy for 3 months alone and
consider chemoradiation at investigator’s discretion if no evidence of
progressive disease. On retrospective analysis, the group found that
chemoradiation significantly improved survival compared with chemotherapy
alone (overall survival 15 vs. 11.7 months; p = 0.009). This strategy was
further evaluated in the international phase III LAP-07 study, with results
presented at ASCO 2013 meeting but not yet published. This study
demonstrated that the addition of radiation did not improve outcomes
following 4 months of systemic therapy in patients with locally advanced
pancreas adenocarcinoma. This study randomized 442 patients to receive
gemcitabine alone or in combination with erlotinib for 4 months. Patients
with controlled disease (269 patients) were then randomized to either 2
additional months of chemotherapy or 2 months of chemoradiation with 54
Gy of radiation therapy with capecitabine. The primary end point was overall
survival after second randomization and no difference was found (16.5
months for chemotherapy arm and 15.3 months for chemoradiation arm).
 3) Given the discrepant data on the benefit of radiation therapy for locally
advanced pancreatic cancer and benefit of FOLFIRINOX in metastatic
pancreatic cancer, a phase III study of modified FOLFIRINOX with or
without radiation therapy in patients with locally advanced pancreatic cancer
was launched in 2013. This study will randomize 172 patients to modified
FOLFIRINOX alone or modified FOLFIRINOX with stereotactic body
radiation therapy (SBRT).
H. Chemotherapy for metastatic disease
Patients with pancreatic cancer are often poor candidates for chemotherapy because of
severe weight loss, poor performance status, severe pain, lack of measurable or
evaluable disease, and presence of jaundice or hepatic involvement, which may
interfere with clearance of therapeutic agents. The primary goals for advanced
pancreatic cancer are palliation and improved survival. Randomized clinical trials
have demonstrated survival and quality-of-life benefits to chemotherapy in selected
patients with advanced pancreatic cancer compared with best supportive care alone.
1. Single agents
A number of single agents have demonstrated clinical activity; however, no agent has
demonstrated consistent complete or partial response rates greater than 20%.
Gemcitabine has been accepted as first-line therapy for metastatic pancreatic cancer
in patients with adequate performance status based on a phase III trial that compared
bolus 5-FU with gemcitabine, with a primary end point being the “clinical benefit
score.”8 Clinical benefit was defined as sustained (more than 4 weeks) improvement
of one of the following parameters without worsening of any of the others:
performance status, composite pain measurement (average pain intensity and
narcotic analgesic use), and weight. The improvement in clinical benefit score in the
gemcitabine and 5-FU arms were 23.8% and 4.8%, respectively (p = 0.0022). In
addition, there was a significant improvement in median survival (5.65 vs. 4.41
months, p = 0.0025) and in survival at 12 months (18% vs. 2%). Therapy was
generally well tolerated with a low incidence of grade 3 or 4 toxicities. The
toxicities with gemcitabine include bone marrow suppression, lethargy, flulike
syndrome, nausea and vomiting, and peripheral edema.
2. Combination chemotherapy
a. For many years, despite promising phase II studies, the combination of
gemcitabine with other cytotoxic drugs, including 5-FU, cisplatin, oxaliplatin,
and irinotecan, had not been proven to be superior to gemcitabine alone in
demonstrating a survival benefit. The first phase III trial to demonstrate a benefit
with combination chemotherapy was the U.K. National Cancer Research Institute
study. This study randomized 533 patients to higher doses of gemcitabine and
capecitabine versus gemcitabine alone and identified a trend toward improved
median overall survival (7.1 vs. 6.2 months, p = 0.077) and a statistically
significant improvement in overall progression-free survival at 12 months
 (13.9% vs. 8.4%, p = 0.004). A second phase III trial of 319 patients similarly
showed a nonstatistically significant trend in median overall survival (8.4 vs.
7.2 months, p = 0.234) and 1-year survival rates (32% vs. 30%) in combination
gemcitabine/capecitabine compared with gemcitabine alone. However, subgroup
analysis showed that patients with a good performance status (KPS of 90 to 100)
had a statistically improved median overall survival (10.1 vs. 7.4 months, p =
0.014) and progression-free survival (HR 0.69, p = 0.022) when treated with
combination gemcitabine/capecitabine compared with gemcitabine alone. In
addition, a meta-analysis of these randomized trials comparing combination
gemcitabine/capecitabine with gemcitabine alone identified a significant
survival benefit in favor of the gemcitabine/capecitabine combination (p = 0.02).
b. The addition of platinum to gemcitabine failed to improve survival over
gemcitabine alone in several phase III trials.9 The largest trial enrolled 400
patients randomized to gemcitabine with cisplatin versus gemcitabine alone and
did not reveal any difference in median overall survival (8.3 vs. 7.2 months, p =
0.38) or progression-free survival (3.9 vs. 3.8 months, p = 0.80). However, a
meta-analysis of five platinum-based randomized trials with a total of 623
patients did reveal a significant improvement in median overall survival (HR =
0.85; p = 0.01) for the combination over gemcitabine alone. A retrospective
review from Johns Hopkins University evaluated 468 metastatic pancreatic
cancer patients who received a cisplatin-based regimen. Patients with a strong
family history of breast, ovarian, or pancreatic cancer had a median overall
survival of 22.9 versus 6.3 months (p < 0.01) for patients with no strong family
history of these cancers. The NCCN has endorsed the combination of a platinum
analog with gemcitabine in the advanced setting, but generally for only patients
with possible hereditary pancreatic cancer.
c. A better understanding of the biology of cancer has led to the development of
novel agents targeting pathways of cancer cell survival. Clinical trials have
explored the combination of gemcitabine with a variety of biological “targeted”
agents such as bevacizumab, cetuximab, and erlotinib over the past decade.
Despite their promise in preclinical studies, most of these studies have not
shown a survival advantage over standard monotherapy gemcitabine. Results of
the Cancer and Leukemia Group B phase III trial, which evaluated gemcitabine
plus bevacizumab (antivascular endothelial growth factor antibody) compared
with gemcitabine plus placebo, and the Southwest Oncology Group phase III
trial, which assessed gemcitabine plus cetuximab (targets epidermal growth
factor receptor [EGFR]) versus gemcitabine alone, did not reveal any
improvement in survival with the addition of the biologic agent. However, in a
phase III trial of 569 patients with advanced or metastatic pancreatic cancer
randomly assigned to receive either erlotinib (inhibitor of EGFR tyrosine
kinase) plus gemcitabine or gemcitabine alone, patients in the erlotinib arm
 showed statistically significant improvement in median and 1-year survival
(6.24 vs. 5.91 months, p = 0.038, and 23% vs. 17%, respectively).10 There was
a slight increase in incidence of grade 3 to 4 skin rash and diarrhea in the group
receiving erlotinib, although there was no overall difference in quality of life
between the two groups. On the basis of this study, the U.S. Food and Drug
Administration approved erlotinib in combination with gemcitabine for first-line
treatment of patients with locally advanced or metastatic pancreatic cancer.
d. In 2011, combination chemotherapy in metastatic pancreatic cancer finally
showed a meaningful survival benefit over single-agent gemcitabine. The
ACCORD phase II/III trial studied 342 patients with previously untreated
pancreatic cancer and randomized patient to FOLFIRINOX versus gemcitabine
alone.11 Patients treated with FOLFIRINOX had a significantly improved median
overall survival (11.1 vs. 6.8 months; p < 0.001) as well as improved
progression-free survival (6.4 vs. 3.3 months; p < 0.001). A higher tumor
response rate was also seen in the FOLFIRINOX arm (31.6% vs. 9.4%; p <
0.001). However, there was a significantly increased incidence of grade 3 and 4
toxicities in the FOLFIRINOX arm compared with gemcitabine.
e. Nab-paclitaxel is the most recently approved first-line treatment for metastatic
pancreatic cancer in combination with gemcitabine.12 Nanoparticle albumin-
bound paclitaxel (nab-paclitaxel) uses nanotechnology to combine human
albumin with paclitaxel, which allows for delivery of an insoluble drug in the
form of nanoparticles to the tumor, increasing the bioavailability of paclitaxel. In
a phase III randomized multicenter trial (MPACT), 861 patients were
randomized to receive gemcitabine plus nab-paclitaxel or gemcitabine alone.
Median overall survival was improved (8.5 vs. 6.7 months, p < 0.001) as was
progression-free survival (5.5 vs. 3.7 months, p < 0.001) in the gemcitabine plus
nab-paclitaxel arm compared with gemcitabine alone. Tumor response rate was
also significantly improved in the combination arm (23% vs. 7%, p < 0.001). As
expected, patients treated with gemcitabine plus nab-paclitaxel combination had
a higher incidence of myelosuppression and peripheral neuropathy.
f. The new combination regimens of gemcitabine with nab-paclitaxel or
FOLFIRINOX have emerged as new frontline options for patients with good
performance status in the treatment of metastatic pancreatic cancer.
3. Current recommendations
a. FOLFIRINOX
■ 5 FU 400 mg/m2 IV on day 1 followed by 2,400 mg/m2 continuous IV
infusion over 46 hours, leucovorin 400 mg/m2 IV on day 1, irinotecan 180
mg/m2 IV on day 1, and oxaliplatin 85 mg/m2 IV on day 1 given every 14
days
■ Gemcitabine plus nab-paclitaxel. Gemcitabine 1,000 mg/m2 IV and nab-
paclitaxel 125 mg/m2 IV weekly for 3 weeks with 1 week off
 b. Gemcitabine plus erlotinib
■ Erlotinib 100 to 150 mg po daily plus gemcitabine 1,000 mg/m2 IV weekly
for 3 weeks with a 1-week break
c. Capecitabine and gemcitabine
■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off and
capecitabine 1,500 mg/m2 IV daily in twice-daily divided doses on days 1
to 14 every 21 days
d. Capecitabine and oxaliplatin
■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off plus
oxaliplatin 130 mg/m2 on day 1 every 3 weeks
e. Single-agent therapy with gemcitabine
■ Gemcitabine 1,000 mg/m2 IV weekly for 3 weeks with 1 week off
4. Second-line chemotherapy
a. Nearly half of the patients with advanced pancreatic cancer who progress on
frontline therapy are able to receive second-line therapy. In a phase III
randomized trial, patients who had progressed on gemcitabine-based
chemotherapy were randomized to best supportive care versus 5-FU, leucovorin,
and oxaliplatin. This study was terminated early because of poor recruitment, but
despite this the combination regimen showed a median survival of 4.82 versus
2.3 months (p = 0.008) and a median overall survival benefit of 9.1 versus 7.9
months (p = 0.031). More recently, the results of the CONKO-003 trial were
published, which was a randomized phase III trial in which 168 patients with
advanced pancreatic cancer who had progressed on gemcitabine were
randomized to 5-FU/leucovorin (FF) versus oxaliplatin and 5-FU/leucovorin
(OFF). Median overall survival was higher in the OFF group compared with FF
alone (5.9 vs. 3.3 months, p = 0.010). On the basis of these trials, the NCCN
recommends 5-FU plus oxaliplatin as second-line treatment in patients who
progressed on gemcitabine-based therapy. However, recently the results of the
recent phase III randomized PANCREOX trial showed that the addition of
oxaliplatin to 5-FU/leucovorin in second-line treatment may be detrimental. This
trial randomized 108 patients with advanced pancreatic cancer who progressed
on gemcitabine-based treatment to receive second-line mFOLFOX6 or
infusional 5-FU/LV. Median overall survival was worse in FOLFOX arm (6.1
vs. 9.9 months, p = 0.02). Furthermore, the addition of oxaliplatin resulted in
increased toxicity with rates of grade 3/4 adverse events of 63% in FOLFOX
arm and 11% in 5-FU/leucovorin.
b. For patients who received FOLFIRINOX in the frontline setting, the second-line
option is gemcitabine-based therapy, although there is no clear evidence to
support this approach. There is no standard of care currently recommended for
patients who progressed beyond two lines of therapy and therefore clinical trials
are recommended for these patients.
 c. Many clinical trials are currently in phase II/III development with different
chemotherapeutic combinations. Recent results of the phase III NAPOLI-1 trial
that looked at irinotecan encapsulated into liposomal-based nanoparticles (MM-
398) were recently released. This study randomized 417 patients with metastatic
pancreatic cancer who progressed on gemcitabine-based regimens to MM-398
and 5-FU/leucovorin versus 5-FU/leucovorin. Median overall survival was
improved with the combination therapy of MM-398 plus 5-FU/leucovorin
compared with 5-FU/leucovorin (6.1 vs. 4.2 months, p = 0.012).

II. PANCREATIC NEUROENDOCRINE TUMORS (PNETS)

A. Epidemiology
Neuroendocrine tumors (NETs) are a heterogeneous family of tumors with a wide and
complex spectrum of clinical behavior. Pancreatic NETs (PNETs) are rare
malignancies with an overall incidence in the United States of 0.32/100,000
people/year. Pancreatic NETs account for approximately 22% to 28% of all
neuroendocrine tumors. The incidence of these tumors has been increasing over the past
30 years with no significant changes in survival. They account for less than 2% of all
digestive malignant tumors and 1% of all endocrine tumors. These tumors cover a
spectrum of neoplasms, many, but not all, of which originate from the pancreatic islets
of Langerhans and are therefore are known as “islet cell tumors.” The peak incidence
occurs between the ages of 70 and 79 years, with rates significantly increasing after 40
years of age.
B. Presentation
The majority of pancreatic neuroendocrine tumors are sporadic; however, they may
arise as a result of familial syndromes such as MEN 1 syndrome, von Hippel-Lindau
disease, and neurofibromatosis type I. PNETs have complex clinical behavior and
clinical presentation depends on the ability of the tumor to secrete hormones and
bioamines. They are broadly categorized into those with and those without a clinical
syndrome and therefore have been termed “functional” or “nonfunctional.” Less than
50% of these tumors secrete one or more hormones excessively, which may cause
clinical symptoms of excessive hormone release: most commonly, insulin or gastrin;
less commonly, glucagon, serotonin, or adrenocorticotropic hormone; and rarely
vasoactive intestinal peptides (VIPs), growth hormone–releasing hormone, or
somatostatin. More than 50% are nonfunctional and are generally discovered through
symptoms related to tumor burden itself or as incidental findings. Most neuroendocrine
tumors (with the exception of insulinomas, of which 90% are benign) are malignant and
have the ability to metastasize, most commonly to lymph nodes or the liver and less
commonly to bone, lung, brain, or other organs. However, these tumors are usually slow
growing with low mitotic activity and often have an insidious presentation. Management
of PNETs depends on the pathologic differentiation, stage at diagnosis, and presence of
symptoms related to hormone secretion. Somatostatin analogs are effectively used to
 inhibit hormonal secretion and improve symptoms in about 75% of patients with
functional tumors and carcinoid syndrome.
C. Primary treatment
1. The majority of pancreatic neuroendocrine tumors are metastatic at the time of
diagnosis and the liver is the predominant area of metastatic disease. In patients with
localized well-differentiated PNETs, 5-year survival is 60% to 100%, while
patients with well-to-moderately differentiated distant metastases have 5-year
survival of 35% and poorly differentiated metastatic PNETs have less than 5% 5-
year survival. Surgical resection is the optimal treatment for pancreatic endocrine
tumors and is the only curative option. However, since more than 50% of patients
are metastatic at time of diagnosis, curative surgery is often not feasible. In these
patients, palliative debulking surgery for the primary tumor and therapy directed to
the liver are recommended. Before resection, the first goal of treatment must be to
control endocrine syndromes.
2. The H+/K+-adenosine triphosphatase inhibitors omeprazole and lansoprazole
successfully control gastric acid secretion in patients with gastrinoma. For patients
with insulinoma, diazoxide, an insulin release inhibitor, is the therapy of choice for
hypoglycemia when dietary measures fail. A diuretic should be given with diazoxide
to prevent water retention. Octreotide acetate is a somatostatin analog that inhibits
gut hormone secretion. It is generally useful for carcinoid and VIPoma syndromes
and is possibly useful for controlling symptoms in patients with glucagonomas,
gonadotrophic hormone–releasing tumors, and gastrinomas. In patients with
unresectable insulinoma, it can reduce insulin secretion by 50% and return blood
glucose levels to normal. However, it must be initiated cautiously in patients in the
hospital because profound hypoglycemia may occur. The usual starting dose of
octreotide is 50 μg subcutaneously twice a day; thereafter, the dose and frequency of
injections can be increased to 100 μg three times a day. More recently, a long-acting
preparation (octreotide LAR) has become available. The dose should be 20 to 30
mg intramuscularly monthly, depending on doses that the patient was requiring of the
short-acting preparation. It is designed to provide the convenience of once-a-month
or twice-a-month injections once a stable dose of the shorter-acting preparation is
established.
a. The treatment of pancreatic NETs is dependent upon grade and proliferation
index. The WHO classification system of 2010 differentiates between the terms
NET and neuroendocrine carcinoma (NEC). This classification system uses the
proliferation index (Ki-67, MIB-1), angioinvasion, and mitoses as important
factors to divide tumors into well-differentiated NETs (<2 cm in size, <2% Ki-
67 index), well-differentiated NEC (>2 cm in size, >2% Ki-67 index or
angioinvasive), and poorly differentiated NECs (>20% Ki-67 index). The
European Neuroendocrine Tumor Society (ENETS) has proposed a grading
system for these tumors (G1, G2, G3) on the basis of the mitotic count and the
 Ki-67 index. G1 tumors exhibit Ki-67 in <2% of tumor cells, G2 tumors in 2%
to 20%, and G3 tumors in >20%. In general, G1 and G2 refer to well-
differentiated NETs and G3 refers to poorly differentiated NECs.
b. Adjuvant therapy. Currently, no evidence exists to support the use of adjuvant
therapy in cases of fully resected PNETs. Consideration should be given for
surgically resected high-grade (G3) lesions given high risk of recurrence.
Extrapolation from the adjuvant treatment of small cell lung cancer may be
considered.
3. Management of locally advanced or metastatic islet cell tumors
a. Surgical resection and somatostatin analogs
Surgical resection is recommended for resectable locoregional recurrence.
Patients with metastatic disease to the liver should be considered for surgical
resection as well. However, for patients who are found to be unresectable and
have symptomatic or clinically significant tumor burden, somatostatin analogs
can be helpful in the management of symptomatic disease related to hormonal
secretion.13 The most commonly utilized somatostatin analogs in clinical studies
for PNETs are octreotide, lanreotide, and pasireotide. A phase III placebo–
controlled randomized study comparing long-acting octreotide with placebo for
the treatment of midgut neuroendocrine tumors demonstrated a 66% reduction in
risk of disease progression.14 The PROMID study showed antitumor benefit in
patients with functioning and nonfunctioning tumors treated with octreotide LAR.
In an analysis of patients with nonfunctioning tumors, time to tumor progression
for patients receiving octreotide LAR was 28.8 versus 5.9 months for those on
placebo (HR = 0.25). For patients with functioning tumors, time to tumor
progression for patients receiving octreotide LAR was 14.3 and 5.5 months for
those on placebo (HR = 0.23). The utility of somatostatin analogs was recently
validated by the CLARINET trial in which 204 advanced nonfunctioning G1 or
G2 NET patients including PNETs were randomized to lanreotide versus
placebo and showed a significant improvement in progression-free survival.
4. Standard chemotherapy
a. PNETs are more responsive to systemic chemotherapy than non-PNETs, and
chemotherapy is typically considered for patients with progressive disease (G3)
and rapidly growing G1/G2 tumors. The systemic chemotherapeutic agents that
have shown most benefit in PNETs are streptozocin, doxorubicin, 5-FU, and
temozolomide. Streptozocin is the most active single agent, with a 50% response
rate but has considerable renal and hematologic toxicity. The addition of other
agents such as 5-FU and doxorubicin was associated with even higher response
rates up to 70% and prolonged progression-free survival. The combination of
streptozocin and doxorubicin was demonstrated to have a superior response rate
(69%), median survival (26.5 months), and time to tumor progression (20
months) than the combination of streptozocin and 5-FU or single-agent
 chlorozotocin in a North Central Cancer Treatment Group study.15 The dosing of
this regimen was streptozocin 500 mg/m2 IV on days 1 to 5 and doxorubicin 50
mg/m2 IV on days 1 and 22; this regimen was repeated every 6 weeks. Toxicity
from this regimen was common, with renal impairment occurring in about 30%
of patients receiving a streptozotocin-based regimen; nausea and vomiting in
about 60% of patients; and leukopenia in about 75%. A more recent phase III
study comparing streptozotocin and 5-FU with doxorubicin and 5-FU
demonstrated improved median survival in the streptozotocin/5-FU arm (24.3
vs. 15.7 months, p = 0.03).
b. Another agent that has demonstrated efficacy against PNETs in phase II trials is
temozolomide. A single-arm retrospective review investigating the use of oral
temozolomide and capecitabine therapy observed a 70% objective response rate
with a median progression-free survival of 18 months and an overall survival of
92% at 2 years. This combination has not been tested in a randomized phase III
trial to date and it is unknown whether temozolomide monotherapy is as
effective as the combination therapy.
c. Platinum-based therapy remains the standard first-line option for patients with
high-grade or G3 PNETs. Commonly used regimens include cisplatin +
etoposide, carboplatin + etoposide, and carboplatin + paclitaxel. The
combination of cisplatin and etoposide remains the standard of care for patients
who have high-grade or G3 PNETs, with an observed 41.5% objective response
with duration of response of 9.2 months. Currently there are no phase III trials
that have investigated second-line chemotherapy for high-grade or G3 NETs.
Temozolomide +/− capecitabine has demonstrated 33% response rate with a
median response duration of 19 months in patients who received
cisplatin/etoposide as first-line therapy.
5. Targeted therapies
a. For cases with disease stabilization as primary goal, targeted therapy is a
recommended treatment option. Recent investigations related to the molecular
biology of PNETs have revealed elevated expression of several cellular growth
factors and their receptors. Studies have particularly focused on the role of
VEGF and mTOR pathways. Recent trials associated with targeted agents have
indicated antitumor activity associated with bevacizumab and several tyrosine
kinase inhibitors that inhibit VEGFR, as well as the mTOR inhibitor everolimus.
These agents seem to be more effective in PNETs than in advanced
gastrointestinal NETs.
b. A recent phase III clinical trial (RADIANT-3) examined the use of everolimus
(10 mg daily) in 410 patients with advanced low- or intermediate-grade PNETs
and showed a progression-free survival of 11 months with everolimus versus 4.6
months with a placebo (HR 0.35; p < 0.001). The benefit from everolimus
appeared to be primarily stable disease and minor tumor shrinkage. There was
 no difference in overall survival between the two groups. Adverse events in
>30% of patients included stomatitis, rash, diarrhea, fatigue, and infections. The
grade 3 or 4 adverse events occurring in at least 5% of patients were anemia,
hyperglycemia, and stomatitis.
c. Another international phase III trial in patients with advanced well-differentiated
PNETs comparing sunitinib (37.5 mg once a day) with placebo was closed
prematurely after accruing 171 patients. Interim analysis revealed a significant
difference in progression-free survival (11.4 vs. 5.5 months; HR 0.42; p <
0.001). Adverse events in >30% of patients included diarrhea, nausea, asthenia,
vomiting, and fatigue. Grade 3 or 4 adverse events occurring in at least 5% of
patients with sunitinib were diarrhea, asthenia, fatigue, neutropenia, abdominal
pain, hypertension, and palmar-plantar erythrodysesthesia.
d. Currently no data have been used to compare everolimus with sunitinib or to
assess the sequencing of these agents. The choice of agent should be based on
patient preference, comorbidities, toxicity profile, tolerance, and availability.
6. Radionuclides
Peptide receptor radionuclide therapy delivers radioisotopes in a targeted fashion
and is considered a standard approach among patients with octreotide avid disease.
Studies have demonstrated a 36% partial response rate in nonfunctional PNETs 3
months after last administration. Grade 3 hematologic and renal toxicities are
typically reported in 5% to 40% of patients.

III. CARCINOMA OF THE BILE DUCTS (CHOLANGIOCARCINOMA) AND

GALLBLADDER CARCINOMA
A. Introduction
Biliary tract cancers are invasive adenocarcinomas that arise from the epithelial lining
of the gallbladder and intrahepatic (peripheral) and extrahepatic (hilar and distal
biliary tree) bile ducts. Biliary tract cancers affect approximately 14,000 people in the
United States annually. In 2015, there will be an estimated 10,910 new cases and 3,700
deaths in the United States. However, this figure does not include cases of intrahepatic
biliary cancers, which are included with primary liver cancers in national databases.
Although the incidence of extrahepatic cholangiocarcinoma has remained constant, the
incidence of intrahepatic cholangiocarcinoma has increased markedly over the past two
decades.
B. Epidemiology and presentation
The development of biliary tract cancers appears to be related to chronic inflammatory
conditions, autoimmune disease, biliary calculi, several infectious agents, and certain
carcinogens. Risk factors for gallbladder cancer, of which cholelithiasis is the most
prevalent, are associated with the presence of chronic inflammation. Calcification of
the gallbladder (porcelain gallbladder), a result of chronic inflammation, has also been
associated with gallbladder cancer. No predisposing factors have been found in most
 patients diagnosed with cholangiocarcinoma, although there is evidence that particular
risk factors may be associated with the disease in some patients. These risk factors are
associated with chronic inflammation and include cholelithiasis, ulcerative colitis, liver
flukes, exposure to thorium oxide (Thorotrast), primary sclerosing cholangitis, and
congenital anomalies such as choledochal cysts. Recently, intrahepatic
cholangiocarcinoma has been associated with hepatitis C viral infection and may be
partly responsible for an increased incidence of intrahepatic cholangiocarcinoma.
Biliary tract cancers are usually diagnosed at a late stage because of the aggressive
nature and rapid spreading of these tumors. Patients with gallbladder cancer can present
with a clinical presentation that mimics biliary colic or chronic cholecystitis. Primary
gallbladder malignancy is incidentally found in 0.4% to 2% of laparoscopic
cholecystectomy specimens. Carcinoma of the gallbladder most commonly presents
with pain, nausea and vomiting, and weight loss. Other possible clinical presentations
of gallbladder cancer include a suspicious mass detected on ultrasound or jaundice.
About one-third of patients present with jaundice, which is typically associated with
advanced disease not amenable to surgical resection. Patients with intrahepatic
cholangiocarcinoma are likely to present with nonspecific symptoms such as fever,
weight loss, or abdominal pain; symptoms of biliary obstruction are uncommon.
Alternatively, intrahepatic cholangiocarcinoma may be detected incidentally as an
isolated intrahepatic mass on imaging. In contrast, patients with extrahepatic
cholangiocarcinoma are more likely to present with jaundice with evidence of biliary
obstruction on subsequent imaging.
C. Natural history and pathogenesis
Biliary tract malignancies are related anatomically and are characterized by local
invasion, regional lymph node metastasis, vascular encasement, and distant metastasis.
The only chance for cure of biliary tract cancers is complete surgical resection;
however, only 10% of patients present with early-stage disease and are considered
surgical candidates. The key prognostic factors are completeness of resection, lymph
node status, and tumor differentiation. However, recurrence rates even in this group of
resectable patients remains quite high and thus systemic chemotherapy in either the
adjuvant or palliative setting is the mainstay of the treatment plan for almost all patients.
Median overall survival in patients with unresectable or metastatic biliary tract cancer
is less than 1 year. Gallbladder cancer appears to be the most aggressive of biliary tract
cancers and has the shortest median survival. Although biliary tract cancers are similar
in their aggressive course and resistance to chemotherapy, gallbladder cancer,
intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma have different
molecular profiles and ideally should be studied independently. However, because of a
relatively small number of patients, these diseases have been combined in most clinical
trials analyzing systemic chemotherapy.
D. Chemotherapy
1. The advantage of systemic chemotherapy over supportive care alone in improving
 survival and quality of life was first suggested in an evaluation of 5-FU plus
leucovorin and etoposide therapy versus best supportive care among a group of
patients with pancreatic and biliary tract cancer.16 The overall survival in the
chemotherapy group was 6 versus 2.5 months for the supportive care group but only
37/90 patients had biliary tract cancers. More recently, a randomized controlled
phase II study randomized 81 patients with unresectable gallbladder cancer to either
best supportive care versus 5-FU/leucovorin or GEMOX (gemcitabine and
oxaliplatin). Median survival was 4.5 months in BSC arm, 4.6 months in 5-
FU/leucovorin arm, and 9.5 months in the GEMOX arm.
2. In 2010, the randomized phase III Advanced Biliary Cancer (ABC)-02 study was
published and compared gemcitabine with gemcitabine and cisplatin.17 This study
randomized 410 patients with locally advanced or metastatic intrahepatic and
extrahepatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma.
The median overall survival was significantly longer in the patients treated with
gemcitabine and cisplatin versus gemcitabine alone (11.7 vs. 8.1 months; HR 0.64; p
< 0.001). Interestingly, the survival advantage seen with cisplatin and gemcitabine
was achieved without an increase in grade 3 or 4 toxicity. Similar results were seen
in a Japanese randomized phase II trial and in a pooled analysis of clinical trials.
Patients with a good performance status (PS 0-1) seemed to have the most benefit
while those with poor performance status (PS 2) and ampullary carcinoma had the
smallest benefit. Therefore, the combination of gemcitabine and cisplatin (cisplatin,
25 mg/m2 of body surface area followed by gemcitabine, 1,000 mg/m2 on days 1 and
8 every 3 weeks) is the standard treatment for nonresectable cholangiocarcinoma in
the first line. When contraindications exist for treatment with cisplatin such as renal
insufficiency, cisplatin may be replaced with oxaliplatin. The combination of
gemcitabine and oxaliplatin has demonstrated efficacy and safety in several phase II
studies. Treatment with gemcitabine as a single agent is still considered appropriate
for elderly patients and patients with comorbidities. Also those with a poor
performance status may benefit from gemcitabine as symptom control was better in
patients treated with gemcitabine than with best supportive care only.
3. In addition to gemcitabine-based chemotherapy, fluoropyrimidines have shown
efficacy in treatment of cholangiocarcinoma. Combined treatment with gemcitabine
plus 5-FU as well as gemcitabine plus capecitabine revealed response rates of 30%
in multiple phase II randomized studies. Similar results have been seen in phase II
randomized trials of platinum-based agents used in combination with 5-FU or
capecitabine. The combination agents consistently demonstrated response rates and
median survival times greater than 5-FU alone.
4. Currently, most ongoing trials in patients with advanced cholangiocarcinoma are
looking to extend the benefit of gemcitabine and cisplatin, potentially by adding one
or more targeted agents to the combination. The recently published phase II study
BINGO randomized 150 patients to GEMOX with or without cetuximab and did not
 reveal any benefit to the addition of cetuximab. There are numerous other phase II
trials ongoing looking at role of VEGF inhibitors, MEK inhibitors, and multikinase
inhibitors.
5. Other studies are trying to identify effective regimens for patients who have
progressed on first-line chemotherapy. Currently, there are no randomized trials that
have shown a benefit to second-line chemotherapy. Recently, the results of a large
retrospective review of second-line chemotherapy outcomes for patients with
advanced biliary tract cancers were published. The authors concluded that patients
who obtained a second-line treatment had a survival benefit compared with those
who received best supportive care. This study also provides a context for future
clinical trials to improve upon the 2.8-month median progression-free survival that
was observed.
E. Current recommendations
1. Patients with a good performance status
a. Gemcitabine/cisplatin
■ Cisplatin, 25 mg/m2 on day 1 with gemcitabine 1,000 mg/m2 on days 1 and
8 every 3 weeks or
b. Gemcitabine/oxaliplatin (patients with contraindication to cisplatin, i.e., renal
insufficiency).
■ Oxaliplatin 130 mg/m2 on day 1 with gemcitabine 1,000 mg/m2 on days 1
and 8 every 3 weeks or
c. Gemcitabine/capecitabine
■ Capecitabine 1,500 mg/m2 daily in twice-daily divided doses on days 1 to
14 and gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks or
d. Capecitabine with cisplatin or oxaliplatin
■ Capecitabine 1,500 mg/m2 daily in twice-daily divided doses on days 1 to
14 plus oxaliplatin 130 mg/m2 or cisplatin 25 mg/m2 on day 1 every 3
weeks or
e. Fluorouracil with cisplatin or oxaliplatin
■ Leucovorin 400 mg/m2 IV infused over 2 hours prior to 5-FU plus 5-FU 400
mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV infused over 46 hours
plus oxaliplatin 100 mg/m2 IV on day 1 every 2 weeks
2. Patients with lesser performance status
Single-agent gemcitabine, capecitabine, or fluorouracil

IV. PRIMARY CARCINOMA OF THE LIVER

A. Epidemiology
Hepatocellular carcinoma (HCC) accounts for 80% to 90% of primary liver cancer.
Hepatocellular carcinoma is a major health problem worldwide with more than
750,000 cases diagnosed each year. It is the fifth most common cancer worldwide and
the second most common cause of cancer-related death, with most cases occurring in
 Asia. Although less common in the United States, the incidence is rising with an
estimated 35,660 to be diagnosed in 2015 with an estimated 24,550 deaths (but this
number also includes intrahepatic bile duct cancer as well). Ninety percent of primary
cancers of the liver are HCC or hepatoma; the remaining cancers include
cholangiocarcinomas (about 7%), hepatoblastomas, angiosarcomas, and other
sarcomas. In the United States, the peak incidence is in the sixth decade of life, whereas
in Asia and Africa it occurs much earlier in life.
B. Etiology and risk factors
The rates of HCC are two to four times higher in males than females. Eighty to ninety
percent of cases of HCC develop in a cirrhotic liver, and cirrhosis is the strongest
predisposing factor for HCC. Overall, 80% of cases of HCC are attributable to chronic
infections with either hepatitis B or hepatitis C virus. Chronic hepatitis B viral infection
is common in Asian and African countries and accounts for most cases of HCC. Chronic
carriers of hepatitis B have a 100-fold relative risk for developing HCC with an annual
incidence rate of 2% to 6% in cirrhotic patients. In contrast, chronic hepatitis C viral
infection is more common in Western countries. Other causes of HCC include alcoholic
liver cirrhosis, aflatoxin (a natural product of the Aspergillus fungus found in various
grains), hereditary hemochromatosis, autoimmune hepatitis, α1-antitrypsin deficiency,
and Wilson disease.
The incidence of HCC is increasing in the United States, particularly among the
population infected with the hepatitis C virus. Approximately 4 million people in the
United States are chronically infected with hepatitis C virus, and the annual incidence
among hepatitis C patients with hepatitis C–related cirrhosis is estimated to be between
2% and 8%. Approximately 1.5 million people are chronically infected with hepatitis B
in the United States; the annual incidence of HCC in patients with hepatitis B–induced
cirrhosis is 2.5%. In those carriers without cirrhosis, the annual incidence is 0.5%.
C. Presenting signs and symptoms
Patients with primary carcinoma of the liver commonly complain of right upper
quadrant pain, abdominal distention, or weight loss. The pain is usually dull or aching
but may be acute and radiate to the right shoulder. Fatigue, loss of appetite, and
unexplained fever may occur. Patients with underlying cirrhosis may present with
hepatic decompensation: new ascites, variceal bleeding, jaundice, or encephalopathy.
Rarely, patients present with paraneoplastic syndromes. Erythrocytosis is the most
common; hypercalcemia, hyperthyroidism, and carcinoid syndrome have also been
described. Physical findings include nodular hepatomegaly with an arterial bruit and
hepatic rub. Extrahepatic spread occurs in about 50% of patients during the course of
the illness. Twenty percent of patients have lung metastases.
D. Diagnostic evaluation and screening
There are several published studies that have demonstrated reduction in HCC mortality
with the utilization of screening programs for high-risk individuals such as those with
cirrhosis or chronic hepatitis viral infections. Serum α-fetoprotein (AFP) and liver
 ultrasound are the most widely used methods for screening for HCC. Most groups
recommend periodic testing with AFP and ultrasonography every 6 to 12 months.
Additional imaging is recommended in the setting of a rising serum AFP or following
identification of a liver nodule on liver ultrasound. HCC lesions are characterized by
arterial hypervascularity, deriving most of their blood supply from the hepatic artery.
This is in contrast to surrounding liver, which receives most of its blood supply from
the portal venous system. Therefore, the most commonly utilized tests for diagnostic
imaging of HCC are triphasic helical CT or triphasic dynamic contrast-enhanced
magnetic resonance imaging (MRI). CT or MRI for lesions greater than 2 cm
demonstrating classic arterial enhancement is diagnostic for HCC. For lesions 1 to 2 cm
in size, a classic arterial enhancement pattern on both CT and MRI is considered
diagnostic for HCC. Liver lesions less than 1 cm should be followed closely with
periodic repeat imaging. Liver lesions greater than 1 cm that do not demonstrate classic
arterial enhancement should undergo tissue biopsy to confirm the diagnosis.
E. Laboratory tests
AFP is a tumor marker that is elevated in 60% to 70% of patients with HCC. Serum
AFP is not a sensitive or specific test for HCC. However, results of AFP testing can be
used in conjunction with imaging to guide management of patients with suspected AFP.
An AFP greater than 200 in a patient with a liver lesion greater than 2 cm has a high
predictive value for HCC and can be considered diagnostic even without the classic
enhancement pattern on imaging.
F. Staging and preoperative evaluation
1. Staging
Patients diagnosed with HCC should undergo an extensive workup that includes
determination of the etiology of underlying liver disease including hepatitis panel,
assessment of other comorbidities, imaging studies to evaluate for metastatic disease
(chest imaging and bone scan as most common sites for metastases are lung, bone,
and abdominal lymph nodes), and evaluation of underlying hepatic function,
including a determination of any evidence of portal hypertension. An effective
staging system should incorporate tumor characteristics and underlying liver disease
(Child-Pugh classification), as both of these factors impact choice of treatment and
patient survival. A number of staging systems for patients with HCC have been
devised. Some of the most commonly utilized include the Okuda staging system,
Cancer of the Liver Italian Program score, Japanese Integrated Staging score,
Chinese University Prognostic Index, simplified (Vauthey) staging for HCC, Izumi
TNM modification, French classification system, and the Barcelona Clinic Liver
Cancer staging classification. Each of these scoring systems has limitations, and
therefore no one staging system has been universally accepted. Following workup,
patients are stratified into one of the following groups: metastatic disease, locally
advanced unresectable disease not amenable to transplantation, resectable or
transplantable but performance status precludes operation, and resectable or
 transplantable with appropriate performance status.
2. Preoperative evaluation
The selection of patients with HCC for surgical resection incorporates information
regarding tumor extent, severity of underlying liver disease, assessment of liver
functional reserve, and general medical condition of the patient. The general criteria
for unresectability of HCC includes large size of tumor with insufficient hepatic
remnant after liver resection, multifocal bilobar lesions, extrahepatic tumor
metastases, and tumor with main portal vein or hepatic vein/inferior vena cava
involvement. In addition, resection is generally recommended only in the presence
of preserved liver function with no evidence of portal hypertension.
G. Primary therapy
At presentation, only 25% of patients with HCC have potentially resectable lesions.
Results of large retrospective studies have demonstrated 5-year survival of 50% to
70% in select patients undergoing liver resection for HCC in the setting of preserved
liver function. However, the number of patients with HCC considered good candidates
for resection in the United States is quite low because the majority of patients have
underling child grade B or C cirrhosis. In addition, recurrence rates at 5 years
following liver resection for HCC are quite high and approach 70%. Liver
transplantation may permit resection of small tumors in patients with advanced
cirrhosis, and survival is similar to or better than that seen after resection without
transplantation. Patients with HCC who meet the Milan criteria for transplantation are
those patients with one nodule less than 5 cm or two to three nodules that are less than 3
cm and no evidence of macrovascular involvement or extrahepatic disease. These
select patients treated with liver transplantation have low recurrence rates with 5-year
survival rates of greater than 75%. The main problem with transplantation is timely
organ availability. Patients with localized disease who are not candidates for either
resection or transplantation should be considered for ablative therapies or
embolization. In addition, for patients awaiting liver transplantation, a number of
studies have investigated the role of locoregional therapies in controlling disease as a
bridge to transplantation. The locoregional therapies available include ablative
therapies such as RFA, microwave ablation, cryoablation, or percutaneous ethanol
injection and embolization therapies such as bland embolization, chemoembolization,
drug-eluting beads, and radioembolization. Newer experimental techniques such as PHP
may also have a role in this setting.
H. Therapy of advanced HCC
1. The majority of patients diagnosed with HCC have advanced disease at presentation
and are not candidates for surgery or locoregional therapies. Unfortunately, HCC is
a relatively chemoresistant tumor and is highly resistant to cytotoxic chemotherapy.
Clinical studies evaluating the use of cytotoxic chemotherapy such as doxorubicin
have reported low response rates to therapy and evidence for a favorable impact on
survival is lacking. Doxorubicin has been the most extensively studied chemotherapy
 in this disease. At doses of 75 mg/m2 every 3 weeks, tumor shrinkage of at least
25% was reported in only 8% of patients and there is small survival benefit
compared with best supportive care. In the past, this had been the standard treatment
of unresectable HCC; however, the toxicities limited its use. In clinical practice,
cumulative doses of more than 400 mg/m2 significantly increase risk of cardiac
damage and cardiomyopathy. Neutropenia also occurs and can lead to sepsis in
setting of biliary obstruction.
2. More recently, two phase III studies have found sorafenib to be beneficial in the
treatment of patients with metastatic or locally advanced HCC. Sorafenib is an oral
multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis. In a
large multicenter, randomized, placebo-controlled phase III trial (SHARP), the
efficacy of sorafenib versus placebo in patients with advanced HCC was
evaluated.18 In this study, 602 patients with advanced measurable HCC, no prior
systemic therapy, good performance status, and preserved liver function were
randomized to either sorafenib 400 mg twice a day or placebo with best supportive
care. Median survival was significantly longer in the sorafenib arm (10.7 vs. 7.9
months, HR = 0.69, p < 0.001). Another phase III trial with similar design, the Asia-
Pacific study, randomized 226 patients in a 2:1 fashion to either sorafenib or
placebo. Patients in this study were Asian and tended to be younger, with underlying
hepatitis B and a higher number of tumor sites compared with the SHARP trial. This
study also demonstrated improved median survival in the sorafenib arm (6.5 vs. 4.2
months, HR = 0.68, p = 0.014). Overall, sorafenib is well tolerated with limited
side effects, the most common being diarrhea, hypertension, and hand-foot skin
reaction. As a result of these studies, sorafenib is now considered the standard of
care for patients with advanced and metastatic HCC who are not candidates for
curative or locoregional therapies, but at present only patients with good liver
function have been rigorously studied.
3. Since the approval of sorafenib by the FDA in November 2007, multiple small
molecule TKIs or monoclonal antibodies to VEGF have shown promising activity in
phase II clinical trials but none of the therapies have been superior to sorafenib in
the phase III setting. Currently there are multiple ongoing clinical trials looking at
role of sorafenib in combination with liver-directed therapies such as SBRT,
radiofrequecy ablation (RFA), and transarterial chemoembolization (TACE). There
are also ongoing clinical trials looking at second-line therapies for patients who
have progressed on sorafenib and have preserved adequate liver function. Agents
such as regorafenib and c-met inhibitors are currently in phase III trials as potential
second-line therapies.
4. Current recommendations
a. Sorafenib
Sorafenib 400 mg po twice daily.
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2. Klinkenbijl JH, Jeekel J, Shamoud T, et al. Adjuvant radiotherapy and 5-fluorouracil
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I. NATURAL HISTORY AND MODES OF TREATMENT
A. Epidemiology and risk factors
Breast cancer, accounting for 25% of all cancers, remains the second most common
cause of cancer worldwide, with an estimated 1.67 million new cancer cases diagnosed
in 2012.1 It is by far the most common cancer in women, both in more and less
economically developed regions, with slightly more cases in less developed (883,000
cases) than in more developed (794,000) regions.1
Incidence rates vary nearly fourfold across the world regions, with rates ranging
from 27 per 100,000 in Middle Africa and Eastern Asia to 96 in Western Europe.1 The
higher incidence of breast cancer in women in Western Europe and the United States is
possibly associated with higher median population age, robust early detection
programs, better control of other causes of early life mortality, and recent increases in
obesity. It has been suggested that inflammation could play a role in the pathogenesis of
breast and other cancers in obese and overweight patients.2–4 The rising breast cancer
incidence in women of developing nations has also been attributed to “westernized”
lifestyle changes including dietary changes, decreased exercise, and reproductive
changes such as delayed childbearing, lower parity, and reduced breast-feeding.5,6
Breast cancer incidence has, however, declined in developed countries since 2003
and is associated with the marked decrease in the use of HRT among postmenopausal
women following publication of the Women Health Initiative report that showed an
increased breast cancer risk of about 10% for every 5 years of HRT use and even
greater risk with combined estrogen/progesterone products than with estrogen therapy
alone.7 Since 2004, overall breast cancer incidence rates have remained relatively
stable.8
Breast cancer is less lethal than many other solid tumors and ranks as the fifth cause
of death from cancer overall (522,000 deaths). It is, however, the most frequent cause
of cancer death in women in less developed regions (324,000 deaths, 14.3% of total)
but the second cause of cancer death in more developed regions (198,000 deaths,
15.4%) after lung cancer.1 The range in mortality rates between world regions is less
than that for incidence because of the more favorable survival of breast cancer in (high
incidence) developed regions, with rates ranging from 6 per 100,000 in Eastern Asia to
20 per 100,000 in Western Africa.1 Currently, more women survive because of earlier
 diagnosis and better therapy,9 and the absolute number of deaths per year has been
declining since about 1990 with a disease-specific mortality decrease of 2.2%/year
since then, with a more prominent decline noted in women younger than 50 years
(3.1%/year) than women 50 and older (1.9%/year).8
The incidence of breast cancer varies among different racial groups and ethnicities.
Caucasian women in the United States are more likely to develop breast cancer
compared with African American women for most age groups; however, African
American women have a higher incidence rate before age 40 and are more likely to die
from breast cancer at every age.10
This is confounded, however, by the general increase in cancer-related mortality for
lower socioeconomic groups regardless of specific ethnicity.
Although discrete causes of breast cancer cannot be identified in most individual
women, many factors increase a woman’s risk of developing the disease. Among the
strongest of the risk factors is family history, particularly if more than one family
member has developed breast cancer at an early age.11
More precisely, genetic linkage analysis led to the discovery of dominant germ-line
mutations in two tumor-suppressor genes, BRCA1 and BRCA2, localized to
chromosomes 17 and 13, respectively, which are associated with a high risk of female
breast cancer as well as ovarian cancer (BRCA1 and BRCA2), male breast cancer
(BRCA2), and other cancers.12–17 Although these mutations account for less than 10% of
all cases of breast cancer, together they account for about 45% of families with multiple
cases of breast cancer and up to 90% of families with both breast and ovarian
cancer.18,19 These mutations are present in less than 1% of the general population, but
occur more often in certain ethnic groups such as those of Ashkenazi (Eastern
European) Jewish descent.18 However, if a woman with breast cancer is below the age
of 50 years and has any relative who developed breast cancer before she was 50 years
old, her chance of having a mutation in BRCA1 or BRCA2 rises to as much as 25%.19
Other factors that increase her probability of a mutation include any relative with
ovarian cancer or a personal history of bilateral breast cancer or ovarian cancer.
Carriers of these mutations have up to a 70% lifetime risk of breast cancer, depending
on familial history, perhaps the specific mutation, and other cellular genes that may
modify penetrance.17 The 5-year survival rate of patients with either of the BRCA
mutations is not significantly less than for other patients with breast cancer after
adjusting for the specific subtypes of breast cancer carriers tend to develop.
It is important to note that most patients with a family history of breast cancer do not
have a defined inherited mutation and other, less common, causative mutations are
sometimes seen.19,20 Rarer inherited conditions associated with increased breast cancer
risk include Li-Fraumeni (germ-line mutations in p53) and Cowden syndromes (80%
due to mutations in PTEN) and a number of more common genetic mutations. PALB2
(partner and localizer of BRCA2) has been previously identified as a moderate-risk
 gene in breast cancer and germ-line loss-of-function PALB2 mutation carriers have a
lifetime risk of breast cancer as high as the risk borne by BRCA2 mutation carriers.21,22
Beyond molecular testing for BRCA1/2, multiplex test panels are now commercially
available, identifying both high- and moderate-penetrance genes for use in families who
test negative for known familial cancer syndromes. However, a limited understanding of
the risk associated with moderate-penetrance genes and the potential for detection of
variants of uncertain clinical significance (VUCS) complicate the interpretation of test
results. Comprehensive genetic counseling should be done prior to testing, to ensure test
results appropriately modify the clinical care of these patients.23,24
Additional factors that increase breast cancer risk are early menarche, late
menopause, nulliparity, late age at birth of first child, and prior benign breast disease
(particularly if there is a high degree of benign epithelial atypia).25,26 Although breast
cancer may occur among men, such cases represent less than 1% of all breast cancers.
Male carriers of BRCA2 mutations have a 6% lifetime risk of breast cancer,
significantly increasing their risk in comparison with the general population.
B. Prevention
The risk of hormone receptor–positive breast cancer can be reduced. At least three
trials using selective estrogen receptor modulators (SERMs) have demonstrated that 3
to 5 years of preventive treatment with these agents reduces the rate of breast cancer
development over the short term.27–30 Women at increased risk because of family
history, age, and other risk factors, who are treated with the SERM tamoxifen, 20
mg/day, were found to have a 45% reduction in the rate of occurrence of invasive breast
cancer compared with women treated with placebo. Noninvasive disease and
preneoplastic breast lesions were also decreased. Raloxifene, 60 or 120 mg/day, also
appears to reduce the risk of breast cancer in postmenopausal women (who had
osteoporosis and a standard or reduced risk of breast cancer), with a relative risk of
0.26.31 Despite these benefits, SERMs are associated with an increased risk of both
venous thromboembolism and endometrial cancer, although the risks with raloxifene
appear to be lower than tamoxifen, which has been associated with an increased risk
for endometrial cancer of 1.5 to 2 times that of untreated women.27 In addition, neither
of these agents have demonstrated an improvement in survival when used for breast
cancer prevention. In the Study of Tamoxifen against Raloxifene trial, these agents were
compared and although there were no significant mortality differences, raloxifene was
found to have 76% of the effectiveness of tamoxifen in preventing invasive disease and
grew closer over time to tamoxifen in preventing noninvasive disease, with far less
toxicity (e.g., highly significantly less endometrial cancer and less thromboembolic
events).32 A meta-analysis of all nine prevention trials with tamoxifen, raloxifene,
arzoxifene, and lasofoxifene showed an overall 38% reduction in breast cancer
incidence.33 Indeed after 20 years of follow-up, the long-term benefits of 5 years of
tamoxifen remain with a number needed to treat (NNT) of 22 to prevent one breast
 cancer (95% CI, 19 to 26).34 These agents have similar but not identical toxicity
profiles that may guide clinical decisions.
Aromatase inhibitors (AIs) have also been shown to be beneficial as prevention in
the postmenopausal population at high risk. Five years of exemestane significantly
reduced the incidence of invasive breast cancers by 65% with only minimal changes in
health-related quality of life and without serious toxic effects.35 Similarly, anastrozole
was shown to reduce the risk of developing hormone receptor–positive invasive breast
cancer and preinvasive cancers by 50%.36
There are several options in the management of women at very high risk because of
family history or known gene mutations. Increased surveillance, through the addition of
magnetic resonance imaging (MRI) screening on a yearly basis as a supplement to
standard mammography, was effective in a high-risk population. In mutation carriers
who are at risk for both breast and ovarian cancer, bilateral oophorectomy after
childbearing age (before age 50 years but possibly as early as 35) has been
recommended because of the inadequacy of screening tests for ovarian cancer and
because it reduces the risk of both primary breast cancer by approximately 50% and the
risk of ovarian cancer by approximately 80% and is associated with a lower all-cause
mortality.37–39 Risk-reducing mastectomy is an effective option with a relative risk
reduction of about 90%.37,40 Note that despite risk-reducing mastectomy, there is always
a small risk of breast cancer in residual breast glandular tissue. SERMs may be useful
in patients with BRCA1 and BRCA2 mutations as well. Analysis of blood samples of
women who participated in the P-01 (tamoxifen) trial showed that mutation carriers
also had a 47% lower risk of breast cancer.41,42 Tamoxifen has also been shown to
reduce contralateral breast cancer incidence in this high-risk population.43
C. Detection, diagnosis, and pretreatment evaluation
1. Screening
Because more lives can be saved if breast cancer is diagnosed at an early stage,
many screening programs have been designed to detect small, early cancers.
Monthly breast self-examination for all women after puberty and yearly breast
examinations by a physician or other trained professional after a woman is 20 years
of age is generally recommended, although evidence of effectiveness is limited.
Mammography reduces breast cancer mortality by 25% to 30% in women older than
50 years.44 The benefit for women aged 40 to 50 years has been more difficult to
demonstrate because the incidence of breast cancer is lower.45,46 Hence, more
examinations are needed to find a cancer and save a life. However, additional
benefits of early detection via mammography include the option for less disfiguring
surgery, reduced utilization of radiation therapy, and decreased need for
chemotherapy and other systemic treatments. Therefore, the absolute benefits extend
beyond the simple end point of survival. As a result, mammography is recommended
at age 40 years as a baseline, once every 1 to 2 years between the ages of 40 and 50
 years (depending on risk factors and the recommending organization), and yearly
after 50 years of age. An upper age of effectiveness is not established. For high-risk
women and in family members of mutation-positive patients, annual mammography
should be initiated 10 years earlier than the youngest diagnosed relative. Patients
with Hodgkin lymphoma (regardless of a history of mantle field irradiation) should
have a baseline mammogram by age 25. In BRCA1/BRCA2 mutation carriers,
beginning at age 25, annual MRI of the breast in addition to annual mammography is
recommended as its use has detected more interval and earlier stage cancers and has
reduced the incidence of large or lymph node–positive breast cancers.47,48
Mammography has clearly led to the discovery of many earlier cancers and sharply
increased the discovery of preinvasive cancers (ductal carcinoma in situ [DCIS]).
These latter are not (yet) invasive and their treatment can be far less complicated
than that of invasive breast cancer. Other screening modalities can include
ultrasound, but it is more typically used diagnostically to evaluate palpable lesions.
2. Presenting signs and symptoms
Although a large number of nonpalpable cancers are found by mammography,
invasive breast cancer is still often discovered by a woman herself as an isolated,
painless lump in the breast. If the mass has gone unnoticed, ignored, or neglected for
a time (or if it is particularly rapidly growing or aggressive), there may be fixation
to the skin or underlying chest wall, ulceration, pain, or inflammation. Some early
lesions present with discharge or bleeding from the nipple. Occasionally, the
primary lesion is not discovered, and the woman presents with symptoms of
metastatic disease, such as pleural effusion, nodal disease, or bony metastases.
About half of all lesions are in the upper outer quadrant of the breast (where most of
the glandular tissue of the breast is). About 20% are central masses and 10% are in
each of the other quadrants. Up to one-quarter of all women with breast cancer have
axillary node metastasis at the time of diagnosis, although this is less common when
the primary tumor has been detected by screening.
3. Staging. Carcinoma of the breast is staged according to the size and characteristics
of the primary tumor (T), the involvement of regional lymph nodes (N), and the
presence of metastatic disease (M). The TNM classification of breast cancer and
stage grouping are used, which is published by the American Joint Commission on
Cancer.49 Although preliminary staging is commonly done before surgery, definitive
staging that can be used for prognostic and further treatment planning purposes
usually must await postsurgical pathologic evaluation when the primary tumor size
and the histologic involvement of the lymph nodes are established. In up to 30% of
patients with palpable breast masses (not found by mammography) but without
clinical evidence of axillary lymph node involvement, the histologic evaluation of
the nodes reveals cancer. In patients with negative nodes by routine histologic
evaluation, serial sectioning may reveal microscopic cancer deposits in additional
patients. The principal changes in the new staging system take into consideration the
 widespread use of immunohistochemical (IHC) and molecular biologic techniques
that afford pathologists the ability to detect microscopic metastatic lesions down to
the level of isolated tumor cells. It is not clear that there is prognostic value if
cancer cells in nodes are detected by enhanced examination, and the current staging
system designates nodes as pathologically negative if cells are identified by IHC
alone and are in clusters of less than 0.2 mm. The identifier “(i)” is used to indicate
isolated tumor cells such that pN0 (i+) indicates node-negative disease but the
presence of such cells in the node. Similarly, “(mol +)” indicates that a molecular
examination such as polymerase chain reaction has found evidence of malignant
cells.
D. Diagnostic evaluation
1. Before biopsy the woman should have a careful history, during which attention
should be paid to risk factors, and a physical examination, with a focus not only on
the involved breast but also on the opposite breast, all regional lymph node areas,
the lungs, bone, and liver. This examination should be followed by bilateral
mammography to help assess the extent of involvement and to look for additional
ipsilateral or contralateral disease.
2. Excisional or core needle biopsy of the primary lesion is performed, and the
specimen is given intact (not in formalin) to the pathologist, who can divide the
specimen for histologic examination, hormone receptor assays, and HER2 testing
(by immunohistochemistry examination or fluorescence in situ hybridization
[FISH]).
3. After confirmation of the histology, the patient is evaluated for possible metastatic
disease. It is important to emphasize that history and physical examination are the
most critical components of this assessment.
a. Typical studies include a complete blood count, and blood chemistry profile.
b. Other studies that may be considered based on symptoms or signs or abnormal
blood work, include radionuclide scan of the bones, skeletal survey (usually
obtained only if the radionuclide scan is positive), and computed tomography
(CT) scan of the liver (abdomen) and chest. PET CT is another option that may
be helpful in the evaluation of locoregional disease.
c. Histology
About 75% to 90% of all breast cancers are infiltrating ductal carcinomas, and
up to 10% are infiltrating lobular carcinomas; these two types have similar
overall behavior but the latter tend to be hormone responsive and HER2-
negative. In addition, their patterns of metastatic spread can vary even if the
overall risks of metastases are similar. The remainder of the histologic types of
invasive breast carcinoma may have a somewhat better prognosis but are usually
managed more according to the stage than to the histologic type. Microarray
technology has added nuance to the traditional, histology-based categorization of
breast cancer and supports the view that this is a disease with distinct subtypes.
 About 15% of breast cancers are basal-like (basal epithelial subtype), with a
relatively high concordance with the conventionally defined “triple negative”
(hormone-receptor and HER2-negative) subset.50 Luminal tumors are generally
hormone receptor–positive, but it is the luminal A subtype that is most clearly
hormone responsive, and the luminal B subtype is clinically distinguished by
either expression of HER2 or high proliferation rates.51
Basal-like tumors are seen in association with BRCA1 mutations and are
more common in African American women.52 Each of these subtypes (luminal A,
B, basal-like, HER2-positive, etc.) is associated with a distinct typical natural
history in terms of time to develop distant metastases.53
E. Approach to therapy
Many institutions have established multidisciplinary teams or centers to facilitate
coordinated treatment planning. It may be useful in some settings to pursue this
particular clinical care structure, but there are other reasonable strategies to employ in
the development of an optimal care plan for individual patients.
1. Consultation with a surgeon, radiotherapist, and medical oncologist is generally
required once the diagnosis of carcinoma is suspected or histologically confirmed or
after definitive surgery has been accomplished. Multimodal therapy has had a
profound impact on the outcome of breast cancer as it has allowed for organ
preservation and improved disease-free survival (DFS) and overall survival. Any
clinician treating patients for breast cancer should be very familiar with the roles
and interventions offered by the other members of the team. It is also critical to have
the patient (and her family if she desires) share in the therapy decisions after hearing
the options, the relative advantages and disadvantages of each approach, and the
recommendations of the consultants. The patient should be given an opportunity to
hear why the recommended treatment is thought by the physicians to be best and to
decide whether the treatment is appropriate for her.
2. Goals of therapy differ depending on the stage of disease being treated.
3. For early-stage invasive disease, the goal of therapy is to eradicate the primary
tumor and to suppress the growth of or eliminate micrometastases, thereby
preventing recurrence and death. In the postoperative setting, this is called adjuvant
therapy. There are three broad classes of systemic adjuvant therapy: hormone
therapy (tamoxifen or, in postmenopausal women, an aromatase inhibitor),
chemotherapy (any of a large number of standard combination regimens), and HER2-
directed therapy (trastuzumab +/− pertuzumab for patients with HER2-positive
tumors). These options are weighed and combined on an individualized basis based
on careful risk-benefit analyses. Of course, while treating postoperative patients
who may be cured by their surgery (and radiation therapy), we seek to avoid
unnecessary short- and long-term drug-induced toxicities. Of particular concern is
the increased incidence of second cancers (myelodysplasia and leukemias in
particular with chemotherapy, and uterine cancer with tamoxifen) arising years after
 the completion of therapy. Other risks can include osteoporosis with AIs and cardiac
dysfunction following anthracycline or trastuzumab use. It is important to emphasize
that despite these toxicities, overall survival has generally been improved in the
patient populations treated with these modalities.54 However, one goal of ongoing
investigational studies is to determine the minimum therapy that is effective for
preventing the maximum number of recurrences in any given clinical situation.
4. For locally advanced disease defined as stage IIIA or T3–T4 disease or more,
including inflammatory breast cancer, the goal of systemic therapy changes
somewhat. In addition to critically important systemic control, there is the added
potential benefit of local response facilitating less disfiguring surgery and, in some
cases, any surgery. This is referred to as neoadjuvant or preoperative systemic
therapy, and it specifically can reduce the size of an initially unresectable tumor or
convert the planned surgical intervention from mastectomy to breast conservation. In
the research setting, preoperative administration of systemic therapy allows the
opportunity to test both the therapeutic efficacy of novel drugs and regimens as well
as the ability to conduct correlative science studies, thereby potentially optimizing
drug development.
5. For advanced (metastatic) disease the goal of therapy is to lengthen survival when
possible and to palliate or limit symptoms and signs of the disease using therapy
with an acceptable toxicity profile. In this setting, long-term toxicity is not usually of
great importance, but short-term toxicity is a major focus for both physician and
patient because the aim of therapy is to improve how the patient feels (quality of
life) as well as to prolong survival. The general approach is to use hormone therapy
if possible, anti-HER2 therapies when HER2 is amplified or overexpressed in the
tumor, and chemotherapy as sequential single agents. There are a myriad of novel
targeted therapies in development and an increasing number of treatments with
proven impact on overall survival.
6. Surgery remains the most frequently used mode of primary therapy for the vast
majority of women with breast cancer. Over the past half century, the extent of
surgery has evolved toward less disfiguring procedures. Hence, breast conservation
(lumpectomy) with radiation therapy and an examination of the sentinel nodes (or in
some cases, an axillary node dissection) is now routine. Surgical margins should be
free of tumor, but an exact definition of the safe width is not uniformly accepted.
Complete axillary node dissection is unnecessary in most cases when a sentinel
node procedure, performed by an experienced surgeon, reveals no cancer.55
Following breast conservation (and generally after the completion of chemotherapy),
radiotherapy is delivered to control any microscopic cancer remaining in the breast.
The decision to radiate nodal fields varies with the stage of the cancer. In terms of
distant DFS and overall survival, appropriate candidates for breast conservation
have the same outcomes as if they were treated with mastectomy.56 Therefore, many
patients opt for breast-conserving surgery and radiotherapy over mastectomy. Apart
 from patient preference, mastectomy is indicated when the tumor is too large or
locally advanced to allow breast conservation (although preoperative systemic
therapy can facilitate breast conservation in this situation), if the tumor is
multicentric/multifocal, when the patient has a contraindication to radiation therapy,
if it is an ipsilateral recurrence in a previously radiated breast (again, a
contraindication to additional radiation therapy), or when margins free of tumor
cannot be obtained.
There remain wide geographic variations in the use of breast-conserving
surgery throughout the United States and without obvious medical justification. For
patients who have had mastectomy, reconstruction can be accomplished by several
approaches and requires a skilled plastic surgeon. It may be done at the time of
mastectomy or delayed for a period (usually 1 to 2 years). There is no evidence that
any (or no) reconstructive approach has any impact on the natural history of breast
cancer.57
7. Radiation therapy. The role of radiation therapy in the management of carcinoma of
the breast has been expanded since the early 1970s. Radiotherapy is now commonly
used in conjunction with breast conservation as part of the primary therapy. In this
circumstance, the radiotherapy is commonly delivered to the entire breast with a
boost of therapy to the tumor bed using external-beam therapy. More recently,
shorter courses of external-beam radiation may be considered for treating the breast
only.58 In addition, radiation therapy to only the affected part of the breast is now
used in early-stage disease. Partial breast irradiation may be delivered by
brachytherapy or focused external-beam treatment. Radiotherapy may also be
employed following mastectomy in women who have a particularly high likelihood
of local recurrence. When the risk of local recurrence is high, radiation therapy is
associated with improved overall survival.59 Typically, postmastectomy radiation is
indicated if the primary tumor is larger than 5 cm or if four or more positive lymph
nodes were found in the axilla, although there is potential benefit on survival even in
lower risk patients, such as those with one to three positive axillary lymph nodes.59
Following breast conservation, radiation may be omitted in patients older than 70
years of age with estrogen receptor–positive tumors smaller than 2 cm if they are
treated with antiestrogen therapy.60 However, with longer follow-up, an increase in
breast recurrences is found without radiation, but with no detectable impact on
survival.60 Radiation therapy is generally administered after completion of cytotoxic
therapy (when indicated). Radiation therapy is also helpful as adjunctive therapy for
metastatic or locally advanced and unresectable disease. Local recurrences and
isolated or specific (e.g., painful bone lesions particularly with impending fracture)
distant metastases also are frequently treated successfully with radiotherapy.
8. Systemic therapy is used to reduce the likelihood of recurrence after local therapy
for early-stage disease and to treat more advanced disease with or without distant
metastasis. For operable (curable) breast cancer, The Early Breast Cancer Trialists’
 Collaborative Group (EBCTCG) analysis of adjuvant therapy demonstrates a clear
benefit of postoperative chemotherapy or hormonal therapy (including ovarian
ablation in premenopausal women).54 Although the precise estimates of benefit vary
with each half-decade review and update, in very general terms systemic therapy
reduces the risk of recurrence by as much as 50%. Similarly, the odds of death are
also reduced by as much as 30%. Similar proportional risk reductions are seen in
node-positive as well as node-negative disease with the proviso that lower risk
disease yields proportionately smaller absolute benefits for therapy.61 Historically,
medical oncologists relied on node status, tumor size and grade, hormone receptor
status, HER2 status, and perhaps DNA synthesis rate (percentage of cells in the
synthesis phase), as well as any of a number of other factors to aid in determining
risk for individual patients so that the oncologists could then estimate the benefits of
specific systemic therapies and guide patients. More recently, commercially
available tests (genomic assays) that provide prognosis, or more importantly,
prediction of benefit for specific systemic therapies, have become available.62,63 As
always, physiologic age of the patient and comorbid conditions are also important
considerations in adjuvant therapy decisions.
9. Endocrine therapy includes surgical, radiotherapeutic, or drug-induced ablation or
inhibition of ovarian function. It also includes antiestrogens (typically SERMs), AIs,
progestins, androgens, and even corticosteroids. Tumors with no expression of
either the estrogen or the progesterone receptor will generally not respond to
hormone therapies, and the greater the expression of these receptors the greater the
probability of benefit.64 However, there is no clear threshold (above zero) below
which one can be certain that endocrine therapy will be ineffective.65 Similarly,
when the estrogen receptor is detected, it is not clear that the level of the
progesterone receptor is important. Variations in test quality and results remain
important challenges in this area.
A. Prognosis
Breast cancer can vary from aggressive and rapidly fatal to relatively indolent disease
with late-appearing metastasis. Molecular studies increasingly support the view that
breast cancer is a collection of diseases rather than one single entity. At present,
clinicians can use the following factors to provide crude estimates of the likelihood of
relapse and survival, but this is an area where newer diagnostics may rapidly improve
our current approach.
3. Stage. Axillary node involvement and the size of the primary tumor are major
determinants of the likelihood of survival.66–68
a. Nodes. In the first National Surgical Adjuvant Breast and Bowel Project
(NSABP) study, before the use of modern adjuvant therapy, 65% of all patients
who underwent radical mastectomy survived 5 years, and 45% survived 10
years.69 When no axillary nodes were positive, the 5-year survival rate was
nearly 80% and the 10-year survival rate 65%. If any axillary nodes were
 positive, the 5-year survival rate was less than 50% and the 10-year survival
rate 25%. If four or more nodes were positive, the 5-year survival rate was 30%
and the 10-year survival rate less than 15%.
Since that time (1975), there has been an improvement, with 5-year survival
rates of 99% for stages I and II, 85% for stage III, and 25% for stage IV breast
cancer.70 Lymph node involvement by conventional light microscopy remains the
single most important prognostic factor in making survival predictions and
treatment decisions. It is important to distinguish modern cases in which
malignant cells are detected in lymph nodes using higher sensitivity techniques.
Their prognosis is not as clearly established.
a. Primary tumor
Patients with large primary tumors generally face higher risks of relapse and
death compared to patients with small tumors, irrespective of the nodal status,
although patients with large primary tumors are more likely to have node
involvement. Tumors that are fixed to the skin or to the chest wall have
worsened prognoses compared to those that are not. Patients with inflammatory
carcinomas have a particularly poor prognosis, with a median survival time of
less than 2 years and a 5-year survival rate of approximately 30%.71,72
Neoadjuvant systemic therapy has improved the outcome significantly for this
subset of patients by enabling local control surgery and improving long-term
rates of relapse and death.73,74
2. Estrogen and progesterone receptors
Although stage of disease is critical in determining the risk of recurrence, the timing
of events is heavily influenced by tumor biology, particularly hormone receptor
status. Patients with tumors that do not express estrogen or progesterone receptors
(or do so at only very low levels) are much more likely to experience recurrence
during the first few years after diagnosis than those who have receptor-positive
disease.75 This observation is true for both premenopausal and postmenopausal
patients within each major node group (zero, one to three, and four or more). Over
decades, the risk of relapse and death is approximately the same but the distribution
of these events is more even with hormone receptor–positive disease and skewed to
the earlier years when the receptors are absent.75
3. HER2/neu gene amplification and overexpression of its transmembrane receptor is
associated with impaired survival in early-stage breast cancer. Amplification (as is
seen in 20% to 30% of early breast cancer) results in worse prognosis with earlier
appearance of metastatic disease.76 However, it is now clear that this gene and
receptor are predictive factors for response to HER2-directed therapies and as a
result of which, outcomes for patients with HER2-positive disease may be superior
to that of other subtypes.
4. Gene profiling
There are several tools and assays using divergent technologies to provide more
 precise individualized estimates of the risk of relapse (“prognosis”) and the benefits
of specific treatments (“prediction”). The MammaPrint test (Agendia, Inc.,
Huntington Beach, CA) provides prognosis for node-negative breast cancer
regardless of receptor status.77 The OncotypeDx (Genomic Health, Inc., Redwood
City, CA) provides prognosis for node-negative, hormone receptor–positive breast
cancer treated with tamoxifen and predicts the benefits of conventional combination
chemotherapy as an additional treatment for this cohort.62,63 It may be similarly
useful in hormone receptor–positive, node-positive disease. These technologies are
based on our ability to determine gene expression on fresh frozen or paraffin-
embedded tissues.
With regard to the OncotypeDx, the following are some considerations:
■ Patients with a result (recurrence score [RS]) of less than 18 (about 50% of
patients in most series) are considered low risk and will probably not benefit
from the addition of cytotoxic therapy to their hormonal manipulation.
■ Patients with an RS of greater than 30 have a high risk of systemic disease and
will obtain the maximum benefit from chemotherapy.
■ Patients with an intermediate score (18 to 30) currently represent a decision-
making dilemma and a large trial is under way to better define the value of
chemotherapy in this patient population.78,79
5. Other prognostic factors are still undergoing study as to whether they can provide
information as independent prognostic factors, particularly for node-negative
cancers. In all cases, the key is whether or not they are reliable, validated,
reproducible, and additive or supplemental in a meaningful way to the existing tools.
6. Adjuvant! Online is a Web-based decision-making tool (see
www.adjuvantonline.com) that allows clinicians and patients to input key individual
variables, model the impact of specific treatments, and display the benefits both
numerically and graphically.80 There are well-recognized limits to this approach
including its lack of inclusion of HER2 status, but it can be very useful in providing
easily interpretable information and it has served as an early generation attempt to
illustrate the approach to making adjuvant therapy recommendations.

II. SYSTEMIC THERAPY OF BREAST CANCER

A. Cytotoxic therapy
As with other cancers, the basis for the effectiveness of cytotoxic drugs in the treatment
of carcinoma of the breast is not completely understood. In general, a combination of
two or more drugs is more effective in the adjuvant setting than single agents, and nearly
all treatment programs use a variety of drugs either in concurrent combination or
sequentially.81 In addition to their cytotoxic effects, chemotherapeutic agents may induce
menopause in premenopausal women and this may represent an additional anticancer
effect.82–85
1. Response to therapy
 In the adjuvant setting, it is impossible to determine whether individual patients have
responded to treatment for micrometastatic disease unless they relapse as there are
no parameters to measure. Relapse means that treatment did not eradicate all
disease, did not prevent the development of new disease, or only slowed the growth
of microscopic metastases. Determination of the appropriate adjuvant therapy option
for individuals must therefore depend on extrapolations from large randomized
studies.
2. Treatment of early disease (adjuvant therapy)
As discussed previously, standard treatment of early disease depends on a variety of
factors; there is not yet a single agreed-on optimal chemotherapy regimen for any
subset of women with breast cancer. Therefore, as a first priority, patients should be
encouraged to participate in clinical trials. If none is available or the patient
declines, Table 10.1 can be used as a guide for assessing risk.
a. Choice of therapy
Cytotoxic therapy is recommended for most otherwise healthy patients with
hormone receptor–negative tumors that are 0.5 to 1 cm in size or greater,
regardless of node status.87 Patients with HER2 overexpression or gene
amplification generally receive chemotherapy and trastuzumab. Regardless of
whether they receive cytotoxic therapy, most patients with hormone receptor–
positive invasive cancer of any size should be treated with hormone therapy
(tamoxifen if premenopausal and an aromatase inhibitor—alone or after
tamoxifen—if postmenopausal). The goal of adjuvant chemotherapy is to
decrease the risk of death and systemic disease. Because of the risks of
competing causes of death, cytotoxic therapy is less commonly recommended in
the adjuvant treatment of older women (based on physiologic and not solely on
absolute chronologic age); for this subgroup particularly recommendations
should be individualized considering comorbid conditions.88 The value of
cytotoxic therapy when added to antiestrogen therapy in low-risk node-negative,
hormone receptor–positive patients is partially addressed by the OncotypeDx
discussed previously, although a number of additional tests may become
available for this purpose.
b. Traditional chemotherapy options
Currently, a wide range of chemotherapy options exists, which generally
developed as sequential experimental arms in lineages of clinical research.
Although cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) remains an
option for some low-risk patients, four cycles of dose-dense doxorubicin
(Adriamycin) and cyclophosphamide (AC) with sequential paclitaxel delivered
every other week (“dose-dense”) or weekly is a standard and NCCN
“preferred” regimen, particularly for higher risk disease.88 Anthracyclines have
been shown to have a moderate but significant advantage over CMF (recurrence
rate ratio 0.89 [SE 0.03], 2p = 0.001; breast cancer death rate ratio 0.84 [0.03],
 2p < 0.00001).54 The 2011 EBCTCG update showed a 2.8% absolute survival
benefit with a taxane-plus-anthracycline-based regimen versus anthracycline-
based control regimens at 8 years.61 We highly recommend reviewing both the
2005 and 2011 EBCTCG update in Lancet for a better understanding of the
evolution of breast cancer therapy.54,61

TABLE
Prognostic Factors for Assessing Risk of Recurrence of Breast Cancer
10.1
Value Parameter
Nodal status Risk increases with presence of metastasis and numbers of nodes involved
Tumor size Risk increases with tumor size independent of nodal status
Estrogen and progesterone receptors Positive receptors confer better prognosis
Complex factor (biology chronology): Women aged 45–49 years have best
Age prognosis, with increasing likelihood of deaths from breast cancer in older and
younger age groups
Higher nuclear grade, higher histologic grade, tumor necrosis, peritumoral
Morphology lymphatic vessel invasion, increased microvessel density tumors have worse
prognosis 86
Tumors that are diploid and have low synthesis–phase fraction do better than
DNA content and proliferative capacity those that are aneuploid or have a high synthesis–phase fraction (by flow
cytometry)
Amplification is associated with earlier relapse and shorter survival. HER2/neu
(c-erbB-2) testing by either FISH expressed as molecules/gene copy ratio (2.0
HER2/neu (c-erbB-2)
or more copies) or by IHC staining expressed as 0–3+, where 3+ correlates best
with FISH positivity.
Provides risk of recurrence (“prognosis”) and benefit of combination
OncotypeDx Recurrence Score chemotherapy with CMF (and possibly cyclophosphamide, doxorubicin, and
fluorouracil) (“prediction”) for hormone receptor–positive tumors
MammaPrint Provides prognosis regardless of hormone receptor status

CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry.

c. Addition of taxanes
Multiple phase III trials have evaluated the addition of taxanes (paclitaxel or
docetaxel) to chemotherapy regimens for early-stage breast cancer. Both the
pivotal Cancer and Leukemia Group B protocol 9344 and the NSABP B28 trial
supported the use of paclitaxel after AC for node-positive breast cancer
regardless of receptor status, tamoxifen use, patient age, or the number of
positive lymph nodes.89,90 Retrospective analysis suggests that the benefit is
limited in patients with hormone receptor–positive, HER2-negative disease, but
other studies have not been consistent in this regard. A slightly differently
designed trial (Breast Cancer International Research Group 001) addressed the
same question. In this trial, six cycles of concurrent docetaxel, doxorubicin, and
cyclophosphamide (TAC) were compared to six cycles of fluorouracil,
 doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for node-
positive patients. The study showed superiority of TAC in all patient groups.91
Similar findings were noted when epirubicin was used instead of doxorubicin.
Three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed
by three cycles of docetaxel were found to be superior to six cycles of FEC in
node-positive patients by the French Adjuvant Study Group.92 An overview
[meta-analysis] of the available taxane studies showed a 3% absolute
improvement in OS.93
a. Use of trastuzumab and pertuzumab in the adjuvant setting
HER-neu–positive breast cancer accounts for 20% to 30% of all cases of breast
cancer. In the absence of treatment, these patients have a higher risk of
recurrence and earlier death, this is even true of small (T1a and T1b) HER2+
node-negative tumors.94 Trastuzumab prolongs survival in the metastatic setting
and prevents recurrence and death in the adjuvant setting as well.95,96 The use of
trastuzumab along with chemotherapy (a taxane was included in most of these
trials) in high-risk node-negative as well as node-positive patients was
associated with a 39% to 52% reduction in the risk of recurrence and significant
improvements in survival.97–99 Adjuvant trastuzumab is recommended for a year
and should be given concurrently with the taxane portion of adjuvant
chemotherapy.100,101 Although an anthracycline-containing regimen—
Doxorubicin/Cyclophosphamide/Paclitaxel/Trastuzumab (ACTH) remains the
preferred choice for higher risk patients, trastuzumab may also be given with
Taxotere/Carboplatin (TCH) with comparable efficacy and less cardiac toxicity
and risk of secondary leukemia.96 A phase II study showed that node-negative
HER2+ patients treated with adjuvant trastuzumab and paclitaxel alone can
obtain excellent DFS (3-year DFS 98.7%) with minimal toxicity, offering a
reasonable adjuvant strategy for low-risk stage I HER2+ tumors.102
Trastuzumab does not cross the blood-brain barrier, and the rates of
recurrence in the brain, as opposed to all other sites, may not be reduced in the
adjuvant setting. There are many active anti-HER2 agents either approved or in
development for metastatic disease including trastuzumab-DM1, pertuzumab,
neratinib, and several heat shock protein-90 inhibitors. Newer agents target
signaling components downstream of HER2.
Recently, pertuzumab, already shown to significantly prolong progression-
free survival (PFS) and overall survival in the metastatic setting, was also
shown to increase pathologic complete response rates when administered with
trastuzumab and a taxane preoperatively.103–106 The drug was granted
accelerated approval for neoadjuvant use on this basis and an adjuvant trial was
completed.107 Given its potential availability for patients with early-stage
disease, the NCCN has endorsed conventional adjuvant use of pertuzumab even
 while the results of the randomized adjuvant trial are pending.108 Lapatinib, a
small molecule tyrosine kinase inhibitor was similarly active in the preoperative
setting but did not add benefit to the standard adjuvant treatment of HER2-
positive breast cancer when tested in combination with trastuzumab in the phase
III ALTTO trial.109
e. High-dose chemotherapy
Dose escalation beyond “standard” dose levels, including those that require
support with autologous bone marrow or peripheral blood progenitor cell
reinfusion, has not been shown to offer advantage over conventional therapy and
should not be offered.89,110
f. Dose and duration of chemotherapy
More recently, six cycles of FEC were shown to be equivalent to four cycles of
AC in terms of DFS and OS, but was associated with greater toxicity.111 Dose-
dense therapy, consisting of standard doses administered more frequently, was
developed in recognition of the lack of benefit for higher dose regimens. It relies
on the increased cytotoxicity of more frequent standard doses but generally
requires growth factor support and has been shown to be superior in several
randomized trials.112,113 For AC and paclitaxel, this is now a standard approach.
At the same time, six cycles of standard regimens (AC or paclitaxel) have been
shown to be no better than four, but more toxic.114 In the absence of targeted anti-
HER2 therapies, single-agent therapies have not been as effective as
combinations.115
g. Some commonly used regimens (refer to previous discussion about choice of
regimen based on nodal status) are as follows
1) AC plus taxane (dose-dense)
■ Doxorubicin 60 mg/m2 IV push through a rapidly running intravenous
(IV) line.
■ Cyclophosphamide 600 mg/m2 IV. Repeat every 2 weeks with growth
factor support. After four cycles, switch to paclitaxel 175 mg/m2 IV 3-
hour infusion every 2 weeks for four cycles.
2) Docetaxel and cyclophosphamide
■ Docetaxel 75 mg/m2 IV push through a rapidly running intravenous line.
■ Cyclophosphamide 600 mg/m2 IV. Repeat every 3 weeks.
3) FEC
■ Fluorouracil 500 mg/m2 IV on day 1.
■ Epirubicin 100 mg/m2 IV on day 1.
■ Cyclophosphamide 500 mg/m2 IV on day 1. Repeat cycle every 21 days.
4) TAC
■ Docetaxel 75 mg/m2 on day 1.
■ Doxorubicin 50 mg/m2 on day 1.
 ■ Cyclophosphamide 500 mg/m2 on day 1. Repeat cycle every 21 days.
As mentioned previously, for patients with HER2-positive disease,
trastuzumab may be added to a taxane after completion of four cycles of AC.
Pertuzumab may be added for patients with presentations that would have
qualified them for preoperative use. Options include the following:
1) Paclitaxel 80 mg/m2 weekly for 12 weeks given concurrently with
trastuzumab 4 mg/m2 as an initial loading dose, followed by 2 mg/m2 weekly,
which is continued for 52 weeks or
2) During the paclitaxel component of the dose-dense therapy using the same
schedule of trastuzumab as previously mentioned or
3) Conventionally administered docetaxel (100 mg/m2 every 3 weeks for four
cycles) with trastuzumab.
Alternatively, adjunctive therapy for HER2-positive patients may begin
with docetaxel 100 mg/m2 with carboplatin (area under the curve = 6) once
every 3 weeks for six cycles with trastuzumab.
In all cases, trastuzumab is generally administered with and after
chemotherapy for one full year.
h. Tips
■ Limit the number of cycles of doxorubicin in any combination regimen to six
(300 to 360 mg/m2 or less) to limit enhanced cardiotoxicity from the
combination.
■ Avoid concurrent administration of trastuzumab in combination with
anthracyclines.
■ Monitor for peripheral neuropathy with taxanes, especially in diabetics and
older patients.
3. Treatment of locally advanced disease (neoadjuvant therapy)
For stage III or locally advanced disease, neoadjuvant (preoperative) chemotherapy
is generally preferred. This strategy permits breast conservation in the group of
operable stage III tumors and tests the disease biology of inoperable stage III
disease, allowing better prognostication. This approach was not shown to improve
survival116; however, the attainment of a pathologic complete response (pCR) to
neoadjuvant chemotherapy is associated with a more favorable prognosis in the
triple negative subgroup.117,118 The choice of therapy is as recommended for high-
risk disease in the adjuvant setting and should consist of anthracycline- and taxane-
based regimens.119
For HER2-positive patients, the addition of trastuzumab in this setting has been
shown to improve pCR rates and reduce the risk of recurrence and death.120 In the
phase III NeoALTTO study, the addition of lapatinib to trastuzumab and paclitaxel
improved pCR rates.121 The combination of pertuzumab, trastuzumab, and docetaxel
in the phase II Neosphere trial led to improved pCR rates.105 As mentioned
 previously, these results combined with the survival advantage seen with
pertuzumab in the metastatic setting led to its accelerated approval for use in the
neoadjuvant setting.104,107
For the triple negative subgroup the addition of carboplatin to a taxane, and
anthracycline regimen has been shown to significantly increase pCR rate but benefits
for survival remain unknown.122,123
Postoperatively, the HER2-positive patients should complete a year of
trastuzumab and the estrogen receptor–positive patients should begin standard
adjuvant hormonal therapy. Radiation should be administered to the chest and
supraclavicular region and internal mammary region if involved.88
4. Cytotoxic therapy of advanced (metastatic) disease
Among the cytotoxic drugs, the most commonly used agents include doxorubicin,
cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, albumin-bound
paclitaxel, gemcitabine, capecitabine, vinorelbine, ixabepilone, and eribulin. Each
of these agents has a response rate of 12% to 40% when used as a single agent
(depending on the prior therapies and patient population). With very few exceptions,
the data have not supported a survival advantage in the metastatic setting with
combination chemotherapy, and toxicity is generally greater, so most patients are
best palliated with sequential single agents.124
Cytotoxic chemotherapy is used as first-line treatment for advanced disease in
patients with hormone receptor–negative disease. Its use in lieu of hormone therapy
in patients with hormone receptor–positive disease when multiple organ systems are
involved is controversial, as some clinicians believe it offers more rapid responses
whereas endocrine therapy may offer longer disease stabilization.
Cytotoxic chemotherapy produces clinical benefit (response and disease
stabilization) in 60% to 80% of patients regardless of their estrogen receptor status.
The responses to therapy at times are durable, but the median duration of treatment
in most studies is less than 1 year. Clearly, improved survival is desirable, but the
impact of many regimens on survival is modest.
However, for patients with HER2-positive metastatic breast cancer,
trastuzumab has improved survival, demonstrating that translational science can lead
to therapeutic advances once the appropriate biologic target is identified. In support
of this, the benefits of trastuzumab are limited to patients who are HER2 3+ positive
by immunohistochemistry or those who are FISH positive. Continuing trastuzumab
beyond progression has also been shown to be beneficial.125
Significant advances have been made for the HER2-positive patient
population. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits
receptor dimerization, has been shown in the phase III CLEOPATRA study to
improve response rates, PFS, and overall survival when added to trastuzumab and
docetaxel.103,104 Pertuzumab has been approved in the first-line setting and can also
be combined with other active cytotoxics (paclitaxel, vinorelbine).126,127
 Trastuzumab emtansine (T-DM1), an antibody-drug conjugate has shown
improvement in RR, PFS, and OS with less toxicity than lapatinib plus capecitabine
in patients with HER2-positive advanced breast cancer previously treated with
trastuzumab and a taxane.128,129
Second-line chemotherapy is dependent on the specific prior treatments
received by an individual patient. If the patient relapses while on treatment or within
6 months after finishing treatment for micrometastatic disease (adjuvant therapy), it
is not likely that these drugs used in combination can be helpful in achieving a
second remission. In addition, in selecting appropriate therapeutic approaches, the
side effect profiles of the multiple treatment options should be considered in
conjunction with patient-related considerations such as symptoms and residual
toxicities from prior treatments.
Effective individual drugs and regimens in addition to those used in the
adjuvant setting include the following (Note: This is by no means an all-inclusive
list. Regimens listed are commonly used in clinical practice):
■ Paclitaxel 150 to 175 mg/m2 IV over 3 hours every 3 weeks, or 80 mg/m2 over 1
hour weekly (the latter is generally preferred).
■ Docetaxel 60 to 100 mg/m2 IV over 1 hour every 3 weeks (premedication with
oral corticosteroids such as dexamethasone 8 mg twice a day for 5 days starting
1 day prior to starting docetaxel is necessary to reduce the severity of fluid
retention and hypersensitivity reactions).
■ Vinorelbine 20 to 30 mg/m2 IV over 6 to 10 minutes weekly.
■ Capecitabine 1,250 mg/m2 orally twice daily on days 1 to 14 followed by a 1-
week rest. Repeat cycle every 3 weeks.
■ Gemcitabine/paclitaxel
■ Gemcitabine 1,250 mg/m2 IV days 1 and 8 followed by a 1-week rest, plus
■ Paclitaxel 175 mg/m2 IV on day 1. Repeat every 3 weeks.
■ Nab-paclitaxel 260 mg/m2 IV over 30 minutes given every 3 weeks or 100 to
130 mg/m2 over 30 minutes weekly.
■ Weekly trastuzumab and paclitaxel (for HER2-positive disease)
■ Trastuzumab 4 mg/m2 IV as an initial loading dose, followed by 2 mg/m2
weekly with
■ Paclitaxel 200 mg/m2 IV every 3 weeks, or Nab-paclitaxel as discussed
previously.
■ Lapatinib may be given at a dose of 1,250 mg orally once a day on days 1 to 21
continuously in combination with capecitabine 2,000 mg/m2/day on days 1 to 14
in patients with advanced, refractory HER2-positive breast cancer who have
failed prior therapies including anthracyclines, taxanes, or trastuzumab.
Lapatinib can also be given in combination with letrozole (2.5 mg daily) in
postmenopausal, HER2-positive, hormone receptor–positive breast cancer at a
 dose of 1,500 mg.
5. Dose modifications are regimen-specific. Readers must review the original source
references for any regimen they administer.
B. Endocrine (hormonal) therapy
This therapy is effective because breast cancers retain hormone dependence. In
premenopausal women, if breast cancer growth is supported by estrogen production
from the ovary, antiestrogen therapy, and removal of endogenous estrogen by
oophorectomy, or suppression of estrogen production using a luteinizing hormone–
releasing hormone (LHRH) agonist, can result in regression of the cancer. Complicating
the anticipated actions of SERMS are the presence of different classes of estrogen
receptors, different ligands, many receptor-interacting proteins, a host of transcription-
activating factors, and several response elements. In some tissues, this class of
“antiestrogen” has estrogenic effects (i.e., bone).
1. Treatment of early disease (adjuvant therapy)
Among the antihormonal drugs, the most commonly used agents are tamoxifen (a
SERM), anastrozole, and letrozole and exemestane (AIs). Toremifene is an
alternative to tamoxifen, but raloxifene is used for the treatment of osteopenia and as
a chemopreventive and not as adjuvant therapy. The AIs (anastrozole, letrozole, and
exemestane) block estrogen production at the cellular level by inhibiting reversibly
or irreversibly to the aromatase enzyme (responsible for conversion of male
hormones and other precursors to estrogen). Tamoxifen has been the traditional
standard of care recommendation for premenopausal women with early-stage
estrogen receptor–positive breast cancer. In postmenopausal women, AIs offer
additional benefit to what was observed with 5 years of tamoxifen, with a
comparative 5% absolute reduction in disease recurrence.130 Both the ATAC trial
and the BIG 1–98 trials demonstrated an advantage to upfront use of an AI
(anastrozole and letrozole, respectively) over tamoxifen therapy.131,132 Results of the
IES study demonstrated a superior DFS with sequential therapy using exemestane
following 2 to 3 years of tamoxifen to 5 years of tamoxifen alone.133,134 Fewer side
effects are seen in this population with the use of AIs in comparison to tamoxifen.
Letrozole after about 5 years of tamoxifen was also effective with modest
improvements in DFS, DDFS, and OS.135 Importantly, the AIs offer lower incidence
of venous thromboembolic events and endometrial carcinoma compared to
tamoxifen but are associated with a higher incidence of osteoporosis and
musculoskeletal complaints.
Tamoxifen, 20 mg daily, is recommended in premenopausal women with
hormone receptor–positive disease. Ten years of therapy has been shown to be
superior to 5 years in reducing breast cancer recurrence and improving OS in both
the ATLAS and aTTOM studies.136,137 In receptor-positive patients, its benefits are
additive to those of chemotherapy (when used) and it has a relatively low risk in the
adjuvant setting, and our current recommendations generally include tamoxifen
 where it is indicated in addition to chemotherapy in Figure 10.1.

FIGURE 10.1 Systemic adjuvant therapy for breast cancer—suggested guidelines. a, Risk is
determined by a balance of the prognostic factors listed in Table 10.1 (pt age, tumor size,
grade, nodal status etc.), particularly inclusive of gene profiling (e.g., OncotypeDx) in ER/PR+
disease to more finely discern tumor biology and quantify inherent risk for recurrence; b, Adj
Tx recommendation should be individualized, balancing comorbid conditions and individual pt
tolerance for risk and toxicity associated with Adj Tx; c, CT to be considered for tumors >0.6
cm and recommended for >1 cm; d, Limited data to support use of Adj CT in those aged >70;
e, TAM for premenopausal pts; AI for postmenopausal pts; AI+ OFS can be used for
premenopausal pts deemed at high risk. CT, chemotherapy; ER, estrogen receptor; PR,
progesterone receptor; TAM, tamoxifen; AI, Aromatase inhibitor; OFS, ovarian function
suppression with an LHRH agonist or oophorectomy; LN, Lymph node ; TH, Taxol Herceptin;
TCH, Taxotere Carboplatin Herceptin; ACTH, Adriamycin cyclophosphamide taxol Herceptin;
P, Pertuzumab; CMF, Cyclophosphamide Methotrexate 5FU; TC, Taxotere Cyclophosphamide;
Adj, Adjuvant; Tx, Treatment; Pts, patients.

Tamoxifen and AIs (for postmenopausal patients) improve DFS and overall
survival in most patients with estrogen receptor–positive tumors. Although the
proportional reduction (about 25%) in death rate is similar for both high- and low-
risk patients (e.g., node-positive and node-negative), the absolute benefit is greater
for those at higher risk of recurrence and death. The improvement in DFS is superior
with all AIs, and there is an associated more significant reduction in contralateral
breast cancer with these drugs in comparison to tamoxifen.131,132,138–140
Tamoxifen is metabolized by CYP2D6, and this activity can be inhibited by
certain selective serotonin reuptake inhibitor antidepressants and by inherited
variations in single nucleotide polymorphisms (SNPs).141 However, there is no
prospective evidence that SNP testing can yet guide individual patients to better
selection of hormone therapy and improved outcomes.
2. Ovarian suppression
Suppression of ovarian (OS) estrogen production can be achieved by the
administration of luteinizing hormone–releasing hormone (LHRH) agonists such as
leuprolide, goserelin, and deslorelin or through ovarian ablation (OA) by surgical
oophorectomy or radiation therapy. OS alone in premenopausal women reduces
 breast cancer recurrence and improves survival.54,142,143
The benefit of adding OS to adjuvant chemotherapy and tamoxifen in this
population has been less clear and may be more important in those aged under 40
years given they are more likely to regain ovarian function after chemotherapy.144–146
Given the demonstrated benefit of AIs over tamoxifen in the postmenopausal
population,131,132 recent studies have asked the question whether premenopausal
women rendered postmenopausal through OS could garner a similar superior benefit
from AIs compared with tamoxifen. The joint analysis of the SOFT and TEXT trials
showed that 5 years of exemestane plus OS significantly reduced recurrence
compared with tamoxifen plus OS in premenopausal women.147 Consistent with
previous studies, the addition of OS to tamoxifen did not provide a significant
benefit in the overall study population. However, in those younger women who
remained premenopausal after chemotherapy, the addition of OS improved disease
outcomes, further improved with the use of exemestane instead of tamoxifen plus
OS.148
The toxicities associated with this choice of therapy need to be balanced
against breast cancer risk for the individual patient.
3. Treatment of advanced (metastatic) disease
Hormonal therapy is indicated in women who have had a positive test for estrogen
or progesterone receptors in their tumor tissue. This approach is not generally
recommended for women who have previously been shown to be unresponsive to
hormonal manipulation. It is also not appropriate therapy for women with visceral
crises. For premenopausal women, oophorectomy still may be the treatment of
choice. As previously mentioned, the LHRH analogs goserelin and leuprolide can
achieve the equivalent of a medical oophorectomy. This treatment may then be
combined with an AI or tamoxifen in such patients.149 For postmenopausal women,
an AI should be used as the initial hormonal therapy. Responses to endocrine therapy
tend to last longer than responses to cytotoxic chemotherapy, frequently lasting 12 to
24 months. Second-line hormonal manipulation (e.g., using fulvestrant, a selective
estrogen receptor downregulator) is a reasonable option if the tempo of disease
progression allows such. Sequential hormone manipulation may be most appropriate
for patients with indolent hormone receptor–positive breast cancer, such as those
with bone-dominant disease. In endocrine therapy in naïve patients there has been
demonstrated benefit in PFS and OS for the combination of fulvestrant with an
AI.150–152
Doses of commonly used drugs are as follows:
■ Tamoxifen 20 mg by mouth daily
■ Anastrozole 1 mg by mouth daily
■ Letrozole 2.5 mg by mouth daily
■ Exemestane 25 mg by mouth daily
■ Fulvestrant 500 mg intramuscularly (into buttock) monthly after loading with 500
 mg on days 1 and 15
■ Megestrol acetate 40 mg by mouth four times a day.
Improved understanding of therapeutic resistance mechanisms has led to
ongoing trials of several therapies that target the phosphoinositide-3-kinase (PI3K)-
Akt-mTOR pathway, an important signaling pathway implicated in endocrine therapy
resistance.153,154 Everolimus, a rapamycin analog that inhibits mTOR is approved
for use in combination with exemestane following progression on first- or second-
line hormonal therapy. Despite a substantial improvement in PFS seen with the
combination this did not translate into a statistically significant OS benefit.155,156
C. Complications of therapy
A large range of possible side effects have been associated with treatments for breast
cancer and vary extensively between agents and individuals. Acute toxicities are
primarily hematologic and gastrointestinal. Subacute toxicities include alopecia,
hemorrhagic cystitis, hypertension, edema, and neurologic abnormalities. Chronic or
long-term toxicities may be cardiac, neoplastic, or neurologic. Premenopausal women
need to be aware of menstrual irregularities, early menopause, and infertility as a
consequence of chemotherapy and should be referred for consideration of fertility
preservation when desired. Dose modifications for specific regimens must be based on
the original sources. Readers are urged to review the original reports for any regimen
they prescribe. In addition, because of individual differences, toxicities that are worse
than expected may occur, and the responsible physician must always be alert to special
circumstances that dictate further attenuation of the drug doses. The drug data listed in
Chapter 28 should be consulted for the individual toxicities, precautions, and toxicity
prevention measures for each drug.
Like all therapeutic interventions, adjuvant tamoxifen therapy also has
consequences. These include a twofold to fourfold increase in endometrial cancer, an
increase in cataracts, and an increase in thromboembolic disease. Hot flashes are
common but can be ameliorated in some women with venlafaxine 25 to 50 mg daily.
While there is also reduction in the hot flashes from using a progestin, such as
megestrol, 20 mg twice a day, the effect of the progestin on the risk of recurrence is not
known. Adverse effects on vaginal mucosa may be ameliorated with minimal systemic
estrogen effect by the estradiol vaginal ring or by an estradiol tablet administered
intravaginally (Vagifem). Although fractures related to osteoporosis decrease with
tamoxifen, there does not appear to be any reduction in cardiovascular events. AIs, on
the other hand, may worsen osteoporosis despite an absence of increased fracture
incidence in many trials. Caution and possibly anticoagulation should be exercised in
treating women with Factor V Leiden who begin treatment with tamoxifen in the
prevention or adjuvant setting.
Bisphosphonates are commonly administered IV to all patients with bone metastases
because of their role in reduction of skeletal events.88,157 Randomized studies in the
adjuvant setting have demonstrated reductions in the risk of disease recurrence but no
 impact on survival.158,159 IV bisphosphonate options include zoledronic acid 4 mg over
15 minutes or pamidronate 60 to 90 mg over 1 to 2 hours. An alternative option
administered via the subcutaneous route is denosumab, a fully human monoclonal
antibody against RANK-ligand, a mediator of osteoclast survival.160

Acknowledgments
The authors are indebted to Drs. Iman Mohamed and Patrick Morris, who contributed to
previous editions of this chapter. Several sections in this revision of the handbook represent
their work.

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I. CERVICAL CANCER
In the United States, the American Cancer Society (ACS) estimates approximately 12,000
women are diagnosed with cervical cancer each year and 4,000 die of disease. Among the
gynecologic cancers it is the third most common diagnosis, but among women 20 to 39
years it is the second leading cause of death. As many as 300,000 women die globally each
year as a result of cervical cancer. Historically a common disease, cervical cancer has
become relatively rare in the developed world, thanks to successful screening with the
Papanicolaou (Pap) test, which has allowed for early detection and therefore drastically
reduced mortality rates. In developing countries, however, where access to effective and
regular screening is not always available, the incidence of disease is much higher.
The vast majority of cervical cancers are caused by human papillomavirus (HPV)
infection. The development of an effective HPV vaccine has made the disease all the more
preventable, and the mortality associated with cervical cancer in developed countries
should decrease further in the coming decades. Still, global rates will remain high until
both the vaccine and screening test are readily and consistently available in both resource-
poor and developed countries.
A. Histology
Cervical cancer is classified as squamous cell carcinoma (keratinizing, nonkeratinizing,
verrucous): 80% to 85%; endometrioid and adenocarcinoma: 15%; and
adenosquamous: 3% to 5%.
B. Screening
For asymptomatic women, preinvasive lesions are found only after abnormal routine
screening Pap smear of the ecto-/endocervix (transformation zone) junction. Cervical
cancer mortality has decreased in the United States by more than 70% since the Pap test
was introduced in 1941.
The Pap test is simple, safe, inexpensive, and well validated. Conventional cytology
screening is reported to be 60% (30% to 87%) sensitive for dysplasia. Newer
techniques using an ethanol medium (Sure-Path, BD Diagnostics, Franklin Lakes, NJ;
Thin-Prep, Hologic, Bedford, MA; MonoPrep, MonoGen, Lincolnshire, IL) are as
effective as conventional methods, are easier to read, and allow for sexually transmitted
infection and HPV testing.
Approximately 3.5 million women have an abnormal Pap smear every year in the
United States. The American Congress of Obstetricians and Gynecologists (ACOG) and
 ACS recommend that if a patient is exposed to diethylstilbestrol or is
immunosuppressed (e.g., due to human immunodeficiency virus [HIV] infection),
screening should be indefinite. In addition, HIV-positive women should be provided
cervical cytology screening twice (every 6 months) within the first year after initial HIV
diagnosis and, if both tests are normal, annual screening can be resumed thereafter.
The older terminology (mild, moderate, severe dysplasia) was replaced with
cervical intraepithelial neoplasia I to III, based on the replacement of each third of the
epithelium. This has since been replaced by the present system of “abnormal squamous
cells of unknown significance” (ASCUS), which represents two-thirds of all abnormal
Pap smears, and squamous intraepithelial lesions (SILs), which can be further
classified as low-grade SIL or high-grade SIL.
An ASCUS Pap should trigger HPV testing. If positive, the patient should be
referred for colposcopy. Women older than 40 years with normal endometrial cells on
Pap smear require endometrial biopsy (EMB), although the yield of endometrial
neoplasia is low. There is a clear correlation between cytologic diagnosis and
histologic diagnosis at colposcopy in approximately half of patients.
In the United States, both the United States Preventive Services Task Force
(USPSTF) and the ACS recommend against routine yearly testing. Instead, the
guidelines recommend testing every 3 years for women ages 21 to 65; routine cervical
cancer screening for women below 21 and above 65 is no longer recommended. The
two groups also introduced the option of a lengthened, 5-year screening interval for
women ages 30 to 65 when screened with a combination of Pap testing and HPV
testing.1
Cervical cancer in the absence of demonstrable HPV infection is extremely rare.
Beyond the Pap test, HPV testing appears to be more sensitive and superior to standard
Pap screening.2
C. Clinical disease and staging
1. Clinical presentation
The most common symptoms of invasive cervical cancer are abnormal vaginal
bleeding, either postcoital or intramenstrual, and vaginal discharge. Larger tumors
may also interfere with urination and defecation and may be accompanied by pelvic
pain. Locoregional disease can manifest as unilateral lower extremity swelling, back
pain, neuropathic pain, and/or postobstructive renal failure. It should be noted that
many women with cervical cancer do not present with any symptoms, but rather with
disease detected during pelvic examination or screening procedures.
The most common clinical sign of cervical cancer is an abnormal lesion on the
cervix, usually detected by a physician during a pelvic exam. The exophytic lesion
often presents as necrotic and friable. Involvement of surrounding tissues should be
assessed, including the parametria, sidewalls, and uterosacral ligaments, as well as
the superficial groin and femoral lymph nodes and the supraclavicular region.
Infiltration of surrounding tissues is the most common reason to consider
 chemoradiation therapy over surgery.
2. Diagnosis
Once an abnormal cervical lesion has been assessed by a physician, a tissue biopsy
should be performed to either confirm or rule out malignancy. The physician should
make sure the biopsy is deep enough so as to include non-necrotic tissue, thus
ensuring a diagnostically relevant sample.
3. Prognostic factors
Stage, histologic grade and type, tumor size, depth of stromal invasion, involvement
of parametrium, and lymphovascular space invasion (LVSI) all influence prognosis.
Pelvic lymph node metastasis significantly decreases the survival rate of patients.
In a report of whole-exome sequencing analysis of 115 cervical carcinoma
normal paired samples, transcriptome sequencing of 79 cases and whole-genome
sequencing of 14 tumor-normal pairs was performed. Novel somatic mutations in 79
primary squamous cell carcinomas included recurrent E322K substitutions in the
MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in
EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%), and ERBB2 (6%). The
authors also observed somatic ELF3 (13%) and CBFB (8%) mutations in 24
adenocarcinomas. In this study, squamous cell carcinomas had higher frequencies of
somatic mutations in the Tp*C dinucleotide context than adenocarcinomas. Gene
expression levels at HPV integration sites were significantly higher in tumors with
HPV integration compared with expression of the same genes in tumors without viral
integration at the same site.3
4. Staging
Cervical cancer is staged clinically and includes palpation, colposcopy, cystoscopy,
endocervical curettage, proctoscopy, hysteroscopy, intravenous (IV) urography, and
radiograph. Many centers also use magnetic resonance imaging (MRI) to define the
local extent of disease and positron emission tomography (PET)/computed
tomography (CT) to determine if there is any metastatic spread. Postoperatively,
pathologic staging does not change clinical International Federation of Gynecology
and Obstetrics (FIGO) staging.4
5. Treatment
Over the last decades, the management of cervical preinvasive and invasive disease
has changed significantly. Colposcopy is being used with increasing frequency to
treat preinvasive disease, surgery is preferred to radiation therapy for early-stage
invasive disease, and adoption of chemoradiation therapy over radiation as primary
or adjuvant therapy.
6. Dysplasia and in situ carcinoma
Options for treatment include cervical conization (loop diathermy or cold knife) or
hysterectomy. Lymphadenectomy is not required if stage IA-1 disease is
demonstrated, as risk of metastases is very small (1%). If margins are positive,
completion of hysterectomy might be required. For patients with positive excisional
 margins, reexcision is recommended before offering hysterectomy for definitive
treatment in order to rule out a more deeply invasive tumor that would require
radical hysterectomy over simple or extrafascial hysterectomy. In patients with
negative conization margins, careful follow-up is adequate.
7. Early-stage disease
Early-stage disease can be treated with either chemoradiation or surgery. Surgery
generally results in definitive treatment, an improvement in survival over primary
radiotherapy (RT), and may provide a better quality of life. Retrospective data from
case-control and nonrandomized studies showed that stage IB/IIA cancer of the
cervix can be treated equally well with radical surgery and radical radiation
therapy. A randomized controlled trial (RCT) of 343 patients with stage IB/IIA
carcinoma cervix showed that these two modalities were equally effective in
controlling the disease judged by the disease-free and total survival as well as by
the relapse rates. This trial also conclusively showed that surgery has a survival
advantage over radiation therapy for patients with adenocarcinoma cervix.
However, surgery was associated with more serious adverse events (28% vs. 12%),
and 64% of the surgical patients required postoperative radiation, likely associated
with increased morbidity.5 Surgery should be considered in premenopausal women
where ovarian function can be preserved, in patients with an undiagnosed pelvic
mass, in patients with more risk of bowel toxicity from RT (adhesions because of
pelvic inflammatory disease, endometriosis, inflammatory bowel disease, or in very
thin women), or when compliance with the RT schedule may be difficult (with
socially disadvantaged patients, for example).
An important goal is to identify patients who would likely need RT and then
avoid surgery; most clinicians now use PET/CT scans to screen for metastatic
disease and MRI to evaluate the extent of local disease. This allows patients with
more advanced disease to be triaged and treated with chemoradiation.
Morbidly obese patients are typically not considered for standard surgery
because of high surgical risk, though robotically assisted surgery may prove safer.
Age does not appear to be a significant contraindication to radical hysterectomy.
Treatment should be appropriately tailored in unusual circumstances such as
pregnancy or patients with HIV.
Lymphadenectomy is a standard part of surgical management of any early-stage
disease being treated with radical hysterectomy. Sentinel node biopsy is still
investigational. Retrospective analysis of lymph node debulking of palpable nodes
prior to RT suggests a survival advantage in the prechemoradiation era, but is now
more controversial with modern imaging (MRI and PET/CT) and chemoradiation.
Based on a prospective study, the Gynecologic Oncology Group (GOG)
defined an intermediate-risk group using various combinations of three factors
(LVSI, deep stromal invasion, and tumor size). This approach resulted in the
following “GOG criteria”: (a) positive capillary-LSVI, deep and middle third
 penetration, and clinical tumor size of 2 cm; (b) superficial third penetration and
clinical tumor size of 5 cm; and (c) negative capillary-lymphatic space involvement
with middle or deep third penetration and clinical tumor size of 4 cm. In an RCT, in
women with intermediate risk factors, adjuvant pelvic radiation following radical
hysterectomy reduced the number of recurrences among women with stage IB
cervical cancer.6 The role of chemoradiation in this population is currently being
investigated.
In contrast, adjuvant chemoradiation is necessary for women who have high-
risk features after radical hysterectomy (positive lymph nodes, margins, or
parametrium). A Southwest Oncology Group RCT in 243 women revealed that
chemoradiation with cisplatin and 5-fluorouracil (5-FU) was significantly superior
to RT alone (overall survival [OS] at 4 years of 81% with chemoradiation vs. 71%
with RT), though it had more toxicity.7
If fertility preservation is desired, radical trachelectomy (removal of only the
cervix and parametria) with concomitant lymphadenectomy for small (less than 2
cm) tumors may be considered. This procedure appears to be associated with
retention of fertility (with up to 50% of patients becoming pregnant after radical
trachelectomy) along with acceptable risk of recurrence in carefully selected
patients. Tumor size is the single most important criterion in considering fertility-
preserving surgery, but other criteria, including grade, canal involvement, and LVSI,
may be important.8 Patients being evaluated for radical trachelectomy should have
pretreatment imaging studies including pelvic MRI and PET/CT to exclude
extracervical disease.
8. Locally advanced disease (stage IIB–IVA)
In 1999, the National Cancer Institute (NCI) released a clinical alert highlighting the
survival advantage documented in five NCI-sponsored clinical trials evaluating the
use of concurrent chemoradiation. A systematic review of 18 randomized trials
revealed absolute benefit in progression-free survival (PFS) and OS of 16% (95%
confidence interval 13% to 19%) and 12% (8% to 16%), respectively, but with
twice the gastrointestinal (GI) toxicity. Late toxicity is anticipated to be less with
concurrent chemotherapy because of the total lower dose of RT.
Weekly cisplatin 40 mg/m2 during RT has been adopted as the preferred
strategy because of its more favorable toxicity profile when compared with cisplatin
and 5-FU. There has not been a direct comparison of cisplatin versus cisplatin and
5-FU, though many extrapolate their equivalence from GOG-120, which compared
RT with cisplatin versus the combination of cisplatin, 5-FU, and hydroxyurea versus
hydroxyurea alone in 526 patients with stages IIB, III, IVA cancer. In both groups
who received radiation and cisplatin, the 3-year survival rate was 65% compared
with 47% for women receiving radiation and hydroxyurea.9
Combining cisplatin with another agent improves response at the expense of
considerably worse toxicity. In an international RCT of women with stages IIB and
 III cervical cancer, the investigators compared standard concurrent weekly cisplatin
and pelvic radiation with intensification of pelvic treatment with the addition of
potentially radiosensitizing concurrent weekly gemcitabine and two further courses
of adjuvant gemcitabine/cisplatin, a doublet with some independent systemic
activity. Patients in the combination arm had a 9% improvement in PFS at the fixed
time point of 3 years of follow-up.10 In addition, the International Gynecologic
Cancer Intergroup is currently comparing standard therapy with concurrent weekly
cisplatin and radiation with that same therapy followed by three additional courses
of systemic adjuvant carboplatin and paclitaxel (OUTBACK trial).
9. Adenocarcinoma
Adenocarcinoma is associated with a worse prognosis, although we do not stratify
treatment based on histology. Therefore, these patients are typically the same as that
for squamous cell carcinomas.
10. Neoadjuvant and adjuvant chemotherapy
Primary chemotherapy (neoadjuvant) with combination platinum-based
chemotherapy (cisplatin, vincristine, bleomycin) can have a very high response rate
(90% in stage IB2) with consolidative adjuvant radiation.11 In parts of the world
where access to radiotherapy is limited, neoadjuvant chemotherapy before surgical
treatment is administered for locally advanced cervical cancer. However, there are
no data that this approach is equally or more effective than primary chemoradiation.
11. Chemotherapy for recurrent and advanced-stage disease
Three contemporary RCTs (GOG-204, GOG-240, and Japanese Clinical Oncology
Group 0505 [JCOG-0505]) have investigated the optimal chemotherapy regimen in
advanced and recurrent cervical cancer. GOG-204 was conducted to reconcile the
relatively high overall response rate of 36% observed using the cisplatin-paclitaxel
doublet in an earlier trial and the 2.9-month OS benefit attributed to the US Food and
Drug Administration (FDA)–approved cisplatin-topotecan doublet. In GOG-204, a
final definitive comparison of four cisplatin-based chemotherapy doublets was
undertaken: cisplatin plus paclitaxel (standard arm), cisplatin plus vinorelbine,
cisplatin plus gemcitabine, and cisplatin plus topotecan. Despite hope for progress
with newer agents, no regimen outperformed the standard cisplatin-paclitaxel arm,
in which a trend for improved response and survival rates was observed.12
The Japanese GOG reported that the more convenient and better-tolerated
regimen of paclitaxel 175 mg/m2 over 3 hours with carboplatin at area under the
serum concentration-time curve 5 every 21 days was not inferior to cisplatin plus
paclitaxel. Thus, both the cisplatin and carboplatin combinations are acceptable
with cisplatin having more renal, nerve, and intestinal toxicities but carboplatin
having more marrow-related adverse events, especially thrombocytopenia.
Finally, GOG-240 study used a 2 × 2 factorial design; patients were assigned
to either of two chemotherapy regimens involving cisplatin plus paclitaxel or
topotecan and paclitaxel, and then randomly assigned to receive 15 mg/kg of
 bevacizumab or not. Treatment cycles were repeated every 21 days until disease
progression, unacceptable toxicity, or complete response. More than 70% of patients
in both groups had received prior platinum-based therapy. Importantly, in this trial
the incorporation of bevacizumab showed a significantly improvement in the median
OS as compared with chemotherapy alone (17.0 vs. 13.3 months). These data have
led to the FDA approval of bevacizumab plus chemotherapy for these patients
(Table 11.1).13
12. Novel biologics
There is a desperate need for more effective therapy for recurrent cervical cancer.
Agents that target the vascular endothelial growth factor, epidermal growth factor,
and HER2/neu receptors are currently in clinical trial and look promising. However,
there are no targeted treatments (beyond bevacizumab) that have a role in the current
treatment of cervical cancer.

TABLE
Gynecologic Oncology Group (GOG) 240 Bevacizumab Arm Regimens
11.1
1. Bevacizumab 15 m/kg IV every 3 weeks and cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 on day 1
2. Bevacizumab 15 mg/kg IV every 3 weeks and topotecan 0.75 mg/m2 days 1 to 3 plus paclitaxel 175 mg/m2 on day 1

13. Palliative care

Supportive care, which addresses physical, psychological, social, and spiritual
issues, is an essential part of the holistic care of patients as they approach the end of
their life. Common medical problems include pain, nausea and vomiting,
lymphedema, obstruction (genitourinary and GI), and fistulas, and require
multiprofessional care.

II. ENDOMETRIAL CANCER

In the United States, endometrial cancer is the most common gynecologic malignancy. The
ACS estimates that approximately 49,500 women are diagnosed with endometrial cancer
every year in the United States, and 8,000 deaths attributable to the disease. The cancer
typically presents at an early stage with vaginal bleeding in postmenopausal women.
Because it usually presents while still confined to the uterus, it is often cured with surgery
alone. Tamoxifen use is a significant risk factor for developing endometrial cancer. Given
the continued and expanding use of tamoxifen in the prevention and treatment of breast
cancer, a growing number of women have an increased risk of developing endometrial
cancer.
A. Histology
Endometrial cancer includes epithelial endometrial carcinomas (95%) and
mesenchymal tumors (5%). Two broad histologic categories of epithelial endometrial
cancer have been described, termed types I and II carcinomas. They appear to have
 different patterns of molecular alterations that underlie their pathogenesis and clinical
outcomes. Type I endometrial cancers are associated with unopposed estrogen exposure
and are often preceded by premalignant disease. They are usually early stage at
diagnosis, low-grade tumors (predominantly of endometrioid histology), and carry a
favorable prognosis. Obesity and family history remain two of the strongest risk factors
for this type of endometrial cancer.14
In contrast, type II endometrial cancers represent estrogen-independent tumors and
are associated with a more aggressive clinical course. Unlike type I tumors, there is no
readily observed premalignant phase. Both clear cell and serous carcinoma and perhaps
grade 3 endometrioid tumors comprise these histologic phenotypes. Some experts also
classify uterine carcinosarcomas as a representative of type II histology.
Mesenchymal tumors are composed of uterine sarcomas (leiomyosarcomas [LMS]
and endometrial stromal sarcoma) and mixed epithelial/stromal tumors
(carcinosarcomas and adenosarcomas).
B. Screening
Screening is not necessary for endometrial cancer as the disease typically presents early
with postmenopausal vaginal bleeding and has a good prognosis. Although screening
patients by ultrasound for thickened endometrial stripe has been evaluated, specifically
for patients who are on tamoxifen, there is no clear survival advantage over clinical
surveillance. By contrast, patients at higher-than-average risk of endometrial cancer
because of a family history of colorectal cancer (Lynch II syndrome or hereditary
nonpolyposis colorectal cancer syndrome) should undergo screening ultrasound and in-
office EMB starting at age 30 to 35 years or prophylactic hysterectomy and bilateral
salpingo-oophorectomy (BSO) if fertility is no longer desirable.15 Lynch-associated
endometrial cancer survivors should also undergo colorectal cancer screening.
Family members who have not yet been diagnosed with any cancers should undergo
screening for both endometrial cancer and colorectal cancer. Colorectal surveillance is
the only surveillance protocol in Lynch syndrome proved to be effective. Regular
colonoscopy every 3 years leads to a reduction of colon cancer-related mortality and
also to a significant reduction of overall mortality in contrast with colon cancer
screening in the general population. Women with Cowden syndrome, an autosomal-
dominant syndrome, are also associated with a 13% to 28% increased lifetime risk of
developing endometrial cancer. Although there are no specific guidelines for
endometrial screening in these patients, most advocate the same strategy used for
women with Lynch II syndrome.
C. Clinical disease
1. Clinical presentation
The most common symptoms of endometrial cancer are abnormal vaginal bleeding
and discharge. Because such bleeding can be caused by disorders other than cancer,
special attention should be paid to women with abnormal bleeding who are either
postmenopausal or women who are at high risk for endometrial cancer and are
 above the age of 35 years. Metastatic intraperitoneal (IP) disease may also cause
symptoms similar to those seen in advanced-stage ovarian cancer, including
abdominal distention, pelvic pressure, and pelvic pain. In women with
postmenopausal bleeding, a thickened endometrium on pelvic ultrasound is a sign of
possible endometrial cancer and should be followed up with endometrial sampling.
D. Diagnosis
Definitive endometrial cancer diagnosis requires tissue sampling, which can be
procured either via EMB or fractional dilation and curettage (D&C). EMB is the
preferred method of evaluating abnormal uterine bleeding. It should be noted that EMB
has proven more effective in postmenopausal, rather than premenopausal, women and is
better at confirming the presence of cancer rather than its absence. In cases where
outpatient EMB is not possible, or if abnormal bleeding persists despite negative
biopsy, fractional D&C should be performed.
E. Prognostic factors
The 5-year survival rate for endometrial cancer is 83%, and tumor-related prognostic
factors at diagnosis include histologic subtype, stage, grade, depth of myometrial
invasion, and LVSI. The prognosis of type I carcinomas is more favorable than that of
type II.
The presence of certain molecular abnormalities also contributes to poor prognosis.
One such abnormality is the overexpression of the epidermal growth factor receptor
(EGFR). In endometrioid adenocarcinomas, overexpression of EGFR decreases the
overall 5-year survival rate from 89% to 69%; in serous and clear cell, the presence of
EGFR overexpression decreases the survival rate from 86% to 27%.
Recently the results from The Cancer Genome Atlas’ (TCGA) analysis of 373
endometrial tumor samples utilizing array- and sequencing-based technologies have
classified the disease into groups with differing prognoses. According to the study,
some endometrial tumors with similar histologic features actually differ in their
molecular profile and might benefit from different treatments. Uterine serous tumors and
approximately 25% of high-grade endometrioid tumors had extensive copy number
alterations, few DNA methylation changes, low estrogen receptor/progesterone receptor
levels, and frequent TP53 mutations. Most endometrioid tumors had few copy number
alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA,
ARID1A, and KRAS and novel mutations in the SWI/SNF chromatin remodeling
complex gene ARID5B. A subset of endometrioid tumors that were identified had a
markedly increased transversion mutation frequency and newly identified hotspot
mutations in POLE. With these results the authors classified endometrial cancers into
four categories: POLE ultramutated, microsatellite instability hypermutated, copy
number low, and copy number high. The POLE group, with 17 tumors, or less than 10%
of the cohort, was associated with the best prognosis in the study, while those in the
high–copy number alterations had the worst outcomes.16
F. Staging
 Endometrial cancer is surgically staged.4
Although historically this procedure has been carried out by laparotomy,
laparoscopic management has increasingly been integrated into the forefront of surgical
staging. The GOG performed a large prospective trial from 1996 to 2005 that included
more than 2,600 women with clinically early-stage endometrial cancer. Women were
randomized in a 2:1 ratio to laparoscopic versus open hysterectomy, BSO, and pelvic
and aortic lymph node sampling. The first report from the study (Laparoscopic Surgery
or Standard Surgery in Treating Patients with Endometrial Cancer or Cancer of the
Uterus [LAP2]) confirmed the presumed short-term advantages of laparoscopy,
including shorter hospital stays, fewer perioperative complications, reduced blood
loss, and improved body image. Recurrence rates at 3 years after surgery were 11.39%
in the laparoscopy group and 10.24% in the open surgery group (hazard ratio [HR] for
laparoscopy 1.14; 95% CI, 0.92 to 1.46). Although the difference in 3-year survival
was small, the trial was deemed inconclusive because laparoscopy could not be
demonstrated with 95% confidence to have a HR below the predetermined threshold of
1.4 for noninferiority.17
As per FIGO recommendation, surgery for endometrial cancer includes, at the
minimum, examination of the omentum, liver, adnexal surfaces, peritoneal cul-de-sac,
and enlarged aortic and pelvic nodes, and total extrafascial hysterectomy with BSO. To
complete the surgical staging of endometrial cancer, the removal of bilateral pelvic and
paraaortic lymph nodes is also required. Many gynecologic oncologists have moved
toward performing comprehensive surgical staging for nearly all patients with
endometrial cancer. The rationale for uniform staging includes the lack of a patient
population for whom nodal disease is so low that nodes should be omitted, the
inaccuracy of preoperative or intraoperative assessments predicting the risk for nodal
disease, the potential for therapeutic benefit in node-positive and -negative patients, and
the lack of significant morbidity associated with the procedure. Postoperative adjuvant
decisions are best made with the most complete information. If nodal assessment is the
predominant factor by which to categorize patients into risk groups, routine nodal
dissection is the best method by which to determine which few patients will require
adjuvant therapy.
It should be noted, however, that the role of complete lymphadenectomy is
controversial after the publication of two negative randomized studies.
A Study in the Treatment of Endometrial Cancer (ASTEC) randomized patients with
endometrial cancer treated with hysterectomy to pelvic lymphadenectomy or not.
Following surgery, patients with stages I and IIA diseases were then randomized again
to observation or pelvic radiation therapy if they had grade 3, serous, or clear cell
histology, more than 50% myometrial invasion, or endocervical glandular invasion
(stage IIA). Treatment centers were also permitted to use vaginal cuff brachytherapy
regardless of pelvic radiation assignment. The results show no evidence of benefit in
terms of overall or recurrence-free survival for pelvic lymphadenectomy in women
 with early endometrial cancer.18
A similar study was performed by Italian investigators (CONSORT trial). In this
trial, 514 patients were assigned to hysterectomy with or without pelvic
lymphadenectomy. Patients were required to have myometrial invasion, and patients
with grade 1 tumors and less than 50% invasion were excluded. In the no-lymph no-
dissection (LND) group, 22% of patients had nodal dissections due to clinical
suspicion with 14% of these cases, or 3% of the entire no-LND arm, having node-
positive disease. In the LND group, the median number of nodes removed was 26.
Paraaortic dissection could be performed at the surgeon’s discretion and was done in
26% of cases. In the LND group, 13% were found to have positive nodes.
Postoperative therapy was not protocol prescribed, but the use of radiation therapy was
more common in the no-LND group (25% vs. 17%). The 5-year disease-free survival
was 81% in both groups, and 5-year survival was 90% in the no-LND group versus
86% in the LND group (HR 1.2, p = 0.5). The authors concluded that pelvic
lymphadenectomy could not be recommended as a routine procedure for therapeutic
purposes.19
Although the new FIGO staging continues to require the collection of peritoneal
cytology, positive pelvic washings are no longer formally considered part of the staging
system, and consequently, do not alter staging. Positive cytology alone is generally not
deemed to be a high-risk tumor criterion in the formulation of adjuvant treatment
planning of patients with endometrial cancer. Treatment decisions in women with
endometrial cancer should be based on extent of disease, as determined by staging, and
final pathologic tumor features.4
G. Treatment
1. Surgery
Surgical resection alone can be curative in many patients with endometrial cancer.
ACOG recommends at least a total hysterectomy and BSO. The role of concomitant
assessment of lymph nodes in all patients with endometrial cancer remains
controversial. For patients with high-grade histologic subtypes of endometrial
cancer, lymph node dissection at the time of hysterectomy and BSO is appropriate.
For patients with low-grade tumors (grade 1 to 2) of endometrioid histology,
lymphadenectomy should be based on other tumor risk factors, such as size of
primary lesion, depth of myometrial invasion, and cervical stromal involvement.
Laparoscopic surgery is associated with significantly shorter hospital stays and
better quality of life. The use of robotically assisted laparoscopic hysterectomy has
increased dramatically, especially in the obese patient population, and has resulted
in significantly lower perioperative complications compared with abdominal
surgery. However, whether robotic surgery is cost-effective has yet to be seen.
Prophylactic total hysterectomy and BSO have been reported to prevent 100%
of uterine cancers of women undergoing risk-reducing surgery for Lynch II syndrome
or hereditary nonpolyposis colon cancer.
 2. Radiotherapy
Radiation is given adjuvantly to reduce the risk of local recurrence (brachytherapy to
the vaginal vault postoperatively) to reduce the risk of a local recurrence, although a
benefit in OS has not been shown. External-beam RT is indicated for completely
resected, node-positive disease (stage IIIC) and is also considered for higher-risk
patients (poor grade, or adverse histology, deep invasion, advanced age) with early-
stage disease. In addition, brachytherapy is a reasonable and less toxic treatment.
More extensive RT (extended field) may be indicated in carefully selected patients
with small-volume residual disease, but the benefit has to be weighed against the
risk of late complications.20
Two prospective randomized trials compared surgery alone to surgery and
postoperative external-beam radiation in early-stage endometrial cancer. The first
trial was conducted by the GOG (GOG 99) where 390 patients with stages IB and
IIB endometrial cancers who underwent a total abdominal hysterectomy and BSO
and pelvic/paraaortic lymph nodes sampling were randomized to observation (n =
202) or postoperative pelvic radiation (n = 190). With a median follow-up of 69
months, the 4-year survival rate was 92% in the irradiation arm, compared with
86% in the observation arm (p = 0.6). The 2-year estimated PFS rate was 97%
versus 88% in favor of the irradiation arm (p = 0.007), with the greatest decrease
seen in vaginal/pelvic recurrences.21 The second trial was the PORTEC study where
714 patients with stage IB grades 2, 3 and stage IC grades 1, 2 were randomized
after total abdominal hysterectomy and BSO and no lymph nodes sampling to
observation (n = 360) or pelvic radiation (n = 354). With a median follow-up of 52
months, the 5-year vaginal/pelvic recurrence rate was 4% in the radiation arm
compared with 14% in the observation arm (p < 0.001). The corresponding 5-year
survival rates were 81% and 85%, respectively (p = 0.37).22
In a follow-up study including 427 patients with higher-risk disease (age >60
years plus either grade 1 to 2 and outer 50% invasion, or grade 3 with inner 50%
invasion, or stage IIA [1988 FIGO] disease), the PORTEC 2 study compared pelvic
radiation therapy with vaginal brachytherapy. None of the patients underwent nodal
assessment, and 5-year PFS (78% to 83%) and survival (80% to 85%) suggested
that in this population vaginal brachytherapy was equivalent to pelvic radiation.23
Medically infirmed patients can be treated with primary RT with good clinical
benefit, and radiation is very good palliation of symptomatic metastases (brain or
bone metastases, pelvic pain, or bleeding).
3. Endocrine therapy
Endocrine therapy has been used for patients with endometrial cancer, although it is
limited to the treatment of metastatic or advanced disease.24 While it is most often
administered to patients with a low- or intermediate-grade cancer, the predictive
impact of hormone receptor status is not clear. For example, in one GOG trial that
evaluated megestrol acetate alternating with tamoxifen in 56 women, the overall
 response rate was 27% and OS was 14 months.25 Interestingly, patients with a grade
3 tumor had a 22% response rate. Progestins and tamoxifen as single agents are
reasonable options as well; although data are far more limited, the aromatase
inhibitors appear to have little activity in this disease with response rates less than
10% in two small trials.
4. Chemotherapy (Table 11.2)
Increasingly, systemic therapy is being used earlier for patients with endometrial
cancer. Adjuvant chemotherapy has been reported to increase 5-year survival rates
(from 78% to 88%, HR 0.51, p = 0.02) in high-risk early-stage disease and is
commonly recommended for deep-penetrative, node-positive, high-grade tumors.
The data to support chemotherapy come from the GOG-122 trial, which included
396 patients with stage III and optimally debulked stage IV disease that were
randomly assigned to treatment with whole abdomen radiation or to doxorubicin-
cisplatin (AP) chemotherapy. There was significant improvement in both PFS (50%
vs. 38%; p = 0.007) as well as OS (55% vs. 42%; p = 0.004), respectively, in favor
of chemotherapy.26
The GOG conducted a randomized trial (GOG-163) for patients with primary
stages III and IV or recurrent endometrial cancer with measurable disease
comparing doxorubicin and cisplatin to doxorubicin with 24-hour paclitaxel and
granulocyte colony-stimulating factor (G-CSF). There were no significant
differences in response rate, PFS, or OS. The disadvantage of GOG-163 was the
lack of platinum in the taxane-containing arm, however. The addition of a taxane was
subsequently studied in GOG-177 evaluating doxorubicin with cisplatin as the
standard arm versus paclitaxel, doxorubicin, and cisplatin (TAP regimen) and G-
CSF as the investigational regimen. Overall, TAP chemotherapy increased 12-month
survival to 59% compared with 50% with doxorubicin and cisplatin with a HR of
0.75 (0.56 to 0.99). Although the TAP regimen produced an improvement in
response rate and PFS, survival was minimally increased, and was associated with
greater toxicity.27

TABLE
Chemotherapy Regimens for Endometrial Cancer
11.2
1. Doxorubicin and cisplatin
■ Doxorubicin 60 mg/m2 IV every 3 weeks
■ Cisplatin 50 mg/m2 IV every 3 weeks
2. Megestrol acetate 80 mg twice a day
3. Topotecan 1.2–1.5 mg/m2/day IV on days 1–5 every 3 weeks
4. TC
■ Carboplatin AUC 6 IV on day 1
■ Paclitaxel 175 mg/m2 IV on day 1 every 3 weeks
 5. TAP
■ Doxorubicin 45 mg/m2 IV on day 1
■ Cisplatin 50 mg/m2 IV on day 1
■ Paclitaxel 160 mg/m2 IV on day 2

AUC, area under the curve; IV, intravenous; TAP, paclitaxel, doxorubicin, and cisplatin; TC, carboplatin and paclitaxel.

On the basis of GOG 209, carboplatin and paclitaxel are now the more
routinely administered regimen. In this trial, almost 1,300 women with recurrent or
advanced endometrial cancer (including stage III disease) were randomly assigned
to TAP or carboplatin plus paclitaxel. As presented at the 2012 Society of
Gynecologic Oncologists Annual Meeting, women who were treated with
carboplatin and paclitaxel had a similar overall response rate to those treated with
TAP (51% in both arms). In addition, survival results were no different (PFS, 13
months in each arm; OS 37 vs. 40 months, respectively). However, carboplatin and
paclitaxel were significantly more tolerable.
Recurrent disease (especially ER/PR-negative disease) is often treated with
further palliative chemotherapy. However, response rates are very low and benefit
is rarely durable.28
5. Uterine papillary serous carcinoma
All uterine papillary serous carcinomas are typically treated with chemotherapy
after initial surgery, although patients with a serous carcinoma limited to a uterine
polyp may not require adjuvant chemotherapy.
6. Novel biologics
Multiple molecular pathways of cellular proliferation have been identified, and
several targets within these pathways have been explored. A growing understanding
of the underlying molecular biology of endometrial cancer has established the
mammalian target of rapamycin, angiogenesis, and the EGFR family as relevant
therapeutic targets. In addition, a subgroup of tumors have overexpression or
amplification of HER2/neu; however, the role of HER2-directed therapies remains
unclear and use of these drugs should be considered investigational.
The limited efficacy of systemic therapy for patients with advanced or
recurrent disease has led to the initiation of several clinical trials that have tested
targeted approaches against the key drivers of these pathways. Unfortunately, even
though there is an initial response with these therapies, some epithelial tumors have
intrinsic mutations that make them primarily resistant or eventually resistant during
the course of the treatment. The mutations give the tumor the ability to bypass the
blockage of one pathway and, since most pathways are redundant, tumors are still
able to grow.
7. Multimodality therapy
GOG-122 (doxorubicin-cisplatin vs. whole-abdominal irradiation) changed the
landscape of endometrial cancer treatment with proof that chemotherapy improved
 survival compared with radiation alone for stages III and IV disease. These patients
need tailored multimodality therapy; however, the sequence and schedule are not
optimally defined. Therapy most commonly consists of surgery, followed by
chemotherapy and tailored RT.
8. Follow-up
Surveillance requires a pelvic exam every 3 months in the first 2 years to detect a
potentially curable local recurrence, and supportive care should address functional,
psychological, social, and spiritual issues.

III. UTERINE SARCOMAS

A. Histology
Endometrial stromal sarcomas (ESSs) and undifferentiated endometrial sarcomas are
rare forms of uterine sarcomas. ESSs, whose cells resemble endometrial stromal cells,
are of low grade. Other uterine sarcomas include LMS.
B. Uterine leiomyosarcomas
Uterine LMS are rare aggressive tumors, with high recurrence rates, even when
confined to the uterine corpus at the time of diagnosis. These tumors are large
myometrial masses, which typically spread hematogenously. Patients present with vague
symptoms similar to those of patients with leiomyomas. Most patients are diagnosed
with LMS postoperatively.
In the presence of metastatic disease, complete surgical cytoreduction should be
attempted when feasible. Lymphadenectomy should be performed only in patients with
nodes suspected of harboring metastatic disease and as part of a cytoreductive effort.
There are conflicting data to support adjuvant chemotherapy or radiation therapy for
early-stage disease. Patients with advanced-stage disease should receive gemcitabine
and docetaxel adjuvant chemotherapy. Patients with recurrent disease are candidates for
a wide variety of second-line treatments, of which many are investigational. Although
prognosis remains dismal, ongoing studies are investigating the role of advanced
imaging, multimodality treatment, prognostic nomograms, and unique biomedical
pathways to increase understanding of LMS and improve therapeutic options for
patients.
C. Endometrial stromal sarcoma
ESSs are a specific histologic subtype within the larger group of mesenchymal tumors
of the uterine corpus. The most common symptom experienced by women with ESS is
abnormal vaginal bleeding. ESS tumors are almost always of low grade and on gross
examination usually present as a single mass. They can occur in sites other than the
uterus, including the ovary, fallopian tube, cervix, vagina, vulva, pelvis, abdomen,
retroperitoneum, placenta, sciatic nerve, or round ligament. ESS can be mistaken for
endometrial stromal nodules; two distinguishing characteristics are infiltrating margins
with or without angioinvasion, both of which are found in sarcomas but are absent in
nodules. A definitive diagnosis of ESS is not possible from endometrial curettage
 specimens alone, and a full hysterectomy is required.
Undifferentiated endometrial sarcomas are marked by extensive cytologic atypia to
the point where they can no longer be recognized as arising from the endometrial
stroma. Grossly, these tumors resemble undifferentiated mesenchymal tumors and mimic
high-grade sarcomas in behavior.
Stage and grade for all three types are important when considering a patient’s
prognosis. ESS has a good prognosis, in part due to its low-grade characteristics, and
most are cured surgically. However, low-grade ESS behaves aggressively if the
following characteristics are present: high expression of androgen receptors or low
expression of estrogen receptors. ESS is typically treated with surgery and possible
hormonal therapy, including progestins or aromatase inhibitors. The relapse rate for
ESS is 62%. Recurrence commonly includes pulmonary metastases and responds to
hormonal therapy. In patients with recurrent or metastatic endometrial stromal sarcoma
who have developed progression of disease after hormone therapy, chemotherapy with
agents such as ifosfamide or doxorubicin may be indicated. Chemotherapy may also be
indicated for patients with undifferentiated endometrial sarcoma tumors, although no
studies to date have been able to show a definite benefit associated with the use of
adjuvant chemotherapy. Active agents include ifosfamide, doxorubicin, gemcitabine,
docetaxel, liposomal doxorubicin, and paclitaxel. Although, the response rate with
these agents is low.29

IV. OVARIAN CANCER

Ovarian cancer is a relatively rare disease, with an incidence of about 1 in 70 women. In
the United States, according to the ACS, there are approximately 22,000 new cases of
ovarian cancer every year and 14,000 deaths attributable to the disease. As early-stage
ovarian cancer is rarely symptomatic, and due to the fact that there are no effective
screening protocols, patients with ovarian cancer typically present with advanced-stage
disease (stages III to IV). These tumors can be chemotherapy sensitive, enabling many
patients to live for years with their disease. However, cure rates remain low. Five-year
survival rates for women with advanced disease range from 20% to 40%; however, for
women who are diagnosed when the disease is confined to the ovary, cure rates are
approximately 70% to 90%.30 The cause of epithelial ovarian cancer remains unknown, but
theories relate it to incessant ovulation or abnormalities in the fallopian tube fimbria.
A. Histology
Epithelial ovarian carcinomas are classified as serous (70%), endometrioid (20%),
clear cell (<10%), and more rare types including mucinous, transitional cell,
carcinosarcomas, and undifferentiated or mixed epithelial tumors. Seventy-five percent
of papillary serous carcinomas of the ovary are diagnosed in the advanced stages, while
only 40% of mucinous, endometrioid, and clear cell carcinomas are diagnosed in the
advanced stages. Gene profiling studies suggest that treatment will be tailored to
genotype or histology. However, these studies are only in the planning stages.
 B. Screening
Screening for ovarian cancer would carry an important benefit given that most patients
present with advanced, and therefore incurable, disease. However, there are no data
that suggest that screening improves survival. The challenges of developing an effective
screening regimen are considerable: (1) there is no clear premalignant precursor, (2)
serous carcinoma appears to develop rapidly, (3) the morbidity from the diagnostic
procedure requires that the screening tests be very specific, and (4) most biomarkers
are developed and initially evaluated using samples from patients with clinically
diagnosed and often advanced cancer given the small number of true early-stage, high-
grade carcinomas detected often making it necessary to make inferences using cases of
advanced disease rather than early-stage disease. The serum marker CA-125 is
elevated in only 50% of patients with stage I disease, but is elevated in 90% of stages II
to IV ovarian cancers. CA-125 testing typically has a specificity of 97% to 99%, but
with a 1 in 70 lifetime risk of ovarian cancer, occult disease is present in only 1 of
2,300 postmenopausal women. As a result, a false-positive rate of 1% to 3% is
unacceptably high.31
In the ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening,
202,638 postmenopausal women aged between 50 and 74 years who were deemed to
be at average risk for ovarian cancer were randomly assigned to no treatment (control
group), transvaginal ultrasound (TVUS) screening alone (TVUS group), or a multimodal
screening (MMS) group with annual measurement TVUS. Prevalence (initial) screening
from this study found 42 primary ovarian and tubal cancers in the MMS group; 8 tumors
were borderline and 16 of the 34 invasive cancers (47%) were stage I or II. The
sensitivity, specificity, and positive predictive value were 89.4%, 99.8%, and 43.3%,
respectively, for all primary ovarian and tubal cancers and 89.5%, 99.8%, and 35.1%
for primary invasive cancer. Additional testing was required in 8.7% (4,355) of the
MMS participants and surgery was performed in 0.2% (97). Specificity was
significantly greater for MMS compared with TVUS. In the year after screening,
ovarian cancer was diagnosed in 13 subjects with negative results on screening (8 in
the TVUS group and 5 in the MMS group). The impact of screening on mortality from
ovarian cancer is still unclear and the results are pending.
In the ovarian component of the Prostate, Lung, Colorectal, and Ovarian Cancer
Screening (PLCO) trial, 78,237 healthy women aged between 55 and 74 years were
randomly assigned to screening and control groups; 39,115 women were assigned to
screening with annual serum CA-125 testing and TVUS. A CA-125 value at or above 35
U/mL or TVUS with evidence of an abnormal ovarian volume or an ovarian cyst with
papillary projections or solid components was considered a positive screen. In an
initial report, among 28,506 women with results for both tests, 1,703 had at least one
abnormal test: 1,338 had an abnormal TVUS, 399 had abnormal serum CA-125 levels,
and only 34 had abnormalities in both. Among 570 women who underwent a surgical
procedure, a total of 29 malignant neoplasms were identified; 9 were tumors of low
 malignant potential (LMP) and 1 was an ovarian sex-cord stromal tumor (granulosa cell
cancer). Of note, only 1 of the 19 invasive epithelial ovarian cancers was detected as
stage I. The PPV was 3.7% for an abnormal CA-125 test, 1.0% for an abnormal TVUS,
and 23.5% if both tests were abnormal. In a subsequent report after 4 years of
screening, 3,388 women had a positive result (either CA-125 or TVUS). Of these
women, 1,170 (34.5%) underwent surgery. Of the women who underwent surgery, 60
(5.1%) were found to have ovarian cancer; 72% of these tumors were stage III or IV.
The screening effort did not change the expected stage distribution from that of a normal
unscreened population. The PPV of a positive screening test was 1.0% to 1.3% during
the 4 years of screening. Twenty-nine cases of ovarian cancer that were diagnosed
during this study period were not detected by screening.
In an RCT of 83,000 postmenopausal women in Japan, 42,000 women were invited
to participate in annual screening with pelvic ultrasound and CA 125. The control group
in the same prefecture received usual care. There was no significant difference in the
detection of ovarian cancer, at an average follow-up of 9.2 years, between patients who
received screening (27 cases) and control patients (32 cases). There was a
nonsignificant trend toward earlier-stage disease in the screened group. Thirty-three
surgeries were performed to detect each case of ovarian cancer. Mortality data are not
yet available.
There are no randomized clinical trials on screening in high-risk populations. In the
largest cohort study, the United Kingdom Familial Ovarian Cancer Screen Study (UK
FOCSS), 3,563 women with a familial ovarian cancer syndrome (estimated minimum
lifetime risk of 10%) who had declined or deferred risk-reducing salpingo-
oophorectomy, participants were screened annually for a mean of 3.2 years with a
combination of TVUS and CA-125. The reported sensitivity for the detection of incident
ovarian cancer/fallopian tube cancer was 81.0% to 87.5%, depending on whether
occult cancers detected at the time of risk-reducing salpingo-oophorectomy (in women
who underwent the procedure prior to the end of the study period) were classified as
false-negative or true positive. The positive predictive value of incident screening was
25.5%, which exceeds the threshold of 10% considered necessary for ovarian cancer
screening. Four women underwent surgery for each case of detected cancer.
In high-risk population, evidence for screening effectiveness has not been
demonstrated, and the decision to screen this patient population is based on their very
high lifetime risk of ovarian cancer. The optimal screening protocol, or frequency for
screening, has not been determined. In the absence of randomized trials, the American
College of Obstetricians and Gynecologists (ACOG) recommends screening women
with BRCA mutations, starting at age 30 to 35 years or 5 to 10 years before the earliest
diagnosis in a family member, using a combination of serum CA 125 and TVUS every 6
to 12 months. Risk-reducing salpingo-oophorectomy reduces the risk of subsequent
cancer by 90% to 95% and is a safer strategy once a woman has finished bearing
children.32
 C. Clinical disease
1. Clinical presentation and diagnosis
The most common symptoms experienced by women with ovarian cancer usually and
heralding advanced-stage disease include persistent bloating, pelvic or abdominal
pain, early satiety, and urinary urgency or frequency. While these symptoms are
common and not specific to women with cancer, they have been found to be much
more common and severe in women with an ovarian malignancy. Other symptoms
reported include fatigue, indigestion, back pain, pain during intercourse,
constipation, and menstrual irregularities, although these do not appear to be any
more common in women with cancer. The most common clinical sign of ovarian
cancer is an adnexal mass as found on a pelvic ultrasound or through manual
palpation during a pelvic exam. Most masses do not prove malignant in
premenopausal women. As such, a simple cyst less than 8 cm in diameter in a
premenopausal woman can be followed up by the treating physician in 1 to 3
months. Adnexal masses in premenarchal or postmenopausal women, however, are
much more concerning for malignancy, especially if they are large and complex.
Physical features of an adnexal mass commonly associated with malignancy, as seen
on a pelvic ultrasound, include irregular borders, multiple echogenic patterns due to
presence of solid elements, multiple irregular septa, and bilateral tumors. A serum
CA-125 level greater than 35 U/mL in postmenopausal women should also be a
cause for concern for ovarian cancer. Typically, a conclusive diagnosis is not
possible until after surgery, followed by an assessment of the surgical specimen by a
pathologist.
2. Prognostic factors
Prognostic factors for epithelial ovarian cancer include stage, volume of residual
disease, grade, and histologic subtype. With respect to stage, the 5-year survival is
directly correlated. Stage I disease has a 90% 5-year survival, while stage II
disease has an 80% 5-year survival. The percentage decreases dramatically for
stage III (15% to 20%, 5-year survival) and stage IV (less than 5%, 5-year
survival). Optimally cytoreduced patients (<1 cm) have a higher median survival
than suboptimally cytoreduced patients.
Epithelial ovarian cancer subtypes have different overall patient survivals with
respect to both histology and stage at diagnosis. Among early-stage (I and II) ovarian
carcinomas, patients with endometrioid and mucinous tumors have a 10-year
survival rate of 85% and 79%, respectively, while those patients with clear cell and
high-grade serous tumors have a 10-year survival rate of 70% and 57%,
respectively. However, compared with endometrioid and serous tumors, clear cell
and mucinous tumors have a dramatically poorer prognosis in late-stage (III and IV)
disease.
Low-grade and LMP cancers have better survival rates than high-grade
cancers, but are more likely to be refractory for chemotherapy. The grade of the
 ovarian cancer affects the overall patient survival due to differences in the gene
expression of proliferative markers. Late-stage high-grade tumors express high
levels of genes involved in cell proliferation and metastasis, such as PDCD4, E2F3,
MCM4, CDC20, and PCNA. LMPs and low-grade serous tumors exhibit low
expression of proliferation markers such as CDC2, KIF11, TOP2A, CCNB1, and
MKI67, as well as activation of wild-type p53.
The TCGA Research Network analyzed the messenger RNA expression,
microRNA expression, promoter methylation, and DNA copy number in 489 high-
grade serous ovarian adenocarcinomas and the DNA sequences of exons from
coding genes in 316 of these tumors. The authors reported that high-grade serous
ovarian cancer is characterized by TP53 mutations in almost all tumors (96%); low
prevalence but statistically recurrent somatic mutations in nine further genes
including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy
number aberrations; and promoter methylation events involving 168 genes. Analyses
delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes,
four promoter methylation subtypes, and a transcriptional signature associated with
survival duration, and shed new light on the impact that tumors with BRCA1/2 and
CCNE1 aberrations have on survival. Pathway analyses suggested that homologous
recombination is defective in about half of the tumors analyzed, and that NOTCH
and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.33
3. Staging
Staging for ovarian cancer occurs at surgery.34 Per FIGO, complete exploration of
the abdomen and pelvis with resection of all gross disease as well as total
hysterectomy, BSO, omentectomy, peritoneal biopsies, and pelvic and paraaortic
lymphadenectomy are recommended. If desired, fertility-conserving surgery may be
performed on patients with low-stage, low-grade lesions.
D. Treatment
1. Cytoreductive surgery
Ovarian cancer may be one of the only solid tumors where resection of metastatic
disease is a standard part of initial management. Laparotomy is often both the
diagnostic procedure and initial therapeutic intervention, and the key to cure.
Griffiths was one of the first to pioneer the concept that successful surgical
debulking to a residual tumor size of ≤1.5 cm (now 1 cm) maximum diameter results
in superior survival. Surgical cytoreduction (debulking) has several purposes: (1) it
removes some or all of the tumors, (2) it improves physiology (GI obstruction and
protein loss to ascites), (3) it removes de novo chemotherapy-resistant clones, and
(4) it facilitates drug delivery by removing tumor with a compromised blood supply.
Patients are stratified into “optimally” (<1 cm residual disease) or “suboptimally”
cytoreduced; it is the second most powerful predictor of outcome after stage.
However, current data suggest that cytoreduction to no residual disease should be
the goal.
 The role of neoadjuvant chemotherapy with interval debulking surgery (NACT-
IDS) as the primary strategy in the treatment of advanced-stage ovarian cancer has
been controversial.35 Multiple studies suggest that the survival of advanced ovarian
cancer patients treated with NACT-IDS is similar to that of patients who undergo
primary debulking surgery, with improvement in performance status, decrease in
extent and morbidity of surgery, and increase in the percentage of patients having
optimal cytoreduction. The European Organization for the Research and Treatment
of Cancer (EORTC) 55971 trial enrolled 670 women with stage IIIC/IV epithelial
ovarian cancer who were randomly assigned to either primary debulking surgery
followed by six cycles of platinum-based chemotherapy or to NACT-IDS with
carboplatin and paclitaxel for three cycles followed by interval surgical
cytoreduction and adjuvant chemotherapy. The authors concluded that, in advanced-
stage IIIC and IV ovarian carcinoma, NACT-IDS was not inferior to primary
debulking surgery. Of note, in this trial, 10% of patients receiving NACT never had
debulking surgery because of disease progression or other clinical reasons.36 One
important criticism of this trial that potentially favored the NACT-IDS arm was that
fewer than half of patients who underwent a primary debulking surgery were
optimally debulked to less than 1 cm residual disease. This is a low rate compared
with reports of more than 80% optimal cytoreduction in centers in the United States.
2. Early-stage ovarian cancer
Although only 15% of ovarian cancers present as early-stage disease, one-third to
one-half of all cured patients are from this group. Formal staging is required by a
surgeon with subspecialty training with an exploratory laparotomy, total
hysterectomy, BSO, omentectomy, complete examination of the peritoneal surfaces,
multiple biopsies, peritoneal washings, and paraaortic and pelvic lymph node
sampling. The role of laparoscopy has not been formally evaluated. Patients
diagnosed with apparently early-stage ovarian cancer without adequate staging
should undergo a second exploratory surgery for definitive staging. Approximately
one-quarter will be upstaged with positive lymph node metastasis.
The 5-year survival of patients with stage I epithelial cancer is ≥90%. Patients
with stages IA and IB disease of low grade do not need adjuvant chemotherapy. All
other patients require adjuvant platinum-based chemotherapy based on the joint
International Collaboration in Ovarian Neoplasia (ICON I) and EORTC’s ACTION
study for an 8% improvement in OS.37
GOG-157 compared three with six cycles of carboplatin and paclitaxel (TC) in
early-stage disease. While more cycles were associated with more toxicity, there
was no OS benefit, though six cycles improved PFS.38 In addition, this study showed
that patients with serous carcinomas may be more likely to benefit from six rather
than three cycles.
3. Advanced-stage ovarian cancer
The principles of treatment for patients with advanced ovarian cancer are to (1)
 surgically cytoreduce, or debulk, tumor with surgery, followed by (2) chemotherapy
(Table 11.3). A remission (normal CA-125 and CT scan) only translates into cure
for a minority, but 5-year survival rates for patients treated with platinum-based
regimens are >40%. Even after a complete response to first-line chemotherapy, only
approximately half of patients with negative second-look operations are eventually
cured.
4. Platinum-based first-line chemotherapy
Chemotherapy has improved through the last 40 years from single-agent alkylators
(melphalan and cyclophosphamide) to anthracycline combinations and finally
platinum- and taxane-based therapy. Current options for treatment of women with
advanced disease can be stratified by whether or not they were completely or
optimally cytoreduced (to <1 mm of residual disease) or not. For those who were
treated with IP chemotherapy in combination with IV chemotherapy is associated
with the longest survival advantage, compared with standard chemotherapy
delivered every 3 weeks. For those who were not optimally or completely
cytoreduced, and those who are not candidates for an IP-delivered treatment,
treatment with IV chemotherapy every 3 weeks is indicated. One alternative, the
delivery of carboplatin every 3 weeks plus paclitaxel weekly (known as dose-dense
treatment), appears promising, though its role in the management of patients with
advanced disease is not entirely clear. In addition, while bevacizumab is approved
for use in this setting in Europe (alongside chemotherapy and then as extended
treatment over 1 year total time), its role is controversial in the United States.
 TABLE
Chemotherapy Regimens for Ovarian Cancer
11.3
First-line Therapy
1. Paclitaxel and carboplatin
■ Carboplatin AUC 5–7.5 IV on day 1
■ Paclitaxel 175 mg/m2 IV over 3 hours on day 1 every 3 weeks for six cycles
2. Paclitaxel and cisplatin
■ Paclitaxel 135 mg/m2 IV over 24 hours on day 1
■ Carboplatin 75–100 mg/m2 in normal saline IP on day 2
■ Paclitaxel 60 mg/m2 in normal saline IP on day 8 every 3 weeks for six cycles
3. Dose-dense paclitaxel and carboplatin
■ Carboplatin AUC 6 IV on day 1
■ Paclitaxel 80 mg/m2 IV over 1 hour on days 1, 8, and 15 every 3 weeks for six
■ Cycles

Platinum-sensitive Therapy
1. Paclitaxel and Carboplatin
■ Carboplatin AUC 5–7.5 IV on day 1
■ Paclitaxel 175 mg/m2 IV over 3 hours on day 1 every 3 weeks for six cycles
2. Gemcitabine Carboplatin
■ Gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8
■ Carboplatin AUC 4 IV on day 1 every 3 weeks for six cycles
3. PLD and carboplatin
■ PLD 30 mg/m2 on day 1
■ Carboplatin AUC 5 IV on day 1 every 4 weeks for six cycles

Platinum-resistant Therapy
1. PLD 40 mg/m2 IV over 1 hour every 4 weeks
2. Paclitaxel 80 mg/m2 over 1 hour weekly (FDA-approved regimen is every 21 days)
3. Bevacizumab 15 mg/kg IV every 3 weeks (NCCN preferred drug, FDA-approved for the treatment of patients with platinum-resistant,
recurrent epithelial ovarian cancer)
4. Topotecan
■ Regimen 1 (every 21 days): 1–1.5 mg/m2/day IV over 30 minutes on days 1–5 (often 1.25 mg/m2 on days 1–4) every 3 weeks
■ Regimen 2: 3.75–4 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 4 weeks
5. Gemcitabine 800–1,000 mg/m2 IV on days 1 and 8 every 3 weeks for six cycles
6. Etoposide 50 mg PO twice a day on days 1–10 or 14 every 21 days (related to WCC tolerance)

AURELIA Trial Bevacizumab Arm Regimens

1. Bevacizumab 10 m/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks and PLD 40 mg/m2 IV every 4 weeks
2. Bevacizumab 10 m/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks and Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 of each 4-
week cycle
3. Bevacizumab 10 m/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks and Topotecan 4 mg/m2 IV on days 1, 8, and 15 of each 4-week
cycle, or 1.25 mg/kg on days 1–5 of each 3-week cycle

AUC, area under the curve; FDA, US Food and Drug Administration; IP, intraperitoneal; IV, intravenously; NCCN, National
Comprehensive Cancer Network; PLD, pegylated liposomally encapsulated doxorubicin; PO, by mouth; WCC, white blood cell
count.

5. Intraperitoneal chemotherapy
Delivering regional chemotherapy with the highest possible concentration of drug at
 the tumor appears rational. Three randomized studies have suggested a substantial
survival advantage. However, unacceptable toxicity has been a barrier to utilization
of IP, which is not considered standard therapy.
GOG-104 was a randomized trial of IV cyclophosphamide with either IP or IV
cisplatin and associated with an 8-month median survival advantage. GOG-114
included IV paclitaxel with IP cisplatin and two initial cycles of moderate-dose
carboplatin and an 11-month survival advantage.39 The third study (GOG-172) led to
an NCI alert about the potential advantage of IP therapy in patients with optimally
debulked ovarian cancer because of an unprecedented 16-month survival advantage.
The “Armstrong regimen” of paclitaxel 135 mg/m2 over a 24-hour period (to reduce
neurotoxicity) followed by IP cisplatin 100 mg/m2 on day 2 with IP paclitaxel 60
mg/m2 on day 8 given every 3 weeks for six cycles was associated with more fatigue
and hematologic, GI, metabolic, and neurologic toxicity, with significantly worse
quality of life, but an improvement in median duration of OS from 50 to 66 months
(p = 0.03).40
Concerns remain that IP chemotherapy may not reach subperitoneal disease,
lymph nodes, or areas walled off by adhesions. However, the biggest concerns are
about catheter complications (infection, pain, and blockage), which are serious in a
quarter of patients and prevented 58% of patients from completing IP therapy in
GOG-172. Technical challenges remain a barrier to its use in some settings, and
GOG-252 is currently evaluating IP carboplatin, dose-dense paclitaxel, and the role
of bevacizumab.
6. Bevacizumab
GOG-218 investigated the integration of bevacizumab in the upfront treatment of
advanced ovarian cancer with paclitaxel and carboplatin (TC). In this three-arm
randomized phase III study, women with advanced epithelial ovarian cancer (stage
III or IV, after maximal attempt at surgical debulking) were assigned to treatment
with TC followed by placebo (TC-P), TC plus bevacizumab followed by placebo
(TC-B), or TC plus bevacizumab followed by bevacizumab maintenance (TCB-B).
Bevacizumab or placebo was administered at 15 mg/kg every 3 weeks, with the first
five cycles administered concurrently with cycles 2 to 6 of chemotherapy and an
additional 17 cycles delivered as single-agent maintenance treatment. PFS was 10.3
months in the TC-P arm; 11.2 months, TC-B; and 14.1 months, TCB-B. The 3.8-
month improvement in PFS came at the cost (in terms of patient inconvenience and
toxicity) of women receiving treatment every 3 weeks for an additional 51 weeks
beyond the standard duration, a 23% risk for developing grade 2 hypertension, 10%
risk for grade 3 to 4 hypertension, and 2.3% risk for grade 3 or worse GI
perforation, hemorrhage, or fistula formation.41 At present, there seems to be no
difference in OS among the treatment arms, although data are not yet mature.
The Gynecologic Intergroup Trial (ICON7) randomly assigned 1,528
previously untreated women with high-risk early-stage (I or IIA clear cell or grade
 3) or advanced epithelial ovarian cancer to standard chemotherapy with TC for six
cycles with or without bevacizumab (7.5 mg/kg) during chemotherapy and then as
maintenance treatment for 12 additional cycles. Compared with standard
chemotherapy, the incorporation of bevacizumab resulted in a significant increase in
the overall response rate (67% vs. 48%) and significant improvement in the median
PFS at 42 months follow-up (24 vs. 22 months) but no difference in OS. Patients in
the experimental arm had more serious (grade 3/4) adverse events (66% vs. 56%)
including a higher rate of mild to serious (grade 2 or higher) hypertension (18% vs.
2%).42
7. Maintenance therapy
In patients with suboptimally debulked disease, who are destined to have relapse,
maintenance therapy is a rational strategy. GOG-178 compared 1 year of single-
agent paclitaxel with a 3-month maintenance agent defined in the study as the control
arm. The use of paclitaxel as maintenance for 1 year resulted in a 7-month PFS
without a documented OS advantage. Though it is not a standard of care, it provoked
GOG-212, which investigates a potentially less neurotoxic agent, polyglutamated
paclitaxel (Xyotax). As discussed above, neither GOG 218 nor ICON-7 showed an
OS benefit associated with the use of bevacizumab concurrently with chemotherapy
or as maintenance therapy.
8. Dose-dense (weekly) paclitaxel
Weekly paclitaxel in the recurrent setting is associated with more peripheral
neuropathy but less overall toxicity, both hematologic and nonhematologic, and has
become a popular option. A recent RCT of AUC 6 carboplatin with either paclitaxel
180 mg/m2 every 21 days or 80 mg/m2 every 7 days (dose-dense paclitaxel and
carboplatin [dd-TC]) in 631 Japanese patients reported better median PFS (28 vs.
17 months), and OS at 2 years (84% vs. 78%, p = 0.05). Grade 3 and 4 anemia was
reported more frequently in the dd-TC group, and other toxicities were similar in
both groups.43 This strategy is currently being tested in GOG-262.
9. Poly(ADP-ribose) polymerase (PARP) inhibition
Possibly the most promising area of investigation is the inhibition of PARP. PARP
adds nicotinamide adenine dinucleotide polymers to histones and other nuclear
proteins, thereby improving cell survival after DNA damage. If this system is
inhibited, PARP-1 activation cannot lead to DNA repair through the base excision
repair pathway. If there is no other repair system, such as when a patient carries a
BRCA-1 or -2 mutation, or has functional impairment in the repair pathways, which
has been reported in up to nearly half of serous ovarian tumors (synthetic lethality),
apoptosis results.44
Olaparib (AZD2281) is an oral PARP-1 and PARP-2 inhibitor that to date has
undergone the most extensive clinical investigation thus far of PARP inhibitors in
ovarian cancer. Olaparib has been tested in phase I and II studies; as a single agent,
olaparib has demonstrated anticancer activity in both germline BRCA-mutated
 ovarian cancer in addition to sporadic HGSC without known germline BRCA
mutations. In one trial, 296 women with platinum-sensitive high-grade serous
recurrent ovarian cancer who achieved a response to their most recent treatment
were randomly assigned to treatment with olaparib (400 mg orally twice a day) or
placebo. Patients had received a median of three prior regimens with approximately
60% in each arm having a PFI of >12 months. Olaparib resulted in a significant
improvement in PFS compared with placebo (8 vs. 5 months), but interim analysis
found no OS benefit (30 months in both). Olaparib was associated with a low rate of
serious (grade 3/4) toxicity. Adverse events (any grade) more commonly reported in
the olaparib group than in the placebo group included nausea (68% vs. 35%), fatigue
(49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%). A separate
analysis of these data evaluated the results specifically in patients with a known
BRCA mutation and suggested that the clinical benefit was greatest among these
patients. This has led to an ongoing trial that will reexamine the role of olaparib as a
maintenance treatment, specifically in patients with a known BRCA mutation.45,46
At least two additional PARP inhibitors, niraparib and rucaparib, are being
evaluated as maintenance therapy in patients with platinum-sensitive high-grade
serous ovarian cancer. Rucaparib is a PARP-1 and PARP-2 oral inhibitor that has
entered into clinical trial testing for recurrent ovarian cancer and has shown in vitro
as well as in vivo anti-ovarian cancer activity. Rucaparib is currently undergoing
further testing at the 600 mg BID dose in recurrent ovarian cancer as part of two
clinical trials: ARIEL2 and ARIEL3. ARIEL2 is a phase II biomarker study of 180
patients with high-grade serous cancer or endometrioid cancer who have received
one or more prior platinum-based chemotherapy regimens and whose last treatment
regimen was platinum-based. ARIEL3 has the same histological requirements as
ARIEL2 and is a phase III randomized trial of oral rucaparib versus placebo (2:1
randomization) following platinum-based therapy. In addition, Niraparib is a
selective PARP-1 and PARP-2 inhibitor that has been tested with promising results.
Currently, a phase III study of niraparib versus placebo as maintenance therapy
called NOVA is open and currently accruing patients with platinum-sensitive
recurrent high-grade serous cancer who have achieved a partial or complete
response to both their current as well as their penultimate platinum course. This is a
double-blind study with a 2:1 randomization of niraparib versus placebo for either
germline BRCA or sporadic BRCA recurrent platinum-sensitive high-grade serous
cancer.46
10. Docetaxel and carboplatin
The SCOTROC study demonstrated that docetaxel was significantly less neurotoxic
than paclitaxel and equally effective in combination with carboplatin, and is a valid
but less used alternate to paclitaxel.47
11. Recurrent disease
Follow-up for patients should include a pelvic examination and CA-125, initially
 every 3 months, though early detection of recurrence does not appear to improve
survival.
Most patients develop recurrent disease, and will respond to several
sequential lines of treatment in this setting. However, ultimately, recurrent ovarian
cancer is not curable. Drug development and supportive therapies have allowed for
many patients with ovarian cancer to live with their disease for many years, on and
off treatment and with good quality of life.
Recurrent ovarian cancer is triaged by the predictive factor, platinum-free
interval, and divided into potentially platinum sensitive (more than 6 months since
prior platinum) with a median survival measured in years and platinum-resistant
disease with survival measured in months.48
The definition of relapse is important as a rising CA-125 typically has a lead
time of 2 to 6 months before symptoms develop. Patients with an asymptomatic
rising marker can be managed expectantly, as palliative chemotherapy has toxicities
and OV05/55955 clearly demonstrated that treating women with an asymptomatic
rising CA-125 adversely affected quality of life and did not impact survival. The
study was designed to detect a 10% improvement in 2-year OS and randomized
1,442 patients to (1) immediate chemotherapy if CA-125 levels rose to greater than
twice the upper limit of normal (a median of 5 months earlier), or (2) patient and
clinician were blinded to the CA-125, and then got treatment at symptomatic
progression of disease.49
12. Platinum-sensitive disease
Rechallenge with a platinum combination is appropriate with a platinum-free
interval of at least 6 months and standard combinations include (1) paclitaxel and
carboplatin50; (2) gemcitabine and carboplatin51; and (3) pegylated liposomal
doxorubicin (PLD) and carboplatin.52
ICON 4 demonstrated an absolute improvement in the 1-year PFS of 10% and
18% reduction in risk of death (p = 0.02) for paclitaxel and carboplatin over
conventional platinum-based chemotherapy.50 The AGO (German) study led to the
FDA approval of the combination for platinum-sensitive recurrent ovarian cancer
with a 28% improvement in PFS for carboplatin and gemcitabine over carboplatin
(p = 0.003).51 In addition, the combination of carboplatin and PLD studied in the
CALYPSO trial showed a significant improvement in median PFS (11.3 vs. 9.4
months), with less alopecia, neurotoxicity, and substantially fewer episodes of
carboplatin hypersensitivity reactions.52
In the recurrence setting, a phase III trial (OCEANS study) studied the
combination of bevacizumab together with carboplatin and gemcitabine
chemotherapy followed by bevacizumab maintenance therapy in the setting of
platinum-sensitive disease. Bevacizumab with chemotherapy resulted in an
improvement in PFS (12 vs. 8 months). However, with a median follow-up of 35
months, OS was not different between the two arms (33 vs. 35 months). There was
 also a higher objective response rate in the experimental arm (79% vs. 57%, p <
0.001). In addition to a higher rate of treatment discontinuation for adverse events
(23% vs. 5%), including higher rates of serious hypertension (17% vs. <1%),
proteinuria >grade 3 (9% vs. 1%), and non–central nervous system bleeding (6% vs.
1%). Of note, there were no cases of GI perforation reported.53
13. Platinum-resistant disease
When disease becomes resistant to platinum, goals of car should focus on controlling
cancer-related symptoms, minimizing toxicity, and maintaining quality of life. The
choice of chemotherapeutic agent should be based on efficacy, toxicity profile, and
scheduling convenience for the patient. Documented response rates are poor (15% to
20%). Continual, sequential, single-agent palliative chemotherapy has been the
mainstay of treatment for recurrent disease. CA-125 may better predict response to
treatment and outcome than CT scans. PLD, topotecan, a different taxane schedule
(e.g., a weekly paclitaxel), rechallenge with platinum, gemcitabine, altretamine,
pemetrexed, or oral etoposide are all reasonable options. Appropriately eligible
patients should be considered for enrollment in clinical trials. Endocrine therapy
may be appropriate for patients with asymptomatic recurrences. Phase II data exist
for tamoxifen, anastrazole, letrozole, and fulvestrant. Response rates are low, and
primarily result in stable disease. Studies with letrozole and fulvestrant have shown
higher response rates in patients with estrogen receptor-positive tumors. However,
we do not routinely perform nor recommend estrogen receptor testing in women with
recurrent epithelial ovarian cancer.
In the AURELIA study, 361 patients with platinum-resistant ovarian cancer
were randomly assigned to chemotherapy with or without bevacizumab (15 mg/kg
every 3 weeks). Chemotherapy options were based on the investigator’s choice of
one of the following: weekly paclitaxel 80 mg/m2 days 1, 8, 15, and 22 every 4
weeks (n = 115), topotecan 4 mg/m2 days 1, 8, and 15 every 4 weeks (or 1.25 mg/m2
on days 1 through 5 every 3 weeks), and PLD 40 mg/m2 day 1 every 4 weeks (Table
11.3). Of note, patients who received chemotherapy alone were allowed to cross
over to single-agent bevacizumab at the time of disease progression. With a median
follow-up of 13.5 months, compared with chemotherapy alone, chemotherapy plus
bevacizumab resulted in a statistically significant improvement in the overall
response rate (ORR) (31% vs. 13%, respectively), a reduction in the risk of disease
progression (HR 0.48, 95% CI, 0.38 to 0.60; median duration 6.7 vs. 3.4 months),
but no statistically significant improvement in OS (HR 0.85, 95% CI, 0.66 to 1.08;
median 16.6 vs. 13.3 months). In addition, in the experimental arm there was an
increase in the rate of grade 2 or greater adverse events, including hypertension
(20% vs. 7%) and proteinuria (0.6% vs. 11%). Four patients (2.2%) experienced a
GI perforation.54 In November of 2014, the FDA-approved bevacizumab plus
chemotherapy for the treatment of platinum-resistant epithelial ovarian cancer.
14. Palliative care
 Bowel obstructive symptoms typically herald the last months of patients’ lives and
require intense and multidisciplinary care. Surgery should be limited to patients with
chemotherapy-responsive disease, and for others a gastric venting tube may be
appropriate to alleviate symptoms. Total parenteral nutrition does not substantially
alter the clinical course, and attending to end-of-life issues is an essential part of
compassionate care.

V. VULVAR CANCER
Vulvar cancer is rare, representing 4% of all gynecologic malignancies and 0.6% of all
cancers in women. The ACS estimates that 4,000 women are diagnosed with vulvar cancer
every year, with 900 deaths attributable to the disease. Older women are at increased risk,
with less than 20% of cases occurring in women under the age of 50, and roughly half
occurring in women 70 years and older. Vulvar cancer in younger women tends to be
associated with HPV infection. The disease usually presents with symptoms at an early
stage, making it a highly treatable disease. However, due to its very personal nature, as
well as its relative rarity, symptoms may often go unaddressed for some time, allowing the
disease to progress beyond the early stages.
A. Histology
Carcinoma of the vulva is classified as squamous (80% to 90%), melanoma (9%), and
Bartholin gland cancer and sarcomas (1% to 11%).
B. Screening
There are no routine screening protocols for the detection of vulvar cancer, and clinical
presentation is the earliest detection point for the disease. However, patients should be
encouraged to be vigilant about their genital health, and clinicians should be proactive
in examining and performing biopsies on vulvar abnormalities.
C. Clinical disease
1. Clinical presentation and diagnosis
The majority of women who present with early-stage vulvar cancer have a
recognizable lesion on the vulva, along with local symptoms, including soreness and
itching. The treating clinician should proceed directly to tissue biopsy in order to
avoid delay in diagnosis. The biopsy should include both the cutaneous lesion in
question and the underlying stroma in order to determine the depth of invasion, if
any. If left untreated for a long period of time, advanced-stage disease may result,
and the patient will often present with local pain, bleeding, and surface drainage.
Advanced disease can also metastasize to the regional lymph nodes and eventually
more distant tissues.
2. Prognostic factors
Age of patient, clinical stage, grade, depth of tumor invasion, and presence of lymph
node metastasis are significant prognostic parameters, with depth of tumor invasion
being an independent factor. Patients with metastasis to the inguinal lymph nodes
will experience recurrences within 2 years of first-line therapy, and the long-term
 survival is reduced by 50%. In addition, the overexpression of p53 has been linked
to tumor aggressiveness.
3. Staging
The method of staging vulva cancer is surgery with histologic findings.4
D. Treatment
1. Early-stage disease
Vulvar cancer is surgically staged. Early-stage tumors (microinvasive, stages I and
II) are treated with surgical approaches. Microinvasive tumors can usually be
successfully treated with local resection, but multifocal disease remains a problem.
All patients should be carefully followed.
2. Stage IA
Stage I disease is subdivided based on depth of stromal invasion. For stage IA
lesions, invading less than 1 mm into the stroma, the treatment of choice is radical
local excision without lymph node dissection, as the risk of nodal invasion for these
lesions is less than 1%.
3. Stage IB
Stage IB lesions have ≥1 mm stromal invasion. As the risk of inguinofemoral node
involvement is ≥8%, it is recommended that patients undergo inguinofemoral lymph
node dissection. Whether patients need a unilateral or bilateral lymph node
dissection (for midline lesions) depends on the location of the lesion. For patients
with a negative groin on physical exam, a sentinel lymph node biopsy is an
alternative to inguinofemoral lymphadenectomy, provided the expertise to perform
this examination is available. This technique results in less morbidity without
compromising detection of lymph node metastases or increasing the risk of a groin
recurrence. The best candidates for intraoperative lymphatic mapping are women
with uninfected tumors limited to the lateral vulva and <4 cm in diameter, with no
palpable enlarged groin nodes or markedly abnormal nodes on imaging and no
history of vulvar surgery that could alter normal lymphatic drainage.55–57
4. Stage II
Surgical resection of stage II lesions needs to procure a ≥1 cm circumferential
tumor-free margin around the primary lesion. To achieve this goal, the excision may
involve a radical local excision, a partial radical vulvectomy, an excision using a
three-incision technique, or the involvement of plastic surgery and skin flaps.
In general, given the long-term side effects and morbidity of RT, this treatment
modality is avoided in the management of early-stage disease. For patients whose
tumors have a positive margin, following initial surgical excision, the
recommendation is for surgical reexcision unless this is anatomically not feasible or
the patient is not an appropriate surgical candidate for reexcision. Reexcision is
favored over RT given the toxicity associated with RT.
RT is usually recommended for patients with two or more microscopically
positive groin nodes, one or more macroscopically positive lymph nodes, evidence
 of extracapsular nodal involvement, or in some aggressive cases where only a small
number of lymph nodes were retrieved.
5. Advanced-stage disease; stages III and IV
In general, the treatment of advanced-stage disease is individualized. Although many
of these lesions can be resected surgically, this treatment modality may significantly
impair quality of life. For example, for tumors involving the urethra, anus, bladder,
or pelvic bone, surgical resection would require removing vital structures or pelvic
exenteration with creation of a urinary conduit and colostomy.
Given the morbidity of this surgical procedure, for these patients, the favored
treatment modality is chemo-RT. In these cases, chemo-RT can be given
preoperatively in order to reduce tumor volume and allow for a less radical surgical
resection. For tumors that completely respond to chemo-RT, surgical resection can
be omitted. In general, these patients are treated with RT and concurrent single-agent
cisplatin or cisplatin and 5-FU chemotherapy as radiation sensitizers. While data in
vulvar cancers is limited, the benefits seen in cervical cancer provide the rationale
to pursue more aggressive therapy for these patients.58
6. Palliative chemotherapy
In patients with advanced-stage disease, those too medically infirm for surgery, or
those with inoperable disease, palliative chemotherapy may be appropriate as
treatment when curative intent is not feasible. Therapeutic options are limited and
agents active in other squamous cancers, such as cisplatin, 5-FU, doxorubicin,
methotrexate, mitomycin C, bleomycin, cisplatin, and paclitaxel, are associated with
low response rates in vulvar cancer.

VI. OVARIAN GERM CELL TUMORS

Germ cell tumors represent a rare subset of ovarian cancer. They usually present in a
younger age group compared with epithelial ovarian cancers. The etiology of these tumors
remains unknown. They are highly chemosensitive, and, as such, are usually highly curable.
A. Histology
Germ cell tumors account for 2% to 3% of ovarian cases and are composed of the
following subtypes: dysgerminoma, yolk sac tumor, embryonal carcinoma,
polyembryoma, nongestational choriocarcinoma (CCA), mixed germ cell tumor, and
teratoma. The majority of patients (50% to 75%) are diagnosed in the early stages (I
and II).
B. Screening
There is currently no screening strategy. However, diagnosis should be considered
preoperatively in the young, and markers should be drawn so that treatment can be
planned accordingly (especially for fertility-sparing surgery).
C. Clinical disease
1. Clinical presentation and diagnosis
Malignant ovarian germ cell tumors usually occur in women much younger than with
 epithelial ovarian cancer, with a median age between 16 and 20 years, depending on
the specific histologic type. Common signs and symptoms of the disease include a
pelvic mass, usually detected during a pelvic exam, and abdominal pain, often
resulting from ovarian rupture, hemorrhage, or torsion. Other symptoms include
abdominal distention, fever, and vaginal bleeding, although these are less common.
Many germ cell tumors will produce biologic markers, which are useful in the
diagnosis and observation of the disease. The two most common are human
chorionic gonadotropin (hCG) and α-fetoprotein (AFP). Elevated AFP suggests a
teratoma rather than dysgerminoma, the most common histologic subtype. As with
epithelial ovarian cancer, CA-125 may also be elevated in patients with germ cell
tumors.
2. Prognostic factors
Patients diagnosed with germ cell tumors have a relatively good prognosis due to
sensitivity to chemotherapy. A combination of complete resection of tumors, proper
surgical staging, and effective therapy ensures a high survival rate. Long-term
survivorship can be achieved even without complete tumor resection or with
advanced tumors at presentation.
3. Staging
Per FIGO recommendation, staging follows the same principles as for epithelial
ovarian tumors.34
D. Treatment
Surgery is the first step in the management of malignant ovarian germ cell tumors. In
young women with ovarian germ cell tumor, fertility-sparing surgery, with optimal
tumor resection, may be appropriate. If only one ovary is involved, then a unilateral
salpingo-oophorectomy is performed while the contralateral ovary and uterus are
preserved. Debulking of advanced-stage disease, however, is important. Second-look
surgery may be advantageous for patients whose primary tumor was incompletely
resected and contained a teratoma.
Most patients are candidates for platinum-based chemotherapy following surgery,
except patients whose tumor was stage IA dysgerminoma or immature, grade I teratoma,
in which surveillance is appropriate. Three courses of bleomycin 30 U weekly IV,
etoposide 100 mg/m2 on days 1 to 5, and cisplatin, 20 mg/m2 on days 1 to 5 (BEP) is
the standard treatment for completely resected disease; four courses of BEP are
necessary for residual disease.59
The majority of recurrences develop in the first 2 years after completion of therapy.
Recurrence is usually detected by a rise in serum tumor markers or the evolution of new
disease on radiographic studies. Given the rarity of these tumors, the data to inform the
management of patients are of very limited quality. For patients who were previously
treated with chemotherapy (as adjuvant therapy or first-line treatment of stage IV
disease) and did not exhibit refractory disease (i.e., no evidence of disease progression
during or immediately after prior treatment), repeat treatment with a platinum-based
 regimen is indicated. For patients who relapse despite first-line treatment for recurrent
disease and those with refractory disease, most experts utilized a similar approach to
men with relapsed and refractory testicular cancer.

VII. STROMAL OR GRANULOSA CELL TUMORS

Stromal or granulosa cell tumors (GCTs) are very rare, hormone-secreting tumors that can
cause precocious puberty in young girls.
A. Histology
GCTs account for 70% of malignant sex-cord stromal tumors but only 5% of malignant
ovarian tumors. GCTs are composed of adult type (AGCT; 95%) and juvenile type
(JGCT; 5%).
B. Clinical disease
1. Clinical presentation
The most common symptoms of AGCT are abnormal vaginal bleeding, abdominal
distention, and abdominal pain. The pain and distention are due to the usually large
size of the tumor at diagnosis. Some patients may have ascites, and premenopausal
women may experience menometrorrhagia, oligomenorrhea, or amenorrhea. Because
GCTs are estrogen-secreting, breast tenderness, uterine myohypertrophy, and
endometrial hyperplasia are also common signs and symptoms. In JGCT, prepubertal
patients commonly present with isosexual precocious pseudopuberty. Patients will
also almost always present with increasing abdominal girth, and a palpable mass
will be found during abdominal, pelvic, or rectal exam. Finally, abdominal pain,
dysuria, and constipation are common.
2. Prognostic factors
Stage at diagnosis, increasing tumor size, rupture and nuclear grade in stage I
patients, nuclear atypia, and increased mitotic activity all contribute to poorer
prognosis for patients with AGCTs. For JGCTs, however, surgical stage and mitotic
activity are the most significant prognostic factors.
3. Staging
Per FIGO recommendation, the staging system used for GCTs is the same as that
used for epithelial ovarian cancer.34
C. Treatment
Standard treatment for GCTs includes hysterectomy with BSO followed by platinum-
based chemotherapy along the lines derived from experience with epithelial ovarian
tumors. Surgery alone is the acceptable treatment for most women with GCTs, since the
majority are stage IA and confined to one ovary at the time of diagnosis. Many reports
indicate that more than 90% of these neoplasms are unilateral and confined to the ovary.
The low incidence of sex-cord ovarian tumors, their multiplicity of histologic patterns,
and their variable biologic behavior limit our knowledge on the optimal management of
these tumors. Contemporary treatment principles have generally been developed based
on observations of small groups of patients and on information extrapolated from
 clinical management of epithelial tumors. For women with stage IC–IV disease, some
groups do not recommend postoperative therapy, while others recommend platinum-
based chemotherapy, most frequently bleomycin, etoposide, and cisplatin (BEP).59–61

VIII. GESTATIONAL TROPHOBLASTIC NEOPLASM

A. Histology
The histologic patterns of gestational trophoblastic neoplasms (GTNs) depend on the
state of the preceding pregnancy. After molar pregnancy, GTN presents with the
histologic pattern of either molar tissue or CCA. Following a miscarriage or term
pregnancy, GTN presents with the histologic pattern of CCA. Following ectopic
pregnancy, the histologic pattern is either of molar tissue or CCA. Placental-site
trophoblastic tumor is a rare form of GTN.
B. Screening
Following either a partial or complete molar pregnancy, patients should have weekly
hCG serum level measurements until they are normal for 3 weeks, followed by monthly
hCG screening for 6 months. If nondetectable hCG levels are reached, the risk of
developing GTN approaches zero.
C. Clinical disease
1. Clinical presentation
The signs and symptoms for GTNs vary depending on the extent of disease. Locally
invasive disease usually presents with IP bleeding or vaginal hemorrhage resulting
from the tumor perforating the myometrium or uterine blood vessels. Metastatic
disease is usually found in the lungs, vagina, brain, and liver, and is usually
hemorrhagic, causing hemoptysis, IP bleeding, and acute neurologic deficits. GTN
can cause various radiologic patterns in the lungs, including pleural effusion,
alveolar or snowstorm pattern, discrete rounded densities, or embolic pattern.
Vaginal lesions may also be present and are highly hemorrhagic; biopsy of these
lesions should be completely avoided. Patients with cerebral metastases have a high
rate of fatal hemorrhage during the first week of treatment and may need RT first
(standard in the United States) or low-dose chemotherapy to “cool off” (standard in
the United Kingdom). Finally, patients with liver metastases usually present with
jaundice, intra-abdominal pain, or epigastric pain.
2. Diagnosis
During diagnostic workup, all patients should have a baseline hCG measurement,
and hepatic, thyroid, and renal function tests. If chest radiography is negative for
metastatic disease, a chest CT scan should also be performed. It is unlikely that
asymptomatic patients with normal pelvic exam and negative chest CT scan would
have brain or liver metastasis. However, if vaginal or lung metastases are present, a
head or CT or MRI or abdomino-pelvic CT should be obtained to evaluate for the
presence of brain or liver metastases, respectively.
3. Prognostic factors
 Site of involvement, tumor volume (hCG level, size and number of metastases), prior
chemotherapy, and duration of disease all contribute to poor prognosis. Delayed
diagnosis, high levels of hCG, and brain or liver metastases could lead to resistance
to single-agent chemotherapy. The development of CCA following term pregnancy
also has poor prognosis.
4. Staging
Per FIGO recommendation, an anatomic staging system is used in the case of GTN.62
The World Health Organization (WHO) prognostic scoring system is important in the
medical management of patients with complete hydatidiform moles, partial
hydatidiform moles, and CCAs (Tables 11.4 and 11.5). The FIGO staging system
incorporates a modified WHO prognostic scoring system. The scores from the eight
risk factors are summed and incorporated into the FIGO stage, separated by a colon.
Scores of 0 to 6 are considered low risk. Scores of 7 and greater are considered
high risk.

TABLE
Prognostic Scoring Index for Gestational Trophoblastic Tumors
11.4
 TABLE
Multiagent Chemotherapy Regimens for Gestational Trophoblastic Disease
11.5

D. Treatment
For patients with early-stage or low-risk GTN, the choice of treatment plan is based on
whether the patient desires to preserve fertility. If the ability to conceive is no longer a
concern, management should include hysterectomy with single-agent adjuvant
chemotherapy. The chemotherapy is necessary as a precaution against tumor cells
spread to locations outside the primary site and to treat occult metastases. If the patient
wishes to preserve fertility, single-agent chemotherapy should be administered with
methotrexate or actinomycin D (ACT-D). Both treatments are well tolerated, but
patients on ACT-D do have a higher instance of side effects. These include nausea
(61% vs. 50%), emesis (33% vs. 14%), and alopecia (26% vs. 14%). Currently, the
preferred regimen is methotrexate 100 mg/m2 by IV bolus and 200 mg/m2 by IV infusion
over 12 hours, followed by folinic acid 15 mg intramuscularly or orally every 12 hours
for 4 doses starting 24 hours after the start of methotrexate. An 8-day regimen of
methotrexate (1 mg/kg IM every other day for four doses) and leucovorin calcium (0.1
mg/kg, given once, 24 hours after each dose) is easy to administer and well tolerated. It
is associated with remission rates in excess of 90% for patients with stage I GTN and
approximately 70% of those with low-risk stage II or III disease. If the tumor is
resistant to methotrexate, ACT-D should be used.
A randomized GOG study comparing weekly methotrexate with pulsed biweekly
dactinomycin showed that the complete response rate with weekly methotrexate was
particularly low (9%; 1 of 11 patients) for women with high-risk disease (WHO score
5 to 6) or CCA. It should be noted, however, that the methotrexate dose utilized in this
study was 30 mg/m2/week, the lowest weekly regimen used in clinical practice.63
Disease remission requires three consecutive normal hCG values (less than 5
mIU/mL) over a period of 14 to 21 days. When weekly or biweekly chemotherapy
regimens are used, the regimen is continued until the third negative result is obtained.
 When infusional methotrexate is given as a one-time dose, hCG levels are then
followed weekly, with additional therapy given only if an inadequate response is
observed.
If resistance to single-agent therapy develops, treatment with an alternative single
agent is recommended (i.e., ACT-D in patients who received methotrexate or vice
versa), provided the disease is of low risk. For patients who relapse on single-agent
therapy and have high-risk disease, treatment with combination therapy is indicated. For
these women, the choice usually consists of methotrexate, ACT-D, and
cyclophosphamide or etoposide, methotrexate, ACT-D, cyclophosphamide, and
vincristine (EMA-CO; Table 11.4).
Patients who present with de novo stage IV disease should be treated with rigorous
combination chemotherapy (EMA-CO) and selective RT and surgery. If the patient has
cerebral metastases, the dose of methotrexate should be increased to 1 g/m2 and RT
should be applied.64
Patients with stage I, II, or III disease should be followed up after treatment with
weekly hCG tests until levels reach normal for 3 consecutive weeks, then monthly for
12 months. Patients with stage IV disease should have weekly hCG tests until normal
for 3 weeks, followed by monthly tests for 24 months. Risk of recurrence after initial
remission varies by stage of disease: 2.9% for stage I disease, 8.3% for stage II, 4.2%
for stage III, and 9.1% for stage IV.
For patients who require further treatment due to persistent or recurrent disease
after EMA-CO, other alternative regimens are available, including EMA alternating
with etoposide and cisplatin (EP). Of note, this regimen may also be administered as
the first-line combination regimen of choice in specific subsets of women with
advanced GTN, particularly those with placental-site trophoblastic tumors.
Surgical management is rarely necessary in women with GTN. However, adjuvant
surgical procedures could be excellent adjuncts to salvage chemotherapy in removing
known foci of chemotherapy-resistant disease in selected patients with persistent GTN.
Hysterectomy might be curative for subsets of patients, including those with epithelioid
or placental-site trophoblastic tumors.65

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I. UROTHELIAL CANCER
A. General considerations and staging
Urothelial cell carcinomas arise from the transitional epithelium that lines the urethra,
bladder, ureter, and renal pelvis. More than 90% of patients with bladder cancer have
transitional cell carcinoma (TCC), which is not uncommonly found admixed with
limited squamous cell, adenocarcinoma, or neuroendocrine carcinoma elements. Pure
adenocarcinomas, squamous cell carcinomas, and neuroendocrine (small cell) cancers
represent 5% to 10% of bladder cancers. TCC of the bladder can be considered as
presenting in two disease states, non–muscle invasive and muscle invasive (MIBC).
Approximately two-thirds of patients have low-grade, noninvasive tumors
characterized most commonly by FGFR3 mutations, and one-third have high-grade
and/or invasive disease characterized by loss of critical tumor suppressor genes such as
p53, pRB, and p21. The significant improvement in our understanding of the underlying
molecular biology of bladder cancer derives from the publication of the Human Cancer
Genome Atlas’s molecular characterization of urothelial bladder cancer.1
Whereas the vast majority of lethal events occur among patients with high-
grade/invasive tumors, most patients have noninvasive, low-grade forms of bladder
cancer, and many live for years after the initial diagnosis with evidence of recurrent
tumors, making bladder cancer among the most prevalent cancers as well as the most
costly to treat.
Patients with bladder cancer typically present with painless hematuria, with or
without irritative voiding symptoms including frequency, urgency, and dysuria. Patients
with more advanced disease may present with progressive flank or pelvic pain from
direct extension of disease or as a consequence of ureteral obstruction.
The bladder wall consists of four layers, the urothelium, the innermost epithelial
lining, the lamina propria, muscularis propria (detrusor muscle), and the adventitia
(serosa). Most (75% to 85%) bladder tumors are non–muscle invasive at diagnosis and
are typically low-grade, stage Ta tumors (TaLG) or stage T1 tumors, which have
penetrated the epithelial basement membrane but have not invaded the muscle. The
remaining 20% to 30% present with de novo invasion of the muscle wall of the bladder
(stages T2 to T4). The TNM staging system for bladder cancer is summarized in the 7th
edition of the AJCC Cancer Staging Manual.2
Patients who present with a clinical picture worrisome for bladder cancer should
 undergo an evaluation including cystoscopy with the collection of urine cytology and
evaluation of renal function. Findings on cystoscopic evaluation may lead to a
transurethral resection of bladder tumor (TURBT), a procedure performed under
anesthesia to obtain tissue for histologic diagnosis. Inclusion of muscle in the
pathologic specimen is required to evaluate the potential for muscle invasion. Evidence
of the presence of muscle-invasive disease on biopsy should be followed by a
metastatic evaluation with CT imaging of the chest and abdomen/pelvis (if not obtained
prior to TURBT), assessment of complete blood cell count, and serum chemistries.
B. General approach to therapy
1. Non–muscle invasive bladder cancer
The guiding principle of the management of non–muscle invasive disease is to
diminish the frequency of recurrent disease while at the same time minimizing the
potential for disease progression to muscle-invasive and potentially lethal disease.
The vast majority of patients with TaLG have a nonlethal form of bladder cancer that
is likely to recur but is far less likely to progress to high-grade and/or muscle-
invasive disease (<10%). The therapeutic goals for these patients are to monitor for
bladder tumor recurrences, typically by surveillance cystoscopies with collection of
urine cytology at 3-month intervals. Level I evidence supports the use of post-
TURBT (within 24 hours) administration of intravesical chemotherapy with agents
such as mitomycin-C to attempt to reduce the risk of tumor recurrences for those
with multiple or large (>3 cm) tumors for whom a bladder preservation strategy is
planned.
For patients with Ta high-grade (TaHG), carcinoma in situ (CIS) or T1 bladder
cancer, the goals of therapy are to prevent progression to clinical metastasis while
preserving quality of life through bladder preservation or reconstructive strategies
that are consistent with the patients’ preferences. The primary therapeutic dilemma
is determining which patients should be considered for immediate cystectomy and
which are suitable candidates for a bladder preservation approach using intravesical
BCG (Bacillus Calmette–Guérin). Cystectomy should be the primary therapeutic
approach for patients with TaHG, CIS, or TI bladder cancer with a long (>10 to 15
years) life expectancy with other high-risk features including large or multifocal T1
tumors, evidence of variant histology such as micropapillary, and or lymphovascular
invasion. For other patients and those who refuse cystectomy, intravesical BCG is a
reasonable approach.
Full-dose induction BCG is administered weekly for 6 weeks, starting at least
2 weeks after TURBT. Patients with negative cystoscopy and cytology at restaging at
3 months are appropriate candidates for maintenance BCG typically given as three-
weekly installations at 3, 6, 12, 18, 24, 30, and 36 months after diagnosis. Patients
who manifest persistent or recurrent disease may be considered for a second
induction course of BCG based on their clinical status; however, cystectomy remains
the preferred management approach.
 2. Muscle-invasive bladder cancer
Patients with muscle-invasive disease (T2 to T4, N0, M0) are usually managed by
radical cystectomy or radiotherapy. There is increasing evidence that an extended
lymphadenectomy as part of the radical cystectomy is associated with an
improvement in 5-year progression-free survival.3 Appropriate patients may be
offered continent diversions instead of an ileal loop diversion. Despite appropriate
local therapy, the recurrence rates of patients with MIBC range from 40% to 100%.
Systemic chemotherapy administered in the perioperative setting has the potential to
improve the cure rates of patients undergoing cystectomy. The role of cisplatin-
based neoadjuvant therapy has been tested prospectively in two large randomized
trials providing definitive evidence of a survival benefit in patients undergoing
radical cystectomy and is the standard of care for patients who are suitable to
receive cisplatin.4,5 Patients with high-risk pathology who did not receive
neoadjuvant chemotherapy may benefit from cisplatin-based adjuvant therapy.
a. Neoadjuvant chemotherapy
In patients with MIBC, cisplatin-based combination chemotherapy followed by
radical cystectomy has been demonstrated to improve survival compared with
surgery alone.6 It is important to note that survival benefit has not been
demonstrated with non-cisplatin-based regimens, and for patients unfit or
unwilling to receive cisplatin-based chemotherapy, the standard of care remains
surgery alone. Although in some clinical settings, it may be reasonable to
consider cisplatin-based chemotherapy in the adjuvant setting, there is no level I
evidence that therapy in this setting improves overall survival.7 The only
regimens that have been tested in the phase III settings include the MVAC
regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) (Table 12.1) and
the CMV regimen (cisplatin, methotrexate, vinblastine), though the latter regimen
is rarely used. Many oncologists have adopted the gemcitabine, cisplatin
regimen (GC) (Table 12.1) for use in the neoadjuvant setting extrapolating from
the results of a phase III study in metastatic urothelial cancer, which compared
GC with MVAC, which demonstrated comparable efficacy, duration of response,
and less toxicity with GC.8 More recently, several phase II trials have
demonstrated the potential utility and safety of administering accelerated/dose-
dense MVAC (Table 12.1) in the neoadjuvant setting.9,10 The optimal number of
cycles remains unknown, but three to four cycles are most commonly
administered. Upon completion of therapy, most patients go on to radical
cystectomy 3 to 6 weeks postchemotherapy.
 TABLE
Common Chemotherapy Regimens for Cancer of the Bladder
12.1
Regimen Doses and Schedules
Methotrexate 30 mg/m2 IV on days 1, 15, and 22
■ Vinblastine 3 mg/m2 IV on days 2, 15, and 22
■ Doxorubicin 30 mg/m2 IV on day 2
MVAC (standard) ■ Cisplatin 70 mg/m2 IV on day 2 (with adequate pre- and posthydration)
Give methotrexate and vinblastine on days 15 and 22 if white blood cell count >2,000/µL
(ANC >1,000) and platelet count >50,000/µL
Cycles should be repeated every 28 days
Methotrexate 30 mg/m2 IV on day 1
■ Vinblastine 3 mg/m2 IV on day 1
■ Doxorubicin 30 mg/m2 IV on day 1
A-MVAC (accelerated or dose dense) ■ Cisplatin 70 mg/m2 IV on day 1
■ Pegfilgrastin 24–48 hours after chemotherapy
Vinblastine, doxorubicin and cisplatin may be given day 1 or 2
Cycle is repeated every 14 days
■ Gemcitabine 1,000 mg/m2 days 1, 8, and 15
■ Cisplatin 70 mg/m2 on day 2
Gemcitabine/cisplatin Give gemcitabine on days 8 and 15 if white blood cell count >2,000/µL (ANC >1,000) and
platelet count >50,000/µL
Cycles should be repeated every 28 days

b. Bladder-sparing therapy
External-beam radiation therapy is widely used in parts of the world as the
standard curative-intent local therapy, with recent level I evidence demonstrating
an improvement in survival in those patients receiving chemo-radiotherapy
versus radiotherapy alone.11 Patients who undergo radiotherapy do require
ongoing bladder surveillance with periodic cystoscopic evaluations.
Chemotherapy and radiation can be offered to patients with MIBC who
desire bladder preservation or are not candidates for radical cystectomy.
Cisplatin chemotherapy concurrent with radiation increases local control.
Approximately 30% of patients are free of recurrence 5 years after combined
modality therapy for muscle-invasive disease. Salvage cystectomy has been used
in some patients who do not achieve a complete response or recur after a
bladder-sparing approach. There have been no randomized trials comparing
bladder preservation therapy with radical cystectomy. Local symptoms from
radiation including urinary frequency, incontinence, and proctitis usually
resolve, but can persist in some patients. Candidates for a bladder-sparing
approach are patients with favorable tumors (e.g., no involvement of the trigone
or ureter) or patients who are unfit for radical cystectomy due to comorbidities.
3. Renal pelvis urothelial cancers
The management of transitional cell cancer of the renal pelvis is primarily surgical
 with nephroureterectomy the procedure of choice, and the role of perioperative
chemotherapy in this setting is the subject of ongoing clinical trials.
4. Metastatic urothelial cancer
The prognosis for locally advanced and metastatic urothelial bladder cancer has
changed little over the past 30 years. In the untreated metastatic settings, favorable
prognostic factors include good performance status, the absence of visceral
metastases, and normal albumin and hemoglobin values.12 Randomized trials of
cisplatin-based combination regimens have demonstrated the ability to cure a small
subset of patients ranging from 5% to 15%.13,14
C. Systemic therapy regimens and evaluation of response
1. Initial therapy
As noted above, the MVAC (standard/dose dense) and GC regimens are the most
widely used in the management of advanced urothelial cancers (Table 12.1).
Although cisplatin is the most active single agent in advanced urothelial cancers
many patients as a consequence of the disease or other comorbidities are not
appropriate candidates for cisplatin-based regimens.15 Agents such as carboplatin,
docetaxel, paclitaxel, and gemcitabine as single agents and in combination have
demonstrated overt antitumor activity, but none have demonstrated curative
potential.
Cisplatin-based multiagent chemotherapy produces median progression-free
and overall survival rates in the 7-to-8-month and 14-to-15-month ranges,
respectively.8 The toxicity of these regimens can be substantial and patient selection
in regard to medical comorbidities and performance status is important. Response to
chemotherapy is monitored by periodic assessment of tumor responses typically
with CT imaging, with the expectation that most patients who will respond will do
so within the first one or two cycles of treatment.
2. Salvage therapy
Patients with disease progression following initial platinum-based chemotherapy
currently have very poor outcomes with no established standard of care. Antitumor
activity has been demonstrated with a large number of chemotherapeutic agents
primarily in phase II studies but to date, no evidence of improved survival has been
demonstrated.16 Goals of therapy need to be carefully reviewed with patients before
initiating therapy. Enrolling fit patients onto next-generation clinical trials should be
a primary consideration for those patients desiring additional therapy.
3. Next-generation therapeutics
Recently, next-generation immunomodulatory (anti-PD1/PDL1) agents have
demonstrated significant activity in advanced urothelial cancer. Several phase II
trials have demonstrated objective response rates in the 30 to 40 range with subsets
of patients having sustained responses with a good safety profile. Phase III studies to
define the role of these agents are underway.17
D. Nontransitional cell histologies
 Management of the non-TCC histologies, typically adenocarcinoma, squamous cell, or
small cell carcinomas, is challenging. Primary adenocarcinomas and squamous cancers
of the bladder are managed surgically, as there is no defined role for chemotherapy in
the neoadjuvant or adjuvant settings. Patients with metastatic disease should be
considered for phase I studies, as there is no evidence of meaningful response rates to
standard chemotherapeutic agents. Neuroendocrine tumors of the bladder are usually
treated similar to small cell lung cancer with cisplatin and etoposide chemotherapy and
bladder radiotherapy or cystectomy in selected patients with bladder-confined disease.
Subsets of these patients with clinically organ-confined disease may be long-term
survivors; however, patients with metastatic disease have similar outcomes to patients
with extensive small cell lung cancer, demonstrating a relatively high response rate to
chemotherapy, but very poor survival rates.

II. PROSTATE CANCER

A. General considerations and staging
Carcinoma of the prostate is the second most common cancer in the United States after
non-melanoma skin cancer. Following the introduction of prostate-specific antigen
(PSA) into clinical practice in the late 1980s a significant increase in prostate cancer
diagnoses as a consequence of a broadly applied screening paradigm led to a dramatic
increase in the number of men with low-grade and low-stage disease undergoing
curative-intent therapy with surgery or radiotherapy. Large randomized prostate cancer
screening trials from the United States and Europe have reported mixed results, leading
to much more nuanced recommendations for prostate cancer screening from major
medical societies in the United States18–21 Active surveillance (AS) as a management
strategy for low-risk patients and recent developments in genomic- based diagnostics
may improve our ability to risk-stratify patients to enable curative-intent therapy for
patients at risk of dying from prostate cancer while minimizing the side effects of
therapy for those patients destined to die with, but not of prostate cancer.22,23
Definitive pathologic staging of prostate cancer requires surgical excision of the
prostate and regional nodes, whereas clinical staging of prostate cancer uses
pretreatment clinical parameters to predict the extent of disease and the patient’s
prognosis as well as to inform the therapeutic decision process. Pretreatment modalities
used to predict disease extent in prostate cancer patients include the digital rectal exam,
prostate cancer features obtained from needle biopsy, PSA, and imaging with prostate
MRI. Pathologic staging more accurately estimates disease burden and is more useful
than clinical staging for outcome prediction. The most important pathologic criteria in
the assessment of a radical prostatectomy specimen are tumor grade, the presence or
absence of seminal vesicle invasion and extracapsular disease, surgical margin status,
and pelvic lymph node involvement. The most commonly used staging for prostate
cancer is the TNM system.2
B. Clinically organ-confined disease
 As a consequence of widespread prostate cancer screening, the potential for clinical
understaging, and the heterogeneity of prostate cancer, the therapeutic decision process
for men with localized prostate cancer is complex. The guiding principal of disease
management should be to offer curative-intent therapy to men who need to be cured and
to avoid the side effects of the intervention in men who are not destined to die of
prostate cancer.24
Our ability to make risk-based therapeutic recommendations can be refined by using
available clinical and pathologic criteria to provide insight into the clinical behavior of
patients with newly diagnosed prostate cancer. A number of prostate cancer risk
classification systems are in broad use such as those promulgated by the National
Comprehensive Cancer Network (NCCN), which stratify men into very low, low,
intermediate, high, or very high-risk groups using clinical parameters including T stage,
Gleason score, PSA values, and number of positive biopsy cores involved.25
1. Active surveillance
As many men with low-risk prostate cancer may not in fact need therapy, AS is a
management strategy that delays curative treatment until it is warranted on the basis
of defined indicators of disease progression. AS is increasingly being considered
for subsets of patients with favorable disease features such as those with very low
NCCN risk criteria defined as T1c, Gleason ≤6, PSA <10 ng/mL, <3 prostate biopsy
cores positive with <50% cancer in each core, PSA density <0.15 ng/mL/g and low
NCCN risk criteria defined as T1 to T2 ac, Gleason ≤6, and PSA <10 ng/mL.
Although there is no universally accepted follow-up protocol, most experts require a
repeat biopsy within 6 months of the original diagnostic biopsy to confirm the
presence of low-grade, low-stage disease. Subsequent PSA and digital rectal exams
should be performed at 3-to-6-month intervals with repeat biopsy upon either
clinical or PSA progression or a selected time interval.22
Curative-intent therapies include radical prostatectomy, radiotherapy by means
of external beam (photons or protons), brachytherapy, or a combination of
brachytherapy and external beam. No randomized comparative outcome data
between radiotherapy and surgery exist; however, ample data suggest excellent
outcomes irrespective of modality in favorable risk patients. The decision on which
modality to use in the curative setting requires a full discussion of the differences in
therapy-related side effects, consideration of patient comorbidities, and patient
preference.
2. Radical prostatectomy
Radical prostatectomy is a surgical procedure in evolution as it is increasingly
performed as a robotic-assisted radical prostatectomy, with good data suggesting
that patient outcomes from open versus robotic are similar if the surgeon has
significant experience in the technique used.26 The major procedure-related side
effects include urinary incontinence and erectile dysfunction, the rates of which are
variable based upon individual patient characteristics, baseline issues with
 continence and erectile dysfunction, and surgical experience.27
3. Radiation therapy
Radiotherapy for prostate cancer encompasses a number of technologies. Modern
external-beam radiotherapy utilizes sophisticated computer modeling to allow
higher doses to be delivered on target, attempting to minimize damage to normal
local structures. These include intensity-modulated radiotherapy, image-guided
radiation therapy, stereotactic radiosurgery, and proton beam radiotherapy.
Brachytherapy includes both low-dose-rate brachytherapy (iodine123,
pallidium103), which involves the permanent implantation of radioactive seeds
typically using ultrasound guidance (under anesthesia) typically as an outpatient
procedure. High-dose rate brachytherapy involves short-term placement of
radioactive seeds instilled into catheters placed under anesthesia, and may at times
require an overnight hospital stay. Side effects associated with brachytherapy
include cystitis, incontinence, erectile dysfunction, and rectal bleeding.
C. Treatment of metastatic prostate cancer: general considerations and goals of
therapy
Metastatic prostate cancer is an incurable, but treatable disease entity. Androgen
deprivation therapy (ADT) achieved by medical or surgical castration has a very high
response rate and has the potential to both improve disease-related symptoms (pain,
fatigue, anorexia) and prostate cancer-specific survival. Primary ADT is associated
with an overall response greater than 90% of patients with metastatic prostate cancer,
with response duration typically in the 12-to-24-month range, followed by the
emergence of metastatic castration-resistant prostate cancer (mCRPC). Luteinizing
hormone-releasing hormone (LHRH) agonists/antagonists or bilateral orchiectomy are
the primary treatment options and produce clinically equivalent outcomes. Patient
preference almost universally drives this decision, with medical castration being the
primary method of treatment in the United States today. Patients managed with androgen
ablation experience a loss of libido, hot flashes, muscle mass loss, weight gain,
increased risk of metabolic syndrome and diabetes, and osteoporosis.
Although primary ADT remains the mainstay of initial therapy, recent randomized
trial evidence supports the addition of six cycles of docetaxel (75 mg/m2 intravenously
[IV] every 3 weeks) in men with “high volume” disease (defined as presence of
visceral metastases and/or four or more bone lesions with at least one beyond the
vertebral bodies and pelvis) within 4 months of initiating ADT.28
1. Androgen deprivation therapy
a. Bilateral orchiectomy
Remains a standard treatment for metastatic disease with castrate levels of
testosterone (defined as ≤50 ng/dL) typically achieved within 8 to 11 hours of
surgery. In comparison with medical therapy, it is more cost-effective and is not
associated with testosterone escape, which is observed in 2% to 13% of patients
managed with LHRH agonists. However, as it is associated with significant
 psychological impact its use has decreased significantly following the
introduction of sustained-release formulations of LHRH analogs.
b. LHRH agonists
LHRH agonists are synthetic peptides administered by parenteral injection
typically intramuscular or subcutaneous (SC) administration with a number of
commercial products available in 1-, 3-, 4-, 6-, and 12-month depot
formulations. LHRH agonists exert a nonpulsatile, constant stimulation to the
anterior pituitary gland, which in turn decreases luteinizing hormone (LH) and
testosterone production. After treatment, LH release is transiently increased up
to 2 weeks after the initial dose, which may lead to a “testosterone flare,”
following which LH and follicle-stimulating hormone production is
downregulated and testosterone production is inhibited, with serum levels
typically in the 20 to 30 ng/dL range. Although testosterone flare-related
exacerbation of disease-related symptoms is rare, patients are typically started
on first-generation antiandrogens (bicalutamide, flutamide, nilutamide) for a
course of 30 days, which mitigate the testosterone surge. Continuous use of
concomitant antiandrogen therapy has been termed “combined androgen
blockade” (CAB). A meta-analysis of a large number of randomized trials
suggests about a 2% to 3% improvement in overall survival at 5 years in those
patients treated with CAB compared with LHRH agonist monotherapy.29
c. LHRH antagonists
These agents are peptide molecules that compete with LH for binding to LH
receptors in the anterior pituitary, thus leading to a direct inhibition of
testosterone production, without the LH/testosterone surge with LHRH agonists.
Degarelix is currently the only FDA-approved agent in this class. It is
administered monthly as a SC injection.
d. Intermittent ADT
Two major randomized trials have been conducted testing the concept of
intermittent periods of testosterone suppression compared with continuous
suppression given the potential for improvement in quality of life during periods
of testosterone recovery. One trial conducted in men with PSA-only disease
following surgery or radiotherapy (no radiographic evidence of metastatic
disease) demonstrated that intermittent ADT was noninferior to continuous
therapy with respect to overall survival, with some quality-of-life measures
improved in the intermittent arm. A larger noninferiority trial conducted in men
with metastatic prostate cancer receiving primary ADT demonstrated an
improvement in overall survival favoring the continuous-therapy group;
however, the trial was interpreted as statistically inconclusive as there were
insufficient evidence to rule out significant inferiority of intermittent therapy.30,31
2. Treatment of castration-resistant metastatic disease: general considerations
and goals of therapy
 Although no uniform definition exits, mCRPC is typically defined as evidence of
radiographic and/or biochemical (PSA) progression in men metastatic prostate
cancer with documented serum testosterone values of <50 ng/dL following
antiandrogen withdrawal (in those patients initially treated with CAB). Historically,
men with mCRPC had limited therapeutic options with survival rates typically less
than 1 year. Over the last decade, significant insights into the molecular biology of
prostate cancer have led to clinically meaningful therapeutic developments including
next-generation androgen-receptor-targeted agents, a novel prostate cancer vaccine,
the first alpha emitter for cancer therapy and a second-generation taxane, all of
which have the potential to improve overall survival in patients with mCRPC.
a. Sipuleucel-T
Sipuleucel-T is currently the only FDA-approved therapeutic vaccine in
oncology. Patients undergo leukapheresis in which antigen-presenting cells
(APCs) are extracted and shipped to a production facility where they are
incubated with a fusion protein consisting of prostate acid phosphatase and
granulocyte-macrophage colony-stimulating factor to create the activated blood
product (APC8015), which is reinfused into the patient. This process is repeated
a total of three times over the course of 4 to 5 weeks. This therapy is very well
tolerated, with some patients experiencing mild fever when the cellular product
is reinfused. Although randomized trials demonstrated a survival benefit for
patients receiving Sipuleucel-T, this therapeutic vaccine has no overt antitumor
activity, i.e., typically no decline in PSA or radiographic or clinical evidence of
response. The optimal patient for this approach has asymptomatic or minimally
symptomatic mCRPC with some retrospective evidence suggesting that
improved survival is associated with a lower tumor burden.32,33
b. Abiraterone
Abiraterone inhibits CYP17, an enzyme that is expressed in testicular, adrenal,
and prostatic tumor tissues, and which drives the synthesis of glucocorticoids
and sex hormones. Inhibition of CYP17 with agents such as ketoconazole and
abiraterone leads to a significant decrease in circulating levels of testosterone
and cortisol production with the unmasking of mineralocorticoid toxicities (the
latter effect mitigated by coadministration of abiraterone with prednisone).
Randomized trials in men with mCRPC prior to or following treatment with
docetaxel demonstrated improvement in both progression-free and overall
survival.34,35 Abiraterone is typically dosed at 1,000 mg/day (dosed at one time)
in between meals to mitigate the impact of food effect on absorption, with 5 to
10 mg of prednisone/day. The agent is typically well tolerated with mild fatigue,
edema, and hypertension as known side effects. In asymptomatic patients, PSA
response indicates activity and many symptomatic patients will have clinical
benefit within few days to weeks. Twenty to thirty percent of patients will be
unresponsive indicated by PSA and/or clinical or symptomatic progression.
 c. Enzalutamide
Enzalutamide is a second-generation androgen receptor (AR) inhibitor, which
acts by inhibiting nuclear translocation and DNA binding of the AR by inducing
a conformational change in the receptor.36 In phase III trials that closely mirrored
trials of abiraterone/prednisone with mCRPC prior to or following treatment
with docetaxel, enzalutamide demonstrated improvement in both progression-
free and overall survival.37,38 Enzalutamide is typically dosed as 160 mg/day.
Side effects include fatigue and a potential risk of lowering the seizure
threshold.
d. Docetaxel
Docetaxel was the first chemotherapeutic agent FDA approved for men with
mCRPC to demonstrate an improvement in overall survival. Two phase III trials
demonstrated median survival benefits compared with the comparator arms in
the 2-to-3-month range.39,40
Of note, despite the modest survival benefit seen with docetaxel, this agent
has a very high level of clinical activity. It is not uncommon for patients with
symptomatic mCRPC to begin to improve following a single dose of therapy.
Docetaxel is typically dosed at 75 mg/m2 administered IV every 21 days along
with prednisone at 10 mg/day. This agent can cause neutropenia, peripheral
neuropathy, and diarrhea.
e. Cabazitaxel
Cabazitaxel is a semisynthetic taxane developed in docetaxel-resistant
preclinical models. The efficacy and safety of cabazitaxel in combination with
prednisone were evaluated in a phase III trial in which patients with mCRPC—
many previously pretreated with docetaxel—were randomized to receive
cabazitaxel/prednisone or mitoxantrone/prednisone. The median survival time of
patients in the cabazitaxel group was 15.1 months compared with 12.7 months
for patients in the mitoxantrone group.41 Although cabazitaxel is frequently
administered with growth factor support at the 25 mg/m2 dose, an ongoing phase
III trial is comparing cabazitaxel at 20 mg/m2 with the FDA-approved 25 mg/m2
dose and may provide evidence of utility at a lower dose without the need for
routine growth factor use (NCT01308580).
f. Mitoxantrone
Mitoxantone was FDA-approved for its palliative benefit in advanced prostate
cancer. In small phase III trial, patients who received mitoxantrone + prednisone
demonstrated improved pain control and reduced need for analgesic medications
compared with patients treated with prednisone alone although without any
impact on overall survival. Although mitoxantrone/prednisone has a very
favorable side-effect profile, its use has declined following the recent approval
of multiple new agents that can prolong survival in patients with mCRPC.
g. Radium-223
 Radium-223 is an alpha-particle–emitting radioisotope that is believed to exert
its cytotoxic action by inducing damaging double-strand breaks in DNA. As a
calcium mimetic, radium-223 targets only bone, forming complexes with the
bone mineral hydroxyapatite and preferentially targets areas of high bone
turnover.42 A phase III trial in patients with mCRPC demonstrated both a
survival benefit and a lower rate of symptomatic skeletal events (pathologic
fractures, need for radiotherapy or spinal cord compression) and is FDA
approved for management of mCRPC in both chemotherapy-pretreated and
chemotherapy-naïve patients. Its primary excretion is in the gastrointestinal (GI)
tract; thus, GI symptoms (nausea, vomiting, diarrhea) predominate. Its limited
penetration in bone is likely responsible for its relatively low bone marrow
toxicity profile.43
D. Bone-targeted supportive therapy
In a bone tropic neoplasm like prostate cancer, management of bone-related issues cuts
across the disease continuum from the management of ADT-related osteoporosis to
prevention of bone metastases and ultimately to the mitigation of skeletal-related events
(SREs), typically defined as pathologic fractures, spinal cord compression, and the
need for surgery or radiation for a symptomatic bone lesion.44
1. ADT-related osteoporosis
The use of ADT decreases bone mineral density and is associated with greater
fracture risk. The NCCN and National Osteoporosis Foundation have published
guidelines for the treatment of secondary osteoporosis associated with ADT and
fracture prevention. These guidelines suggest that all men being treated with ADT
over 50 years old should be treated with calcium (1,200 mg/day) and vitamin D
(1,000 IU/day). They also recommend additional pharmacologic therapy for fracture
prevention for any individual with a 10-year probability of hip fracture ≥3% or a
20-year probability of major osteoporotic fracture ≥20%.45 Denosumab is a human
monoclonal antibody that binds and inactivates RANK ligand, which mediates the
interaction between osteoblasts, and osteoclasts are currently the only FDA-
approved therapy for fracture prevention in men receiving ADT. The recommended
dose of denosumab for this indication is 60 mg administered subcutaneously once
every 6 months.
2. Skeletal-related event prevention in castration-resistant prostate cancer
Phase III trials of both zolendronic acid (a potent bisphosphonate) and denosumab
have been demonstrated to decrease SREs in patients with mCRPC.44 In a large trial
comparing a standard dose and schedule of denosumab with zolendronic acid,
patients treated with denosumab had a statistically improved longer time to first
skeletal event compared with patients receiving zolendronic acid.46
For prevention of SREs, zolendronic acid is typically administered IV at a
dose of 4 mg every 4 weeks, denosumab 120 mg subcutaneously every 4 weeks. It is
important to monitor both renal function and calcium levels during therapy and to
 have patients avoid invasive dental procedures given the association with these
agents and osteonecrosis of the jaw.
E. Evaluation of response
Prostate cancer is a highly bone tropic neoplasm, as illustrated by the near universal
presence of bone metastases in men dying of the disease. The lack of objective means to
reproducibly assess response to treatment in bone has limited the utility of objective
response (changes in bone or CT scans) as a means of assessing therapeutic benefit in
patients with mCRPC. While PSA has some utility as a response parameter in patients
treated with AR-targeted agents or cytotoxic chemotherapy, it is typically unaffected in
patients treated with Sipuleucel-T or radium-223. Improvement in disease-related
symptoms (pain, fatigue, appetite) is a useful clinical surrogate for therapeutic decision
making.

III. TESTICULAR CANCER (GERM-CELL TUMORS)

A. General considerations and staging
Although primary neoplasms of the testis can arise from Leydig or Sertoli cells, more
than 95% of testicular cancers are of spermatogenic or germ-cell origin. Germ-cell
tumors (GCTs) are rare, accounting for 1% of all malignancies in men. However, they
are important malignancies because they represent the most common solid tumor in
young men and because of their high degree of curability. With the advent of cisplatin-
based chemotherapy, accurate tumor markers, and aggressive surgical approaches,
overall cure rates for patients with disseminated disease exceed 90% and patients with
early-stage disease are nearly always cured. GCT is also one of the few solid tumors
for which salvage chemotherapy can be curative.
GCTs are categorized as either seminomatous or nonseminomatous (which includes
a variety of other histologies such as embryonal cell carcinoma, choriocarcinoma, and
yolk sac tumors). Pure seminoma accounts for 40% of patients with GCTs. Although
mild elevations of the β-subunit of human chorionic gonadotropin (hCG) may be seen,
pure seminoma is never associated with an elevation of α-fetoprotein (AFP).
Nonseminomatous GCT can cause elevations of hCG, AFP, or both.
Pretreatment staging should include serum tumor markers (AFP, hCG) and CT
imaging of chest, abdomen, and pelvis. Other radiographic procedures should be
undertaken only if symptoms or physical examination dictate.
1. Stage I
Tumor confined to the testis with or without involvement of the spermatic cord or
epididymis.
2. Stage II
Tumor with metastasis limited to retroperitoneal lymph nodes (IIA, 5 or fewer
nodes, all ≤2 cm; IIB, more than 5 nodes or any node >2 to 5 cm; IIC, any node mass
>5 cm).
3. Stage III
 Tumor spread beyond retroperitoneal lymph nodes.
B. General approach to therapy
The therapeutic approach to the patient with testicular cancer depends on the
histology of the tumor and the clinical or pathologic stage of the disease.
1. Seminoma
a. Stage I
Over 75% of patients with testicular seminoma present with early-stage disease
and are often cured with orchiectomy alone. The former paradigm of adjuvant
radiation therapy is rapidly being replaced by AS for clinical stage I disease.
Both the European and Canadian consensus guidelines list AS as the primary
option for clinical stage I disease and this practice is being rapidly adopted in
the United States. Precise guidelines for surveillance imaging guidelines are in
evolution; however, developing recommendations are centering on a total of 3 to
5 CT scans over 3 to 5 years. These recommendations limit or eliminate pelvic
CTs and chest imaging. Lower radiation exposure techniques produce high-
quality images of the retroperitoneum and are being used at high-volume
centers.47 Adjuvant radiation therapy or consideration of adjuvant carboplatin
should be reserved for uncommon circumstances.
b. Stage II
Traditional management of the small fraction of patients with stage II disease has
been allocated by tumor volumes. Patients with small-volume retroperitoneal
disease (stage IIA disease) have often been given therapeutic radiation at doses
slightly higher than the doses given as adjuvant therapy (3,000 to 3,500 cGy) and
chemotherapy reserved for the 20% or so of patients who recurred after
therapeutic radiation therapy. Patients with bulky disease (>5 cm) are given
combination chemotherapy (usually bleomycin, etoposide, and cisplatin [BEP] ×
3 or etoposide and cisplatin [EP] × 4 as described below for nonseminoma)
with a very high expectation of cure.
2. Non-seminoma
a. Stage I
The currently preferred option for patients is surveillance without a
retroperitoneal lymph node dissection (RPLND). Because 30% of these patients
eventually experience relapse, they must be followed closely with serum
markers, exam, and interspersed CT scans of the abdomen. Most patients who
recur will do so within the first 2 years. Historically these patients had been
pathologically staged and treated with an RPLND. Patients with pathologically
confirmed stage I disease do not need any further therapy because only
approximately 10% show relapse. In about 25% of patients, clinical stage I
disease is found to be stage II pathologically at RPLND and treatment for these
patients is discussed in the following section. The major complication of
RPLND has been retrograde ejaculation with subsequent infertility, although this
 is rare in experienced centers using nerve-sparing procedures.
b. Stage II
Patients with clear-cut radiographic evidence of stage II disease and elevated
serum markers should be treated primarily with chemotherapy. If the lymph
nodes are equivocal and markers are negative, an RPLND can be considered or
close observation with repeat CT to document growth. Patients with
pathologically confirmed and completely resected stage II disease have a
relapse rate of about 30%. Patients with fully resected pathologic stage II
disease either can be treated with two cycles of adjuvant chemotherapy after
RPLND or can be followed closely and treated with standard chemotherapy if
they show relapse.
c. Stage III
About 30% of patients present with stage III disease. The most common site of
involvement is the lungs, but liver, bone, and brain can also be involved with
metastatic disease. These patients are further categorized as good, intermediate,
or poor risk based on the primary site, level of marker elevation, and
involvement of brain, liver, or bone. An international germ-cell prognostic
classification has been developed based on a retrospective analysis of more than
5,000 patients with metastatic GCTs. Poor-risk (poor prognosis) patients
according to the International Germ Cell Cancer Consensus Classification
System include those with the following:
■ Mediastinal primary site or
■ Nonpulmonary visceral metastasis (e.g., liver, bone, and brain) or
■ Elevation of AFP >10,000 ng/mL, hCG >10,000 ng/mL, or LDH >10 ×
upper limit of normal.
Patients with nonseminoma without mediastinal primary or nonpulmonary
visceral metastasis
■ Have a good prognosis with the AFP <1,000 ng/mL, hCG <1,000 ng/mL,
and LDH <1.5 × UNL
■ Have an intermediate prognosis if any of the markers is in the intermediate
range (AFP 1,000 to 10,000 ng/mL, hCG 1,000 to 10,000 ng/mL, and LDH
1.5 to 10 × UNL).
All patients with stage II or III disease who require chemotherapy should
receive cisplatin-based chemotherapy, as follows:
1) BEP
■ Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5, and
■ Etoposide 100 mg/m2 IV on days 1 to 5, and
■ Bleomycin 30 U IV push weekly on days 1, 8, and 15
■ Repeat every 21 days regardless of blood cell counts for two (adjuvant
therapy), three (good risk patients), or four (intermediate or poor risk)
cycles.
 If the patient has fever associated with granulocytopenia, give the next
cycle at the same doses, followed by daily SC injections of granulocyte
colony-stimulating factor (filgrastim) or a single dose of pegfilgrastim. Other
chemotherapy regimens such as VIP (etoposide, ifosfamide, cisplatin) have
not improved outcome and are more toxic. Substitution of carboplatin for
cisplatin is inferior therapy and should not be used.
C. Postchemotherapy management
Patients who have a complete response with chemotherapy should be followed and do
not require any further treatment. Patients whose marker levels normalize but who have
not achieved a radiographic complete response should undergo complete surgical
resection of residual disease. If the resected material reveals only teratoma, necrosis,
or fibrosis, then no further therapy is necessary and the patient should be followed. If
there is carcinoma in the resected specimen, the potential role of two more cycles of
cisplatin-based chemotherapy (cisplatin and etoposide) should be discussed with the
patient.
Most patients who experience relapse do so within the first 2 years, although late
relapses do occur. In general, patients should be followed with every 2-month physical
examination, chest x-ray studies, and serum marker measurements during the first year
and every 4 months during the second year. Patients should then be followed about
every 6 months for the third and fourth year and yearly thereafter. Because tumors can
arise in the contralateral testis, patients should be taught to do testicular self-
examination.
D. Management of recurrent disease
1. Standard-dose therapy
Patients who respond to first-line chemotherapy and then relapse are still curable
with salvage regimens such as VIP or TIP:
a. VIP
■ Vinblastine 0.11 mg/kg (4.1 mg/m2) IV push on days 1 and 2, and
■ Ifosfamide 1.2 g/m2 IV over 30 minutes on days 1 to 5, and
■ Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5.
b. TIP
■ Paclitaxel 250 mg/m2 CI over 24 hours day 1
■ Ifosfamide 1.5 g/m2 IV days 2 to 5
■ Cisplatin 25 mg/m2 IV days 2 to 5.
Repeat every 21 days for four cycles. Any radiographic abnormalities that
persist after salvage chemotherapy should be considered for surgical resection.
2. High-dose chemotherapy with autologous stem-cell transplantation
High-dose chemotherapy with carboplatin and etoposide with or without
cyclophosphamide or ifosfamide followed by autologous stem-cell transplantation
(ASCT) should be considered for patients requiring salvage chemotherapy. Overall,
about 15% to 25% of these patients are long-term survivors. The role of ASCT in
 the initial salvage setting is still under evaluation. Patients with incomplete
response, high markers, high disease volume, and late relapse may be best
candidates for initial salvage ASCT.
With these strategies, the overall cure rate for patients with stage I disease is
more than 98%, stage II disease more than 95%, and stage III disease more than
80%.
E. Complications of therapy
Because patients are cured, the short- and long-term toxicities are of considerable
importance. The short-term toxicities of the described chemotherapy regimens include
nausea and vomiting, myelosuppression, renal toxicity, and hemorrhagic cystitis. The
major long-term morbidities include infertility, pulmonary fibrosis, and a small but
definite risk of secondary leukemia.
F. Mediastinal and other midline GCTs
GCTs can arise in several midline structures including the retroperitoneum,
mediastinum, and pineal gland. All patients with GCTs at these sites should have a
testicular ultrasound examination to exclude an occult primary tumor. Mediastinal
nonseminomatous GCTs are associated with Klinefelter syndrome and with rare
hematologic malignancies (particularly acute megakaryocytic leukemia). Small
mediastinal seminomas can be treated with radiation therapy alone. Widespread tumors
or nonseminomatous tumors should be treated with four cycles of BEP chemotherapy.
Salvage chemotherapy (including autologous bone marrow transplantation) in patients
with nonseminomatous mediastinal GCT is ineffective.

IV. PENILE CANCER

A. General considerations and management
Penile cancer is rare in North America but is a significant health problem in many
developing countries. These tumors are nearly always squamous cell in origin and are
associated with the presence of a foreskin and poor hygiene. Typically, these tumors
present as a nonhealing ulcer or mass on the foreskin or glans. The most common
treatment is wide surgical excision or penectomy, depending on the size and location of
the lesion. Prophylactic inguinal lymph node dissection is indicated in certain
subgroups of patients. Radiation therapy can also provide local control, especially with
small tumors. However, local relapse may be up to 30% and surgery is still considered
standard management, especially for larger tumors.
B. Chemotherapy for systemic disease
Currently used chemotherapeutic agents are primarily palliative as the rarity of the
disease and the absence of very active agents precludes randomized studies. Active
single agents include bleomycin, cisplatin, and methotrexate, with response rates of
20% to 50%. Combination chemotherapy results in high response rates, but whether
clinical benefit is improved over that with single agents is unknown. A reasonable
regimen is cisplatin 100 mg/m2 on day 1, with fluorouracil 1,000 mg/m2/day given by
 continuous infusion on days 1 to 4. Cycles can be repeated every 21 days. For
appropriate patients, investigational therapy options should be considered in the initial
or salvage settings.

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invasive bladder cancer. N Engl J Med. 2012;366:1477–1478.
12. Apolo AB, Ostrovnaya I, Halabi S, et al. Prognostic model for predicting survival of
patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy. J
Natl Cancer Inst. 2013;105(7):499–503.
13. Saxman S, Propert K, Einhorn L, et al. Long-term follow-up of a phase III intergroup
study of cisplatin alone or in combination with methotrexate, vinblastine, and
doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
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14. von der Maase H, Sengelov L, Roberts J, et al. Long-term survival results of a
randomized trial comparing gemcitabine and cisplatin with methotrexate, vinblastine,
doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602–
4608.
15. Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with
metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet
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16. Narayanan S, Harshman LC, Srinivas S. Second-line therapies in metastatic urothelial
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17. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical
activity in metastatic bladder cancer. Nature. 2014;515(7528):558–562.
18. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a
randomized European study. N Engl J Med. 2009;360(13):1320–1328.
19. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized
prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310–1319.
20. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA
Guideline. J Urol. 2013;190(2):419–426.
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recommendation statement. Ann Intern Med. 2012;157(2):120–134.
22. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up of a large, active
surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28(1):126–131.
23. Canfield SE, Kibel AS, Kemeter MJ, et al. A guide for clinicians in the evaluation of
emerging molecular diagnostics for newly diagnosed prostate cancer. Rev Urol.
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24. Montie JE, Smith JA. Whitmoreisms: memorable quotes from Willet F. Whitmore, Jr,
M.D. Urology. 2004;63(1):207–209.
25. Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology:
prostate cancer. J Natl Compr Cancer Netw. 2010;8(2):162–200.
26. Gandaglia G, Trinh QD. Models of assessment of comparative outcomes of robot-
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27. Chen RC, Clark JA, Talcott JA. Individualizing quality-of-life outcomes reporting: how
localized prostate cancer treatments affect patients with different levels of baseline
urinary, bowel, and sexual function. J Clin Oncol. 2009;27(24):3916–3922.
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chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic
prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol.
2014;35(5, suppl):Abstract LBA2. Special issue on ASCO Annual Meeting.
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advanced prostate cancer: an overview of the randomised trials. Lancet.
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31. Hussain M, Tangen C, Berry D, et al. Intermittent versus continuous androgen deprivation
in prostate cancer. N Engl J Med. 2013;368:1314–1325.
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in men with hormone-refractory prostate cancer: results of the cancer and leukemia group
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previous chemotherapy. N Engl J Med. 2013;368(2):138–148.
36. Tran C, Ouk S, Clegg N, et al. Development of a second-generation antiandrogen for
treatment of advanced prostate cancer. Science. 2009;324:787–790.
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after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.
38. Beer T, Armstrong A, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve
metastatic prostate cancer (mCRPC): results of phase 3 PREVAIL Study. N Engl J Med.
2014;371:424–433.
39. Tannock I, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–1512.
40. Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with
mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med.
2004;351:1513–1520.
41. de Bono J, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone
for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a
randomised open-label trial. Lancet. 2010;376:1147–1154.
 42. Bruland ØS, Nilsson S, Fisher DR, et al. High-linear energy transfer irradiation targeted
to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional
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43. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in
metastatic prostate cancer. N Engl J Med. 2013;369(3):213–223.
44. Saad F, Gleason, DM, Murray R, et al. A randomized, placebo-controlled trial of
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46. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of
bone metastases in men with castration-resistant prostate cancer: a randomised, double-
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clinical stage I testicular cancer. J Clin Oncol. 2013;31(28):3490–3493.
I. RENAL CELL CARCINOMA (RCC)
Known as “the internist’s tumor” for its diverse clinical manifestations, advances in the
understanding of the biology of renal carcinoma have led to a revolution in the medical
management and a refinement of surgical approaches and other local modalities. With
seven new therapeutic medications approved for the treatment of advanced disease since
December 2005, novel agents targeting angiogenesis, intracellular signaling, and host
immune activation have provided a model that may be applied across the spectrum of solid
tumor malignancies.1,2
A. Histopathology
Clear cell carcinoma, an adenocarcinoma that arises from the proximal convoluted
tubule, is the most common histologic subtype, representing 75% to 85% of primary
renal neoplasms.3,4 Papillary carcinomas comprise 10% to 15% of renal malignancies.
More likely to be multifocal, there are two primary subtypes: types I and II. Type I
typically are lower grade, may be hereditary, and have a more indolent biology. Type II
have a more aggressive behavior and a poorer prognosis.5 Chromophobe carcinomas
are composed of sheets of darker cells lacking in lipid and glycogen. They have a more
favorable prognosis. Oncocytomas are made of large well-differentiated cells with
granular eosinophilic cytoplasm due to a rich population of mitochondria. They
originate from intercalated cells of the collecting ducts. Multiple and bilateral
oncocytomas are associated with tuberous sclerosis complex (TSC) and Birt-Hogg-
Dube (BHD) syndrome. These tumors generally exhibit benign behavior. Collecting
duct carcinomas are rare and tend to affect younger patients. They tend to have an
aggressive behavior and frequently show sarcomatoid differentiation. Unclassified
carcinomas are less than 5% of renal neoplasms and have an unfavorable prognosis
when compared with clear cell carcinomas.6
B. Genetic alterations
Loss of 3p is commonly seen in sporadic clear cell carcinoma. Genes included in this
region include Von Hippel-Lindau (VHL), BRCA1 Associated Protein-1 (Ubiquitin
Carboxy-Terminal Hydrolase) (BAP1), and Polybromo 1 (PBRM1). Diseases
associated with PBRM1 include clear cell renal cell carcinoma and renal cell
carcinoma.
VHL gene (3p25-26) is altered in more than 90% of patients with clear cell
carcinoma. Inactivation or deletion of VHL is associated with increased production of
 vascular endothelial growth factor (VEGF), a key regulator of tumor angiogenesis.7,8
Hereditary RCCs and their genetic abnormalities are outlined in Table 13.1.
C. Epidemiology
In the United States in 2015, about 61,560 cases of kidney cancer and renal pelvis
cancer are expected to occur and lead to more than 14,080 deaths. The incidence is
rising, attributed in part to an increase in incidental diagnoses from the widespread use
of advanced imaging studies.
This cancer accounts for about 4% of all the adult malignancies. The male-to-female
ratio is 1.5:1.

TABLE
Hereditary Renal Cell Carcinoma Syndromes
13.1

D. Risk factors
Tobacco smoking doubles the risk of developing kidney cancer, with a direct
correlation to pack-years. Exposure to industrial toxins including cadmium, asbestos,
 and petroleum by-products, along with the use of certain analgesics (phenacetin and
aspirin) confer an increased risk. Other factors implicated include hypertension,
obesity, polycystic renal disease (hereditary and acquired), childhood exposure to
cytotoxic chemotherapy, and chronic hepatitis C infection. Of interest, sickle cell trait
(more so than hemoglobin SS disease) raises the risk of renal medullary carcinoma.
Hereditary syndromes, including VHL and BHD, are associated with renal neoplasms.10
E. Clinical characteristics
Many renal cancers are asymptomatic and diagnosed incidentally.11 While the classic
triad of hematuria, a palpable abdominal mass, and flank pain is seen in only 9% of
patients at diagnosis, individually these are common presenting complaints.12 Also
reported are weight loss and fever. Typically, signs and symptoms are frequently a
reflection of a site of metastatic involvement. At diagnosis, 25% of patients are
symptom-free. The diversity of initial signs of a renal neoplasm mirrors the complex
heterogeneity of its biology.
Nearly one-third of patients present with metastatic disease, most frequently
involving lungs, soft tissue, bone, and liver. Paraneoplastic syndromes include humoral
hypercalcemia, erythrocytosis, hypertension, hyperglycemia, and hepatic dysfunction in
the absence of liver metastases (Stauffer syndrome).13
F. Staging
1. TNM staging. Renal carcinoma is staged using the AJCC TNM system.14
2. Prognostic systems. University of California Los Angeles (UCLA) Integrated
Staging System, first published in 2001, improves upon the AJCC staging system by
taking into account a person’s performance status and the Fuhrman grade of the tumor
(see Table 13.2). The Fuhrman nuclear grading system is best applied to clear cell
carcinomas and takes into account nuclear size, shape, and prominence of nucleoli.
This grading system plays a significant role in survival outcomes for renal cancers.
Thus, these factors are combined to divide people into low-, intermediate-, and
high-risk groups.14
Factors other than stage contribute to overall survival. Certain findings correlate
with shorter survival times in patients with metastatic (stage IV) disease using the
Memorial Sloan Kettering Cancer Center (MSKCC) criteria first published in 1999.
Table 13.3 presents the risk stratification system for metastatic RCC per MSKCC.
■ High blood lactate dehydrogenase (LDH) level
■ High blood calcium level
■ Anemia (low red blood cell count)
■ Cancer spread to two or more distant sites
■ Less than a year from diagnosis to the need for systemic treatment (targeted therapy
or chemotherapy)
■ Poor performance status (a measure of how well a person can do normal daily
activities)
 TABLE
UISS Staging for Patients With Localized Disease
13.2

TABLE
MSKCC Risk Stratification for Metastatic Disease
13.3
Risk Factors Number of Risks Two-Year Survival (%)
No prior nephrectomy 0 45
KPS <80
Hgb < normal 1–2 17
Calcium > normal
LDH > normal 3–5 3

Hgb, hemoglobin; KPS, Karnofsky Performance Scale.

People with none of the above factors are considered to have a good prognosis; one
or two factors are considered intermediate prognosis, and three or more of these factors
are considered to have a poor prognosis and may be more or less likely to benefit from
certain treatments.
G. Treatment considerations
1. Localized disease
Laparoscopic- and robotic-assisted nephrectomy, associated with less pain and a
faster recovery, has supplanted open radical nephrectomy as the optimal technical
approach. When possible, nephron-sparing surgery is preferred.15 Risk of
recurrence after nephrectomy is stratified per TNM staging, and there are multiple
guidelines for surveillance including those from the American Urological
Association (AUA) and the National Comprehensive Cancer Network (NCCN). The
recommendation is to perform a computed tomography scan of the chest and
abdomen more frequently in the intermediate- and high-risk groups.16
For elderly or frail patients, ablative therapy (cryoablation, radiofrequency,
microwave) is a surgical alternative.17,18 Active surveillance appears to be a safe
strategy for patients with small (<4 cm), incidentally discovered lesions, especially
 those with comorbidities or a limited life span.19
2. Metastatic disease
Cytoreductive nephrectomy offers a survival benefit for patients with favorable
features who then go on to treatment with immunotherapy. Likewise, there is a clear
role for surgical metastatectomy, either with oligometastatic disease at presentation
or at relapse that may result in a durable remission.20,21
Radiation therapy, utilizing both conventional external-beam and stereotactic
approaches, is reserved for the palliation of painful bone metastases, recurrence in
the renal fossa, or involvement of the central nervous system (CNS).22
3. Systemic therapy
a. Immunotherapy
First approved by the FDA in 1992, high-dose interleukin-2 results in long-term
remission in 10% to 20% of patients. A cytokine resulting in the expansion of
cytotoxic T lymphocytes, IL-2 has no direct antitumor effect.23 Recently studied
in the SELECT trial, 120 patients with clear cell RCC and history of
nephrectomy with good performance status (ECOG 0 to 1 and good organ
function—serum creatinine less than 1.5) were administered IL-2. The tumor
specimens were separated into good and poor risk on the basis of histologic
features. Both groups benefited from high-dose IL-2 with durable remissions and
prolonged survival. The overall response rate was 25%, which was higher than
historical overall response rates. It was noted that 11% of these patients were
progression free at 3 years and median overall survival was around 42.8 months.
There was no significant difference in response between good- and poor-risk
groups. The trial proved to highlight the need for biomarkers with the use of IL-2
and introduced the possible use of programmed death ligand 1 (PD-L1) as a
predictor of response to immunotherapy.24
Multiple trials have been performed in metastatic RCC evaluating dosage of
IL-2 and its comparison to interferon. For example, in McDermott et al.,25
patients were randomized to high-dose IL-2 versus subcutaneous IL-2 with
interferon.25 This study noted that high-dose IL-2 improved response rate, and in
patients with bone metastases, liver metastases, or primary tumor in place,
survival improvement was statistically significant. The multiple trials for IL-2
suggest that it is appropriate in select group of patients and proves to provide
durable responses in a greater portion of patients compared with other standard
agents such as interferon.
Eligibility for this treatment is limited both by patient characteristics (clear
cell histology, ECOG performance status 0 or 1, adequate cardiopulmonary
reserve, no uncontrolled brain metastases) as well as limited availability. The
side effects are protean and include hemodynamic instability with a capillary
leak syndrome requiring vasopressor support.26
Interferon-α has both immune-enhancing and direct cytotoxic effects. The
 response rate is similar to IL-2 but without the striking durability. There are
various doses and schedules including the use of once-weekly pegylated
formulation. IL-2 and interferon are beginning to fall out of favor with the advent
of newer immunotherapy approaches, specifically the advent of immune
checkpoint inhibitors.27
The use of agents to remove negative immune regulators, first proposed by
the immunologist James P. Allison, led to the development of immune checkpoint
inhibitors. The inhibitory function of the checkpoint molecule cytotoxic T-
lymphocyte-associated protein 4 prevents T-cell activation. Blocking this
molecule with therapeutic antibodies may result in an antitumor immune
response. Additionally, it is known that programmed death 1 receptor (PD-1) is
expressed on T cells, and interaction with its PD ligands (PD-L) expressed on
immune cells and cancer cells blocks immune response. Targeting this
interaction and removal of PD-1 or PD-L unleashes the immune system to
directly attack the tumor.
Nivolumab is a human IgG4 programmed death inhibitor that serves to
block both ligands, PD-L1 and PD-L2, allowing for reactivation of the host
cellular immune response against the tumor. Nivolumab has most recently been
studied in the second and third line of metastatic RCC with a clear cell
component (after antiangiogenic therapy) demonstrating a median overall
survival benefit of 25 months, compared with 19.6 months for everolimus in the
phase III CheckMate-025 trial and significant difference in objective response
rates 25% with nivolumab versus 5% for everolimus.
In targeting the immune system, there may be significant side effects in
checking fatigue, nausea, pruritus, and diarrhea; however, it is notable that
nivolumab had less grade 3 or 4 events compared with everolimus.28
Further studies are ongoing with novel immune checkpoint inhibitors as
well as with combination therapy in an effort to identify an optimal therapeutic
strategy.
b. Molecular targeted agents—VEGF inhibitors
Sorafenib was approved in December 2005, and was originally developed as an
RAF inhibitor. VEGF inhibitor effects were noted. Despite a low rate of
objective response, the majority of patients were found to have disease
stabilization. Sorafenib is a tyrosine kinase inhibitor (TKI), which at doses of
400 mg orally twice per day has been shown to improve progression-free
survival (PFS) versus placebo (24 vs. 12 weeks) after cytokine failure.29,30
Sunitinib is a multikinase VEGF receptor TKI approved by the FDA in
January 2006, and yields a response rate of 40% with an additional 40% of
patients achieving stable disease. Typical dosing is 50 mg orally per day for 4
weeks followed by a 2-week rest. Partial response rates up to 40% with median
time to disease progression greater than 8 months have been reported. Overall
 survival using sunitinib as a first-line agent is 26.4 months.31 Common adverse
events of these TKIs involve altered taste, diarrhea, fatigue, change in hair color,
anemia, thrombocytopenia, and rash of hands and feet.
Bevacizumab is a recombinant human monoclonal antibody that binds to
soluble VEGF blocking VEGF receptor binding leading to inhibition of
angiogenesis and endothelial cell proliferation.32 It was approved in
combination with interferon-α in July 2009. Doses of up to 10 mg/kg
intravenously every 2 weeks have been utilized.33 Trials were performed in
combination with interferon and showed improved overall survival. The
relatively low response rate, development of newer effective therapies, and the
need for parenteral administration have made this approach unpopular.34 Patients
should be monitored for hypertension and proteinuria.
Pazopanib is a VEGF receptor TKI approved in October 2009, with a
similar response rate and mechanism of action as sunitinib. Although relatively
more hepatotoxic than sunitinib, it has been preferred by patients and physicians
on the basis of tolerability.
The usual dosage is as follows:
■ Pazopanib 800 mg by mouth daily without food.
■ Pazopanib 200 mg by mouth daily without food, if moderate hepatic
impairment.
■ Pazopanib 400 mg or less by mouth if strong inhibitors of CYP3A4 cannot
be avoided, as it is metabolized primarily by enzyme.
The overall response rate is 30% and PFS increased from 2.8 months for
placebo to 11.1 months for pazopanib. Overall survival data are not yet
available.35
Axitinib is a VEGF receptor TKI approved in January 2012 when it showed
improved PFS when compared with sorafenib (8.3 vs. 5.7 months, respectively).
It is approved for the treatment of advanced renal carcinoma after failure of one
prior systemic therapy.36
c. Molecular targeted agents—mammalian target of rapamycin (mTOR)
inhibitors
Temsirolimus, approved in May 2007, targets mTOR, considered to be a master
intracellular regulator of cell growth and angiogenesis. Compared with
interferon in poor-risk patients, temsirolimus provides a survival advantage. It is
administered as a weekly intravenous infusion. The usual dosage and schedule is
25 mg intravenously weekly.37
Everolimus is a daily oral mTOR inhibitor approved in March 2009. It is
indicated following progression after treatment with a VEGFR TKI.
The usual dosage and schedule is as follows:
■ Everolimus 10 mg by mouth once daily.
■ Reduce dose to 5 mg by mouth once daily for patients with Child-Pugh class
 B hepatic impairment or as needed to manage adverse drug reactions.
■ If strong inducers of CYP3A4 are required, increase daily dose in 5 mg
increments to a maximum of 20 mg once daily.38
Patients on mTOR inhibitors should be monitored for anemia, stomatitis,
hypertriglyceridemia, hyperglycemia, hypertension, infection, and rarely
pneumonitis.
d. Emerging treatments
Cabozantinib is a small-molecule TKI initially approved in November 2012, for
the treatment of medullary thyroid cancer. It targets VEGFR and additionally
MET and AXL receptor tyrosine kinases (RTKs) that are implicated in
mechanisms of resistance to VEGFR inhibitors in RCCs noted in preclinical
studies. Additionally, it is known that MET and AXL RTKs are upregulated in
RCC in the setting of VHL inactivation and are associated with poorer
prognosis.39 Cabozantinib has been studied in comparison with everolimus in the
METEOR phase III trial in which patients with metastatic RCC with clear cell
type and history of at least one line of VEGF TKI prior were randomized to
cabozantinib versus everolimus in a 1:1 ratio with primary endpoint of PFS.
Patients receiving cabozantinib had improved median PFS when compared with
the everolimus arm (7.4 vs. 3.8 months, respectively). Furthermore, objective
response rates observed were significantly different in cabozantanib versus
everolimus (21% vs. 5%, respectively). The most common grade 3 adverse
events with cabozantanib were fatigue, diarrhea, and hypertension—similar to
most other TKIs.40
Lenvatinib is an oral TKI of multiple targets (VEGF receptors 1–3, FGF
receptors 1–4, PDGFR alpha, RET, and KIT) being studied in metastatic RCC of
clear cell type and compared with everolimus or in combination with
everolimus after patients have received at least one prior line of VEGF therapy.
The arms evaluate lenvatinib in combination with everolimus versus lenvatinib
alone and everolimus alone, and results demonstrate a significant improvement
in PFS when lenvatinib is combined with everolimus versus lenvatinib alone or
everolimus alone (14.6, 7.4, and 5.5 months, respectively). Additionally, there
has been a significant overall response rate improvement in the combination arm
(22%, 14%, and 3%, respectively). A phase III trial is planned.9
Regorafenib is a multikinase inhibitor approved in September 2012 for the
treatment of metastatic colon cancer (and in 2013 for GIST that had failed two
prior treatments). Testing is ongoing in advanced kidney cancer.
Immunotherapy with checkpoint inhibitors as previously discussed is an
emerging new class of agents with significant potential. Pembrolizumab, a PD-
L1 inhibitor, was approved in September 2014 and nivolumab, a PD-1 inhibitor,
was approved in December 2014 for the treatment of metastatic melanoma. See
Section I.G.3.d.
 4. Cytotoxic chemotherapy/hormonal therapy
The benefits of traditional cytotoxic chemotherapy are limited to non–clear cell renal
cancers along with collecting duct carcinoma. There is no established role in clear
cell histology.
The use of progestational agents and selective estrogen receptor modifiers is
not recommended.
5. Vaccines
Given the significant RCC response in the past to IL-2, interferon, and now
immunotherapy checkpoint inhibitors, it is clear that regulation of the immune system
has a key role in controlling and treating kidney cancer. Vaccine therapy is an
experimental treatment that uses the patient’s own tumor cells or tumor-associated
peptides to immunize the patient against tumor-specific antigens. With proper
immune surveillance, the immune system recognizes foreign tumor cells through
activated dendritic cells and lymphocytes. Dendritic cells serve as antigen-
presenting cells presenting small peptides to major histocompatibility complexes
allowing for clonal expansion of T cells and production of cytotoxic T cells
providing tumor immunity. Tumor cells have the ability to alter this pathway in
suppressing cytotoxic T cells via altered antigen presentation and downregulate the
host’s tumor immunity. Thus, with vaccination, the goal is to restimulate the immune
system/defenses in order to recognize and fight cancer.41
Vaccine therapy remains investigational. Clinical trials are ongoing. Examples
include:
■ A phase III trial of dendritic cell immunotherapy AGS-003, being developed by
Argos Therapeutics, plus standard treatment for patients with advanced RCC
(ADAPT) (NCT01582672).
■ A phase I/II trial of DCVax, being developed by Northwest Biotherapeutics, in
patients with solid tumors (NCT01882946).
■ A phase I study of vaccine therapy with or without sirolimus in treating patients
with NY-ESO-1 expressing solid tumors (NCT01522820).
6. Adoptive cellular therapy
Tumor-infiltrating lymphocytes (TILs) are removed from a patient’s tumor,
genetically modified or treated with cytokines to enhance their immune reactivity,
and then reintroduced into the patient with the goal of improving the immune
system’s anticancer response. This therapy was initially studied in melanoma and
proved beneficial in small single-center studies in which patients received CD8+
selected TILs with low-dose IL-2 achieving 34.6% response rate (complete +
partial response).42 Subsequent phase III trial of TILs, however, proved less
effective when compared with placebo. There were significant TIL production
issues in addition to variable TIL phenotypes that may have contributed to its
outcome.43
Subsequent studies have been focused on production of effective TILs from
 primary and metastatic tumors.44 Listed below are several ongoing trials continuing
to evaluate the use of TILs.
■ A phase I/II study treating metastatic cancer, including renal cancer, with
anti-VEGFR2 gene-engineered CD8+ cells (NCT01218867).
■ A phase I trial to test natural killer cells, important innate immune cells, in
patients with advanced cancer, including kidney cancer (NCT00720785).
7. Adjuvant therapy
There is no established role for adjuvant systemic therapy. Trials with sunitinib,
sorafenib, and everolimus have to date been negative.
Adjuvant therapy with sorafenib (Nexavar) or sunitinib (Sutent) failed to
improve disease-free survival in patients with locally advanced kidney cancer in the
randomized, placebo-controlled, multicenter, phase III adjuvant Sorafenib and
Sunitinib for Unfavorable Renal Carcinoma (ASSURE) trial. ASSURE enrolled
1,943 patients with resected, intermediate- or high-risk kidney cancer (both clear
cell and non–clear cell) and randomly assigned them to 1 year of treatment with
sorafenib, sunitinib, or placebo. Median disease-free survival was 5.8 years in both
the sorafenib and sunitinib arms and 6 years in the placebo arm. Five-year disease-
free survival rates were 52.8%, 53.8%, and 55.8%, respectively. Five-year overall
survival rates were 80.7%, 76.9%, and 78.7%, respectively. Although neither drug
improved outcomes compared with placebo, both agents had significant toxicity.45
Two studies are currently evaluating the duration of VEGF TKI therapy in the
adjuvant setting. The SORCE trial is comparing 1 year of sorafenib, 3 years of
sorafenib, and placebo in resected clear cell and non–clear renal cell cancers. The
ATLAS study is exploring prolonged adjuvant therapy with axitinib (Inlyta) for 3
years in very high-risk RCC.
Additionally, the EVEREST trial is randomizing patients with clear and non–
clear cell histologies to 1 year of adjuvant everolimus versus placebo.
Mature data from these studies are not yet available. Until results are
available, adjuvant therapy is considered to be investigational.
8. Combination therapy
With the exception of lenvatinib and everolimus as discussed prior (see Emerging
Therapy section) and bevacizumab with interferon-α (see Molecular Targeted
Agents—VEGF inhibitors section), combining targeted agents has thus far been
largely unsuccessful and is best reserved for clinical trials given potential for
significant toxicity.
H. Treatment strategies for metastatic renal carcinoma
Enrollment on clinical trials should be considered as initial treatment as well as
following progression. High-dose interleukin-2, with its potential for long-term durable
remission, is the treatment of choice for qualifying patients. For others, frontline therapy
with either sunitinib or pazopanib is recommended. The optimal sequence of agents for
disease that has progressed is unknown, but on the basis of clinical trials, options may
 be considered as seen below (see Table 13.4).

II. TREATMENT FOR NON–CLEAR CELL CARCINOMA

For patients with metastatic non–clear cell RCC, VEGFR TKI rather than immune-based
treatment is the most standard approach. The ESPN prospective phase III trial patients with
non–clear cell RCC were randomized to sunitinib versus everolimus in the first-line setting
with primary endpoint of PFS. The study did not reach statistically significant PFS outcome
but a few points can be observed. Sunitinib was associated with higher overall response
rate compared with everolimus (12% to 0%, respectively).46
The preliminary results of the phase II ASPEN trial studying sunitinib versus
everolimus in patients with non–clear cell RCC (majority with papillary type) at the
American Society of Clinical Oncology reveal improved PFS in sunitinib arm (8.3 vs. 5.6
months) as well as higher overall response rate (ORR) in sunitinib group (18% vs. 9%). It
should be noted that subgroup analysis (good, intermediate, and poor risk) shows
significant variability in which poor-risk patients seemed to benefit more from everolimus
initially.47

TABLE
Treatment in Metastatic Renal Cell Carcinoma—Clear Cell Type
13.4
First-Line Treatment
Risk Group Standard Options
Good/intermediate Sunitinib High-dose IL-2
Pazopanib Bevacizumab + low-dose IFN-α
Poor Temsirolimus Sunitinib
Second-Line Treatment
Prior Treatment Standard Options
Cabozantinib*
Axitinib
TKI Sorafenib
Everolimus
Nivolumab*

Third-Line Treatment
Prior Treatment Standard Options
Nivolumab* Levatanib + Everolimus*
TKI (at least two lines)
Cabozantinib* Sorafenib

*Under Review by the FDA.

Additionally, in an evaluation of the non–clearcell RCC in the RECORD 3 trial in

which sequence of sunitinib followed by everolimus was compared with everolimus
followed by sunitinib, patients had improved PFS when initially treated with sunitinib
 rather than everolimus (7.2 vs. 5.1 months).48
For patients with carcinomas of the collecting ducts or renal medulla, cytotoxic
chemotherapy should be offered. Following progression after VEGF inhibition, agents
targeting mTOR or enrollment on a clinical trial are a reasonable second-line strategy.
There is a paucity of information given these cancers are such a small percentage of kidney
cancers and it is difficult to power trials to achieve reasonable outcomes.49
As technology develops to allow interrogating a tumor’s molecular profile, there are
ongoing attempts at individualizing treatments created to exploit specific cell-surface
receptors or intracellular enzymatic pathways. These strategies remain nonstandard and are
best studied in the setting of a clinical trial.

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I. THYROID CARCINOMA
A. Incidence 1–3
The incidence of thyroid cancer is rising in both men and women. The National Cancer
Institute has estimated that 62,450 new cases of thyroid carcinoma are diagnosed in the
United States annually, accounting for approximately 1,950 deaths. The incidence of
thyroid carcinoma is now about 9 per 100,000, with approximately 2.7 to 3.1 times as
many women as men affected. The peak incidence occurs at age 35 for women and age
44 for men. The incidence rates for thyroid cancer in men and women were 6.1 and
18.2 per 10,000 in the population, respectively, between 2006 and 2010. The incidence
of thyroid cancer is increasing—in women at a rate >5% per year. With the mortality
rate also up by one-third in the last decade, it has been argued that the increasing
incidence is real and not due to better screening/detection. Thyroid carcinoma is now
over twice as common in the United States as it was 10 years ago, and it is now the fifth
most common cancer in U.S. women. The 5-year survival rate of all people with thyroid
cancer is about 98%.
B. Etiology and prevention4
In most patients, the cause of thyroid carcinoma is unknown, but the best-established
risk factor is head and neck radiation exposure during childhood for diseases such as
Hodgkin lymphoma or an enlarged thymus; hereditary factors, family history of thyroid
cancer, and history of goiter and/or preceding autoimmune thyroid disease are
implicated in some patients as the cause of the increased risk of thyroid cancer.
Autoimmune thyroid disease is more prevalent in women and this may explain why
thyroid cancer is more common in women than in men. Thyroid cancer has been
observed 20 to 25 years after radiation exposure among atomic bomb survivors, and in
some regions of Japan the incidence of thyroid cancer in screened populations is as high
as 0.1%—10-fold greater than expected on the basis of U.S. incidence rates. In cases of
accidental radioisotope exposure, expeditious use of potassium iodide can block the
thyroid uptake of radioactive iodine (RAI).
Some cases of thyroid cancer are associated with familial syndrome. Medullary
thyroid cancer (MTC) occurs in patients with multiple endocrine neoplasia syndrome
types 2A and 2B (MEN2) and in familial MTC (FMTC) and accounts for 3% to 5% of
all thyroid cancer. MEN2 and FMTC are autosomal dominant syndromes caused by a
germline mutation of the RET proto-oncogene that affect 1 in 30,000 individuals. In
 these syndromes, prophylactic thyroidectomy should be undertaken in at-risk
individuals at young ages. Somatic RET mutations also occur in approximately 50% of
sporadic MTC.
C. Histologic types5
The most common types of thyroid carcinoma are as follows.
1. Differentiated thyroid cancer (88%)
More than 90% of all thyroid cancers are a subtype of differentiated thyroid cancer
(DTC), with papillary thyroid cancer (PTC) the most common type (80% to 85%).
PTC is generally unilateral but it can also be multifocal within a lobe. Histologic
subtypes of PTC that have a worse prognosis include tall cell variant, columnar cell
variant, and diffuse sclerosing variant. A worse prognosis is also seen with highly
invasive variants of follicular cancer. The latter are characterized by extensive
vascular invasion and invasion into extrathyroidal tissues or extensive tumor
necrosis with many mitoses. Other poorly differentiated aggressive tumor
histologies include trabecular, insular, and solid subtypes. Genetic alterations in the
mitogen-activated protein kinase (MAPK) signaling pathway are found in at least
75% of PTC cases, with a BRAFV600E mutation found in approximately 45% of
PTC. Activating mutations in the RAS oncogenes occur in approximately 10% of
cases. RET rearrangements are found in approximately 25% and upregulation of
vascular endothelial growth factor (VEGF) signaling is also common in metastatic
disease.
Follicular thyroid cancer (FTC) is the second most common DTC (10% to
15%). FTC typically disseminates hematogenously, with metastasis to both lung and
bone more common in advance disease. Both RAS point mutations and mutations on
chromosome 3 (PAX8-PPAR mutations) have been described in FTC. Hürthle cell
cancer (HCC; 3%) also referred as oxyphilic or oncocytic thyroid cancer is a
histological variant of FTC that often behaves more aggressively, and has been
subsumed under the FTC classification rather than being considered a unique
histotype. DTCs are derived from thyroglobulin (TG)-producing follicular cells
(thyrocytes), often secrete TG and are typically initially RAI responsive. Hence, TG
can be used as a tumor marker in antithyroglobulin antibody–negative patients.
2. Medullary thyroid cancer (4%)6,7
MTC is a calcitonin-producing tumor derived from thyroid parafollicular or C cells,
which derive from the neural crest. MTC presents worldwide as part of an
autosomal dominant inherited disorder with about 20% to 25% of cases and as
sporadic tumor in about 75% of cases. Sporadic tumors tend to be solitary, whereas
familial tumors tend to be bilateral and multifocal. Activating mutations of the RET
proto-oncogene are characteristic, with germline activating RET mutations as seen in
FMTC and MEN2 a predisposing factor. MTC most often produces both
immunoreactive calcitonin and carcinoembryonic antigen, and these can be used as
tumor markers.
 3. Anaplastic thyroid cancer (2%)
Anaplastic thyroid cancer (ATC) is a rare, aggressive malignancy that accounts for
2% to 5% of all thyroid cancers. In several countries, the prevalence of ATC has
decreased dramatically due in part to increased dietary iodine and better
management of DTC. Furthermore, up to 50% of patients have a concurrent history
of DTC. ATC patients have a median survival of 3 to 7 months and account for a
significant portion of thyroid cancer deaths. Disease specific mortality is nearly
100%, with only 10% overall survival 1 year from diagnosis. As a result, improved
therapies are needed. Approximately 90% will have locoregional or distant
metastases at time of diagnosis; however, most deaths result primarily from systemic
disease.
4. Thyroid lymphoma (5%)
Thyroid lymphomas are uncommon and represent cancers of lymphoid tissues, as
discussed in Chapters 22 and 23.
5. Thyroid sarcoma (<1%)
Thyroid sarcomas are also rare and should be treated in accordance with their
underlying histology, as discussed in Chapter 17.
6. Squamous cell carcinoma of the thyroid (<1%)
Rarely, squamous cell cancers arise in the thyroid; they are best treated as primary
squamous cell carcinomas of the head and neck (see Chapter 6).
D. Prognosis8–12
1. Cell types/histology
Prognosis varies by thyroid cancer subtype. PTC is the subtype with the best
survival, and mixed PTC/FTCs have similar, generally favorable biologic and
prognostic behaviors with less than 15% mortality at 20 years. Even patients with
lung metastases have a 20-year survival rate exceeding 50% with a 10-year survival
of nearly 93% to 98%. FTCs have a somewhat worse prognosis than cancers with
papillary elements, with 10-year survival of 85%. Recent studies have shown that
FTCs with vascular invasion have a relatively worse prognosis, whereas FTC
patients without vascular invasion do almost as well as PTC patients. MTCs often
occur with regional nodal and distant metastases and can occur in early stages of the
disease in MTC, with 10-year survival after surgical resection of MTC at 40% to
60%. Patients with ATC have an abysmal prognosis, with a median survival of only
4 months and a historical 10% survival 1 year from diagnosis.
2. Other factors
Prognosis is worse if tumor size is >4 cm, patient age >40 years of age and/or male
gender, distant metastases are present, and/or DNA content is aneuploid. DTC tends
to metastasize first to lymph nodes, then to lung, and somewhat less commonly bone,
with 5-, 10-, and 15-year survivals of 53%, 38%, and 30%, respectively. Other sites
of metastases in DTC include subcutaneous structures, liver, and also brain. In
contrast to most other cancers, limited regional lymph node metastasis of DTC does
 not influence survival substantially, and radiation-induced DTC is not associated
with a worse prognosis. Several systems are used to predict outcomes in DTC,
including, for example, the MACIS scoring system (metastases, +3 if metastases;
age, ≤39 years of age = 3.1, >40 = age in years × 0.08; completeness of resection,
+1 if primary resection is incomplete; invasion, +1 if pathologically invasive; and
size, 0.3 × largest dimension in centimeters) with median prognosis estimated on the
basis of the total score as indicated in Table 14.1.
E. Diagnosis and staging
Generally, thyroid nodules >1 cm should be evaluated, since they have a greater
potential to be clinically significant cancers, and neck ultrasound is an important
supplemental approach. Occasionally, thyroid nodules <1 cm require evaluation
because of suspicious ultrasound findings, associated with lymphadenopathy, head and
neck irradiation, or a family history of thyroid cancer. Because most thyroid tumors
spread primarily by local extension and regional nodal metastasis, assessment of the
extent of disease in the neck is critical. With any palpable thyroid nodule, further
evaluation with thyroid-stimulating hormone (TSH) and thyroid ultrasound needs to be
performed. If a nodule is seen on ultrasound and TSH is normal or high, a fine needle
aspiration (FNA) needs to be performed. If TSH is subnormal, a radionuclide thyroid
scan should be performed either with 99mTc pertechnetate or 123I to see if it is
hyperfunctioning. Hyperfunctioning nodules are benign and patients with them should be
treated for hyperthyroidism. Up to 30% of FNAs are indeterminate; therefore, a
definitive diagnosis is often not made until the nodule is resected. A new gene
expression classification assay was able to predict benign pathology when FNA
cytology is indeterminate (e.g., BRAF, RAS, RET/PTC, Pax8-PPAR, galectin-3). If the
cytology reading reports follicular neoplasm, a lobectomy or total thyroidectomy should
be considered. Surgery should also be considered if the reading is reported as
suspicious for PTC or Hürthle cell neoplasm. Chest radiography should be performed
before surgery to rule out macroscopic pulmonary metastasis. If there is any clinical or
laboratory suggestion of bone or other metastases, skeletal radiographs, computed
tomography (CT) scan, positron emission tomography (PET) scan, and/or a
radionuclide bone scan should be considered on a case-by-case basis.
 TABLE
MACIS Prognostic Scoring System for Thyroid Cancer
14.1
Total MACIS Score 20-Year Survival (%)
<6 99
6 89
7–8 56
>8 24

Source: Edge SB, Byrd DR, Compton CC. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

Also worthy of comment is that PET imaging should be used judiciously in thyroid
cancer. In ATC, PET can be very helpful; however, some DTCs do not image well via
PET. In DTC, PET avidity tends to correlate with more aggressive tumor behavior.
Patients with thyroid carcinoma are typically euthyroid; however, elevated TSH
with increased thyroid peroxidase antibodies may be seen with Hashimoto thyroiditis,
which may coexist in 20% of patients with thyroid lymphoma and also sometimes in
DTC.
The most widely accepted tumor staging system, the TNM system, uses tumor size
and extent, lymph node involvement, and distant metastasis. An ATC is considered stage
IV (A, B, or C), and there are no TNM stage III or IV patients with DTC who are
younger than 45 years. This staging system is suboptimal in thyroid cancer, prompting
use of algorithms such as the MACIS system discussed above.13
F. Treatment
The therapeutic approaches utilized in thyroid cancer depend on the histologic type,
extent of disease, patient symptoms, and rate of disease progression. Careful
management of disease residing in the neck so as to protect airway, esophagus, and
other critical structures is also of paramount importance.
1. Differentiated thyroid cancer14
a. Surgery. Total thyroidectomy is recommended for a DTC lesion >1 cm, taking
into considering that with DTC the incidence of disease in the contralateral lobe
is 20% to 87%. It is also recommended in lesions that extend beyond the thyroid,
or in patients with prior exposure to ionizing radiation to the head/neck area.
Further, total thyroidectomy is conducive to RAI surveillance, and simplifies
follow-up in patients with high-risk disease. Total thyroidectomy with modified
neck dissection is often preferred for those who have lateral cervical lymph
node involvement. Unilateral lobectomy with en bloc resection of tumor maybe
considered for a DTC <1 cm or follicular lesion with no evidence of
multicentric disease. Mortality consequent to thyroidectomy in DTC is extremely
low. Complications include recurrent laryngeal nerve damage in 2% of patients
and hypoparathyroidism that is lifelong in 1% to 2% of patients.
 b. TSH suppression. TSH suppression via administration of “supra-therapeutic”
levothyroxine is an essential component in the treatment of high-risk DTC, as
residual cancer cells are usually initially responsive to TSH growth stimulation.
Levothyroxine (T4, usual dosage range 125 to 200 μg by mouth daily) is
administered to keep the TSH level suppressed below 0.1 mIU/L in high-risk
(macroscopic tumor invasion, incomplete tumor resection, distant metastases) to
intermediated-risk patients (microscopic invasion of tumor into the perithyroidal
soft tissues, cervical lymph nodes metastases, tumor with aggressive histology or
vascular invasion). For low-risk patients, the goal is to maintain TSH below the
lower limit of normal 0.1 to 0.5 mIU/L. However, suppression of TSH below
0.1 mIU/L imposes long-term adverse effects on bone and can negatively impact
quality of life, sometimes producing symptoms of thyrotoxicosis. Angina can
also be provoked by suppressive dosages of levothyroxine, as can tachycardia
or sometimes even frank cardiac arrhythmia, so care must be used in the
selection of patients in whom the risks of aggressive TSH suppression is
justified.
c. Adjuvant therapy/radiotherapy—RAI. Treatment with RAI is used to ablate
normal residual thyroid tissue, treat micrometastases, and decrease cancer-
related death as well as tumor recurrence and development of distant metastases.
Destruction of residual normal thyroid tissue after thyroidectomy with RAI (131I)
is termed radioactive remnant ablation (RRA). RRA is different from “RAI
therapy”; in RAI therapy, larger doses of RAI are used to attempt to destroy
persistent cancer, whereas RRA is used to eliminate residual normal thyroid
tissue remaining after primary surgery. When ablation is carried out
postoperatively, it is usually done 4 to 6 weeks after thyroidectomy. RRA allows
for better subsequent imaging with RAI when looking for metastasis and also
improves the utility of TG in the detection of residual thyroid cancer (as remnant
thyroid tissue is destroyed). Successful remnant ablation is usually defined as an
absence of visible RAI uptake on a subsequent diagnostic RAI scan or an
undetectable stimulated serum TG RRA doses of 30 mCi to 100 mCi generally
show similar rates of successful remnant ablation. RAI ablation is recommended
for patients with known distant metastases, gross extrathyroidal extension of the
tumor regardless of tumor size, primary tumor size >4 cm even in the absence of
other concerning features.
Treatment with RAI (131I) is usually recommended for patients with DTC
and known postoperative residual disease, patients with distant metastases,
and/or patients with locally invasive lesions. For patients with nodal metastases
that are not large enough to excise, a dose of 100 to 175 mCi of RAI is
commonly given. Locally invasive cancer that is not completely resected is often
treated with 150 to 200 mCi of RAI while patients with distant metastasis are
treated with 200 to 250 or even 300 mCi. The potential exception to this schema
 is lung metastasis; a dose of up to 80 mCi of RA whole body retention by
dosimetry at 48 hours is generally used to avoid radiation-induced pulmonary
fibrosis or empiric treatment with 100 to 200 mCi.
Effective and safe use of RAI treatment requires that tumor cells are
capable of concentrating iodide (i.e., DTC), and appropriate patient preparation
to raise TSH levels by either temporarily withholding thyroid hormone
replacement or via administration of recombinant TSH. In the former situation,
because of its long half-life, T4 is discontinued and T3 is initiated for a period of
6 weeks prior to the scan, with all thyroid medication withheld in the 2-week
period prior to RAI administration. Ideally, a TSH level of 25 to 30 μm/mL is
required for successful ablation or radiotherapy. Alternatively, recombinant TSH
can be used to stimulate thyroid cell uptake of RAI in the absence of T4
withdrawal; this approach maintains better quality of life but adds considerably
to expense. A low iodine diet is also required for RAI efficacy, as dietary iodine
can compete with RAI for uptake in normal thyrocytes and tumor and thereby
reduce RAI therapeutic efficacy. Compliance with a low iodine diet is assessed
via measurement of 24-hour urinary iodine excretion.
Patients receiving high dose RAI (150 to 300 mCi) must be treated at
centers with special lead-lined containment rooms, with monitoring of treated
patients to assure compliance with environmental radiation safety regulations
and patient and population safety. The duration of hospitalization depends on the
dose given, the post-therapy method of transportation home, and contact of
patient with the general public. Potential side effects of RAI include temporary
bone marrow suppression (this can last weeks or even months with repeated
high RAI dosage), transient nausea, sialoadenitis/dry mouth (with possible
permanent cessation of salivary flow), skin reaction over the tissue concentrating
the radioiodine, and pulmonary fibrosis. The use of very high cumulative RAI
doses (usually when approaching 1,000 mCi) has also rarely been associated
with acute myelogenous leukemia, as well as rarely with bladder and breast
cancers. Scintigraphy should be performed 4 to 10 days after RAI therapy to
assess uptake of RAI by tumor and to detect residual carcinoma perhaps not
otherwise seen using other imaging approaches.
d. Radiotherapy—local approaches including external beam radiotherapy.
External beam radiation therapy in DTC is used infrequently except as a
palliative treatment for locally advanced, unresectable disease in the neck that
does not concentrate iodine. External beam radiotherapy is also used for
localized painful bony metastasis, for other local disease that could lead to
fractures, neurological or compressive symptoms that are not amenable to
surgery; for example, vertebral, CNS, or pelvic metastases, or subcarinal lymph
nodes. Stereotactic radiosurgical approaches are also used in patients with
recurrent cancer at previously irradiated sites and when tumors are proximal to
 critical radiation-sensitive tumors.
e. Systemic therapies. Several putative VEGFR inhibitors have been shown to
have activity in well-differentiated thyroid cancers and two—sorafenib and
lenvatinib—have received Food and Drug Administration (FDA) approval on
the basis of randomized phase III trials. Sorafenib is an inhibitor of several
protein tyrosine kinases (VEGFR and PDGFR) and some intracellular
serine/threonine kinases (e.g., C-Raf, wild-type and mutant B-Raf). Safety and
effectiveness were established in a randomized trial involving 417 participants
with locally recurrent or metastatic, progressive DTC that had not responded to
RAI treatment. The sorafenib dose was 400 mg twice a day. The median
progression-free survival (PFS) was 10.8 months with sorafenib compared with
5.8 months with placebo (p < 0.0001). Partial responses were observed in
12.2% of patients receiving sorafenib compared with 0.5% in the placebo arm
(p < 0.0001). The most common side effects with sorafenib were diarrhea,
fatigue, alopecia, hand-foot skin reaction, rash, weight loss, anorexia, nausea,
gastrointestinal and abdominal pains, and hypertension. TSH, a potential
promoter of thyroid cancer, may increase while on sorafenib, requiring
adjustment of replacement therapy. Lenvatinib is an inhibitor of the VEGF
receptor 2 (VEGFR2). The approval of lenvatinib was based on a multicenter,
double- blind, placebo-controlled trial that enrolled 392 patients with locally
recurrent or metastatic RAI-refractory DTC and radiographic evidence of
progression within 12 months prior to randomization. Patients received
lenvatinib 24 mg orally per day. Median PFS was 18.3 months in the lenvatinib
arm and 3.6 months in the placebo arm (p < 0.0001). Objective response rates
were 65% and 2% in the lenvatinib and placebo arms, respectively. No
statistically significant difference in overall survival between the two arms was
demonstrated. The most common adverse reactions were hypertension, fatigue,
diarrhea, arthralgia/myalgia, anorexia, weight loss, nausea, stomatitis, headache,
vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome,
abdominal pain, and dysphonia. Adverse reactions led to dose reductions in
68% of patients receiving lenvatinib and 18% of patients discontinued lenvatinib
for adverse reactions. Thus, it is not clear whether the recommended dose will
be tolerable, and the extent of efficacy thus remains uncertain.
2. Medullary thyroid cancer6,7,15
a. Surgery. In patients with MTC, total thyroidectomy with central lymph node
dissection is recommended. Patients with FMTC syndromes should undergo
early prophylactic thyroidectomy.
b. Radiotherapy. External beam radiation can be used for residual or recurrent
disease; however, the survival benefit is still unclear. As MTC does not uptake
iodine, RAI has no role.
c. Systemic therapies. As with WDTC several putative VEGFR inhibitors have
 been shown to have activity in MTC with FDA approval granted to two
inhibitors that also have activity against the RET tyrosine kinase. Approval of
the first, vandetanib, was based on an international multicenter randomized
double-blind trial in patients with unresectable locally advanced or metastatic
MTC. An improvement in PFS was observed with vandetanib compared with
placebo (HR = 0.35; p < 0.0001). The overall response rate (ORR) was 44%
with vandetanib, compared with 1% placebo. The most common (at least 20%)
grade 1 to 4 adverse reactions included diarrhea/colitis, rash, dermatitis
acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and
abdominal pain. The recommended daily dose of vandetanib is 300 mg orally.
Cabozantinib, the second drug, inhibits the activity of multiple tyrosine kinases,
including RET, MET, and VEGF receptor 2 and its approval was based on an
international, multicenter, randomized (2:1), placebo-controlled trial enrolling
330 patients with metastatic MTC. Patients were required to have progressive
disease within 14 months prior to entry. The estimated median PFS was 11.2 and
4.0 months for the cabozantinib and placebo arms, respectively (p < 0.0001).
The ORR was significantly higher with cabozantinib (27% vs. 0%; p < 0.0001)
and all were partial responses. The median response duration was 14.7 months
(95% CI, 11.1 to 19.3).No statistically significant difference in overall survival
was observed. Adverse reactions observed in ≥25% of cabozantinib-treated
patients were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome
(PPES), decreased weight, anorexia, nausea, fatigue, oral pain, hair color
changes (hypopigmentation/graying), dysgeusia, hypertension, abdominal pain,
and constipation. While the recommended dose and schedule for cabozantinib is
140 mg orally once daily, dose reduction was required in 79% of patients again
raising questions as to the actual efficacy of a tolerable dose.
3. Anaplastic thyroid cancer16
a. Surgery. Surgical resection does not improve local control or survival in
patients and most of the time the treatment is palliative. A total lobectomy or
total or near-total thyroidectomy with a therapeutic lymph node dissection
should be performed in patients with intrathyroidal ATC. If there is
extrathyroidal invasion, an en bloc resection should be considered if grossly
negative margins could be achieved. If surgery is performed, it should be
followed by locoregional radiotherapy usually within 2 to 3 weeks after surgery.
Local control is desirable in patients with ATC because of the likelihood of
asphyxia from the rapidly enlarging tumor.
b. Radiotherapy. Radiotherapy has an established role in the locoregional
treatment of ATC. In patients with resectable disease and no distant metastases,
locoregional radiation should be considered (with or without systemic therapy)
and in patients with unresectable locoregional disease, radiation therapy can
achieve long-term local control. Furthermore, treatment with external beam
 radiotherapy, with systemic therapy, appears to achieve local control in two-
thirds of patients with ATC; however, almost all subsequently die of distant
metastases.
c. Systemic therapies for ATC. About 60% of all ATCs are unresectable or
metastatic at the time of presentation and chemotherapy has offered little in
improving survival in these patients. Even if a patient with advanced ATC
responds to chemotherapy, a prolongation of the median survival time by several
months is generally all that can be achieved. In terms of single-agent
chemotherapy, there are two classes of cytotoxic agents with the greatest
evidence in support of efficacy: anthracyclines (e.g., doxorubicin) and taxanes
(e.g., paclitaxel), each with response rates in advanced disease as high as 50%.
Improved survival may be achieved in patients with advanced disease who
respond to these agents. Furthermore, there is accumulating rationale that the use
of these agents in combination with radiation therapy in the adjuvant setting may
also extend survival. Combination chemotherapy has been used in ATC, but it is
uncertain whether multiagent therapy impacts survival more than single-agent
therapies. Since there is no systemic therapy (cytotoxic, novel, targeted) of
proven benefit in terms of improved survival and/or quality of life in advanced
ATC, novel therapeutic approaches should be strongly considered. A number of
novel agents have been preliminarily studied in ATC such as fosbretabulin
assessed in phase II trial with increased overall survival in some patients.
Tyrosine-kinase inhibitors (TKIs) such as sorafenib, axitinib, gefitinib have been
studied with no evidence of RECIST response; however, a limited number of
patients were reported to have stable disease. Ongoing studies are examining the
use of MAPK and B-Raf inhibitors alone or in combination in patients with ATC
whose tumors harbor B-Raf mutations. Some responses have been observed.

II. ADRENOCORTICAL CARCINOMA

A. Incidence and etiology17
Adrenocortical cancer (ACC) is a rare malignancy that presents many management
challenges and requires a multidisciplinary approach to treatment. Across the world,
the incidence of ACC is estimated at 1.5 to 2/million/year. While strides have been
made in the management of these patients, ACC remains a difficult to treat disease, with
a 5-year survival of 10% to 25% and an average survival from diagnosis of about 14.5
months. The majority of ACCs are sporadic without identifiable risk factors. However,
a small percentage occurs in association with certain genetic syndromes including the
Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN-1, and familial
adenomatous polyposis.
B. Clinical manifestations18,19
Among patients with a diagnosis of ACC, approximately 50% present with biochemical
evidence of hormone excess including 10% to 20% who present with Cushing
 syndrome. The remaining present with less florid manifestations such as hirsutism in
females and gynecomastia in males, or have no overt clinical symptoms. Several recent
reviews provide in-depth summaries. While the diagnosis is obvious in a patient
presenting with systemic or biochemical manifestations of endocrine hypersecretion,
patients can also present without symptoms or only vague symptoms, or with local
symptoms from a large, locally invasive primary tumor.
C. Evaluation and workup19,20
A history, physical examination, and blood and urine studies to determine if the tumor is
functional should be part of the initial evaluation, followed by either a CT or a magnetic
resonance (MR) study. Both CT and MR can differentiate benign adenomas from
malignant lesions and help establish the diagnosis, and can also guide management.
Because ACCs have lower lipid content than adenomas, they usually have higher
density values on CT scans; while on magnetic resonance imaging (MRI) they are
usually iso-intense with liver on T1 images, and have intermediate-to-high intensity on
T2 images. Attributes of an MRI include its superiority in identifying liver metastases
and the extent of vascular invasion, especially the inferior vena cava (IVC), thus
providing valuable information prior to surgery and for monitoring disease response in
the liver. An 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) should
not be used as the primary modality nor can it be considered definitive in discriminating
benign from malignant adrenal masses, nor a primary adrenal tumor from other from
other tumors with high metabolic activity. However, in a patient in whom a surgical
intervention is planned, FDG-PET can help assess extent of disease and ensure all
disease has been identified and that surgery should proceed as planned.
D. The role of a biopsy21
For most patients presenting with an adrenal mass that is suspicious for malignancy,
surgery and not a biopsy should be performed. While a risk of seeding tumor, and
difficulty differentiating benign from malignant in a small biopsy sample are often cited
as reasons, the most important reason is that a biopsy rarely if ever changes
management. It is prudent to proceed to surgery without a prior biopsy in a patient (1)
with either Cushing syndrome or biochemical evidence of hormone excess, where there
is no doubt as to the diagnosis of ACC or (2) without evidence of hormone production
but with an isolated adrenal mass found during evaluation or incidentally on an imaging
scan. In the latter, surgical resection is both a diagnostic and a therapeutic intervention.
A biopsy should only be performed only if (1) disease elsewhere suggests a primary
location other than adrenal, or (2) widespread metastases make surgical resection
unlikely to be beneficial.
E. Pathology22,23
In 1984, Weiss first proposed a set of criteria to help distinguish a small ACC without
local spread or distant metastases from a benign adenoma. He reported nine criteria he
felt were most useful and today a malignancy is presumed if three or more criteria are
identified in the tumor. The nine properties, now often referred to as the “Weiss
 criteria,” include (1) nuclear grade III/IV; (2) mitotic rate greater than 5 per 50 high-
power fields (HPFs); (3) atypical mitoses; (4) tumors with 25% or less clear cells; (5)
diffuse architecture; (6) microscopic necrosis; (7) venous invasion; (8) sinusoidal
invasion; and (9) capsular invasion.
Despite the recognized value of the Weiss criteria in discriminating a small
adenoma from a small carcinoma, their prognostic value in larger tumors has not been
established. Although the nine properties often cluster, whether a greater number of
criteria are associated with a worse prognosis is not clear. Indeed, the prognostic value
of pathologic findings other than mitotic rate remains unconfirmed. Indeed, in 42
patients with a diagnosis of ACC, Weiss and colleagues found a strong statistical
association with outcome only for mitotic rate; with tumor weight greater than 250 g,
size greater than 10 cm, atypical mitoses, and capsular invasion demonstrating marginal
associations with poor survival (p < 0.06). A recent study that attempted to simplify
histopathologic classification of ACCs confirmed the importance of mitotic rate.
F. Management of ACC24
Approaches used in the management of ACC include surgical resection, oral mitotane,
intravenous chemotherapy, and palliative radiation. While the fact that it is a rare
disease and that data from controlled trials is generally lacking, this does not mean
there is no evidence nor does it mean anything is an option. For patients whose disease
progresses after commonly used approaches, referral to a clinical trial must be seen as
the best option.
1. Surgical resection24–28
Because surgery remains the only proven curative option for a patient with ACC, it
must always be aggressively pursued at presentation and at relapse. At presentation
less than complete resections should not be entertained given that survival is less
than 1 year in patients who undergo incomplete resection.
At the time of presentation, an experienced oncologic surgeon, not a general
surgeon, should perform an open procedure. A laparoscopic approach should never
be used. While such an approach may appear attractive to a surgeon and even more
so to a patient who sees a short hospital stay and quick recovery as ideal,
intraoperative tumor spill rates as high as 50% should discourage any approach
other than an open resection. Not everyone agrees. A study summarizing outcomes in
152 ACC patients concluded that for localized ACCs ≤10 cm in diameter,
laparoscopic adrenalectomy was not inferior to open adrenalectomy. However,
extensive preselection occurred, laparoscopy resection was attempted in only 23%,
and one-third of the latter were converted to open resections. Furthermore, these
results in specialized tertiary referral centers have very limited-to-no applicability
in the general community. In addition to a high likelihood of peritoneal seeding,
laparoscopic resections have been reported to have a higher incidence of positive
margins and more rapid recurrence. Given our still limited systemic chemotherapy
options, an earlier peritoneal recurrence not amenable to surgical resection is a
 serious adverse event that should be avoided, as should any recurrence. Finally, a
systematic review of laparoscopic surgery for different cancers concluded, “There
is no prospective randomized series to guide or endorse the use of laparoscopic
resection for adrenocortical carcinoma or malignant pheochromocytoma,” a
conclusion with which we agree.
At the time of relapse, an aggressive surgical posture may emerge as the
preferred option in selected patients. While metastasectomy of defined disease is
likely to be of value, it must be recognized that all or the majority of studies
addressing this approach have an inherent bias: those undergoing surgery likely have
more limited disease, a better performance status, and possibly tumors whose
biology might be considered “more indolent.” But the fact these recurrences are
often aggressive and if left unattended would likely lead to death suggest that
carefully planned metastasectomies might benefit patients without evidence of
widespread recurrence. It is likely the literature will eventually validate this
approach.
2. Mitotane 29,30
The use of mitotane as an anticancer agent for ACCs dates back to the 1960s when
the insecticide, DDT, was identified as an adrenolytic agent. The enthusiasm for
mitotane during that time—an era when assessment of an agent’s activity was much
less precise with quantitation of tumor relying on physical examination and clinical
presentation—seems in retrospect to have been not well founded. As a potent
inhibitor of adrenal hormone synthesis it is likely that investigators’ assessments of
mitotane’s antitumor effects were likely influenced by improved symptoms of
hormone hypersecretion that were erroneously thought to represent tumor reduction.
Indeed, although mitotane is approved for “the treatment of inoperable adrenal
cortical carcinoma of both functional and nonfunctional types,” its clinical utility and
value is primarily as an antihormonal agent and only marginally as a tumoricidal
agent. Mitotane’s most valuable attribute is its ability to impair hormone synthesis
by cells of adrenal origin and to modify the peripheral metabolism of steroids. Thus
mitotane is indispensable in patients with hormone-producing tumors and it must be
started as soon as possible and continue indefinitely. Indeed, in a patient with excess
hormone production, mitotane should be continued even in the face progression on
imaging studies—not as an anticancer agent but as an antihormonal agent to which
other therapies may be added.
Whether mitotane should be used as an adjuvant therapy has not been resolved,
although most physicians who treat patients with ACCs used it albeit variably.
Several small and one large retrospective studies suggest mitotane given as an
adjuvant therapy and continued indefinitely, can at a minimum delay and possibly
prevent a recurrence of disease. Ongoing studies are attempting to begin to better
define those who may experience benefit. Identifying those who will benefit is
important since mitotane is well tolerated by only a fraction of patients, with the
 majority finding it a difficult therapy that impacts the quality of their lives.
Administering mitotane to all patients after an initial resection means that as many as
35% to 40% of patients incur toxicities without benefit given that they have been
cured by surgery. Whereas patients who present with large tumors, uncertain
margins, and many of the histopathology findings described by Weiss as well as a
Ki67 index higher than 10% to 15% should receive mitotane indefinitely. The
decision made in other cases will be more nuanced. Thus, pending an accurate
predictor of recurrence, clinical judgment based on experience is paramount.
Finally, as regards the administration of mitotane, many recommendations
including those in the current package insert
(http://packageinserts.bms.com/pi/pi_lysodren.pdf) are impractical and likely to
lead to its discontinuation. One should recognize that aggressive administration of
mitotane has never been shown to lead to a rapid response and that mitotane’s effect
comes only with time. Consequently, an aggressive administration schedule
invariably leads to intolerance and discontinuation. Especially in a patient in whom
it is given as an adjuvant where no disease is visibly present, an aggressive
schedule that aims to reach a “threshold level” is unfounded. Mitotane as a therapy
should be viewed a marathon not a sprint and its administration adjusted
accordingly. A starting dose of 1 to 2 g/day should be gradually advanced to a
maximum of 4 to 6 g/day over 2 to 3 months, with further adjustments guided by
serum levels. Replacement steroids can be started with the initiation of mitotane or
when clinical and laboratory parameters indicate the emergence of adrenal
insufficiency. Both hydrocortisone and fludrocortisone should be given. It is
important that patients receiving mitotane for prolonged periods of time be
instructed to wear a bracelet labeled adrenal insufficiency and that this be worn for
up to a year after mitotane is discontinued, since it takes many months for mitotane to
be eliminated from the body.
3. Systemic chemotherapy31
There is very little clinical data to guide the practicing oncologist on what a patient
with adrenocortical cancer should receive, but it is sufficient that it should not be
disregarded, nor discarded in favor of a “novel targeted therapy,” none of which
have been proven of efficacy to date. In the case of ACC, assessment of response
rate has been the principal mode of evaluation with PFS quantitated in a few studies.
The FIRM-ACT trial (First International Randomized trial in locally advanced
and Metastatic Adrenocortical Carcinoma Treatment) was a randomized
international trial that compared the two therapeutic regimens that had emerged as
the preferred options for ACC: A combination of etoposide, doxorubicin, and
cisplatin (EDP) with mitotane and single-agent streptozocin also in combination
with mitotane. The study found a significantly better response rate (23.2% vs. 9.2%,
p < 0.001) and PFS (5.0 vs. 2.1 months; hazard ratio, 0.55; p < 0.001) with EDP
plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar
 rates of toxic events. There was no significant difference in overall survival,
possibly because crossover was allowed. The investigators noted “the tumor
response in our study compares favorably with the results obtained with novel
therapies …” although “the poor overall survival rates … confirm … the need for
improved treatment options,” emphasizing both the value, albeit limited, of these
regimens and the need for better therapies. Importantly, given that among the 185
patients who received EDP-mitotane as second-line therapy, the median PFS was
essentially unchanged at 5.6 months despite a median of 2.1 months of streptozocin,
one could argue that in a patient with a good performance status and a modest
amount of disease, there exists a window to enroll in an experimental regimen and
this should be encouraged. We would also note that the FIRM-ACT study found
similar results for EDP plus mitotane and streptozocin with mitotane as first- or
second-line therapies suggesting they are not cross-resistant and thus they may be
administered in succession if a response is not achieved with the first regimen.
One should emphasize that the efficacy of EDP versus a simpler regimen has
never been addressed. An unproven alternative that can be considered in patients
with severe hormonal excess who may be receiving full doses of ketoconazole is
cisplatin at a dose of 40 mg/m2 administered weekly. This allows one to achieve a
higher dose intensity with cisplatin, the drug many would agree is the most active in
ACC. Finally, although many patients with ACC have undergone a nephrectomy, one
cannot recommend that carboplatin be substituted for cisplatin given that in other
cancers the activity profiles of these two agents have been dissimilar, and the data in
ACC is largely with cisplatin.
4. Radiation therapy32
While there is no definitive data, the use of palliative radiation therapy can be
beneficial for patients with metastatic disease. However, the use of radiation therapy
nor following primary surgery is not supported. Given it is unlikely radiation
therapy after a primary surgery has the potential to eradicate microscopic disease,
the benefit remains uncertain while risk is guaranteed. The latter includes not only
the well-known acute complications of radiation therapy but also the real possibility
that a salvage surgery that may be the only curative option will be made more
difficult. Postsurgical radiation should only be considered in a patient with known
positive margins after surgery performed by a highly qualified surgical oncologist
and only if a re-operation is deemed not possible.
5. Interventional radiology as a treatment modality33
Given the undisputed value of surgery as the only curative modality in the
management of ACC, less invasive options including radiofrequency ablation (RFA)
and cryoablation have emerged as potential surgical adjuncts or as stand-alone
modalities in patients who have suffered a recurrence. But just as partial surgical
resections to “debulk” disease should never be performed, an RFA or cryoablation
that does not eradicate the tumor also should not be done. The value of embolization
 to reduce tumor size and reduce vascular supply making a subsequent surgical
intervention is established, albeit not with randomized data. The combination of
RFA or cryoablation with embolization, either bland or with chemotherapy-loaded
beads, needs formal evaluation, but offers promise.
6. Management of hormonal excess and deficiency34
In the preoperative setting, a patient’s hormonal status should be assessed carefully
since a functioning tumor can suppress corticotropin (ACTH) and this can be
complicated by involution of the contralateral adrenal. Keeping this in mind is
important to ensure that in the postsurgical period any needed steroid replacement is
administered once the hormone-producing tumor is removed.
In patients with hormonal excess, the need for aggressive and sustained
attention to this problem must be recognized. Looking to chemotherapy to solve the
problem of hormonal excess is a flawed strategy since chemotherapy only benefits a
minority of patients leaving a majority increasingly debilitated by the continued and
increasing hormonal excess. Consequently, in addition to mitotane, identified earlier
as the cornerstone for managing hormonal excess, ketoconazole, metyrapone, and
etomidate, should be added singly or in combination to mitotane. The management
must be proactive and forward thinking since what is felt adequate for today’s tumor
burden will be insufficient for the larger quantity of tumor that will inevitably occur
in a short time.
G. A multidisciplinary approach to managing patients with ACC
Managing patients with ACC requires a multidisciplinary approach involving medical,
surgical, and radiation oncologists, interventional radiologists, and endocrinologists.
As we have noted given that the only curative option is surgery, it must always be
aggressively considered both at presentation and at relapse. However, in patients with
rapid recurrences or widespread metastases, a trial of chemotherapy should be given.
Given the rarity of achieving a long-lasting compete response with chemotherapy, in
this setting chemotherapy is used to address metastatic disease, for example, in the
lungs, and with the hope of improving the possibility of a surgical option by shrinking a
tumor mass and possibly helping sterilize microscopic disease.
H. Conclusion
In the management of ACC, a multidisciplinary effort is mandatory. Surgery remains the
cornerstone both at the time of presentation and when a limited recurrence occurs. In the
latter, RFA and cryoablation may be of value. Chemotherapy can benefit many patients
but new paradigms are needed. Referral to a clinical trial is strongly recommended.
Radiation therapy should be reserved for palliation. Patients whose tumors are
producing excess hormones should have this complication managed aggressively since
it can have a great effect on the quality of their life.

III. PHEOCHROMOCYTOMA AND PARAGANGLIOMA

A. Description and diagnosis35–40
 Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that arise from
chromaffin cells. Pheochromocytomas account for 90% of cases and arise in the adrenal
glands, whereas paragangliomas, the extra-adrenal counterpart of pheochromocytomas,
arise from ganglia along the sympathetic and parasympathetic chain (e.g., carotid
body/skull base, urinary bladder, heart, organ of Zuckerkandl). Most
pheochromocytomas represent sporadic tumors and 15% of these are associated with
somatic mutations. However, about 35% are familial in origin and harbor germline
mutations in susceptibility genes. The number of genes associated with susceptibility to
pheochromocytoma/paraganglioma was recently increased to 19, and includes the von
Hippel-Lindau (VHL) tumor suppressor gene, the rearranged during transfection (RET)
proto-oncogene, the neurofibromatosis type 1 (NF1) tumor suppressor gene, the genes
encoding the four succinate dehydrogenase complex (SDH) subunits (SDHA, -B, -C, -
D), and the gene encoding the enzyme responsible for flavination of the SDHA subunit
(SDHAF2). Additionally, new susceptibility genes, transmembrane protein 127
(TMEM127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2α
(HIF2A), have been identified. Others include the kinesin family member 1B, transcript
variant β (KIF1Bβ), prolyl hydroxylase 1 and 2 (PHD1/EGLN2 and PHD2/EGLN1),
Harvey rat sarcoma viral oncogene (H-RAS), Kirsten rat sarcoma viral oncogene (K-
RAS), isocitrate dehydrogenase 1 (IDH1), fumarate hydratase (FH) and BRCA1-
associated protein-1 (BAP1). Finally, germline mutations in malate dehydrogenase 2
(MDH2) and somatic mutations in alpha thalassemia/mental retardation syndrome X-
linked (ATRX) genes were identified in pheochromocytoma/paraganglioma. Sporadic
pheochromocytomas are usually unicentric and unilateral while familial
pheochromocytomas are often multicentric and bilateral. Despite this low incidence,
pheochromocytoma must always be considered because they can be cured in about 90%
cases, whereas if left untreated, could be fatal.
The incidence of malignancy is about 10%, with metastases the only definite proof
of malignancy, as there are no definitive histopathologic criteria for malignancy.
Oncologists must read the literature carefully given that descriptions of benign and
malignant are often combined. The overall 5-year survival rate for patients with
malignant pheochromocytoma is 36% to 44%. About 50% or more of SDHB mutation
carriers will develop malignant paragangliomas, and up to 60% of patients with a
malignant paraganglioma harbor a SDHB mutation.
Pheochromocytomas are usually diagnosed on the basis of the measurement of
plasma or urinary metanephrines and methoxytyramine since 30% do not secrete
catecholamines. Imaging modalities employed include CT and MRI. 123I-MIBG
scintigraphy has limited sensitivity but is of value in deciding if 131I-MIBG therapy is
an option.
B. Management of pheochromocytomas and paragangliomas41,42
1. Surgery
Surgery, remains the only curative treatment option with
 pheochromocytoma/paraganglioma. Minimally invasive adrenalectomy is
recommended for most adrenal pheochromocytomas and open resection for large or
invasive tumors to ensure complete resection and avoid local recurrence. Patients
with hormone secreting tumors should undergo preoperative blockade for 7 to 14
days with α-adrenergic receptor blockers such as phenoxybenzamine, doxazosin to
prevent perioperative cardiovascular complications. Many patients require the
addition of β-blockers, which are indicated for persistent tachycardia; however, to
prevent hypertensive crisis secondary to unopposed vasoconstriction, β-blockers
should not be given before α-antagonists. In patients in whom elevated blood
pressure and arrhythmia cannot be controlled with α- and β-blockade, α-methyl-
para-tyrosine (metyrosine, Demser) a competitive inhibitor of tyrosine hydroxylase
can be used. Importantly, normal postoperative biochemical test results do not
exclude microscopic disease. Long-term periodic follow-up is recommended
especially important if the tumors harbor mutations of disease-causing genes.
2. Radiation therapy
For patients whose tumors are positive 123I-MIBG scintigraphy, 131I-MIBG therapy
can be a valuable treatment modality. However, this approach has bone marrow
toxicity so it is best used in the context of a clinical trial. External beam
radiotherapy, Gamma Knife, and CyberKnife stereotactic approaches can provide
local control in focally symptomatic or threatening metastases.
3. Chemotherapy
Because of its rarity clinical data on the efficacy of chemotherapy is very limited.
Single agents and multidrug regimens in limited numbers of patients have been
reported with variable results. A combination of cyclophosphamide, vincristine, and
dacarbazine (CVD) is the most active chemotherapy regimen, producing remissions
of moderate duration in symptomatic patients. In 18 patients with a diagnosis of
pheochromocytoma/paraganglioma treated with CVD, 2 (11%) and 8 (44%)
achieved complete or partial responses, respectively, with amelioration of
symptoms related to catecholamine excess and objective improvements in blood
pressure. CVD was well tolerated with only grade I/II toxicities (38).

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8. Lo CY, Chan WF, Lam KY, et al. Follicular thyroid carcinoma: the role of histology and
staging systems in predicting survival. Ann Surg. 2005;242:708–715.
9. D’Avanzo A, Treseler P, Ituarte PH, et al. Follicular thyroid carcinoma: histology and
prognosis. Cancer. 2004;100:1123–1129.
10. van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular
invasion alone: a non-threatening malignancy. Surgery. 1992;112:1130–1136.
11. Sanders LE, Silverman M. Follicular and Hürthle cell carcinoma: predicting outcome
and directing therapy. Surgery. 1998;124:967–974.
12. Baloch ZW, LiVolsi VA. Prognostic factors in well-differentiated follicular-derived
carcinoma and medullary thyroid carcinoma. Thyroid. 2001;11:637–645.
13. National Cancer Institute. Thyroid Cancer Treatment–for health professionals (PDQ®).
Retrieved November 28, 2015, from http://www.cancer.gov/types/thyroid/hp/thyroid-
treatment-pdq#link/stoc_h2_2
14. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and
Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American
Thyroid Association management guidelines for patients with thyroid nodules and
differentiated thyroid cancer. Thyroid. 2010;20:674–675.
15. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines
for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610.
16. Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for
management of patients with anaplastic thyroid cancer. Thyroid. 2012;22:1104–1103.
17. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin
Endocrinol Metab. 2013;98:4551–4564.
18. Ayala-Ramirez M, Jasim S, Feng L, et al. Adrenocortical carcinoma: clinical outcomes
and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013;169:891–
899.
19. Terzolo M, Daffara F, Ardito A, et al. Management of adrenal cancer: a 2013 update. J
Endocrinol Invest. 2014;37:207–217.
20. Groussin L, Bonardel G, Silvéra S, et al. 18F-fluorodeoxyglucose positron emission
tomography for the diagnosis of adrenocortical tumors: a prospective study in 77
operated patients. J Clin Endocrinol Metab. 2009;94:1713–1722.
 21. Williams AR, Hammer GD, Else T. Transcutaneous biopsy of adrenocortical carcinoma
is rarely helpful in diagnosis, potentially harmful, but does not affect patient outcome.
Eur J Endocrinol. 2014;170:829–835.
22. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing
adrenocortical tumors. Am J Surg Pathol. 1984;8:163–169.
23. Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years
later. Hum Pathol. 2009;40:757–768.
24. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma.
Surgery. 1992;112:963–970.
25. Leboulleux S, Deandreis D, Al Ghuzlan A, et al. Adrenocortical carcinoma: is the
surgical approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol.
2010;162:1147–1153.
26. Miller BS, Ammori JB, Gauger PG, et al. Laparoscopic resection is inappropriate in
patients with known or suspected adrenocortical carcinoma. World J Surg.
2010;34:1380–1385.
27. Brix D, Allolio B, Fenske W, et al. Laparoscopic versus open adrenalectomy for
adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur Urol.
2010;58:609–615.
28. Bellantone R, Ferrante A, Boscherini M, et al. Role of reoperation in recurrence of
adrenal cortical carcinoma: results from 188 cases collected in the Italian National
Registry for Adrenal Cortical Carcinoma. Surgery. 1997;122:1212–1218.
29. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical
carcinoma. N Engl J Med. 2007;356:2372–2380.
30. Huang H, Fojo T. Adjuvant mitotane for adrenocortical cancer—a recurring controversy.
J Clin Endocrinol Metab. 2008;93:3730–3732.
31. Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced
adrenocortical carcinoma. FIRM-ACT Study Group. N Engl J Med. 2012;366:2189–
2197.
32. Fassnacht M, Hahner S, Polat B, et al. Efficacy of adjuvant radiotherapy of the tumor bed
on local recurrence of adrenocortical carcinoma. J Clin Endocrinol Metab.
2006;91:4501–4504.
33. Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and
adrenocortical carcinoma metastases. Cancer. 2003;97:554–560.
34. Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of
mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol.
2009;27:4619–4629.
35. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet.
2005;366:665–675.
36. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma:
which test is best? JAMA. 2002;287:1427–1434.
37. Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens. 2002;4:62–72.
 38. Lodish MB, Adams KT, Huynh TT. Succinate dehydrogenase gene mutations are strongly
associated with paraganglioma of the organ of Zuckerkandl. Endocr Relat Cancer.
2010;17:581–588.
39. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional
paraganglioma. J Clin Oncol. 2005;23:8812–8818.
40. Favier J, Gimenez-Roqueplo AP. Genetics of paragangliomas and pheochromocytomas.
Med Sci. 2012;28:625–632.
41. Pacak K, Del Rivero J. Pheochromocytoma. Endotext [Internet]. South Dartmouth:
MDText.com, Inc.; 2000–2013. Retrieved from
http://www.ncbi.nlm.nih.gov/books/NBK278970/
42. Martucci V, Pacak K. Pheochormoyctoma and paragnglioma: diagnosis, genetics,
management and treatment. Curr Probl Cancer. 2014;38:7–41.
I. INTRODUCTION
More than two million Americans were diagnosed with skin cancer in 2014, making it the
most common malignancy in the United States and accounting for considerable morbidity.
Most of the skin cancers are basal or squamous cell in origin with approximately 80% of
these representing basal cell carcinomas (BCCs). Of these nonmelanoma skin cancers,
most are curable but still approximately 2,000 people die each year from squamous cell
carcinoma (SCC) or BCC.1 Melanoma accounted for approximately 76,100 cases and was
responsible for an estimated 9,710 deaths in 2014, which far surpasses the number of
deaths due to all other skin malignancies combined.2 Melanoma continues to increase in
incidence at a higher rate than any other cancer in the United States, except for non–small-
cell lung cancer in women. Approximately 5,120 cases of nonepithelial skin cancer cases
with 3,270 deaths were diagnosed in 2014.1 These less common tumors of the skin include
Merkel cell cancer, Kaposi sarcoma (see Chapter 25), and mycosis fungoides (MF).

II. MELANOMA
A. Natural history
1. Etiology and epidemiology
Melanoma arises from pigment-producing melanocytes that migrate to the skin and
eye from the neural crest during embryologic development. Approximately 5% of
melanoma occurs in noncutaneous sites such as the eye and mucous membranes of
the oropharynx, sinuses, vagina, and anus.3 Patients can present with regional lymph
node involvement or distant metastatic disease without any primary being identified.
This occurs in approximately 5% of patients. Melanoma occurs more commonly in
men than women and has a peak age at incidence of approximately 50 years. Owing
to the young age of many melanoma patients, this disease takes a striking toll in
terms of the average number of years of life lost per patient in the United States. The
incidence of the disease has increased in the United States to the point where
melanoma is now the sixth most common cancer in men or women. The substantial
increase in incidence is presumably due to increased exposure to sunlight (primarily
ultraviolet B radiation), with the greatest risk of melanoma felt to be in those who
have intermittent intense sun exposure, particularly in fair-skinned, light-haired
individuals with red and blonde hair, and blue or green eyes. The cultural emphasis
 on sun-tanned skin as an indicator of physical health and beauty has played a major
role in this increase. Depletion of the ozone layer may contribute as well. Sunny
parts of the United States have the highest incidence of the disease, especially
California, Florida, Arizona, and Texas, which include three of the four most
populous states in the United States. One particular melanoma subtype, lentigo
maligna melanoma, which often occurs on the face, may be more closely associated
with long-term occupational sun exposure and is seen in farmers and other outdoor
workers. Patient education in prevention, including use of sun-protective clothing,
performing outdoor activities at times other than the brightest sunlit hours of the day,
use of topical sunscreens, refraining from use of sun-tan parlors, use of skin self-
examination, and avoiding sun-tanning (“tanned skin = damaged skin”), should be
emphasized. Individuals with xeroderma pigmentosa, an autosomal-recessive
disorder, typically incur multiple basal and squamous skin cancers and melanoma
because their skin lacks the ability to repair damage induced by ultraviolet radiation.
2. Precursor lesions, genetics, and familial melanoma
Melanomas arise not only from sporadic or familial atypical nevi but also from other
congenital and acquired nevi; however, approximately half of cutaneous melanomas
arise without a clear-cut precursor lesion. Individuals who have more than 20
benign nevi are at increased risk for melanoma. Approximately 10% of patients with
melanoma have a family history of this cancer. Careful surveillance should be
carried out in patients with these risk factors. Suspicious-appearing lesions or
lesions that appear to have changed coloration, shape, height, or have bled should be
excised. The familial atypical multiple mole melanoma syndrome is characterized
by a young mean age at diagnosis (34 years) and multiple lesions. The most common
germline mutation seen in familial melanoma occurs in the tumor suppressor gene
CDKN2A. CDKN2A, PTEN, NRAS, and BRAF mutations have also been seen in
nonfamilial melanoma.4,5
3. Types and appearance of primary lesions
Clinical features, classically known as “ABCDE,” that raise suspicion for melanoma
include:
■ Asymmetry of a lesion
■ Borders that are irregular
■ Color that is multihued
■ Diameter greater than 6 mm (i.e., “larger than the diameter of a pencil eraser”)
■ Evolution indicating a changing lesion
Other characteristics of concern include history of recent growth, change in
pigmentation, ulceration, itching, or bleeding. Any pigmented lesion that returns after
excision should be reevaluated with biopsy. Nonpigmented skin lesions that behave
like melanoma should be examined with immunohistochemical stains S-100 and
HMB-45 as 1% to 2% of melanomas are amelanotic.3
There are four clinical types of primary cutaneous melanoma.3 Superficial
 spreading melanoma is the most common type, accounting for 70% of melanomas. It
is commonly found on the trunks of men and lower extremities of women. Nodular
melanoma comprises 10% to 15% of melanomas and has an early vertical growth
phase. It is commonly found on the trunks of men. Those lesions associated with
intermittent sun exposure are often (50% to 60%) BRAF mutated but C-KIT wild
type. Lentigo malignant melanoma accounts for approximately 10% of cases. It is
characterized by flat, large (1 to 5 cm) lesions located on the arms, hands, and face
of the elderly (median age 70 years) in particular and is known for a relatively
longer radial phase. Acral lentiginous melanoma is seen in approximately 3% to 5%
of cases and occurs primarily on the palmar surfaces of the hands, plantar surfaces
of the feet, and under nails on the digits. This melanoma subtype is most commonly
seen in individuals with darker-pigmented skin and is felt not to be as closely
related to sun exposure as the other subtypes. Mutations in exons 9 and 11 of the C-
KIT gene are more commonly observed in acral lentiginous and mucosal melanomas
than other subtypes, but still only occur in about 20% to 30% of these cases.4
In general, melanoma is felt to show two distinct growth phases: an initial
radial phase during which the melanoma enlarges in a horizontal/superficial pattern
above the basal lamina of the skin, followed eventually by a vertical growth phase
characterized by invasion deeply with exposure to lymphatic vessels and the
vasculature. It is during the vertical growth phase that metastases are felt to be most
likely to occur (Table 15.1).

TABLE
Clark Levels of Invasion
15.1
Level Description
I Limited to the epidermis
II Invades papillary dermis
III Extends to papillary–reticular dermal junction
IV Invades reticular dermis
V Invades subcutaneous fat

4. Patterns of metastases
Melanoma has a proclivity for direct nodal spread presumably through the
lymphatics, but a significant proportion of lesions exhibit hematogenous spread as
well. Common sites of metastases include lung, liver, bone, subcutaneous areas, and,
primarily in late stages, brain. However, melanoma can spread to virtually any site
and can imitate virtually any solid malignancy in its pattern of spread. Following
diagnosis, approximately 25% of patients will develop visceral metastases. An
 additional 15% may develop disease limited to lymph nodes. Patients who present
with lymph nodal or metastatic involvement without any obvious primary site may
have undergone spontaneous remission of the primary, a phenomenon that may be
attributable to some degree of immune system involvement. Interestingly, those
patients may have a better outcome than similarly staged patients with known
primaries. Patients with “cancer of unknown primary” should have their biopsy
material analyzed with the immunohistochemical stains S-100 and HMB-45 to
consider the possibility of melanoma.
5. Ocular melanoma
Ocular melanoma is the most common malignancy of the eye in adults. It may occur
in any eye structure that contains melanocytes, although uveal tract sites
predominate, followed by choroid, ciliary body, and iris in decreasing frequency.
Standard therapy may consist of either enucleation (often utilizing a “no touch”
technique) or brachytherapy with radioisotopes such as iodine-125. A recently
published large randomized study of those two treatments revealed that for primary
uveal tumors less than 5 mm in depth, the outcome for survival was identical. This
tumor metastasizes most frequently to the liver and appears to be less sensitive to
both biologic agents and chemotherapy than is cutaneous melanoma.
B. Staging
Melanoma is staged according to the American Joint Committee on Cancer staging
system.6 All patients should have a careful history and physical examination with
special attention to the skin including scalp, mucous membranes, and regional lymph
nodes. Pathology report should include thickness of the primary lesion, presence of
absence of ulceration, number of mitoses per millimeter squared, and presence of
lymphatic invasion.2,7,8 Laboratory studies should include complete blood count, blood
urea nitrogen, serum creatinine, liver panel, alkaline phosphatase, and serum lactate
dehydrogenase at baseline. A baseline chest radiograph is obtained to evaluate for
pulmonary lesions. A computed tomography (CT) scan can be considered if clinically
warranted. Elevation of liver function tests warrants further imaging of the liver, most
typically with CT. Unexplained bone pain should also be evaluated with CT or
magnetic resonance imaging. Primary lesions equal to or thicker than 1.0 mm are at
higher risk of regional lymph node involvement; therefore, the use of sentinel node
mapping is recommended for lesions between 0.76 and 1 mm and above. Important
recent additions to the staging criteria include the concept of nodal disease burden,
especially at the time of the sentinel node biopsy, and the presence or absence of
mitoses in the primary lesion, which is a very significant negative prognostic factor.7,8
C. Surgical treatment
The standard treatment for skin lesions suspected of being melanoma is excisional
biopsy rather than incisional or “shave” biopsies. A subsequent wide and deep excision
is required to provide adequate tumor-free margins as melanoma has a known
propensity for local recurrences. While there is some variation in recommendations,
 most experts would advocate a 1-cm tumor-free margin for melanomas less than 1 mm
in thickness and 1- to 2-cm margins for deeper primary lesions if technically possible,
following current National Comprehensive Cancer Network guidelines.9 Additionally,
for primary lesions of at least 1 mm, sentinel node mapping is recommended. Lymph
node “drainage areas” are assessed via a specific lymph node (sentinel node[s]—
sometimes more than one) into which lymph-borne metastases generally first occur.10
The absence of tumor involvement in the lymph node is associated with a reduced risk
of nodal spread and systemic relapse in general and eliminates the need for subsequent
dissection of that nodal basin.11,12 In the recent Multi-Center Sentinel Lymph Node
Trials 1, 1,347 patients with primary melanomas of 1.2 to 3.5 mm, felt to be at
intermediate risk of recurrence, were randomly allocated to receive either observation
or a sentinel node biopsy, with completion of lymphadenectomy if the sentinel node was
positive and observation only if negative.13 A delayed lymph node dissection was
performed in case of nodal recurrence in either group. Preliminary results from that trial
suggest that there was no survival advantage for the performance of a sentinel lymph
node biopsy in this risk group, although it reduced the relative risk of recurrence at any
site by 26%, reduced the absolute chance of recurrence locoregionally from 15.6% to
3.4%, and confirmed that those with a positive sentinel node had a worse outcome than
those with a negative sentinel node biopsy.
D. Adjuvant therapy
Eastern Cooperative Oncology Group (ECOG) protocol E1684 was a large randomized
adjuvant trial of interferon (IFN)-α2b in patients with deep primary lesions (>4 mm
thick) or regional lymph node involvement that showed statistically significant
improvement in overall survival in the treated group compared with the observation
group.14 The regimen used was IFN 20 million IU/m2 intravenously (IV) 5 days/week
for 4 weeks (as a “loading phase”) followed by 10 million IU/m2 subcutaneously (SC)
3 days/week for 48 weeks as a maintenance phase. Toxicity was significant, but quality-
of-life analysis demonstrated overall benefit. The follow-up study of observation
versus the same IFN regimen versus a lower-dose regimen, ECOG 1690, also showed a
significant disease-free survival advantage over the observation arm but not a benefit in
overall survival for the high-dose regimen.15 The difference between these two studies
may be that patients on the observation arm in the subsequent trial (1,690) may have
been treated with immunotherapy (including IFN or interleukin [IL]-2) at the time of
relapse. The final published randomized adjuvant study of high-dose IFN compared
with a vaccine demonstrated a benefit in terms of relapse-free and overall survival for
the IFN arm.16 A phase II study that evaluated a month of high-dose IFN versus the
standard 1 year of drug for high-risk resected melanoma patients pioneered in ECOG
1684 suggested that the 1-month regimen was inferior.17 One month of high-dose IFN
was also compared with chemotherapy for resected mucosal melanoma patients, with
no advantage for the IFN cohort.18 Several recent meta-analyses of randomized trials of
 high-dose IFN have shown that while there is a statistically significant and consistent
advantage in relapse-free survival, the benefit for overall survival is very modest, at
2% to 3%.19,20 Nonetheless, given that patients with deep cutaneous primaries and/or
lymph node involvement are at high risk for metastatic recurrence and that the majority
of patients who suffer metastatic relapse will die of their disease, it is reasonable to
treat such high-risk patients with either adjuvant high-dose IFN or to consider entrance
into a clinical trial. While predictive biomarkers for the utility of adjuvant IFN are
sought after and have not been clearly defined, the onset of vitiligo is often associated
with a favorable outcome, as are other manifestations of autoimmunity, although their
assessment is complicated by lead-time bias.21 This is because patients that appear to
benefit from treatment will stay on therapy longer, increasing the likelihood of
developing vitiligo.
Peginterferon, which prolongs the half-life of the drug, allowing it to be delivered
weekly, has been tested in several adjuvant trials in resected melanoma. In patients
whose lesions were detected at sentinel node biopsy, there was an advantage in
disease-free survival for peginterferon. In long-term follow-up of an EORTC
randomized trial of peginterferon compared with placebo in patients with stage III
resected disease, patients with ulcerated primary lesions that had nodal disease proven
only by a sentinel lymph node biopsy had clear prolongation of survival with
peginterferon.22,23 Ipilimumab, a CTLA-4-blocking human antibody, has been tested in a
randomized phase III trial compared with placebo in patients with resected stage III
melanoma. There was an increase in relapse-free survival for patients receiving up to 3
years of ipilimumab at 10 mg/kg compared with those receiving placebo, albeit at the
cost of significantly increased side effects, chiefly so-called immune related adverse
events.24 Chemotherapy as a single adjuvant modality has not been shown to be more
beneficial than observation alone, and high-dose IFN with chemotherapy confers no
difference in relapse-free or overall survival compared with the single-agent arms.25
Biochemotherapy was also compared with IFN in the adjuvant setting, though
improvement was seen in relapse-free survival, no improvement was seen in overall
survival plus there was increased toxicity in the biochemotherapy arm.26
Given the current data, IFN or observation remains the standard adjuvant option in
the United States. Ongoing studies of ipilimumab and nivolumab hope to change this
standard in the future.
E. Therapy of metastases
1. General considerations about systemic therapy
a. Patient selection
While melanoma is considered relatively resistant to chemotherapy, certain
favorable prognostic factors do lend themselves to longer survivals with single-
agent or multiagent chemotherapy, high-dose IL-2, or even newer approved
agents like ipilimumab, pembrolizumab, or nivolumab. These include ECOG
performance status 0 or 1; subcutaneous, lymph node, or pulmonary metastasis
 with normal lactate dehydrogenase (M1a or M1b disease); no prior
chemotherapy; normal marrow, renal, and hepatic function; and absence of
central nervous system (CNS) metastases. The biologic basis for these findings
has not been fully elucidated. When reviewing potential therapy for stage IV
melanoma patients, patient characteristics as well as the natural history of their
metastatic disease must be considered. Surgical resection should be considered
for one or even multiple sites of metastases that are resectable with a reasonable
surgical procedure associated with modest morbidity. Failing that, for
unresectable disease, an evaluation should be made whether the patient has
indolent disease, suggesting that immunotherapy with frontline ipilimumab, or
second-line pembrolizumab or nivolumab might be more appropriate, or more
aggressive disease, indicating that other approaches are warranted, particularly
a BRAF plus MEK combination if the patient’s tumor has a BRAF V600
mutation. While a clinical trial should generally be a first consideration for
treatment-naïve or second-line patients with metastatic disease, high-dose IL-2
could also be considered in any line of therapy for the subset of patients that
qualify for that rigorous therapy (Table 15.2).

TABLE
Approximate Survival in Melanoma Based on Stage Grouping
15.2
Stage TNM (Pathologic) Five-Year Survival (%)
IA T1a 95
T1b 90
IB
T2a 89
T2b
IIA 77
T3a
T3b
IIB 65
T4a
IIC T4b 45
N1a 53
IIIA
N2a 49
N1b 51
IIIB
N2b 46
IIIC N3 27
IV M1a 19
All others M <10

Source: Balch CM, Gershenwal JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin
Oncol. 2009;27:2199–2206.

2. Biologic agents
This class of agents has been extensively tested in melanoma, a histology where they
 have met with some success.
a. Ipilimumab is a human immunoglobulin G1 (IgG1) antibody directed against the
immune checkpoint protein cytotoxic T-lymphocyte antigen-4, expressed on
activated T cells.27 It has been extensively tested in stage IV melanoma and is an
active drug, with objective response rates of 7% to 20%.28 Many responses are
sustained over time, and ipilimumab has been shown to induce novel patterns of
response, with slow regression over 6 to 12 months, progression followed by
regression, and new lesions appearing while other baseline lesions continue to
regress. This drug has also demonstrated unique side effects that are directly
related to its immune mechanism of action, called immune-related adverse
events, consisting of rashes, colitis with diarrhea, hepatitis, pancreatitis, and
hypophysitis leading to pituitary insufficiency. In relapsed/refractory melanoma
at 3 mg/kg, ipilimumab plus a peptide vaccine had superior overall survival
compared with the peptide vaccine alone, which is the first positive controlled
randomized trial in stage IV melanoma ever conducted, and established a new
standard of care.29 A subsequent randomized trial of ipilimumab with
dacarbazine compared with dacarbazine plus placebo showed a statistically
significant improvement in median and overall survival, further establishing
ipilimumab as a front- or second-line standard of care drug in melanoma.30,31
Recent work has suggested that CTLA-4 blockade with ipilimumab induced
recognition of mutated “neo-antigens” expressed by melanomas and expanded
the repertoire of antigen-specific T-cell recognition.32
b. Pembrolizumab is an IgG4 humanized antibody directed against the checkpoint
protein programmed death-1, or PD-1, expressed on T and B cells. In phase I
and II trials, it showed a 40%+ response rate in patients with treatment-naïve
melanoma, and a 21% to 25% response rate in patients who had failed prior
ipilimumab. Grade 3 to 4 dose-limiting toxicity was 12% or less, and only 3%
to 4% of patients had to stop treatment because of side effects.33 In a recent
randomized trial of two different doses of drug at 2 mg/kg or 10 mg/kg, no
differences in response or progression-free survival were observed, and with a
response rate of 24% and excellent duration of response the dose of 2 mg/kg
given IV every 3 weeks was recently approved by the FDA for patients who
failed ipilimumab, or if BRAF mutated, both ipilimumab and a BRAF inhibitor.34
In a recent phase III randomized trial, progression-free and overall survival
were significantly prolonged in ipilimumab-refractory patients who received
pembrolizumab compared with chemotherapy. Ongoing trials will determine the
role and potential benefit of pembrolizumb in treatment-naïve patients.
Biomarker analyses of the trials above have shown that tumor PD-L1 expression
and T-cell infiltrate are associated with a favorable outcome.35
c. Nivolumab is an IgG4 human antibody directed against PD-1 that has very
recently been approved by the FDA for patients with ipilimumab-refractory
 melanoma, or those who failed both a BRAF inhibitor and ipilimumab if their
melanoma was BRAF V600 mutated. In initial trials it demonstrated activity in
heavily pretreated, therapy-refractory melanoma patients at doses ranging from
0.1 to 10 mg/kg, with excellent duration of response and long median survival of
18 months.36,37 It induced a 32% response rate with long duration of response in
that population, compared with 11% for chemotherapy, and a 9% rate of dose-
limiting grade 3 to 4 toxicities, compared with 31% for chemotherapy.38,39 It
adds another agent to the melanoma armamentarium for treatment-refractory
disease. In a randomized trial of nivolumab compared with DTIC chemotherapy
in previously untreated melanoma patients, the response rate was a robust 40%,
with significantly better PFS and OS observed for the immunotherapy.40
d. PD-L1 antibody MPDL 3280A
A humanized antibody against the ligand of programmed-death-1, called PD-L1,
has been tested in melanoma. The PD-L1-blocking antibody demonstrated a 25%
response rate with prolonged duration of responses.41 Response to this antibody
in melanoma, and other histologies like bladder cancer was associated with PD-
L1 expression by tumor tissue.42
e. Ipilimumab plus nivolumab in a concurrent combination regimen has been tested
in melanoma with an impressive 43% response rate, 85% of patients with
ongoing responses, and a 2-year overall survival of 79%, an outstanding result.43
In contrast, the rate of grade 3 to 4 toxicities was quite high at 62%, with
biochemical hepatitis and pancreatitis as common manifestations of this regimen.
The concurrent combination is being tested as a frontline regimen compared with
either single agent alone.
f. IL-2 is a currently approved single agent for patients with metastatic melanoma,
and appears to be active as any line of treatment in those with visceral
metastases. It is most commonly used in a high-dose regimen of IL-2 at 600,000
IU/kg given in 15-minute infusions IV every 8 hours for a maximum of 14 doses
on a day 1 and day 15 schedule every 6 to 8 weeks. This schedule produces
responses in 15% to 20% of patients, with 5% to 6% complete response, many
of long duration.44 A review of National Cancer Institute data with high-dose IL-
2 showed a response rate of 50% in patients with disease limited to
cutaneous/subcutaneous sites only (i.e., M1a disease). Because this drug is
associated with a capillary leak syndrome that can include hypotension, fluid
retention, renal and hepatic hypoperfusion, and pulmonary edema, the previously
discussed dose and schedule require inpatient care in a monitored setting with
nursing staff and physicians who are experienced and skilled in its use. Given
these effects, patients must be in relatively good health, and a cardiac stress test
should be performed prior to treatment in anyone above 50 years of age or any
patient with multiple cardiac risk factors. It should be noted that the older
literature may express IL-2 dosing in other than international units. Therefore,
 when comparing various studies, a rule of thumb for conversions is 1 mg = 3 ×
106 Cetus Units = 6 × 106 Roche Units = 18 × 106 IU. Given the toxicity and
complexity of high-dose IL-2, and availability of less toxic simpler drugs like
checkpoint protein inhibitors, high-dose IL-2 is now a second- or even third-
choice regimen in those who are eligible to receive it.
g. IFN (α2b and α2a) has been examined as a treatment for metastatic disease with a
wide range of doses, schedules, and routes from 3 to 50 × 106 IU/m2 given SC,
intramuscularly, or IV, administered three to five times per week. These agents
have been found to have response rates of approximately 10% to 15% in a
variety of studies.45 Additionally, some patients may have stable disease lasting
many months or longer. In regard to dosing, some investigators believe that
higher doses of IFN (20 MIU/m2 IV, such as those given in adjuvant therapy) act
more by inhibiting tumor cell proliferation, while lower doses of IFN (≤5
MIU/m2 SC) may be more immunostimulatory. IFN is in general not commonly
used in the metastatic setting, though a select population of patients with limited
disease may benefit from this treatment.
h. Tyrosine kinase/signal transduction inhibitors
1) BRAF inhibitors
These “small-molecule” inhibitors, including pan-tyrosine kinase inhibitors
sorafenib and sunitinib which likely inhibit tumor-related angiogenesis, have
been investigated and have little activity as single agents or when added to
chemotherapy in stage IV melanoma. Clinical trials have been conducted with
carboplatin and paclitaxel with sorafenib on the basis of promising phase II
single-center data. Unfortunately, the PRISM trial sponsored by Bayer did not
show a median or overall survival difference between carboplatin and
paclitaxel with or without sorafenib administered to patients as second-line
therapy.46
The recent discovery that up to 50% of melanomas have a common
activating mutation in the BRAF gene, at the V600E position, has provoked
the testing of a number of small-molecule RAF inhibitors in stage IV
melanoma.47,48
Vemurafenib was the first inhibitor of mutated V600 BRAF to be tested
in large trials, and was approved by the FDA in 2011 for the treatment of
untreated or previously treated metastatic melanoma.49 Response rates were
50% in either group of patients with a V600E mutation, with median
survivals of 16 months in a second-line phase II trial,50 and 13.6 months in a
frontline trial compared with DTIC chemotherapy.51,52 Median progression-
free survivals were in the range of 5.5 to 6.5 months. A 25% rate of new
keratoacanthomas and squamous skin cancers was noted, as well as profound
photosensitivity. Dabrafenib is another BRAF inhibitor that was tested in
 patients with tumors bearing the BRAF V600E or V600K mutation.53
Response rates in treatment-naïve metastatic melanoma were close to 50%,
with median overall survival of 16 months compared with 10 months for
chemotherapy with DTIC. Fewer than 10% of patients had new squamous
skin cancers, and fevers were common side effects, albeit with a lower
incidence of photosensitivity. This drug was approved by the FDA in 2013. It
has been subsequently shown to have significant antitumor activity in the
CNS, quite unique for most antimelanoma agents.54
2) MEK inhibitors
The MEK inhibitor trametinib was evaluated in previously untreated patients
with metastatic disease with BRAF V600E or K mutations in a large
randomized study compared with dacarbazine alone.55 The MEK inhibitor
significantly prolonged both progression-free, as well as median and overall
survival in that population, and was approved by the FDA in 2013 as first- or
later-line therapy. Currently, few patients receive MEK inhibition alone
because of the excellent results of phase II and randomized phase III trials of
combination of BRAF + MEK inhibitors noted below.
3) BRAF + MEK combinations
Early testing of the combination of BRAF + MEK inhibitors in patients
demonstrated high response rates and a decrease in the paradoxical
activation of the MAP kinase pathway in skin that led to the high proportion
of early squamous cancers and other skin toxicities in patients receiving
BRAF inhibitors alone. Response rates as high as 76% and median survival
of 25 months were seen in a randomized phase II trial of the BRAF inhibitor
dabrafenib and the MEK inhibitor trametinib, which led to its approval early
in 2014 for the treatment of metastatic melanoma with the BRAF V600E or
V600K mutation.56 Subsequent phase III randomized trials of the combination
compared with BRAF inhibition alone with either vemurafenib or dabrafenib
demonstrated higher response rates and significantly prolonged median
progression-free and overall survival, establishing combined BRAF + MEK
inhibition as the frontline standard of care for patients with melanomas
bearing the BRAF V600 mutation.57,58 While the combination results in fewer
skin toxicities, and notable fewer squamous cancers and papillomas, the rate
of fevers and lethargy increased. The combination of BRAF inhibitor
vemurafenib, and cobemetinib, a MEK inhibitor has also shown high
response rates above 70% and superiority in progression-free survival to
vemurafenib alone.59
Approximately 20% of patients with mucosal melanoma have been
shown to harbor an activating C-KIT mutation in exons 9, 11, or both. This
also can lead to amplification of C-KIT. In a small pilot trial, and in a
number of anecdotal publications, blockade of C-KIT with the oral inhibitor
 imatinib induced rapid and dramatic regression in patients with C-KIT-
mutated mucosal melanoma; however, the duration of these responses is yet
to be known.60
3. Chemotherapy
a. Single-agent chemotherapy
Most cytotoxic agents commonly used in other tumor types are inactive in this
disease. Several agents possess modest activity in melanoma with responses
obtained primarily in lung and nonvisceral sites and typically in ambulatory
patients with few or no symptoms of their disease. These agents have become
third- or fourth-line drugs because of the recent approvals of targeted immune
drugs for melanoma.
1) Dacarbazine has historically been the most widely utilized single agent for
the treatment of metastatic melanoma. The most commonly used doses are
200 mg/m2 IV on days 1 to 5 every 3 weeks or 750 to 800 mg/m2 IV on day 1
every 4 to 6 weeks. Most responses to this agent occur in subcutaneous or
lymph node sites. Response rates are between 10% and 20% and the median
time to progression is 2 to 3 months.61
2) Platinum-containing drugs. Cisplatin 100 mg/m2 IV every 3 weeks or
carboplatin 400 mg/m2 IV every 3 weeks appears to have similar efficacy.
3) Taxanes. Docetaxel 60 to 100 mg/m2 is given in 1-hour infusions IV every 3
weeks, or paclitaxel 135 to 215 mg/m2 is given in 3-hour infusions IV every
3 weeks.
4) Temozolomide is an oral imidazole agent that is biochemically converted to
the active (dacarbazine) intermediate monomethyl triazeno imidazole
carboxamide in an acid environment with significant CNS penetrance and
therefore the potential for clinical responses in the difficult subpopulation of
patients with CNS metastases. Typical doses are 150 to 200 mg/m2 by mouth
daily for 5 days every 28 days, or continuous administration for 6 of 8 weeks
at 75 mg/m2, both with equivalent efficacy.
5) Vinca alkaloids such as vinblastine and nitrosoureas such as carmustine have
been used primarily in combinations and have modest single-agent activity in
melanoma.
b. Multiagent chemotherapy
Despite decades of trials, no combination chemotherapy has emerged as a
standard therapy. While multiple regimens have shown high response rates in
single-arm phase II or nonrandomized trials, there are no convincing data from
randomized trials to show both statistically significant improvements in response
rate and median survival compared with single-agent therapy (usually
dacarbazine).62,63 While a phase II study of the “Dartmouth Regimen” suggested
a higher response rate than dacarbazine alone, a phase III trial demonstrated no
 significant difference in progression-free or overall survival compared with
dacarbazine alone. Cisplatin, vinblastine, and dacarbazine/temozolomide are
currently an acceptable off-protocol combination regimen (Table 15.3).
Carboplatin combined with paclitaxel every 3 weeks is emerging as the most
common combination treatment used off protocol on the basis of the results of the
PRISM trial control arm discussed above (see Section II.E.2.h.1).
c. Biochemotherapy
Three randomized studies have compared the combination of polychemotherapy
(cisplatin, vinblastine, and dacarbazine) with the biologic agents IL-2 and IFN
versus the chemotherapy regimen alone. The first published randomized
comparison showed improved response rate and median time to progression (4.9
vs. 2.4 months) in favor of the combined chemotherapy with biotherapy.64
Unfortunately, confirmatory studies have shown no difference in median time to
disease progression or median survival. A recently published phase II study of
biochemotherapy delivered with IL-2 in a decrescendo regimen, followed in
stable or responding patients by maintenance IL-2, resulted in a favorable
median survival of over 12 months.65 While patient selection may have played a
role in this favorable outcome, the high response rates seen with that regimen
suggest that it is a reasonable alternative for untreated patients with rapidly
growing disease that are BRAF V600 wild type, or as a neoadjuvant regimen
prior to a planned resection of bulky stage III locoregional disease in that same
population.66 The recent results of the randomized phase III trial of
biochemotherapy compared with chemotherapy alone in high-risk stages 3 and 4
disease did show an improved relapse-free survival for the biochemotherapy,
but because of the complexity and the toxicity associated with caring for those
patients, that regimen is used little in the community.26
 TABLE
Multiagent Systemic Therapy for Melanoma
15.3
Regimen Drug Dosages
■ Carmustine 150 mg/m2/day on day 1 every 6 weeks
■ Cisplatin 25 mg/m2/day on days 1–3 every 3 weeks
BCDT (“dartmouth regimen”)
■ Dacarbazine 220 mg/m2/day on days 1–3 every 3 weeks
■ Tamoxifen 20 mg by mouth daily
■ Cisplatin 20 mg/m2/day on days 1–4 every 3 weeks
CVD ■ Vinblastine 1.6 mg/m2/day on days 1–4 every 3 weeks
■ Dacarbazine 800 mg/m2 on day 1 only every 3 weeks
■ CVD as above, together with:
■ IL-2 9 MIU/m2/once a day by continuous infusion IV on
days 1–4 (96 hours)*
Biochemotherapy *
■ IFN-α2b 5 MU/m2 SC on days 1–5, 7, 9, 11, and 13
■ G-CSF 5 μg/kg SC once a day on days 7–16
■ Repeat cycle every 21 days for maximum of four cycles
■ Cyclophosphamide 350 mg/m2 IVPB on day 1
Cyclophosphamide and moderate-dose IL-2
■ IL-2 22 MIU/m2 IVPB on days 4–8 and 11–15
■ Repeat cycle every 21 days for three cycles. Thereafter
give every 28–42 days

G-CSF, granulocyte colony-stimulating factor; IVPB, intravenously (piggy-back).

*On day 1, begin IL-2 2 to 3 hours after chemotherapy.

d. Regional therapy
1) Local perfusion
For patients with subcutaneous metastases limited to a single extremity,
arteriovenous cannulation and perfusion of that limb with agents such as
melphalan, cisplatin, or tumor necrosis factor-α, often with hyperthermia,
yield higher tissue concentrations of the drugs than are achievable by
intravenous administration. Phase II studies often show impressive response
rates of 80% or more.67 Whether there is any survival advantage to this
therapy compared with systemic treatment remains controversial. Because of
issues such as cost, the equipment required, and the physician training needed
to implement this approach, its practicality is limited. Hepatic arterial
infusion and percutaneous hepatic perfusion (PHP) therapy is theoretically
appealing for ocular melanoma metastatic only to the liver; ongoing studies
are being conducted currently to further evaluate this treatment modality, and
the few randomized studies done suggest an advantage for the PHP
approach.68 This therapy looks more active than systemic chemotherapy in
 ocular melanoma, although it is unclear that such an approach improves
median survival.
2) Intralesional therapy with Bacillus Calmette-Guérin , IFN-α, granulocyte-
macrophage colony-stimulating factor, IL-2, and other agents has also been
used with varying degrees of success in treatment of very small dermal
metastases.69–71 More recently, an engineered oncolytic herpesvirus
expressing GM-CSF called talimogene lapaherivac or T-VEC has been tested
as a direct injection modality in patients with unresectable stages III and
IVA/B melanoma. The rate of regression of visceral metastases after injection
of accessible dermal or subcutaneous lesions was 16%, leading to a
significant rate of response sustained for 6 months compared with GM-CSF
injection alone. This treatment is under consideration by the FDA for
registration.72
3) Treatment of CNS metastases
Dexamethasone 10 mg IV followed by 6 mg every 6 hours IV or by mouth is
given to reduce cerebral edema. As soon as possible, radiation should be
started by either stereotactic, gamma knife, or three-dimensional conformal
techniques. For solitary lesions, surgical resection followed by radiotherapy
may yield a significant group of survivors over 1 year who experience good
quality of life. The role of temozolomide needs to be further explored in this
group of patients.73 Both the immunotherapy ipilimumab and BRAF + MEK
inhibitors have been shown to have activity in inducing regression of brain
metastases.54
4) Radiotherapy is of variable efficacy in the treatment of symptomatic regional
or bony metastases but sometimes may yield symptomatic benefit. We
routinely add daily temozolomide at 75 mg/m2 to whole brain radiation to
augment its antitumor activity when administered to patients with multiple
CNS metastases.73
5) Surgery
When utilized judiciously, surgery can result in long-term disease-free
survivals of up to 20% in individuals with isolated metastatic sites. The
median survival for those patients is 30 to 36 months. Indications for surgical
resection of metastases include gastrointestinal metastases that are
chronically bleeding or if there is impending bowel obstruction or
perforation and single brain metastases, especially if bleeding prior to the
start of biologic therapy (as long-term steroid use, which is frequently needed
in the setting of brain metastasis, is antagonistic with biologic agents). The
role of adjuvant therapy in patients who have undergone and are clinically
free of disease is being evaluated in several trials, and such metastasectomy
patients should always be considered for vaccine or other adjuvant trials
when available. An alternative approach is to treat such patients with IFN as
 described previously.
e. Experimental and future therapies
Experimental and future therapies are of great importance in this disease. Only a
few salient approaches will be discussed here. A variety of references are
available for further reading (see section References).
1) Therapeutic vaccine remains an area of intense interest, and much potential
is expected in the coming years, although current clinical results have shown
limited activity. In general, toxicity from vaccine therapy tends to be quite
low, usually limited to local reactions to the vaccine or the immunologic
adjuvant that may be combined with the antigenic stimulus. Most vaccine
studies have dealt primarily with patients who have been rendered surgically
free of all macroscopic disease but thus far have been without significant
benefit. Vaccination with peptides derived from tumor-associated antigens
specifically designed to associate with T-cells in the context of major
histocompatibility complex class I or II molecules and vaccines based on
vaccinia-infected melanoma cell lysates are examples of other approaches of
note. Potential advantages to vaccine-based therapy include relatively little
toxicity, the possibility of long-term disease stabilization, and an
immunologic effect that may continue long after dose administration.74,75
2) Cellular therapy
The administration of ex vivo activated cells such as cytotoxic T-cells
theoretically specific for melanoma continues to be of interest. Currently,
there is no randomized evidence that the addition of cultured T-cells to IL-2
therapy, for instance, is superior to IL-2 alone. A significant advance is the
development of tumor-infiltrating lymphocyte (TIL) therapy.76 These effector
T-cells are grown from enzyme-digested tumors and are expanded in tissue
culture over 3 to 6 weeks, often resulting in an oligoclonal population of
highly tumor-specific T-cells. On adoptive transfer with high-dose IL-2,
response rates of up to 50% were seen. Newer approaches including the use
of lymphoid depletion prior to adoptive transfer of TIL, which allows the
effectors to proliferate during the process of homeostatic lymphoid
proliferation, have produced a significant rate of long-term complete and
excellent partial responses, with some patients alive 10 years later without
progression.77–80 During that time, many memory effector cells will populate
the T-cell pool, resulting in long-lasting tumor-specific T-cells in the
peripheral circulation. The addition of total body irradiation to TIL therapy
with high-dose IL-2 results in even higher response rates of up to 72%, with
favorable median survivals of greater than 12 months in recurrent melanoma
patients who have failed IL-2 and chemotherapy. A randomized phase III trial
of TILs is now open in Europe, and at least 10 centers worldwide are now
involved in this treatment.
III. NONMELANOMA SKIN CANCER
A. Etiology and epidemiology
The American Cancer Society estimates that there were nearly 3.5 million new cases of
BCC and SCC diagnosed globally each year.1 These lesions occur twice as frequently
in men than in women. BCC occurs four times more commonly than SCC (70% to 80%
vs. 10% to 30%). Both are seen predominantly in the elderly. Risk factors for these two
lesions include age greater than 60 years, prior heavy sun exposure, fair complexion,
and light-colored eyes or hair. Sun exposure, especially sunburns early in life, is the
most important risk factor for development of these lesions, similar to melanoma. Other
etiologic factors include prior irradiation to the skin for benign disorders, chronic
inflammation, scarring or burns, and arsenic exposure. Patients who are chronically
immunosuppressed such as those with chronic lymphocytic leukemia and prior organ
transplant are also at increased risk, as are individuals with genetic disorders including
xeroderma pigmentosum. There is evidence that human immunodeficiency virus
infection may predispose to a clinically more aggressive SCC or BCC. Multiple BCCs
or SCCs frequently occur in 30% to 50% of individuals. Patients with basal cell nevus
syndrome (BCNS) have a hereditary disease with a germline mutation in the PTCH
gene, which predisposes them to increased number of more aggressive BCCs at an early
age on onset.
B. Diagnosis and clinical features
1. Diagnosis of both SCC and BCC is made by biopsy including incisional,
excisional, or sometimes “shave,” depending on the clinical situation. Staging
systems are not typically utilized for these tumors as both have generally low
potential for metastases. BCC originates in the basal layer of the epidermis and often
presents as a nodular, ulcerative lesion (“rodent ulcer”) with pearly or translucent
edges and central ulceration. Approximately 30% of BCCs are found on the nose.
Only about 0.1% of BCCs metastasize. Metastases typically occur when a long-
standing lesion has been neglected. Lymph node metastases are the most common
site (60%), with lung and bone metastases occurring less frequently. Despite being
uncommon, once metastases occur, survival is significantly decreased to 8 to 10
months. SCCs often arise from crusty-appearing sun-damaged skin areas and
demonstrate a higher rate of metastases (2%) than BCCs. Patients whose SCC arises
from causes other than actinic damage (e.g., immunosuppression) may display a
more rapid course with higher rates of metastases (20% to 50%). Neglected lesions,
large ulcerated lesions, and poorly differentiated histology are risk factors for
metastases. The great majority of metastases initially occur in lymph nodes (90%),
with approximately 50% of patients developing metastases to other sites such as
lung and bone. SCCs may begin as premalignant lesions called actinic keratoses
(AKs) that are rough, pink or flesh-colored areas on sun-exposed skin. In situ SCC,
known as Bowen disease, exists prior to dermal invasion and appears as red-
colored patches and is larger than AKs.81–83
 2. Local treatment
Surgical excision, electrodesiccation, curettage, Mohs micrographic surgery,
radiation therapy, and cryotherapy all result in similar cure rates of approximately
95% when lesions are identified early. Treatment options are typically based on
individual factors including the area involved, available treatment facilities, and
physician skill. Surgical excision to attain margins of at least 3 to 10 mm is the
preferred treatment in SCC because of the higher metastatic potential. BCC, which
has a lower metastatic potential, can be treated with any of the above techniques as
well as cryotherapy. Radiation therapy is the treatment of choice for areas where
extensive surgical resection would result in poor cosmetic outcome, such as near
eyelids, ear lobes, or the tip of the nose.
Mohs micrographic surgery is an involved procedure in which thin layers are
meticulously removed, chemically fixed, and immediately reviewed microscopically
to be assured of clear margins. Although this therapy is highly operator dependent,
Mohs surgery currently has the highest 5-year cure rate and has become the standard
of care for local primary or recurrent BCC and SCC lesions.
Topical treatment delivery of fluorouracil is used for AK and SCC in situ and
is applied directly to the involved skin. It is generally not systemically absorbed;
therefore, almost no systemic toxicity is seen. Local side effects include red
discoloration of the skin and photosensitivity. Imiquimod is approved by the US
Food and Drug Administration for local therapy of AKs and some small BCCs. Both
agents are applied locally daily for up to 3 weeks.
3. Treatment of metastatic disease
Metastases from either BCC or SCC may be treated with cisplatin-containing
chemotherapy regimens. Despite response rates as high as 70% with chemotherapy,
once metastases have occurred, cure is no longer possible and survival is typically
less than 1 year. Hedgehog signal transduction inhibitors are front line in the
treatment of metastatic or locally advanced BCC over chemotherapy.84–86
Upregulation in the hedge hog signaling pathway is nearly universal in all BCCs,
both sporadic and hereditary. Patched (PTCH) mutations are present in BCNS and in
90% of sporadic BCCs, with the other 10% sporadic cases having a Smoothened
(SMO) mutation. PTCH is a transmembrane protein that normally inhibits SMO.
When this inhibition is lifted, SMO can signal through the cell via GLI, which can
then enter the nucleus and affect cellular DNA that promotes cellular proliferation.
Vismodegib is an approved inhibitor of this pathway via SMO inhibition and has
been shown to improve outcomes in both BCNS and sporadic cases of advanced
BCC that are not amenable to surgery or radiation. In the BCNS population, rates of
new surgery-eligible BCCs were lower with visomodegib than with placebo (2 vs.
29 cases per group per year). A phase II trial with vismodegib evaluated 104
patients with locally advanced BCC and metastatic BCC and found a 43% and 30%
response rate objectively by independent review. Investigator-assessed response
 rate was 60.3% and 48.5% for locally advanced and metastatic BCC. Major toxicity
was alopecia, dysguesia, weight loss, and muscle spasms. Other hegdgehog
inhibitors are in development, including sonidegib, which is also an SMO inhibitor.
C. Merkel cell carcinoma
1. Etiology and epidemiology
Merkel cell cancer is a rare cutaneous neuroendocrine tumor that arises in the basal
layer of the epidermis. Approximately 500 cases are diagnosed yearly in the United
States. Its microscopic appearance is that of small blue cells with scant cytoplasm
and hyperchromatic nuclei (“small cell cancer of the skin”). Merkel cell cancer is
20 times more likely to occur in Caucasians than non-Caucasians, occurs more
frequently in males than females, and affects persons at a median age of 65 to 70
years. Sun exposure is felt to be the major risk factor. Recent studies have identified
a polyomavirus in Merkel cell tumors.87–89
2. Clinical features
Initially, it may be seen as a blue or bluish red, nontender, firm skin lesion, starting
as a nodule but increasing in size rapidly over weeks to months. The most commonly
involved sites are the face and neck (50%) and the extremities (40%). There is no
universally accepted staging system for this uncommon tumor; however, stage I is
considered localized disease, stage II is involvement of regional lymph nodes, and
stage III represents systemic metastases. In general, Merkel cell cancer has a
tendency toward an aggressive, recurrent course similar in some ways to small-cell
lung cancer or melanoma. Most patients experience recurrence within 12 months of
initial treatment. Fifty percent of patients experience local and regional nodal
recurrences and one-third later develop metastatic disease. The most frequent distant
metastatic sites are liver, lung, and bones. The overall 5-year survival rate for all
stages is 50%.
3. Treatment
The rarity of this tumor precludes any prospective randomized treatment data.
Standard therapy for this disease includes surgical resection with 2-cm margins
when possible, followed by lymph node dissection. Sentinel lymph node surgery has
become the preferred technique as a negative lymph node precludes more extensive
surgery.
Because of the risk of local recurrence, radiation therapy to the primary site
and to the site of pathologically involved lymph nodes should be considered,
especially in stage I disease. There has been no established role for adjuvant
chemotherapy. High-risk patients may be offered chemotherapy; however, there is no
data that it offers a survival advantage. For metastatic disease, the two most common
regimens used have been cyclophosphamide, doxorubicin, and vincristine or
cisplatin and etoposide at doses utilized for small-cell lung cancer. Response rates
for these regimens are about 60%.
D. Mycosis fungoides
 1. Etiology and epidemiology
MF is a cutaneous T-cell–derived lymphoma with a CD4 T-helper cell
immunophenotype. It is an uncommon lymphoma, with just over 500 new cases
diagnosed in the United States per year. It is seen predominantly in males with a
median age of approximately 60 years. The lymphocytic infiltrate seen in this
disease is present in the upper aspect of the dermis, obscures the junction between
the dermis and epidermis, and characteristically infiltrates the epidermis in clusters
of cells that are called Pautrier microabscesses. Involved lymph nodes have similar
histologic findings. Biopsies early in the course of the disease (the “premycotic
phase”) may show nonspecific, nondiagnostic skin changes.90–92
2. Clinical features
Patients with this disorder tend to display a skin rash that is erythematous, somewhat
scaling, and pruritic. Over time, patches, plaques, and even ulcers can be seen.
Patients may exhibit erythroderma and lymphadenopathy. Sézary syndrome is a
leukemic phase of MF with circulating lymphoma cells noted on peripheral smear.
The course of MF can be variable, with a minority of patients having “skin-only”
involvement to patients having extensive visceral metastases to the liver, lungs,
spleen, and gastrointestinal tract. Staging is according to the TMN (B) system6 and
is based on the amount of skin involved and the presence of patches, plaques, or
tumors. Patients with stage IA to IIA MF have an excellent prognosis with median
survival greater than 11 years. Individuals with stages IIB to III disease have median
survival of 3 to 4 years. Among patients with T4 lesions, a subgroup characterized
by younger age (less than 65 years), less advanced stage (III), and no evidence of
blood involvement has been shown to have a favorable prognosis with a median
survival of approximately 10 years. Stage IVA/IVB has a poor prognosis with a
median survival of less than 1.5 years. A subgroup of MF cases may undergo
transformation to a large-cell lymphoma characterized by CD30 positivity, which
also heralds a poor prognosis.
3. Treatment
For individuals whose disease is confined only to the skin, electron beam radiation,
the combination of a photosensitizing substance such as psoralen and ultraviolet
radiation (PUVA), extracorporeal photopheresis, bexarotene gel, or topical
application of nitrogen mustard or carmustine can lead to complete response of
disease and potential for cure.93–95 Thick plaque disease may be better treated with
electron beam therapy because PUVA and topical nitrogen mustard may be less able
to penetrate the deep lesions. Imiquimod is being evaluated for this use as well.
Patients who fail one of the local/topical therapies can be treated with a different
type of local therapy and still have good control of the disease. For visceral disease
or Sézary syndrome, systemic therapy such as IFN-α 3 million units SC three times a
week given continuously or gradually escalated to a cumulative weekly dose of 18
million units can yield response rates of over 60%. Combined regimens of IFN-α
 and retinoids such as bexarotene (150 mg/day) are being evaluated for enhanced
immune modulation. “Traditional” anti-lymphoma chemotherapy agents such as
cyclophosphamide, doxorubicin, vincristine, and prednisone appear less active in
this type of lymphoma than in other non-Hodgkin lymphomas and are typically
reserved for those cases of MF that transform to large B-cell lymphomas or when
disease becomes refractory to other systemic or local agents. Purine analogs such as
fludarabine and pentostatin have some activity with response rates of 20% to 70%.
Novel uses of gemcitabine (1,200 mg/m2 weekly × 3 every 28 days) and liposomal
doxorubicin (20 to 40 mg/m2 every 2 to 4 weeks) used as single agents are being
studied with reports of overall response rates of approximately 80% in refractory
patients. Another agent, denileukin diftitox, has been approved for refractory disease
with response rates of 30% to 70%.

Acknowledgments
The authors are indebted to Drs. Karen S. Milligan and Walter D. Y. Quan Jr, who contributed
to previous editions of this chapter. Several sections in this revision of the handbook represent
their work.

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I. PRIMARY BRAIN TUMORS
A. Epidemiology, risk factors, and survival
Primary brain tumors (PBT) constitute a wide spectrum of neoplasms that have cellular
origin in the central nervous system (CNS). In the United States, a nationwide collection
of nonmalignant brain tumors began in 2004 following the passage of the “Benign Brain
Tumor Cancer Registries Amendment Act.” These data, along with statistics on
malignant PBT collected by various state and nationwide cancer registries, is tracked
by the Central Brain Tumor Registry of the United States (CBTRUS). The most recent
report covered a 4-year trend (2004 to 2007) in nonmalignant PBT and a 27-year trend
(1980 to 2007) in malignant PBT across the nation. On the basis of age-adjusted
incidence rates between 2007 and 2011, it is estimated that 68,470 new cases of
primary malignant and nonmalignant brain and CNS tumors will be diagnosed in the
United States in 2015. Of these, about 23,180 will be primary malignant and 45,300
nonmalignant.1
Nonmalignant tumors were about twice as common as malignant tumors among
adults (aged ≥20 years). Women had an overall brain tumor incidence rate of 23.26 per
100,000 persons; men had a corresponding rate of 19.42. Incidence rates among
children aged 0 to 19 years were much lower than among adults (5.42 vs. 21.42 per
100,000 adults), but the tumors were much more likely to be malignant in children:
65.2% versus 33.7% malignant in adults. It is estimated that 13,770 deaths will be
attributable to PBT and CNS tumors in the year 2015.1
No underlying etiologies have been clearly identified for primary glial tumors
except exposure to ionizing radiation, although findings of studies on electromagnetic
fields, head trauma or other environmental factors such as pesticides are still being
debated.
Optimal strategic recommendations are being made in the context of a
multidisciplinary clinic and tumor board that includes neurosurgeons, radiation and
medical oncologists, neuropathologists, neuroradiologists, and supportive care staff and
physicians.
B. Malignant gliomas
Malignant gliomas represent a heterogeneous category of invasive tumors with a wide
range of clinical outcomes. These tumors are classified on the basis of standard
 morphologic evaluation by light microscopy techniques, but the latest technology using
Next Generation Sequencing is being evaluated for better prognostication and
therapeutic stratification.2,3
The World Health Organization (WHO) grading scheme classifies PBT into benign
(WHO grade I), low-grade (WHO grade II), anaplastic (WHO grade III), and malignant
(WHO grade IV) gliomas. Malignant gliomas (WHO grade IV, glioblastoma multiforme,
GBM) can arise either de novo or as a result of progression from low-grade gliomas
(LGG, i.e., secondary GBM). This classification is based on the presence or absence of
nuclear atypia, mitoses, endothelial proliferation, and necrosis. In addition to the grade,
astrocytic, oligodendroglial or mixed (oligoastrocytic) tumors are reported by the
neuropathologist. A large range of genetic alterations have been extensively reported in
gliomas and include (but are not limited to) EGFR amplification, deletion or mutations,
PTEN mutations, Olig2 expression, IDH 1/2 mutations, LOH 10q and/or 19q, PI3kinase
alterations, RB mutations, and VEGFR overexpression. A new molecular classification
has recently been proposed for GBM, and it identifies 4 molecular subtypes (proneural,
neural, classic, and mesenchymal) whose clinical relevance is determined by six
molecular markers (TP53, IDH1, PDFGRA, EGFR, NF1, and CDKN2A).4
1. Grade I glioma
Pilocytic astrocytomas are WHO grade I tumors that most commonly arise in the
posterior fossa. These tumors are most common in the pediatric population and have
a very low rate of recurrence when a gross total resection (GTR) is achieved.5 Even
in the setting of subtotal resection (STR), itis often recommended that re-resection
be considered, if possible, versus observation. Often radiation is deferred if the
patient is young, but can be considered in select situations such as unresectable
disease (i.e., thalamic, hypothalamic).
2. Grade II glioma
WHO grade II gliomas, or LGG, are most commonly observed in the third and fourth
decades of life. This tumor typically appears as a nonenhancing, diffuse, hypointense
mass on T1-weighted magnetic resonance imaging (MRI) and a diffuse, hyperintense
mass on T2-weighted FLAIR sequence. A biopsy is necessary in these cases to
identify the histologic subtype and rule out foci of high-grade malignancy because up
to 30% of nonenhancing tumors are shown to be anaplastic (WHO grade III) at the
time of surgery. The clinical course of these tumors is tied to the histologic subtype
of tumor cells and associated genetic abnormalities. The 5-year overall survival
(OS) ranges from 58% to 72%, and the progression-free survival (5-PFS) at 37% to
55%, with oligodendrogliomas having the best 5-OS, at 70%, followed by mixed
gliomas, at 56%, and astrocytomas, at 37%. Conducting two prospective radiation-
based clinical trials, EORTC 22844 (construction set) and EORTC 22845
(validation set), Pignatti et al.6 demonstrated that unfavorable, “high-risk”
prognostic factors included age exceeding 40 years, predominant astrocytoma
histology, largest tumor size exceeding 6 cm, tumors crossing midline, and the
 presence of a preexisting neurologic deficit. Several other studies have similarly
characterized relevant prognostic factors for LGGs.
The first course of treatment is to offer a maximal safe surgical resection of
tumor. Overall, surgery provides a change in mean OS of 5.1 years with STR to 7.5
years with GTR. Despite inconsistencies in defining the extent of resection
(volumetric vs. nonvolumetric methods), it is becoming clear that delaying surgery
places the patient at an increased risk of malignant degeneration (decreasing
malignant progression-free survival, MPFS), neurologic deficits becoming
permanent, emergence of a more resistant seizure disorder, and the eventual need for
surgical resection in an older patient. In a recent meta-analysis of the role of extent
of resection (EOR) in LGG involving 11 large studies with at least 75 patients per
study, multivariate analysis showed >98% 5-year OS in patients with 100% EOR
based on volumetric analysis. Seven out of 8 studies with nonvolumetric assessment
of EOR also confirmed a similar advantage of GTR on 5-OS. The 10-year OS in this
series was 76% after GTR and 49% after STR, while MPFS was 12.5 and 7 years,
respectively. Another series of 216 patients with a mean follow-up of 4.4 years
showed that predicted OS was negatively influenced by a minimal residual tumor
volume (as small as 10 cm3). The obvious caveat is that OS is not a valid tool in
assessing outcomes in LGG because survival is often long. Therefore, achieving
maximal survival with good quality of life (QoL) depends on the balance between
decreasing oncologic burden (EOR) and respecting functional surgical boundaries.
Data from three prospective randomized clinical trials in adults with LGG
provide guidelines for the timing of radiation as well as the appropriate
postoperative dose to use. The EORTC 22845 study demonstrated that the use of
immediate versus delayed postoperative radiotherapy in patients improved median
PFS (5.3 vs. 3.4 years), but did not affect median OS (7.4 vs. 7.2 years).
Furthermore, there was no difference in the rate of malignant transformation between
groups. However, this study observed that the use of immediate radiotherapy
improved 1-year seizure control rates. Therefore, radiotherapy should be used for
symptomatic patients as it can improve patient overall QoL.7,8 EORTC 22844 and
INT/NCCTG both examined the use of high- versus lower-dose radiation regimens,
and found that radiation doses of 45 to 54 Gy resulted in similar outcomes compared
with higher doses (59 to 65 Gy) and were associated with improved tolerance
without a decrement in OS when using the lower dose.9,10 Acceptable postoperative
radiation doses for LGG range between 50.4 and 54 Gy, although a retrospective
analysis by Shaw et al.11 suggested that postoperative radiation doses >53 compared
with those <53 Gy were associated with a superior 5- and 10-year OS (67% and
40% vs. 50% and 20%, respectively).
On the basis of these data, postoperative radiation therapy is often
recommended for patients after a STR or biopsy, particularly if there are additional
“high-risk” features. There is, however, no definitive effect of radiotherapy on OS.
 Chemotherapy (temodar or PCV) is similarly reserved for patients with poor
prognostic factors. A recent report of RTOG 0424, a phase II trial examining the use
of postoperative radiation (54 Gy) combined with concurrent and adjuvant
temozolamide in patients with ≥3 high-risk features showed a 3-year OS of 73.1%.12
The study was not randomized, but when compared with historical control OS, there
was a significant improvement in OS, and so further study is warranted. There is at
least one report on the use of neoadjuvant temozolomide in diffuse LGG to improve
EOR.13
WHO grade II oligodendrogliomas and anaplastic oligodendrogliomas (grade
III) deserve special therapeutic recommendations as allelic loss of the short arm of
chromosome 1p and the long arm of chromosome 19q occurs in 50% to 70% in both
and predicts better response to chemotherapy and longer survival. PCV has been
shown to prolong disease-free survival (DFS) but not OS in two randomized phase
III trials in patients with anaplastic oligodendrogliomas. However, in a subset of
high-risk LGG patients from RTOG 9802, the use of postoperative radiotherapy with
PCV over radiotherapy alone demonstrated a significant improvement in median OS
(13.3 vs. 7.8 years). Similar results have been shown with RTOG 9402 and EORTC
26951. The emergence of temozolomide, which is far more tolerable than PCV, with
demonstrated benefit in patients with WHO grade IV glioblastoma multiforme in
addition to the concern for delayed radiotherapy-induced neurocognitive toxicity in
patients predicted to have potentially longer survival, and the discovery of
molecular-chromosomal markers makes the findings of these phase III studies
difficult to apply. For example, temozolomide has shown a 31% objective response
rate as initial therapy for low-grade oligodendrogliomas in patients with clinical
and/or radiographic progression and no prior therapy other than surgery.14 However,
the question of whether temozolamide alone can be used to manage LGG patients
and whether it can truly replace PCV chemotherapy when combined with radiation
is highly controversial and will need to be addressed in future prospective clinical
studies.
At the time of recurrence, surgery is still considered the first line of treatment
aiming to offer the maximum EOR and also to update histopathologic grading so that
postoperative therapy (based on prior medical treatment(s)) can be added when
there is evidence of malignant transformation. If surgical resection to GTR is not an
option because of extensive areas of brain involvement, upfront radiation can be
used in patients who have not received prior radiotherapy. In the setting of prior
radiotherapy, salvage chemotherapy is routinely used. Another option, in recurrent
disease, is the use of stereotactic radiosurgery or hypofractionated radiotherapy,
which, retrospectively, has been shown to be effective (median OS and PFS from
reirradiation was 23 and 12 months, respectively) and tolerable.15
3. Grades III and IV glioma (high-grade gliomas)
High-grade gliomas (HGG) represent over 70% of all newly diagnosed PBT every
 year, making them the most common type. Anaplastic astrocytoma (AA, WHO grade
III) occurs most commonly in the fourth and fifth decades, whereas glioblastoma
(GBM, WHO grade IV) occurs most commonly in the fifth and sixth decades.
Median OS is 24 to 36 months for AA and 12 to 16 months for GBM. These two
types of tumors may appear quite similar on MRI because both often appear as
diffuse hypointense lesions on T1-weighted images and both readily enhance after
administration of intravenous contrast. These tumors are most commonly observed in
the cerebral hemispheres and can have cystic, necrotic, or hemorrhagic components.
While the etiology of most HGG is unclear, ionizing radiation, tuberous sclerosis,
and NF1/NF2 mutations are known risk factors. Without treatment, median survival
is <3 months, whereas with best treatment, median survival is 12 to 15 months for
GBM, with only <25% of patients surviving up to 2 years. In the light of this poor
outcome, patients must be encouraged to participate in prospective therapeutic
clinical trials.16
a. Role of surgical resection in newly diagnosed malignant gliomas
The Glioma Outcomes Project studied patterns of care for adults with newly
diagnosed malignant gliomas (grade III and IV). A total of 788 patients were
followed across 52 sites and 154 physicians in the United States. Perioperative
corticosteroid and antiepileptic use was common for both types of lesions, while
grade IV GBMs were more likely to have a GTR and adjuvant RT compared
with AA. Data from the Glioma Outcomes Project similarly provided class II
evidence to support tumor grade, patients’ age, and performance status as
prognostic factors for survival in patients with newly diagnosed malignant
gliomas. It also showed that surgical resection was better than biopsy alone.
Like LGG, surgical resection is the mainstay of treatment in HGG.17
Although there is no level I study comparing the effect of EOR on clinical
outcomes in HGG, several prospective and retrospective studies have shown
that (a) surgical resection is better than biopsy alone, (b) GTR is better than near
total resection (NTR), and (c) NTR is better than STR. A meta-analysis of 14
large HGG studies (>200 patients each) showed survival benefit with greater
EOR for both grade III and IV malignant gliomas on multivariate analysis.
Chaichana et al.18 showed a greater than 70% volumetric resection and <5 cm3
of residual tumor volume as independent surgical thresholds affecting survival
and recurrence in newly diagnosed GBM.
Multifocal and multicentric GBMs account for 0.5% to 20% of all GBMs
and carry a less favorable prognosis. Multiple craniotomies in a single session
to achieve GTR for these lesions, in highly selected cases, have similarly shown
to be feasible and provide survival advantage.
Several recent technological advances, such as use and availability of
intraoperative MRI and fluorescence-guided surgery, along with pre- and
intraoperative mapping (functional MRI, awake procedures) have significantly
 improved EOR in modern surgical series.
b. Postoperative management and prognostic factors for newly diagnosed
WHO grade III gliomas
Despite advances in surgical resection, treatment of malignant gliomas has
resulted only in a modest increase in survival. Postoperative management of AA
remains controversial in 2015 because of a lack of randomized prospective data.
However, postoperative radiotherapy (59.4 to 60 Gy) with concurrent
temozolomide is the most common treatment approach. The potential benefit of
combined modality therapy and adjuvant therapy is currently being evaluated in
a prospective trial (CATNON) through NRG Oncology.19
Positive prognostic factors include high Karnofsky Performance Score
(KPS), GTR, and younger age (<60). In addition, multiple studies have now
shown that methylation of the O6-methylguanine-DNA methyltransferase
(MGMT) promoter is prognostic of improved survival, and may be predictive of
increased responsiveness to temozolomide chemotherapy in GBM.
c. Postoperative therapies in newly diagnosed WHO grade IV gliomas
1) Chemotherapy and radiation
Postoperative radiation treatment has played an important role following
GTR, NTR, or biopsy. Clinical studies have helped to refine the method,
technology, and the dose for how radiation is now delivered for malignant
gliomas. Early studies demonstrated a benefit with whole brain radiotherapy
(WBRT) followed by a boost to the operative site compared with
observation or BCNU therapy alone. Modern radiation has moved away from
WBRT to the use of MRI imaging to help with delivering directed
radiotherapy, and this has improved QoL. In 2005, a study conducted by the
European Organisation for Research and Treatment of Cancer (EORTC) and
the National Cancer Institute of Canada (NCIC) demonstrated that the
addition of temozolamide could improve OS and PFS.20 In this large
randomized phase III study, postoperative radiation (60 Gy in 30 fractions
over 6 weeks) has been compared with the combination of radiation plus the
oral alkylating agent temozolomide (75 mg/m2/day during radiation followed
by dosing for 5 days in a 28-day cycle [for 6 cycles] given at 150 to 200
mg/m2/day). The combination arm showed an acceptable toxicity profile and
provided a survival advantage (14.6 vs. 12.1 months, p < 0.001).20 This
combination, also known as the “Stupp regimen,” is now considered the
standard of care therapy and is used as the control arm in current prospective
clinical trials.
Attempts at modifying the classic Stupp regimen with additional
biologics and hypofractionated radiotherapy (higher dose per fraction, fewer
fractions) to date have been unsuccessful in improving survival. Two recent
prospective randomized phase III trials conducted in the US and in Europe
 have failed to demonstrate a survival advantage when bevacizumab
(Avastin), a monoclonal antibody against vascular endothelial growth factor
(VEGF), is combined with radiation and temozolomide in the adjuvant
setting.21 An identical result has been observed with cediranib, a VEGFR
tyrosine kinase inhibitor, in a prospective trial.22 Therefore, until a patient
subgroup has been defined, these results do not support the use of
antiangiogenics for newly diagnosed glioblastoma. A phase II trial at the
University of Colorado combining postoperative hypofractionated
radiotherapy (60 Gy delivered over 10 fractions) with concurrent
temozolamide and avastin followed by adjuvant temozolamide and avastin
demonstrated a median PFS and OS of 12.8 and 16.3 months, respectively.23
In comparison, a similar phase II trial from Memorial Sloan Kettering Cancer
Center (MSKCC) utilized a similar chemotherapy regimen, but a lower
hypofractionated dose of radiotherapy (36 Gy delivered over 6 fractions)
showed a median PFS and OS of 10 and 19 months, respectively, which was
favorable to historic controls.24 Both these aggressive radiotherapy regimens
demonstrated safety in addition to improved convenience for patients over
traditional radiotherapy regimens, and further study of these regimens is
warranted. Adjuvant chemotherapies for malignant gliomas are outlined in
Table 16.1.
d. Electrical field therapy
A recent phase III randomized trial has successfully tested the impact of
NovoTTF-100A in the adjuvant setting.25 Tumor treating fields (“TTFields”)
stop the growth of tumor cells, resulting in cell death of the rapidly dividing
cancer cells in vitro and in vivo. The NovoTTF-100A System is a portable
battery or power-supply operated device that produces changing electrical
fields, and is applied to the head of the patient by electrically insulated surface
electrodes. The frequency of the TTFields used for a particular treatment is
specific to the size of the cell type being treated. The percentage of patients alive
at two years when treated with TTFields together with temozolomide was 43%
compared with 29% when treated with temozolomide alone. Patients treated
with TTFields together with temozolomide demonstrated a significant increase
in OS compared with temozolomide alone (median OS from randomization of
19.4 months compared with 16.6 months, hazard ratio = 0.75, p = 0.022). QoL
surveys demonstrated an improvement with the NovoTTF-100A System in
recurrent GBM subjects compared with best standard of care options alone.
e. Recurrent GBM
GBM recurrence can occur at 34 to 36 weeks after primary resection. There is
mounting evidence in support of multiple reoperations to improve survival in
carefully selected patients, and that a PFS of >3 months significantly predicts
survival after repeat surgery. Recurrent glioblastoma is treated by surgical
 debulking for selected cases with or without carmustine (BCNU) wafers,
bevacizumab, stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT),
nitrosoureas (lomustine), or other single-agent therapies such as carboplatin (see
Table 16.2).

TABLE
Chemotherapy for Malignant Gliomas (Adjuvant)
16.1

Bevacizumab was approved in 2009 by the Food and Drug Administration

(FDA) as a single agent for use in the treatment of recurrent glioblastoma based
on two prospective clinical trials. The response rate varies from 20% to 30%
and is associated with significant clinical improvement and reduced steroid
dependence. More recently, a randomized phase II study of bevacizumab versus
bevacizumab plus lomustine versus lomustine in patients with recurrent
glioblastoma showed a significant advantage in terms of PFS for the combination
arm (bevacizumab plus high-dose lomustine).26 Retrospective and prospective
studies have demonstrated that the use of salvage SRS or SRT when combined
with bevacizumab in a previously irradiated postoperative bed can be effective
and tolerable in controlling isolated sites of recurrence in patients refusing or
ineligible for re-resection.27 Furthermore, the use of bevacizumab in the
reirradiation setting may help to decrease the risk of radiation necrosis.
A phase III randomized clinical trial comparing NovoTTF-100A with
physician’s best choice chemotherapy in patients with recurrent GBM revealed
that TTFields have similar efficacy to standard chemotherapy with a more
favorable side-effect profile and improved QoL.28 This study prompted FDA
approval of the NovoTTF-100A System in April 2011 as an option for treatment
of recurrent GBM after initial frontline therapy.
 TABLE
Regimens for Recurrent GBM
16.2

A wide range of targeted agents and immune therapies (vaccines, immune

checkpoint inhibitors) are being tested through ongoing clinical trials. In
particular, specific therapies directed against EGFRvIII-positive tumors have
shown promising results in recurrent tumors. Rindopepimut (Rintega, CDX-110)
is a therapeutic vaccine targeting a mutant peptide called EGFRvIII, which is
expressed in approximately one-third of glioblastomas. The FDA granted
rindopepimut a Breakthrough Therapy Designation—which expedites the
process for getting FDA approval—for patients with EGFRvIII-positive
glioblastoma, based on a randomized, placebo-controlled phase II trial
(ReACT), indicating that rindopepimut has a survival benefit among recurrent
patients.29
C. Pineal region tumors
The pineal region is defined as the area of the brain bound dorsally by the splenium of
corpus callosum and tela choroidea, ventrally by brain stem tectum and quadrigeminal
plate, rostrally by the third ventricle, and caudally by the cerebellar vermis. It has been
considered one of the most technically challenging areas to approach surgically. The
pineal gland itself is an evagination of the diencephalic ependymal roof. Tumors of the
pineal region account for 3% to 8% of all pediatric tumors and <1% of adult tumors,
are histologically diverse, and are divided into germ cell and nongerm cell neoplasms.
Patients with pineal region tumors often present with hydrocephalus as a result of
obstruction of the cerebral aqueduct. Other common features may be Parinaud syndrome
and precocious puberty.
1. Pathology
More than 17 different pathologic entities have been identified in the pineal region.30
These can be broadly classified into four subtypes: (a) germinonas and
 nongerminomatous germ cell tumors (NGGCT) including teratomas, dermoid,
epidermoid cysts, embryonal carcinomas, and choriocarcinomas, (b) primary Pineal
Parenchymal tumors (PPT) including pineocytomas, pineoblastomas, and pineal
parenchymal tumors of intermediate differentiation, (c) glial cell tumors including
astrocytomas, ependymomas, and oligodendrogliomas, and (d) miscellaneous tumors
and cysts including benign pineal cysts, meningiomas choroid plexus papillomas,
and metastatic tumors. Germinomas are the most common pineal region tumors and
are highly radiosensitive with high long-term survival rates. Pineoblastomas are
aggressive tumors that tend to behave poorly compared with pineocytomas.30
2. Management algorithm
Management starts with diagnosis using high-resolution contrast-enhanced MRI
followed by germ cell serum/cerebrospinal fluid (CSF) markers including βHCG
and AFP.31 If these are positive, then chemotherapy (CDDP/etoposide) and
radiotherapy are given owing to high response rates. Radiotherapy for
pineoblastomas are treated similarly to medulloblastomas, and the use of cranial
spinal irradiation (CSI) followed by a local consolidative operative bed
radiotherapy boost with concurrent chemotherapy is recommended. For germinomas
and NGGCT, if the neuroaxis is negative, often local, consolidative radiotherapy is
given. However, in the presence of neuroaxis involvement, CSI followed by local
consolidative therapy is recommended. Some authors recommend histologic
confirmation with stereotactic biopsy regardless of serum markers. If histology
suggests nongerm cell origin, surgery is considered.
3. Surgical treatment
Surgical management of pineal region tumors has evolved over the years.32 In the
presence of hydrocephalus, either endoscopic third ventriculostomy or
ventriculoperitoneal shunt is placed.33 In general, GTR is recommended for benign
or low-grade histology, especially for meningiomas, epidermoids, teratomas, and
pineal cysts. Surgical resection has no role in the management of germinomas and
NGGCTs. GTR is superior to STR for pineocytomas, while its role in
pineoblastomas is controversial at best.
D. Medulloblastomas (WHO grade IV)
Medulloblastomas are malignant embryonal tumors of the posterior fossa and the most
common primitive neuroectodermal tumor (PNET). This neoplasm is found in 80% of
children under the age of 15 and accounts for 20% of all pediatric brain tumors. They
arise in the roof of the fourth ventricle in the cerebellar vermis and frequently present
with symptoms of obstructive hydrocephalus. Histologically, they are characterized by
poorly differentiated, densely packed, hyperchromatic, nucleated, small round, blue
cells. This is an invasive tumor that tends to metastasize through the CSF to the rest of
the CNS. Therefore, during the initial workup of these patients, the entire neuraxis
(brain and spine) should be imaged using contrast-enhanced MRI. A lumbar puncture
for CSF cytopathology, if considered safe, is often part of the workup.
 Surgical resection, with a goal of GTR is the first line of treatment, followed by
CSI.34 At the time of diagnosis and following surgery, patients are stratified as being
either standard risk (age >3, GTR/STR with <1.5 cm2 residual disease and M0) or high
risk (age <3 or >1.5 cm2 residual or M+).
1. Treatment
Management of this disease draws primarily from the pediatric literature where
multiple successful trials have helped to shape the treatment paradigm for the rare
adult patient. In standard-risk pediatric patients, treatment involves maximally safe
resection to GTR-STR, followed by CSI to 23.4 Gy, followed by a posterior fossa
boost to a total dose of 54 to 55.8 Gy with concurrent vincristine therapy. This is
followed with adjuvant PCV chemotherapy, which has demonstrated 5-year disease-
free survival and OS rates of approximately 80% and 85% to 87%, respectively.35
Current trials are attempting to further lower CSI doses in an attempt to minimize the
late neurocognitive side effects in young children.
There are multiple chemotherapy regimens for medulloblastomas. A common
approach involves the use of the following drugs in combination: etoposide,
cisplatin, cyclophosphamide or CCNU, and vincristine.35 In infants (<3 years old) or
patients with recurrent medulloblastoma, high-dose chemotherapy with autologous
stem-cell rescue may be beneficial. Recent molecular subtyping has identified four
distinct subgroups (WNT, SHH, Groups C and D) of medulloblastomas with unique
demographics, clinical presentation, genetic abnormalities, and clinical outcome
based on key molecular pathways.36,37 WNT, in particular, has been identified with
an excellent prognosis (OS of 90%), and SHH with an intermediate prognosis (OS
of 60%). The other two subtypes have been shown to have a poor OS. Future studies
involving targeted therapies may improve clinical outcome in these patients.
E. Primary CNS lymphoma in immunocompetent patients
Primary CNS lymphoma (PCNSL) is extranodal, malignant non-Hodgkin lymphoma of
the diffuse large B-cell type that is confined to the brain, eyes, leptomeninges, or spinal
cord in the absence of systemic disease.38 This tumor accounts for 3.1% of all PBTs
with a median age of 60 years at diagnosis and a rising incidence in the elderly. Sixty
percent of tumors are supratentorial and commonly involve the periventricular regions
and corpus callosum. At the time of diagnosis, 25% to 50% of cases have multifocal
disease. The lesions are hypointense to isointense on T1-weighted MRI and enhance
homogeneously with gadolinium. The tumors are responsive to corticosteroids, and, as
a result, steroid administration should be avoided until a diagnosis has been
established. The only role for surgery in PCNSL is to establish the diagnosis by
stereotactic biopsy. These tumors should not be resected except in the rare circumstance
of brain herniation from mass effect.39 The prognosis of PCNSL remains poor, but
substantial progress has been made in the past two decades. Depending on the
complexity of initial diagnosis, clinical presentation, and multimodal therapies, patients
with PCNSL should be managed in highly specialized units with a high level of
 expertise. Age and performance status have been identified as robust treatment-
independent prognostic factors.
1. Management algorithm
Extent of disease evaluations for patients with PCNSL should include gadolinium-
enhanced MRI of the brain and spine; whole-body FDG-PET; lumbar puncture for
CSF cytopathology, flow cytometry, and immunoglobulin heavy gene rearrangement
testing; serum lactate dehydrogenase level; and a bone marrow biopsy. Patients
should also be tested for the human immunodeficiency virus. PCNSL is diagnosed
according to the WHO classification, and immunohistochemistry with pan-B-cell
markers is required.
The management of PCNSL is one of the most controversial topics in neuro-
oncology. The following may be used as guidelines in managing PCNSL:
■ Chemotherapy should include high-dose methotrexate at doses of at least 3 g/m2,
and should be given every 2 to 3 weeks for a minimum of 4 to 6 cycles. High-
dose methotrexate in combination with other chemotherapeutic agents known to
cross the blood-brain barrier improves response rate and probably OS.
■ The value of intrathecal chemotherapy as prophylaxis is unclear and can be
recommended when meningeal involvement is documented.
■ Rituximab combined with chemotherapy seems to be efficient, but should be
used as an experimental regimen in clinical trials.
■ Standard chemotherapy regimens (CHOP, EPOCH) used for peripheral
lymphomas are not efficacious in PCNSL.
■ In patients older than 60 years, WBRT and high-dose methotrexate expose
patients to a high risk of neurotoxicity. Consolidation with WBRT after
induction high-dose methotrexate chemotherapy remains controversial and has
been considered for salvage therapy or in older patients who have achieved a
complete response to chemotherapy. The aim of holding WBRT is to try and
delay the effects of leukoencephalopathy in this older population.
■ In patients who are younger than 60 years old, the role of consolidation WBRT
may provide improved disease control as one-third of patients often have
leptomeningeal disease at presentation or experience a partial response to
chemotherapy. Involvement of the eye at initial presentation is another
consideration for ocular or orbital radiotherapy versus intraocular
chemotherapy. Those patients who are not appropriate for chemotherapy (renal
dysfunction or KPS <40%) should be considered for palliative WBRT and/or
focal radiotherapy to sites of CNS disease.
■ High-dose chemotherapy with autologous stem-cell transplantation is efficacious
in relapses of refractory PCNSL in a selected population. Other indications
remain investigational.
■ Patients with relapsed or refractory disease should be enrolled in clinical trials.
■ Elderly patients should be evaluated for specific therapeutic options, depending
 on the morbidity of the standard therapies.
See Table 16.3 for chemotherapy regimens used in PCNSL.
F. Sellar and parasellar tumors
Tumors of the sellar and parasellar region include pituitary adenomas,
craniopharyingiomas, Rathke cleft cyst (nonneoplastic lesion) and meningiomas.
1. Pituitary adenomas
These are common tumors and constitute 8% to 10% of all intracranial neoplasms.40
They arise from the anterior pituitary gland and are classified by size into
microadenomas (<10 mm), macroadenomas (>10 mm), and giant adenomas (>30
mm). Their clinical presentation varies from primary endocrinologic (in secreting
tumors) to anatomic (owing to mass effect) or emergent (pituitary apoplexy
involving hemorrhage/necrosis into the tumor resulting in acute endocrinologic or
visual deterioration).
a. Anatomic considerations
Depending on their location, they can grow inferiorly into the sphenoid sinus,
causing CSF rhinorrhea, superiorly toward the third ventricle, causing
hydrocephalus, toward the optic apparatus, causing visual field deficits (most
commonly bitemporal hemianopsia), laterally into the cavernous sinus, causing
ophthalmoplegia, or dorsally toward the clivus, causing brainstem compression.
b. Hormonal considerations
Functioning pituitary adenomas can present with syndromes of hormonal access.
Most commonly, they secrete prolactin (prolactinomas), causing infertility and
galactorrhea-amennorhea syndrome, ACTH, causing Cushing disease, or growth
hormone, causing acromegaly. Over 80% of macroadenomas are nonsecretory
and cause symptoms due to mass effect.

TABLE
Chemotherapy Regimens Used in PCNSL
16.3
Regimen Dose Comments
Rituximab 500 mg/m2 day 1 “MSKCC” regimen
Hydration and leucovorin rescue
Methotrexate 3.5 g/m2 day 2
Intra-Ommaya methotrexate (12 mg) is CSF
Vincristine 1.4 mg/m2 day 2 malignancy
R-MVP
Methotrexate-cytarabine Procarbazine 100 mg/m2/day days 1–7 (odds cycles 5 cycles every 14 days
only) “Ferreri” regimen
Methotrexate 3.5 g/m2 day 1 Hydration and leucovorin rescue
Cytarabine 2 g/m2 day 2 4 cycles every 3 weeks

c. Management algorithm
Management includes detailed radiologic assessment with dedicated MRI of the
 sellar region. Early endocrinologic and ophthalmologic consults are necessary to
both document and manage visual and hormonal deficits. Prolactinomas are
primarily treated medically with bromocriptine. Incidentally found tumors are
followed with serial imaging studies until they become symptomatic. Surgery is
indicated for medically refractory functioning adenomas (e.g., giant
prolactinomas, primary Cushing disease, and acromegaly) as well as for
nonfunctioning macroadenomas causing mass effect.
d. Surgical and postoperative management
Surgery is usually performed transnasally either with a microscope or using an
endoscope because it offers a midline corridor to the tumor without the need for
brain manipulation. With the advent of modern endoscopic transphenoidal
surgery, GTR is often achieved even with multilobulated tumors using varying
degrees of angled scopes.41 Giant tumors with significant suprasellar extension
(i.e., toward the third ventricle) require both transcranial and transnasal
approaches. Although transphenoidal surgery results in clinical improvement in
most patients, it rarely cures hormonal dysfunction. EOR is associated with
prolonged recurrence-free survival. Progression in young patients should be
treated surgically, followed by SRT or SRS. Additionally, patients with
persistent hypersecreting lesions despite surgical resection or large tumors with
extrasellar extension or with medically inoperable disease should be managed
with SRT or SRS. The use of radiotherapy alone is comparable to that of surgery
followed by radiotherapy in nonsecreting versus secreting lesions, with a slight
advantage (10%) favoring combined modality therapy.
2. Craniopharyngiomas
Craniopharyngiomas comprise 2% to 5% of all intracranial tumors and 5% to 15%
of all pediatric brain tumors. These are classified by WHO as grade I neoplasms.
Histologically, they are of two distinct types: the adamantinomatous type, which is
more common in children, and the papillary type, which is seen exclusively in
adults. Although histologically benign, these tumors are closely adherent to the
pituitary stalk, optic apparatus, and hypothalamus, and their growth and management
can have devastating consequences for the patients. On MRI, they often have
irregular borders with a cystic component that often enhances along the cyst wall.
a. Management algorithm
With modern surgical techniques (transcranial or trasnasal), GTR can be
achieved in most patients.42 A recent prospective pediatric trial showed an 80%
reduction in risk of recurrence with GTR, with local control rates around 85% to
100%. However, STR followed by adjuvant RT provides improved local
control rates (75% to 90%) compared with observation alone (30%).43 The use
of SRS for small lesions or recurrent disease has been reported. Hormonal
dysfunction is managed with medical supplementation. Recurrent disease is
managed surgically to relieve mass effect and also to implant radioactive and
 chemotherapeutic agents into the cyst. Diabetes insipidus (DI) is the most
common side effect, while bilateral hypothalamic injury is the most dreaded
surgical complication. In most series, mortality is 5% to 10% with a median 5-
OS of 55% to 85%.

II. METASTATIC BRAIN DISEASE

A. Incidence
Brain metastases are much more common intracranial tumors in adults and are 10 times
more common than primary malignant CNS tumors. Every year, 170,000 patients are
estimated to die in the United States from brain metastases. Hematogenous spread is the
most likely mechanism, with most metastases occurring at the gray-white junction in
cerebral hemispheres (considered terminal watershed areas of arterial supply). Most
commonly, cerebral metastases arise from cancer of the lung (>50%), breast (10% to
20%), and melanoma (5% to 15%), while in children, the most common etiologies are
neuroblastoma, rhabdomyosarcoma, and Wilm tumor. Hemispheric lesions are most
common, with a predilection for the frontal lobe.44
Recent evidence suggests that astrocytes protect cancer cells from chemotherapy by
stimulating upregulation of antiapoptotic genes in those cancer cells, independently of
the presence of the tumor blood-brain barrier.45
B. Management algorithm
Although surgery is the mainstay of treatment, risk stratification and outcome analysis
must be done with reference to key prognostic factors. Also, before obtaining tissue
from cranial site, a thorough systemic metastatic workup should be performed in the
absence of an identified primary. In addition, 11% of patients with an imaging
abnormality and a history of systemic cancer do not have brain metastases. A review of
the RTOG database retrospectively evaluated key prognostic factors determining
outcomes in 1,200 patients with cerebral metastases, and using recursive partitioning
analysis (RPA), categorized patients into three subgroups for outcome analysis.
Prognostic variables included KPS <70, age, extracranial metastases, and whether the
brain is the sole site of extracranial disease. According to this scheme, the best class
(RPA class I) had a median survival of 7.1 months, while RPA class III had a 2.3-month
survival.46 A modern, updated stratification, known as the Graded Prognostic Index
(GPI), utilizing two additional RTOG trials and the prior RPA trials, has helped to
further refine predicting patient OS.47 Certain malignancies have been further
substratified according to histology and outcome, adding further complexity and
predictive value to the GPI.48,49
C. Steroids and anticonvulsants therapy
In patients who are symptomatic with increased intracranial pressure, pain, or
neurologic dysfunction are likely to benefit from the use of steroids. Dexamethasone is
the steroid of choice, in view of its lower mineralocorticoid effect and longer half-life.
Randomized studies examining the efficacy of low- versus high-dose steroid use in
 symptomatic patients failed to demonstrate a statistically significant benefit between
doses, although the higher doses numerically demonstrated an improvement in
symptoms.50 Nonetheless, the use of a total dose of 4 to 8 mg for patients who are
mildly symptomatic and 16 mg for moderate to severely symptomatic patients is an
accepted dosing recommendation with a high likelihood of improving symptoms within
24 to 72 hours of administration. Long-term use of steroids is likely to induce steroid-
induced gastritis, insomnia, and increased appetite. GI prophylaxis in addition to other
supportive care should be considered in those taking steroids over a 2-week period.
Doses should also be tapered over a 2-week period for patients in long-term treatment
or in those administered high doses. The use of steroids in asymptomatic patients is not
recommended.
As tumors are spherical, they tend to be less epileptogenic compared with primary
tumors. However, anticonvulsants are routinely used in patients with symptoms with
preference for medications like levetiracetam (Keppra), given improved tolerance.
Multiple studies have demonstrated that prophylactic use of anticonvulsants in
asymptomatic patients with primary or metastatic tumors does not lead to improved
survival or prevention of seizure. Therefore, the use of anticonvulsants in the
asymptomatic brain metastasis patient should be avoided.
D. Surgical management
There is class I evidence suggesting that surgical resection is the best management for
solitary, surgically accessible lesions with a KPS >70. Tumors such as renal cell
melanoma and sarcomas that are considered radioresistant warrant aggressive surgical
resection and the use of systemic targeted therapies. Only patients in RPA class I with
multiple metastases will benefit from surgical resection. In a recent series, obtaining a
margin of 5 mm into adjacent brain reduced local recurrence, and en bloc resection was
recommended over piecemeal removal to prevent leptomeningeal dissemination. In
one-third of all brain metastasis patients who have single or solitary lesions, surgery
followed by WBRT results in longer survival than WBRT alone (40 vs. 15 weeks for
cerebral metastases from lung cancer).51
E. Radiation therapy
The use of WBRT and SRS for managing brain metastasis has evolved significantly and
is currently an area of active discussion within the radiation oncology community.
Often, patients with an excellent performance status and a solitary lesion are considered
to have an excellent prognosis per the RPA/GPI and recommended for surgical
resection followed by WBRT. Two randomized studies that examined WBRT with or
without upfront surgery demonstrated a survival benefit over WBRT alone. In contrast,
resection followed by randomizing WBRT showed that the addition of WBRT
demonstrates improvement in brain local control both in the resection bed and distantly.
Furthermore, these studies indicate that the risk of neurocognitive decline/death is
diminished with the addition of WBRT and has been considered standard following
surgical resection, particularly for large bulky lesions. Standard WBRT doses are 30
 Gy in 10 fractions or 37.5 Gy in 15 fractions.
For those with multiple brain metastases, the traditional paradigm has been to offer
WBRT alone with consideration of SRS boost for persistent radiographic disease
versus observation. One study showed that patients with solitary brain metastasis
managed with WBRT followed by SRS demonstrated a significant survival benefit (6.5
vs. 4.9 months). However, no survival benefit was observed in the setting of multiple
brain metastasis.52 For patients with poor performance status, one could consider a
palliative radiotherapy dose of 20 Gy in 5 fractions; however, in light of the recent
British Quartz study comparing best supportive care versus 20 Gy in 5 fractions with
best supportive care and demonstrating no difference in OS (51 vs. 49 days), one
should consider best supportive care as an appropriate option.
However, in light of modern trials demonstrating excellent local control with SRS
and a lack of survival benefit associated with SRS with or without WBRT, there is an
increasing tendency to defer WBRT because of the late neurocognitive sequelae in
patients with multiple brain metastases. Radiosurgery is often delivered using either of
two modalities: Gamma Knife Stereotactic Radiosurgery (GK-SRS) or LINAC-based
radiosurgery. To date, SRS has been used to manage patients with 1 to 4 brain
metastasis, but select institutional series have demonstrated excellent local control
outcomes with acceptable toxicity for managing 10 or more of these lesions using the
GK-SRS approach. Generally, smaller lesions enjoy superior 1- and 2-year local
control rates compared with larger lesions. Furthermore, reirradiation with SRS in the
setting of newly developed brain metastasis is considered safe and tolerable.
F. Chemotherapy
Chemotherapy has a limited role in the treatment of brain metastases, owing to the
presence of the blood-brain barrier, but, more importantly, to the microenvironment
(astrocytes). However, metastatic brain lesions from germ cell tumors and breast cancer
respond well to systemic therapy. Recent studies with targeted therapies have shown
similar activity in brain lesions and systemic disease, in particular with BRAF
inhibitors in metastatic melanoma (vemurafenib). Immune checkpoint inhibitors are
currently being evaluated in several tumor types for the treatment of brain metastases.44

III. LEPTOMENINGEAL CARCINOMATOSIS (LMC)

Also known as carcinomatous meningitis, this occurs when tumor cells invade CSF and
meninges.53 Its prevalence is 10% and is associated with progressive disseminated disease
with an OS of 2.8 months, regardless of treatment. Large retrospective data show that
piecemeal resection of cerebral metastatic lesions compared with en bloc resection results
in LM dissemination irrespective of primary histology. The treatment of leptomeningeal
metastases includes palliative radiation therapy to symptomatic areas of the CNS (e.g., to
the base of the brain for cranial nerve dysfunction, or lumbosacral spine for cauda equina
disease) and intrathecal (IT) chemotherapy with methotrexate, or liposomal cytarabine
(ara-C), administered through an Ommaya reservoir to increase drug delivery and patient
 comfort.53 Chemotherapy regimens for the treatment of LMC are shown in Table 16.4.

TABLE
Chemotherapy Regimens for the Treatment of LMC
16.4
Drug Dose Comments
Methotrexate 12–15 mg Twice a week until cytologic remission
Every 2 weeks
Cytarabine Liposomal (Depocyt) 50 mg
With oral steroids

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I. EPIDEMIOLOGY OF SOFT-TISSUE AND VISCERAL SARCOMAS
Soft-tissue and visceral sarcomas are a group of malignant diseases characterized by
neoplastic proliferation of specialized or nonspecialized cells of mesenchymal tissues.
Sarcomas represent about 1% to 2% of cancers in humans, with an incidence close to
5.9/105/year.1–4
The four most frequent histologic subtypes—gastrointestinal stromal tumors (GISTs),
liposarcomas (LPSs), leiomyosarcomas (LMSs), and undifferentiated pleomorphic
sarcomas—have an incidence of 8 to 12/106/year and represent about 50% of all
sarcomas. All other histologic subtypes have an incidence of less than 5/106/year, and are
therefore very rare tumors.2
Few risk factors for the development of soft-tissue and visceral sarcomas have been
identified. Previous radiotherapy is a well-identified risk factor for these tumors (e.g.,
after conservative surgery in breast cancer). The presence of tumor-suppressor gene loss in
the germ line, such as TP53 (Li-Fraumeni syndrome), Rb, or NF1, significantly increases
the risk of developing sarcoma over a lifetime.3,4
A. Classification and epidemiology
1. Histologic subtypes of soft-tissue and visceral sarcomas
Despite their overall rarity, the histologic classification of soft-tissue and visceral
sarcomas is complex, encompassing a large variety of histologic subtypes. This
classification has been evolving substantially in the past 20 years: an increasing
number of different histotypes and molecular subtypes have been progressively
identified,and their nosology and histogenesis are being refined over time.3–5
Over 80 different histologic subtypes of sarcomas have been identified in the
most recent World Health Organization (WHO) classification. Sarcomas are
classified according to the lines of differentiation resembling that of normal tissues.
For example, rhabdomyosarcomas show evidence of skeletal, striated, muscle
fibers, LPSs show fat production, and GISTs resemble the interstitial cells of Cajal
(the pacemaker cells of intestinal motility).4–6 Importantly, among these histologic
subtypes, molecular subtypes are being identified, with different natural histories
and treatment approaches, as illustrated here with LPSs. Some sarcomas lack a line
of differentiation and are considered to be of “uncertain histogenesis” or within the
“unclassified sarcoma” subgroup, often with pleomorphic features. Pleomorphic
 tumors previously classified as malignant fibrous histiocytoma (MFH) are now
frequently referred to as unclassified high-grade pleomorphic sarcomas. Of note,
sarcomas similar to primary bone sarcoma may arise in soft tissue: extraskeletal
osteosarcoma, extraskeletal Ewing sarcoma (30% of Ewing sarcomas), and
extraskeletal chondrosarcoma.
2. Molecular classifications
In addition to immunohistochemistry, molecular characterization tools such as
fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or
direct sequencing can be powerful to facilitate and refine the diagnosis of soft-tissue
sarcoma, when morphologic analysis is insufficient to guide the final diagnosis.
Different categories of sarcomas are now being identified on the basis of the
presence of characteristic molecular hallmarks: sarcoma with translocations (e.g.,
Ewing sarcoma, synovial sarcoma, myxoid and round-cell LPS), sarcoma with
kinase mutations (e.g., GIST with mutations of KIT or PDGFRA, angiosarcoma with
mutations of VEGFR2), sarcoma with deletion of a key tumor-suppressor gene
(malignant peripheral nerve sheath tumors [MPNSTs] with NF1 deletion), sarcoma
with chromosome 12q13 amplification (e.g., well-differentiated LPS [WDLPS],
dedifferentiated LPS [DDLPS], intimal sarcomas), and a group of sarcomas with
complex genetic alteration not yet fully characterized, representing about 50% of all
sarcomas (Table 17.1).3–6

TABLE
Examples of Molecular Subtypes of Sarcomas
17.1
Primary Mutation Histotype Mutation
Ewing sarcoma t(11,22)
Translocation Synovial sarcoma t(X,18)
Myxoid liposarcoma t(12,16)
KIT exon 11
Kinase mutation GIST
PDGFRA exon 18
WD liposarcoma
12q13 amplification DD liposarcoma 12q12 amplification
Intimal sarcoma
Tumor-suppressor gene loss Malignant peripheral nerve sheath tumor NF1 loss
PEComa TSC1/2 loss
Undifferentiated
Complex genetic rearrangements Unknown
Pleomorphic sarcoma

DD, dedifferentiated; GIST, gastrointestinal stromal tumor; WD, well-differentiated.

LPSs are categorized into the following groups: WDLPS and DDLPS
characterized by a specific amplification of 12q13 (along with additional genetic
 alterations for DDLPS), myxoid LPSs exhibiting specific translocations, and
pleomorphic LPSs displaying complex genetic alterations. These distinct LPSs have
a different natural history and prognosis, and require different treatment approaches.
In GIST as well, the precise identification of the kinase mutation is an important
parameter to decide on a specific treatment (e.g., imatinib—close to 20% of primary
gastric GISTs express a PDGFRA mutation, and the majority of these mutations are
missense mutations arising on codon 842 (D842V). The protein encoded by this
mutated gene is resistant to the kinase inhibitory effects of imatinib, both in vitro and
in vivo. These tumors have a limited risk of progression following definitive
surgery. Surgery should be the preferred treatment option for these tumors whenever
possible. GISTs with wild-type KIT and PDGFRA are often affected by NF1
mutations, BRAF mutations, or mutations of the SDHA,B,C,D genes, and also have
specific natural histories. The clinical activity of imatinib in these subtypes is less
important than in tumors bearing the classical mutations of the KIT exons 11 and 9.
B. Clinical presentation and natural history
1. Clinical presentation
Sarcomas can arise in any part of the body and from any tissue and organ. Most
commonly, they arise from the soft tissue of the extremities (in particular the thigh),
the trunk (in particular the retroperitoneal area), and more rarely from upper limb,
trunk wall, or head and neck areas. Sex ratio is close to one, with heterogeneity
across histologic subtypes. Age distribution varies considerably across histologic
subtypes: rhabdomyosarcomas are most often diseases occurring in children and
adolescents; synovial sarcomas occur at a median age in the third decade of life; and
undifferentiated sarcomas or LPSs are diagnosed at a median age close to 60
years.3–5
A progressively growing lump, swelling, or pain is the usual revealing
symptom of sarcomas. Sometimes the lump has been noticed for years by the patient
and his or her family, and was mistakenly regarded as a benign lesion requiring no
further exploration. The consultation is often triggered by a recent change in the
clinical behavior of the tumor.
For deeply seated tumors, gastrointestinal or gynecologic bleeding is the initial
symptom, and weight loss and fever are the constitutional symptoms.
Not unusually, sarcomas are detected incidentally at the occasion of an
unrelated clinical or radiologic examination.
Sarcomas are rare tumors, and will be rarely encountered by any
nonspecialized physician. An inappropriate initial biopsy or surgical removal can
affect the risk of relapse, survival, and the overall success of the final treatment.7,8 It
is therefore important to remember, as proposed by the Scandinavian Sarcoma
Group, that any tumor mass above 5 cm with no obvious cause should be considered
as a sarcoma unless proven otherwise. Discussion with an expert team and then
carefully planned biopsy should be advised at this stage.
 2. Tumor progression
Primary sarcoma tumors tend to grow progressively and invade the adjacent organ.
This is particularly observed in tumors occurring in sites where symptoms are late,
for example, in the retroperitoneal area.
Metastatic spread of all sarcomas tends to be through the blood rather than
through the lymphatic system. The lungs are the most frequent site of metastatic
disease. Liver metastases are observed mainly in abdominal sarcoma, such as GIST
or peritoneal sarcomas. Metastases to soft tissue are observed selectively in a
molecular subtype of myxoid LPSs and in some LMSs. Bone and central nervous
system (CNS) metastases are rare except for certain histologic subtypes, such as
alveolar soft-part sarcoma. Lymph node metastases are also observed in selected
subtypes (e.g., epithelioid sarcomas, alveolar soft part sarcomas).
3. Grading and staging
Sarcoma staging is based on the size of the primary tumor (T), the presence of
invaded lymph nodes (N), the presence of metastasis (M), and the grade of the
tumor.3,4
a. WHO grade and TNM
Tumor grade is an important parameter to be determined for an optimal staging of
the tumor. The WHO classification is usually recommended, and it considers
three grades (G1, G2, or G3) depending on mitotic rate, differentiation, and the
presence of necrosis in the primary tumor. This grading is applied to most but
not all histologic subtypes of sarcomas. When unknown, the grade is considered
as GX.
The primary tumor (T) is T1 when the maximal size of the primary tumor is
5 cm (2 in.) or less, and T2 when above. T1a or T2a indicates a tumor above the
superficial fascia, and T1b or T2b, beneath. When unknown, it is classified as
TX.
The tumor is N0 when it has not spread to the regional lymph nodes, and N1
if the tumor has spread to the regional lymph nodes. When unknown, it is
classified as NX.
The tumor is M0 if no distant metastases of sarcoma are found, and M1
otherwise. When unknown, it is classified as MX.
b. Stage
The clinical stage is determined by grouping the information on T, N, M, and G.
■ Stage IA is T1, N0, M0, and G1 or GX.
■ Stage IB is T2, N0, M0, and G1 or GX.
■ Stage IIA is T1, N0, M0, and G2 or G3.
■ Stage IIB is T2, N0, M0, and G2.
■ Stage III is either T2, N0, M0, and G3 or any T, N1, M0, and any G.
■ Stage IV is any T, any N, M1, and any G.
For specific histological subtypes, specific parameters and prognostic tools
 are applied. The prognostic classification of GIST, for example, can be made
with different classification models that use 2 digits (size, mitotic rate; NIH
Classification), 3 digits (the same, with organ origin; Miettinen Classification),
4 digits (the same, with tumor rupture, in the revised NIH
classification/Joensuu), and 5 digits (same with the nature of the mutation).

II. CLINICAL MANAGEMENT OF SOFT-TISSUE AND VISCERAL SARCOMAS

A. Imaging, biopsy, histologic classification by an expert team
A possible sarcoma should be suspected in the presence of a deep-seated tumor over 5
cm, without a clear etiologic diagnosis. Obviously, tumors smaller than 5 cm can be
sarcomas, but the frequency is much lower in this subgroup.
Ultrasound can be proposed for specific presentations. However, magnetic
resonance imaging (MRI) for limb and pelvic tumors and computed tomography (CT)
scan for any site should always be performed when a sarcoma is suspected, to establish
the size and location of the tumor.
A careful biopsy should be first considered, either needle biopsy or open surgery,
optimally after a multidisciplinary discussion with a team with experience in sarcoma
management.3,4,7,8
Histologic diagnosis, as mentioned previously, is complex and often requires a
review by a specialized sarcoma pathologist for optimal classification. It is sometimes
difficult to distinguish a benign tumor (e.g., lipoma) from a very well differentiated
liposarcoma—WDLPS—(aka atypical lipomatous tumor [ALT]). A molecular analysis
to detect the presence of the 12q13 amplicon of ALT/WDLPS is needed. It has been
shown that, even when unsolicited, secondary opinions resulted in modification of the
definitive diagnosis of sarcoma in 20% to 30% of the cases, including major changes
from benign to malignant tumors, sarcoma to carcinoma, and so on.7
Because sarcomas are rare, it is useful to manage them within a multidisciplinary
team with greater collective experience.
B. Treatment of primary tumor
Despite the heterogeneity of histologic and molecular subtypes, soft-tissue and visceral
sarcomas are still treated according to clinical practice guidelines, which have
traditionally proposed similar approaches of treatment across histotypes.3,4
However, specific treatment approaches are now more frequently adapted to the
different histologic or molecular subtypes of sarcomas, in both localized-phase and
metastatic settings. Specific surgical (re-resection) or adjuvant (radiotherapy or
chemotherapy) strategies are proposed, depending on the nature of the primary treatment
applied to the patient and the quality of histologic resection of the primary tumor.
The emergence of specific cytotoxic and targeted therapies has led to a rationally
based, personalized management for subsets of sarcoma, with significant survival
improvement. The rapid emergence of novel molecular subsets, within several sarcoma
types, is now guiding the clinical development of novel agents.
 Still, the quality of the initial diagnostic procedure and of the primary surgery
remains the key predictive factor for the risk of relapse and death.
1. Surgery and radiotherapy
Surgery is the foundation of the treatment of primary tumor.3,4
The objective of surgery is to remove a tumor with a planned en bloc
resection, without opening the tumor, removing the adjacent organ or tissues if
invaded. This can be technically complex in sites such as the retroperitoneum, where
tumors often invade multiple organs. In limb sarcoma, conservative surgery, wide
local resection, is most often feasible. Still, a proportion of patients will require
excision of the involved muscle group from origin to insertion, compartmentectomy,
or more rarely amputation. When complete surgical removal is not feasible, this
defines a locally advanced tumor. Neoadjuvant treatment can be proposed in this
case to enable resection matching the oncologic rules for sarcoma.
Histologic examination of the resection specimen will be important to evaluate
prognosis and subsequent therapeutic strategy: when surgical resection was
macroscopically incomplete, it is qualified as R2. It is qualified as R1 when
complete resection was performed, but tumor cells are present on the margins of the
resected specimen, and R0 when normal tissue is present on all margins of resected
specimens. Re-resection of R2 or R1-resected sarcomas should be discussed in an
expert multidisciplinary board.
2. Neoadjuvant and adjuvant radiotherapy
Treatment of the primary tumor involves surgery combined with radiation therapy for
all G2 or G3 tumors, as well as for most T1b or T2 lesions. Radiation therapy can
be given in the neoadjuvant setting, or in an adjuvant setting, with a similar tumor
control rate in the single randomized trial that compared these two treatment
modalities.9 Adjuvant radiotherapy reduces the risk of local relapse. It is most often
given in the form of external beam radiotherapy, with 50 Gy given in 2-Gy fractions
over a 5-week period, even if brachytherapy has also been used.9–11
3. Neoadjuvant and adjuvant chemotherapy
The role of adjuvant chemotherapy remains controversial.12–16 A meta-analysis of
individual patient data, including randomized trials performed from 1970 to 1990,
indicated a significant decrease in the risk of disease recurrence (either local or
distant) and a marginally significant decrease in the risk of death in patients treated
with adjuvant chemotherapy.12 More recent studies exploring the role of adjuvant
chemotherapy (in comparison with no adjuvant chemotherapy) reported no
consistent results: the largest EORTC 62931 study in particular, which included
over 350 patients, failed to demonstrate a significant improvement in relapse-free
survival (RFS) or overall survival,13 while a smaller trial from the Italian Group
showed a significant improvement of RFS.14 Age more than 40, male gender, and R1
resection were reported as predictive factors for a beneficial adjuvant
chemotherapy, and some investigators believe that adjuvant therapy is indicated for
 patients whose histologic type, grade, or location is known to convey a poor
prognosis.15 No strong recommendations can be issued regarding the population in
whom to propose adjuvant cytotoxic chemotherapy in soft-tissue sarcomas. If
proposed, a doxorubicin (Adriamycin)-based adjuvant chemotherapy should be
recommended for non-GIST sarcoma. Other adjuvant therapeutic strategies remain
under evaluation, including a combination of cytotoxic agents with hyperthermia, as
well as isolated limb perfusion with tumor necrosis factor and melphalan.2,16 It may
be of interest to note that a single randomized study testing neoadjuvant
chemotherapy in operable patients was conducted, but it failed to demonstrate an
improvement for overall survival or RFS, or for the nature of surgery allowed by
neoadjuvant treatment.17
For GIST, the administration of imatinib during 3 years in an adjuvant setting is
associated with a significant improvement in both RFS and overall survival.
Adjuvant imatinib is given for patients at high risk of relapse. Whether adjuvant
imatinib prevents or merely postpones relapse in these patients is, however, still
unclear.18–20
C. Treatment of metastatic or locally advanced tumors
1. Locally advanced nonresectable tumors, local and distant relapses
Isolated local relapses should be treated with a curative intent, with the same rules
as those described for the primary tumor. Metastatic relapse may also be amenable
to a curative surgical strategy.3,4,21 Surgical resection of minor lung metastases can
be proposed in patients with a prolonged time between surgery of the primary tumor
and metastatic relapse. About 20% of the patients achieving complete remission
achieve long-term progression-free survival (PFS) and cure.21
2. Chemotherapy
Despite their diversity, there are a few differences regarding responsiveness to a
standard soft-tissue sarcoma regimen across sarcomas. GISTs, rhabdomyosarcomas,
Ewing sarcoma, dermatofibrosarcoma protuberans, solitary fibrous tumors (also
called hemangiopericytomas), inflammatory myofibroblastic tumors, alveolar soft
part sarcoma, clear cell sarcomas, and epithelioid sarcomas respond differently to
different regimens. GISTs, in particular, should not be treated with cytotoxic
chemotherapy.3,4
The goal of therapy for patients with advanced disease is primarily palliative.
However, about 20% of patients who achieve complete remission are in fact cured,
and in about 3% to 4% of patients the “partial remission” or “stable disease” does
not reprogress in the following 10 years.
■ The most important chemotherapeutic agent is doxorubicin, which can be used
either as a single agent, or in combination with ifosfamide or dacarbazine
(DTIC), or both.22,23 In a first-line setting, no significant improvement in overall
survival was observed with a combination treatment, even though response rate
and PFS were found to be superior in patients aged under 60 using combination
 treatment.23
■ Ifosfamide may be used either as a single agent in second line, or can be
included in frontline chemotherapy combinations. It is always given together
with the uroprotective agent mesna to prevent hemorrhagic cystitis.23,24
■ Trabectedin is a drug that has been found to be active in patients with advanced
sarcoma progressing after treatment with doxorubicin. It is used as a single
agent over a 24-hour infusion. Long-term administration provided prolonged
PFS in a randomized trial, and select molecular subtypes of sarcomas showed
high response rates to this agent. Trabectedin is not approved in all countries.25–
29
■ Pazopanib is a multitarget tyrosine kinase inhibitor targeting VEGFR2 in
particular. It has demonstrated antitumor activity in all sarcomas except LPS,
and is approved in all countries.30
■ Dacarbazine, a marginal agent by itself, adds significantly to doxorubicin or
gemcitabine in prolonging remission duration and survival, as well as in
increasing the response rate.22,31
■ Gemcitabine is an active agent, more so when combined with DTIC or
docetaxel.31,32
■ Paclitaxel, but not bevacizumab, has demonstrated single-agent activity in
angiosarcoma.33
■ Ewing sarcoma and rhabdomyosarcoma—particularly in children—are
responsive to dactinomycin, vincristine, or etoposide, while other histologic
subtypes of sarcoma do not generally respond to these agents (see Chapter 18).
■ GISTs have a high response rate with prolonged remissions after treatment with
imatinib (400 mg daily). Patients who do not respond or who have a relapse
after initial therapy may respond to higher doses of imatinib (up to 800 mg daily,
in divided doses), to sunitinib as second-line, or to regorafenib as third-line.
Patients with GIST and exon 9 mutations respond better and for longer periods
to 800 mg of imatinib (than to 400 mg).34–36
a. First-line chemotherapy in patients with advanced disease
The highest response rates and PFS with first-line chemotherapy regimens are
obtained with combinations of doxorubicin and ifosfamide (high-dose AI) with
or without the addition of DTIC.22,23 Vincristine at a dose of 2 mg maximum or
1.4 mg/m2 weekly for 6 weeks and then once every 3 to 4 weeks is
recommended only for treatment of rhabdomyosarcoma and Ewing sarcoma (see
also Chapter 18).
A high-dose anti-inflammatory regimen combines doxorubicin (75 mg/m2
IV, 25 mg/m2/day for 3 days), ifosfamide (2.5 g/m2 IV over 2 to 3 hours daily for
4 days), mesna (500 mg/m2 with the first ifosfamide dose), and ifosfamide
(1,500 mg/m2 as a continuous infusion over 24 hours for 4 days in 2 L of alkaline
 fluid). Granulocyte colony-stimulating factor must be administered
subcutaneously (SC) until granulocyte recovery to 1,500/μL. Alternatively,
pegfilgrastim at a dose of 6 mg is given on day 5. The cycles are repeated every
3 weeks.
A recent clinical trial comparing doxorubicin and gemcitabine plus
docetaxel as first-line treatment of soft-tissue sarcoma in advanced phase
showed a higher toxicity and lower response rate with gemcitabine plus
docetaxel, confirming that doxorubicin regimens remain standard in first line.37
b. Specific protocols for first-line treatment of Ewing sarcoma and
rhabdomyosarcomas
For Ewing sarcoma and rhabdomyosarcoma, therapy may be continued, and
dactinomycin (2 mg/m2 as a single dose or 0.5 mg/m2 daily for 5 days) may be
substituted for doxorubicin, with continuation of the regimen for a total of 18
months.
In Ewing sarcoma, the VDC/IE regimen uses ifosfamide and etoposide,
alternating with the so-called vincristine, Adriamycin, and cyclophosphamide
(VAdriaC) regimen. Vincristine (1.5 mg/m2) is given weekly three times for the
first two cycles of VAdriaC and then on day 1 only. Doxorubicin is given at a
dose of 75 mg/m2 and cyclophosphamide at 1,200 mg/m2 with mesna. After 3
weeks, the IE regimen combines ifosfamide at a dose of 1,800 mg/m2 daily for 5
days (with mesna) and etoposide at a dose of 100 mg/m2 daily for 5 days.
Chemotherapy cycles are alternated every 3 weeks for 39 weeks. Alternatively,
the EuroEwing protocol uses an induction treatment with six courses of VIDE,
combined in a single-treatment containing vincristine, ifosfamide, doxorubicin,
and etoposide.
c. Second-line chemotherapy
Secondary chemotherapy for patients with sarcoma provides relatively low
response rates, but sometimes durable PFS, at a median duration of 4 months for
active agents, with prolonged PFS observed in a proportion of patients.
Ifosfamide provides response rates in about 20% of patients. High-dose
ifosfamide (9 to 12 g/m2, sometimes still higher in some research teams) may
produce responses in patients resistant to lower doses in combination.24,38
Trabectedin is known to be active in patients after doxorubicin and
ifosfamide treatment. Published reports account for a median PFS close to 4
months, with a response rate generally close to 10%. Improvement in overall
survival was recently reported in a randomized study comparing trabectedin
versus no treatment in sarcoma with translocation. A recently reported
randomized study in LMS and LPS demonstrated an improvement in PFS.
Importantly, administration of trabectedin beyond six courses was found to
prolong PFS in a recent randomized study, and some patients have received up to
30 courses of treatment and are progression-free over 5 years after initiation of
 this treatment. Trabectedin is administered at a dose of 1.5 mg/m2 IV over 24
hours on day 1 only, preceded by dexamethasone (8 mg orally).24–29
Gemcitabine as a single agent in LMS or in combination with docetaxel or
DTIC in other sarcoma types, is also an actively used drug. The combination of
gemcitabine and docetaxel improved response rate, time to progression, and
survival in a randomized trial as against gemcitabine alone, while gemcitabine
significantly improved PFS, overall survival, and response rate over DTIC
alone in an another clinical trial. No study has compared yet gemcitabine plus
DTIC (GemDTIC) with gemcitabine plus docetaxel (GemTax), and both are
treatment options for soft-tissue sarcomas in second- or third-line therapies.3,4
The GemTax regimen combines gemcitabine, 900 mg/m2 over 90 minutes on
days 1 and 8, with docetaxel, 100 mg/m2 on day 8 only, every 21 days. The
duration of gemcitabine infusion is critical, as it can be converted to its active
metabolite, gemcitabine triphosphate, only at a rate of 10 mg/m2/minute. Doses
are reduced by 25% to 675 and 75 mg/m2, respectively, for patients with
extensive prior therapy or pelvic radiation.
The GemDTIC regimen combines gemcitabine, 1,800 mg/m2 over 180
minutes on days 1 and 15, with DTIC, 500 mg/m2 on days 1 and 15, every 28
days.
Patients who have progressed or are not candidates to doxorubicin,
ifosfamide, GemTax, or trabectedin should be entered in a phase II study of a
new agent to see if some activity can be established, because other reasonably
good alternatives do not exist.
D. Targeted treatment of GIST and other sarcomas
Imatinib (400 mg/day) is the standard drug for treatment of advanced GIST, with the
exception of tumors with mutations on exon 9 of the KIT receptor; the latter tumors
should receive upfront a dose of 800 mg/day. When multifocal progression is
demonstrated with imatinib 400 mg/day, dose escalation up to 800 mg/day provides
transient tumor control in 40% of the patients for a median PFS close to 4 months. In a
second-line setting, sunitinib at a dose of 50 mg/day, 4 weeks on and 2 weeks off,
provides a median PFS close to 5 months. A continuous dose of 37.5 mg/day is
proposed as an alternative by some teams. It has been shown that if imatinib and
sunitinib fail, regorafenib at a dose of 160 mg/day, 3 weeks on and 1 week off,
improves PFS over placebo, with a median PFS close to 5 months.19
Pazopanib is a multitarget tyrosine kinase inhibitor that is active in advanced soft-
tissue sarcoma after a doxorubicin-containing regimen. In a phase III randomized trial
comparing this agent with placebo, it was found to significantly improve PFS, but not
overall survival. The activity of pazopanib in LPS could not be demonstrated in a single
trial that studied different molecular subtypes of LPS. Additional clinical trials are
exploring the activity of pazopanib in the different subtypes of LPS.
 Metastatic dermatofibrosarcoma protuberans also shows high rates of response and
tumor control with imatinib, which blocks the PDGF/PDGFR autocrine loop active in
these tumors.2
Response to mammalian target of rapamycin (mTOR) inhibitors have been reported
in malignant PEComa, as a consequence of the losses of the TSC1 or TSC2 genes
observed in these tumors.2
E. Complications of cytotoxic chemotherapy
About 40% of patients have documented or suspected infection related to drug-induced
neutropenia at some time during their course of treatment. These infections require
prompt management with broad-spectrum antibiotics at the onset of febrile neutropenia.
Grade 4 thrombocytopenia (i.e., lower than 25,000/μL) is observed rarely with
single agent doxorubicin and even rarely with high-dose combination treatment. Platelet
transfusion is required in case of bleeding if platelets drop below 10,000/μL.
Mucositis occurs in fewer than 25% of patients, may interfere with oral intake, or
may act as a source of infection.
Congestive heart failure can be caused by doxorubicin in a dose-dependent manner.
When a dose below 450 mg/m2 is given, congestive heart failure occurs in fewer than
5% of patients.
Renal failure is a rare complication associated with ifosfamide. Fanconi syndrome,
particularly manifested by a significant loss of bicarbonate, is a dose-related
complication of ifosfamide, occurring in 10% to 30% of patients at standard ifosfamide
doses and in close to 100% with high-dose regimens; the morbidity can be minimized
by the routine use of alkaline infusions and correction of electrolyte levels with
intravenous or oral replacement therapy. Only rarely does the nephrotoxicity progress to
renal failure, often precipitated by dehydration or administration of minimally
nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs). Patients
treated with ifosfamide should be instructed to avoid NSAIDs, even years after
chemotherapy!
CNS toxicity is a rare but serious complication connected with ifosfamide therapy:
patients frequently demonstrate minor confusion, disorientation, or difficulty with fine
movements. Somnolence and coma are rarely seen in patients.
Hemorrhagic cystitis is a complication associated with cyclophosphamide and
ifosfamide therapy, which can be prevented in most cases by administration of another
agent, mesna, before and after each ifosfamide dose, allowing higher doses of
ifosfamide to be used.
Liver toxicity is a frequent side effect of trabectedin, and increased transaminase
levels are observed in the first 10 days after administration of trabectedin. It then
normalizes progressively before the next course. The drug should not be given when
alkaline phosphatase (ALP) is more than 2.5 times the upper normal limit (UNL).
Nausea and vomiting are frequent complications that accompany doxorubicin,
DTIC, and ifosfamide therapy. Alopecia and fatigue are frequently observed after
 doxorubicin, cyclophosphamide, ifosfamide, and docetaxel administration.
F. Special precautions
1. Ifosfamide
Patients must be well hydrated and in an alkaline pH to prevent CNS toxicity and to
minimize nephrotoxicity. Sodium bicarbonate should be added to IV fluids, and fluid
administration should be adjusted to produce a urine output of at least 2 L/day and to
maintain the serum bicarbonate concentration at 25 mEq/L or higher. Other
electrolytes should be adjusted as needed on a daily basis.
2. Doxorubicin
Extravasation should be avoided, and doxorubicin must be administered through a
central venous catheter. Attention to cumulative dose administered (which varies
according to the schedule of administration) is critical to minimize the risk of
cardiac toxicity.
3. Trabectedin
Extravasation should be avoided, and trabectedin should be administered through a
central venous catheter.
G. Treatment response
CT, MRI, and positron emission tomography (PET) are the most frequent methods used
to evaluate response to treatment in sarcoma. Response is measured using classical
volumetric and dimensional measurements such as RECIST 1.1.39 Changes in the
density of the tumor (Choi criteria) and metabolic response (PET-CT) are also used to
further refine the evaluation. These tools are particularly useful in distinguishing a false
progression (i.e., a biologic response from a volumetric increase in the size of the
lesion).

III. CONCLUSIONS
The treatment of sarcoma requires management by an experienced team for the initial
diagnosis, the treatment of primary tumor, and the management of advanced disease.
Histologic diagnoses are complex and often involve molecular biology. Surgery represents
the mainstay in treatment and requires perfect adherence to clinical practice guidelines.
Advanced sarcomas are curable in a small proportion of patients. Treatment in localized
and advanced phases is now routinely modified in accordance with the clinical
characteristics of the patients as well as the histologic and molecular characteristics of the
sarcoma.

Acknowledgments
Supported by grants from the LYRIC (INCA 4664), NetSARC (INCA), RREPS (INCA), LabEx
DEvweCAN, Eurosarc (FP7-278742), and Ligue contre le Cancer, Comité de L’Ain.

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I. INCIDENCE AND NOSOLOGY
Bone sarcomas account for about 10% of all sarcomas, and, therefore, 0.1% to 0.2% of all
malignant tumors in adult patients. They make up 5% to 10% of malignant tumors in
children, and 30% to 50% of bone sarcomas arise in children.1,2 The histologic subtypes of
bone sarcomas are less heterogenous than those of soft tissue sarcomas, yet these tumors
show very heterogenous behavior and require very different treatments.
Osteogenic sarcoma (OS), chondrosarcoma, Ewing sarcoma (ES), and a composite
group of rarer histologic subtypes (e.g., undifferentiated pleomorphic sarcoma,
leiomyosarcoma) represent the most common histologic subtypes of bone sarcomas. The
term osteosarcoma refers to OS of the bone, that is, a malignant tumor of the bone,
producing osteoid matrix. OS is the most frequent primary tumor of bone with an incidence
of 0.2 to 0.3/100,000/year. The incidence is higher in adolescents and peaks at the age of
15 to 19. OS arise most often from the limbs, specifically in the superior extremity of the
tibia and lower extremity of the femur, but can be observed in any bone site, including the
toes and head and neck.
Chondrosarcoma is the most common bone sarcoma of adults, with an incidence of
close to 0.2/100,000/year. The age at diagnosis is most often between 30 and 60.
Chondrosarcomas arise most often from the pelvic or shoulder girdle, and from flat bones,
including the skull, but can also arise from any other bone site.
ES is the third most common bone sarcoma, occurring most frequently in children and
teenagers with a median age of 15 years at diagnosis, and in about 30% of cases in adults,
up to 80 years. Together with primitive neuroectodermal tumors, they constitute the Ewing
Family of Tumors (EFT), defined by a specific set of translocations, the most frequent
being the t(11;22) chromosome translocation that results in the EWS-FLI-1 gene
rearrangement. Members of the EFT should be regarded as the same tumor. ES may arise
from any bone, and soft tissues as well, in 30% of the cases, and its treatment in both cases
is similar. The pelvic bones, thoracic wall, and vertebrae are frequent primary sites.
A small subgroup of patients present with primary sarcoma of the bone with different
histologic subtypes. Most of these were designated as malignant fibrous histiocytosarcoma
(MFH) of the bone, but are now categorized more often as undifferentiated pleomorphic
sarcoma of the bone or bone leiomyosarcoma. They tend to occur at an adult age, and often
affect the long bones, with a clinical presentation close to that of osteosarcoma of the
bones. They are usually treated with osteosarcoma protocols, but have distinct age
 distributions and clinical behavior.
Chordoma is another rare malignant tumor of the bone, arising from remnants of the
notochord mostly in the sacrum, vertebrae, and from the base of the skull, with an incidence
of 0.1/100,000. The median age at diagnosis is 60, with skull-base presentations generally
affecting a younger population, including children.
Giant cell tumors of the bone are most often locally aggressive tumors arising from the
long bone of young adults, with frequent local relapses, and occasional distant metastases
in 15% to 20% of patients. Giant cell tumors of the bone have an incidence of close to
0.2/100.000/year.
There are several other rarer malignant bone tumors, such as adamantinoma. It is
important to remember, however, for differential diagnosis, that the first cause of bone
tumors is secondary cancers, which should be investigated thoroughly, particularly in adult
patients aged above 50.

II. PREDISPOSING FACTORS FOR BONE SARCOMA

Several risk factors for the development of bone sarcoma have been identified. These
include genetic predispositions, predisposing diseases, and previous radiation therapy.2
There are a variety of genetic familial predispositions associated with an increased
risk of cancer. Li-Fraumeni syndrome is caused by a mutation of a tumor suppressor gene
TP53. Patients with this rare syndrome are more prone to developing a variety of cancers,
including bone and soft tissue sarcomas. Hereditary retinoblastoma is caused by a mutation
in the RB1 gene. Affected patients are prone to developing bilateral retinoblastoma and
have an increased risk of developing bone or soft tissue sarcomas, including osteosarcoma
or leiomyosarcoma at adolescence or in early adulthood. Bessel-Hagen disease, also
known as hereditary multiple exostosis, is a rare inherited skeletal disorder, caused by
mutations of the EXT1 or EXT2 genes, which causes short stature and deformities of the
limbs and extremities. Each osteochondroma can potentially develop into a malignant bone
sarcoma, most often chondrosarcoma. Ollier disease, or multiple enchondroma, is also a
rare disease often caused by mutations of IDH1 and IDH2 genes. OD has a wide variety of
clinical presentations. The multiple enchondromas characteristic of this disease have a risk
of developing into a bone sarcoma (most often, a chondrosarcoma).
Paget disease of bone is a benign disorder characterized by increased bone resorption
accompanied by aberrant new bone formation. Bone sarcomas (mostly osteosarcomas)
develop in about 1% of people with Paget disease, usually when many bones are affected.
It affects mostly people older than 50. The prognosis of these tumors is generally poor. The
incidence of transformation seems to have decreased since the introduction of
bisphosphonates for the treatment of Paget disease.
Radiotherapy increases the risk of bone sarcomas. Sarcomas can arise following
exposure to radiation given to treat other cancers in the area. The average time between
radiation exposure and diagnosis of a bone sarcoma is about 10 years. Radiation exposure
is, however, a very rare cause of bone sarcomas.
III. CLINICAL SYMPTOMS AND DIAGNOSIS OF BONE SARCOMAS
Because of their rarity and the complexity of histologic classification as well as of
multimodal treatment, all patients with a suspected primary bone sarcoma should be
referred to a specialized reference center with expertise in the treatment of primary bone
tumors, involving dedicated pathologists, radiologists, orthopedic surgeons, radiation
oncologists, medical oncologists, and pediatric oncologists.1,2
Symptoms of bone sarcomas depend on the size and location of the tumor. The most
common symptom is bone pain, progressively increasing, at night, together with swelling,
and functional impairment. Pathologic fractures can be the first symptom. Nerve or
vascular compression is less frequent. Less common also are fever, unexplained weight
loss, fatigue or anemia.
After a clinical examination, bone X-rays will generally be proposed: bone
destruction, cortical fracture, and abnormal osteogenesis in the soft part are the features of
bone tumors (Fig. 18.1). Often, the radiologic presentation enables one to recognize a bone
tumor such as OS. Magnetic resonance imaging (MRI) of the whole anatomical
compartment with adjacent joints is required for the diagnosis of extremities and pelvic
tumors, and enables the clinician to assess the size and spread in the bones or in the
surrounding soft tissues. Computerized tomography scan (CT scan) is recommended for the
precise assessment of the primary bone tumor of the trunk and head and neck. Thoracic,
abdominal, or pelvic CT scan is also an essential part of the workup for staging, enabling
the clinician to assess the metastatic spread of the sarcoma in the lungs and beyond.
Positron emission tomography (PET scan) with F18 glucose and bone scintigraphy with
Tc99 are also frequently used to assess the tumor spread and to analyze bone remodeling
and metabolic activity.
Biopsy must be performed by an experienced radiologist or surgeon after
multidisciplinary assessment of the clinical and radiologic file, to define the biopsy track
(which will be subsequently removed en bloc). Core needle biopsies or
incisional/excisional biopsies can be performed, depending on the presentation. The
histopathologic assessment of the tumor must be performed by an experienced
pathologist.1,2 The determination of the molecular alteration of the tumor, for example, the
presence of a fusion transcript EWS-FLI-1, or of the t(11,22) translocation for ES is of
growing importance for the management of bone sarcomas, as it is for soft tissue sarcomas
as well. Grading of the sarcoma is also a key parameter in selecting the treatment, and
should be determined by an experienced pathologist. Blood samples are part of the workup
to evaluate the function of the liver, kidneys, and blood cells. An increase in blood levels
of alkaline phosphatase and lactate dehydrogenase is often detected in bone sarcoma, and
may reflect the importance of tumor mass, and have prognostic value.
FIGURE 18.1 Osteosarcoma of the lower extremity of the femur.

After the workup, the histologic subtype of the bone tumors as well as the stage of the
tumor will be established, enabling the determination of a therapeutic strategy and
refinement of the prognosis.

IV. STAGING
Bone tumors are staged according to the American Joint Committee on Cancer (AJCC)
criteria as well as the criteria of the Musculoskeletal Tumor Society.
The criteria in the AJCC staging system are tumor grade, tumor size, and presence and
sites of metastases. There are four tumor grades:
■ Grade 1: Well differentiated—low grade
 ■ Grade 2: Moderately differentiated—low grade
■ Grade 3: Poorly differentiated—high grade
■ Grade 4: Undifferentiated—high grade
Tumors are divided into size categories of 8 cm or more. Tumor size determines A
and B, substages of stages I and II, and stage III.
■ T1 = ≤8 cm
■ T2 = >8 cm
■ T3 = Discontinuous tumors in the primary bone site
Metastatic status is subdivided by presence and location of metastases:
■ M0 = No distant metastases
■ M1 = Distant metastases
■ M1a = Lung
■ M1b = Other distant sites, including lymph nodes
The AJCC stage grouping is provided in the AJCC Cancer Staging Manual, 7th
edition.
The Musculoskeletal Tumor Society staging system stages sarcomas according to
grade and compartmental localization. The Roman numeral reflects the tumor grade.
■ Stage I: Low grade
■ Stage II: High grade
■ Stage III: Any-grade tumor with distant metastasis
■ Stage A: Confined to bone
■ Stage B: Extending into adjacent soft tissue
Stage IA tumor is a low-grade tumor confined to bone, and a stage IB tumor is a low-
grade tumor extending into soft tissue, and so forth.
Because the histologic subtypes of sarcoma require specific treatment, the following
sections will focus on the general principles of the treatment of each of these tumor types.

V. OSTEOSARCOMA
High-grade OS, also called conventional osteosarcoma, is a tumor with a poor prognosis
in the absence of effective chemotherapy. Two randomized clinical trials comparing the
administration of neoadjuvant and/or adjuvant chemotherapy have led to the conclusion that
the administration of cytotoxic chemotherapy reduces the risk of metastatic relapse, which
is the primary cause of death in these patients.3–5 Conventional osteosarcoma should be
distinguished from low-grade juxtacortical or parosteal OS, which is rarer and often
affects the lower femur in young women, and should not receive cytotoxic chemotherapy
unless a dedifferentiated component exists in the tumor. OS is the most common primary
bone sarcoma, typically affecting patients 10 to 25 years old, in two-thirds of cases in the
lower femur or upper tibia. About 10% of patients have metastases at initial diagnosis.
Relapses of OS occur most often in the lung, more rarely in the bones. Because
conventional osteosarcoma is a high-grade tumor, by definition, and is accompanied by a
soft tissue mass in 90% or more of patients, it is usually staged as IIB or IIIB, depending on
 the demonstration of metastatic disease in lung or bone.
A. Treatment strategy
The management of high-grade OS is multimodal, generally requiring the administration
of specific cytotoxic chemotherapy regimens in a neoadjuvant setting, followed
generally after 3 months of neoadjuvant treatment by a surgical resection of the primary
tumor. The administration of neoadjuvant chemotherapy makes it possible to organize
conservative surgery, in particular, the elaboration of the specific prosthesis for the
replacement of the affected joint.5–8 The rules of surgical resection of the tumor are
those of all sarcomas, with an en bloc complete macroscopic resection aiming for R0
staging (no tumor cells on the margins of the resection specimen). Adjuvant
chemotherapy is administered after the local treatment and is usually guided by and
adapted to the quality of response observed on the resection specimen after neoadjuvant
treatment.1,2,9 This parameter, the percentage of residual tumor cells in the tumor, is one
of the most important prognostic factors in high-grade OS. When surgical removal of the
tumor is not possible, or when it is exceedingly mutilating, exclusive radiotherapy is
generally discussed, even though the local control rate remains poor using radiotherapy
alone in this histologic subtype (in contrast to ES). When the tumor has been treated by
a primary excision of the whole tumor, adjuvant chemotherapy is proposed, with a
discussion of a surgical removal of the tumor bed at the multidisciplinary board.
B. Cytotoxic chemotherapy
Chemotherapy is therefore administered either in the neoadjuvant or, more often, in the
neoadjuvant and/or the adjuvant situation. When administered preoperatively, the
quality of histologic response is used to adapt the treatment in the postoperative phase.
Patients who show a complete response to preoperative chemotherapy, with tumor
destruction of at least 90%, have significantly improved survival and decreased relapse
rates. Response rates in evaluable tumors range from 30% to 80%. Cure of primary
disease with adjuvant chemotherapy is close to 60% in large series.
The four major standard single agents in the treatment of osteosarcoma are cisplatin,
doxorubicin, ifosfamide, and high-dose methotrexate. A variety of regimens may be
recommended on the basis of preliminary or more extensive evaluation. The most
documented regimen is the MAP protocol.
1. MAP
■ Doxorubicin 75 mg/m2 intravenously (IV) at week 1 and week 6, and
■ Cisplatin 120 mg/m2 at week 1 and week 6
■ High-dose methotrexate (with leucovorin rescue): 12 g/m2 at weeks 4, 5, 9, and
10.
Twenty-four hours after the start of the methotrexate infusion, leucovorin 15 to
25 mg is administered by mouth every 6 hours for at least 10 doses or
intramuscularly if the oral medication is not tolerated. Serum methotrexate levels
should be followed and should fall at approximately 1 log/day. When methotrexate
concentration falls below 10−7 M, leucovorin may be safely discontinued. IV
 hydration is required whenever oral intake is inadequate to produce sufficient urine
output as previously defined, for abnormal serum methotrexate concentration, for
persistent vomiting, or for early toxicity.
Two courses of therapy are administered preoperatively. Postoperative therapy
depends on the response of the primary tumor. Patients with tumor necrosis of 90%
or more continue on the same regimen for four postoperative courses without
cisplatin (CDDP) on the last two courses. If there are more than 10% residual tumor
cells, patients are switched to a protocol termed MAPIE, in which high-dose
ifosfamide is administered in combination with doxorubicin at 12 g/m2 dose, or with
etoposide at a 14 g/m2 dose.
2. Alternative regimens
The MAP/MAPIE regimen was tested in large international, multicontinental cohorts
of patients, gathering over 2,000 patients in a single protocol.7,8 Other cooperative
groups have been using regimens combining these four different agents in different
proportions. Importantly, interferon alpha and bisphosphonates have been tested in
randomized trials in OSs, and have failed to improve patient outcome. They are not
recommended outside of a clinical trial in bone OSs.
C. Recurrence and treatment of refractory disease
Surgical resection of pulmonary metastases remains the only viable secondary therapy
for most patients. This modality of treatment is used when the metastases are located in
the lung only, and in limited number (usually fewer than five). Late relapses (over 18
months) and a small number of metastases are correlated with patient outcome after
complete resection of metastatic lesions. For this reason, careful follow-up for
detection of metastases while they are still at the stage of resectability is indicated.
Patients with osteosarcoma who are refractory to a combination of doxorubicin and
cisplatin may respond to high-dose methotrexate. Patients refractory to high-dose
methotrexate may respond to doxorubicin plus cisplatin; and patients refractory to both
may respond to ifosfamide or, rarely, to gemcitabine and docetaxel combinations.
However, treatment of refractory disease is usually disappointing, and participation in
studies of new agents is indicated for patients whose disease cannot be resected. High-
dose bone marrow transplantation or peripheral stem cell rescue programs have not
been demonstrated to improve prognosis.

VI. CHONDROSARCOMA
Chondrosarcomas represent again a heterogenous group of bone tumors. Low-grade
chondrosarcoma is mostly a locally aggressive disease, while grade 2 or grade 3
chondrosarcomas, which are rarer, are associated with an increased risk of metastatic
spreading and death due to the disease. Dedifferentiated chondrosarcoma is a high-grade
neoplasm with a particularly poor prognosis related to a high risk of rapid
dissemination.1,10
Chondrosarcoma is largely considered to be a chemoresistant disease, and
 chemotherapy is not considered to be a component of the standard treatment approach in
the first-line setting. Most patients with bone chondrosarcoma are candidates only for
surgical management. The rules of surgical resection of the tumor are those that apply to all
sarcomas, with an en bloc complete macroscopic resection aiming for R0 staging (no tumor
cells on the margins of the resection specimen). This is sometimes accomplished with a
mutilating procedure, including amputation. When the tumor does not allow for a complete
resection, radiotherapy can be proposed; proton beam therapy, in particular, is being
investigated in this patient group. Dedifferentiated chondrosarcoma is treated as
osteosarcoma, including the administration of neoadjuvant and adjuvant chemotherapy
similar to those used in osteosarcoma, by several teams, considering the very poor
outcome of these patients and the difficulty of performing a prospective randomized trial
given the rarity of the tumor.11 Metastatic disease should be treated with phase II protocols
in an attempt to determine some effective type of chemotherapy that may be recommended
in the future. Recently, retrospective studies and prospective trials testing targeted agents
have, however, challenged the concept that chondrosarcoma represents a uniformly
chemoresistant disease. Guidance of novel drug development with a better understanding
of the molecular biology of these tumors should enable better management of these tumors
in the near future.12

VII. EWING SARCOMA

ES is a highly malignant, small, round-cell tumor of bone and belongs to the EFT, defined
by a specific set of translocations, the most frequent being the t(11;22) chromosome
translocation that results in the EWS-FLI-1 gene rearrangement. Members of the EFT
should be considered the same tumor and require identical treatment strategies. EFT occurs
most commonly in the second decade of life, and 30% of patients are older than 18. The
most common locations of ESs are in the pelvis or the diaphysis of long tubular bones of
the extremities. Systemic symptoms of fever, weight loss, fatigue, and biologic symptoms
of inflammation such as increased ESR, CRP, and leukocytosis are not infrequent. The
predominant feature of ES of the bone is osteolysis (Fig. 18.2), sometimes with a
periosteal reaction described as an “onion skin pattern.” Metastatic disease in lung (IVA),
bone (IVB), or both is observed in up to 20% of the patients at diagnosis. Bone marrow
involvement is also not infrequent, and bone marrow aspiration and/or biopsies are a part
of the workup in ES. Bone metastases are associated with the worst prognosis.
FIGURE 18.2 Ewing sarcoma of the ulna.

A. Treatment strategy
The management of ES is multimodal, requiring first the administration of specific
cytotoxic chemotherapy regimens in a neoadjuvant setting, followed generally after 3
months of neoadjuvant treatment by a surgical resection of the primary tumor and then
radiotherapy.13–18 The rules of surgical resection of the tumor are those that apply to all
sarcomas, with an en bloc complete macroscopic resection aiming for R0 staging (no
tumor cells on the margins of the resection specimen). Adjuvant chemotherapy is
administered after the local treatment. When surgical removal of the tumor is not
possible, or when it is exceedingly mutilating, exclusive radiotherapy is generally
administered. When the tumor has been treated by a primary excision of the whole
tumor, the same rules are applied, with a discussion of a surgical removal of the tumor
bed at the multidisciplinary board.
B. Chemotherapy
Before the use of chemotherapy, the prognosis of EFT was extremely poor, with a 5-
year survival rate lower than 10% and almost half of patients dying within 1 year of
diagnosis. Chemotherapy is a major component of the treatment of EFT. The most
documented chemotherapy regimens for neoadjuvant and adjuvant treatment in a first-
 line setting are vincristine, doxorubicin, and cyclophosphamide (VDC) or
cyclophosphamide (IE), and the EuroEwing regimens.15–17
1. The VDC/IE regimen is as follows
a. The VDC regimen
■ Vincristine: 2 mg/m2 (2 mg total dose) on day 1
■ Doxorubicin: 37.5 mg/m2 IV on days 1 and 2 up to 375 mg/m2, then
Dactinomycin 1.25 mg/m2 (2 mg maximum dose)
■ Cyclophosphamide: 1.2 g/m2 IV on day 1.
Then 2 to 3 weeks later, the second part of the regimen is given. The dose-
dense regimen every 2 weeks was recently demonstrated to provide a longer
relapse-free survival and overall survival than the classic 3-weekly regimen.17
b. The IE regimen
■ Ifosfamide: 1,800 mg/m2 IV daily from D1 to D5 (with Mesna), and
■ Etoposide: 100 mg/m2 IV daily from D1 to D5.
Three dose-dense cycles of VDC/IE are given prior to surgery and local
treatment preoperatively, and four courses are given after the local treatment.
Dactinomycin is given on courses six and seven of VDC replacing doxorubicin.
2. The EuroEwing regimen
The EuroEwing protocol uses the VIDE regimen, combining vincristine, ifosfamide,
doxorubicin, and etoposide given every 21 days, for six courses with hematopoietic
growth factor support prior to the surgical intervention.18
a. The VIDE regimen
■ Vincristine: 1.5 mg/m2 (2 mg maximum total dose) on day 1
■ Doxorubicin: 20 mg/m2/day for 3 days
■ Ifosfamide: 3 g/m2/day, on days 1, 2, and 3 (with Mesna)
■ Etoposide: 150 mg/m2/day on days 1, 2, and 3
■ G-CSF (granulocyte colony-stimulating factor) is given until granulocyte
recovery to 1,500/μL
■ Cycle is repeated every 3 weeks.
In the postoperative setting, the VAI or VAC regimens are given up to seven
courses:
b. The VAI regimen
■ Vincristine: 1.5 mg/m2 (2 mg maximum total dose) on day 1
■ Dactinomycin: 0.75 mg/m2/day, day 1 and day 2 (maximum 1.5 mg/day)
■ Ifosfamide: 3 g/m2 IV daily, days 1 and 2 (with Mesna).
c. The VAC regimen
■ Vincristine: 1.5 mg/m2 (2 mg maximum total dose) on day 1
■ Dactinomycin: 0.75 mg/m2/day IV, day 1 and day 2 (maximum 1.5 mg/day)
■ Cyclophosphamide 1.5 g/m2 IV on day 1.
It is not known whether the EuroEwing and VDC/IE regimens provide
 similar long-term results in EFT. A randomized trial (EuroEwing 2012) is
ongoing to address this question.
C. Outcome after first-line treatment
When chemotherapy is used in the treatment of primary disease with surgery or
radiation therapy, prognosis depends on the size and location of the primary tumor.
Patients with large flat-bone lesions have a lower cure rate compared with those with
long-bone lesions. Most patients without metastatic disease obtain complete remission.
Patients with metastatic disease may also obtain complete remission, even though this is
rarer with bone metastases. 5-year survival is close to 70% in patients with localized
disease, compared with 20% to 30% for patients with metastatic disease. Late relapses
after 10 years are occasionally observed. Secondary sarcomas in irradiated fields are
not infrequent after ES. Most patients with bone metastases experience relapses and
ultimately die of disease.
1. Second-line chemotherapy
Occasional responses have been seen with etoposide (VP-16), topoisomerase I
inhibitors, other alkylating agents (especially ifosfamide), the nitrosoureas, and
cisplatin. A combination of etoposide and ifosfamide is now frequently used in
patients for whom those drugs were not used in initial therapy. For patients receiving
the five most active drugs (vincristine, ifosfamide/cyclophosphamide, doxorubicin,
dactinomycin) in primary treatment, second-line therapy includes topoisomerase I
inhibitor plus an alkylating agent (irinotecan, temozolomide or cyclophosphamide,
and topotecan). Secondary responses are short-lived, and the survival of a relapsed
patient with ES is measured in weeks, unless the relapse occurs after a disease-free
interval of more than 2 years. Antiangiogenic oral agents (tyrosine kinase inhibitors)
are now being tested in clinical trials.
2. High-dose chemotherapy with stem cell transplantation
Bone marrow transplantation or peripheral stem cell rescue programs are still being
investigated in patients presenting with poor prognostic features (large pelvic
primary tumors, metastatic disease, poor response to induction chemotherapy), but
have not yet been demonstrated to improve prognosis. Such regimens have been
tried with negative results in patients relapsing after standard chemotherapy, and
have been demonstrated to have no significant benefit. Clearly, this approach should
not be used outside of a clinical trial in patients.

VIII. OTHER HISTOLOGIC SUBTYPES OF PRIMARY SARCOMA OF THE BONE

(FORMER MALIGNANT FIBROUS HISTIOCYTOMA OF BONE)
These high-grade bone sarcomas, which are not classified as OSs, ESs, or
chondrosarcomas, gather more heterogenous entities than previously anticipated.1,2,19,20
Previously lumped together as MFH of the bone, these tumors have more recently been
reclassified as undifferentiated pleomorphic sarcomas, myxofibrosarcomas,
leiomyosarcomas, liposarcomas, and so on.
 Their clinical presentation is close to that of OSs, although they occur at a much older
age. On X-ray or CT scan, they are usually characterized by a purely osteolytic lesion in
bone. These tumors have a poor prognosis when treated with surgery alone, although the
number of reported series remains limited and mostly heterogenously small. Histologic
classification may often be challenging: as an example, these tumor may often be difficult
to distinguish from fibroblastic osteosarcoma with minimal (i.e., no detectable) osteoid
production, requiring review from an expert bone pathologist.
These bone sarcomas respond to the classic osteosarcoma chemotherapy regimens
that use high-dose methotrexate, doxorubicin, ifosfamide, and CDDP. Several groups have
reported the use of regimens without high-dose methotrexate, considering the age of these
patients. The optimal chemotherapy treatment of these rare tumors remains to be defined.
However, the general treatment strategy is generally that applied in osteosarcomas.19

IX. GIANT CELL TUMOR OF THE BONES

Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic bone tumor, typically
occurring in young adults between the second and third decades of life. The clinical
symptoms are those of a bone tumor with swelling, reduced joint mobility, and pain that is
often severe and intractable.
GCTB tumors contain osteoclast-like giant cells that express RANK and stromal
cells, which are the genuine neoplastic cellular component of the tumor, that express
RANK ligand (RANKL). RANKL is a key mediator of osteoclast formation, activation,
function, and survival. The overexpression of RANKL in stromal cells is likely to be
resulting from a specific point mutation of histone H3A3, which is the molecular hallmark
of this disease. GCTB grows rapidly, destroying bone and spreading into surrounding soft
tissues. In the absence of treatment, the natural history of GCTB is continued growth,
complete destruction of the affected bone, and massive tumor formation, all of which can
lead to loss of limb.21–23
Surgical intervention, often extensive curettage with burring, is the recommended
therapy for patients with resectable tumors. However, surgery is often associated with
significant morbidity, in large tumors of the limbs or of the pelvic and shoulder girdles. Not
infrequently, the site of the primary tumor (e.g., vertebrae, base of the skull, sacrum)
precludes a complete resection of the tumor. About 30% of patients with GCTB will
relapse locally, and about 10% to 15% of patients will present with lung metastases. These
lung metastases may have an indolent course in a large proportion of patients, although
aggressive behavior can also eventually be observed. GCTB may rarely develop into a
more aggressive histologic subtype of high-grade sarcoma, sometimes after radiotherapy
(which is much less frequently used in 2016).
Until recently, the systemic treatments tested (cytotoxics, bisphosphonates, interferon
alpha, etc.) had not demonstrated consistent antitumor activity. Denosumab, a monoclonal
antibody directed against RANKL, was shown to induce tumor shrinkage and growth arrest
in close to 95% of GCTB without signs of transformation. This is a recommended
 treatment, therefore, for GCTB that are not accessible to surgical resection. The optimal
duration of treatment is not known. Relapses were seen in unresected tumors after treatment
interruption several years after the initiation of therapy. The role of denosumab in the
neoadjuvant setting is currently being investigated.

X. CHORDOMAS
Chordoma is a rare bone malignancy that develops from the notochordal remnant of the
skull, arising at a median age of 60, but often diagnosed at a younger age, including in
pediatric patients, for chordomas of the base of the skull. Chordoma is a locally invasive
malignancy, and local progression is usually a major determinant of patient outcome.
However, close to 30% of patients will develop metastases, typically late in the course of
their disease, and after local recurrence.24,25
Surgical resection, en bloc, aiming for R0 resection, is the mainstay of the treatment of
these patients. However, R0 or R1 surgery is often mutilating for lesions arising in the
sacrum above S4, and cannot always be performed. In this case, radiotherapy alone is
generally proposed, using proton beams, or carbon ions for the most recent clinical trials.
After local or systemic relapse, the chances of cure are very limited. Treatment usually
combines surgical approaches, radiofrequency ablation, radiotherapy, and systemic
treatments, in particular targeted therapies directed against the mTOR signaling pathway,
as well as the PDGFR signaling pathway.

XI. CONCLUSIONS
Bone sarcomas represent a heterogenous group of malignant tumors for which a high cure
rate can be achieved using multimodal treatments. Biopsy and accurate histologic
classification is the first key step of management. The role of chemotherapy in first-line
treatments, the importance of the quality of the surgery, the complexity of clinical
presentation from pediatric age to older adults, and the rarity of these tumors require
management by an experienced team.

Acknowledgments
Supported by Grants from the LYRIC (INCA 4664), NetSARC (INCA), RREPS (INCA),
LabEx DEvweCAN, Eurosarc (FP7- 278742), Ligue contre le Cancer, Comité de L’Ain.

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I. GENERAL FEATURES OF ACUTE LEUKEMIAS
The acute leukemias are a heterogeneous group of disorders characterized by clonal
proliferation and abnormal differentiation of neoplastic hematopoietic progenitor cells.
Accumulation of immature hematopoietic cells, or blasts, in the bone marrow and
peripheral blood ultimately leads to inhibition of normal hematopoiesis. If left untreated,
acute leukemias are rapidly fatal.
Over the last 40 years, significant therapeutic advances have been made and many
younger patients can now be cured of their disease. The general treatment approach for
most patients with acute leukemia includes eradication of the leukemic clone with intensive
systemic chemotherapy, followed by some form of consolidation and, in certain cases,
maintenance therapy. Despite this strategy, most adults below the age of 55 years and the
vast majority of older adults die from their disease.
Numerous questions regarding optimal therapeutic strategies for patients with acute
leukemia remain unanswered. Hence, all patients with acute leukemia should be
considered candidates for clinical trials and treated in centers where appropriate intensive
and comprehensive care can be provided.
A. Epidemiology
The incidence of acute myeloid leukemia (AML) and acute lymphoblastic leukemia
(ALL) is 2.7 and 1.5 per 100,000 of the population, respectively, and is slightly higher
in males than in females. Sixty percent of patients with ALL are children, with a peak
incidence in the first 5 years of life. The second peak emerges after the age of 60 years.
The incidence of AML rises exponentially after the age of 40 years, with the median age
of disease presentation at 72 years. In contrast, the median age of patients diagnosed
with acute promyelocytic leukemia (APL), a distinct subtype of AML, is 40 years, and
the incidence of the disease does not increase with advanced age. While in general the
incidence of acute leukemias is slightly higher in the populations of European descent,
the incidence of APL may be higher among patients of Hispanic origin.
B. Etiology and risk factors of acute leukemias
Although the association of the acute leukemias with various infectious, genetic,
environmental, and socioeconomic factors has been evaluated extensively, the etiology
remains obscure in most cases.
1. Infection
There is a strong association between Epstein-Barr virus, a DNA virus causing
 infectious mononucleosis, and Burkitt lymphoma/leukemia.
2. Genetic factors
Genetic factors have been implicated in the pathogenesis of acute leukemia on the
basis of epidemiologic studies showing the 25% increased risk of ALL within 1 year
in a monozygotic twin of an affected infant. There is also a fourfold increase in the
risk of developing leukemia in dizygotic siblings. The risk of developing acute
leukemia is significantly higher in patients with Down and Klinefelter syndromes,
and conditions with excessive chromosome fragility such as Fanconi anemia, ataxia
telangiectasia, and Bloom syndrome.
3. Exposures to chemotherapy and radiation
Exposures to chemotherapy and radiation significantly increase the risk of
developing acute leukemias. AML with chromosome 5 and/or 7 abnormality has
been reported to occur 2 to 9 years after therapy with alkylating agents.
Topoisomerase inhibitors have been linked to the development of AML and ALL
with 11q23 aberration, characteristically 1 to 3 years after the exposure. An
increased incidence of acute leukemias has been reported after radiation exposure
such as atomic bomb explosion, the Chernobyl accident, and therapeutic radiation.
Increased incidence of leukemia has also been linked to exposure to gasoline,
benzene, tobacco, diesel, motor exhaust, and electromagnetic fields.
C. Clinical and laboratory features
Clinical and laboratory features of acute leukemias and their associated signs and
symptoms are shown in Table 19.1.
D. Diagnosis, classification, and prognostic features in acute leukemias
The acute leukemias are generally and broadly divided into AML and ALL on the basis
of the morphologic, immunohistochemical, and immunophenotypic characteristics of
leukemic blasts, along with the differing cells of origin. Although the peripheral blood
smear may be highly suggestive of the diagnosis (if ≥20% blasts), examination of the
bone marrow aspirate and core biopsy is essential to confirm the diagnosis and to
determine the extent of the disease. Cytogenetic analysis and molecular studies may aid
in establishing an accurate diagnosis, estimate prognosis, and guide therapy.
1. AML classification
Currently, the World Health Organization (WHO) classification is used to define
AML. The morphology-based Fr​ench-​American-British (FAB) classification,
devised in 1976, generally of historical value, utilizes cytochemical stains and, more
recently, immunophenotyping by flow cytometry to differentiate myeloid from
lymphoid blasts (Table 19.2). According to the FAB classification, eight
subcategories of AML are established on the basis of the type of cell involved and
the degree of differentiation ​(Table 19.3). A more recent WHO classification
created in 1999 and updated in 2008 generated 17 subclassifications of AML, on the
basis of the presence of dysplasia, chromosomal translocations, and molecular
markers (see Table 19.3).1 Additional changes included the decrease of the
 diagnostic threshold to 20% blasts (from the original classification of 30%, hence
eliminating the refractory anemia with excess blasts in transformation category of
myelodysplastic syndrome [MDS]) and the diagnosis of AML regardless of the
percentage of marrow blasts in marrows with clonal cytogenetic abnormalities such
as t(8;21), t(15;17), and t(16;16) or inv(16), along with evidence of abnormal
hematopoiesis.

TABLE
Clinical and Laboratory Features of Acute Leukemia
19.1
Clinical and Laboratory Findings Signs and Symptoms
Anemia Pallor, fatigue, exertional dyspnea, CHF
Neutropenia Fever, infection
Thrombocytopenia Petechiae, ecchymosis, retinal hemorrhages
Hepatomegaly, splenomegaly, lymphadenopathy (more common in
Leukocytosis (10% of patients with WBC >100,000)
ALL)
Bone pain (40%–50% of children with ALL, 5%–10% of adults)
Gingival hypertrophy (particularly when derived from monocytic

lineage)
Leukemia cutis
Solitary mass or “granulocytic sarcoma” (<5% of AML at
presentation), composed of leukemia myeloid cells, in any organ,

including bones, breast, skin, small bowel, mesentery, and
obstruction lesions of genitourinary and hepatobiliary tracts
Leukostasis Dyspnea, hypoxia, mental status changes
Mediastinal mass (80% of patients with T-cell ALL, rare in AML) Cough, dyspnea, chest pain
CNS involvement (<1% in AML at presentation, 3%–5% of adult Headache, diplopia, cranial neuropathies, particularly CN VI, VIII,
ALL) papilledema, nausea, vomiting
Elevated PT, PTT, low fibrinogen Intracranial bleeding, DIC (particularly in APL)
Acute renal failure (uncommon), acidosis, hyperkalemia,
Tumor lysis syndrome
hyperphosphatemia, hypocalcemia, elevated LDH and uric acid level

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CHF, congestive heart
failure; CN, cranial nerve; CNS, central nervous system; DIC, disseminated intravascular coagulation; LDH, lactate
dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell.
 TABLE
Antigens Commonly Demonstrated by Flow Cytometry Techniques
19.2
Cell Lineage Antigens
Lymphoid B CD19, CD20, cytoplasmic CD22, CD23, CD79a
Lymphoid T CD1, CD2, cytoplasmic CD3, CD4, CD5, CD7, CD8
Myelomonocytic Myeloperoxidase, CD11c, CD13, CD14, CD33, CD117 (c-KIT)
Erythrocytic Glycophorin A
Megakaryocytic Von Willebrand factor, GPIIb (CD41), GPIIIa(CD61)
Natural killer cells CD16, CD56
Nonlineage specific TdT, HLD-DRTdt, terminal deoxynucleotidyl transferase.

Tdt, terminal deoxynucleotidyl transferase.

TABLE
WHO Classification of AML (Simplified)
19.3
■ AMLs with recurrent cytogenetic translocations
■ AML with t(8;21) (q22;22); RUNX1-RUNX1T1
■ AML with inv(16)(p13q22) or t(16;16)(p13;q22); CBFβ/MYH11
■ APL (FAB M-3; t(15;17)(q22;q12) (PML/RAR-α) and variants
■ AML with t(9;11)(p23q23); MLLT3-MLL
■ AML with t(6;9)(p23;q34); DEK-NUP214
■ AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN-EVI1
■ AML (megakaryoblastic) with t(1;22)(p13;q13); PBM15-MKL1
■ Provisional entity: AML with mutated NPM1
■ Provisional entity: AML with mutated CEBPA1
■ AML with myelodysplasia-related changes
■ Therapy-related myeloid neoplasms
■ AML, NOS (correlated with FAB subtype)
■ AML minimally differentiated (FAB M0)
■ AML without maturation (FAB M1)
■ AML with maturation (FAB M2)
■ Acute myelomonocytic leukemia (FAB M4)
■ Acute monocytic leukemia (FAB M5)
■ Acute erythroid leukemia (FAB M6)
■ Acute megakaryocytic leukemia (FAB M7)
■ Acute basophilic leukemia
■ Acute panmyelosis with myelofibrosis
■ Acute leukemias of ambiguous lineage
■ AUL
■ MPAL with t(9;22)(q34;q11.2); BCR-ABL1
■ MPAL with t(v;11q23); MLL rearranged
■ MPAL, B/myeloid, NOS
■ MPAL, T/myeloid, NOS
■ Provisional entry: Natural killer cell lymphoblastic leukemia/lymphoma

AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; AUL, acute undifferentiated leukemia; CEBPA1, CCAAT
enhancer binding protein alpha 1; FAB, French-American-British; MPAL, mixed phenotype acute leukemia; MLL, mixed lineage
leukemia; NOS, not otherwise specified; NPM1, nucleophosmin 1; PML, promyleocytic leukemia; RAR-α, retinoic acid receptor
α.

2. Prognostic factors in AML

Prognostic factors in AML can be viewed as patient-related (age, performance status
[PS]) and leukemic clone–related characteristics. Advanced age is an adverse
prognostic factor. Even after accounting for risk factors such as cytogenetics,
molecular genetics, presence of antecedent hematologic disorder, and PS, older
patients have worse outcome than younger patients: 40% to 60% complete response
(CR) rates, and only 5% to 16% 5-year survival.
However, chronologic age alone should not be the only determinant of whether
patients receive potentially curative chemotherapy because age is not the most
important prognostic factor for either treatment-related mortality (TRM) or
resistance to therapy (see Section IV.H.1).
AML-related prognostic characteristics include WBC count at presentation,
presence of antecedent hematologic disorder, prior exposure to the cytotoxic
therapy, as well as cytogenetic and molecular changes. In fact, cytogenetic and
molecular genetic changes in leukemic cells at diagnosis are the most important
prognostic characteristic for predicting the rate of remission, relapse, and overall
survival (OS). Patients are commonly separated into three risk groups: favorable,
intermediate, or adverse (Table 19.4).
On the basis of a retrospective analysis of 1,213 patients with AML treated on
Cancer and Leukemia Group B (CALGB) protocols, the 5-year survival for patients
with favorable, intermediate, and poor-risk cytogenetics was 55%, 24%, and 5%,
respectively.2
a. Favorable-risk AML. Core binding factor (CBF)-AMLs (inv(16), t(8;21) and
t(16;16)) have the most favorable outcomes. Normal karyotype (cytogenetically
normal [CN]-AML) consists of a molecularly heterogenous group of
malignancies. In several, but not all studies, presence of nucleophosmin 1
(NPM1) mutation and absence of internal tandem duplication (ITD) of the FMS-
like tyrosine kinase-3 (FLT3) (FLT3-ITD) in CN-AML confers an improved
outcome with higher CR, relapse-free survival (RFS), and event-free survival
(EFS) rates, demonstrating rates of CR and OS similar to those of CBF
leukemias.
 TABLE
AML Prognostic Groups Based on Cytogenetic and Molecular Data at
Presentation*
19.4
Group Cytogenetics Molecular Abnormlities
Normal karyotype:
t(15;17)
Favorable-risk NPM1 mutation in the absence of FLT3-ITD
CBF: inv(16) or t(16;16) or t(8;21)
Or isolated biallelic CEBPA mutation
Normal karyotype
t(8;21), inv(16), t(16;16):
Intermediate-risk Trisomy 8 alone t(9;11)
with c-KIT mutation
Other nondefined
Normal karyotype: with FLT3-ITD
Complex (≥3 clonal chromosomal abnormalities) mutationCBF, core binding factor; CEBPA,
Adverse-risk Monosomal karyotype −5, 5q−, −7, 7q 11q23− CCAAT enhancer binding protein alpha FLT3-
non-t(9;11) inv(3), t(3;3) t(6;9) ITD, internal tandem duplication (ITD) of the
FMS-like tyrosine kinase-3 (FLT3).

*Determined by conventional cytogenetic techniques, fluorescent in situ hybridization, or polymerase chain reaction.

b. Intermediate-risk AML. This category includes cases with normal karyotype

(CN-AML), trisomy 8, and t(9;11). Presence of c-KIT mutations exert a negative
influence of outcome in patients with CBF-AML in retrospective studies;
however, the negative influence may be more pronounced in cases with t(8;21)
than those with inv(16).
c. Adverse-risk AML. Complex karyotype, defined by the presence of three or
more (in some studies five or more) chromosomal abnormalities, occurs in 10%
to 12% of patients and is associated with very poor outcome. Monosomal
karyotype, a recently proposed cytogenetic category, has a particularly poor
survival (5-year OS of 4%). Monosomal karyotype’s poor prognosis may be
attributed to its association with p53 mutations. Patients with monosomy of
chromosome 5 (−5), and/or 7 (−7), deletions (del) of the long arms of
chromosome 5 (del 5q) or 7 (del 7q) and abnormalities of 3q have worse
prognosis. CN-AML with ITD of the FLT3 (FLT3-ITD) predict inferior
outcomes.
 TABLE
WHO 2008 Classification of ALL
19.5
■ Precursor B lymphoblastic leukemia/lymphoma NOS
■ Precursor B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
■ t(9; 22) (q34; q11.2); BCR-ABL1
■ t(v; 11q23); MLL rearranged
■ t(12;21)(p13;q22); TEL/AML1 (ETV6-RUNX1)
■ B-ALL with hyperdiploidy
■ B-ALL with hypodiploidy
■ t(5;14)(q31;q32); IL3-IGH
■ t(1;19)(q23;p13.3); E2A-PBX1 (TCF-PBX1)
■ Precursor T-cell ALL

ALL, acute lymphoblastic leukemia; NOS, not otherwise specified; MLL, mixed lineage leukemia.

3. ALL classification
The diagnosis and classification of ALL is based on cell morphology,
immunohistochemistry, as well as immunophenotypic and cytogenetic features.
Marrow involvement of more than 25% lymphoblasts is used to differentiate ALL
from lymphoblastic lymphoma, in which the preponderance of tumor bulk is in nodal
structures.1 Approximately 70% to 75% of adult ALL cases are of precursor B-cell
origin; 20% to 25% are of T-cell origin (​Tables 19.5 and 19.6).

TABLE
Immunophenotypes of ALL
19.6
Frequency in Adult
Type and Subtype Characteristic Markers
ALL (%)
■ CD19+, CD22+, CD79a+, cIg +/−, PAX5, sIgμ−, HLA-
DR+
B-cell precursors ~70–75
■ CD20, CD34 variable expression
■ CD45 may be absent
Early precursor (pre–pre- or pro-) B cell CD19+, cCD79a+, cCD22+, TdT+, CD10− 11
Common (early pre-) B cell CD10+ 52
Pre-B cell CD10+/−, c-μ+ 9
Mature B cells CD19+, CD22+, CD79a+, cIg +, sIgμ+, sIgλκ+, sIgλ + ~5
T lineage Most common: CD7+, cCD3+ (lineage specific) ~20–25
Precursor T-cell TdT+, HLA-DR+/−, CD2−, CD1−, CD4−, CD8− 6
T-cell TdT+/−, HLA-DR−, CD2+, CD1+/−, CD4+/−, CD8+/− 18

ALL, acute lymphoblastic leukemia; cCD3, cytoplasmic CD3; c-μ+, cytoplasmic chains; cIg, cytoplasmic immunoglobulin; HLA,
human leukocyte antigen; sIg, surface immunoglobulin; PAX5, paired box 5; TdT, terminal deoxynucleotidyl transferase.
 4. Prognostic factors in ALL
Although modern intensive chemotherapy regimens have abolished multiple
prognostic factors identified in the past, several biologic and clinical features of
ALL still predict response to therapy, remission duration, disease-free survival
(DFS), and help to determine the intensity of the induction and postremission
therapy. Similar to the patients with AML, the outcome of therapy for patients with
ALL worsens with increasing age. In multivariate analysis, age over 60 years is
associated with a particularly poor prognosis, with shorter remission durations and
worse survival.
Presenting WBC counts of greater than 30,000/μL in precursor B-lineage ALL
and greater than 100,000/μL in T-cell ALL are adverse prognostic factors predicting
shorter duration of remissions. The time required to achieve CR (more than 4
weeks) following induction chemotherapy has been demonstrated to be an adverse
prognostic factor in several, but not all, clinical trials.
Similar to AML, cytogenetic abnormalities are one of the most important
factors predicting outcome in ALL. Approximately half of the patients with ALL
have cytogenetic abnormalities, which usually take the form of translocations rather
than deletions, which are seen more commonly in AML. The landmark International
ALL trial (UKALLXII/Eastern Cooperative Oncology Group [ECOG] E2993)
conducted by the Medical Research Council (MRC; now the National Cancer
Research Institute) in United Kingdom and the ECOG in United States identified in a
very large number of patients the incidence and clinical associations of more than 20
specific cytogenetic abnormalities.3 t(4;11), t(8;14), complex karyotype (five or
more abnormalities), and hypodiploidy (<44 chromosomes) were all associated
with poorer EFS and OS compared with patients with other abnormalities. Other
adverse cytogenetic abnormalities include t(9;22) (BCR-ABL1), t(1;19),
abnormalities in 9p, and rearrangements involving 11q23 (MLL).
BCR-ABL1–like (or Ph-like) ALL is a newly described common subtype of
high-risk ALL, which has a gene-expression profile similar to that of BCR-ABL1–
positive ALL, including alterations in IKZF1, but lacks the BCR-ABL1 fusion gene.
Further mutations in the Ras and JAK/STAT5 pathways are the common mechanism
of transformation. This discovery is clinically important owing to the presence of
kinase-activating alterations (ABL1, EPOR, JAK2, PDGFRB, EBF1, FLT2, IL7R,
SH2B3) that are amenable to treatment with currently available tyrosine kinase
inhibitors (TKIs).4
Alternatively, patients with high hyperdiploidy (>50 chromosomes) or a
del(9p) were associated with an improved outcome.
5. Acute leukemias of ambiguous lineage
With the expansion of immunophenotyping panels, use of electron microscopy, and
gene rearrangement studies for the characterization of acute leukemias, an increasing
degree of infidelity of myeloid and lymphoid markers is demonstrated. Cases in
 which differentiation between AML and ALL is difficult are described by the WHO
as “acute leukemia of ambiguous lineage” and comprise those cases that show no
evidence of lineage differentiation (i.e., acute undifferentiated leukemia [AUL]) or
those with blasts that express markers of more than one lineage (mixed phenotype
acute leukemia [MPAL]; see Table 19.3). AUL often expresses human leukocyte
antigen (HLA)-DR, CD34, and/or CD38, but by definition lacks ​lineage-specific
markers.

II. INITIAL SUPPORTIVE MEASURES

Once the diagnosis of acute leukemia has been established, the next 24 to 48 hours are
spent preparing the patient for the initiation of cytotoxic chemotherapy. The following
issues need to be addressed in almost all individuals facing induction chemotherapy.
A. Hyperleukocytosis, leukostasis, and leukapheresis
Hyperleukocytosis, defined as an absolute blast count of more than 100,000/μL,
predisposes to rheologic problems and is associated with increased induction mortality
in AML. Leukostasis, manifesting as cerebral and cardiopulmonary dysfunction due to
vascular obstruction and/or vessel wall necrosis with hemorrhage, occurs almost
exclusively in AML and represents an oncologic emergency. Given the increased risk of
early death with hyperleukocytosis, steps to rapidly reduce the blast counts should be
undertaken as soon as the diagnosis is made. In the hemodynamically stable patient,
leukapheresis is the most rapid way to lower the blast count; however, no impact on
long-term outcome has been shown. With very high blast counts (more than 200,000/
μL), decreasing the blast count by 50% may have to be the initial goal because
mathematic modeling suggests that prolonged leukapheresis after a “3-L exchange” does
not significantly decrease the blast count further. Leukapheresis may be repeated daily.
Systemic chemotherapy should be initiated immediately after emergent leukapheresis or
if leukapheresis cannot be performed. Hydroxyurea 3 to 5 g/m2/day split into three
doses daily until WBC are less than 10,000 to 20,000/μL is commonly used. In patients
presenting with hyperleukocytosis, an allopurinol dose of 100 mg/m2 every 8 hours
(maximum 800 mg/day) is well tolerated for the first 2 days, followed by 300 mg twice
a day for 2 to 3 days. Emergent cranial radiation for hyperleukocytosis and cranial
nerve palsies (or other severe neurologic deficits) is another treatment modality that
may be used.
Blood transfusions in the anemic patient with hyperleukocytosis should be
undertaken with great care as an aggressive packed red blood cell transfusion in such
patients may precipitate symptoms of hyperviscosity. Unless the patient has symptoms
due to anemia, a packed cell volume (hematocrit) of 20% to 25% is a reasonable goal.
B. Hydration and correction of electrolyte imbalance
Dehydration needs to be corrected and adequate urine output maintained to prevent
renal failure due to the deposition of cellular breakdown products resulting from the
tumor lysis syndrome. In the absence of cardiac disease, normal saline with or without
 5% dextrose (D5W) is infused to maintain the urine output at more than 100 mL/hour.
The concomitant use of loop diuretics may be necessary in patients with congestive
heart failure (CHF).
A variety of electrolyte abnormalities, such as hypocalcemia, hyperphosphatemia,
and hyperkalemia, may occur in patients with acute leukemia. Hyperkalemia, defined by
a potassium level of greater than 6 mmol/L, caused by massive cellular degradation,
may precipitate significant neuromuscular (muscle weakness, cramps, paresthesias) and
potentially life-threatening cardiac (asystole, ventricular tachycardia, and ventricular
fibrillation) abnormalities. Patients should be treated with oral sodium–​potassium
exchange resin, such as sodium polystyrene sulfonate 15 to 30 g every 6 hours and/or
combined glucose/insulin therapy.
Serum electrolytes, uric acid, phosphorus, calcium, and creatinine should be
monitored several times a day, depending on the severity of the clinical condition and
degree of metabolic abnormality. Early hemodialysis may be required in patients who
develop oliguric renal failure or recalcitrant electrolyte disturbances. An
electrocardiogram should be obtained and cardiac rhythm monitored while these
abnormalities are corrected.
C. Prevention of uric acid nephropathy
Hyperuricemia is common at presentation and may also occur with the tumor lysis
caused by chemotherapy. Allopurinol is the mainstay of prevention of uric acid
nephropathy. The usual initial adult dose is 300 mg (150 mg/m2) twice per day for 2 to
3 days, which is then decreased to 300 mg once a day. Allopurinol should be stopped
after 10 to 14 days to lessen the risk of rash and hepatic dysfunction. If chemotherapy
needs to be initiated urgently, allopurinol at a dose of 100 mg/m2 every 8 hours
(maximum 800 mg/day) is well tolerated for 1 to 2 days. With the advent of allopurinol,
the role of urine alkalinization has become less clear.
Rasburicase, a recombinant urate oxidase, is a safe and effective alternative to
allopurinol. Although the recommended dose of rasburicase is 0.15 to 0.2 mg/kg/day for
5 days, at our institution an excellent control of hyperuricemia was achieved with a
lower dose of 3 mg/day.
D. Correction of coagulopathy
Hemostatic defects secondary to thrombocytopenia may be potentiated by the presence
of consumption coagulopathy (disseminated intravascular coagulation [DIC]). Life-
threatening bleeding complications are particularly common in patients with APL
because of the presence of DIC and primary and secondary fibrinolysis, and proteolysis
(see Section V). Lysozyme released from monoblasts in M4 and M5 subtypes of AML
may trigger a clotting cascade leading to consumption coagulopathy. In ALL, therapy
with L-asparaginase (L-Asp) may lead to DIC. Additionally, sepsis may contribute to
coagulopathy in newly diagnosed patients with acute leukemias. Frequent monitoring of
coagulation parameters and adequate replacement with cryoprecipitate or fresh frozen
plasma products in appropriate patients is critical.
 E. Blood product support
Most patients with acute leukemia present with evidence of bone marrow failure.
Symptomatic anemia, hemoglobin less than 8 g/dL, thrombocytopenia less than 10,000/
μL, as well as signs of bleeding, must be treated. The threshold below which platelet
transfusion is needed may be higher (e.g., 20,000/μL) if conditions known to increase
the risk of bleeding such as severe mucositis, fever, anemia, and coagulopathy are
present. Blood products should be leukoreduced to decrease the risk of febrile
nonhemolytic transfusion reaction; alloimmunization to HLAs, which may lead to
subsequent refractoriness to platelet transfusion; and transmission of cytomegalovirus
(CMV). Additionally, blood products should be gamma irradiated to reduce the risk of
transfusion-related graft-versus-host disease (GVHD). Patients who are potential
candidates for stem cell transplant (SCT) should be screened for CMV and receive
CMV-negative blood until CMV status is determined.
F. HLA typing
Patients who are candidates for SCT should be HLA typed prior to the initiation of
therapy because chemotherapy-induced severe myelosuppression will not leave enough
lymphocytes for HLA typing.
G. Fever or infection
Patients frequently have a fever or an infection at initial diagnosis. The cardinal rule is
that all patients with acute leukemia and fever are presumed to have an infection until
proved otherwise. Given the additional myelosuppressive and immunosuppressive
effects of chemotherapy, severe infections should be treated aggressively before
initiating chemotherapy. However, the antibiotic treatment frequently needs to be
administered concurrently with induction chemotherapy. Patients with acute leukemia
need a careful physical examination daily. There should be close attention toward
potential sites of infection, including the fundi, sinuses, oral cavity, intertriginous areas,
perineum (attempts are made to avoid internal rectal examination during neutropenia),
and catheter sites. A dental consultation at the time of diagnosis is often useful.
H. Vascular access
Because of the need for several sites of venous access for at least 1 month, a multiple-
lumen implantable catheter (e.g., Hickman catheter or peripherally inserted central
catheter line) must be placed as soon as possible (except in patients suspected to have
APL). An implantable port is not recommended for patients with leukemia because
there is higher risk of infection and hematoma at the access site. Because of the
coagulopathy in patients with APL, the placement of a long indwelling catheter is
avoided altogether if at all possible and certainly until the coagulopathy has been
completely corrected and the patient is in a CR. A risk of life-​threatening bleeding in
patients with APL is present even when most or all of the routine coagulation studies
are normal.
I. Suppression of menses
A serum human chorionic gonadotropin (β-hCG) assay (pregnancy test) should be done
 in all premenopausal women prior to initiation of chemotherapy. It may be desirable to
prevent menses during chemotherapy to avoid the severe menorrhagia due to the
thrombocytopenia. Medroxyprogesterone (Provera) 10 mg twice per day may be started
5 to 7 days before the expected starting time of the next menstrual period. It may be
increased to 10 mg three times per day or higher if breakthrough bleeding occurs.
Medroxyprogesterone acetate IM (Depo-Provera) is contraindicated in the
thrombocytopenic and neutropenic patient.
J. Birth control and fertility
Given the potential teratogenic effects of cytotoxic chemotherapy, appropriate measures
for preventing conception must be addressed with women of reproductive age
undergoing chemotherapy. Although there are no clear data linking chemotherapy in the
male partner to teratogenic effects in the fetus, it is prudent to suggest that appropriate
birth control measures be undertaken in this situation as well.
Late effects of chemotherapy, such as infertility, need to be considered in younger
patients. Sperm cryopreservation should be offered to men of reproductive age prior to
initiation of chemotherapy.
Gonadal function in women seems to be less affected by cytotoxic chemotherapy.
Cryopreservation of fertilized eggs is currently available, while cryopreservation of
unfertilized eggs may be conducted on the investigational basis.
K. Psychosocial support
Patients with acute leukemia are usually previously healthy individuals who have
suddenly had to accept the possibility of their own imminent mortality. Intensive
psychological and spiritual support by the health care team, family, and religious
leaders is critical for maintaining the patient’s sense of well-being.

III. THERAPEUTIC PRINCIPLES AND APPROACH TO THE THERAPY OF ACUTE

LEUKEMIA
A. Therapeutic aim
The goals of chemotherapy are to eradicate the leukemic clone and reestablish normal
hematopoiesis in the bone marrow. Long-term survival is seen only in patients in whom
a CR is attained. Although leukemia therapy is toxic and infection is the major cause of
death during therapy, the median survival time of untreated (or unresponsive) acute
leukemia is 2 to 3 months, and most untreated patients die of bone marrow failure and
its complications. The doses of chemotherapy are never reduced because of cytopenia,
because lowered doses still produce the unwanted side effects (further marrow
suppression) without having as great a potential for eradicating the leukemic clone and
ultimately improving marrow function.
B. Forms of chemotherapy and response criteria
1. Induction chemotherapy
Induction chemotherapy is initial intensive chemotherapy given in an attempt to
eradicate the leukemic clone and to induce a CR. The term complete response
 depicts patients who achieve recovery of normal peripheral blood counts with
recovery of bone marrow cellularity, including the presence of less than 5% blast
cells, in the absence of extramedullary disease. The aim of induction chemotherapy
is to reduce the leukemia cell population by several logs from the clinically evident
total-body tumor burden of 1012 leukemia cells (about 1 kg), commonly seen at
diagnosis, to below the cytologically detectable level of 109 cells. It is important to
note that because achievement of initial CR represents only a 3- to 6-log leukemia
cell reduction, a substantial leukemia cell burden persists, and patients usually
relapse within months if further therapy is not administered. Induction therapy is
typically initiated as soon as diagnostic workup has been completed, as there is
retrospective data suggesting that treatment outcome might be adversely impacted
when treatment is delayed by more than 5 days from the diagnosis.
2. Postremission chemotherapy
Postremission chemotherapy is administered subsequently to achievement of a CR in
a further attempt to eradicate the residual, but often undetectable, leukemic clone. In
a younger patient population, considering the relatively high rate of CR after the
induction, future advances are likely to occur through improved postremission
therapy. Patients older than 60 years tend to achieve suboptimal CR rates and should
be enrolled in investigational protocols aimed at improving induction and
consolidation therapy.
a. Consolidation therapy involves repeated courses of the same drugs at similar or
higher doses as those used to induce the remission, which are given soon after
the remission has been achieved. Consolidation often requires further
hospitalization.
b. Maintenance therapy pertains primarily to ALL and includes low doses of
drugs designed to be administered on an outpatient basis for up to 2 years. In
AML, this strategy applies only to APL.
3. The definition of response
The definition of response is based on the peripheral blood counts and the status of
the recovered bone marrow. If the marrow is hypoplastic, it is imperative to repeat
the bone marrow biopsy to document remission on recovery.
a. CR is the return of the complete blood count to a “normal” absolute neutrophil
count (ANC) of more than 1,500/μL and to a platelet count of more than
100,000/μL in conjunction with a normal bone marrow (i.e., normal cellularity,
less than 5% blasts or promyelocytes and promonocytes, an absence of obvious
leukemic cells, and absence of extramedullary disease). Presence of minimal
residual disease (MRD) as determined by flow cytometry or PCR analysis is a
predictor of the relapse. Relapse rates range from 0% in patients with a
reduction to less than 10−4 leukemic cells detected at the completion of the
induction (compared with leukemia cell burden at diagnosis) to 14% in those
with 10−3 to 10−4 cells to 89% in patients with 1% residual disease.
 b. Partial response is the persistence of morphologically identifiable residual
leukemia (5% to 15% leukemic cells in the bone marrow).

IV. THERAPY FOR ADULT AML (OTHER THAN APL)

The day that induction chemotherapy is started is arbitrarily called day 1. Bone marrow
aspiration and biopsy are typically repeated on day 14. If the bone marrow is severely
hypoplastic with fewer than 5% residual blasts or if the bone marrow is aplastic, no further
chemotherapy is given, and the patient is supported until bone marrow recovery occurs
(usually 1 to 3 weeks more). A bone marrow examination is repeated 2 weeks later (about
days 26 to 28). Once a CR has been documented, the potential benefit of further
consolidation therapy should be determined on an individual basis.
A. Induction therapy
Factors that influence the choice of the initial chemotherapeutic agents include the
patient’s age, cardiac function, and PS. Historically, an age of 60 years has been
considered a cutoff point to recommending induction chemotherapy due to the higher
prevalence of unfavorable cytogenetics, antecedent myelodysplasia, expression of
multidrug-resistant protein, as well as frequency and severity of comorbid conditions
affecting the ability to tolerate intensive chemotherapy. However, age alone should not
be used as the sole determinant of whether given older adults should receive intensive
induction chemotherapy or alternative less intensity strategy. The initial drug doses
outlined below are based on the presence of normal hepatic and renal function and do
not require modification for depressed (or elevated) peripheral blood counts.
1. “3 + 7”
During the last 40 years, a series of clinical trials have identified an induction
regimen of 3 days of anthracycline (daunorubicin [DNR] 60 to 90 mg/m2/day,
idarubicin 10 to 12 mg/m2/day, or mitoxantrone, an anthracenedione, 12 mg/m2/day)
and 7 days of cytarabine (Ara-C) 100 to 200 mg/m2, which is considered standard
(Table 19.7). With such regimens, the anticipated rate of CR in younger patients
(younger than 55 to 60 years) is 60% to 80%. No other intervention has been
convincingly demonstrated to be better. Several randomized trials have compared
DNR at 45 to 60 mg/m2 with idarubicin, mitoxantrone, aclarubicin, and amsacrine;
with respect to OS, none of the agents appeared to be superior to DNR at the
equivalent doses. In younger patients, idarubicin, which attains a higher intracellular
drug concentration, was shown to induce higher remission rates, longer response
duration, and improved OS. However, in older adults, a randomized trial showed no
benefit of one anthracycline/anthracenedione over the other. In a randomized clinical
trial, a higher dose of DNR (90 mg/m2/day) resulted in a higher rate of CR (70.6 vs.
57.3, p < 0.001) and improved OS (23.7 vs. 15.7 months, p = 0.003) as compared
with a lower (than standard) dose (45 mg/m2/day).5,6 Doses that exceed 45
mg/m2/day for induction are now considered standard. Those with an unfavorable
cytogenetic profile, FLT3-ITD and mixed lineage leukemia partial tandem
 duplication (MLL PTD) mutations did not benefit from the higher doses of DNR in
an initial ECOG analysis.5
2. Cytarabine dose intensification
The merit of cytarabine dose intensification has been explored in several clinical
trials. The results indicate that the rate of CR was not affected by the administration
of high-dose cytarabine (HiDAC) compared with the standard dose.
Induction therapy with HiDAC plus DNR is associated with greater toxicity
than standard dose Ara-C plus DNR, but without improvement in CR rate or
survival. Following CR induction with SDAC, consolidation with HiDAC increases
the toxicity but not survival or DFS. Hence, the use of HiDAC induction outside the
clinical trial is not recommended.

TABLE
Commonly Administered Induction Regimens in AML
19.7
“3 + 7”: For patients able to withstand rigorous therapy
Cytarabine 100 mg/m2/24-hour continuous IV infusion on days 1 to 7 and
■ DNR 60–90 mg/m2 IV bolus on days 1 to 3 or
■ Idarubicin 12 mg/m2 IV bolus on days 1 to 3 or
■ Mitoxantrone 12 mg/m2 IV bolus on days 1 to 3.
HiDAC for patients with cardiac disease
■ Cytarabine 2 to 3 g/m2 IV infusion over 1–2 hours every 12 hours for 12 doses, or
■ Cytarabine 2 to 3 g/m2 IV infusion over 2 hours every 12 hours on days 1, 3, and 5

AML, acute myleiod leukemia; HiDAC, high-dose cytarabine; IV, intravenous.

3. Other regimens
Many permutations to the standard “7 + 3” regimen have been studied over the years
in an attempt to improve the CR rate of induction therapy and prolong survival. The
addition of other agents such as 6-thioguanine and etoposide (3 + 7 + 3) to the “7 +
3” regimen have improved the CR rate and response duration in some studies, but
these regimens produce increased toxicity without improvement in OS.
Addition of gemtuzumab ozogamicin (GO) to conventional chemotherapy did
not improve CR rates or DFS. As a consequence, the U.S. Food and Drug
Administration (FDA)–​accelerated approval from 2000 was withdrawn. However,
a recent meta-analysis found that the addition of GO significantly reduced the risk of
relapse and improved 5-year OS when added to induction chemotherapy,
particularly in those with favorable (5-year OS of 55.2% vs. 76.3%, p = 0.0005)
and intermediate-risk (5-year OS of 34.1% vs. 39.4%, p = 0.007) disease.7
The use of an anthracycline or an anthracenedione is contraindicated in patients
with severe underlying cardiac disease, particularly if the patient has had a recent
myocardial infarction or has an ejection fraction of less than 50%. The choice of
 therapy in this situation is HiDAC, although the optimum dose and schedule of
HiDAC therapy are not known (i.e., number of doses, dosage, infusion rate; see
Table 19.7).
B. Residual disease
Patients who have residual disease at day 28 should be considered primary treatment
failures and have alternative therapy initiated. If a significant response has been
demonstrated at the marrow examination on days 10 to 14 (greater than 50% to 60%
reduction in leukemic infiltration) but residual leukemia persists, a second course of
similar chemotherapy is given (or an alternative regimen such as HiDAC). Patients with
significant involvement with leukemia on days 10 to 14 (less than 40% to 50%
leukemic reduction) should receive an alternative chemotherapy regimen. There is no
dose modification for the second course based on blood cell counts. The doses of drugs
may be decreased for the second cycle if the total dose of anthracycline would be
cardiotoxic or if hepatic dysfunction attributed to the chemotherapy develops.

TABLE
HiDAC Consolidation Regimens
19.8
■ Cytarabine 3 g/m2 IV infusion over 1–3 hours every 12 hours on days 1, 3, and 5 for two to four monthly courses, or
■ Cytarabine 3 g/m2 IV infusion over 2 hours every 12 hours on days 1 to 6 for one to three monthly courses (most patients cannot
tolerate more than one or two courses of standard HiDAC), or
■ For patients over age 60: Cytarabine 1.5 g/m2 IV infusion over 1–3 hours every 12 hours on days 1, 3, and 5 for one or two monthly
courses in younger patients, but for only one course for patients >60 years as there is no evidence that any postremission therapy is
effective in prolonging CR in older adults compared to induction therapy alone.

CR, complete response; HiDAC, high-dose cytarabine; IV, intravenous.

C. Postremission therapy
Despite attaining a CR, the majority of patients with AML relapse, necessitating further
therapy aimed at eradication of the residual yet undetected leukemic clone. There are
three general treatment strategies for postremission therapy: consolidation
chemotherapy, autologous (auto-), or allogeneic (allo-) hematopoietic stem cell
transplant (HSCT). Although the optimum postremission strategy remains to be defined,
almost all younger adults with AML benefit from further therapy. The type of
postremission therapy should be determined on the basis of prognostic factors,
particularly age, cytogenetic, and molecular genetic findings at diagnosis. Patients with
AML in first CR should be considered candidates for investigational protocols
examining postremission therapy options. For patients who cannot be enrolled in
protocol studies, the approach to postinduction therapy is shown in Table 19.8.
Consolidation should be initiated when the peripheral blood counts have returned to
normal (ANC more than 1,500/μL and platelet count more than 100,000/μL), marrow
cellularity is normal, infections have resolved, and mucositis has cleared.
 Current data suggest that HiDAC offers a distinct advantage over SDAC
consolidation in patients younger than 55 to 60 years of age. A landmark study
conducted by CALGB demonstrated that four cycles of HiDAC (3 g/m2 every 12 hours
on days 1, 3, and 5) are superior to four courses of intermediate cytarabine (400 mg/m2
continuous intravenously [IV] on days 1 to 5) or SDAC (100 mg/m2 continuous IV on
days 1 to 5). More than 40% to 50% of patients will be in a continuous CR 5 years after
consolidation with HiDAC. The beneficial effect of cytarabine dose intensification,
however, was restricted to patients with CBF-AML and, to a lesser extent, to patients
with CN-AML, whereas outcome of patients with other cytogenetic abnormalities was
not affected by the cytarabine dose.8
The addition of other agents such as DNR or amsacrine to HiDAC consolidation
therapy has failed to show improvements in long-term outcomes.
1. Favorable-risk AML
Postremission therapy with three to four cycles of HiDAC or other intensive
cytotoxic regimen is considered standard for younger adults with c-KIT− CBF-
AML, NPM1+/FLT3-ITD−, and double-mutated CEBPA (see Table 19.8). A
retrospective study conducted by CALGB demonstrated that three or more cycles of
HiDAC (cumulative dose: 54 to 72 g/m2) are superior to a single cycle (18 g/m2);
however, in a joint collaboration between the M.D. Anderson Cancer Center,
SWOG, and ECOG, reporting a large number of patients with CBF-AML, the
outcome even among patients treated with HiDAC or any postremission therapy was
not as favorable as previously reported in earlier series with many fewer patients.
Neither auto- nor allo-HSCT showed an advantage over consolidation therapy in
first remission.
However, several subsets of CBF-AML, such as t(8;21) with high WBC, CBF-
AML with c-KIT mutation, or persistence of MRD, do poorly with the conventional
therapy and may benefit from the allo-HSCT.
2. Intermediate-risk AML
Long-term survival for patients presenting with intermediate cytogenetics is 40% to
45%. For patients younger than age 60, with intermediate cytogenetics or CN-AML
with unfavorable molecular markers (lack of mutated NPM1, double CEBPA, or
presence of FLT3-ITD mutation), data (although not all prospective) support the use
of allo-HSCT. The largest collection of prospective cohort data in this subgroup by
the MRC documented superior 3-year relapse rates of 18% for allo-HSCT, 35% for
auto-HSCT, and 55% for chemotherapy consolidation, and 3-year survival rates of
65%, 56%, and 48%, respectively. The U.S. Intergroup Study did not demonstrate an
advantage for allo-HSCT, although analysis was based on a much smaller cohort of
patients. The optimal timing of allo-HSCT is yet to be established, although
retrospective data collected from the Center for Blood and Marrow Transplant
Research demonstrated lack of additional benefit from receiving consolidation
chemotherapy prior to matched-sibling HSCT in the first CR. In other words,
 patients in postinduction CR may proceed immediately to allo-HSCT.
Auto-HSCT has been studied in this subgroup of patients but has not been
shown to represent an advantage over consolidation chemotherapy alone in
randomized studies conducted during the last decade.
3. Adverse-risk AML
Despite the CR rates of up to 60%, this group of patients with AML has a 5-year OS
of 11% (ranging from 3% to 20%) depending on the specific cytogenetic
abnormality at diagnosis (e.g., 4% of patients with MK are alive at 4 years). The
U.S. Intergroup Study demonstrated a significant long-term survival advantage for
patients with unfavorable cytogenetics who received allo-HSCT for consolidation
as compared with auto-HSCT or conventional chemotherapy. Although the total
number of patients analyzed in this and similar trials has been small, matched-
sibling ​allo-HSCT likely represents the therapy with the best potential to prevent
relapse. Data from the European Organization for Research and Treatment of Cancer
GIMEMA AML-10 trial and from three consecutive studies of the Hemato-Oncology
Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-
SAKK) group demonstrated an advantage of allo-HSCT among younger patients
with adverse cytogenetics. The outcome after allo-HSCT from fully matched
unrelated donor (MUD), based on molecular high-resolution HLA typing, ​appears to
be similar to that of allo-HSCT from matched siblings. The Center for International
Blood and Marrow Transplant Research reported a long-term survival probability
of 30% for patients with AML with adverse cytogenetics transplanted in first CR
from MUD.
Given the poor outcome of high-risk AML patients treated with the
conventional therapy, allo-HSCT from either matched related or unrelated donors in
first CR is considered a reasonable treatment option.
D. Primary refractory AML
Several studies have shown that lack of response to induction (usually two courses of
chemotherapy with at least one being a HiDAC-containing regimen) is a major
predictor of poor survival and conventional therapies offer almost no chance of cure for
these patients. Even with the allo-HSCT, the most aggressive approach available, the
rates of relapse and mortality are high, yielding OS of 20% to 30%. Alternative
conditioning regimens are being studied in this setting. Patients with induction failure,
who are not eligible for allo-HSCT, should be considered for clinical trial evaluating
novel agents.
E. Relapsed AML
1. Prognostic factors
A significant number of patients with AML who achieve a remission will ultimately
relapse. Unfortunately, the prognosis of patients with relapsed disease is poor and
treatment options remain unsatisfactory. The long-term survival depends on the
ability to achieve a remission and receive consolidation with allo-HSCT. Initial
 remission duration, cytogenetics, and age determine which therapeutic approach
should be undertaken: curative, palliative, or in the context of a clinical trial (Table
19.9).

TABLE
Prognostic Index for Younger Adults With AML in Relapse
19.9

2. Interventions at relapse
Interventions at relapse include intensive chemotherapy with conventional agents,
investigational therapies on a clinical trial, palliative intent chemotherapy, or best
supportive care. Individuals who relapsed after allo-HSCT may be eligible for
immunosuppression withdrawal and/or donor lymphocyte infusions as an
immunologic maneuver to generate a graft-versus-leukemia (GVL) effect.
3. Standard chemotherapy
The selection of conventional salvage therapy, the optimal dose of cytarabine, and
the benefits of the addition of an anthracycline or other agents all remain important
unanswered questions. ​HiDAC (2 to 3 g/m2 for 8 to 12 doses) paired with
mitoxantrone, etoposide, methotrexate (MTX), and fludarabine have produced short-
lived (4-to-6-month) CRs in 40% to 60% of patients with relapsed AML. A
randomized trial conducted by SWOG failed to demonstrate a significant benefit to
the addition of mitoxantrone to cytarabine 3 g/m2 every 12 hours for six doses. The
German AML Cooperative Group trial compared cytarabine 3 with cytarabine 1
g/m2 administered twice daily on days 1, 2, 8, and 9 in patients younger than 60
years of age. All patients received mitoxantrone. There was no substantial
difference in CR rate or median OS. Thus, dose-intense cytarabine should probably
be viewed as an essential component of a conventional salvage program, but
 escalation to 3 g/m2 is probably not justified given the increased toxicity. There
appears to be no value to adding standard-dose anthracyclines. However, there are
multiple single-arm trials using escalated doses of anthracyclines that may present a
reasonable alternative. A combination of topotecan and cytarabine induced CR in
35% to 70% of patients with AML and high-risk MDS. Nucleoside analogs, such as
cladribine and fludarabine, showed activity in pediatric and adult AML. A study
reported a 61% CR rate and 7-month CR duration in patients with AML treated with
a combination of fludarabine, Ara-C, G-CSF, and idarubicin.
a. “7 + 3.” Up to half of patients who undergo induction with the “7 + 3” regimen
respond to a repeat course of “7 + 3.” Patients who relapse within 6 to 12
months of the last chemotherapy are unlikely to respond to the same regimen
again. Thus, a different regimen should be considered.
b. HiDAC regimens. Fifty to seventy percent of patients respond to HiDAC.
Although HiDAC combination regimens may have a slightly higher response
rate, their increased toxicity may not make them significantly better than single-
agent HiDAC. Patients who relapse within 6 to 12 months of HiDAC
intensification are unlikely to have a significant response to further HiDAC. The
doses given for HiDAC are those originally described for each regimen. Options
include the following:
1) HiDAC plus anthracycline
■ HiDAC 3 g/m2 IV infusion over 3 hours every 12 hours on days 1 to 4,
plus
■ Mitoxantrone 10 mg/m2/day IV on days 2 to 5 or 2 to 6.
2) Mitoxantrone, etoposide, and cytarabine (MEC) may produce significant
gastrointestinal and cardiac toxicity. It is not recommended for patients older
than 60 years of age or those with borderline cardiac function. A variation of
MEC currently used by the ECOG is as follows:
■ Etoposide 40 mg/m2/day IV infusion over 1 hour on days 1 to 5,
followed immediately by
■ Cytarabine 1 g/m2/day IV infusion over 1 hour on days 1 to 5, and
■ Mitoxantrone 4 mg/m2/day IV on days 1 to 5, given after completion of
HiDAC each day.
3) Fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA)
■ Fludarabine 30 mg/m2/day IV over 30 minutes on days 1 to 5, and
■ Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and
■ Idarubicin 10 mg/m2/day on days 1 to 3, and
■ G-CSF 5 μg/kg subcutaneously (SC) 24 hours after the completion of
chemotherapy and until neutrophil regeneration.
c. Non-HiDAC regimens
1) Etoposide 100 mg/m2/day IV on days 1 to 5 and mitoxantrone 10 mg/m2/day
 IV on days 1 to 5 represents an active and well-tolerated combination that is
commonly used for relapsed or refractory leukemia.
2) High-dose etoposide 70 mg/m2/hour continuous IV infusion for 60 hours and
high-dose cyclophosphamide 50 mg/kg (1,850 mg/m2)/day IV infusion over 2
hours on days 1 to 4 is a highly toxic but active regimen that does not require
bone marrow support. It is active against HiDAC-​resistant AML (30% CR).
This regimen may be useful for young patients who are good candidates for
allo-HSCT while waiting for an unrelated donor search to be completed.
This regimen may also be associated with substantial toxicity.
4. Second postremission with HSCT
Allo-HSCT is the preferred postremission therapy once second remission has been
achieved. Sources of stem cells include HLA identical sibling, MUD, umbilical cord
(UCB) unit (typically use two), or a haploidentical donor. HSCT with reduced-
intensity conditioning (RIC) regimen is associated with an increased risk of relapse
compared with that of standard conditioning regimen and is being evaluated
prospectively. Although retrospective studies in selected patients demonstrate a
20% to 50% probability of long-term survival with auto-HSCT, it is often
impossible to collect leukemia-free stem cells at this phase of the disease.
Patients who sustain a relapse after allo-HSCT can be managed with
withdrawal of immunoprophylaxis with or without donor lymphocyte infusions. Such
interventions would not be possible in patients who already suffer from GVHD.
Transplant recipients who relapse a year or longer after undergoing HSCT may be
offered a second HSCT.
5. Investigational strategies and novel agents
Improved understanding of the molecular pathogenesis of AML and the identification
of novel leukemic targets have led to the development of molecularly targeted and
immunotherapeutic approaches in treating AML (Table 19.10). However, as the
AML phenotype (aside from APL) results from multiple genetic/epigenetic lesions
affecting differentiation, proliferation, and apoptosis, it is likely that eradication of
the leukemic clone will require a combination of multiple agents.
a. Clofarabine, a novel nucleoside analog, has shown significant efficacy in
patients with intermediate- and high-risk AML, particularly when combined with
cytarabine. However, its efficacy in elderly patients is controversial.
Randomized clinical trials comparing clofarabine and cytarabine and
clofarabine with “7 + 3” are currently underway.
 TABLE
Some of the Novel and Investigational Agents Being Evaluated for the AML
Therapy
19.10
New chemotherapy agents
■ Sapacitabine
■ CPX-351 (Liposomal carrier containing Cytarabine and Daunorubicin)
Novel immunotherapies
■ SGN-CD33A (Anti-CD33 antibody)
■ CSL362 (Anti-CD123 antibody)
■ AMG 330 (CD3/CD33-bispecific T-cell-engaging antibody)
■ MGD006 (CD3/CD123-dual affinity retargeting bispecific antibody)
Targeted therapies
■ FLT3 inhibitors
■ Sorafenib
■ Quizartinib
■ Crenolanib
■ ASP2215
■ DOT1L inhibitor
■ EPZ-5676
■ IDH1 and IDH2 inhibitors
■ AG-221
■ AG-120
■ PLK (Polo-like Kinase) inhibitor
■ Volasertib
■ LSD1 (Lysine Specific Demethylase 1) inhibitor
■ GSK2879552
■ BET (Bromodomain and Extraterminal) inhibitors
■ CPI-0610
■ GSK 525762
■ OTX015
■ Hedgehog signaling pathway inhibitor
■ PF-04449913

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase-3.

F. Central nervous system (CNS) prophylaxis

Patients with an increased risk of meningeal involvement (initial WBC greater than
40,000/μL or those with myelomonocytic [FAB M4] or monocytic [FAB M5]
differentiation) should be considered for CNS evaluation with a lumbar puncture (LP)
upon achieving complete remission. Patients treated with HiDAC (greater than 7.2
g/m2) may not require intrathecal (IT) therapy as they achieve therapeutic drug level in
the cerebrospinal fluid (CSF). If required, IT therapy with MTX 12 mg or Ara-C 30 mg
is used. For patients with CNS involvement (uncommon on presentation), chemotherapy
should be administered via Ommaya catheter together with 30 mg of hydrocortisone.
G. AML in older adults
1. Background
AML is a disease of older adults, as the median age of diagnosis is 72 years. Despite
the refinements in supportive care and chemotherapy programs, the long-term
survival rates have improved little over the last 35 years for patients over age 55.
Standard remission-induction and postremission therapy results in a median DFS of
10 months and rare long-term survival. Because of the effects of comorbid disease
 and age on normal physiology, older adults are less able to withstand the inherent
toxicity of induction chemotherapy than young adults. Intrinsic differences in the
biology of AML in older adults also exist, including—a higher percentage of
leukemic cells expressing P-glycoprotein (Pgp) at diagnosis (71% vs. 35% in
younger patients), the existence of an overt or covert antecedent hematologic
disorder that predisposes to drug resistance, along with complex karyotypes,
monosomies (especially in chromosome 5 and 7), and p53 mutations. As reported by
the MRC, favorable cytogenetic risk groups are less common in patients over the age
of 55 (7% vs. 26% in patients younger than 55), while complex karyotypes are more
common (13% vs. 6%). Furthermore, patients over the age of 55 with complex
karyotype predicted a poor outcome with OS of 2% at 5 years. The MRC recognized
a predictive hierarchical cytogenetic classification for older adults similar to
previous analysis for younger patients, although 5-year OS for favorable cytogenetic
group patients above age 55 was 34% compared with 65% for younger patients (and
13% and 41%, respectively, for intermediate cytogenetic risk).
The decision to forgo therapy in an older patient with AML should not be made
a priori solely on the basis of age; rather, the decision to treat or not to treat should
be based on more substantive factors such as the presence of comorbid disease, PS
before diagnosis, quality of life before diagnosis, and projected long-term survival.
Studies suggest that remission-induction chemotherapy provides better quality of life
and longer survival compared with supportive care only.
2. Induction therapy
Older patients with excellent PS and a lack of comorbidities may expect a CR rate of
50% and mortality under 15% from the standard induction therapy. Patients with
similar PS but adverse cytogenetics may expect CR rates of only 20% to 30% and
poor long-term survival.
Although attenuated doses of “7 + 3” have been recommended in the past, full-
dose therapy is now generally recommended in older adults without significant
comorbidities, in part owing to improvements in supportive care. In fact, the AML
Study Group (AMLSG) has been using 60 mg/m2 of DNR in the elderly patient
population without unexpected morbidity and mortality and recently, HOVON-
SAKK/AMLSG demonstrated that the dose of 90 mg/m2 was safe in patients up to
65 years of age.
Continuous attempts have been made to improve the efficacy of this regimen by
varying the doses of Ara-C; comparing one anthracycline or anthracenedione with
another; combining with other chemotherapeutic agents; using growth factors as
priming agents; or as supportive care. Improved CR rates in many of the phase II
studies were not confirmed in the randomized phase III trials.
Although karyotype may be unknown at diagnosis, delays in initiating therapy
may not be harmful in older patients, thus allowing an individual approach to care.
a. Standard “7 + 3.” Cytarabine 100 mg/m2/day or 200 mg/m2/day IV continuous
 infusion on days 1 to 7, and either
■ DNR 60 to 90 mg/m2/day for 3 days or
■ Idarubicin 8 to 12 mg/m2/day IV bolus on days 1 to 5.
b. Modified HiDAC decreases the cytarabine dose to try to diminish the
neurotoxicity that is dose-limiting in older adults. Modified HiDAC is generally
believed to be more toxic than the “7 + 3” regimen. We do not routinely
recommend the use of HiDAC for induction in older patients given the lack of
data to support a higher CR rate and the significantly increased morbidity and
mortality associated with HiDAC during the induction period. In selected older
patients with excellent PS and a decreased ejection fraction, one can consider
using modified HiDAC. Although the optimum dose and schedule are not known,
1.5 to 2 g/m2 IV over 2 hours every 12 hours for 8 to 12 doses is commonly
used.
Hypomethylating agents (e.g., azacitidine, decitabine) target the aberrant DNA
methylation seen in AML. They confer response rates comparable to standard
therapies and with less toxicity. The efficacy of HMAs appears to be independent of
cytogenetic risk. In one study, a CR rate of 52% was achieved in CN-AML versus
50% among those with complex karyotypes. Hypomethylating agents are also seen to
be efficacious independent of antecedent MDS, and may yield better outcomes in
patients harboring DNMT3A and TET2 epigenetic mutations.
■ Azacitidine 75 mg/m2/day SC for 7 days every 28 days.
■ Decitabine 20 mg/m2/day IV for 5 days every 4 weeks.9
3. Postremission therapy
Older patients may tolerate one or two cycles of lower doses of HiDAC (1.5 g/m2
every 12 hours on days 1, 3, and 5) than is usually given for younger adults, although
a beneficial impact of HiDAC consolidation chemotherapy on long-term outcome is
not proven. The CALGB trial of varying doses of cytarabine (100 mg/m2/day, 400
mg/m2/day, and 3 g/m2) reported similar 5-year DFS and OS within each arm (each
less than 15% and 8%, respectively). Auto-HSCT may be considered for fit patients,
although, as in younger patients, the exact integration of this therapy is not known.
RIC allo-HSCTs have allowed allo-HSCT in older patients, but this modality should
still be considered experimental in this setting. Current treatment options include the
following:
■ HiDAC 1.5 g/m2 IV infusion over 3 hours every 12 hours on days 1, 3, and
5 (better tolerated) for one course (with careful attention to cerebellar
toxicity and to renal function; if either is noted to be apparent, HiDAC
should be immediately discontinued).
■ Cytarabine 100 mg/m2/day for 5 days per course.
However, there are no definitive data showing that postremission therapy
benefits older adults.
 4. Other therapeutic approaches
a. RIC (mini)-HSCT
Older adults are increasingly offered an option of undergoing nonmyeloablative or
mini-HSCT as a postremission therapy. Although most of the studies evaluating
mini-HSCT are limited to a single institution experience, they show feasibility of
this potentially curative approach in the older patient population. A retrospective
study from the Cooperative German Transplant Study Group of 368 patients
demonstrated that survival is comparable between patients receiving stem cells from
the sibling donor or MUD.
H. Therapy-related AML
1. Background
Therapy-related AML (t-AML) is a recognized clinical syndrome occurring after
exposure to cytotoxic and/or radiation therapy. AML that develops after the exposure
to the alkylating agent is characterized by the cytogenetic abnormalities involving
chromosomes 5 and/or 7, a long latency (7 to 10 years), and, frequently, an
antecedent MDS. Patients who develop AML following exposure to topoisomerase
II inhibitors have a rearrangement of chromosome 11q23 (MLL) or 21q22 (RUNX1),
a relatively short latency period (2 to 3 years), and myelomonocytic or monocytic
differentiation. High-dose chemotherapy with auto-HSCT has been increasingly
implicated in the pathogenesis of secondary leukemias. In one study, the estimated
cumulative probability of developing therapy-related MDS or AML was
approximately 8.6% ± 2.1% at 6 years among 612 patients undergoing high-dose
chemotherapy and HSCT for Hodgkin lymphoma and non-Hodgkin lymphoma. The
most important risk factor appears to be large cumulative doses of alkylating agents.
However, patient age and previous radiotherapy, particularly total-body irradiation
as part of the conditioning regimen, are additional risk factors.
2. Therapy
Although up to 50% of patients with t-AML may achieve a CR with chemotherapy,
the median remission duration is approximately 5 months. Therapeutic options
include supportive care, “7 + 3,” HiDAC, or other chemotherapy regimens.
Younger patients with t-AML should be considered for ​allo-HSCT in first
remission. Nonmyeloablative allo-HSCT is under investigation for those who are
not eligible to undergo standard HSCT. The European Group for Blood and Marrow
Transplantation Registry reported 35% 3-year OS in 65 patients with t-AML treated
with auto-HSCT.
The main considerations for patients with t-AML include the status of primary
malignancy, the patient’s PS, age, and the leukemic karyotype. All patients should be
treated on a clinical trial if at all possible, and those eligible should be transplanted.
I. AML during pregnancy
The outcomes of both the mother and the fetus must be considered when discussing the
therapeutic options for a pregnant woman who develops AML. Pregnancy does not
 appear to alter the course of AML, with more than 75% of patients achieving a CR after
standard chemotherapy. Therapeutic abortion must be considered if AML develops
during the first trimester. If therapeutic abortion is not an option or if AML develops
during the second or third trimester, induction chemotherapy may be undertaken.
Although there is a slightly increased risk of premature labor and fetal death, in most
cases “7 + 3” appears to be well tolerated by both the patient and the fetus. Idarubicin
is more lipophilic, favoring an increased placental transfer and has a higher DNA
affinity, compared with other anthracyclines; hence, DNR should be offered instead.

V. ACUTE PROMYELOCYTIC LEUKEMIA

APL is a distinct subtype of AML, designated M3 by the FAB classification. It accounts for
10% to 15% of cases of adult AML in the general population and perhaps 20% to 25% of
AML cases in Latin America. The median age at presentation (40 years) is significantly
lower than that of patients diagnosed with other AML subtypes (72 years). Because of the
remarkable sensitivity of APL to anthracyclines, all-trans-retinoic acid (ATRA), and
arsenic trioxide (ATO; As2O3), it has become the most curable acute leukemia in adults;
recent data show OS exceeding 90% with ATRA and ATO-based induction and
consolidation strategies.
A. Cytogenetic abnormalities and prognostic factors
The characteristic molecular genetic abnormality in APL is a balanced reciprocal
translocation between the gene for retinoic acid receptor α (RARα) located on
chromosome 17 and the gene for promyelocytic leukemia (PML) located in
chromosome 15, resulting in two hybrid gene products: PML-RARα and RARα-PML.
The PML-RARα fusion protein that inhibits transcription necessary for differentiation is
detectable by the PCR technique, and is essential for the diagnosis and identification of
MRD. Four alternative chromosomal translocations have been identified (PLZF-RARα,
NPM-RARα, NuMA-RARα, and STAT5b-RARα). Prognostic factors are listed in Table
19.11.

TABLE
Adverse Prognostic Features in APL
19.11
■ Age (>50–60 years)
■ Male gender
■ High WBC (>10,000/μL)

APL, acute promyelocytic leukemia; WBC, white blood count.

B. Management of coagulopathy in APL

Coagulopathy, a peculiar presenting feature of APL, must be managed aggressively at
the suspicion of APL diagnosis, as it results in a high rate of spontaneous and
 potentially fatal hemorrhage. Pooled data through the late 1980s suggested that under the
best of circumstances with cytotoxic induction chemotherapy, 5% of APL patients
would die of CNS hemorrhage within the first 24 hours of hospitalization and another
20% to 25% would die of CNS hemorrhage during induction chemotherapy. With
intensive supportive care and the introduction of ATRA and ATO therapy, the most
recent studies suggest that less than 5% of patients will die of hemorrhage during
induction chemotherapy, while overall induction mortality in APL remains
approximately 10%, as reported in clinical trials. However, the mortality rate is
considerably higher when data from population-based studies are considered.
Regardless of clinical manifestations, essentially all patients with APL have laboratory
features of DIC. Table 19.12 outlines the general management plan to minimize
complications of the coagulopathy in APL.
C. APL therapy (Table 19.13)
In the past two decades, therapy for newly diagnosed APL has evolved from an ATRA
plus chemotherapy backbone to the addition of ATO to ATRA with omission of
chemotherapy in low-risk patients as a new standard of care. The combination of ATRA
and ATO demonstrated synergism in inducing differentiation, and apoptosis allows for
targeted therapy of APL without exposure to chemotherapy. This synergism between
ATRA and ATO has been demonstrated to eradicate APL-initiating cells through PML-
RARα degradation.
1. Induction
Simultaneous administration of ATRA and anthracycline-based chemotherapy results
in 95% CR rates. Development of primary resistance has been reported in a few
anecdotal cases only and essentially does not exist in true APL. Several randomized
clinical trials demonstrated not only that addition of ATRA to chemotherapy leads to
the improved EFS and OS compared with chemotherapy alone, but also that a
simultaneous administration of ATRA and chemotherapy is superior to a sequential
one in terms of CR rates (87% vs. 70%), 4-year relapse rate (RR; 20% vs. 36%),
and 4-year OS (71% vs. 52%).11 The choice of anthracycline is still debated; there
are no definitive data to suggest the superiority of one anthracycline over another, as
no prospective studies have been conducted comparing idarubicin with DNR in
APL; in the ATRA era, idarubicin is more frequently used as a monotherapy, while
DNR is mainly used in combination with other drugs (typically cytarabine).
The role of cytarabine in the induction regimens for APL remains
controversial, as comparable CR rates have been reported using
ATRA/DNR/cytarabine and ATRA/idarubicin regimens. In a randomized trial
reported by the European APL group (APL2000), patients treated with ATRA/DNR
had higher rates of CR, but demonstrated increased rates of relapse compared with
those of patients treated with ATRA/DNR/cytarabine.12 Another randomized trial
demonstrated similar rates of CR, RR, and OS between ATRA/idarubicin and
ATRA/DNR/cytarabine arms; additionally, a small increase in mortality in
 remission was noted in the group receiving cytarabine. A single-armed study by the ​-
Australasian group (APLM4) using triple induction with ATRA, ATO, and
idarubicin, followed by two courses of consolidation with ATRA and ATO and 2
years of maintenance with ATRA, methotrexate, and 6-MP, reported 5-year OS and
EFS rates of 94% and 90%, respectively, in all risk groups.13 The favorable results
of the APML4 study, which does not include cytarabine in induction (or
consolidation), resulted in an alternate approach now recommended by the National
Comprehensive Cancer Network (NCCN), which includes ATRA plus idarubicin
and ATO. Another randomized multicenter trial comparing ATRA plus idarubicin
with ATRA plus ATO conducted in patients with low-risk APL reported 2-year OS
of 99% in the ​ATRA-ATO group compared with 91% in the ATRA-​chemotherapy
group.10 ATRA-ATO has emerged as the new standard of care for patients with low-
risk APL. Furthermore, ATRA-ATO therapy also may serve as an attractive
alternative for patients who are considered unfit for conventional treatment with
severe comorbidities, such as older adults and patients with cardiac dysfunction or
other severe organ dysfunction.

TABLE
Management of Coagulopathy in APL
19.12
■ Initiate ATRA therapy at the first suspicion of the diagnosis
■ Monitor DIC panel at least twice daily
■ Maintain fibrinogen level >150 mg/dL with cryoprecipitate and fresh frozen plasma
■ Maintain platelet count ≥50,000/μL with platelet transfusions three or four times a day if necessary
■ Avoid central line placement
■ Avoid aminocaproic acid

APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; DIC, disseminated intravascular coagulation.
 TABLE
Therapeutic Recommendations for APL
19.13
Induction recommendations
■ Induction therapy should consist of the administration of concomitant ATRA and anthracycline-based chemotherapy
■ On the basis of the available data, induction therapy should not be modified due to the presence of features such as secondary
chromosomal abnormalities, FLT3 mutations, CD56 expression, and BCR3 PML-RARα isoform.
■ ATRA 45 mg/m2/day by mouth is divided into two doses with food given every day until CR (no longer than 90 days) plus an
anthracycline, either DNR 50–60 mg/m2/day for 3 days or idarubicin 12 mg/m2 every other day for four doses. In the modified regimen
used by the PETHEMA group, the fourth dose of idarubicin was omitted in patients older than 70 years of age.
■ It appears reasonable to initiate treatment with ATRA first for 2–3 days in patients with clinical evidence of bleeding to ameliorate the
coagulopathy before initiating anthracycline-based therapy, provided the WBC count is not high (<10,000/μL). Otherwise, concurrent
ATRA plus anthracycline-based therapy has been routine practice and may have the advantage of decreasing the incidence of
retinoic acid syndrome (now referred to as the APL differentiation syndrome; see subsequent discussion).
■ Treatment with ATRA should be continued until occurrence of terminal differentiation of blasts and achievement of the CR, which
occurs in virtually all patients after the conventional ATRA + anthracycline induction schedules.
■ No therapeutic modifications should be made based on the presence of incomplete blast maturation (differentiation) detected up to 90
days after the start of therapy, as demonstrated by morphology, cytogenetics, or molecular studies.
■ Presence of MRD (demonstrated in up to 50%) after induction, as determined by RT-PCR, does not have prognostic implications and
does not warrant change in therapeutic approach.
■ The role of cytarabine in induction among patients with low and intermediate risk remains unclear; however, cytarabine plays a major
role in patients with high-risk disease.
■ For low-risk (WBC ≤10,000/μL) patients: ATRA 45 mg/m2/day by mouth is divided into two doses with food given every day until CR
(no longer than 60 days) plus ATO 0.15 mg/kg IV over 2 hours daily until bone marrow remission (no longer than 60 days).10

Consolidation recommendations
■ The goal of consolidation therapy is an achievement of molecular remission as determined by the RT-PCR, as it has been convincingly
correlated with the improved outcome.
■ Addition of ATRA to chemotherapy in consolidation seems to provide a clinical benefit; typically given 45 mg/m2/day in two divided
doses for 7–15 days.
■ Two to three cycles of anthracycline-based chemotherapy are considered standard:
■ DNR 50–60 mg/m2/day IV for 3 days, or
■ Idarubicin 5 mg/m2/day on days 1 to 4 (consolidation #1), mitoxantrone 10 mg/m2/day on days 1 (consolidation #2), and idarubicin
12 mg/m2 on day 1 only (consolidation #3), as in PETHEMA regimen, or
■ DNR 60 mg/m2/day IV for 3 days and Ara-C 200 mg/m2/day IV for 7 days, as in European APL 93 regimen
■ For low-risk (WBC ≤10,000/μL) patients: ATRA 45 mg/m2/day by mouth is divided into two doses with food given for 2 weeks every 4
weeks for a total of 7 cycles plus ATO 0.15 mg/kg IV over 2 hours daily for 5 days/week for 4 weeks every 8 weeks for a total of 4
cycles.10
■ High-risk patients (WBC >10,000/μL) younger than 60 years should receive at least one cycle of intermediate- and HiDAC:
■ Idarubicin 5 mg/m2/day × 4; Ara-C 1,000 mg/m2/day × 4; ATRA 45 mg/m2/day × 15 (consolidation #1)
■ Mitoxantrone 10 mg/m2/day × 5; ATRA 45 mg/m2/day × 15 (consolidation #2)
■ Idarubicin 12 mg/m2/day × 1; Ara-C 150 mg/m2/day/8 hours × 4; ATRA 45 mg/m2/day × 15 (consolidation #3)
Arsenic can be considered for two cycles as an early consolidation followed by two courses of anthracycline and ATRA as given in the
North American C9710 Intergroup trial
■ Arsenic therapy should be considered in the context of a clinical trial or for the patients not fit to receive chemotherapy.
Maintenance recommendations
■ ATRA 45 mg/m2/day by mouth, divided into two doses with food for 15 days every 3 months (or 7 days on/7 days off plus 6-
mercaptopurine 90–100 mg/m2/day plus MTX 10–15 mg/m2/week all for 2 years), or
■ ATRA 45 mg/m2/day by mouth divided into two doses with food for 1 year, or
■ ATRA 45 mg/m2/day divided into two doses with food for 15 days every 3 months for 2 years.
■ Because early treatment intervention in patients with evidence of MRD results in better outcome than treatment in hematologic
relapse, follow-up of PCR for PML-RARα every 3 months for up to 3 years is recommended for high-risk patients. Patients with low-
and intermediate-risk disease can be monitored much less frequently or perhaps not at all (standard-risk disease).

APL, acute promyelocytic leukemia; Ara-C, cytarabine; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete
response; DNR, daunorubicin; IV, intravenous; MRD, minimal residual disease; PCR, polymerase chain reaction; PML,
promyelocytic leukemia; RARα, retinoic acid receptor α; RT, reverse transcription; WBC, white blood cell.
 2. Consolidation
High rates of molecular remissions (approximately 95%) after at least two cycles of
postinduction anthracycline-based chemotherapy have led to the adoption of this
strategy as the standard for consolidation. Whereas a benefit from the addition of
ATRA to consolidation chemotherapy has not been demonstrated in randomized
trials. However, historical comparison of consecutive trials carried out
independently by GIMEMA and PETHEMA groups showed a statistically significant
improvement in outcome with the addition of ATRA to chemotherapy in
consolidation. There is no consensus whether a specific chemotherapy regimen is
optimal in consolidation. The focus of past research efforts has been to develop
risk-adapted strategies to provide more intensive treatment in high-risk patients
while minimizing toxicities in low-risk patients. A cooperative group multicenter
studies done separately by PETHEMA (LPA2005) and GIMEMA (AIDA2000)
administered cytarabine in high-risk patients only and reported an improved
incidence of relapse compared with historical controls. However, this improved
outcome is likely related to the use of ATRA in consolidation as the historical
comparator received chemotherapy without ATRA.
With the discovery of ATO, first-line ATRA-based consolidation regimens
using ATO as a substitute for chemotherapy were developed. The North American
Intergroup has shown in a randomized trial (C9710) that adding ATO to
consolidation significantly improved DFS and OS in all risk groups.14 Subsequently,
studies omitting chemotherapy and using only ATRA and ATO for consolidation
reported excellent outcomes with 3-year OS of 85%.
As mentioned above, randomized prospective data from a phase III trial
demonstrated that ATRA/ATO after ATRA/ATO induction achieves excellent
outcomes in low-risk patients.10 Therefore, in patients presenting with a WBC of
≤10,000/μl who do not have contraindications to ATO, a non–chemotherapy-based
consolidation approach (as with induction) can be considered the new standard of
care. In high-risk patients, ATRA/ATO combined with idarubicin for induction
followed by ATRA/ATO consolidation without chemotherapy has demonstrated very
favorable results and is commonly considered regimen of choice in these patients.
Alternatively, a course of ATRA and idarubicin alone (without ATO) for induction
followed by ​intermediate-dose cytarabine as the first consolidation is also an
effective treatment strategy and can be used in high-risk ​patients. Although
cytarabine appears to benefit high-risk ​patients when incorporated into ATRA and
anthracycline-based regimens, its role in combination with ATO, if any, is unknown.
3. The role of HSCT
Because of the high cure rates with ATRA/ATO and chemotherapy combinations,
there is no role for a routine use of HSCT for patients with APL in molecular
remission after consolidation chemotherapy.
4. Maintenance
 Prolonged maintenance therapy is typically included in modern APL treatment
protocols, although its importance remains controversial. Traditionally,
consolidation has been followed by 2 years of maintenance therapy with ATRA, 6-
MP, and methotrexate. Now that ATO is being used in induction and/or
consolidation, need for maintenance has been questioned. The results of recent
studies showed no advantage of maintenance therapy in patients who achieved
complete molecular remission after consolidation, especially for standard-risk
patients. Therapeutic recommendations for APL outside of clinical trials are given in
Table 19.13.
D. APL differentiation syndrome
APL differentiation syndrome (DS) (formerly retinoic acid syndrome [RAS]) is the
main life-threatening complication of therapy with differentiating agents (ATRA and/or
ATO) that manifests as unexplained fever, hypotension, respiratory distress with
pulmonary infiltrates, pericardial and pleural effusions, peripheral edema, weight gain,
and acute renal failure. Typically, DS occurs between the second day and the third week
of ATRA and/or ATO therapy, with the incidence between 5% and 27% and a mortality
rate (for those who develop DS) between 5% and 29%. Early recognition and prompt
initiation of corticosteroids are key to managing this complication. Although a rising
WBC count may be a risk factor for DS, it may occur with a WBC count below 5,000/
μL. Regardless of the WBC count or the risk of neutropenic sepsis, at the first sign of
DS, dexamethasone (10 mg IV twice a day) should be initiated. If the symptoms are
mild, ATRA may be continued concomitantly with steroids under careful observation.
However, if the symptoms are severe or do not respond to steroid therapy, ATRA
should be temporarily discontinued. For induction regimens that include both ATRA and
ATO, prophylaxis with prednisone (0.5 mg/kg/day) can be given from day 1 through
completion of induction therapy. It is recommended that the prophylaxis regimen follow
the specific protocol used. If a patient develops DS, it is recommended that treatment be
changed from prednisone to dexamethasone 10 mg twice a day until acute DS resolves.
The patient may then be returned to the previous prednisone dose.
E. Relapsed APL
Approximately 10% to 20% of patients treated with a combination of ATRA and
chemotherapy eventually relapse. Although second remissions with standard therapy are
common, particularly if the last exposure to ATRA occurred more than 6 to 12 months
prior to relapse, they are not durable. Several clinical trials show that ATO has
remarkable activity in this patient population, leading to its FDA approval in this
setting. Preclinical mechanisms of action of ATO include apoptosis and APL cell
differentiation. Chinese investigators demonstrated CR rates of at least 85% and 2-year
DFS of 40% in patients with relapsed APL. A U.S. multicenter study of ATO for
induction and consolidation therapy for relapsed APL confirmed the high CR and long-
term survival rates, and most importantly, an 85% rate of molecular remission after the
completion of the consolidation therapy.
 Two studies conducted in the pre-ATO era suggested a benefit for preemptive
therapy at the development of the molecular relapse compared with treatment initiated
at the time of frank hematologic relapse. Although the benefit of early intervention with
ATO-based therapy remains to be proven, the high risk of hemorrhagic death and
development of APL MRD associated with overt disease argues strongly in favor of an
early intervention. Hence, molecular monitoring of MRD every 3 months for 3 years is
recommended particularly for high-risk patients (Table 19.14).
F. Early death rate
Early death, and not relapse, has emerged as the single most important limitation of cure
for the majority of APL patients. This is related to the characteristic bleeding diathesis.
Current recommendations are that when a diagnosis of APL is suspected on the basis of
clinical presentation and/or morphology, the disease should be treated as a medical
emergency. Urgent administration of ATRA should be initiated with aggressive
supportive measures including blood product support with platelets and cryoprecipitate
while the genetic diagnosis is rapidly established.15

TABLE
Recommendations for Relapsed APL
19.14
■ For patients with confirmed molecular relapse (two successive PCR-positive results, demonstrating stable or rising PML-RARα
transcript levels), preemptive therapy must be initiated to prevent frank relapse.
■ ATRA and chemotherapy combination may be used as a salvage regimen; however, ATO-based regimens are considered the first
option in the setting of relapsed APL.
■ ATO
■ Induction: 0.15 mg/kg IV over 2 hours daily until bone marrow remission occurs, up to cumulative maximum of 60 doses. Bone
marrow biopsy should be obtained on or before day 28 of therapy, and subsequently weekly until CR.
■ Consolidation: start 3–4 weeks after completing the induction therapy at 0.15 mg/kg IV over 2 hours daily or 5/7 days, for a
cumulative total of 25 doses.
■ Maintain potassium >4 mEq/L and magnesium >1.8 mg/dL.
■ Frequent EKG monitoring for prolonged QTc interval assessment.
■ Monitor WBC count and for signs of APL differentiation syndrome. Institute steroids (dexamethasone 10 mg IV twice a day) at the
earliest suggestion of the APL differentiation syndrome.
■ HSCT. Patient should be referred for the evaluation for the HSCT
■ Allogeneic-HSCT if fails to achieve a molecular remission
■ Autologous-HSCT if in molecular remission.
■ For patients in whom HSCT is not feasible, repeated cycles of ATO with or without ATRA with or without chemotherapy should be
considered.

APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete response; EKG,
electrocardiogram; HSCT, hematopoietic stem cell transplantation; IV, intravenously; PCR, polymerase chain reaction; WBC,
white blood cell.

G. HSCT in relapsed APL

Despite the high initial CR rates in relapsed disease, many patients relapse following
ATO-based treatment. Results of retrospective studies have demonstrated that HSCT
may be an effective option at this point or on achievement of second CR following ATO
therapy. Auto-HSCT is associated with lower ​transplant-related mortality and is a
reasonable option for patients in molecular remission and prolonged (greater than 1
 year) first CR. Allo-HSCT is associated with a higher rate of transplant-related
mortality but offers greater antileukemic activity due to the GVL effect. It could be
recommended for patients who fail to achieve a complete molecular remission or those
with short CR duration. Table 19.14 gives recommendations for treatment of relapsed
APL.

VI. THERAPY FOR ADULT ALL

Over the last 40 years, significant advances have been made in the management of adult
ALL. Current therapeutic strategies incorporate a more intensive induction and
postremission regimens and take into account biologic and clinical features of the disease.
Despite an excellent initial response to therapy (CR 80% to 90%), the overall long-term
DFS is 40% to 50% in adult patients with ALL. Most chemotherapeutic regimens for ALL
have been developed as complete programs without testing the contributions of the
individual components, and they have not been compared with one another in a rigorous
prospective randomized fashion. All patients undergoing therapy for ALL should be
enrolled in clinical trials.
The goals of intensified therapy are to eliminate leukemia cells, as determined by light
microscopy and flow cytometry, prior to the emergence of drug-resistant clones, to restore
normal hematopoiesis and to provide adequate chemoprophylaxis for the sanctuary sites
such as the CNS. A typical ALL regimen consists of induction, ​-
consolidation/intensification, and maintenance; CNS prophylaxis is usually administered
during induction and consolidation.
Recent data from clinical trials demonstrate that young adults who were treated on
adult protocols fared significantly worse than the same age group treated on pediatric
protocols. This superior outcome has been attributed to the more intensive treatment on
pediatric protocols, which includes high-dose steroids and L-Asp as well as better
adherence to the therapy by patients, parents, and doctors. Currently, clinical trials
evaluating the pediatric-type therapy in adult patients up to the age of 40 years are ongoing.
A. Induction
The addition of an anthracycline to the standard pediatric ALL induction regimen of
vincristine, prednisone, and L-Asp increased CR rates in adults from 50–60% to 70%–
90%, and median duration of the disease remission to approximately 18 months. In
some studies, dexamethasone has been substituted for prednisone because of its higher
in vitro activity and better CNS penetration. However, findings of a small, randomized
study showed that an augmented dose of prednisone produced results comparable to
those achieved with dexamethasone in the context of intensive chemotherapy. Although
L-Asp proved to be of value in the preanthracycline era, and in pediatric trials
produced better survival when administered during induction and/or postinduction
phases, its role in anthracycline-based adult programs is evolving. Given the significant
toxicity of L-Asp, many investigators do not recommend its use in older patients;
however, incorporation of L-Asp in intensive regimens for young adults is actively
 investigated. The newer PEGylated form of L-Asp (peg-asp) has a prolonged half-life
and has been FDA-approved for pediatric ALL. The CALGB 9511 trial substituted peg-
asp for native asparaginase and demonstrated CR rate of 76%, median OS of 22
months, and DFS at 7.5 years of 21%.
Attempts to further improve the outcome of patients with ALL led to the
incorporation of agents such as cytarabine, cyclophosphamide, etoposide, mitoxantrone,
and MTX in induction and postinduction therapy. It is unclear whether intensification
with additional agents or using multiple phases of induction therapy improved CR rates
in the unselected patients; however, it may benefit certain subgroups. In a double blind,
randomized trial conducted by CALGB, administration of G-CSF shortened the duration
of neutropenia from 29 days in the placebo group to 16 days in G-CSF group. The CR
rates were higher with G-CSF (90% vs. 81%), whereas induction mortality was higher
in the placebo group (11% vs. 4%).16
B. Consolidation (intensification) therapy
This typically includes three to eight cycles of non–cross-​resistant drugs administered
after the remission induction. As mentioned previously, no randomized studies have
compared the plethora of existing regimens (Linker trial, French LALA-94 trial,
CALGB 8811 study, the MRC UKALL XA, GIMEMA ALL 0288 trial, the PETHEMA
ALL-89 randomized trial, hyper-​cyclophosphamide, vincristine, doxorubicin, and
dexamethasone [CVAD], or R-hyper-CVAD).
C. Maintenance
The benefit of maintenance therapy in adult patients with ALL has not been proven in
randomized clinical trials, but is considered routine practice for most subtypes of ALL.
In patients with low-risk disease, who enjoy outcomes similar to pediatric patients,
maintenance therapy appears to be justified. Considering that more than half of the high-
risk patients relapse while undergoing maintenance therapy, alternative strategies of
eradicating MRD are urgently needed. The utility of maintenance therapy has been
questioned for patients with T-cell ALL, and it is not given for patients with mature B-
cell ALL or those with Philadelphia (Ph) chromosome–positive disease.
The traditional maintenance regimen is given for approximately 2 years and
includes daily doses of 6-mercaptopurine, weekly doses of MTX, and monthly doses of
vincristine and prednisone. Dose intensification or extension of maintenance beyond 3
years does not appear to be of benefit, whereas its omission has been associated with
shorter DFS.
D. Recommendations for the therapeutic regimens for pre–B- and T-cell lineage ALL
Although T-cell ALL previously had a poor prognosis with standard induction and
maintenance chemotherapy, with the advent of more intensive chemotherapy regimens,
response rates and long-term DFS are comparable to those for precursor B-cell ALL. A
response rate of 100% and a projected long-term DFS of 59% were demonstrated by
the regimen devised by Linker and colleagues in 2002 for T-cell ALL. The CALGB
8811 protocol produced a 100% CR rate with a 63% 3-year RFS for a similar group of
 patients. Precursor B-cell and T-cell ALL are treated with similar regimens in most
contemporary protocols.
1. Berlin-Frankfurt-Muenster (BFM)-like regimens (MRC/ECOG)
The MRC UKALL XII/ECOG E2993 treatment regimen should be considered for
patients regardless of age who are thought to be able to withstand the rigors of an
intensive program.17
a. Induction
(Consisting of two phases):
1) Phase I, weeks 1 to 4.
■ Vincristine1 1.4 mg/m2 (maximum 2 mg) IV push on days 1, 8, 15, and
22, and
■ Prednisone 60 mg/m2 by mouth on days 1 to 28 ​(followed by rapid taper
over 7 days), and
■ DNR23 60 mg/m2 IV push on days 1, 8, 15, and 22, and
■ L-Asp 10,000 U IV (or intramuscularly) once daily on days 17 to 28.
2) Phase II, weeks 5 to 8, should be postponed until the total WBC exceeds 3 ×
103/μL.
■ Cyclophosphamide 650 mg/m2 IV on days 1, 15, and 29, and
■ Cytarabine 75 mg/m2 IV on days 1 to 4, 8 to 11, 15 to 18, and 22 to 25,
and
■ 6-Mercaptopurine 60 mg/m2 by mouth once daily on days 1 to 28.

Direct Bilirubin Dose of Vincristine to Give Dose of DNR to Give

2–3 mg/dL 100% calculated 50% calculated

>3 mg/dL 50% calculated 25% calculated

b. CNS treatment and prophylaxis

If CNS leukemia is present at diagnosis, MTX IT or via an Ommaya reservoir is
given weekly until blasts are cleared from the CNS fluid. Additionally, 24 Gy
cranial irradiation and 12 Gy to the spinal cord are administered concurrently with
phase II induction. If CNS leukemia is not present at diagnosis, MTX 12.5 mg IT on
day 15 in phase I and MTX 12.5 mg IT on days 1, 8, 15, and 22 in phase II are
given.
c. Intensification therapy begins 4 weeks after induction phase II and should be
postponed until the WBC is greater than 3 × 103/μL.
■ MTX 3 g/m2 IV on days 1, 8, and 22
■ Leucovorin rescue starting at 24 hours 10 mg/m2 by mouth or IV every 6
hours × 12 or until the serum MTX concentration is less than 5 × 10−8 M,
and
■ L-Asp 10,000 U on days 2, 9, and 23.
 d. Consolidation therapy (for patients not proceeding to ​allo-HSCT). Given after
intensification when the WBC is higher than 3,000/μL and the platelet count is
higher than 100,000/μL.
1) Cycle I consolidation
■ Cytarabine 75 mg/m2 IV on days 1 to 5, and
■ Vincristine 2 mg IV on days 1, 8, 15, and 22, and
■ Dexamethasone 10 mg/m2 by mouth on days 1 to 28, and
■ Etoposide 100 mg/m2 IV on days 1 to 5.
2) Cycle II consolidation (begins 4 weeks from day 1 of first cycle or when
WBC exceeds 3,000/μL)
■ Cytarabine 75 mg/m2 IV on days 1 to 5, and
■ Etoposide 100 mg/m2 IV on days 1 to 5.
3) Cycle III consolidation (begins 4 weeks from day 1 of second cycle or when
WBC exceeds 3,000/μL)
■ DNR 25 mg/m2 IV on days 1, 8, 15, and 22, and
■ Cyclophosphamide 650 mg/m2 IV on day 29, and
■ Cytarabine 75 mg/m2 IV on days 31 to 34 and 38 to 41, and
■ 6-Thioguanine 60 mg/m2 by mouth on days 29 to 42.
4) Cycle IV consolidation (begins 8 weeks from day 1 of third cycle or when
WBC exceeds 3,000/μL).
■ Cytarabine 75 mg/m2 IV on days 1 to 5, and
■ Etoposide 100 mg/m2 IV on days 1 to 5.
e. Maintenance for adult ALL by MTX- and 6-mercaptopurine-based therapy
Pulses of vincristine and prednisone are given as “reinforcement” because they have
relatively little toxicity. Maintenance therapy should be continued for 2.5 years from
start of intensification.
■ 6-Mercaptopurine 75 mg/m2/day by mouth, and
■ Vincristine 2 mg IV every 3 months, and
■ Prednisone 60 mg/m2 by mouth for 5 days every 3 months with vincristine,
and
■ MTX 20 mg/m2 by mouth or IV once per week for 2.5 years.
2. CALGB 8811 consists of a five-drug combination devised to achieve more rapid
cytoreduction during the induction phase. For B-​cell–lineage ALL, it produced an
82% CR rate with 41% DFS at 36 months. Patients in remission receive multiagent
consolidation treatment, CNS prophylaxis, late intensification, and maintenance
chemotherapy for a total of 24 months. CALGB 8811 should be considered for
patients, regardless of age, who are thought to be able to withstand the rigors of an
intensive program.
a. Induction for patients 60 years or younger
■ Cyclophosphamide 1,200 mg/m2 IV on day 1, and
 ■ DNR 45 mg/m2 IV on days 1, 2, and 3, and
■ Vincristine 2 mg IV on days 1, 8, 15, and 22, and
■ Prednisone 60 mg/m2/day by mouth on days 1 to 21, and
■ L-Asp 6,000 IU/m2 SC on days 5, 8, 11, 15, 18, and 22.
b. Induction for patients older than 60 years
■ Cyclophosphamide 800 mg/m2 on day 1, and
■ DNR 30 mg/m2 on days 1, 2, and 3, and
■ Prednisone 60 mg/m2/day on days 1 to 7.
c. Early intensification (two cycles)
■ IT MTX 15 mg on day 1, and
■ Cyclophosphamide 1,000 mg/m2 IV on day 1, and
■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 14, and
■ Cytarabine 75 mg/m2/day SC on days 1 to 4 and 8 to 11, and
■ Vincristine 2 mg IV on days 15 and 22, and
■ L-Asp 6,000 U/m2 SC on days 15, 18, 22, and 25.
d. CNS prophylaxis and interim maintenance
■ Cranial irradiation 2,400 cGy on days 1 to 12, and
■ IT MTX5 15 mg on days 1, 8, 15, 22, and 29, and
■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 70, and
■ MTX 20 mg/m2 by mouth on days 36, 43, 50, 57, and 64.
e. Late intensification
■ Doxorubicin 30 mg/m2 IV on days 1, 8, and 15, and
■ Vincristine 2 mg IV on days 1, 8, and 15, and
■ Dexamethasone 10 mg/m2/day by mouth on days 1 to 14, and
■ Cyclophosphamide 1,000 mg/m2 IV on day 29, and
■ 6-Thioguanine 60 mg/m2/day by mouth on days 29 to 42, and
■ Cytarabine 75 mg/m2/day SC on days 29 to 32 and 36 to 39.
f. Prolonged maintenance (monthly until 24 months from diagnosis)
■ Vincristine 2 mg IV on day 1, and
■ Prednisone 60 mg/m2/day by mouth on days 1 to 5, and
■ MTX 20 mg/m2 by mouth on days 1, 8, 15, and 22, and
■ 6-Mercaptopurine 60 mg/m2/day by mouth on days 1 to 28.
3. Other vincristine, prednisolone, and daunorubicin (VPD)-based regimens
A number of variations on the basic VPD program have been described. VPD should
be used for patients who are thought not to be able to tolerate a more intensive
chemotherapy program. Some options are shown in parentheses.
a. Induction
■ Vincristine 2 mg IV on days 1, 8, 15, (22), and
■ Prednisone 40 or 60 mg/m2 by mouth on days 1 to 28 or days 1 to 35,
 followed by rapid taper over 7 days, and
■ DNR 45 mg/m2 IV on days 1 to 3, and
■ L-Asp 500 IU/kg (18,500 IU/m2) IV on days 22 to 32.
b. CNS prophylaxis is given as six doses of IT MTX and whole-brain irradiation
starting on approximately day 36.
c. Maintenance is usually started once the marrow suppression and the oral
toxicity of the CNS prophylaxis have cleared. Maintenance may be given in a
pulse or a continuous manner. Although allopurinol is usually not needed after
remission is achieved, the dose of 6-mercaptopurine should be decreased by
75% when given concomitantly with allopurinol.
d. Pulse maintenance is an 8-week cycle consisting of three courses of MTX and
6-mercaptopurine given every 2 weeks, followed by a 2-week pulse of
vincristine and prednisone.
■ MTX 7.5 mg/m2 by mouth on days 1 to 5 during weeks 1, 3, and 5, and
■ 6-Mercaptopurine 200 mg/m2 by mouth on days 1 to 5 during weeks 1, 3,
and 5, and
■ Vincristine 2 mg IV on day 1 during weeks 7 and 8, and
■ Prednisone 40 mg/m2 by mouth on days 1 to 7 during weeks 7 and 8.
Oral MTX should be taken in a single daily dose because splitting the daily
dose significantly increases the mucositis. Approximately three doses of IT MTX
are needed once maintenance has started. The schedule should be coordinated so
that the IT MTX is given on day 1 of the 5 scheduled days of oral MTX. On those
days when IT MTX is given, the oral MTX is not given. Pulse maintenance is given
for 3 years.
Dose adjustments for hematologic toxicity from the MTX and 6-
mercaptopurine should be made on the basis of blood cell counts obtained before the
start of each course.

Dose ANC (/μL) Platelets (/μL)

100% ≥2,000 ≥100,000

75% 1,500–1,999 75,000–99,999
50% 1,000–1,499 50,000–74,999
0% <1,000 <50,000

Intensification with cytarabine and DNR given as “7 + 3” and “5 + 2” does

not improve remission duration or OS compared with pulse maintenance in
randomized, prospective trials.
4. Hyper-CVAD18
a. Odd cycles (1, 3, 5, and 7)
■ Cyclophosphamide 300 mg/m2 IV every 12 hours on days 1 to 3, and
 ■ Mesna 600 mg/m2/day by continuous infusion on days 1 to 3, and
■ Vincristine 2 mg IV on days 4 and 11, and
■ Doxorubicin 50 mg/m2 IV on day 4, and
■ Dexamethasone 40 mg/day on days 1 to 4 and days 11 to 14.
■ IT therapy: MTX 12 mg day 2 each course, and
■ Cytarabine 100 mg day 7 each course (if CNS leukemia is present, increase
therapy to twice weekly until the CSF cell count normalizes).
b. Even cycles (2, 4, 6, and 8)
■ MTX 1 g/m2 IV over 24 hours on day 1, and
■ Leucovorin 50 mg IV to start 12 hours after MTX, then 15 mg IV every 6
hours until serum MTX less than 1 × 10−8 M, and
■ Cytarabine 3 g/m2 IV infusion over 1 hour every 12 hours × 4 doses on days
2 and 3 (reduce cytarabine dose to 1 g/m2 for patients older than 60 years
old), and
■ IT therapy: MTX 12 mg day 2 each cycle, and
■ Cytarabine 100 mg day 7 each cycle (if CNS leukemia is present, increase
therapy to twice weekly until the CSF cell count normalizes).
c. Maintenance therapy for 2 years
■ 6-Mercaptopurine 50 mg by mouth twice a day, and
■ MTX 20 mg/m2/week by mouth.
5. R-Hyper-CVAD (CD20+ ALL)
■ Rituximab 375 mg/m2 IV over 2 to 6 hours on days 1 and 11 of odd cycles
and days 2 and 8 of even cycles; total of eight doses over the first four
cycles.
E. Mature (Burkitt) B-cell ALL
Mature B-cell ALL is rare, constituting 2% to 4% of cases of adult ALL and is
associated with human immunodeficiency virus (HIV) syndrome. The leukemic cells are
characterized by FAB-L3 morphology, expression of monoclonal surface
immunoglobulins, and specific nonrandom chromosomal translocations: t(8;14)
(q24;q32), t(2;8)(q12;q24), t(8;22)(q24;q11). Characteristic clinical features include
frequent CNS involvement, lymphadenopathy, splenomegaly, and high serum LDH level.
In the past, the results of the treatment of B-cell ALL in both children and adults had
been poor, with a CR rate of about 35% and long-term leukemia-free survival (LFS) of
less than 10%. Current pediatric studies designed specifically for B-cell ALL, utilizing
shorter duration, dose-intensive systemic chemotherapy, and early CNS
prophylaxis/treatment, have substantially improved the CR rate to about 90% and the
DFS to 50%–87%.
With use of these therapeutic strategies in children as a template, clinical trials with
young adults have demonstrated long-term survival rates of 70% to 80%. The German
BFM group reported an improvement in the CR rate from 44% to 74%, the probability
 of DFS from 0% to 71%, and the OS from 0% to 51% when intensive treatment was
compared with standard ALL regimens.
The hyper-CVAD regimen induced a CR rate of 90% and a cure rate of 70% in
patients younger than 60 years of age, and a CR rate of 67% with a cure rate of only
15% in older patients.
Addition of anti-CD20 antibody rituximab to the hyper-CVAD regimen induced CR
in 86% of patients, with 3-year OS, EFS, and DFS of 89%, 80%, and 88%,
respectively.19 Nine elderly patients achieved a CR with 3-year OS rate of 89% (one
patient died from infection in CR).
Hyper-CVAD therapy in combination with a highly active antiretroviral therapy
(HAART) regimen in HIV-positive patients resulted in a CR rate of 92%, with more
than 50% of patients alive at 2 years after the diagnosis. The outcome appeared to be
improved in patients taking HAART medications early in the course of the therapy.
For all adult patients with mature B-cell ALL, we recommend HIV testing, CNS
prophylaxis, and hyper-CVAD plus rituximab therapy.
F. Minimal residual disease in ALL
The aim of induction therapy in ALL is to reduce the leukemia cell population from 1012
cells to below the cytologically detectable level of 109 cells. Many studies have
demonstrated that detection of MRD at specified time-points (usually following
induction or early consolidation therapy) is associated with high relapse rates and poor
survival. For instance, in a study from the German Multicenter Group for Adult ALL,
detection of MRD following early consolidation therapy was associated with a 5-year
CR of only 12%. Conversely, the absence of MRD following induction or consolidation
therapy has been associated with excellent DFS rates.20 MRD monitoring is an essential
component of an optimal treatment strategy for adult ALL and we recommend
considering referral for allogeneic transplant if MRD persists following early
consolidation therapy.
G. CNS disease
Although uncommon at diagnosis (less than 10%), without CNS-​directed therapy, 50%
to 75% of patients will develop CNS disease. Prophylaxis is therefore an essential part
of ALL therapy, as it has clearly been shown to reduce the incidence of CNS disease.
1. Principles of diagnosis, prophylaxis, and management of CNS disease
a. Obtain a diagnostic LP once leukemic blasts are cleared from peripheral blood
(to preclude CNS contamination in the event of traumatic LP). The first dose of
IT chemotherapy could be given at the same time.
b. Presence of lymphoblasts in the CSF (5 lymphocytes/μL and blasts on the
differential or any lymphoblasts in the CSF) usually signifies CNS disease.
c. Patients presenting with clinical symptoms consistent with CNS involvement,
such as headache, altered sensorium, and cranial nerve (particularly cranial
nerve VI) palsy warrant an immediate CNS imaging and LP because neurologic
dysfunction is most amenable to therapy within the first 24 hours. Infectious
 meningitis also must be excluded in the immunocompromised host.
d. Consider an Ommaya reservoir placement for patients with diagnosed CNS
involvement.
e. Isolated CNS relapse usually heralds bone marrow relapse if systemic therapy is
not changed. Therefore, isolated CNS relapse is usually treated with systemic
reinduction chemotherapy and IT chemotherapy, followed by cranial irradiation.
Depending on the protocol, CNS prophylaxis includes IT chemotherapy with
MTX, Ara-C, and steroids; high-dose systemic chemotherapy with MTX, Ara-C, L-
Asp, craniospinal irradiation (XRT); or a combination of the above. None of the
combinations have been definitively proven to be superior to the others. The role of
XRT has become controversial because of the significant neurologic complications
such as seizures, intellectual and cognitive impairment, dementia, and development
of secondary CNS malignancy. In addition, most chemotherapy regimens now
administer either or both HiDAC and high-dose MTX.
In adults, features that correlate with a high risk for the development of CNS
disease include mature B-cell ALL, serum LDH higher than 600 u/L, and
proliferative index of less than 14% (% S-phase + G2M-phase).
2. The commonly used regimens for CNS prophylaxis include the following
a. MTX 12 mg/m2 (maximum 15 mg), diluted in ​preservative-free saline, given IT
once a week for 6 weeks. Some investigators also give 10 mg of hydrocortisone
succinate IT to prevent lumbar arachnoiditis. The IT MTX is then given in an
“in-and-out” manner. MTX solution of 1 to 2 mL is injected into the spinal canal.
Then, 0.5 to 1 mL of spinal fluid is withdrawn back into the syringe. This in-and-
out process is repeated until all of the MTX has been given. This method is used
to ensure that the MTX is actually given into the subarachnoid space. Leucovorin
5 to 10 mg may be given orally every 6 hours for four to eight doses to
ameliorate mucositis, although this usually is not needed unless the patient is
receiving concurrent systemic MTX. Complications of MTX include chemical
arachnoiditis and leukoencephalopathy.
b. In the M.D. Anderson hyper-CVAD regimen, IT MTX 12 mg on day 2 and
cytarabine 100 mg was administered on day 8 of each of the eight cycles to high-
risk patients and of each of the four cycles in low-risk patients.
c. Cranial irradiation with IT MTX is usually initiated within 2 weeks of attaining a
CR when classic maintenance is given. Cranial irradiation is usually given to the
cranial vault (anteriorly to the posterior pole of the eye and posteriorly to C2) in
0.2-Gy fractions for a total of 18 to 24 Gy. The spine is not irradiated because
marrow toxicity significantly limits the ability to give further chemotherapy.
Common acute complications of radiation include stomatitis, parotitis, alopecia,
marrow suppression, and headaches. Many regimens have eliminated CNS
radiation since they now often include HiDAC and methotrexate which cross the
blood–brain barrier.
 3. Therapy for overt CNS leukemia
It is similar to the CNS prophylaxis.
a. Cranial irradiation is usually given to a total of 30 Gy in 1.5- to 2-Gy fractions.
b. IT chemotherapy is given in the manner described for CNS prophylaxis and is
repeated every 3 to 4 days, with appropriate laboratory studies being done with
each LP. When blast cells are no longer seen on the cytospin preparation, two
more doses of IT drug are given, usually followed by a monthly “maintenance”
IT injection.
H. ALL in older adults
The therapeutic advances and improved outcomes in children and young adults with
ALL did not occur in older patients with ALL. Likely reasons include fundamental
biologic differences in the spectrum of ALL in this patient population, the presence of
coexisting medical conditions, and a decreased ability to tolerate intensive
chemotherapy. Additionally, older patients have been frequently excluded from clinical
trials. The correlation of age and outcome has been well documented in patients with
ALL treated on the five sequential CALGB studies. Rates of CR in patients younger than
30 years, between 30 to 59 years, and older than 59 years were 90%, 81%, and 57%,
respectively. On the basis of the data provided by Hoelzer and Pagano et al. for patients
older than 60 years treated with intensive chemotherapy from 1990 to 2004, the
weighted mean CR rate was 56%; 23% sustained from early mortality and 30% had
primary refractory disease.21,22
In a randomized clinical trial evaluating the use of growth factors during
chemotherapy for ALL, older patients enjoyed the greatest benefit. Thus, it is
recommended to administer growth factors during ALL treatment in older adults.16
Full doses of VPD-based induction protocols are used in elderly patients with ALL.
Some investigators decrease the dose of vincristine by 50%. The MRC/ECOG
UKALL/ECOG E2993 and CALGB 8811 regimens should be considered for patients
who are thought to be able to tolerate more intensive therapy.
Underlying cardiac disease may preclude the use of an anthracycline for induction
therapy. An active program is MTX, vincristine, peg-asp, and dexamethasone (MOAD),
developed by the ECOG, which is given in sequential 10-day courses (minimum three,
maximum five) until remission is achieved. Once a CR has been attained, two
additional courses of MOAD are given. Novel targeted therapies (Blinatumomab,
Inotuzumab) are likely to play a larger role in older patients with ALL.
1. Induction
■ MTX 100 mg/m2 IV on day 1 (increase by 50% on courses 2 and 3 and by 25%
each additional course until mild toxicity is achieved), and
■ Vincristine 2 mg IV on day 2, and
■ L-Asp 500 IU/kg (18,500 IU/m2) IV infusion on day 2, and
■ Dexamethasone 6 mg/m2/day by mouth on days 1 to 10.
2. Consolidation therapy is repeated every 10 days for six courses.
 ■ MTX (final dose from induction) IV on day 1, and
■ L-Asp 500 IU/kg (18,500 IU/m2) IV infusion on day 2.
3. Cytoreduction begins on day 30 of the last consolidation cycle of MTX and L-Asp.
a. Cytoreduction is given monthly for 12 months.
■ Vincristine 2 mg IV on day 1, 30 minutes before MTX, and
■ MTX 100 mg/kg (3.7 g/m2) IV infusion over 6 hours on day 1, and
■ Leucovorin 5 mg/kg (185 mg/m2) divided into 12 doses starting 2 hours after the
MTX infusion over days 1 to 3, and
■ Dexamethasone 6 mg/m2/day by mouth on days 2 to 6.
4. Maintenance begins on day 30 of the last course of cytoreduction. It is repeated
monthly until relapse.
■ Vincristine 2 mg IV on day 1, and
■ Dexamethasone 6 mg/m2/day by mouth on days 1 to 5, and
■ MTX 15 mg/m2 by mouth weekly, and
■ 6-Mercaptopurine 100 mg/m2 by mouth daily.
I. Therapy for Ph+ ALL
1. Background
In the era before TKIs, despite only slightly lower rates of CR in Ph+ ALL patients
(60% to 80%) compared with those with Ph− disease, the long-term DFS was
dismal (less than 10%), with ​allo-HSCT being the only modality offering a
meaningful DFS. The MRC UKALLXII/ECOG E2993 international prospective ALL
trial compared the outcomes of patients with Ph+ ALL treated with matched-sibling
allo-HSCT, matched unrelated allo-HSCT, auto-HSCT, and
consolidation/maintenance chemotherapy. The 5-year RR was lower in the allo-
HSCT group (29%) than with the auto-HSCT/chemotherapy group (81%), while the
5-year survival rates were 43% and 19%, respectively. The TRM, not surprisingly,
was higher in the patients undergoing allo-HSCT: 43% for matched unrelated allo-
HSCT, 37% for matched-sibling HSCT, 14% for auto-HSCT, and 8% for
chemotherapy.23
However, introduction of TKIs into clinical practice improved the options and
outcomes of patients with Ph+ ALL.
a. Imatinib mesylate (Gleevec), a potent selective inhibitor of the BCR-ABL
tyrosine kinase, has been shown in phase I and II clinical trials to have
substantial (20% to 58% CR), albeit nonsustained (42 to 123 days) activity in
patients with relapsed and refractory Ph+ ALL. Administration of imatinib to 20
patients relapsed after allo-HSCT induced a CR in 55%. Imatinib monotherapy
in previously untreated patients resulted in a CR rate of approximately 95%,
without the associated toxicity of chemotherapy. Incorporation of imatinib in
frontline hyper-CVAD chemotherapy is associated with hematologic CR rates
consistently higher than 90% and molecular responses higher than 50%.
 Concurrent administration of imatinib and chemotherapy results in greater
antileukemic efficacy than sequential administration.24
b. Nilotinib is a second-generation oral TKI that appears to have some activity in
imatinib-resistant Ph+ ALL. One in ten patients with relapsed Ph+ ALL
(hematologic relapse) had a partial hematologic response, and one of three
patients with molecularly relapsed Ph+ ALL had a complete molecular
remission.
c. Dasatinib, another second-generation oral kinase inhibitor that targets BCR-ABL
and SRC kinases, demonstrated significant activity in imatinib-resistant Ph+
ALL. Dasatinib penetrates the blood-brain barrier, whereas imatinib and
nilotinib do not.
d. Ponatinib has shown a 41% major hematologic response in Ph+ ALL after failure
or intolerance of dasatinib or nilotinib, including in patients with the T315I
mutation. Because of its high risk for thrombotic events, it is indicated for
patients with T315I mutation, Ph+ ALL for whom no other TKI therapy is
indicated.25
Despite high remission rates and favorable DFS, long-term outcome in Ph+
ALL treated with TKIs with or without chemotherapy remains to be defined. It has
been our practice to proceed with an allo-HSCT for patients achieving adequate
responses.
2. Recommendations for Ph+ ALL
a. Hyper-CVAD chemotherapy with 600 mg of imatinib, administered daily for 14
days with each cycle; or with induction cycle and then continuously thereafter; if
tolerated, dose may be increased to 800 mg for indefinite maintenance therapy if
allo-HSCT is not possible.
b. Hyper-CVAD chemotherapy with 100 mg of dasatinib, administered for 14 days
with each cycle, followed by maintenance 100 mg of dasatinib with vincristine
and prednisone for 2 years if allo-HSCT is not an option.
c. For eligible patients, allo-HSCT still remains a therapeutic goal although the
role of allo-HSCT is now questioned and its role should be studied in clinical
trials.
d. The role of TKIs posttransplant remains to be defined.
e. A combination of TKIs and low-intensity therapy (vincristine, steroids) is of
benefit to older and frail patients who are not candidates for more aggressive
therapy and who are at a higher risk of induction mortality and death in CR. For
example, the GIMEMA LAL0201-B protocol included only patients older than
60 years. Imatinib (800 mg/day) was given with prednisone 40 mg/m2/day from
day 1 to 45. The CR rate was 100%, with minimal toxicity, and 1 year OS was
74%.26
J. Salvage therapy for ALL
 Although a second remission can usually be achieved in 10% to 50% of adults with
ALL, it tends to be short-lived (6 to 7 months). If a second remission can be attained,
suitable patients with relapsed ALL should be evaluated for the allo-HSCT. Salvage
therapies typically mirror the variety of drug combinations used in the frontline
protocols, including combinations of vincristine, steroids, and anthracyclines;
combinations of MTX and L-Asp; and HiDAC-​containing regimens. Choice of regimens
for salvage therapy takes into consideration features of the patient’s disease
(immunophenotype, extramedullary involvement), patient’s age and comorbidities,
goals of therapy, duration of prior remission, and type of prior therapy. None of the
programs used for relapse is distinctly superior to the others, and any perceived
differences are likely attributable to the usual biases of study selection.
1. Vincristine, doxorubicin, and dexamethasone chemotherapy results in CR rates of
39%, median CR duration of 7 months, and median survival of 6 months; 2-year
DFS was 20% and OS was 8%.
2. “7 + 3” (cytarabine and DNR) as used for the induction of AML is active in ALL.
Vincristine and prednisone may be added.
3. Etoposide and cytarabine are given every 3 weeks for up to three courses until
marrow hypoplasia and remission are achieved. They are then repeated monthly
until relapse.
■ Etoposide 60 mg/m2 IV every 12 hours on days 1 to 5, and
■ Cytarabine 100 mg/m2 IV bolus every 12 hours on days 1 to 5.
4. HiDAC-based regimens have been reported to induce CR rates in 17% to 70% of
patients. HiDAC as a single agent has modest activity in ALL, with a CR rate of
about 34% and a median remission duration of 3.6 months. The addition of
idarubicin or mitoxantrone increases the response rate to 60%, but the median
response time remains 3.4 months.
5. Cytarabine and fludarabine comprise an active noncardiotoxic combination. The
median response duration is 5.5 months. Neurotoxicity is low. A second course can
be given in 3 weeks if needed.
a. Induction
■ Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 6, and
■ Fludarabine 30 mg/m2/day IV over 30 minutes 4 hours before cytarabine on
days 2 to 6.
b. Consolidation is given monthly for two to three courses
■ Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 4, and
■ Fludarabine 30 mg/m2/day IV over 30 minutes 4 hours before cytarabine on
days 1 to 4.
c. Maintenance
■ 6-Mercaptopurine 50 mg by mouth twice a day, and
■ MTX 20 mg/m2/week by mouth.
6. FLAG-IDA induced a 39% CR rate in patients with relapsed/​refractory ALL. The
 responders received the second cycle followed by allo-HSCT and achieved a DFS
of 6 months (3 to 38 months) and an OS of 9 months (7 to 38 months).
■ Fludarabine 30 mg/m2/day IV over 30 minutes on days 1 to 5, and
■ Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and
■ Idarubicin 10 mg/m2/day on days 1 to 3, and
■ G-CSF 5 μg/kg SC 24 hours after the completion of chemotherapy and until
neutrophil regeneration.
7. Hyper-CVAD (see Section VI.D.4) therapy achieves CR rates similar to a
combination of HiDAC, mitoxantrone, and GM-CSF (44% vs. 30%); however,
survival is improved.
8. L-Asp has been administered in combination with MTX, anthracyclines, vinca
alkaloids, and prednisone, with RRs ranging from 33% to 79% and median DFS
from 3 to 6 months. Sequential MTX and L-Asp resulted in significant stomatitis
(dose-​limiting toxicity); 23% of treated patients had allergic reactions to L-Asp.
a. Induction
■ MTX 50 to 80 mg/m2 IV on day 1, and
■ L-Asp 20,000 IU/m2 IV 3 hours after MTX on day 1, followed by
■ MTX 120 mg/m2 IV on day 8, and
■ L-Asp 20,000 IU/m2 IV on day 9.
■ Repeat day 8 and 9 doses for MTX and L-Asp every 7 to 14 days until
remission is attained.
b. Maintenance is repeated every 2 weeks.
■ MTX 10 to 40 mg/m2 IV on day 1, and
■ L-Asp 10,000 IU/m2 IV on day 1.
9. Liposomal vincristine 2.25 mg/m2 IV weekly. Liposomal vincristine (as vincristine
sulfate liposomal injection [VSLI]) constitutes encapsulating vincristine in a
sphingomyelin/cholesterol envelope. It is FDA-approved for the treatment of adult
patients with Ph− ALL in second or greater relapse. An overall response rate of 32%
(CR, CRi, and PR) with a median duration of response of 23 weeks and median OS
of 4.6 months was seen in a single-arm study of 65 adults with heavily pretreated B-
and T-cell ALL.27
10. Blinatumomab. It is given as 28-day continuous infusion (9 mcg/day for days 1 to 7;
28 mcg/day for days 8 to 28) followed by 2 weeks rest for up to 5 cycles.
It is a bispecific T-cell engager (BiTE) monoclonal antibody directed at both
CD3 and CD19, thereby bringing normal cytotoxic T cells into close proximity with
normal and malignant CD19-positive B cells. In a single-arm study that treated 189
adult patients with relapsed or refractory Ph− B-cell ALL, 43% of patients achieved
a CR or CRh after two cycles of Blinatumomab. Of responding patients without
prior SCT, 40% were bridged successfully to allogenic SCT.28 Blinatumomab has
recently been granted accelerated approval by the FDA for relapsed or refractory Ph
 − B-cell ALL.

11. Nelarabine 1.5 gm/m2 days 1, 3, 5

It is a purine analog (soluble prodrug of 9-β-D-arabinofuranosylguanine) that
was FDA-approved in 2005 to treat adults with T-cell ALL that had relapsed or
progressed after two prior chemotherapy regimens. In 126 heavily pretreated
patients (aged 18 to 81 years) with relapsed and refractory disease, a CR rate of
36% and a PR rate of 10% were observed, with 80% of patients who achieved CR
being treated with subsequent allogenic SCT.29 Neurotoxicity is a major side effect
of nelarabine and is both dose- and schedule-dependent; it can be minimized by
administration every other day rather than daily.
K. Novel and investigational strategies for the therapy of ALL
It is unlikely that altering the sequence of currently available chemotherapeutic agents or
increasing their intensity will produce a qualitative improvement in the outcome of
adult patients with ALL. A number of experimental approaches are currently being
evaluated in clinical trials. Among those, Clofarabine, another nucleoside analog, has
received FDA approval for pediatric patients with ALL who have failed at least two
prior induction regimens.
Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin,
appears to be safe and active in relapsed/​refractory ALL, with response rates of 58% to
82% in recent clinical trials.30
L. Hematopoietic SCT in ALL
1. Auto-HSCT for patients in first remission appears to offer no advantage over
chemotherapy, on the basis of the data from the small prospective trials reported to
date and prospective randomized MRC UKALLXII/ECOG2993 ALL data, because
of high rates of relapse.
2. Allo-HSCT. The optimal patient selection and timing of allo-HSCT remains
unresolved. Patients receiving matched-​sibling HSCT in first CR reach a survival
rate of 50% (20% to 81%). Although allo-HSCT for high-risk patients in first CR
has been widely accepted, a large prospective randomized international
collaborative study (MRCUKALLXII/ECOG2993)31 suggests that the advantage may
have been overestimated, particularly owing to a high rate of mortality, but that the
benefit of HSCT may extend to standard-risk patients. This is in contrast to prior
studies that have not demonstrated an advantage to allo-HSCT compared with
standard chemotherapy for patients with ALL without high-risk features in first CR.
However, many of these trials have lacked sufficient numbers of patients, have used
varied patient selection criteria, or did not allow for direct, prospective
comparisons.
According to the data collected by the International Bone Marrow Transplant
Registry, 9-year DFS was not different for patients treated with chemotherapy and allo-
HSCT (32% vs. 34%). High TRM in the HSCT group was the main reason for poor
outcome, whereas the recurrence rate was twice as high in the chemotherapy group
 (66% vs. 30%).
The benefit of allo-HSCT in high-risk patients with ALL was shown by a large
French multicenter trial (LALA87), which compared allo-HSCT with chemotherapy or
auto-HSCT in first CR. Although 5-year OS for all risk groups combined was not
significantly different (48% vs. 35%, p = 0.08), for patients with high-risk disease, both
5-year OS (44% vs. 22%) and DFS (39% vs. 14%) were significantly better with allo-
HSCT. Similarly, the 10-year OS for the high-risk group was 44% with allo-HSCT and
only 11% in the chemotherapy/auto-HSCT arm; in the standard-risk population, the
corresponding numbers were 49% and 39% (p = 0.6), respectively.
Prospective data generated from the MRC UKALLXII/ECOG2993 international
ALL trial, which included 1,929 patients aged 15 to 59 years, allowed patients with
HLA-matched siblings to undergo allo-HSCT; the rest were randomized to receive ​-
auto-HSCT or chemotherapy. The results can be summarized as follows: (1) for all
patients, CR rate was 90% and 5-year OS was 43%; (2) for Ph− patients treated with
matched-sibling allo-HSCT, the 5-year OS was 53% and 45% for the combined cohort
of auto-HSCT and consolidation chemotherapy; (3) the 5-year survival for the standard-
risk group (defined as Ph− ALL, age under 36 years, time to CR less than 4 weeks, and
WBC less than 30,000/μL for B-cell lineage and less than 100,000/μL for T-cell
lineage) was superior for those who had a donor compared with those who had not
(62% vs. 52%; p = 0.02); (4) the 5-year survival rate for high-risk patients was not
significantly different whether patients had a donor or not (41% vs. 35%, p = 0.2;
transplant-related toxicity abrogated the effect of a reduction in the recurrence rate); (5)
postremission chemotherapy produced superior EFS and OS compared with auto-HSCT
(p = 0.02 and p = 0.03, respectively).
Despite the high risk of early toxicity, matched-sibling ​allo-HSCT should be
considered for most patients with ALL in first CR, with standard-risk disease.
As less than 30% of suitable patients with ALL have an HLA-matched-sibling donor
(MSD), extensive work has been aimed at improving the outcome of the transplantations
from alternative donor sources, including partially matched related donors, MUDs, and
UCB. A recently published trial compared the outcomes of auto-HSCT and MUD HSCT
in 260 patients with ALL in first and second CR. Although TRM was higher and risk of
recurrence was lower in MUD HSCT recipients, the 5-year LFS and OS rates were
similar (37% vs. 39% and 38% vs. 39%, respectively). A similar trend toward
comparable outcomes from MUDs and MSDs was observed in other studies. A recently
published retrospective analysis of 623 patients with ALL undergoing HSCT from
autologous (n = 209), MSDs (n = 245), unrelated (n = 100), and UCB (n = 69) sources
demonstrated 5-year OS, LFS, and RRs of 29%, 26%, and 43%, respectively. Two-year
TRM was 28%. Mismatched unrelated donor transplants yielded higher TRM (relative
risk, 2.2; p < 0.01) and lower OS (relative risk, 1.5; p = 0.05) than MSD and UCB
HSCT. Autografting yielded significantly more relapse (68%; p < 0.01) and poor LFS
(14%; p = 0.01). HSCT in the first CR yielded much better outcomes than later HSCT.
 With related donors, MUD, and UCB sources, 5-year LFS was 40%, 42%, and 49%,
respectively, while relapse was 31%, 17%, and 27%, respectively. The authors
concluded that allo-HSCT, not auto-HSCT, results in durable LFS. Additionally, UCB
HSCT led to the outcome similar to that of MSDs or MUDs.
In recent years, the outcomes of allo-HSCT with RIC have been published in small
patient series. Low TRM and OS up to 30% at 3 years suggests that RIC HSCT is a
viable modality for selected patients who are not candidates for HSCT with standard
conditioning.
On the basis of the available data, we advocate the use of HSCT from MSD and
alternative sources for physically fit Ph+ patients in CR1 as well as patients with
relapsed disease in second remission. For Ph+ patients without a suitable donor, we
would continue intensive consolidation chemotherapy accompanied by TKIs, followed
by maintenance chemotherapy with TKIs.

References
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*The vincristine dose should be modified to 50% for paresthesia proximal to the distal
interphalangeal joints and it should be stopped entirely for major muscle weakness, cranial
nerve palsy, or severe ileus.
†DNR and vincristine doses should be modified on a weekly basis according to the serum

bilirubin.
‡Blank.
I. INTRODUCTION
Although the chronic leukemias have traditionally been grouped together to underscore
their differences from the aggressive, acute leukemias, they are a heterogenous collection
of disorders as well. Chronic leukemias can be broadly divided into those arising either
from hematopoietic stem cells or mature lymphocytes. The unifying feature among the
chronic leukemias is that, initially, there is relatively normal maturation of the progeny of
the neoplastic clone. Malignant hematopoiesis is effective and results initially in increased
numbers of mature-appearing cells in the peripheral blood and bone marrow that have few
morphologic abnormalities. Functionally, however, both chronic myelogenous leukemia
(CML) and chronic lymphocytic leukemia (CLL) cells are less competent than their
nonleukemic counterparts. The relatively normal morphologic appearance is in marked
contrast to the acute leukemias where maturation arrest with consequent bone marrow
failure is the hallmark of the disease. Nonetheless, chronic leukemias have a heterogeneous
biology. They differ considerably in pathogenesis, natural history, and treatment
approaches, which are discussed further in detail in this chapter.

II. CHRONIC MYELOGENOUS LEUKEMIA

CML is a relatively uncommon malignancy, accounting for 15% to 20% of adult leukemias
in the United States. The estimated incidence in 2015 is 6,660 new cases.1 The median age
at diagnosis is 53 years, occurring slightly more frequently in men. Less than 10% of cases
are under 20 years of age. Ionizing radiation, including therapeutic radiation, is the only
known risk factor for CML. There is no known genetic predisposition to the disease;
however, there have been reports of families in which multiple members develop
myeloproliferative neoplasms, including CML.
CML is a clonal hematopoietic stem-cell disorder caused by a balanced translocation
between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2)], also known as the
Philadelphia (Ph1) chromosome. The hybrid BCR-ABL gene resulting from the t(9;22) has
been noted in almost all cases of CML and is considered pathognomonic. The BCR-ABL
fusion protein results in constitutive tyrosine kinase signaling activity that mediates the
biologic hallmarks of CML through activation of a mitogenic signaling pathway, altered
cellular adhesion to the extracellular matrix, inhibition of apoptosis, and downstream
activation of a complicated network of signaling pathways including RAS, mitogen-
activated protein kinase, Myc, phosphatidylinositol 3 kinase, NF-k-B, and Janus kinase
 signal transducer and activator of transcription pathways.2
A. Diagnosis
Approximately 90% of patients with CML present in the chronic phase (CP) of the
disease and may be asymptomatic. Symptoms, when present, may include fatigue, bone
aches, weight loss, and abdominal discomfort related to splenomegaly. The
identification of a marked leukocytosis (usually greater than 25 × 109/L) due to a
neutrophilia of all stages of maturation with a myelocyte “bulge” (i.e., myelocytes
outnumbering the more mature metamyelocytes), shift to the left of differentiation,
absolute basophilia and eosinophilia, thrombocytosis, and mild anemia are key factors
in the initial diagnosis. Leukocytes in CML, while morphologically normal, exhibit a
cytochemical abnormality with low leukocyte alkaline phosphatase (LAP). The low
LAP score is thought to be a consequence of relatively low levels of granulocyte
colony-stimulating factor and is useful in differentiating CML from a reactive
leukocytosis or “leukemoid reaction,” typically due to infection and associated with a
normal or elevated LAP score.
While the diagnosis of CML can be suggested by findings in the peripheral blood, a
bone marrow aspiration and biopsy are used for confirmation of the diagnosis. The
bone marrow is invariably hypercellular with a myeloid-to-erythroid ratio in the range
of 10 to 30:1. All stages of myeloid maturation are usually seen with myelocyte
predominance. Megakaryocytes are typically increased in number and are
characteristically smaller than normal. Up to 40% of patients will display increased
reticulin fibrosis, which typically correlates with the degree of megakaryocytosis. The
blast percentage varies with the phase of the disease as described below.
Up to 95% of patients with CML demonstrate the t(9;22)(q32;q11.2) reciprocal
translocation that results in the Ph1 chromosome.3 Complex translocations of other
chromosomes (variant Ph1) and cryptic translocations of 9q34 and 22q11.2 account for
the remaining patients. The latter are unable to be identified by standard cytogenetic
testing and are therefore referred to as “Ph-negative.” Fluorescence in situ hybridization
(FISH) analysis to identify the BCR-ABL1 fusion gene or reverse transcription (RT)-
polymerase chain reaction (PCR) to identify the BCR-ABL1 fusion mRNA is necessary
in these patients for confirmation of the diagnosis. As such, bone marrow samples must
be submitted for standard karyotyping (e.g., chromosomal banding analysis [CBA]),
metaphase/interphase FISH, and RT-PCR. If a bone marrow biopsy is not feasible for
diagnosis, FISH can be performed on the peripheral blood. The molecular pathogenesis
in CML involves three different breakpoint regions in the BCR gene on chromosome 22.
More than 90% of patients with CML express the 210-kDa oncoprotein, which is
referred to as the p210 BCR-ABL1 protein. The remaining patients express either p230
BCR-ABL1 or the p190 BCR-ABL1 fusion proteins. There are no distinct differences
in the clinical courses of these patients.
While the Ph1 is the initiating event in CML, additional nonrandom chromosomal or
molecular changes appear to be necessary for progression to accelerated phase (AP) or
 blast phase (BP).3 Clonal evolution occurs in up to 80% of patients in the accelerated
and blast crisis phases, and, if noted during the CP, confers a worse prognosis. The
most commonly observed karyotypic abnormalities include trisomy 8, trisomy 19,
duplication of the Ph1 chromosome, and isochromosome 17q (causing deletion of the
p53 gene on 17p). Telomere shortening has also been associated with disease
evolution. It is not known how these chromosomal changes contribute to the loss of cell
differentiation that characterizes advanced-stage disease.
B. Classification
CML is characterized by three evolutionary phases, each carrying a different clinical
and hematologic picture, natural history, and treatment outcome.
1. Chronic phase
Approximately 90% of patients present with CP-CML, about half of which are
asymptomatic. This phase is marked by a leukocytosis in the peripheral blood and
marked granulocytic hyperplasia in the marrow; however, less than 10% of
myeloblasts are present in both peripheral blood and bone marrow. Absolute
eosinophilia and basophilia are commonly present (in contrast to reactive
leukocytosis). Without treatment, the CP will typically run an indolent course of 3 to
5 years before progressing to the AP, although the duration can be highly variable.
2. Accelerated phase
The AP is typically characterized by a loss of previously controlled white blood cell
(WBC) counts and clonal evolution, including the development of new chromosomal
abnormalities in addition to the persisting or reemerged Ph1 chromosome or the gain
of a second Ph1 chromosome. Peripheral blood counts show one or more of the
following: 10% to 19% blasts, basophils greater than 20%, platelets <100,000/μL,
unrelated to ongoing treatment or >1,000,000/μL, unresponsive to therapy (Table
20.1).4 These laboratory findings are often accompanied by the re-emergence or
progression of symptoms such as fever, bone pain, and fatigue, or worsening
splenomegaly. Without treatment, the AP lasts 4 to 6 months.
3. Blast phase
The BP, also called “blast crisis,” is the progressed transformation of CML to a
phase resembling acute leukemia. CP patients typically transform to BP at a rate of
1% per year; thus, most patients will have a known prior diagnosis of CML. The BP
lasts a few months without treatment and is defined by the acute leukemia criteria of
at least 20% blasts in the bone marrow or peripheral blood (Table 20.1).4 However,
patients with 20% to 29% blasts seem to carry a better prognosis than those meeting
the older criterion of greater than 30% blasts. Extramedullary tumor masses
(chloromas) can occur in both the APs and BPs. The majority of cases (50% to
60%) will express a poorly differentiated myeloid phenotype (acute myelogenous
leukemia [AML]), while the remainder shows lymphoid (pre-B acute lymphocytic
leukemia [ALL], 30%) or an undifferentiated or mixed-lineage phenotype.
Persistence of the Ph1 chromosome including additional Ph1 chromosomes, other
 cytogenetic abnormalities, and BCR-ABL kinase domain mutations may be present.
The acquisition of del 17p is more commonly associated with a myeloid blast crisis.
Patients with de novo Ph1 chromosome-positive B-cell ALL typically express p190
BCR-ABL1 and lack the Ph1 chromosome in myeloid cells, whereas patients with
lymphoid BP-CML are often characterized by p210 BCR-ABL1 and have
persistence of the Ph1 chromosome even after chemotherapy-induced hematologic
remissions.

TABLE
WHO Criteria for Diagnosis of Accelerated and Blast Phase CML4
20.1
Accelerated Phase Blast Phase
Blasts 10%–19% of WBCs in peripheral blood or bone marrow Blasts ≥20% in peripheral blood or bone marrow
Peripheral blood basophils >20% Extramedullary blast proliferation
Persistent thrombocytopenia <100 × 109/L unrelated to therapy or
Large foci or clusters of blasts in the bone marrow biopsy
persistent thrombocytosis >1,000 × 109/L unresponsive to therapy
Increased spleen size or worsening leukocytosis unresponsive to
therapy
Cytogenetic evidence of clonal evolution

CML, chronic myelogenous leukemia; WBC, white blood cell; WHO, world health organization.

C. Prognosis
A number of factors indicate an increased risk for progression, including older age,
splenomegaly, elevated platelet counts, and higher numbers of peripheral blood
myeloblasts, eosinophils, or basophils. The Sokal prognostic system and the Hasford
classification utilize a formula factoring in age, spleen size, and the hematologic picture
to assign low, intermediate, and high groups differing in prognosis.5,6 The median
overall survival (OS) with the latter score was 96, 65, and 42 months, respectively.
Both classifications were developed in patient cohorts receiving interferon, as opposed
to tyrosine kinase inhibitors (TKIs), limiting their usefulness. The European Treatment
and Outcome Study (EUTOS) score is a newer prognostic model developed and
validated on data from 2,060 patients receiving imatinib.7 On the basis of spleen size
and percentage of basophils, patients could be risk stratified to low- and high-risk
groups, associated with a 5-year progression-free survival (PFS) of 90% versus 82%,
p = 0.006. The model was able to predict that 34% of high-risk patients would not
achieve a complete cytogenetic remission by 18 months. The EUTOS score has not yet
been widely implemented into clinical trial design, nor had it been validated with
second- and third-generation TKIs. Regardless of pretreatment characteristics,
however, the most important and best prognostic predictor of long-term survival is the
quality of the response to treatment by minimal residual disease, which is measured by
 the degree of cytogenetic and molecular response.
D. Therapy
1. Imatinib (gleevec)
Imatinib is a small-molecule TKI of the BCR-ABL tyrosine kinase. Targeting and
inhibiting the BCR-ABL mitogenic pathway with imatinib has achieved dramatic
cytogenetic and molecular levels of responses with prolonged disease control in
CML. The most comprehensive source of information about the imatinib therapy for
patients with CP disease is the International Randomized Study of Interferon and
STI571 (IRIS) trial, a phase randomization of imatinib versus the combination of
interferon-α and cytarabine in previously untreated patients with CP-CML. At 18
months, 76% of patients achieved a complete cytogenetic response (CCyR) with
imatinib compared with 15% with interferon-α and cytarabine (p < 0.001).8 At 8
years of follow-up, the event-free survival (EFS) was 81%, freedom from
progression AP/BP was 92%, and estimated OS was 85%.9 Patients who achieved a
≥3 log reduction in the level of BCR-ABL transcript (major molecular response
[MMR]) by 18 months had minimal risk of disease progression over the next year.
Of the 98 patients who underwent long-term monitoring of BCR-ABL transcript
levels, 86% remained in an MMR (<0.1% BCR-ABL) at 8 years. The results of the
IRIS trial have been supported in several prospective trials and registry surveys
including the PETHEMA, SPIRIT, CAMELIA, GIMEMA, and German CML study
groups.10–14 On the basis of the initial results from the IRIS study, imatinib was
approved for the treatment of CML. The standard initial dosing for CP disease is
400 mg orally daily. Close monitoring of the BCR-ABL transcript is crucial in the
management of CML.
2. Imatinib resistance
Unfortunately, patients can develop resistance to imatinib. Primary resistance
without a complete hematologic response (CHR) occurs within 3 to 6 months of
initiating TKI therapy in 2% to 4% of patients.15 Primary cytogenetic resistance (i.e.,
failing to achieve a partial cytogenetic response at 6 months) occurs in 15% to 25%
of patients. Secondary resistance is the loss of a previously achieved response.
After 7 years of follow-up, 17% of patients treated with imatinib in the IRIS study
developed secondary resistance after achieving a CCyR.16 Resistance to imatinib is
more frequently seen in AP and BP than in CP. When resistance is observed, a repeat
bone marrow with cytogenetics and screening for the new kinase mutations should
be performed in order to identify the most appropriate next TKI. Mechanisms of
resistance can be BCR-ABL dependent, such as gene amplification or point
mutations, or BCR-ABL independent because of mechanisms that alter the drug
uptake and efflux.17 Point mutations of the BCR-ABL tyrosine kinase domain can
occur at various sites and confer different levels of resistance.18 The T315I mutation
that occurs at the ATP-binding site is associated with the highest level of
resistance.19 Switching to second- or third-generation TKIs is presently the standard
 of care for imatinib failure or resistance. An allogeneic stem-cell transplant in
eligible patients with resistance to multiple TKIs may be an additional option.
3. Second-generation TKIs
a. Dasatinib (sprycel)
Dasatinib, a piperazinyl derivative that targets many tyrosine kinases, was
selected for its potent inhibitory activity against SRC and ABL kinases,
including the active conformation of BCR-ABL1 and most mutated forms (except
T315I). The drug was shown to be effective for the treatment of Ph+ leukemia
and was initially approved for the treatment of patients with imatinib-intolerant
and imatinib-resistant disease who have Ph+ CML in CP, AP, and BP in 2006.
The approval was based on data from four single-arm multicenter studies (n =
445).20 Among the patients with CP, the CCyR was 33%. Major hematologic
responses were seen in 59% of AP, 32% of myeloid BP, and 31% lymphoid BP.
For patients receiving 100 mg daily, at 6 years of follow-up, the PFS was 49%
and OS was 71%.21 Forty-two percent of patients had evidence of a MMR with
BCR-ABL <0.1%. Dasatinib was approved in previously untreated CML in
2010 on the basis of the DASISION study in which 519 patients were
randomized to dasatinib 100 mg daily or imatinib 400 mg daily.22 Dasatinib
demonstrated a higher CCyR at 12 months of 77% compared with 66% (p =
0.007) as well as higher rate of MMR at any time (52% vs. 34%). At 3 years of
follow-up, however, there was no significant difference in PFS or OS.23
b. Nilotinib (tasigna)
Nilotinib is an aminopyrimidine derivative that inhibits the tyrosine kinase
activity of the unmutated and several mutated forms of BCR-ABL (except T315I,
and to a lesser extent Y253H, E255K, and E255V) with higher in vitro potency
and selectivity than imatinib. Similar to dasatinib, nilotinib is effective for the
treatment of Ph+ leukemias and was registered for treating imatinib-intolerant
and imatinib-resistant patients with Ph+ CML in CP and in AP at a dose of 400
mg twice daily in 2007. In an international phase II study of 321 patients, 45%
achieved a CCyR.24 The estimated 4-year PFS and OS were 57% and 78%. The
drug was approved for previously untreated patients on the basis of the
ENESTnd study, which demonstrated higher CCyR (87% at 2 years), MMR
(73% at 3 years), and molecular response (MR)4.5 (32% at 3 years; see Table
20.2) compared with imatinib.25–27 Thus far, survival rates are comparable
between the arms.
 TABLE
Response Criteria in CML15,16
20.2
Type of
Definition
Response
Hematologic
WBC <10 × 109/L
Basophils <5%
CHR No myelocytes, promyelocytes, myeloblasts in the differential
Platelet count <450 × 109/L
Spleen nonpalpable

Cytogenetic
Minimal cytogenetic
66%–95% Ph + metaphases
response
Minor cytogenetic
36%–65% Ph + metaphases
response
Partial cytogenetic
1%–35% Ph + metaphases
response
CCyR No Ph + metaphases or <1% BCR-ABL1-positive nuclei of at least 200 nuclei on FISH
Major cytogenetic
0%–35% Ph + metaphases (complete + partial)
response

Molecular
MR3 Detectable disease with ratio of BCR-ABL to ABL (or other housekeeping genes) ≤0.1% (≥3 log reduction)
Detectable disease with ratio of BCR-ABL to ABL ≤0.01% (≥4 log reduction) or
MR4
Undetectable disease in cDNA with ≥10,000 ABL transcripts
Detectable disease with ratio of BCR-ABL to ABL (or other housekeeping genes) ≤0.0032% (≥4.4 log reduction)
MR4.5 on the international scale or
Undetectable disease in cDNA with ≥32,000 ABL transcripts

CML, chronic myelogenous leukemia; CHR, complete hematologic response; CCyR, complete cytogenetic response; FISH,
Fluorescence in situ hybridization; MR, molecular response; PCR, polymerase chain reaction; Ph, Philadelphia; RT, reverse
transcription; WBC, white blood cell.
 TABLE
Milestones and Definitions of Response to First-Line TKI16
20.3

4. Third-generation TKIs
a. Bosutinib
Bosutinib is a dual inhibitor of SRC and ABL tyrosine kinase, which has notable
activity in most imatinib-resistant BCR-ABL kinase domain mutations, except for
T315I and V299L. It was approved in 2012 for Ph+ CP-CML in patients who
were intolerant or resistant to at least one prior TKI. A single-arm study
demonstrated that bosutinib was able to induce CCyR in 46% who were
resistant to imatinib and 54% of patients who were intolerant.28 Neither the
median PFS nor OS had been reached at analysis, but the estimated 2-year PFS
and OS were 81% and 91%. For patients who had received at least two TKIs,
the CCyR was 24% (CHR 73%) with a year 2-year PFS and OS of 73% and
83%.29 Bosutinib has been compared to imatinib in the frontline setting as well,
but did not reach its primary endpoint of a superior CCyR to ensure Food and
Drug Administration (FDA) approval.30
b. Ponatinib
Ponatinib is a pan–BCR-ABL kinase inhibitor with activity despite all kinase
domain mutations including the T315I. It received accelerated approval for CP-,
AP-, or BP-CML that was resistant or intolerant to prior TKIs. In the PACE
study (n = 449), ponatinib induced an MCyR in 54% of CP-CML patients
including 70% of those with the T315I mutation.31 The median duration of
response (DOR) had not yet been reached at the time of analysis. The major
hematologic response rate in AP- and BP-CML was 52% and 31%, whereas the
 DOR was 9.5 months and 4.7 months, respectively. Because of an increased risk
of arterial thrombosis, the drug was temporarily suspended. Ponatinib is
currently recommended only for patients with the T315I mutation or those in
whom no other TKI is appropriate.
5. Disease monitoring during TKI therapy
Patients receiving TKIs should be monitored closely to assess for treatment toxicity
and to evaluate for response. The definitions of response and milestones for
treatment are listed in Tables 20.2 and 20.3, respectively.32,33 A reasonable
approach, modifiable to an individual patient, is as follows:
a. Complete blood count every 2 weeks until CHR has been achieved, then every 3
months.
b. Bone marrow cytogenetics via CBA of marrow cell metaphases (at least 20
metaphases) should be performed at diagnosis, 3, 6, and 12 months after
initiating therapy until a CCyR is achieved, and then every 12 months. FISH on
blood cells can be used instead once a CCyR has been achieved. CBA should be
performed at 18 months if patient is not in MMR or did not achieve a CCyR at
12 months. It should also be performed if the patient develops rising BCR-ABL1
transcript levels without an MMR.
c. Peripheral blood quantitative RT-PCR for BCR-ABL mRNA at diagnosis and
every 3 months with ongoing treatment for 3 years and every 3 to 6 months
thereafter. It should be performed if there is a rising BCR-ABL1 transcript level
with an MMR and repeated within 1 to 3 months for confirmation.
d. BCR-ABL1 kinase domain mutation analysis should be performed in the setting of
suboptimal response or failure with therapy and prior to any change in TKI.34
The timing and level of response are important management milestones. The
earlier a cytogenetic and molecular response is achieved, the longer the ultimate
response will last. Achievement of a CCyR by 12 months was associated with a
longer PFS and OS than for patients who failed to reach a CCyR.35 More recently,
quantitative PCR on peripheral blood has become the monitoring method of choice,
and demonstration of an MMR by 18 months is associated with a durable
remission.36 Several studies have also shown the prognostic benefit of early
molecular response, not only with imatinib, but second-generation TKIs as well.
Achievement of a BCR-ABL1 transcript level ≤10% by 3 months has been
associated with a better estimated OS with imatinib,37 dasatinib,23 and nilotinib.38
6. Choice of TKI
With three TKIs available for the initial treatment of CML, the most appropriate
choice remains unclear. As higher rates of patients reach BCR-ABL1 transcript
levels ≤10% by 3 months with second-generation TKIs than imatinib, many advocate
the use of these newer agents. It should be noted that this decision is extrapolated
from an estimated OS as opposed to a demonstrated benefit in OS. Other factors that
should be considered include financial cost to the patient and comorbidities that may
 be affected by a particular TKI. Imatinib, although tolerated well overall, is
associated with mild nausea, diarrhea, peripheral and periorbital edema,
hepatotoxicity, and cardiotoxicity. Dasatinib is associated with pleural and
pericardial effusions, an increased risk of bleeding, and pulmonary arterial
hypertension. Nilotinib can cause pancreatitis, hyperglycemia, hepatotoxicity, cardio
and peripheral vascular events, as well as QT prolongation. Bosutinib, like
imatinib, is associated with fluid retention and gastrointestinal effects. As
previously mentioned, ponatinib can cause arterial thrombosis; additionally, it can
cause heart failure, hypertension, hepatotoxicity, fluid retention, pancreatitis, and an
increased risk of bleeding.
7. TKI cessation
It should be noted that TKIs can only control, but not completely eradicate the CML
clone. Therefore, patients continue on therapy until progression or intolerable
toxicity. Discontinuation of imatinib was explored in the Stop Imatinib (STIM) study
in which 100 patients with CP or AP and sustained complete molecular remission
for at least 2 years.39 At a median follow-up of 17 months, 54 patients had relapsed.
Of the 42 relapsed patients with long-term follow-up, all were sensitive to imatinib
reinduction and none had developed mutant BCR-ABL phenotypes. Other studies
have also demonstrated that patients are able to maintain the same degree of
response for a period of time and can be successfully reinitiated on therapy on
recurrence.40–42 As these are preliminary data, however, current recommendations
are to continue TKI therapy indefinitely unless dictated otherwise as part of a
clinical trial. Cessation of therapy can be considered in a very select population,
such as pregnant woman, but frequent monitoring is necessary. Trials evaluating the
cession of second-generation TKIs are ongoing.
8. Omacetaxine
Omacetaxine is a reversible protein translation inhibitor that has antileukemic effect
distinct of BCR-ABL kinase mutations. It was approved for CP- and AP-CML with
resistance and/or intolerant to two or more prior TKIs on the basis of results from
two phase II studies demonstrating a major cytogenetic response in 18% with a
median DOR of 12.5 months in CP-CML and a major hematologic response was
seen in 14.3% in AP-CML with a median DOR of 4.7 months. The most common
adverse events were related to myelosuppression and diarrhea.43,44 Its use is
typically reserved for treatment after TKIs have failed.
9. Allogeneic hematopoietic stem-cell transplant (HSCT)
Allogeneic HSCT remains the only known curative treatment for CML. With the
number of safe and effective TKIs available, however, the appropriate patient and
the optimal timing of transplantation for CML have evolved. In general, allogeneic
HSCT is considered for CP patients with inadequate response to initial TKI, patients
who are intolerant to TKIs, or an adjunct therapy for patients with AP or BP. For the
latter, the goal of treatment is to achieve a CP state before proceeding to allogeneic
 HSCT, typically with a TKI (often with chemotherapy in BP). A second- or third-
generation TKI is preferred over imatinib. Mutational analysis should also be
performed to assist in choice of agent for patients who have progressed on an initial
TKI. Eligibility for transplant is typically institutional dependent; however, age,
comorbidities, performance status, compliance, and status of disease are important
criteria. To assist inpatient selection, a transplantation risk score has been proposed
by the European Blood and Bone Marrow Transplantation Group to assess both
transplant-related mortality as well as long-term survival (Table 20.4).45 On the
basis of a scale of 0 to 7, 5-year OS varied from 72% to 22% with transplantation.
Five-year survival rates after myeloablative transplantation range from 50% to 85%
in CP, 30% to 40% in AP, and 5% to 15% in BP. The utility of TKI posttransplant is
not clear for those transplanted in CP-CML with a molecular remission, but it is
generally preferred for patients transplanted for BP-CML. The duration is typically
2 years.

III. CHRONIC LYMPHOCYTIC LEUKEMIA

CLL is the most prevalent type of leukemia in the western world, representing 30% of all
leukemias in the United States. The estimated incidence in 2015 is 14,620.1 CLL is
generally considered a disease of the elderly with a median age of diagnosis of 72 years;
however, 10% to 15% of patients are younger than 50 years of age. Men are affected more
frequently than women. While there is no established etiologic factor for the development
of CLL, there does appear to be a genetic component. An increased incidence of CLL, as
well as other hematologic and solid tumor malignancies, has been noted in first-degree
relatives of patients with CLL. The majority of patients have evidence of a monoclonal B-
cell lymphocytosis (MBL) (<5,000 cells/μL) prior to their diagnosis. Only small
percentage of people with MBL will subsequently develop CLL.46

TABLE
Allogeneic Stem-Cell Transplant and European Group for Blood and Marrow

20.4 Transplantation Risk Score43

Risk Factor Score

Disease phase 0 for CP, 1 for AP, and 2 for BP
Age 0 if <20 years, 1 if 20–40 years, 2 if >40 years
Interval from diagnosis 0 if ≤1 year, 1 if >1 year
Donor type 0 if HLA-matched sibling, 1 for any other alternative donor
Donor–recipient sex match 1 for female donor and male recipient, 0 for any other match

AP, accelerated phase; BP, blast phase; CP, chronic phase; HLA, human leukocyte antigen.

A. Diagnosis
 Patients are frequently asymptomatic at diagnosis, when the disease is identified by an
increased absolute lymphocyte count on routing laboratory testing. Symptoms
associated with the disease include fatigue, unexplained weight loss, night sweats,
fevers, chills, and recurrent infections secondary to hypogammaglobulinemia and
disordered complement activation. Physical exam findings most often include nontender
lymphadenopathy, splenomegaly, and hepatomegaly. Patients may also develop
cytopenias secondary to marrow involvement or autoimmune phenomenon. Examination
of the peripheral blood is notable for a homogenous population of lymphocytes with
occasional smudge cells and/or prolymphocytes, which are larger with prominent
nucleoli.
The National Cancer Institute (NCI)–Sponsored Working Group defines the
diagnostic criteria for CLL as an absolute monoclonal lymphocytosis (≥5 × 103/μL),
with a morphologically mature appearance.47 By flow cytometry the lymphocytes
express CD19, CD23, CD5, low levels of CD20, and surface immunoglobulin, and
have either kappa or lambda immunoglobulin light chain restriction. Expression of
CD38 and Zeta-associated protein 70 (ZAP-70) and molecular cytogenetics are not
diagnostic for CLL, but have prognostic implications. Certain cytogenetic markers are
useful in distinguishing other morphologically similar lymphoproliferative
malignancies.
As the diagnosis of CLL can be made via flow cytometry of the peripheral blood, a
bone marrow biopsy is not necessary. Biopsies should be considered in evaluating
cytopenias, particularly in defining the presence of peripheral destruction, as well as
prior to treatment. If a biopsy is performed, greater than 30% of the marrow should
have lymphocytic involvement to confirm the diagnosis of CLL. Biopsies can be
performed after treatment in order to evaluate response or investigate persistent
cytopenias. Lymph-node biopsies are typically not indicated in CLL unless there is
concern for Richter’s transformation.
B. Staging and prognosis
Staging for CLL is based on the presence of lymphadenopathy, hepatosplenomegaly, and
cytopenias. The three most commonly used staging systems for CLL are the Rai,
modified Rai, and the Binet systems (Tables 20.5 and 20.6).47–49 Contrast-enhanced
computerized tomography (CT), although not required for staging purposes, may be
useful in evaluating the presence of internal lymphadenopathy. A patient’s stage by CT
is more consistent with their disease course as compared with their clinical stage.
Positron emission tomography is not indicated in CLL at this time, except to evaluate for
the presence of high-grade transformation.50
 TABLE
CLL Staging Systems47–49
20.5
Findings Survival (Months)
Rai
0 Lymphocytosis only >120
I Lymphocytosis plus lymphadenopathy 95
Lymphocytosis plus splenomegaly or
II 72
hepatomegaly
III Lymphocytosis plus anemia (Hgb <11 g/dL) 30
Lymphocytosis plus thrombocytopenia
IV 30
(platelets <100,000/μL)

Binet
Hgb ≥10 g/dL, platelets ≥100,000/μL, <3
A >120
involved areas *

Hgb ≥10 g/dL, platelets ≥100,000/μL, ≥3

B 84
involved areas *
C Hgb <10 g/dL or platelets <100,000/μL 24

CLL, chronic lymphocytic leukemia; Hgb, hemoglobin.

*Involved areas include cervical, axillary, or inguinal nodes; spleen or liver.

TABLE
Staging and Prognosis in CLL
20.6

Variability in patient outcomes within the stages highlights the importance of other
prognostic factors. In addition to advanced-stage disease, molecular cytogenetics
 correlate strongly with prognosis (Table 20.7). The presence of deletion 11q (mutation
of ATM) and deletion 17p (mutation of p53) by fluorescent in situ hybridization has
traditionally been associated with a poor prognosis, whereas trisomy 12 or normal
cytogenetics portend an intermediate outcome and deletion 13q a favorable one.51 The
estimated incidence of these mutations in an analysis of 325 patients with CLL was del
11q (18%), del 17p (7%), del 13q (55%), and trisomy 12 (16%).51 Mutations of the
NOTCH1, SF3B1, and BIRC3 genes have recently been identified to have a worse
prognosis.52 Cytogenetic abnormalities can change over time, especially acquisition of
del 17p, and should be evaluated with progression of disease. CLL can also be
distinguished at the level of cellular differentiation on the basis of the presence of an
unmutated (pregerminal center) or mutated (memory B-cell) immunoglobulin variable
region heavy-chain gene (IgVH). The presence of an unmutated IgVH is associated with
an inferior outcome and often coincides with overexpression of ZAP-70 present in
>20% of cells. Other high-risk features include overexpression of CD38 (>30%) and an
elevated serum β2-microglobulin level (≥4). These factors are used solely for the
purpose of prognosis and should not be used to determine the timing of treatment. Until
recently, they did not impact the choice of regimen either. The presence of del 17p
influencing therapy options will be discussed below.

TABLE
Factors Associated with Poor Prognosis in CLL
20.7
■ Older age
■ Advanced stage
■ Male sex
■ Diffuse pattern of bone marrow involvement
■ Short (<6 months) lymphocyte doubling time
■ High β2-microglobulin
■ Poor-risk cytogenetics (del 17p, del 11q, NOTCH1, SFB1, BIRC3, or complex abnormalities)
■ Unmutated IgVH status
■ High CD38 expression
■ High ZAP-70 expression
■ Poor or brief response to therapy

CLL, chronic lymphocytic leukemia; IgVH, immunoglobulin variable region gene; ZAP, zeta-associated protein.

C. Complications of CLL
1. Malignancies
The diagnosis of CLL is associated with an increased risk for common solid tumors,
most often of the skin, gastrointestinal tract, and lung. Thus, patients should be
encouraged to undergo routine screening for appropriate tumor types. In addition,
about 15% of patients with CLL may transform to a more aggressive lymphoid
malignancy including prolymphocytic leukemia (PLL), Richter syndrome (diffuse
 large B-cell lymphoma), and ALL. Patients with CLL may also develop or even have
coexisting AML, CML, and multiple myeloma.
2. Autoimmunity
Autoimmune complications include autoimmune hemolytic anemia (AIHA), pure red
blood cell aplasia (PRCA), or immune-mediated thrombocytopenia (ITP). At least
25% of patients will develop a positive direct antiglobulin test, but fewer than 5%
develop clinical evidence of AIHA. AIHA may also develop as a consequence of
fludarabine-based therapy. AIHA and ITP can often be successfully treated with
corticosteroids or rituximab, whereas cyclosporine is typically used for PRCA.
3. Recurrent infections
An increased risk of bacterial infections can occur as a consequence of
hypogammaglobulinemia, in adequate humoral response, and abnormal activation of
the complement system. Historically, the most common pathogens included
Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.
Prophylactic intravenous immunoglobulin should be considered for patients with
recurrent bacterial infections (>2 episodes/year). Certain chemotherapeutic agents,
such as fludarabine and alemtuzumab, have been associated with an increased risk
for opportunistic infections such as Candida, Listeria, Pneumocystis,
cytomegalovirus, aspergillus, and herpes infections. The occurrence of these types
of infections has decreased recently as these agents are less frequently used.
D. Therapy of CLL
Most patients with CLL are asymptomatic at presentation. Randomized trials have failed
to demonstrate an advantage to early intervention in such patients. Thus, watchful
waiting is an acceptable approach, performing laboratory tests and a physical
examination every 3 to 6 months. Indications for initiating therapy as delineated by the
NCI-sponsored Working Group include the following: significant fatigue, unintentional
weight loss ≥10% in the previous 6 months, persistent fevers >100.5°F (38.0°C) for >2
weeks or night sweats >1 month without evidence of infection, steroid-refractory
autoimmune cytopenias, marrow failure with worsening cytopenias, progressive
splenomegaly (>6 cm below costal margin) or lymphadenopathy (>10 cm), and a
progressive lymphocytosis (increase >50% in 2 months or doubling time <6 months).45
1. Chemoimmunotherapy
a. Fludarabine
Treatment options for CLL have evolved significantly over the past two decades,
and continue to do so. In the early 2000s, fludarabine replaced chlorambucil as
an induction regimen on the basis of higher response rates, longer time to
progression, and a survival advantage. It was combined with rituximab (FR) to
further improve patient outcomes. In the CALGB 9712 study, FR demonstrated
an overall response rate (ORR) of 90% (complete response rate [CR] of 47%)
and median OS of 85 months with concurrent therapy.53 The addition of
cyclophosphamide to FR (FCR) has demonstrated ORRs of 90% to 95% (CR
 44% to 72%) when evaluated by the MD Anderson Cancer Center and German
CLL Study Group (GCLLSG).54,55 The median PFS for the latter study, a
multicenter randomized phase III study, was 51.8 months. Subset analyses
indicate that the addition of cyclophosphamide primarily appears to benefit the
poor prognostic del 11q group, and should be considered in the treatment of
these patients.56 The US intergroup frontline study of FR versus FCR versus FR
followed by lenalidomide, which stratifies patients with del 11q to FCR, has
completed accrual, and results are pending.
b. Bendamustine
Bendamustine, a bifunctional alkylating agent, was approved for the treatment of
CLL on the basis of a superior response rate and PFS when compared with
chlorambucil.57 Because of its efficacy and tolerability, bendamustine is well
suited for older patients and those with medical comorbidities. Moreover, it can
be safely administered to patients with mild to moderate renal impairment
without dose reduction and mild hepatic impairment, if due to disease burden.
Bendamustine and rituximab (BR) in the frontline setting have produced results
similar to those previously reported with fludarabine-based regimens (ORR
88%, CR 23%, median EFS 34 months), a more tolerable toxicity profile, and
responses in traditionally poor-risk cytogenetic groups.58 The GCLLSG CLL-10
study compared BR and FCR in previously untreated, physically fit patients, and
found similar ORRs (97.8%), but a higher CR (40.7% vs. 31.5%, p = 0.026) and
PFS (53.7 vs. 43.2 months) with FCR when evaluating all patients.59 In an
unplanned subset analysis, only younger, healthy patients <65 years old or those
with an unmutated IgVH status experienced a PFS benefit with FCR. FCR was
also associated with higher incidences of grade 3/4 neutropenia and infection.
As there was no difference in OS, either regimen can be considered for patients.
BR is preferred for patients who are older and those with hepatic or renal
dysfunction. In addition, it does not cause AIHA, which can be potentiated with
fludarabine-based regimens.
Chemotherapeutics, including fludarabine, cyclophosphamide,
chlorambucil, and bendamustine, are associated with secondary malignancies
such as myelodysplastic syndrome and AML.
2. Monoclonal antibody-based therapy of CLL
The availability of active and safe monoclonal antibodies has dramatically altered
the treatment of CLL.
a. Rituximab
As a single agent in patients with relapsed or refractory disease, rituximab has
limited activity, inducing about 35% to 45% partial remissions.60,61 Higher
response rates are seen in previously untreated patients (ORR 50% to 90%);
however, it is typically not recommended given a relatively short DOR.62,63
b. Alemtuzumab
 In addition to rituximab, three monoclonal antibodies have been approved in
CLL. The first antibody approved by the FDA was alemtuzumab, a humanized
anti-CD52 antibody. It was initially approved for patients who had received
prior alkylating agents and were fludarabine-refractory, demonstrating ORR of
33% to 42%.64,65 Its approval was expanded on the basis of a frontline
comparison with chlorambucil: ORR 83% versus 55%, CR 24% versus 2%, and
median time to alternative therapy of 14.6 versus 11.7 months.66 Notable
toxicities include severe opportunistic infections (Pneumocystis jiroveci
[carinii] and herpesvirus infections) and infusion-related reactions.
Alemtuzumab is no longer commercially available for CLL, but has recently
been FDA-approved for the treatment of multiple sclerosis.
c. Ofatumumab
Ofatumumab is a fully human anti-CD20 monoclonal antibody that is felt to
induce stronger complement-dependent cytotoxicity (CDC) than rituximab. It
was approved for fludarabine and alemtuzumab-refractory CLL on the basis of a
phase II study showing an ORR of 58% (0 CR) and median OS of 13.7 months.67
It is associated with a greater incidence of infusion-related reactions, requiring
higher doses of premedication, and infection. Ofatumumab has been approved in
combination with chlorambucil for previously untreated patients for whom
fludarabine-based therapy was considered inappropriate because of age and/or
comorbidities.68 The median PFS with the combination was 22.4 months
compared with 13.1 months (p < 0.001) with single-agent chlorambucil.
Ofatumumab is being studied in combination with fludarabine- and
bendamustine-based regimens as well as other biologics.69
d. Obinutuzumab
Obinutuzumab is a humanized anti-CD20 antibody that has been glycoengineered
for superior antibody-dependent cellular cytotoxicity and apoptosis in
comparison with rituximab, but does not utilize CDC as a mechanism of action.
It was approved in combination with chlorambucil in previously untreated
patients with CLL with preexisting comorbidities precluding conventional
chemoimmunotherapy on the basis of a superior PFS (27.2 vs. 11.2 months, p <
0.0001) compared with single-agent chlorambucil.70 Updated results indicate
that the combination was superior to R-chlorambucil (median PFS of 26.7 vs.
14.9 months, p < 0.0001) as well. Obinutuzumab is being studied with
bendamustine and a number of new biologic therapies.
3. Small-molecule inhibitors
The B-cell receptor, a transmembrane immunoglobulin, is a critical mediator of
lymphocyte maturation, proliferation, and survival. Several oral small-molecule
inhibitors have been developed against the various downstream signaling pathways,
thus allowing for targeted antitumor activity.
a. Ibrutinib
 Ibrutinib is a selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK)
that has been approved for relapsed and refractory CLL, and CLL with del 17p.
The accelerated approval was based on a multicenter single-arm study in which
85 patients with previously treated disease achieved an ORR of 71% (2 CR) and
estimated PFS and OS at 26 months of 75% and 83%.71 Activity was similar in
patients with del 17p: ORR 68%, PFS 57%, OS 70%. The most common
adverse events are mild diarrhea, fatigue, upper respiratory tract infection,
arthralgia, and rash. Rare toxicities include bleeding, such as severe intracranial
bleeding, and atrial fibrillation. Ibrutinib was compared with ofatumumab in the
phase III RESONATE study, which noted superiority of ibrutinib in terms of
ORR, PFS, and OS.72 As a single agent in previously untreated patients ≥65
years of age, ibrutinib produced an ORR of 71% (CR 13%) and an estimated 2-
year PFS of 96%.73 When combined with rituximab in both previously treated
and untreated high-risk patients, characterized by either del 17p/TP53 mutation,
del 11q, or PFS <36 months after frontline chemoimmunotherapy, the ORR was
95% and the median DOR was 15.4 months.74 Ibrutinib is now being evaluated
in the frontline phase III trials of BR versus ibrutinib versus R-ibrutinib in
patients ≥65 years old and FCR versus R-ibrutinib in patients ≤70 years old.
b. Idelalisib
Idelalisib, an inhibitor of the delta isoform of phosphoinositide 3-kinase p110
(PI3K-δ), was approved for the treatment of relapsed or refractory CLL in
combination with rituximab in patients for whom chemotherapy was not
appropriate because of other comorbidities. The approval was based on a phase
III study of R-idelalisib vs. R-placebo, which demonstrated a superior ORR
(81% vs. 13%, p < 0.001), median PFS (not reached vs. 5.5 months, p < 0.001),
and 1-year OS (92% vs. 80%, p = 0.02).75 Efficacy was noted regardless of
high-risk features; the median PFS was not reached for patients with del 17p or
del 11q. The most common adverse events are mild fatigue, nausea, diarrhea,
and fever. Severe pneumonitis, diarrhea, and hepatic transaminitis elevations can
also occur. Idelalisib is currently being studied in the phase III trial of BR with
or without idelalisib as well as in combination with the various anti-CD20
monoclonal antibodies in other frontline trials.
4. Other novel therapies
There are a number of investigational therapies in development for CLL.
Lenalidomide, a second-generation immunomodulatory agent approved for multiple
myeloma, myelodysplastic syndrome, and mantle cell lymphoma, has demonstrated
single-agent ORR of 30% to 50% and ORR of 60% when combined with rituximab
in relapsed and refractory CLL.76–78 On the basis of phase II data of an ORR of 65%
in previously untreated patients ≥65 years of age,79 lenalidomide was compared
directly with chlorambucil in the phase III ORIGIN trial. The trial was terminated
early because of an increased occurrence of deaths in the lenalidomide arm.80
 Lenalidomide remains the drug of interest in CLL, particularly in combination with
other biologic therapies. Venetoclax, a selective inhibitor of the antiapoptotic BCL-2
family of proteins, has produced ORR of 79% and median DOR of 20.5 months in
patients with relapsed and refractory CLL.81 Unlike some of the other biologic
therapies, it is able to achieve a complete remission (CR/incomplete CR [CRi]
22%). The rapid depletion in lymphocyte count, which occurs in a matter of hours,
can result in life-threatening tumor lysis syndrome (TLS). As a result, patients must
be monitored closely and may require hospitalization for aggressive TLS
management. Venetoclax has been paired with rituximab, resulting in an ORR of
88% (CR/CRi 32%).82 The combination is currently being compared with BR in a
phase III trial in previously treated patients (NCT02005471). Other therapies in
investigation include Syk (spleen tyrosine kinase) inhibitors, second-generation
PI3K and BTK inhibitors, as well as newer forms of immunotherapy such as immune
checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T). CAR-T cells
are autologous T cells that have been genetically engineered to target CD19 and
coexpress CD137 (a T-cell costimulatory receptor in T cells) and CD3-ζ (a signal-
transduction component of the T-cell antigen receptor). An early phase II study in
relapsed and refractory CLL indicates an ORR of 35% (22% CR) among 23
evaluable patients.83
5. Stem-cell transplantation
Autologous stem-cell transplantation has a limited role in CLL. The data on
allogeneic bone marrow transplantation (BMT) are primarily limited to younger
patients with CLL and are associated with considerable morbidity and mortality.
Submyeloablative preparative regimens may achieve successful engraftment without
substantial acute graft-versus-host disease (GVHD); however, chronic GVHD has
been a serious problem. Nevertheless, long-term disease-free survival can be
achieved, and this option is promising, especially for younger high-risk patients who
are refractory to their initial therapy or who have only a transient response to
treatment.
6. Response assessment in CLL
With the availability of effective treatments for CLL, standardized response criteria
are essential. In 1988, the NCI-sponsored Working Group published the first widely
accepted response criteria that were updated in 1996, and reinforced by the
International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) in 2008
(Table 20.8).84,47 With the increasing number of biologic therapies available, the
response assessment continues to evolve.85 The small-molecule inhibitors of the
BCR signaling pathways are associated with a transient lymphocytosis, which is due
to a demargination of lymphocytes from the lymph nodes. This should not be
considered progressive disease unless the patient has other signs of progression.
The lymphocytosis typically resolves in most patients. Similarly, immunomodulatory
agents can induce a transient tumor flare, which can be confused with progression.
 These patients should continue on their respective therapies and be monitored
closely for other signs of progression before considering discontinuation of therapy.

TABLE
Response Criteria for CLL45
20.8
CR
■ Absence of disease-related symptoms
■ Absence of peripheral blood clonal lymphocytosis (bone marrow only in clinical trials)
■ Absence of lymphadenopathy and hepatosplenomegaly
■ Neutrophils ≥1,500/μL
■ Platelets >100,000/μL
■ Hgb >11 g/dL (untransfused)

CRi
■ Same as CR, but with persistent anemia, neutropenia, or thrombocytopenia (for clinical trials, not yet validated)

PR
■ Decrease by ≥50% in peripheral blood lymphocytes
■ Decrease by ≥50% in the sum of the products of diameters of up to six nodes; no new nodes; no increase in any nodes
■ Decrease by ≥50% in hepatosplenomegaly
■ Plus one of the following
■ Neutrophils ≥1,500/μL or ≥50% from baseline
■ Platelets >100,000/μL or ≥50% from baseline
■ Hgb >11 g/dL or ≥50% from baseline

CLL, chronic lymphocytic leukemia; CR, complete remission; CRi, incomplete CR; Hgb, hemoglobin; PR, partial response.

IV. RELATED B-CELL LEUKEMIAS

A. Prolymphocytic leukemia
PLL may be of either B-cell or T-cell lineage. B-PLL accounts for less than 1% of all B-
cell leukemias. The mean age of diagnosis is 65 to 70 years, and the majority of patients
are Caucasian. There is a similar incidence among men and women. Common
presenting signs include a rapidly rising WBC, massive splenomegaly, constitutional
symptoms, anemia, and thrombocytopenia. Prolymphocytes are large, with a round
nucleus and a prominent nucleolus. In de novo PLL, prolymphocytes comprise most of
the peripheral blood mononuclear cells; however, in the setting of an aggressive
transformation from CLL, there is a dimorphic population in the peripheral blood
(>55% prolymphocytes). The immunophenotype is different from CLL; the cells are
positive for CD19, CD20, and CD24, and strongly express CD22, surface
immunoglobulins, and FMC7. Less than a third express CD5 or CD23. What was
formerly called T-CLL or chronic T-cell lymphocytosis was renamed in the World
Health Organization classification as T-PLL. T-PLL has a median age of diagnosis of 65
years and is associated with a light male predominance. There is a younger variant
 (median age of 30 years) that is associated with ataxia telangiectasia. Patients with T-
PLL present similarly to B-PLL but may also have skin infiltration and serous effusions.
Patients with PLL tend to respond poorly to either single-agent or combination
chemotherapy, with ORRs of less than 25% and rare CRs. The median survival for de
novo PLL is 3 years, and it is less than a year for T-PLL. Small series and anecdotal
cases suggest activity for nucleoside analogs and alemtuzumab in PLL. Allogeneic
stem-cell transplantation should be considered for younger patients whose disease is
responsive to induction therapy.
B. Hairy cell leukemia (HCL)
HCL is diagnosed in about 600 to 800 new patients each year in the United States. The
median age at presentation is 52 years and there is a strong male predominance. Patients
generally present with symptoms referable to cytopenias. The most common signs
include palpable splenomegaly (72% to 86%), hepatomegaly (13% to 20%), hairy cells
in the peripheral blood (85% to 89%), thrombocytopenia (less than 100,000/μL: 53%),
anemia (hemoglobin less than 12/dL: 71% to 77%), and neutropenia (absolute
neutrophil count less than 500/μL: 32% to 39%). The lymphocytes in the peripheral
blood generally have an eccentric, spongiform, kidney-shaped nucleus, with
characteristic filamentous cytoplasmic projections. The malignant cells express the B-
cell antigens CD19, CD20, as well as the monocyte antigen CD11c, and specifically
CD103. Bone marrow biopsy is generally required to confirm the diagnosis, as the
aspirate is often not obtainable.
Treatment is indicated in the setting of massive or progressive splenomegaly,
worsening blood counts, recurrent infections, greater than 20,000 hairy cells/μL of
peripheral blood, or bulky lymphadenopathy. Until the early 1980s, splenectomy was
the standard treatment for HCL. Splenectomy is now reserved for the rare patient who
is refractory to treatment and has splenomegaly that is either symptomatic or is resulting
in cytopenias. Purine analogs and, more recently, monoclonal antibodies are the current
standard for the treatment HCL.
C. Pentostatin
The nucleoside analog, pentostatin (21-deoxycoformycin, DCF), is typically
administered at doses of 4 mg/m2 IV every other week for 4 to 6 months. It has
demonstrated ORR of 79% to 100% with a CR of 76% to 89% in previously untreated
patients.86,87 Responses appear to be durable as long-term follow-up indicated an
estimated 10-year OS of 81%.88
D. Cladribine
Using a 7-day continuous infusion or a 2-hour infusion for 5 to 7 days, cladribine (CdA)
achieves responses in 80% to more than 90% of patients, including 65% to 80%
CRs.89,90 These responses tend to be durable. One study reported a 12-year PFS of 54%
and OS of 87%.90 In many cases, relapse is characterized only by an increase in bone
marrow hairy cells, with no indication for treatment. Most patients who require
retreatment achieve a second durable response.
 The results with DCF are equivalent to those with CdA. The shorter duration of
treatment makes CdA somewhat more attractive, although it may be associated with
greater neurotoxicity and myelosuppression.
E. Rituximab
Rituximab has also shown promise for patients with HCL who fail purine analog
therapy: ORR 50 to 80.91,92 It has been studied both sequentially and concurrently with
pentostatin and CdA, demonstrating promising activity in relapsed and refractory
disease.93 When administered following CdA in previously untreated patients, the CR
was 100% and the median CR duration had not been reached.94 Other biologic
therapies include the immunoconjugates against CD22 and CD25, which are strongly
expressed in classic HCL and have shown promise in relapsed and refractory setting.95
BL22, a recombinant anti-CD22 immunotoxin, produced durable responses in up to
77% (CR 47%) of relapsed and refractory patients in the phase II setting, whereas the
higher-affinity moxetumomab pasudotox is now being studied in a single-arm phase III
trial for a better assessment of efficacy (NCT01829711). The BRAF V600E mutation,
present in most patients, has also become a popular target given the availability of
vemurafenib. Numerous case reports have indicated activity in patients with
chemotherapy-resistant disease.96,97 Vemurafenib is currently under phase II
investigation in the relapsed and refractory setting (NCT01711632), as is ibrutinib
(NCT01841723).

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2013;31(20):e351–e352.
I. BCR-ABL1-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS
A. Overview
The myeloproliferative neoplasms (MPNs) are clonal disorders of pluripotent
hematopoietic stem cells or of lineage-committed progenitor cells. MPNs are
characterized by autonomous and sustained overproduction of morphologically and
functionally mature granulocytes, erythrocytes, or platelets. Although one cellular
element is most strikingly increased, it is not uncommon to have modest or even major
elevations in other myeloid elements (e.g., thrombocytosis and leukocytosis in patients
with polycythemia vera [PV]). Bone marrow (BM) aspirates and biopsy specimens
typically show hyperplasia of all myeloid lineages (panmyelosis). Morphologic
maturation and cellular function are essentially normal, although platelet dysfunction
occasionally contributes to bleeding. The overproduction of blood elements in MPNs
now appears related to “switched-on” tyrosine kinase signaling pathways. For chronic
myelogenous leukemia (see Chapter 19), this arises from the t(9;22) translocation and
the BCR-ABL1 gene product. On the other hand for the BCR-ABL1-negative MPNs, a
single nucleotide mutation in the gene coding for JAK2, a tyrosine kinase normally
activated by erythropoietin and other cytokines, plays an analogous role. This group of
MPNs that encompasses PV, essential thrombocythemia (ET), both primary and
secondary myelofibrosis (MF),1 is discussed in the first section of this chapter. The
incidence of PV ranges from 0.4 to 2.8/100,000/year, ET 0.4 to 3.4/100,000/year, and
primary myelofibrosis (PMF) 0.8 to 2.1/100,000/year.
Ever since the observation of William Dameshek in 1951, that PV, ET, and PMF
were a set of closely interrelated disorders, the understanding of the pathogenesis of
classical MPNs has come a long way. This evolution has been marked by three major
milestones that rendered MPNs among the best genetically characterized malignancies.
The first finding was in 2005, with the detection of somatically acquired mutations of
the gene JAK2 in the majority of patients with MPNs. The point mutation V617F in exon
14 of JAK2 is present in 74% to 97% of patients with PV, and in 30% to 65% of
patients with ET or PMF. The second breakthrough occurred in 2006, with the detection
of the myeloproliferative leukemia (MPL) virus oncogene mutations in 3% to 5% and
8% to 11% of nonmutated JAK2 ET and PMF, respectively. Lastly, the third milestone
 was in 2013, when mutations in calreticulin (CALR) gene were observed in
approximately 50% to 70% of patients with ET or PMF who do not carry a mutation in
either the JAK2 or MPL gene.2 The above-mentioned genetic discoveries have rendered
approximately 90% of patients with MPN carriers of a mutually exclusive mutation in
only one of these three genes: JAK2, MPL, or CALR.3 Therefore, positivity for JAK2
V617F gives important diagnostic confirmation for MPNs, although a negative result is
not basis for exclusion. Other discovered mutations are less specific to MPNs but are
prognostically relevant, such as additional sex combs–like 1 (ASXL1) mutation. The
prognostic value varies by mutation and can be summarized as follows; in ET, JAK2
mutations are associated with increased risk of thrombosis, while in PMF patients, type
1 or type 1–like CALR mutations are associated with superior survival, and ASXL1
mutations with inferior survival.3,4 Major MPN-related complications comprise
thrombosis and leukemic or fibrotic transformation. The management of MPNs was also
revolutionized with the discovery of these new mutations through the development of
molecularly targeted therapy, including JAK inhibitors. JAK inhibitors have shown
promising activity in controlling splenomegaly and constitutional symptoms in PMF and
PV, which led to the recent approval of the JAK inhibitor ruxolitinib for use in
hydroxyurea-resistant PV. In view of these changes, the next sections discuss the
diagnosis, evolution, prognosis, and the recent therapeutic advances for PV, ET, and
PMF.
B. Polycythemia vera
1. Diagnosis
In the golden era of disease description, around the end of the 19th century, Vaquez
was the first to describe the idiopathic entity, PV (maladie de Vaquez). Later on,
Osler established it as a new clinical entity distinguished from secondary and
relative polycythemia.
PV must be distinguished from relative or spurious polycythemia (normal red
blood cell [RBC] mass, decreased plasma volume) and from secondary
erythrocytosis (increased RBC mass due to hypoxia, carboxyhemoglobinemia,
inappropriate erythropoietin syndromes with tumors or renal disease, etc.). PV is
suspected in patients with hemoglobin levels greater than 18.5 g/dL in men or 16.5
g/dL in women or hemoglobin levels greater than 17 g/dL in men or 15 g/dL in
women if associated with a documented and sustained increase of at least 2 g/dL
from an individual’s baseline value. Diagnostic evaluation begins with peripheral
JAK2 V617F mutation screen and measurement of serum erythropoietin levels. This
is because JAK2 is present in 97% of patients with PV and is not associated with
other causes of increased hemoglobin/hematocrit levels; similarly, a subnormal
serum erythropoietin level is expected and encountered in more than 90% of patients
with PV but not in secondary or apparent polycythemia. However, neither the
absence of JAK2 nor the presence of a normal erythropoietin level rules out the
diagnosis of PV.3
 The presence of a JAK2 V617F in suspected PV is highly supportive of the
diagnosis, regardless of the serum erythropoietin level. In the absence of a JAK2
V617F mutation, the serum erythropoietin level is useful to guide further evaluation.
If the serum erythropoietin level is subnormal, a JAK2 exon 12 mutation screen
should be performed. In the setting of a negative JAK2 mutation and a normal
erythropoietin level, the diagnosis of PV is unlikely and evaluation should focus on
secondary causes of erythrocytosis.
The oldest PV diagnostic criteria was developed in the late 1960s by the
French polycythemia vera study group (PVSG). This was prior to the general
availability of assays for erythropoietin and JAK2 mutational analyses, and at a time
when blood volume studies were readily available. Today this diagnostic tool has
its advantages and limitations. The PVSG diagnostic criteria for PV require the
presence of all three major criteria or the presence of the first two major criteria and
any two minor criteria:
a. Major criteria
■ Increased RBC mass: males: ≥36 mL/kg and females: ≥32 mL/kg
■ Arterial oxygen saturation ≥92%
■ Splenomegaly
b. Minor criteria
■ Platelet count >400,000/μL
■ White blood cell (WBC) count >12,000/μL
■ Leukocyte alkaline phosphatase score>100
■ Serum vitamin B12 > 900 pg/mL or serum unbound B12 binding capacity
>2,200 pg/mL.
The World Health Organization’s (WHO) revised diagnostic criteria were
developed to surpass some of the limitations of the PVSG diagnostic criteria.1 The
diagnosis of PV requires meeting either both major criteria and one minor criterion
or the first major criterion and two minor criteria:
a. Major criteria
■ Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women, or other
evidence of increased RBC volume
■ Presence of JAK2 V617F or other functionally similar mutation such as
JAK2 exon 12 mutation
b. Minor criteria
■ BM biopsy showing hypercellularity for age with
trilineagemyeloproliferation
■ Serum erythropoietin level below the normal reference range
■ Endogenous erythroid colony formation in vitro1
The 2008 WHO diagnostic criteria for PV are currently under revision.
Proposed changes in PV include lowering of the diagnostic hemoglobin/hematocrit
level to 16.5 g/dL/49% in men and 16 g/dL/48% in women, in the presence of
 consistent BM morphology, and the inclusion of BM morphology as a major
criterion, along with JAK2 mutation screening. Even though WHO revised diagnostic
criteria are the most used tool for diagnosing PV, two interesting discussion topics
remain unanswered. The first is whether the use of hematocrit rather than
hemoglobin as a measuring tool provides a greater predictive value of the RBC
volume for diagnosis and evaluation of response to therapy. This position is
defended by the clinicians using the revised British Committee for Standards in
Hematology’s definition as an alternative definition based on hematocrit. The second
diagnostic dilemma pertains to the masked PV phenomena described by Barbui et
al., where patients present with normal hemoglobin but with suspicious features as
an unexplained thrombosis or itching.5 The important message here for clinicians is
to maintain a high degree of clinical vigilance in this subset of patients. Figure 21.1
proposes a potential algorithm to guide clinicians in the diagnosis of PV.
2. Aims of therapy
PV is generally an indolent disorder with the decision to treat on the basis of risk
stratification. In patients younger than 60 years, the median survival is
approximately 24 years. Risk factors for survival comprise leukocytosis (leukocyte
count >13,000/μL [to convert to ×109/L, multiply by 0.001]), thrombosis, advanced
age (>70 years), and abnormal karyotype. The respective 10-year relative survival
rates for patients with no risk factors, one, and two risk factors were 84%, 59% and
26% respectively.6
In contrast, low-risk patients (i.e., those with no history of thrombosis, age less
than 60 years, or platelets below 1 × 106/μL) are usually treated with phlebotomy
and/or aspirin (ASA). The goal of phlebotomy is to keep the hematocrit level below
45% in men and below 42% in women. Initially, phlebotomy is used to reduce
hyperviscosity by decreasing the RBC mass, and subsequent phlebotomies help
maintain the RBC mass in a normal range. For patients with high-risk features (i.e.,
history of thrombosis, or an age greater than 60 years), treatment consists of
phlebotomy, ASA, and cytoreductive therapy. Control of hypertension and diabetes
and avoidance of smoking are also important. Although PV patients generally benefit
of good outcomes, the challenges of uncontrolled PV symptoms and refractory
disease are imminent clinical problems. To address these challenges a PV
management algorithm is proposed in Figure 21.2.
FIGURE 21.1 Proposed diagnostic algorithm for PV. BM, bone marrow; EPO, erythropoietin;
PV, polycythemia vera.

3. Treatment regimens
a. Phlebotomy
Removal of 350 to 500 mL of blood every 2 to 4 days (less often in the elderly
or in patients with cardiac disease) is the standard initial approach; the goal is
getting the hematocrit to 40% to 45%. The blood count is then checked monthly,
and phlebotomy is repeated as needed to maintain the hematocrit at no more than
45%. Rapid lowering of the hematocrit may also be achieved in emergency
situations by erythropheresis. Elective surgery should be deferred until the
hematocrit has been stable at no more than 45% for 2 to 4 months. Platelet
function should be evaluated before surgery or invasive procedures.6
b. Antithrombotic therapy
Concomitantly with phlebotomy, use of low-dose ASA is now widely regarded
as standard therapy, following a large European study (European Collaboration
on Low-Dose Aspirin in Polycythemia [ECLAP]) utilizing 100 mg ASA daily
that showed an approximately 60% reduction in thrombotic events.7 Higher
doses of ASA (325 mg daily) carry risk of bleeding, especially in patients with
platelet counts greater than 1.5 × 106/μL, in whom acquired von Willebrand
disease may be seen. The exact thrombogenic role of platelets in MPNs is not
clear, but hydroxyurea and anagrelide have been shown to lower platelet counts
and reduce the risk of thrombosis.6
FIGURE 21.2 Management approach for PV. *European Leukemia Net Definition of
Resistance/Intolerance to hydroxyurea. ASA, aspirin; CV, cardiovascular; HCT, hematocrit;
INFα, interferon α; Plt, platelet; PV, polycythemia vera; WBC, white blood cells.

c. Myelosuppressive agents
Myelosuppressive agents are indicated in conjunction with phlebotomy for
persistent thrombocytosis, recurrent thrombosis, enlarging spleen, or similar
problems. They may also reduce the risk of progression to MF compared with
phlebotomy alone. Most alkylating agents carry a high risk of inducing a
secondary myelodysplastic syndrome (MDS) or leukemia and should no longer
be used.6 Currently recommended choices are as follows:
1) Hydroxyurea 10 to 30 mg/kg by mouth daily. Weekly blood cell counts are
required initially, with dose adjustments to maintain the hematocrit at no
more than 45%, the platelet count at 100,000 to 500,000/μL, and the WBC
count at greater than 3,000/μL. Side effects are usually minimal, but long-
term use may cause painful leg ulcers and aphthous stomatitis. For younger
patients and cases difficult to control with hydroxyurea, acceptable
alternatives include the following.
2) Interferon-α (IFN-α) is usually effective in controlling hematocrit, platelet
count, and splenomegaly and in relieving pruritus. The starting dose is 1 to 3
 × 106 U/m2 three times weekly (pegylated interferon once weekly may also
be an option—see Section I.C.2.5.). Common side effects include myalgia,
fever, and asthenia, usually controlled with acetaminophen. Leukemogenic
effects are presumably absent, but high cost is a deterrent to long-term use.
For high-risk patients during pregnancy IFN-α is the optimal choice of
management. Quintás-Cardama et al. published the results of their phase II
trial with pegylated-IFN-α-2a (PEG-IFN-α-2a) treatment in 43 PV patients.8
This study showed that after a median follow-up of 42 months, complete
hematologic response (CHR) was achieved in 76% of patients with a median
duration to complete response of 40 days. The same study also reported a
complete molecular response (CMR) in 18%, partial molecular response
(<50% reduction) in 35%, and drug-related treatment discontinuation in 20%
of patients. Kiladjian et al. also reported the results of their multicenter phase
II trial evaluating the efficacy, molecular response, and safety of PEG-IFN-
α-2a in 40 PV patients.9 Their findings demonstrated at 12 months follow-up,
94.6% CHR was sustained for a median follow-up of 31.4 months. Partial
molecular response was obtained in 89.6% and CMR in 24.1% of patients,
with only 8% of drug-related treatment discontinuation. These two trials
demonstrate that PEG-IFN-α-2a induces sustained CHR and CMR with
tolerable treatment-related adverse events (AEs) in a subset of PV patients. A
multicenter randomized trial is currently comparing the efficacy and safety
between hydroxyurea and PEG-IFN-α-2a in high-risk PV patients, which
might provide clinicians with the needed evidence to support their choice of
first-line agent for high-risk PV patients. On the other hand, a novel
investigational mono-pegylated-proline-IFN-α-2b administrated every 14
days subcutaneously (SC) has shown efficacy and safety in a phase I/II trial.
The study reported that at 18 months, there was 47% complete remission
(CR) and 42% partial remission, resulting in an overall response rate (ORR)
of 89%, and drug-related treatment discontinuation was reported in 20%. The
more convenient treatment schedule (once every 14 days) along these results
supports further development accordingly, and a phase III clinical study
(PROUD-PV) started recruiting in 2013.
3) Radioactive phosphorus (32P) 2.3 mCi/m2 intravenously (IV) (5mCi
maximum single dose). Repeat in 12 weeks if the response is inadequate
(25% dose escalation optional). Lack of response after three doses mandates
a switch to other forms of therapy. Use of 32P entails an approximately 10%
risk of leukemia by 10 years, and it is best reserved for the elderly and
patients refractory to other modalities. Supplemental phlebotomies may be
required for patients with satisfactory platelet and WBC counts but with
rising hematocrit levels.
4) Busulfan appears to have less leukemogenic potential than other alkylating
 agents and is appropriate in patients whose disease is not controlled by other
treatments or in the elderly. It is best given in short courses over several
weeks (to avoid prolonged marrow suppression) at 2 to 4 mg/day.
5) Anagrelide selectively inhibits platelet production, and platelets start to fall
in 7 to 14 days. The WBC count is unaffected; hemoglobin may fall slightly.
Responses to anagrelide have been reported in more than 80% of patients
with MPNs, and thrombotic risk is reduced. Recommended starting dose is
0.5 mg by mouth once a day. Average dose for control is 2.4 mg daily. Side
effects include headache (44%), palpitations, diarrhea, asthenia, and fluid
retention. It should be used with caution in cardiac patients and is
contraindicated in pregnancy.
6) Ruxolitinib is a potent JAK1/JAK2 inhibitor with a nonspecific
myelosuppressive effect and an anti-JAK-STAT-mediated downregulation of
inflammatory cytokine activity. Well-documented side effects include,
nonexclusively, transaminitis, cholesterol elevation, anemia, and
thrombocytopenia. A recent phase III open-label study (RESPONSE trial)
evaluated the efficacy and safety of ruxolitinib versus standard therapy in
patients with PV who had an inadequate response to, or had unacceptable
side effects from, hydroxyurea.10 The study randomly assigned phlebotomy-
dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib or
standard therapy. The primary endpoint was both hematocrit control through
week 32 and at least a 35% reduction in spleen volume at week 32. The
results showed that at week 32, two-thirds of patients in the ruxolitinib arm
were receiving doses of 10 mg twice per day (BID) or 15 mg BID. The
primary endpoint was achieved in 21% of the patients in the ruxolitinib group
versus 1% of those in the standard-therapy group (p < 0.001).10 Furthermore,
hematocrit control was achieved in 60% of patients receiving ruxolitinib and
20% of those receiving standard therapy, while 38% and 1% of patients in
the two groups, respectively, had at least a 35% reduction in spleen volume.
A complete hematologic remission was achieved in 24% of patients in the
ruxolitinib group and 9% of those in the standard-therapy group (p = 0.003).
Additionally, 49% of patients taking ruxolitinib had at least a 50% reduction
in the total symptom score at week 32, versus 5% of the standard group.
Overall, 77% of patients randomized to ruxolitinib met at least one
component of the primary endpoint and 91% of patients who met the primary
endpoint had a confirmed response at week 48. As for response
sustainability, only one patient lost primary response 37.1 weeks after its
start with a 94% probability of maintaining primary response for 1 year. On
the other hand, the phlebotomy rate at weeks 8 to 32 was more than three
times higher in the standard-therapy arm compared with the ruxolitinib arm.
Also, only 2.8% of patients required three or more phlebotomies during this
 time compared with 20.2% in the standard-therapy group. Regarding the
exposure-adjusted AEs and grade 3 or 4 AEs per 100 patient-years over the
entire course of treatment, they were lower in patients randomized to
ruxolitinib compared with those randomized to standard-therapy arm.
Exposure-adjusted rates of serious AEs per 100 patient-years were
comparable in both arms. In the ruxolitinib group, grade 3 or 4 anemia
occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in
5%; the corresponding percentages in the standard-therapy group were 0%
and 4%. No patients discontinued treatment because of anemia or
thrombocytopenia. Thromboembolic events occurred in one patient receiving
ruxolitinib and in six patients receiving standard therapy. This trial
demonstrated that ruxolitinib was superior to standard therapy in controlling
the hematocrit, reducing the spleen volume, and improving symptoms
associated with PV. This study led to the approval of ruxolitinib as the
preferred second-line agent in patients resistant or intolerant to
hydroxyurea.10,11
4. Ancillary treatments
To control hyperuricemia, allopurinol 300 mg/day is usually effective. Pruritus is a
frequent problem, but usually abates with myelosuppressive therapy.
Cyproheptadine 5 to 20 mg/day or paroxetine 20 mg/day may be helpful; IFN-α is
also frequently effective. ASA is often helpful for erythromelalgia (hot, red, painful
digits) and is commonly used to prevent thrombosis.7 Use of ASA should be avoided
in patients with acquired von Willebrand syndrome, in the presence of less than 20%
activity on risotecin cofactor activity assay.
5. Evolution and outcome
The median survival in patients with PV exceeds 15 years, and the 10-year risk of
developing either MF (10%) or acute myeloid leukemia (AML; 6%) is relatively
low.12 The JAK2 V617F allele burden or JAK2/CALR mutational status has not been
proven to affect survival. To date, drug therapy has not been shown to favorably
affect these figures. Therefore, at present, drugs should not be used with the intent to
either prolong survival or prevent disease transformation into AML or MF. Patients
should be preferably monitored by a hematologist, especially when initiated on
cytoreductive agents for disease/drug-related side effects and blood count every 2
weeks when disease is active. Later, once the disease is stable, monitoring can be
spaced out to every 2 to 3 months. The decrease in WBC and platelet count seems to
be most indicative of a response to therapy. Response to therapy criteria have been
well established by the European Leukemia Net and a complete response is
composed of either (a) hematocrit <45% without phlebotomy or (b) response in
three of the following four criteria: (1) platelet count ≤400 × 109/L; (2) WBC count
≤10 × 109/L; (3) normal spleen size on imaging; (4) no disease-related symptoms.
C. Essential thrombocythemia
 1. Diagnosis
The median age for diagnosis of ET is 55 to 60 years with a significantly higher
incidence in females (female-to-male ratio of up to 2:1). As described previously,
around 90% of patients with ET have exclusive mutations in one of three genes that
are thought to act as drivers of the disease process. Between 50% and 60% of
patients with ET are found to have a mutation in the JAK2 gene, JAK2 V617F, while
5% of patients harbor mutations in the MPL. A more recent advance was the
discovery of CALR mutation, found in up to 50% to 70% of patients who are
negative for JAK2 or MPL mutations.3 These mutational changes define certain
patient characteristics and increased risk of disease-related complications. Indeed,
patients with CALR mutation were males, of younger age, and had a lower incidence
of thrombosis, hemoglobin level, leukocyte counts, and higher platelet counts, when
compared with JAK2 V617F-positive ET. In contrast, patients with the uncommon
MPL mutation were found to have lower hemoglobin, higher platelet count, and an
increased incidence of thrombosis.
Diagnosis of ET requires a persistent elevation of the platelet count above 450
× 103/μL plus the absence of known causes of reactive or secondary thrombocytosis
(e.g., iron deficiency, malignancy, and chronic inflammatory disease). After
excluding obvious causes of reactive thrombocytosis (iron deficiency, trauma,
infection, and so on), peripheral blood testing for the JAK2 V617F mutation is
helpful. The presence of JAK2 V617F confirms clonal thrombocytosis but careful
review of the peripheral blood smear and BM histology with cytogenetics must also
be performed to confirm the diagnosis of ET.13 Chronic myeloid leukemia (CML)
can often present with thrombocytosis; therefore, the presence of BCR-ABL must be
excluded. As stated previously, the absence of JAK2 does not rule out the possibility
of ET given that a large proportion of patients do not carry the mutation. Only 4% of
patients with ET without a JAK2 V617F mutation will have a mutation in the MPL
gene; however, if present, it does suggest clonal thrombocytosis. Performing a BM
biopsy is mandatory to rule out PMF, MDS/MPN, and “prefibrotic” PMF.13 The BM
biopsy in ET will show megakaryocyte proliferation with large and mature
morphology. Moderate leukocytosis is common. Palpable splenomegaly is present in
less than 50% of patients. Platelet function studies may show either spontaneous
aggregation or impaired response to agonists. Microvascular occlusion may cause
digital gangrene, transient ischemic attacks, visual complaints, and paresthesias.
Large-artery thrombotic episodes are also common. Deep venous thrombosis is
uncommon. The risk of hemorrhagic problems is significant, particularly with a
platelet count greater than 1,500 × 103/μL.
The diagnosis of ET requires meeting four criteria, as follows:
■ Sustained platelet count of at least 450 × 103/μL.
■ BM biopsy specimen showing proliferation mainly of the megakaryocytic
lineage with increased numbers of enlarged, mature megakaryocytes. No
 significant increase or left shift of neutrophil granulopoiesis or erythropoiesis.
■ Not meeting WHO criteria for PV or PMF, BCR–ABL–positive CML, or MDS
or other myeloid neoplasm.
■ Demonstration of JAK2 V617F or other clonal marker or, in the absence of JAK2
V617F, no evidence of reactive thrombocytosis.1
The 2008 WHO diagnostic criteria for ET are currently being under revision
and the proposed changes include the inclusion of CALR mutations as a clonal
marker.
2. Treatment regimens
Given its typically indolent course, the primary goal of treatment in patients with ET
is the prevention of complications from thrombocytosis, such as microvascular
disturbances or hemorrhagic events caused by acquired von Willebrand disease.
ASA therapy is often used to reduce microvascular symptoms for patients with all
risk categories. Hydroxyurea, to reduce platelet counts, in combination with low-
dose ASA, has been shown to decrease the risk of arterial thrombosis in patients
with high-risk ET, such as those older than 60 years with platelets greater than 1,000
× 103/μL or a history of hypertension, diabetes requiring treatment, or ischemia;
thrombosis; embolism; or hemorrhage related to ET. For patients with ET whose
platelet counts are refractory to therapy with ASA or other salicylates, therapy with
IFN-α (including in pegylated preparations), anagrelide, or hydroxyurea can be
used. Anagrelide was developed to prevent platelet aggregation but was
subsequently found to reduce platelet counts in ET and PMF when used at low dose.
3. Hydroxyurea
A dosage of 10 to 30 mg/kg by mouth daily, with dosage adjustments on the basis of
weekly blood counts, should give satisfactory response in 2 to 6 weeks. Its use in
combination with low-dose ASA may give optimal protection against arterial
thrombosis and evolution to MF.14
4. Anagrelide
Presents a reasonable alternative to hydroxyurea and perhaps is preferable in
younger patients. Anagrelide plus ASA was inferior to hydroxyurea plus ASA in a
large recent trial.14 This agent should not be used in pregnancy.
5. IFN-α
Along with busulfan, it is considered to be a second-line drug of choice in patients
who are resistant to or intolerant of hydroxyurea. Both controlled and uncontrolled
single-arm studies have demonstrated long-term safety and efficacy of these drugs.
Most patients with ET respond to this agent, at an initial dose of 3 × 106 U/day SC.
Maintenance doses of 3 × 106 U three times weekly usually suffice. Pegylated
interferon at an initial dose of 1.5 to 4.5 μg/kg/week SC seems comparable in
efficacy and side effects. Use of interferon in pregnancy is considered safe.
6. 32P and alkylating agents
These agents are effective but carry increased risk of secondary leukemia. Nitrogen
 mustard (mechlorethamine 0.15 to 0.3 mg/kg [6 to 12 mg/m2] IV) can be helpful
when rapid reduction in platelet count is needed. Busulfan 2 to 4 mg/day initial dose
is appropriate in selected elderly patients resistant to other agents.
7. ASA
A dosage of 81 to 325 mg/day may control erythromelalgia and similar vaso-
occlusive problems but is contraindicated in patients with a history of hemorrhagic
symptoms. ASA may be useful in pregnant patients, in whom the preceding agents
are contraindicated. Twice-daily ASA 81 mg use in low-risk patients whose
microvascular symptoms are resistant has been proven to be more efficacious than
once-daily ASA. In patients with severe thrombocytosis, ASA should be avoided
because of the increased risk of bleeding secondary to acquired von Willebrand
disease.
8. Evolution and outcome
The course of ET is often indolent, particularly in young patients. The median
survival is 24 years for patients older than 60 years, and 33 years for those younger
than 60. The JAK2/CALR mutational status or JAK2 V617F allele burden has not
been shown to affect survival in ET. The only factors predictive of complication
development are age >60 and previous thrombotic events. Interestingly, higher
platelet levels did not correlate with increased risk of thrombotic events. The
international prognostic score of thrombosis in essential thrombocythemia (IPSET-
thrombosis) was proposed to better assess the risk of thrombosis. The final
prognostic score included four risk factors: age ≥60 years (1 point), cardiovascular
risk factors, such as diabetes, hypertension, or smoking (1 point), prior thrombosis
(2 points), and JAK2 V617F mutation (2 points). Patients could be stratified into
three risk categories as follows: low risk (0 to 1 point), intermediate risk (2 points),
and high risk (≥3 points). The annual rate of thrombosis ranged from 1.03% of
patients/year in the low-risk category to 3.56% of patients/year in the high-risk
category. Another prognostic score was recently developed to predict overall
survival (OS) at diagnosis (IPSET) including age ≥60 years (2 points), leukocyte
count ≥11 × 109/L (1 point), and prior thrombosis (1 point) as independent risk
factors for survival. Patients could again be stratified into three risk categories, with
median survival not yet reached in the low-risk group and 14.7 years for the high-
risk group. Transformation to PMF, MDS, or acute leukemia occurs in 5% to 10% of
patients with ET. Thrombosis remains the major cause of ET-related death.15
D. Primary myelofibrosis
1. Diagnosis
This is a clonal disorder of the hematopoietic stem cell, marked by an intense
reactive (nonclonal) fibrosis of the marrow; splenomegaly (frequently massive),
reflecting ectopic hematopoiesis in the spleen and portal hypertension; and the
presence of immature granulocytes and nucleated RBCs in the peripheral blood
(leukoerythroblastic blood picture) plus teardrop RBCs and giant platelets. Mild to
 moderate elevations of WBC and platelet counts are common initially; cytopenias
dominate later on.16 The International Prognostic Scoring System (IPSS) is the most
widely used for patients with PMF at diagnosis. The risk factors included in the
model are (1) age >65 years, (2) presence of constitutional symptoms, (3)
hemoglobin <10 g/dL, (4) leukocyte counts >25 × 109/L, and (5) circulating blasts
≥1%. The prognostic model stratifies patients into four risk categories as follows:
low risk (0 points; median survival 11.3 years), intermediate-1 (1 point; median
survival 7.9 years), intermediate-2 (2 points; median survival 4 years), and high risk
(3 or more points; median survival, 2.3 years).
The JAK2 V617F mutation is present in approximately 50% of patients with
PMF, mutations in MPL are found in 5% to 10% of patients, and CALR mutations in
an additional 25% to 40%. CALR mutations seem to confer a better prognosis for
patients with PMF (median survival, 15.9 years), while triple-negative patients
harbor the worst prognosis (median OS, 2.3 years).3,17 Apart from the three driver
mutations, a number of other mutations have been found at much lower frequencies
in PMF. Even though most of these mutations are relatively less frequent, mutations
in ASXL1, SRSF2, and EZH2 have been shown to be independently associated with
reduced survival and ASXL1, SRSF2, and IDH1/2 with increased risk of
transformation to acute leukemia. In particular, ASXL1 appears to be the most
detrimental in PMF, and was used in a recent trial to establish a mutation-enhanced
international prognostic scoring system (MIPSS) for PMF in the goal to further
stratify patients classified as low risk by standard criteria. This novel scoring
system incorporates four clinical variables (age, hemoglobin, platelet count,
constitutional symptoms) and four molecular variables (triple negativity, JAK2/MPL
mutation, ASXL1 and SRSF2 mutations). This recent trial showed a better survival
predictive value for the MIPSS in comparison with the IPSS and allowed the
identification of a subgroup within the conventional IPSS stratification with less
favorable prognosis. An abnormal karyotype is also demonstrable in approximately
50% and connotes shortened survival time. Although no specific cytogenetic changes
for PMF have been described, common abnormalities are del(13q), del(20q), and
trisomy 8 or 9. Other adverse prognostic factors include advanced age, anemia,
WBC count of less than 4,000/μL or greater than 30,000/μL, thrombocytopenia,
blasts in peripheral blood, and hypercatabolic symptoms (weight loss, night sweats,
fever). Diseases causing secondary marrow fibrosis, such as metastatic carcinoma,
hairy-cell leukemia, and granulomatous infections, must be excluded. Similar to ET,
the presence of a JAK2 V617F, CLAR, or an MPL mutation can be helpful to rule out
reactive marrow fibrosis. However, the absence of these molecular markers does
not exclude the presence of an MPN. Therefore, causes of reactive marrow fibrosis
must be excluded in cases where no clonal marker is found. Again, BM histology in
combination with other clinical and laboratory features helps to establish the
diagnosis of PMF. BCR–ABL should be performed to rule out the presence of CML
 and criteria for another myeloid neoplasm should not be met. The minor criteria,
which help to establish a diagnosis of PMF, include leukoerythroblastosis, increased
serum lactate dehydrogenase, anemia, and palpable splenomegaly. Major causes of
death in PMF include marrow failure, infection, portal hypertension, and leukemic
transformation. Cases of MDS with marrow fibrosis are easily confused with PMF.
Postpolycythemic MF is clinically indistinguishable but carries a poor prognosis,
evolving to acute leukemia in 25% to 50% of patients (compared with 5% to 20%
for de novo PMF). Acute megakaryoblastic leukemia (M7) may also present with a
myelofibrotic picture and be confused with PMF.
The diagnosis of PMF requires meeting all three major criteria and two minor
criteria:
a. Major criteria
■ Presence of megakaryocyte proliferation and atypia, accompanied by either
reticulin or collagen fibrosis; or, in the absence of significant reticulin
fibrosis, the megakaryocyte changes must be accompanied by an increased
marrow cellularity characterized by granulocytic proliferation and often
decreased erythropoiesis (i.e., prefibrotic cellular-phase disease).
■ Not meeting WHO criteria for PV, CML, MDS, or other myeloid disorders.
■ Demonstration of JAK2 V617F or other clonal marker (e.g., MPL
W515K/L); or, in the absence of the above clonal markers no evidence of
secondary BM fibrosis.1
b. Minor criteria
■ Leukoerythroblastosis
■ Increased serum lactate dehydrogenase level
■ Anemia
■ Palpable splenomegaly.1
2. Treatment regimens
PMF has a much more aggressive course than ET and PV, and treatments include
androgen preparations (e.g., fluoxymesterone or danazol), corticosteroids,
erythropoietin, and lenalidomide (LEN). Splenectomy should be considered for
patients with portal hypertension, to improve anemia (due to sequestration) or for
symptomatic relief of abdominal pain or problems with alimentation. Radiation
therapy may be beneficial for palliative relief; however, a significant increase in the
risk of neutropenia and infection is seen. Allogeneic hematopoietic stem-cell
transplantation (allo-HSCT) is considered the only curable treatment option for
patients with PMF. This option should be considered in young patients with
intermediate-/high-risk PMF. For patients older than 60 years, a reasonable option
would be a reduced-intensity conditioning regimen.18 Studies assessing the efficacy
of JAK kinase inhibitor combinations are ongoing and, in the setting of clinical
benefit, may eventually change the course of the disease.19 Intervention is indicated
in the following situations.
 3. Anemia
Androgens (e.g., testosterone enanthate 600 mg intramuscularly weekly or
fluoxymesterone 10 mg by mouth two or three times a day for men; danazol 400 to
600 mg by mouth daily for women) are recommended and reduce transfusion
requirements in 30% to 50% of patients. Corticosteroids (e.g., prednisone 40 mg/m2
by mouth daily) should be tried if overt hemolysis is present. Erythropoietin is
helpful in a small percent of patients but requires large doses; response is unlikely if
serum erythropoietin level is greater than 200 mU/mL. In limited studies,
improvement in cytopenias or transfusion requirements has been reported in 20% to
50% of patients with PMF receiving low-dose thalidomide (50 mg/day) or LEN (5
to 10 mg/day). PMF patients routinely become transfusion-dependent; early
institution of iron-chelating agents is advisable.
4. Splenomegaly
Massive splenomegaly may lead to cytopenias, portal hypertension, variceal
bleeding, abdominal pain, or compression of adjacent organs. Anorexia, fatigue, and
hypercatabolic complaints may be prominent. The first option for control by
myelosuppressive therapy is hydroxyurea, given as for PV. Melphalan (2.5 mg by
mouth three times weekly, with escalations up to 2.5 mg daily as tolerated) and
busulfan (2 mg/day in older patients) can also be considered. IFN-α produces
responses in some cases as well.19
Radiation 50 to 200 cGy is effective in improving splenomegaly but causes
cytopenias in 40% of patients. Radiation occasionally is indicated for
extramedullary hematopoietic tumors causing compression syndromes or for bone
pain. Splenectomy is indicated in carefully selected cases but carries significant
perioperative mortality and morbidity from bleeding, sepsis, and postoperative
thrombocytosis.
5. Curative intent
Allo-HSCT from appropriately matched donors appears to be potentially curative,
but transplant-related mortality is high in patients with PMF who are older than 45
years. Younger patients with expected survival of no more than 5 years may be
reasonable candidates. Engraftment rates are equal to those in other hematologic
disorders, and a “graft versus myelofibrosis” effect has been demonstrated.
Encouraging early results with nonmyeloablative allo-HSCT suggest that this
modality may be the most appropriate option and is feasible in older patients with
PMF.18
6. Novel therapies
a. JAK2 inhibitors
The approval of ruxolitinib in the United States, Europe, and Canada has
significantly changed the treatment landscape for PMF. Regulatory approval of
ruxolitinib for PMF was based on the results of two pivotal phase III trials,
where ruxolitinib showed significantly better reduction in spleen volume
 maintained to week 48 of study (approximately 50% reduction by palpation and
more than 35% by radiology).20,21 Ruxolitinib also significantly improved PMF-
related symptoms and quality of life in comparison with the best available
therapy. Although ruxolitinib has not been shown to eliminate the malignant
clone, long-term follow-up analyses have demonstrated that the effects of
ruxolitinib are durable, associated with delay in transformation and survival
benefit. However, all these are at the expense of thrombocytopenia and anemia
as the most common toxicities associated with ruxolitinib.21,22 These toxicities
can be managed with dose reduction as avoidance of treatment interruption is
important for overall success since symptoms return to baseline within 7 to 10
days. Current recommendations are to use a starting dose of 20 mg BID in
patients with platelets above 200 × 109/L, 15 mg BID in patients with platelets
between 100 and 200 × 109/L, and 5 mg BID for patients with platelet counts
below 100 × 109/L. The dose can then be modified as tolerated to a maximum
dose of 25 mg BID.
b. Ruxolitinib combinations therapy
In the goal of optimizing PMF outcomes a multitude of drug combination with
ruxolitinib is currently being tested.
c. Ruxolitinib plus panobinostat
In the setting of moderate- to high-risk PMF, a phase II trial used 15 mg BID and
panobinostat 25 mg TIW/QOW, which resulted in substantial reductions in
splenomegaly. However, the study did not report improvements in other
symptoms. AEs were within the expected range.
7. Conventional drug therapy
a. Hydroxyurea
Prior to the approval of ruxolitinib for MF by the Food and Drug Administration
(FDA) in 2011, cytoreductive drugs such as hydroxyurea were used to control
hyperproliferation. However, the natural course of the disease remained
undisturbed, hydroxyurea rarely induces complete spleen regression, and
responses are rarely durable.
b. Immunomodulatory drugs (IMiDs)
These agents have engendered an interesting clinical activity in a subset of
patients with PMF, including improvements in anemia, thrombocytopenia, and
splenomegaly, thought to be due to their effect on BM environment. Thalidomide
and LEN induced responses in 16% to 34% of patients. The combination of LEN
and prednisone may be more effective and safer than single-agent IMiD therapy.
New agents like pomalidomide are under study.

II. MYELODYSPLASTIC SYNDROMES

This is a diverse group of hematopoietic stem cell clonal neoplasms characterized by
ineffective hematopoiesis and dysplastic morphologic changes in one or more lineages.
 The disease occurs at a median age of 65 to 70 years, is the most frequent hematologic
malignancy in the above-65 age group, and affects more than 30,000 cases annually in the
United States. For the population above 60 years of age, the incidence is 1 in 500. Eighty
percent of cases occur de novo and have no specific etiology or known cause. In the
remaining 20% of cases, an association with prior chemotherapy use can be identified,
most frequently high-dose alkylator or topoisomerase-II inhibitor-based regimens, or
exposure to radiation. Whether a specific inciting cause can be identified or not, the
pathophysiologic process of MDS is DNA damage in a pluripotential BM stem cell with a
dynamic balance of secondary and associated changes in proliferation, differentiation, and
apoptosis intrinsic cellular pathways along with extrinsic marrow microenvironment,
angiogenic, cytokine, and immune effects. The global DNA hypomethylation with
concurrent silenced hypermethylation of gene promoter region characteristic of MDS
genome provides an epigenetic mechanism for controlling gene expression. The studies that
have proven disease response to hypomethylating agents (HMAs) present added evidence
of the role of DNA methylation in the pathogenesis of MDS. Clonal cytogenetic
abnormalities can be identified in 40% to 50% of de novo cases, most typically a loss of
chromosome material involving chromosomes 5, 7, 11, 20, or Y, or trisomy of chromosome
8. Cytogenetic abnormalities in chromosomes 5 or 7 will be identifiable in 95% of
therapy-related cases, with half of the cases also having complex cytogenetic changes
involving three or more chromosomes.23
A. Diagnosis
The typical clinical picture is an elderly patient with macrocytic anemia, with or
without thrombopenia and neutropenia. In addition to routine history and physical exam,
the documentation of transfusion history is necessary on the initial evaluation. Initial
diagnostic studies needed are complete blood count with differential and peripheral
smear review, BM aspirate and biopsy with cytogenetics, reticulocyte count, serum
erythropoietin level prior to transfusion, thyroid stimulating hormone (TSH) level,
serum iron, total iron binding capacity, serum ferritin, B12 and folate levels, along with
human immunodeficiency virus status if a clinical concern, and human leukocyte antigen
(HLA) typing in young patients if a candidate for transplant or aggressive
immunosuppressive therapy. There is no single diagnostic test, however. A confirmed
diagnosis is made from the hematologic picture of cytopenias and dysplastic lineage
morphology supported by associated marrow cytogenetic findings, if abnormal. The
typical dysplastic features seen in the marrow and peripheral blood include
megaloblastoid precursors, budding and irregular nuclear outline of normoblasts,
hypochromia and basophilic stippling of RBCs, iron-laden sideroblasts,
hyposegmentation (bilobed Pelger-Huet like forms are characteristic) and
hypogranularity of neutrophils, hypolobar and/or micromegakaryocytes, and
hypogranular platelets. Platelet and neutrophil functional abnormalities exist, further
contributing to the symptomatic cytopenias. The BM is most often hypercellular (but
10% to 20% will be hypocellular) with a low reticulocyte count. Abnormal localization
 of immature precursors is often seen on the marrow core biopsy. A variable number of
myeloblasts will be seen from less than 5% up to 20%. Differential diagnosis includes
B12 and folate deficiency, lead poisoning and alcohol abuse in patients with
sideroblastic anemia, aplastic anemia in patients with hypoplastic marrows, PMF if
marrow fibrosis is present, and paroxysmal nocturnal hemoglobinuria (PNH). Further
personalized testing might be considered depending on the clinical presentation: (1) in
case of suspicion of large granular lymphocytic leukemia or PNH, clone flow cytometry
might be helpful to confirm MDS diagnosis; (2) in young patients or patients with family
history of cytopenias, consider further genetic testing to rule out Fanconi anemia and
dyskaretosiscongenita.
B. Classification
The French-American-British (FAB) classification for MDS put forth in 1982 continues
to be useful (Table 21.1). More recently, the WHO classification of MDS was modified
in 2008 to better correlate with more homogenous subsets and natural histories (Table
21.2). The major changes (1) lowered the percentage of marrow blasts to define full-
blown AML at greater than or equal to 20%, removing refractory anemia with excess
blasts (RAEB) in transformation as a category; (2) separated out the 5q– syndrome,
given its different clinical picture and treatment; and (3) moved chronic
myelomonocytic leukemia (CMML) to a separate category of
myelodysplastic/myeloproliferative disease.

TABLE
MDS Subtypes: FAB Classification
21.1
 TABLE
2008 WHO Classification of MDS and Pertinent Features
21.2
Subtype Blood Bone Marrow
RCUD* Single or bicytopenia Dysplasia in ≥10% of one cell line, <5% blasts
≥15% of erythroid precursors with ring sideroblasts,
RARS Anemia, no blasts
erythroid dysplasia only, <5% blasts
Dysplasia in ≥10% cells in ≥2 hematopoietic lineages, ±15%
RCMD Cytopenia(s), <1 × 109/L monocytes
ring sideroblasts, <5% blasts

RAEB-1 Cytopenia(s), ≤2%–4% blasts, <1 × 109/L Uni- or multilineage dysplasia, no Auer rods, 5%–9% blasts
monocytes

RAEB-2 Cytopenia(s), 5%–19% blasts, <1 × 109/L Uni- or multilineage dysplasia, Auer rods, ±10%–19% blasts
monocytes
Unilineage dysplasia or no dysplasia but characteristic MDS
MDS-U Cytopenias
cytogenetics, <5% blasts
MDS with isolated del(5q–) Anemia, platelets normal or increased Unilineageerythroid dysplasia, isolated del(5q), <5% blasts
RAEB-t Cytopenias, 5%–19% blasts Multilineage dysplasia, Auer rods, ±20%–30% blasts

MDS, myleodysplastic syndrome; MDS-U, myelodysplastic syndrome, unclassified; RAEB-1, refractory anemia with excess
blasts-1; RAEB-2, refractory anemia with excess blasts-2; RAEB-t, refractory anemia with excess blasts in transformation;
RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCUD, refractory
cytopenia with unilineage dysplasia; WHO, world health organization.
*This category encompasses refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT).

Cases of RN and RT were previously classified as MDS, unclassified.

C. Prognosis
Acute leukemia transformation potential and survival correlate to some degree with
both the FAB and WHO classifications, but even more so with the IPSS. The IPSS
(Table 21.3) assigns a score on the basis of the percentage of marrow blasts, initial
marrow cytogenetics, and the number of peripheral cytopenias to provide a better
prognostic risk stratification for an individual; the IPSS can be very helpful in guiding
management decisions.24 However, recent studies have highlighted issues with the IPSS
model in relation to the exclusion of many subgroups that now represent a large
proportion of patients with MDS (e.g., secondary MDS, chronic myelomonocytic
leukemia with leukocytosis, prior therapy) and its lack of applicability to most patients
on investigational programs, because many would have received prior therapies and
would have had MDS for a significant length of time. A multivariate analysis of
prognostic factors in 1,915 patients with MDS identified the following adverse,
independent factors as continuous and categorical values (p < 0.001): poor performance
status, older age, thrombocytopenia, anemia, increased BM blasts, leukocytosis,
chromosome 7 or complex (≥3) abnormalities, and prior transfusions. The MD
Anderson MDS prognostic model divides patients into four prognostic groups with
significantly different outcomes (Table 21.4). The new model accounts for duration of
MDS and prior therapy. It is applicable to any patient with MDS at any time during the
 course of MDS.

TABLE
IPSS for MDS
21.3
 TABLE
The MD Anderson Scoring System for MDS
21.4
Prognostic Factor Points
Performance status ≥2 2
Age(years)
1
60–64
2
≥65
Platelets, × 103/μL
3
<30
2
30–49
1
50–199
Hemoglobin <12 g/dL 2
Bone marrow blasts, %
1
5–10
2
11–29
WBC >20 × 103/μL 2
Karyotype: Chromosome 7 abnormality or complex (≥3) abnormalities 3
Prior transfusion, yes 1

MDS, myelodysplastic syndrome; WBC, white blood cell.

Low risk (score 0–4): the median survival is 54 months and the 3-year survival rate is 63%; intermediate-1 risk (score 5–6): the
median survival is 25 months and the 3-year survival rate is 34%; intermediate-2 risk (score 7–8): the median survival is 14
months and the 3-year survival rate is 16%; high risk (score ≥9): the median survival is 6 months and the 3-year survival rate is
4%.

Recently, the Revised International Prognostic Scoring System (IPSS-R) was

considered as the preferred scoring tool for prognosis, although other scoring systems
were deemed to be of important value (Table 21.5).25 The IPSS-R model divides
patient with MDS into five subgroups: (1) very low risk; (2) low risk; (3) intermediate;
(4) high risk; and (5) very high risk. This division was based on a weight scoring
system for the following prognostic variables: (a) cytogenetic; (b) BM blast percentage;
(c) hemoglobin; (d) platelet count; and (e) the absolute neutrophil count (ANC). Table
21.5 highlights in detail the IPSS-R. One of the most relevant modifications that the
IPSS-R provides is a new cytogenetic classification scheme for MDS replacing the
original risk groups proposed in the IPSS. This new cytogenetic classification includes
16 specific cytogenetic abnormalities grouped into 5 prognostic categories. However,
more than 50% of all MDS patients present with a normal karyotype, and even in
patients with identical chromosomal abnormalities, outcome may vary.26 Somatic
mutations are identifiable in around 70% of patients including those with normal
karyotype, making them more common than cytogenetic abnormalities. Therefore, the
addition of such mutations to common prognostic markers might help refine
prognostication in MDS. The study by Kuendegen et al.27 analyzed 182 MDS patients
 using various molecular assays including sensitive next-generation sequencing for
mutations in ASXL1, DNMT3A, EZH2, FLT3-ITD, IDH1, KRAS, MLL-PTD, NRAS,
RUNX1, SF3B1, SFRS2, TET2, and TP53. This study demonstrated through a
univariate analysis a significant influence on survival in five of the above-mentioned
mutations: (1) TP53 (p < 0.001), (2) EZH2 (p = 0.003), (3) SF3B1 (p = 0.016), ASXL1
(p = 0.016), and RUNX1 (p = 0.042). These mutations were detected in 9.9%, 9.0%,
22.9%, 25.4%, and 20.4%, respectively. Till date two additional major studies have
also conclusively showed the strong association between mutations in specific genes
(TP53, EZH2) and disease risk. The same studies also highlighted the challenges that
must be overcome before these data can be used to personalize the care of patients.

TABLE
Revised IPSS for MDS (IPSS-R)
21.5

D. Therapy
The management of MDS is guided by multiple prognostic scoring systems. The 2015
National Comprehensive Cancer Network (NCCN) MDS guideline suggests the IPSS-R
 as the preferred choice for risk stratifying MDS patients. Other scoring systems, like the
previously elucidated MD Anderson scoring system, can also guide risk stratification
and personalization of management options. This scoring system includes patient’s age,
IPSS category, serum erythropoietin level, cytogenetics if 5q− present, and HLA status
in a candidate for allo-HSCT or immunosuppressive therapy.23 All patients should
receive appropriate blood product transfusion support.
1. General approach
Figure 21.3 proposes a general approach for the management of MDS patients that
takes into account their risk stratification, failure of HMAs, and evaluation for
suitability for allo-HSCT.
a. Low-risk patients (IPSS-R: intermediate [>3 to 4.5 points], low [>1.5 to 3
points], or very low [≤1.5 points]):
■ Immediate treatment is not always indicated. Indications include
symptomatic cytopenia (anemia, thrombocytopenia, neutropenia with
recurrent infections). Asymptomatic patients may be closely monitored with
serial examinations and laboratory studies.
■ If serum erythropoietin level is less than 500 mU/mL, treat with growth
factors (erythropoietin analog, adding granulocyte colony-stimulating factor
[G-CSF] if no hematocrit response).
■ Azacitidine (AZA), decitabine, or LEN if no clinical response to growth
factors or erythropoietin level higher than 500 mU/mL
b. High-risk patients (IPSS-R: high [>4.5 to 6 points] or very high [>6 points]):
■ If young and a donor available consider intensive chemotherapy (IC) and
allo-HSCT
■ If not a transplant candidate, AZA, decitabine, LEN, or clinical trials
c. 5q− cytogenetics
■ LEN
d. MDS with hypoplastic features
■ Antithymocyte globulin (ATG)
■ Cyclosporine A
■ Alemtuzumab
FIGURE 21.3 Proposed treatment algorithm for patients with MDS. 5-AZA, azacitidine; allo
SCT, allogeneic stem cell transplantation; BM, bone marrow; EPO, erythropoietin; G-CSF,
granulocyte colony-stimulating factor; INT, intermediate; IPSS, International Prognostic
Scoring System; MTI, methyltransferase inhibitor.

2. Growth factors
Erythropoietin analogs, either epoetin or darbepoetin, can effectively achieve a
meaningful hemoglobin improvement in 15% to 25% of patients.28 In patients with a
serum erythropoietin level less than 500 mU/mL, a trial of an erythropoietin analog
is indicated. Low-risk patients do respond better than high-risk patients. Usually,
higher dosing than used in chemotherapy-associated anemias is needed. An adequate
therapeutic trial of 8 to 12 weeks is appropriate. G-CSF can be synergistic with
erythropoietin therapy, enhancing the erythroid response rate potential up to 40%.
This synergism is particularly effective in patients with greater than 15% ringed
sideroblasts. These growth factors need to be continued to maintain the achieved
benefit.28
a. Recombinant human erythropoietin
Dosage of 40,000 to 60,000 units SC two to three times weekly; taper to smallest
effective dosing schedule if there is response, and continue.
b. Darbepoetin
Dosage of 150 to 300 μg SC weekly. If there is an inadequate or no response to
the erythropoietin analog alone and clinically still indicated, add G-CSF.
c. G-CSF (filgrastim)
Dosage of 1 to 2 μg/kg SC two to three times weekly, with the erythropoietin
analog.
3. Specific agents
 a. Azacitidine
AZA is an HMA-inhibiting DNA methyltransferase, reversing the epigenetic
silencing of gene transcription. The exact mechanism of action in MDS is most
likely multifactorial. In a landmark phase III trial compared with conventional
care, AZA showed a survival improvement (24 vs. 15 months) and improved
quality-of-life parameters.29 It is now approved by the United States Food &
Drug Administration (USFDA) in all types of MDS at the dose of 75 mg/m2 SC
or IV daily for 7 days every 28 days with a possibility of continuing treatment as
long as there is a favorable benefit/tolerance balance. The most common toxicity
is myelosuppression with a 20% treatment-related infection rate. It is generally
very well tolerated and can be administered in the outpatient setting.
b. Decitabine (Dacogen) is another HMA DNA methyltransferase inhibitor that has
shown significant activity in MDS. Initial European phase II studies showed
50% hematologic response rates, notably even higher in IPSS high-risk patients.
A landmark phase III trial compared with supportive care confirmed significant
response rates (17% complete or partial response by International Working
Group criteria, plus an additional 13% with hematologic improvement) and a
longer time to acute leukemia transformation or death, in particular among those
patients with an IPSS intermediate-2/high-risk score, or not previously treated.
OS was prolonged in patients responding to decitabine compared with
nonresponders (23.5 vs. 13.7 months).30 It is now approved by the FDA for use
in MDS. Decitabine was originally approved at the dose of 15 mg/m2 as a 3-
hour infusion IV every 8 hours for 3 consecutive days (9 total doses) every 6
weeks × 4 cycles continuously, as long as it is effective.31 Myelosuppression
with cytopenic complications is an expected and frequent toxicity of decitabine,
especially in the already-cytopenic MDS patient. Other side effects include
nausea, diarrhea or constipation, and cough. More convenient dosing schedules
were evaluated. The MD Anderson experience has reported overall clinical
benefit in 76% of patients treated with a modified schedule of 20 mg/m2 IV over
1 hour daily for 5 consecutive days every 4 weeks. The efficacy of this regimen
was confirmed in the ADOPT trial. Decitabine is currently approved in the
United States at the dose of 20 mg/m2 IV over 1 hour daily for 5 consecutive
days every 4 weeks.
c. Lenalidomide
Is a thalidomide-related immunomodulator with greater potency. It has a wide
range of biologic effects including suppression of angiogenesis, inhibition of
inflammatory cytokines, potentiation of immune pathways, and other cellular
ligand-induced responses. A landmark phase II study showed dramatic erythroid
responses in erythropoietin-resistant patients. Major erythroid responses and
cytogenetic responses occurred in 83% of patients with a 5q− deletion, but were
not limited to this 5q− subset. Overall, 68% of patients had a low IPSS score,
 50% with intermediate-1 IPSS, and over half of patients with normal
cytogenetics had erythroid responses. High-risk MDS patients had a much less
frequent hematologic response (20%) but those patients with RAEB responding
also demonstrated decreased blast counts.32 It is approved by the FDA in
patients with 5q− MDS. LEN 10 mg orally daily is given continuously so long as
this dose is tolerated; the dose can be reduced to a 21- out of a 28-day schedule
or 5 mg dosing if persistent or severe hematologic toxicity occurs. Marrow
suppression with neutropenia and thrombocytopenia, the most frequent toxicity,
is dose dependent and requires dose interruption in over half of patients. Other
systemic side effects include low-grade pruritus, diarrhea, rash, and fatigue.
d. Allogeneic hemapoietic stem-cell transplant
This remains the only curative therapy but is limited to younger patients and
preferably with a matched related donor. Treatment-related mortality and
chronic morbidity remain very high. Given the older age group with MDS, less
than 10% of patients are considered transplant candidates. It should always be
considered in younger patients in IPSS-R high-risk or very high-risk category
with suitable sibling donors. Transplant studies show disease-free survival
ranges from 29% to 40%, nonrelapse mortality of 37% to 50%, and relapse even
with a sibling donor of 23% to 48%. Reduced-intensity conditioning transplants
appear to carry promise for use in an older population but are still fraught with
significantly high mortalities.
4. Intensive chemotherapy
There is no clear consensus regarding the role of IC in MDS. Its use is typically
restricted to patients in IPSS-R high-risk and very high-risk groups. Induction
chemotherapy utilizing acute leukemia-type regimens (e.g., anthracycline/cytosine
arabinoside) can induce complete responses in 50% to 60% of patients with MDS,
but remissions tend to be brief and outcomes correlate strongly with karyotype-
associated chemoresistance mechanisms. Topotecan, a topoisomerase I inhibitor, has
been postulated to have selectively favorable effectiveness in MDS, but its role is
not well established as responses are brief and myelotoxicity is very high. The role
of IC in treating MDS is limited to young patients with high-risk disease serving as a
bridge to an allo-HSCT. A recent study compared 330 patients with newly
diagnosed MDS and BM blasts between 10% and 30%, with 93 (28%) of them
treated with HMA and 237 (72%) treated with IC. This study showed an ORR of
42% for patients treated with HMA and 60% for those treated with IC (p = 0.01).
The median remission duration was similar between the two groups as was the early
induction mortality. The BM blasts percentage did not impact the overall outcome.
Interestingly in multivariate analysis, treatment with IC was associated with
significantly worse OS compared with HMA. This study highlights the fact that
although MDS or AML patients with BM blasts between 10% and 30% initially
achieve a higher ORR when treated with IC, compared with HMA-based therapy,
 the OS was better for patients treated with HMA after accounting for all other
covariates. This study adds to the available evidence guiding clinicians with the
management of both MDS and AML patients with a blast count between 10% and
30%. On the other hand, in hopes of minimizing toxicity, low-dose chemotherapy has
been utilized, most notably with cytarabine at doses of 5 to 20 mg/m2 daily, as an
every 12-hour SC injection, continued for 10 to 20 days. Hematologic responses are
seen in 20% to 30% of patients, but without any significant survival benefit, and
serious marrow suppression may result. The effectiveness, tolerability, and
availability of AZA and decitabine have now largely supplanted the use of low-dose
chemotherapies in MDS.
5. Immunotherapy
The immunosuppressive effects of ATG can be quite effective achieving transfusion
independence along with other cytopenia responses in one-third of a select subset of
patients with MDS, namely those who are younger, with hypocellular marrow,
normal cytogenetics, shorter duration of transfusion dependency, and those who are
HLA DR15 positive.
a. ATG 40 mg/kg/day × 4 days (common toxicities include infusion reactions,
serum sickness [coadministration of prednisone may alleviate this], and
immunosuppression).
Other immunosuppressive agents have been tried with mixed success.
Prednisone is occasionally helpful in improving cytopenias (approximately 10%
response rate overall), particularly in those patients with evidence of hemolysis.
Cyclosporine has shown high response rates in limited studies, utilizing 5 to 6
mg/kg/day initially, then monitored with dose adjustments to maintain serum
levels of 100 to 300 ng/mL.
b. Alemtuzumab given at the dose of 10 mg IV daily was recently used in 21
patients with MDS. Responses were reported in 74%: five out of seven patients
with abnormal cytogenetics achieved a complete cytogenetic response. The
estimated 3-year relapse-free survival (RFS) is 50%.
6. Other agents have shown some limited hematologic benefit in MDS. However,
with the availability of AZA, decitabine, and LEN, and with a very narrow
therapeutic index for either amifostine or arsenic trioxide, their use should be rare
except in a clinical trial.
Pyridoxine 100 to 200 mg daily is a reasonable trial in patients with increased
ringed sideroblasts; however, benefit is infrequent. Developmental therapies
targeting angiogenesis, apoptosis, cytokine, farnesyltransferase, tyrosine kinase, and
histone deacetylase or other DNA methyltransferase epigenetic pathways alone and
in combination are being evaluated in clinical trials.
7. Clinical trials
Currently treatment options for MDS remain limited. The last 8 years did not witness
the approval of many new MDS drugs. HMAs remain the frontline therapeutic
 choice for patients with higher-risk MDS. A number of combination strategies are
under development to improve the results of HMA monotherapy. The next section
highlights some of the promising future therapy options:
a. HMAs combination strategies
1) Combination AZA and Pracinostat. A hydroxamic acid derivative that
showed in combination with AZA an ORR of 89% and CR of 78% in a small
pilot study (n = 9) of patients who either failed HMA or with therapy-related
MDS. Larger trials assessing the combination of HMA plus pracinostat in the
frontline setting therapy of patients with high-risk disease and post-HMA
failure are ongoing.
2) Combination AZA and LEN. A recent phase I/II study was conducted in 88
patients with high-risk MDS placed on sequential AZA and LEN. All
subjects received 75 mg/m²/day AZA on days 1 to 5 of each 28-day cycle
with the initial phase II starting dose of LEN 50 mg daily × 10 days.
However, because of myelosuppression and infections the phase II dose was
amended to LEN 25 mg daily × 5 days. In the entire cohort, ORR was 35%,
with median OS of 33 weeks. Phase I ORR was 14% and phase II ORR was
45%, while the patients receiving the optimal phase II dose had an ORR of
55% with a 75-week median OS. In responding patients, the median response
duration was 29 weeks, with a median OS that has not been reached with a
median follow-up time of 57 weeks, and 42% of responding patients
proceeded with stem cell transplant. This trial identified the combination of
AZA 75 mg/m²/day on days 1 to 5 with 25 mg LEN on days 6 to 10 over a
28-day cycle as an effective frontline regimen for high-risk MDS and AML
with up to 30% blasts. Rapid and durable responses were noted with a well-
tolerated dosing schedule.
3) Combination AZA and vorinostat. A recent randomized phase II trial
compared AZA combined with LEN or with vorinostat to AZA monotherapy
in 282 higher-risk MDS patients showing an ORR of 37%, 22%, and 36%,
respectively. More interestingly, the combination AZA and vorinostat showed
the longest RFS with 11 months compared with 8 and 6 months in AZA with
LEN and AZA monotherapy, respectively.
b. Clofarabine. A second-generation purine nucleoside analog first approved in
2004 for the treatment of pediatric patients with relapsed or refractory acute
lymphocytic leukemia following failure of at least two prior regimens. In MDS,
HMAs remain the standard of care in high-risk patients as they have bettered the
outcomes in this subgroup. Clofarabine alone has proven substantial activity
against MDS and is well tolerated by elderly patients, thus rendering it a
potential therapeutic option. The efficacy and toxicity profile of orally
administered clofarabine was evaluated in patients with higher-risk MDS.33
Results showed 25% of patients achieved CR and an ORR of 43%. The most
 common AEs were gastrointestinal and hepatic. While myelosuppression was
common, a prolonged myelosuppression (>42 days) was rare. The combination
of clofarabine with cytarabine (Ara-C) has demonstrated substantial activity
against MDS. A recent phase II trial was conducted to evaluate the safety and
activity of the combination of clofarabine and low-dose cytarabine in the
treatment of patients with high-risk MDS who failed prior HMA therapy. This
combination showed an ORR of 48% in patients and the median duration of
response was 12 months. This trial is of high interest for a very common
subgroup of MDS patients. Further follow-up on duration of response is
warranted as the trial continues to accrue.
1) Clofarabine plus low-dose cytarabine. For patients with higher-risk MDS
who have relapsed or are refractory to HMAs. The ORR was 44% with best
response being CR in 15% of the patients. The 1-year response duration and
OS rates were 56% and 38%, respectively.
2) Luspatercept (ACE-536). A fusion protein containing modified activin
receptor type IIB that acts on late-stage erythropoiesis, which is a distinct
mechanism from erythropoietin. A phase II trial results showed that
luspatercept increases hemoglobin and reduces transfusion burden in patients
with low- or intermediate-1-risk MDS.
3) Low-dose oral AZA. AZA 300 mg taken orally for either 14-day or 21-day
cycles is currently under investigation in a phase I trial in low- or
intermediate-1-risk, and low–platelet level MDS patients.
4) SGI-110. A novel subcutaneous HMA for intermediate-2- or high-risk MDS
patients.
8. Supportive care
a. Anemia
RBC transfusions will become needed in most patients with MDS to maintain
quality of life. A hemoglobin goal (usually above 9 g/dL) must be individualized
on the basis of symptom need and improvement. Leukocyte-depleted packed
RBC should be used in all patients, with cytomegalovirus (CMV)-negative (if
the patient is CMV negative) and irradiated blood products in potential allo-
HSCT candidates.
b. Iron overload and chelation therapy
Secondary hemochromatosis with cardiac, hepatic, endocrine, and hematopoietic
dysfunction can develop after 20 to 30 units of RBC transfusion. Chelation
therapy can improve visceral and marrow function, and should be a strong
consideration in patients with an ongoing transfusion need who are expected to
survive several years, as well as in patients with overt iron overload-related
visceral dysfunction. Monitoring of ferritin levels should begin at a 20-to-30-
unit transfusion threshold, with institution of a chelating agent when the ferritin is
greater than 2,500 μg/L. The treatment goal is to lower ferritin to less than 1,000
 μg/L.34
1) Deferoxamine (Desferal) 1 to 2 g by overnight (8 to 12 hours) infusion SC 5
to 7 nights per week; or
2) Deferasirox (Exjade) 20 mg/kg oral daily dispersed in water or orange/apple
juice taken on an empty stomach. Toxicities are similar to deferoxamine with
nausea and vomiting, diarrhea, pyrexia, and abdominal pain but also potential
increased serum creatinine. The availability of this more convenient oral
chelator will likely greatly improve this aspect of supportive care in MDS.34
c. Infections
Neutropenia and neutrophil dysfunction contribute to a high risk of bacterial
infections in MDS. Antibiotics remain the mainstay of management, but
prophylactic antibiotics are of unknown benefit. G-CSF can raise the neutrophil
count in 90% of patients with MDS, and its short-term use may be appropriate in
infected, severely neutropenic patients; indications for long-term use of G-CSF
are limited.
d. Bleeding
Symptomatic thrombocytopenia requires platelet transfusion support. Single-
donor platelets delay alloimmunization, but this will eventually develop in the
majority (30% to 70%) of patients, limiting subsequent platelet transfusion
increments. There is not an absolute thrombocytopenia transfusion threshold, but
platelet counts below 10,000/μL carry a spontaneous central nervous system
hemorrhage risk. Two additional adjuncts to thrombocytopenic bleeding control
are as follows:
1) Aminocaproic acid 4 g IV over 1 hour, followed by 1 g/hour continuous
infusion; or orally in a similar dosing schedule, or by a more convenient 2 to
4 g schedule orally every 4 to 6 hours. Tachyphylaxis and loss of
antifibrinolytic stabilization will often occur after 48 consecutive hours of
therapy.
2) Interleukin-11/oprelvekin is a thrombopoietic cytokine that has increased
platelet counts after chemotherapy. A low-dose regimen of 10 μg/kg/day can
raise platelet counts in selected patients with BM failure.35

Acknowledgments
The authors are indebted to Drs. Peter White and Paul R. Walker, who contributed to previous
editions of this chapter. Several sections in this revision of the handbook represent their work.

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I. INTRODUCTION
Hodgkin lymphoma (HL) is an uncommon lymphoproliferative malignancy with
approximately 9,000 cases diagnosed annually in the United States. The average age at
presentation is 32 years with a bimodal incidence curve: one peak occurs in early
adulthood before age 25, and the second around age 55. HL is rare in children younger than
5 years of age and only 10% to 15% of cases are diagnosed in children and teenagers. HL
is slightly more common in males, first-degree relatives of patients with HL, and in
developed nations. Most patients present with disease limited to lymph nodes or to lymph
nodes and the spleen. The bone marrow is involved in only 5% of cases. HL generally
spreads in a contiguous fashion making the incorporation of radiation therapy (RT) feasible
for many patients.
HL is largely a curable disease; up to 95% of cases of early stage HL, and 75% of
advanced HL cases are cured with the initial therapy. Patients with advanced disease can
be cured with combination chemotherapy, while those with limited disease can be cured
either with limited combination chemotherapy and limited RT (combined modality
treatment [CMT]), or with chemotherapy alone. While effective and potentially curative,
extensive RT as a sole modality for early stage disease has largely been abandoned (see
Section IV.B). Despite the gratifying cure rates of initial therapy, about 10% patients fail to
respond to primary therapy, and another 20% to 30% of responding patients subsequently
relapse after treatment. Salvage chemotherapy followed by autologous stem cell
transplantation (ASCT) is the treatment of choice for relapsed or refractory HL, and is
potentially curative. Nevertheless, the potential for cure should not lead clinicians and
patients to lose sight of the fact that approximately 20% to 25% of patients with HL
eventually die of the disease.
Long-term survivors of HL are at risk of developing a range of therapy-related side
effects that include cardiac disease and second malignancies such as leukemia, lung cancer,
and breast cancer.1 While deaths from HL level off after 10 to 15 years, deaths from long-
term complications continue to increase.2–4 Over the last 40 years, the search for initial
therapy with fewer long-term side effects has been a major research focus, leading, for
example, to the abandonment of RT as a sole treatment modality for early stage HL.
Ongoing studies are also evaluating response-adapted treatment in an attempt to limit
cumulative doses of chemotherapy.
For most cancers, disease-free survival (DFS) is a valuable surrogate marker for
 overall survival (OS), and thus evaluating DFS is a useful method for choosing optimal
initial therapy. However, for HL, the success of salvage therapy means that the treatment
options that are associated with superior DFS may not necessarily produce superior OS
when the results of salvage therapy are considered, and this makes the selection of initial
therapy somewhat more nuanced. In fact, because radiation and chemotherapy have
significant and even potentially fatal long-term consequences, DFS may overestimate the
value of a specific therapy. Therefore, for each stage of HL, more than one rational
therapeutic option may exist.

II. PATHOLOGY OF HL
The presence of Reed-Sternberg (RS) cells (or variants) in a mixed inflammatory
background is a key feature of the histopathology of HL. The RS cells of classical HL are
of B-cell origin, stain for CD15 and CD30, and are negative for CD45 and CD20. The lack
of expression of functional surface immunoglobulin is a hallmark of classical HL. Epstein-
Barr virus (EBV) is found in a significant proportion of RS cells (30% to 50% in Western
populations and 90% to 100% in developing countries), lending credence to the role of
EBV in the pathogenesis of HL via viral mimicry of cellular proliferation and antiapoptotic
proteins.
The current World Health Organization classification divides HL into two major
groups: Classical HL and Nodular Lymphocyte-predominant HL (NLPHL). Classical HL
includes four subtypes: nodular sclerosis HL (approximately 70% of cases), mixed
cellularity HL (approximately 20%), lymphocyte-rich HL (less than 5%), and lymphocyte
depletion HL (less than 5%). NLPHL (5% of all HL) is a B-cell neoplasm characterized by
variant RS cells (“L and H cells” or “popcorn cells”), positive for CD20 and negative for
CD30 and CD15. In immunophenotype behavior, NLPHL bears similarities to low-grade
non-HL. While advanced NLPHL is generally treated like classical HL, for some
situations, a low-grade lymphoma-like approach may be used; for example, radiation of a
single site of disease and rituximab for more extensive disease. NLPHL and its
management are not the focus of this review.

III. DIAGNOSIS AND STAGING

A. Diagnosis. The diagnosis of HL requires excisional biopsy of an involved node and
review of the material by a hematopathologist.5 Lymph node biopsy is recommended for
any patient with lymphadenopathy greater than 1 cm in diameter and persisting for more
than 4 weeks. Lymphoma, including HL, may be suspected when the nodes are freely
movable and rubbery rather than stony hard. Other clinical features may include B
symptoms such as fever, night sweats, and weight loss, and symptoms such as pruritus
or alcohol intolerance. However, these clinical features are not specific for HL or for
lymphoma in general. When the diagnosis of HL is made in a patient presenting at an
extranodal site or at a nodal site below the diaphragm, the diagnosis should be
subjected to greater than usual scrutiny.
 B. Staging. Accurate staging of HL is essential for determining an optimal therapy plan. It
also provides a baseline to assess the response to treatment.
1. Cotswold staging system. The Cotswold modification of the Ann Arbor Staging
System (Table 22.1)6 is used for patients with HL. Patients are placed in one of four
stages on the basis of anatomic extent of disease and are further classified as to the
absence, “A,” or presence, “B,” of systemic symptoms (see below). The subscript E
(e.g., IIE) may be used to denote involvement of an extralymphatic site, primarily or,
more commonly, to denote direct extension into an organ, such as a large mediastinal
mass extending into the lung. Stage III HL is subdivided into two substages, stages
III1 and III2, on the basis of the extent of intra-abdominal disease. However, as
current treatment recommendations are the same for both substages, this distinction
is of little clinical relevance.
2. Staging procedures. Before the advent of modern radiographic and nuclear
medicine techniques, clinicians made use of the knowledge that HL tends to spread
in a contiguous manner, and elegant and detailed descriptions of patterns of disease
were made. For instance, it was recognized that because the thoracic duct makes the
left supraclavicular area and the abdomen contiguous sites, abdominal disease is
found in 40% of patients with left supraclavicular presentations and in only 8% of
patients with right supraclavicular presentations. Although these associations were
most useful before modern computed tomography (CT) and positron emission
tomography (PET) were available, they are occasionally useful in the interpretation
of inconclusive imaging. Procedures used in the staging of HL are as follows:

TABLE
Cotswold Modification of the Ann Arbor Staging System for Hodgkin Lymphoma
22.1
Stage I Involvement of a single lymph node region
Stage II Involvement of two or more lymph nodes regions on the same side of the diaphragm

Stage III1 Involvement of lymph node regions on both sides of the diaphragm. Abdominal disease is limited to the upper
abdomen, i.e., spleen, splenic hilar, celiac, and/or porta hepatis nodes.

Stage III2 Involvement of lymph node regions on both sides of the diaphragm. Abdominal disease includes para-aortic,
mesenteric, iliac, or inguinal nodes, with or without disease in the upper abdomen.
Diffuse or disseminated involvement of one or more extralymphatic tissues or organs, with or without associated
Stage IV
lymph node involvement.
A No symptoms
B Fever, drenching sweats, weight loss
X Bulky disease greater than one-third widening of the mediastinum
E Involvement of a single extranodal site contiguous to a nodal site

a. History and physical. As with any patient, the staging of the patient with HL
 begins with a history and a physical examination. Special attention should be
given to symptoms such as bone pain that might signal a specific extranodal site
of disease. Unexplained fever >38, drenching sweats, especially at night, and
weight loss greater than 10% of body weight over 6 months or less are classified
as “B symptoms.” Pruritus is not considered a B symptom, but is not uncommon.
Fever in HL can have any pattern. The pattern of days of high fever separated by
days without fever, so-called “Pel–Ebstein fever,” has been associated with HL
for over a century but is now quite rare as the diagnosis of HL is usually made
and effective therapy is initiated earlier in the course of disease. Pain in the sites
of HL involvement with alcohol ingestion is a rare finding but may indicate
otherwise unsuspected visceral sites of involvement. On physical examination,
attention must be paid to all lymph node regions and the spleen. Splenomegaly is
seen at presentation in approximately 10% of patients with HL but does not
necessarily correlate with pathologic involvement proven by splenectomy or
with PET imaging. Performance status should be assessed.
b. Laboratory tests. Complete blood counts (CBCs), erythrocyte sedimentation
rate (ESR), serum albumin, and tests of liver and kidney function should be
obtained. Hepatic enzymes may be elevated “nonspecifically” in patients with
HL and do not necessarily indicate hepatic involvement by HL. A pregnancy test
should be obtained for appropriate patients. HIV antibody testing is considered
for some patients, as HL has occasionally been the initial manifestation of HIV
infection, and patients with HIV-associated HL may have atypical presentations.
c. Chest x-ray and CT scans. CT scans of the neck, chest, abdomen, and pelvis
with intravenous (IV) contrast are routinely obtained to identify sites of disease.
A posteroanterior (PA) chest x-ray may be used to ascertain whether a
mediastinal mass meets the criteria for bulk (“X” designation in the staging
system).
d. PET with CT attenuation correction (PET/CT). PET/CT scans should be
obtained in all patients. Note that the CT portion of this scan is used for
attenuation correction and localization and is of lower quality than the diagnostic
and contrast-enhanced CTs recommended above. The use of PET/CT has been
shown to yield a more accurate stage than CTs alone.
e. Bone marrow biopsy. The test is rarely positive except in patients who are
found to have at least stage III disease by other tests and/or cytopenias. Because
stages III and IV are treated identically (see below), and because cytopenias are
rare in stage II, marrow biopsy can often be avoided. In addition, PET can be
useful in inferring marrow status, with focal marrow positivity often correlating
with a positive marrow. It should be noted that a homogeneously positive
marrow on PET does not correlate with marrow involvement. In general, the
clinician should consider whether pathologic assessment of the marrow will
change the treatment approach to decide whether or not to do a marrow biopsy.
 C. Organ function testing. Baseline pulmonary function tests with diffusing capacity of
carbon monoxide (DLCO) and an assessment of cardiac ejection fraction should be
performed in most patients as a baseline, as doxorubicin and bleomycin may cause
cardiac and pulmonary toxicity. Fertility preservation should be considered for
appropriate patients and referrals to fertility specialists should be made.
D. Prognostic score for advanced HL (International Prognostic Score [IPS]). In 1998,
Hasenclever and colleagues created a prognostic model for advanced HL on the basis
of a multivariate analysis of patients.7 Seven factors were identified as having
prognostic value: serum albumin <4 g/dL, hemoglobin <10.5 g/dL, male sex, stage IV
disease, age ≥45 years, white blood cell count ≥15,000/cu mm, and lymphocyte count
either <600/cu mm or <8% of the white blood cell count. In the paper presenting the
model, the prognostic score correlated with both freedom from progression and the OS
rate. However, the utility of the IPS may be limited by the fact that most patients had a
score of 0 to 3, with only 12% of patients having a score of 4, and only 7% of patients
having a score of 5 to 7.

IV. TREATMENT OF HL
A. General considerations. The goal of HL therapy may be considered twofold: to deliver
a therapy with a high cure rate, and to minimize long-term toxicity. The majority of
patients can expect to be cured, most with the initial therapy and another significant
percentage with salvage therapy. The choice of therapy depends on anatomic stage and,
in stages I and II, the presence or absence of unfavorable features. Unfavorable features
are age >50 years, the presence of B symptoms or elevated sedimentation rate, large
mediastinal mass, and a larger number of nodal sites (>2 or 3).
B. Radiation therapy. RT is remarkably effective for HL, and potentially curative RT was
available long before curative chemotherapy was developed. Historically, this led to a
bias toward using RT alone or as part of CMT when anatomically feasible. Today,
however, there is clear evidence of the long-term side effects of RT (particularly in
large fields or at high dose), including breast cancer, lung cancer, hypothyroidism,
coronary artery disease, cardiomyopathy, cardiac valvular disease, and musculoskeletal
atrophy.1,3,8,9 The cumulative risk of complications may be as high as 15% at 15 years
following treatment. In particular, the risk of breast cancer is dramatically elevated in
women who have chest irradiation before the age of 30.8,10,11 For these reasons, there is
movement toward limiting the dose and fields or toward eliminating RT entirely as part
of initial therapy.
C. Chemotherapy. Chemotherapy, alone or in CMT, is now standard therapy for all stages
of HL treatment. (Table 22.2)
1. ABVD. The most commonly used chemotherapy for HL is ABVD (doxorubicin,
bleomycin, vinblastine, dacarbazine). This regimen is given every 2 weeks, with
two treatments making up one “cycle.” ABVD’s superiority was established by a
series of U.S. cooperative group studies in the 1980s and 1990s, showing its
superior efficacy and/or lower toxicity than other then-current options.12 In
advanced-stage patients, the failure-free survival rate is as high as 75% to 88%.
ABVD is generally well tolerated; however, it does have acute and long-term side
effects. Important acute toxicities are neutropenia (34%), nausea/vomiting (13%),
and alopecia (31%). Vinca alkaloids may cause peripheral neuropathy and ileus.
Important long-term toxicities include cardiotoxicity due to doxorubicin and
pulmonary toxicity due to bleomycin. It is recognized that maintenance of dose
intensity is important and many experts do not delay the treatment for uncomplicated
neutropenia and do not use growth factor support (which has been associated with
increased pulmonary toxicity of the regimen).13–15 Although ABVD is likely
modestly inferior in complete response (CR) rate and relapse-free survival (RFS)
rate to BEACOPP (see below), patients who do not respond to or relapse after
ABVD can often be salvaged with alternative chemotherapy and stem cell transplant
(see below).16
 TABLE
Chemotherapy Regimens Used in the Treatment of Hodgkin Lymphoma
22.2
ABVD Doxorubicin (Adriamycin) 25 mg/m2 IV on days 1 and 15
Vinblastine 6 mg/m2 IV on days 1 and 15
Bleomycin 10 U/m2 IV on days 1 and 15
Dacarbazine 375 mg/m2 IV on days 1 and 15
Repeat cycle every 28 days
Stanford V Vinblastine 6 mg/m2 IV weeks 1, 3, 5, 7, 9, and 11
Doxorubicin 25 mg/m2 IV weeks 1, 3, 5, 7, 9, and 11
Vincristine 1.4 mg/m2 IV (max 2 mg) weeks 2, 4, 6, 8, 10, and 12
Bleomycin 5 U/m2 IV weeks 2, 4, 6, 8, 10, and 12
Mechlorethamine 6 mg/m2 IV weeks 1, 5, and 9
Etoposide 60 mg/m2 IV daily × 2 weeks 3, 7, and 11
Prednisone 40 mg/m2 PO every other day on weeks
1–10, with tapering weeks 11 and 12
(No repeat)
E-BEACOPP Bleomycin 10 U/m2 IV day 8
Etoposide 200 mg/m2 IV day 1, 2, 3
Doxorubicin 35 mg/m2 IV day 1
Cyclophosphamide 1,200 mg/m2 IV day 1
Vincristine 1.4 mg/m2 IV (not to exceed 2 mg)
Procarbazine 100 mg/m2 PO on days 1–7
Prednisone 40 mg/m2 PO on days 1–14
Repeat every 3 weeks

IV, intravenous; PO, per os.

2. Stanford V. An alternative to ABVD is the Stanford V regimen, a seven-drug

regimen, which is delivered over a shorter period of time (12 weeks for advanced
stage) and has lower cumulative doxorubicin and bleomycin doses. RT is used to
masses >5 cm. In a cooperative trial (ECOG 2496) it was not found to be more
efficacious or less toxic than ABVD.17,18 In an Italian three-arm trial, Stanford V
was inferior to ABVD in response rate, failure-free survival, and progression-free
survival.19
3. Escalated BEACOPP. In Europe, the escalated BEACOPP regimen is widely used
in patients younger than 60 years, especially for advanced and high-risk disease.
This intensive regimen has excellent RFS rates, superior to those of the (likely
inferior) ABVD variant, COPP-ABVD.20 However, it is associated with higher rates
of grade 3 and grade 4 toxicities, causes early ovarian failure in a significant
 percentage of female patients, and may lead to higher rates of myelodysplasia.18,21 It
has not been widely adopted in North America.22
D. Combined modality treatment. The combination of chemotherapy and radiation is
most often used in the treatment of early stage HL. In early stage HL, a number of
studies have shown excellent results, with RFS rates in excess of 90%, using a limited
number of cycles of ABVD (two to four) combined with local (regional, involved field
or involved-node) RT of limited dose (20 to 30 Gy).2 Randomized controlled trials in
this area are relatively rare and somewhat difficult to interpret, but in aggregate suggest
that adding limited RT after chemotherapy in early stage patients improves outcomes by
a small but significant percentage.25 Because of the efficacy of salvage therapy, it has
been easier to show a difference in RFS than OS. A detailed discussion of these studies
is beyond the scope of this chapter. It is assumed, but not proven, that the lower doses
and small fields of modern RT will mitigate the long-term RT side effects discussed
above.
E. Response-adapted therapy. Investigators have attempted to tailor the therapy of HL on
the basis of early response to therapy using PET/CT, with the ultimate goal of reducing
the toxicity of treatment. Gallamini et al.26 studied advanced-stage HL patients, in whom
PET/CT scan was done after two cycles of ABVD chemotherapy. Two-year
progression-free survival was 13% for patients who were PET positive as compared
with 95% in patients who had become PET negative; p < 0.0001.26 A number of
subsequent trials testing a decrease in therapy (for instance, shortening chemotherapy
duration or eliminating RT) for early PET-negative patients, or conversely intensifying
therapy (adding RT or changing to BEACOPP) for those with a positive early PET. The
results of these investigations are emerging.24,25

V. INITIAL TREATMENT BY STAGE OF DISEASE

A. Stages IA and IIA without unfavorable features (“Early favorable HL”). Patients
with early stage disease and no unfavorable features (large mediastinal mass, elevated
ESR, bulky sites, >3 nodal sites) are most commonly treated with three to four cycles of
ABVD followed by limited RT, usually 20 to 30 Gy to the involved field or the
involved nodal sites. A number of reports indicated an RFS of >90% and excellent
tolerability.27,28 An alternative to ABVD is a shortened 8-week course of Stanford V.
The German Hodgkin Study Group (GHSG) defined a group of especially favorable
patients, with two or fewer sites of disease (with the sites defined somewhat differently
than in the Ann Arbor staging). Patients were randomized in a two-by-two design to two
or four cycles of ABVD and to RT of 20 or 30 Gy. All groups had identical outcome,
and thus two cycles of ABVD followed by 20 Gy is the standard in this group.29
Clinicians and patients may wish to avoid RT in certain patients (e.g., a young woman
who would require chest irradiation). In this situation, ABVD alone is often used,
although the optimal number of cycles of chemotherapy is not defined. It is likely this
reduces the RFS rate by some moderate amount. Response-adapted therapy, using
 PET/CT after two or three cycles of chemotherapy to guide additional therapy in
patients with early stage HL, has been investigated in randomized trials.24,25,30 Current
findings from these studies indicate that relapse rates are lower with combined
modality therapy even in patients with negative interim PET. Most recently, the RAPID
trial randomized patients with early HL and negative PET after three cycles of ABVD to
involved field radiation or no further treatment did not meet its end point of
noninferiority. Further trials of response-adapted therapy in this setting are ongoing.
B. Stage I/II with unfavorable features (“Early unfavorable HL” or “Intermediate-
stage HL”). Patients with early stage HL with unfavorable features may be divided into
those in whom the unfavorable features is bulky disease (typically a mediastinal mass
measuring more than one-third of maximal intrathoracic diameter) and those with other
unfavorable characteristics. Those with bulky mediastinal disease are often treated with
four to six cycles of chemotherapy (or 12 weeks of Stanford V) followed by RT to the
mediastinum.31,32 Those with nonbulky but unfavorable characteristics in whom
avoidance of RT is a priority may be treated with four to six cycles of ABVD alone.
C. Stages III and IV (“Advanced-stage HL”). Standard approaches to advanced-stage
HL included ABVD for six to eight cycles. Stanford V for 12 weeks (followed by RT to
bulky sites) or escalated BEACOPP for six cycles (in patients <60 years old with high
IPS).

VI. RELAPSED OR REFRACTORY HL

Despite high success rates in treating HL, 10% to 15% of patients do not achieve CR, and
20% to 30% of patients relapse after initially responding to treatment. Time to relapse
stratifies refractory and relapsed patients with respect to OS. Those with refractory HL and
those who relapse within a year of completion of initial treatment represent the highest risk
cohort. The GHSG reported that primary refractory patients (relapse at <3 months) had a 5-
year OS of 26% compared with 46% for early relapse (3 to 12 months) and 71% for late
relapse (>12 months). Other poor prognostic factors at relapse include advanced stage,
visceral disease, and poor performance status.33
A. Salvage chemotherapy with ASCT. This is the treatment of choice in patients with
relapsed or refractory HL. Widely used salvage regimens include ICE, ESHAP, DHAP,
GDP, and GVD (see Table 22.3) and have overall response rates between 60% and
87%. There are no comparison trials between these regimens. Five-year event-free
survival after successful salvage and ASCT is approximately 50% to 55%.34,35
Achieving a PET-negative response before high-dose therapy and ASCT is an important
favorable prognostic factor and should be attempted even if it requires changing salvage
regimens. Two studies have reported 3-year event-free survival exceeding 80% after
ASCT in those patients with a negative PET after salvage therapy.38 Salvage
chemotherapy without ASCT, often incorporating local RT, has been successfully used,
particularly in patients with localized late relapses.
 TABLE
Salvage Regimens in the Treatment of Hodgkin Lymphoma
22.3
ICE Ifosfamide, carboplatin, etoposide
DHAP Dexamethasone, ara-C, cisplatin
ESHAP Etoposide, methylprednisolone, Ara-C, cisplatin
GDP Gemcitabine, dexamethasone, cisplatin
GVD Gemcitabine, vinorelbine, liposomal doxorubicin

B. Salvage radiotherapy. RT is frequently used adjunctively before or after ASCT to sites

of disease at relapse, with reported improvement in freedom from relapse and a trend
toward improved OS.39,40
C. Second relapse. Patients who fail ASCT represent a group with a particularly poor
prognosis. Further salvage therapy with one of the above regimens may be used. The
antiCD30 monoclonal antibody-toxin conjugate brentuximab vedotin has an overall
response rate of 86% in the heavily treated patients, the majority of whom had ASCT,
and has a favorable toxicity profile.43 Some patients were able to go on to potentially
curative allogenic transplant. The PD-1 blocking agents nivolumab and pembrolizumab
have recently been shown to have activity in heavily pretreated HL.44,45 For example, a
report of nivolumab in 23 relapsed HL patients showed a remarkable 87% overall
response rate with 17% CRs.45

VII. FOLLOW-UP AND SURVIVORSHIP

After successful completion of therapy, patients are followed longitudinally for signs of
relapse or treatment-related complications. The majority of relapses occur in the first 5
years after completion and tend to occur at the site of the original disease, unless those
sites were irradiated. In contrast, late toxicities of treatment often have latencies of 10
years or longer.
A. Surveillance for relapse. Once a negative PET is obtained 1 to 3 months after
completion of planned therapy, there is little utility of surveillance scans. Surveillance
scans are associated with a high rate of false positives, do not improve OS, and expose
patients to additional expense, ionizing radiation, and psychological distress. The
current National Comprehensive Cancer Network guidelines deem “acceptable” a scan
in the first year, with further scans only as clinically indicated. We typically see patients
every 3 months in the first year, every 4 months in the second year, every 6 months in
years 3 to 5, and yearly thereafter. At these visits, symptoms of relapse or long-term
side effects are sought, and a CBC and ESR (and thyroid-stimulating hormone (TSH) in
patients who have had neck irradiation) are reviewed. After 5 years, the focus shifts to
long-term side effects, including the risks of cardiovascular disease, myelodysplasia,
and secondary malignancies (especially breast cancer in women who had breast
 irradiation before age 30).46,47 The specific risk profiles and screening will vary
depending on the specific treatment(s) the patient has had as well as other patient-
specific factors. Referral to survivorship clinics is recommended where available.

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I. INTRODUCTION
Non-Hodgkin lymphomas (NHLs) are a diverse group of malignant neoplasms involving
lymphocytes of B-cell, T-cell, or natural killer (NK)-cell origin.1 Significant variation
exists across individual entities with respect to the natural history, underlying biology, and
response to therapy, but in all lymphomas the malignant clones have acquired properties of
uncontrolled proliferation coupled with dysfunctional apoptosis. Tumor clonality of the
specimen is established by demonstrating immunoglobulin (Ig) gene rearrangement or light-
chain restriction in B-cells, T-cell receptor rearrangement in T-cells, or methods that
identify recurrent translocations by fluorescent in situ hybridization or polymerase chain
reaction (PCR). Most lymphomas predominantly involve the lymphatic system, but they can
arise in almost any extranodal site such as the spleen, bone marrow, bones, central nervous
system (CNS), lung, gastrointestinal tract, and the skin.
It is now appreciated that NHLs arise from a combination of intrinsic genetic events
that occur within the cell and favorable conditions in the tumor cell’s local
microenvironment. The tumor cell and the local microenvironment both contribute to
disease progression and both can be targeted with emerging novel therapies. Advances in
the technology used to study the underlying biology of lymphoid tumors, such as gene-
expression profiling (GEP) of tumors and next-generation sequencing, have improved our
understanding of biologic differences across lymphomas.2–7 Despite these advances, a
complete characterization of the genetic, epigenetic, and environmental events underlying
lymphomagenesis has not been achieved.

II. EPIDEMIOLOGY AND RISK FACTORS OF NHL

A. Epidemiology
NHL is the seventh most common cancer overall and the most common hematologic
malignancy. It is estimated that 70,800 cases of NHL will be diagnosed in the United
States in 2014, and accounting for 4.3% of all new cancer diagnoses.8 Worldwide
incidence of NHL also has important geographical distribution in certain subtypes of
NHL (Table 23.1). B-cell lymphomas represent about 80% to 85% of all cases, with T-
cell lymphomas being represented in the other 15% to 20% of cases and NK-cell
lymphomas extremely rare. There is a male predominance in almost all subtypes for
unknown reasons. Even though NHL occurs in persons of all ages, the incidence rises
steadily with age. The median age of patients at the time of diagnosis of NHL is
 between 65 and 74 years of age, which may affect therapeutic decisions. From the early
1970s to the late 1990s, the incidence of NHL in the United States dramatically rose at a
rate of about 4% per year but since the early 2000s the incidence began to rise slower
and appears to be stable in the last few years. Death rates from NHL overall have been
decreasing by 2.6% per year between 2002 and 2011, but some subtypes such as T-cell
lymphomas have a particularly dismal prognosis. Mortality rates are higher for patients
living in lower socioeconomic neighborhoods, with the disparity being higher among
younger patients.8

TABLE
Geographical Distribution of Certain NHLs
23.1
Lymphoma Distribution
Adult T-cell lymphocytic leukemia Caribbean, Southern Japan, Africa
Angioimmunoblastic T-cell lymphoma Europe > North America
BL (endemic form) Equatorial Africa
Gastric lymphoma Northern Italy, Japan
T-/NK cell lymphomas, nasal-type China, South America

BL, Burkitt lymphoma; NHL, non-Hodgkin lymphoma; NK, natural killer.

Source: Muller AM, Ihorst G, Mertelsmann R, et al. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic
distribution, and etiology. Ann Hematol. 2005;84:1–12.

B. Risk factors
Consistent with a model of acquired somatic mutations that accumulate throughout one’s
life, an increased risk of NHL is associated with advanced age.9 Additional factors that
increase one’s lifetime risk to develop NHL are important to recognize (Table 23.2).
An inherited genetic susceptibility does not appear to account for most cases of
NHL, but there is an increased risk for NHL in close relatives of patients with
lymphoma. Lymphoma is often diagnosed in the setting of underlying immunodeficiency
or autoimmunity highlighting the complex interplay between NHL and the immune
system.10 These conditions can be divided into congenital (or primary)
immunodeficiencies and acquired (or secondary) immunodeficiencies (Table 23.3).
Many lymphomas are associated with an underlying virus that either drives the
lymphoma or impairs the immune surveillance of the host increasing the risk of
developing NHL.11 For example, the increased incidence of NHL in the 1970s to 1990s
was due, in part, to the increase in human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS). It is probable that defects in immune surveillance
(particularly in T-cell immunity) result in unregulated B-cell proliferation in lymphoid
tissue, often in association with chronic antigen stimulation from infections such as the
Epstein-Barr virus (EBV) or Human Herpesvirus-8 (HHV-8). Rare, extranodal T-cell
 lymphomas, such as enteropathy-associated T-cell lymphoma (EATCL), occur in the
setting of celiac sprue, and hepatosplenic T-cell lymphoma (HSTCL) typically occurs in
patients with a history of solid organ transplantation, inflammatory bowel disease,
systemic lupus erythematosus, Hodgkin lymphoma, and malarial infection.12

TABLE
Factors Associated With an Increased Risk of NHL
23.3
■ Immunosuppression, acquired
■ Congenital immunodeficiency syndromes
■ Increasing age
■ Family history of NHL
■ Silicone breast implants
■ Drugs
■ Immunosuppressive agents
■ Phenytoin
■ Methotrexate
■ Tumor necrosis factor inhibitors
■ Radiation therapy
■ Occupational exposures
■ Exposure to herbicides, pesticides, wood dust, epoxy glue, solvents, Agent Orange
■ Farming, forestry, painting, carpentry, tanning

NHL, non-Hodgkin lymphoma.

Source: Zhang Y, Dai Y, Zheng T, et al. Risk factors of non-Hodgkin lymphoma. Expert Opin Med Diagn. 2011;5:539–550.

TABLE
Immune-Related Conditions that Predispose to NHL
23.3
Congenital Acquired
Ataxia telangiectasia Solid organ transplantation
Wiskott-Aldrich syndrome Stem-cell transplantation (higher if T-cell depleted)
AIDS
Severe combined immunodeficiency Sjögren syndrome
Common variable immunodeficiency Rheumatoid arthritis
Hyper immunoglobulin M (Job syndrome) Hashimoto thyroiditis
X-linked hypogammaglobulinemia Inflammatory bowel disease
X-linked lymphoproliferative syndrome Celiac sprue
Malarial infection
Autoimmune lymphoproliferative syndrome
Hodgkin lymphoma

NHL, non-Hodgkin lymphoma.

Source: Engels EA, Cerhan JR, Linet MS, et al. Immune-related conditions and immune-modulating medications as risk factors
for non-Hodgkin’s lymphoma: a case-control study. Am J Epidemiol. 2005;162:1153–1161.

In addition to viruses, other infectious agents have specific clinical associations

 with subtypes of NHL (Table 23.4). Chronic hepatitis C infection increases the risk of
indolent B-cell lymphomas, and Helicobacter pylori infection can be identified in over
90% of cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma.13,14 In
some cases of antigen-driven lymphomas, eradication of the infectious agent can result
in remission of the lymphoma.

TABLE
Infectious Agents Associated With NHL
23.4
Infectious Agent Lymphoma
Burkitt lymphoma, EBV+ DLBCL of the elderly, extranodal NK/T-cell
EBV lymphoma, lymphomatoid granulomatosis, PTLD, systemic EBV+ T-
cell lymphoproliferative disorder of childhood, hydroa vacciniforme-
like T-cell lymphoma
Human T-cell lymphotropic virus type I ATLL
Helicobacter pylori Gastric MALT
Hepatitis C Marginal zone lymphoma; lymphoplasmacytic lymphoma, nodal
Human herpesvirus 8 (formerly KSHV) Primary effusion lymphoma, plasmablastic lymphoma
DLBCL, Burkitt lymphoma, PCNSL, primary effusion lymphoma,
Human immunodeficiency virus (HIV)
plasmablastic lymphoma
Borrelia burgdorferi Cutaneous B-cell lymphoma
Chlamydia psittaci Ocular adnexal MALT
Chlamydia trachomatis Pulmonary MALT
Chlamydia pneumonia Pulmonary MALT
Campylobacter jejuni Small intestine MALT

EBV, Epstein-Barr virus; NK, natural killer cell; PTLD, post-transplant lymphoproliferative disorder; ATLL, adult T-cell
leukemia/lymphoma; MALT, mucosa-associated lymphoid tissue; KSHV, Kaposi’s sarcoma-associated herpesvirus; DLBCL,
diffuse large B-cell lymphoma; PCNSL, primary central nervous system lymphoma.
Source: Engels EA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev.
2007;16:401–404.

Increased scrutiny has recently been placed on the risks of repeated exposure to
ionizing radiation in the form of contrast-enhanced imaging scans as well as the risk of
therapeutic radiation.15,16 It is clear that exposure to radiation increases the lifetime risk
of developing NHL, especially in younger patients. Modern radiotherapy treatment
protocols attempt to mitigate this risk by delivering lower doses of radiation or using
alternative modalities such as proton therapy, but the long-term risk reduction is
currently unknown.

III. CLASSIFICATION OF NHL

The classification systems for lymphomas have changed frequently since they were first
introduced in the 1950s. Ideally, a classification system should identify types of NHL that
 are scientifically and clinically meaningful as well as those that are relatively
homogeneous from a clinical, morphologic, immunologic, and genetic perspective. The
systems have evolved along with available technology and scientific discovery from ones
that rely heavily on morphologic descriptions to the current working system that
incorporates morphology, immunophenotypic characteristics, cytogenetic and molecular
abnormalities, and clinical variables.
In 1956, Henry Rappaport of the U.S. Armed Forces Institute of Pathology proposed a
very simple and reproducible classification system on the basis of the growth pattern of the
disease (nodular vs. diffuse) as well as the appearance of the predominant cell as well
differentiated, poorly differentiated, undifferentiated, or histiocytic. This was followed in
the 1970s by the Lukes-Colins-Lennert classification system that related morphology to
lymphocyte lineage by dividing entities into B-cell and T-cell disorders on the basis of
their cell-surface markers; however, they still did not address clinical concerns and were
not uniformly utilized internationally.17
In the 1980s, the New Working Formulation defined broad categories of lymphoma on
the basis of general clinical prognosis of either low grade, intermediate grade, or high
grade in order to assist the clinician in treating the lymphoma. The system, however, did
not include information regarding immunophenotype, and therefore was difficult to
reproduce and did not foster recognition of new entities.
In 1994, the International Lymphoma Study Group developed a consensus list of
diseases that could be recognized by pathologists and that appeared to be distinct clinical
entities called the Revised European-American Classification of Lymphoid Neoplasms
classification system, which ultimately became the World Health Organization (WHO)
classification system: the first international consensus on the classification of hematologic
malignancies.18 The original classification system, published in 2001, defined diseases by
four features: morphology, immunophenotype, genetics, and clinical information. The
updated 2008 version (Table 23.5) increases the use of both molecular profiles and
clinical presentations to define separate clinicopathologic entities.1
Newly recognized entities in the WHO 2008 classification system include “gray-
zone” lymphomas, which are intermediate between two distinct lymphomas. The inclusion
of these entities demonstrates that, in some cases, the ability to distinguish between
lymphomas is difficult.

IV. STAGING OF NHL

A. Making the diagnosis
The most critical initial step in a patient with suspected NHL is ensuring the accuracy of
the pathologic diagnosis. The adequacy of the original biopsy procurement procedure is
essential and should be representative of the disease (not necessarily the most
accessible). In general, fine-needle aspiration is not sufficient to accurately classify
NHLs, and excisional lymph-node biopsies are preferred. In situations where involved
nodes are not easily accessible, multiple core biopsies can substitute. When T-cell
 lymphomas are suspected, expertise is essential as the discordant rate can be as high as
15%.19

TABLE
WHO 2008 Classification of Lymphoid Neoplasms
23.5
Precursor Lymphoid Neoplasms
■ B lymphoblastic leukemia/lymphoma NOS
■ B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
■ t(9:22)(q34;q11.2); BCR-ABL1
■ t(v;11q23); MLL rearranged
■ t(12:21)(p13;q22); TEL-AML1 (ETV6-RUNX1)
■ With hyperdiploidy
■ With hypodiploidy
■ t(5:14)(q31;q32); IL3-IGH
■ t(1:19)(q23;p13.3); E2A-PBX1(TCF3-PBX1)
■ T lymphoblastic leukemia/lymphoma

Mature B-Cell Neoplasms

■ SLL/CLL
■ B-cell prolymphocytic leukemia
■ Splenic B-cell MZL
■ Hairy cell leukemia
■ Splenic B-cell lymphoma/leukemia, unclassifiable
■ Splenic diffuse red pulp small B-cell lymphoma
■ Hairy cell leukemia-variant
■ Lymphoplasmacytic lymphoma
■ Heavy-chain diseases
■ Gamma heavy-chain disease
■ Mu heavy-chain disease
■ Alpha heavy-chain disease
■ Plasma cell neoplasms
■ Monoclonal gammopathy of undetermined significance
■ Plasma cell myeloma
■ Solitary plasmacytoma of bone
■ Extraosseous plasmacytoma
■ Monoclonal immunoglobulin deposition diseases
■ Extranodal marginal zone B-cell lymphoma of MALT
■ Nodal marginal zone B-cell lymphoma
■ FL
■ Primary cutaneous follicle center lymphoma
■ Mantle cell lymphoma
■ DLBCL, NOS
■ T-cell/histiocyte-rich large B-cell lymphoma
■ Primary DLBCL of the CNS
■ Primary cutaneous DLBCL, leg type
■ EBV-positive DLBCL of the elderly
■ DLBCL associated with chronic inflammation
■ Lymphomatoid granulomatosis
■ Primary mediastinal (thymic) large B-cell lymphoma
■ Intravascular large B-cell lymphoma
■ ALK+ large B-cell lymphoma
■ Plasmablastic lymphoma
■ Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
■ Primary effusion lymphoma
■ BL
■ B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL
■ B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T- and NK-Cell Neoplasms

■ T-cell prolymphocytic leukemia
■ T-cell large granular lymphocyte leukemia
■ Chronic lymphoproliferative disorder of NK cells
■ Aggressive NK-cell leukemia
■ EBV-positive T-cell lymphoproliferative diseases of childhood
■ Systemic EBV+ T-cell lymphoproliferative disease of childhood
■ Hydroa vacciniforme-like lymphoma
■ Adult T-cell lymphoma/leukemia
■ Extranodal NK-/T-cell lymphoma nasal type
■ Enteropathy-associated T-cell lymphoma
■ Hepatosplenic T-cell lymphoma
■ Subcutaneous panniculitis-like T-cell lymphoma
■ Mycosis fungoides (CTCL)
■ Sézary syndrome
■ Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
■ Primary cutaneous PTCLs, rare subtypes
■ Primary cutaneous gamma-delta T-cell lymphoma
■ Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
■ Primary cutaneous CD4-positive small/medium T-cell lymphoma
■ PTCL-NOS
■ Angioimmunoblastic T-cell lymphoma
■ Anaplastic large-cell lymphoma, ALK+
■ Anaplastic large-cell lymphoma, ALK−

Immunodeficiency-Associated Lymphoproliferative Disorders

■ Lymphoproliferative diseases associated with primary immune disorders
■ Lymphomas associated with HIV infection
■ PTLD
■ Plasmacytic hyperplasia and infectious-mononucleosis–like PTLD
■ Polymorphic PTLD
■ Monomorphic PTLD
■ Classical Hodgkin lymphoma–type PTLD
■ Other iatrogenic immunodeficiency-associated lymphoproliferative disorders

BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CTCL, cutaneous T-cell lymphomas;
DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; FL, follicular lymphoma; HHV8, human herpesvirus 8; HIV,
human immunodeficiency virus; MZL, marginal zone lymphoma; NK, natural killer; NOS, not otherwise specified; PTCL,
peripheral T-cell lymphomas; PTLD, posttransplant lymphoproliferative disorder; SLL, small lymphocytic lymphoma; WHO,
World Health Organization.

B. Recommended workup and imaging

Accurate assessment of tumor burden prior to therapy is a prognostic tool and serves as
a baseline for determining treatment response. The staging evaluation of NHL begins
 with a history focused on the pace of the disease at presentation, the presence or
absence of B symptoms (fevers, drenching night sweats, unintentional weight loss
greater than 10% of body weight over 6 months or less), possible sites of nodal and
extranodal involvement, and signs suggestive of a possible underlying
immunodeficiency. When performing the physical examination, special care must be
given to examining the Waldeyer ring, epitrochlear nodes, and popliteal nodes, which
may be difficult to measure on radiographic imaging, as well as examining for sites of
extranodal involvement such as the skin and abdomen for signs of hepatosplenomegaly.
Recommended tests that supplement the history and physical examination at the time of
diagnosis are listed in Table 23.6.
C. Ann Arbor staging
The Cotswold modification of the Ann Arbor classification is generally used to stage
patients with newly diagnosed NHL and is shown in Table 23.7.20 Anatomy-based
imaging such as contrast-enhanced computed tomography (CT) scans (or magnetic
resonance imaging for patients with contrast allergies) is the gold standard for
determining which nodal chains are involved with lymphoma. Lymph nodes are
considered involved if the long axis is ≥1.5 cm (regardless of short axis) or if the long
axis is ≥1.1 cm and the short axis is >1.0 cm. Lymph nodes that are ≤1.0 cm in both axes
are considered uninvolved.21 Determining the stage of lymphomatous involvement on
the basis of anatomic imaging alone misses nodes that are involved but not enlarged and
can easily miss extranodal sites of disease such as bony involvement, which may affect
treatment recommendations.

TABLE
Infectious Agents Associated With NHL
23.6
■ Adequate biopsy specimen with tissue sent for flow cytometry and molecular studies
■ Complete blood count
■ LDH
■ Comprehensive metabolic panel
■ Uric acid
■ Beta-2 microglobulin
■ HIV
■ Hepatitis B surface antigen
■ Chest-abdominal-pelvic CT with contrast
■ 18Fluoro-2-deoxy-D-glucose PET/CT scan
■ Lumbar puncture with flow cytometry of CSF (in select cases)
■ Unilateral bone marrow biopsy with aspirate
■ Assessment of ejection fraction with multigated acquisition scan or echocardiogram
■ Pregnancy testing in women
■ Discussion of pregnancy and fertility issues

CSF, cerebro-spinal fluid; CT, computed tomography; LDH, lactate dehydrogenase; NHL, non-Hodgkin lymphoma; PET,
positron emission tomography.
 TABLE
Staging System for NHL
23.7
Ann Arbor Staging Classification for NHLs
Stage Description
I Involvement of a single lymph-node region (I) or involvement of a single extralymphatic organ or site (IE)
Involvement of two or more lymph-node regions or lymphatic structures on the same side of the diaphragm alone (II) or
II
with involvement of limited, contiguous extralymphatic organ or tissue (IIE)
Involvement of lymph-node regions on both sides of the diaphragm (III), which may include the spleen (IIIS) or limited,
III
contiguous extralymphatic organ or site (IIIE) or both (IIIES)
Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without associated
IV
lymphatic involvement
A Asymptomatic
Unexplained persistent or recurrent fever with temperature higher than 38°C or recurrent drenching night sweats within
B
1 month or unexplained loss of more than 10% body weight within 6 months
E Limited direct extension into extralymphatic organ from adjacent lymph node
Bulky disease (mediastinal tumor width greater than one-third transthoracic diameter at T5–T6 or tumor diameter larger
X
than 10 cm)

NHL, non-Hodgkin lymphoma.

Source: Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin’s disease staging
classification. Cancer Res. 1971;31:1860–1861.

Accurate assessment of disease involvement can be improved with the use of

functional imaging such as positron emission tomography (PET) scans.
18Fluorodeoxyglucose (FDG)-PET scans and PET/CT scans exploit the enhanced rate

of glucose utilization (both uptake and phosphorylation) seen in many tumor cells as
compared with normal surrounding cells (the Warburg effect).22 Thus, 18FDG-PET
scans can provide a semiquantitative measurement of tumor involvement in NHLs, and
have improved sensitivity to identify extranodal and bony lesions.

V. PROGNOSIS OF NHL
A. Clinical prognostic index scores
The prognosis of patients with newly diagnosed NHL involves more than just Ann
Arbor staging, and clinical prognostic index scores were developed as a means to
better understand pretreatment prognosis beyond stage alone. The first example was the
International Prognostic Index (IPI) score that was developed in diffuse large B-cell
lymphoma (DLBCL) to stratify patients into quartiles with differing probabilities of
both complete response as well as 5-year disease-free survival (DFS).23 The IPI score
uses the five variables of age, stage, performance status, number of extranodal sites of
disease, and lactate dehydrogenase (LDH) level. For all patients, 5-year survival was
73% for low-risk patients, 51% for low/intermediate-risk patients, 43% for
high/intermediate-risk patients, and 26% for high-risk patients (Table 23.8). For
 patients under the age of 60 years, a slightly modified age-adjusted prognostic system
was developed, in which the 5-year survival was 83% for low-risk patients, 69% for
low/intermediate-risk patients, 46% for high/intermediate-risk patients, and 32% for
high-risk patients (Table 23.9).

TABLE
International Prognostic Index for NHL
23.8

TABLE
Age-Adjusted International Prognostic Index for DLBCL*
23.9
Patients Aged <60 Years 0 points 1 point
Stage I or II III or IV
Performance status 0 or 1 ≥2
LDH Normal Elevated

DLBCL, diffuse large B-cell lymphoma.

*Risk category: Low risk, 0 points; low/intermediate risk, 1 point; high/intermediate risk, 2 points; high risk, 3 points.

The IPI cannot be extrapolated to other NHL subtypes, so other clinical prognostic
scores have been created to account for other variables that affect outcomes in indolent
 lymphomas. Follicular lymphoma (FL) is typically a widespread disease at presentation
that frequently involves multiple nodal chains and the bone marrow, even in cases in
which the natural history of the tumor growth will be slow. Also, it is common for
patients to experience no symptoms attributable to the disease despite the widespread
amount of tumor burden. On the basis of multivariate analysis collected on over 4,000
patients and ultimately validated on almost 1,000 patients, a five-variable prognostic
index was constructed: the Follicular Lymphoma International Prognostic Index (FLIPI;
Table 23.10).24 Despite its widespread use in clinical trials, however, the FLIPI does
not define for clinicians which patients should be treated at time of diagnosis.
In an attempt to improve on the FLIPI, an international project was conducted on
over 1,000 patients with newly diagnosed FL; all were treated with rituximab-based
regimens. A prognostic score was also determined from this data set of five variables
that could also separate patients into three separate risk groups, termed the F2 (Table
23.11).25 The strengths of the F2 score are that it includes readily available clinical
variables and was derived from patients treated with rituximab.
B. GEP as prognostic tools
As opposed to clinical variables that may be dominated by extent of disease burden,
there has been great interest in attempting to define and predict the clinical behavior of
lymphomas on the basis of the expression of genes on tissue microarray.26 With the
advent of GEP, which can simultaneously analyze the relative expression of thousands
of genes at one time on an individual’s tissue sample, it has become possible to predict
outcomes on the basis of the molecular profile of the tissue. One example of this exists
in DLBCL, which can be subdivided into three categorical subtypes: germinal center B-
cell (GCB) subtype, activated B-cell (ABC) subtype, and primary mediastinal B-cell
lymphoma (PMBL).2,3,27 All three of these subtypes have a widely different prognosis
(independent of IPI score), with the GCB subtype responding more favorably to
standard chemotherapy regimens than the ABC subtype and the mediastinal B subtype
with the best overall prognosis (59%, 30%, and 64% 5-year survivals, respectively).
GEP was first developed using frozen tissue, which is not always readily available.
More recently, a new digital gene-expression technique has been developed that can be
used on formalin-fixed paraffin-embedded tissue, potentially making this means of risk
stratification more readily available in the future.28
 TABLE
Follicular Lymphoma International Prognostic Index (FLIPI)
23.10
■ Score one point for each factor:
■ Age ≥60 years
■ Ann Arbor stage III–IV
■ Hemoglobin level <12 g/dL
■ Serum LDH level > upper limit of normal
■ Number of nodal sites ≥5
Score Risk Group Five-Year OS (% )

0–1 Low 90.6

2 Intermediate 77.6
≥3 High 52.5

OS, overall survival.

Source: Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258–
1265.

TABLE
F2 Prognostic Model
23.11

C. Interim imaging scans performed during therapy

In addition to providing a tool for staging patients, 18FDG-PET scanning also has the
potential to serve as an interim functional biomarker during therapy for aggressive
lymphomas to predict which patients are responding to therapy and which ones are
likely to fail induction.29,30 Patients who achieve a negative PET scan during therapy
have a better prognosis than those who remain PET positive on interim imaging scans.
Thus, risk-adapted or response-adapted approaches were developed on the basis of the
premise that early identification of the patients who are failing therapy allows for an
earlier switch to alternative treatment. Unfortunately, the clinical results from such
 response-adapted approach in DLBCL have not shown that changing therapy can
overcome the poor prognosis of a positive interim PET scan. Future research likely
will continue to test these and other biomarkers during therapy, but treatment decisions
based on interim PET scanning cannot be recommended.
D. Response assessment at the end of therapy
The International Working Group published guidelines in 1999 for response assessment
and outcomes measurement rely mainly on CT scans. However, the widespread use of
PET scans prompted another revision in 2007, referred to as the Revised Response
Criteria for Malignant Lymphoma.31 The guidelines included recommendations on
definition of a positive PET scan, timing of PET scans, and measurement of response.
The most recent modernization of recommendations for initial evaluation, staging, and
response assessment called The Lugano Classification was published in 2014.32 The
major changes included the following: PET is used to assess response in FDG-avid
histologies using the 5-point scale, with CT being preferred in low or variable FDG
avid lymphomas; a complete remission is defined by negative PET even in the presence
of a persistent mass; and surveillance PET scans after remission are discouraged in
aggressive lymphomas.
For indolent lymphoma such as FL, depth of response measured by PET scan also
holds prognostic value. In a pooled analysis of 439 FL patients treated with upfront
regimens and available PET scans at the end of therapy, a negative PET at the end of
treatment was associated with a marked improvement in progression-free and overall
survival (OS) compared with PET-positive patients.33 End-of-treatment PET scans in
indolent lymphomas such as FL are commonly used to define long-term prognosis and
may have a role when considering extended-duration therapy.
Surveillance medical imaging done after patient has achieved a remission is
controversial. Repetitive imaging scans with ionizing radiation are associated with
additional costs and potential long-term health risks, but they may identify lymphoma
recurrence at an earlier time point than clinical signs/symptoms alone.34 The
preponderance of evidence does not support the use of surveillance imaging in patients
who have been treated for curative intent, but it is common practice to follow patients
for up to 5 years after therapy with periodic use of CT scans. Molecular monitoring
tools that can assess for circulating tumor DNA in the serum or plasma may prove
useful in the future and obviate the need for surveillance imaging.35

VI. MANAGEMENT OF INDOLENT NHL

Indolent lymphoma is a term used to describe the natural history of NHLs that may not
cause direct symptoms to patients for months or even years. They should not be considered
“good lymphomas,” however, because the majority of patients ultimately die of their
cancer. Indolent NHLs are generally considered incurable with conventional treatment.
Indolent lymphomas also carry a perpetual risk of transformation into a more aggressive
lymphoma at an estimated 3%/year annual risk; no reliable predictive variables exist to
 identify the patients at highest risk for such transformation.36 The second most frequent
subtype of NHL overall (approximately 20%) and prototypical indolent lymphoma is FL.
The principles applied to the diagnosis and management of FL can be applied to most other
indolent NHLs. Small lymphocytic lymphoma (SLL) is now known to be biologically
identical to chronic lymphocytic leukemia (CLL) and is defined by the lack of a leukemic
component. It is considered separately from NHL in another chapter.
A. FL pathology
FL is characterized by the translocation t(14;18), which places the BCL2 oncogene
under the control of the IgH enhancer, leading to dysregulated and impaired apoptosis.
Histologically, two principal cells exist in the normal follicle center (germinal center):
the centrocyte (small cleaved cell) and the centroblast (large noncleaved cells). In the
2008 WHO classification of FL, a grading system categorizes FL into grades I to IIIa-b
on the basis of the ratio of centroblasts/centrocytes. Grade IIIb FL (sheets of
centroblasts) is clinically indistinguishable from DLBCL and is commonly treated with
algorithms appropriate for aggressive lymphomas, while grades I to IIIa are treated
according to principles governing indolent NHLs.
B. Frontline treatment principles of indolent NHL
Numerous treatment options exist for patients with newly diagnosed FL, but no curative
standard therapy has been identified. The life expectancy of FL patients has been
prolonged with the use of rituximab, but it is still characterized by being highly
responsive to initial therapies with inevitable relapse of disease. Patients typically
undergo multiple sequential therapies throughout the course of disease. The only
potentially curative therapy is allogeneic stem-cell transplantation, which is only an
option for highly selected patients and carries a risk of treatment-related mortality.
C. Low–tumor burden FL
“Watchful waiting” or “dynamic observation” is an appropriate strategy in many
patients until the disease progression causes symptoms, progressive cytopenias, or
threatens the function of an organ.37 Discussing this strategy with patients who are
otherwise fit for therapy can be challenging if patients are uncomfortable with delaying
therapy. Randomized trials, however, have consistently demonstrated that early
administration of therapy does not improve OS. In a recent randomized study of
rituximab monotherapy compared with watch and wait, 46% of patients in the control
arm did not require treatment within the first 3 years, and there was no OS advantage of
early treatment despite an improvement in PFS.38 If a watchful waiting strategy is
employed, then careful attention should be placed on the pace of the disease as well as
the identification of signs of histologic transformation, and PET/CT scanning may add
supplemental information in this regard.
In general, rituximab monotherapy is less effective for patients with bulky nodes and
should be reserved for patients who are not candidates for combination chemotherapy.
The use of rituximab monotherapy in low–tumor burden FL, however, is an attractive
treatment option because it has relatively few side effects, and it can be given to
 patients with underlying organ dysfunction of all ages. The use of rituximab
monotherapy at 375 mg/m2 for four or eight doses yields high response rates and almost
50% of patients achieved long durations of remissions in the 5- to 7-year range.39
A recent randomized study, known as the RESORT study, compared extended
duration therapy with rituximab to a strategy of re-treatment with rituximab at the time
of progression for patients with low–tumor burden FL.40 In this trial, there was no
improvement in time-to-treatment failure for patients on scheduled maintenance.
D. High–tumor burden FL
Patients with high–tumor burden FL are initially treated with one of the standard
combination chemotherapy regimens with the addition of rituximab (Table 23.12). All
of these regimens produce overall response rates in excess of 90% with approximately
50% complete responses, but can vary in the duration of response (DOR) and are
associated with various toxicities. The use of anthracyclines is not mandatory in
patients with untreated FL, but according to the National LymphoCare study, which
examined practice patterns in community- and academic-based institutions, rituximab
plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) remains
the most commonly prescribed regimen in the United States with some geographical
variation.41 Bendamustine-rituximab (BR) is another regimen that compares favorably
with R-CHOP with a different toxicity profile and is another effective initial treatment
option. It has gained popularity owing to its lack of alopecia and ease of administration,
but has not been well studied in grade III histologic variants of FL. A randomized study
of BR compared with R-CHOP demonstrated a superior 3-year PFS with a more
favorable safety profile.42 Both R-CHOP and BR are considered standard first-line
therapy options for high–tumor burden FL.
 TABLE
Indolent Lymphoma Initial Treatment
23.12
Chemoimmunotherapy Treatment Description
R-CHOP Rituximab 375 mg/m2 IV on day 1
Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin 50 mg/m2 IV on day 1
Vincristine 1.4 mg/m2 IV push on day 1 (maximum 2 mg)
Prednisone 50 mg/m2/day PO on days 1–5
Each cycle is 21 days given up to 6 cycles
*BR Rituximab 375 mg/m2 IV on day 1 only
*Bendamustine 90 mg/m2 IV on days 1 and 2

Each cycle is 28 days given up to 6 cycles

†Lenalidomide-rituximab (R2) Rituximab 375 mg/m2 IV weekly × 4 then day 1 of cycles 4, 6, 8, and 10
Lenalidomide 20 mg PO days 1–21 of each 28-day cycle
Each cycle is 28 days for a total of 12 cycles

FDA, US Food and Drug Administration; IV, intravenously; PO, by mouth.

*This dose of bendamustine is lower than the FDA-approved dose of 120 mg/m2 and the cycle length is longer (28 instead of 21

days).
†This dosing regimen and schedule is not FDA-approved at time of publication.

The oral immunomodulatory agent, lenalidomide, has also been studied with
rituximab in patients with untreated FL. A recent phase II study in 50 patients
demonstrated a complete remission rate of almost 90% with a favorable safety
profile.43 A phase III study comparing this regimen with chemoimmunotherapy has
completed accrual.
E. Extended-duration therapy or “maintenance” in indolent NHL
Disease relapse is universal after initial therapy for indolent lymphoma, and effective
strategies to prolong the duration of remission are of great interest. Rituximab has not
demonstrated significant long-term toxicities, making it an attractive agent to administer
in an extended duration or “maintenance” role following the completion of induction
therapy. As previously mentioned, a study of rituximab monotherapy in low–tumor
burden FL demonstrated no difference in time-to-treatment failure for scheduled
maintenance. A large randomized study, known as the PRIMA study, tested the effect of
rituximab maintenance every 2 months for 2 years after induction
chemoimmunotherapy.44 The use of rituximab maintenance after chemoimmunotherapy
resulted in a significant prolongation of PFS at 3 years, but no difference in OS. Until
long-term data exist demonstrating a clear overall benefit, this cannot be recommended
to all patients and the pros and cons of rituximab maintenance should be discussed with
patients.
 As newer oral agents become available, the concept of extended-duration therapy is
gaining significant research interest. When safety profiles allow, extended-duration
therapy can be tested and potentially include more than one agent. For example,
treatment regimens that include lenalidomide with rituximab have tested the safety and
efficacy of continuing both lenalidomide and rituximab for up to 1 year. Further studies
will add to our understanding of these approaches and whether or not extended-duration
therapy contributes to secondary resistance. Similarly, the oral PI3Kδ inhibitor,
idelalisib, was recently approved for indefinite treatment until disease progression in
patients with relapsed indolent NHL.45 As targeted agents with good tolerability
continue to emerge, the concept of extended-duration or maintenance therapies will
undoubtedly expand.
F. Other indolent lymphomas
1. Marginal zone lymphomas (MZLs)
MZL arises from marginal zone B-cells present in lymph nodes and extranodal
tissues. This group of indolent B-cell lymphomas consists of three subtypes: splenic
marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), and
extranodal marginal zone lymphoma or MALT. All three subtypes have similar
immunophenotypic markers that are positive for cluster of differentiation 19 (CD19),
CD20, and CD22 and negative for CD5, CD10, and usually CD23. The presence of
a t(11,18) translocation is usually associated with a worse prognosis in gastric
MALT.
The treatment principles applied to FL do not apply to all indolent lymphomas,
and some lymphomas such as MZL may respond to treatment of underlying
associated pathogens. Determination of cause of chronic infection will help guide
treatment decisions. Antigenic stimulation by bacteria or viruses such as H. pylori in
gastric MALT or hepatitis C in NMZL may induce lymphoid hyperplasia. Treatment
with antimicrobial therapy may eradicate these diseases and will not require
radiation or chemotherapy.46 Given the indolent nature of MZL, watchful waiting is
also an appropriate option. In patients who are symptomatic and have adverse
prognostic factors, chemoimmunotherapy can be used or splenectomy in cases of
SMZL.
2. Cutaneous T-cell lymphomas (CTCLs; mycosis fungoides)
Another subset of indolent NHLs that deserves special attention is the cutaneous
lymphomas.47 Cutaneous lymphomas include a wide variety of diseases of both B-
cell and T-cell origin that present primarily involving the skin and are predominantly
indolent. These NHLs are frequently misdiagnosed as other skin disorders such as
eczema, and it is not uncommon for patients to be followed for many years before an
accurate diagnosis is made. The most common cutaneous lymphoma is CTCL, also
known as mycosis fungoides. When there is generalized erythroderma and
involvement of the peripheral blood, the syndrome is known as Sézary syndrome.
Prognosis in CTCL depends on stage of disease, and special staging systems for
 CTCL exist (Table 23.13). Clinical stage IA disease is so indolent that it does not
impact on normal life expectancy, while prognosis worsens with more advanced
stage of disease. The disease may exist as plaques in the skin for many years before
progressing to involve skin tumors, lymphadenopathy, or visceral disease. Often,
this clinical progression occurs in association with a pathologic transformation to a
more aggressive lymphoma. If disease is limited to the skin, topical therapy such as
topical nitrogen mustard, electron beam radiotherapy, or psoralen (often in
conjunction with ultraviolet radiation) may be employed. Combination
chemotherapy regimens such as those used for intermediate-grade lymphoma may be
used for disease involving nodes (see Chapter 14).

TABLE
Staging System for Cutaneous T-Cell Lymphoma
23.13
Stage I: Limited or generalized plaques without adenopathy or histologic involvement of lymph nodes
Stage II: Limited or generalized plaques with adenopathy, or cutaneous tumors without adenopathy; without histologic involvement of
lymph nodes or viscera
Stage III: Generalized erythroderma, with or without adenopathy; without histologic involvement of lymph nodes or viscera
Stage IV: Histologic involvement of lymph nodes or viscera with any skin lesions; with or without adenopathy

Source: Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–
3785.

VII. MANAGEMENT OF AGGRESSIVE LYMPHOMAS

A. Mantle cell lymphoma (MCL)
MCL is an uncommon NHL derived from naïve small B-lymphocytes that are associated
with a t(11;14) chromosomal translocation.48 MCL is an incurable lymphoma but can be
clinically aggressive. Current management strategies have improved the median
survival of MCL from 3 to 4 years to almost 7 years, but MCL still has one of the worst
prognoses of all B-cell NHLs. The proliferation signature of MCL as defined by GEP
has proven to be highly predictive of outcome and patients with more proliferative
variants of MCL have a worse prognosis.49 In fact, some patients with MCL can often
go several years without therapy and without disease progression.50 Clinical,
pathologic, and radiographic variables have all been used to attempt to identify which
patients can be observed and which patients need immediate therapy, but it is currently
difficult to accurately identify these subsets prospectively. A prognostic score similar to
the IPI, termed the MIPI (Table 23.14), has been developed and has been validated in
numerous prospective studies.51
Despite the poor prognosis, MCL is very sensitive to both chemotherapy and
radiation with the overall response rate being in excess of 90% with R-CHOP therapy.
These responses, however, are usually of brief duration less than 2 years making R-
 CHOP a suboptimal choice in MCL. A common strategy for young individuals with
MCL is to treat with highly intensive cytarabine-based regimens often followed with
autologous stem-cell transplant (ASCT) in first remission (Table 23.15). These
intensive approaches result in very high rates of complete response, but are not curative
and are associated with significant myelosuppression. Most patients with untreated
MCL are not candidates for the intensive regimens, and these patients are often treated
with BR similar to patients with FL.
Recently, the first-generation proteasome inhibitor, bortezomib, was substituted for
vincristine in the cyclophosphamide, doxorubicin, vincristine, and prednisolone
(CHOP) chemotherapy backbone (VR-CAP) (Table 23.15) and compared with R-
CHOP as an induction therapy for MCL.52 In this randomized phase III study of 487
untreated patients, VR-CAP demonstrated an improved PFS of 24.7 months compared
with 14.4 months for R-CHOP after a median follow-up of 40 months. On the basis of
this study, the FDA granted approval to bortezomib in the upfront setting (Table 23.15).
The patients in this study were considered ineligible for ASCT and it is currently
unclear how VR-CAP compares to BR or intensive regimens that include ASCT as this
has not yet been compared.

TABLE
Mantle Cell Lymphoma International Prognostic Index
23.14
 TABLE
Infectious Agents Associated With NHL
23.15
Combination
Chemotherapy Description

R-HyperCVAD/MA
Cycles 1, 3, 5, and 7 Rituximab 375 mg/m2 IV infusional protocol on day 1 only
Cyclophosphamide 300 mg/m2 IV every 12 hours for 6 doses on days 2–4
Vincristine 1.4 mg (maximum 2 mg) IV push on days 5 and 12
Doxorubicin 50 mg/m2 via CIVI over 72 hours on days 5–7
Dexamethasone 40 mg/day IV or PO on days 2–5 and 12–15
Mesna 600 mg/m2 IV daily starting 1 hour before cyclophosphamide and completed 12 hours after
the last cyclophosphamide dose
Cycles 2, 4, 6, and 8 Rituximab 375 mg/m2 IV infusional protocol on day 1 only
Cytarabine 3,000 mg/m2 per dose IV over 1 hour every 12 hours × 4 doses on days 3 and 4 (reduce
cytarabine dose to 1 g/m2 for patients over 60 years old or creatinine >1.5)
Methotrexate 1 g/m2 IV over 24 hours on day 1
Leucovorin 50 mg IV to start 12 hours after methotrexate, then 15 mg IV every 6 hours until serum
methotrexate <1 × 10−8 M
Filgrastim (G-CSF) should be administered starting on day 4 until granulocyte recovery occurs
Treatment cycles started on the basis of blood counts (approximately every 21 days)
MCL 2 regimen
Cycles 1, 3, and 5 Rituximab 375 mg/m2 IV on day 1
Cyclophosphamide 1,200 mg/m2 IV on day 1
Doxorubicin 75 mg/m2 IV on day 1
Vincristine 2 mg IV push on day 1
Prednisone 100 mg/day PO on days 1–5
Cycles 2, 4, and 6 Rituximab 375 mg/m2 IV on days 1 and 9
Cytarabine 3,000 mg/m2 per dose IV over 3 hours every 12 hours × 4 doses (reduce cytarabine
dose to 2 g/m2 for patients over 60 years old)
Filgrastim (G-CSF) should be administered starting on day 4 until granulocyte recovery occurs
*VR-CAP

Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11

Rituximab 375 mg/m2 IV on day 1
Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin 50 mg/m2 IV on day 1
Prednisone 100 mg/m2/day PO on days 1–5
Each cycle is 21 days for up to 6 cycles
BR See Table 23.13 for up to six cycles

CIVI, continuous intravenous infusion; G-CSF, granulocyte colony-stimulating factor; IV, intravenously; PO, by mouth.
*Bortezomib can be given as an IV or subcutaneous injection, but this regimen was studied with an IV infusion.
 Since 2006, three targeted therapies have been FDA-approved for relapsed
refractory MCL (Table 23.16).56 The previously mentioned, bortezomib, was the first
approved on the basis of a study that demonstrated activity in the relapsed setting. The
most common side effect is peripheral neuropathy, and extent of prior neuropathy should
be considered before starting this drug. Lenalidomide also has activity as a single agent
in relapsed MCL and has been approved for use in this setting. Although response rates
are modest, the patients who respond occasionally have long durations of remission.
Most recently, the oral and irreversible inhibitor of Bruton’s tyrosine kinase (BTK),
ibrutinib, was approved for use in relapsed MCL. BTK is an important kinase in the in
B-cell receptor (BCR) signaling pathway and many cases of MCL are addicted to BCR
signaling. As a single agent, ibrutinib resulted in an overall response rate of 68% in
relapsed/refractory MCL and is currently being tested in combinations with other active
agents.

TABLE
Targeted Treatment of Relapsed Mantle Cell Lymphoma
23.16
Agent Schedule
Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21-day cycle until disease progression
Ibrutinib 560 mg PO daily continuously until disease progression
Lenalidomide 25 mg PO daily on days 1–21 of a 28-day cycle until disease progression

B. Diffuse large B-cell lymphoma

DLBCL is the most common lymphoma in adults, representing about 30% of cases
diagnosed in the United States annually. In most cases, it responds to combination
chemoimmunotherapy regimens, and treatment with curative intent is appropriate in
most cases of newly diagnosed DLBCL. Still, up to 40% of patients will relapse after
or be refractory to their initial therapy. The molecular mechanisms underlying DLBCL
are being discovered at the level of individual somatic mutations, and it is evident that
tremendous heterogeneity exists across tumors.57 In addition, molecular profiling and
DNA microarray studies have demonstrated that the relationship with the stroma
(microenvironment) as well as disease subtype as defined by GEP are important in
determining the behavior of DLBCLs.
As previously mentioned, the Lymphoma/Leukemia Molecular Profiling Project
established three subtypes of DLBCL on the basis of cell of origin: the GCB subtype,
the ABC subtype, and PMBL subtype. Each individual DLBCL subtype is dependent on
unique signal transduction pathways for survival. Treatment decisions are not yet
routinely altered on the basis of the underlying molecular subtype, but to define a more
“personalized” treatment approach on the basis of the expression of genes unique to
 individual patients’ tumors is a potentially attainable goal in the future.
Another emerging concept related to the biology of DLBCL is the fact that certain
subsets of DLBCL contain molecular mutations that have prognostic implications. It is
now recognized that 5% to 10% of DLBCL cases possess a rearrangement in the MYC
oncogene, which makes them highly proliferative and less responsive to R-CHOP.58
Two different groups have retrospectively reported their experience with MYC-positive
DLBCLs and both found distinctly poor survival in this subset of patients. The 2008
edition of the WHO classification scheme recognizes that some cases of MYC-positive
DLBCL may be very difficult to distinguish from Burkitt lymphoma (BL), and a
landmark study was able to demonstrate that on the basis of GEP, some cases of DLBCL
may actually have a BL-like molecular signature. In addition to MYC-positive DLBCLs,
another subset of DLBCLs with a poor prognosis are those that have a “double-hit”
with the BCL2 translocation t(14;18) in addition to an MYC translocation.59 These
tumors are particularly troublesome because they have developed mutations in both
proliferation and impaired apoptosis. No consensus exists on the correct approach to
patients in these poor-risk subgroups, but recent data suggest that DA-EPOCH-R (Table
23.17) may be an effective platform for MYC-positive DLBCL.
C. Initial treatment of advanced-stage aggressive NHL
Anthracyclines have established themselves as the most effective class of agents for
curative treatment regimens, and are considered the single most important drug in the
treatment of aggressive lymphomas. In the 1980s, single-institution phase II studies of
dose-intensive regimens such as cyclophosphamide, doxorubicin, etoposide, bleomycin,
vincristine, methotrexate, and prednisone (known as Pro-MACE-CytaBOM);
methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and
dexamethasone (known as m-BACOD); and methotrexate plus leucovorin rescue,
doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (known as
MACOP-B) began to report what appeared to be markedly improved response rates
compared with conventional response rates seen with CHOP therapy. However, a
landmark study in 1993 established CHOP therapy as the de facto standard of care in
DLBCL.60
Rituximab has improved the cure rate of DLBCL in all age groups and the current
standard of care for most cases of DLBCL is to administer R-CHOP for six cycles
every 3 weeks (Table 23.18). The current research focus involves testing strategies
able to move beyond R-CHOP and overcome the drug resistance in the 40% of patients
who will not be cured with R-CHOP. Efforts to give the regimen in a “dose-dense”
fashion every 14 days with support with growth factors (R-CHOP-14) showed no
benefit over the standard R-CHOP-21.61
In comparison with the bolus administration of chemotherapy in the R-CHOP
regimen, the pharmacodynamically dose-adjusted (DA) regimen of etoposide,
doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-
R) utilizes infusional administration of agents over 96 hours in an effort to affect cells
that are not dividing on the first day of administration.62 Also, the regimen adjusts the
dose of the doxorubicin, etoposide, and cyclophosphamide with subsequent cycles
using the absolute neutrophil count as a biomarker. The DA-EPOCH-R regimen is
designed to be effective in more proliferative tumors, and response rates in single-
institution studies and a multi-institutional phase II trial demonstrate response rates that
are higher than those seen in R-CHOP; results of a phase III comparison between DA-
EPOCH-R and R-CHOP should help determine which subgroups (if any) benefit from
infusional therapy.
 TABLE
Chemotherapy Regimens for Aggressive B-NHL
23.17
Combination
Dose and Schedule
Chemotherapy
R-CHOP Rituximab 375 mg/m2 IV on day 1
Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin 50 mg/m2 IV on day 1
Vincristine 1.4 mg/m2 IV push on day 1 (maximum 2 mg)
Prednisone 50 mg/m2/day PO on days 1–5
Each cycle is 21 days
*DA-EPOCH-R
Rituximab 375 mg/m2 IV on day 1
(dose adjusted)
Etoposide 50 mg/m2/day by continuous IV infusion for 96 hours
Doxorubicin 10 mg/m2/day by continuous IV infusion for 96 hours
Vincristine 0.4 mg/m2/day by continuous IV infusion for 96 hours (no cap)
Prednisone 60 mg/m2 per dose PO every 12 hours for 5 days
Cyclophosphamide 750 mg/m2 IV on day 5 only
Filgrastim 5 μg/kg/day SC starting day 6
Treatment is repeated every 21 days
R-ACVBP Rituximab 375 mg/m2 IV on day 1
Doxorubicin 75 mg/m2 IV on day 1
Cyclophosphamide 1,200 mg/m2 IV on day 1
Vindesine 2 mg/m2 IV on days 1 and 5
Bleomycin 10 mg IV on days 1 and 5
Prednisone 60 mg/m2 PO on days 1 through 5
Intrathecal methotrexate 15 mg on day 2
Each cycle is 14 days, 4 cycles total, followed by
Methotrexate 3 mg/m2 IV on day 1with leucovorin rescue
Each cycle is 14 days, 2 cycles total, followed by
Rituximab 375 mg/m2 IV on day 1
Etoposide 300 mg/m2 IV on day 1
Ifosfamide 1,500 mg/m2 IV with mesna on day 1
Each cycle is 14 days, 4 cycles total, followed by
Cytarabine 100 mg/m2 SC on days 1–4
Each cycle is 14 days, 2 cycles total

IV, intravenously; NHL, non-Hodgkin lymphoma; PO, by mouth; SC, subcutaneously.

*The etoposide, doxorubicin, and cyclophosphamide are adjusted with each cycle on the basis of the absolute neutrophil count
nadir and platelet count.
 TABLE
Treatment Options for PTCL
23.18
Chemotherapy Treatment Description
Untreated PTCL
CHOP Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin 50 mg/m2 IV on day 1
Vincristine 1.4 mg/m2 IV push on day 1 (maximum 2 mg)
Prednisone 50 mg/m2/day PO on days 1–5
Each cycle is 21 days
CHOEP Cyclophosphamide 750 mg/m2 IV on day 1
Doxorubicin 50 mg/m2 IV on day 1
Vincristine 1.4 mg/m2 IV push on day 1 (maximum 2 mg)
Etoposide 100 mg/m2 IV on days 1–3
Prednisone 50 mg PO BID on days 1–5
Each cycle is 14 days
Relapsed PTCL
GDP Gemcitabine 1,000 mg/m2 IV on days 1 and 8
Dexamethasone 40 mg PO on days 1–4
Cisplatin 75 mg/m2 IV on day 1
Treatment is repeated every 21 days
EPOCH Etoposide 50 mg/m2/day by continuous IV infusion for 96 hours
(dose adjusted)* Doxorubicin 10 mg/m2/day by continuous IV infusion for 96 hours
Vincristine 0.4 mg/m2/day by continuous IV infusion for 96 hours (no cap)
Prednisone 60 mg/m2 per dose PO every 12 hours for 5 days
Cyclophosphamide 750 mg/m2 IV on day 5 only
Filgrastim 5 μg/kg/day SC starting day 6
Treatment is repeated every 21 days
Pralatrexate 30 mg/m2 IV push weekly × 6 of a 7-week cycle
B12 1 mg IM q8–10 weeks
Folic acid 1 mg PO daily
Romidepsin 14 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle
Belinostat 1,000 mg/m2 iv on days 1–5 of a 21-day cycle
Brentuximab 1.8 mg/m2 IV q3 weeks

IV, intravenously; PO, by mouth; SC, subcutaneously.

*EPOCH is adjusted with each cycle on the basis of the absolute neutrophil count nadir and platelet count.

Intensified chemotherapy with R-ACVBP was recently compared with R-CHOP in a

randomized phase III study of patients ages 18 to 59 with an IPI of 1 and at least stage II
DLBCL.63 In this multicenter study of 380 patients, the experimental regimen R-ACVBP
 resulted in an improvement in both 3-year EFS (81% vs. 67%, p = 0.0035 and OS
(92% vs. 84%, p = 0.0071) over R-CHOP. This was the first randomized study to
demonstrate an improvement over R-CHOP in DLBCL, but because of significant
myelosuppression, questions remain if R-ACVBP can be used in patients of all ages. On
the basis of this study, R-ACVBP should be discussed as a potential treatment option in
young patients with DLBCL.
Efforts to improve the cure rate of R-CHOP alone have also focused on the addition
of novel and more targeted agents.64 As previously mentioned, both ibrutinib and
lenalidomide have single-agent activity that is selective for ABC DLBCL, and they both
appear to have manageable safety profiles when added to R-CHOP. In a phase IB study
of ibrutinib added to R-CHOP in DLBCL, FL, and MCL, no unexpected toxicities were
observed and a maximally tolerated dose was not reached.65 An international
randomized phase III study comparing R-CHOP with R-CHOP plus ibrutinib in DLBCL
is currently accruing patients and will determine if the addition of ibrutinib improves
outcomes.
Similarly, lenalidomide has been safely added to R-CHOP (R2CHOP) therapy in
two phase II studies without an apparent increase in toxicity.66,67 Two phase II studies
have been completed, one in patients over the age of 60, and one in patients of all ages
that demonstrate feasibility of this combination. A randomized phase II study and
randomized phase III study comparing R2CHOP with R-CHOP are ongoing.
D. Initial treatment of localized aggressive NHL
The contemporary treatment options for patients with early-stage (stage I or II) DLBCL
usually employ R-CHOP therapy but utilize fewer cycles. It is not clear that
consolidation with radiation therapy adds much in the rituximab era, but this approach
is commonly utilized. Combined modality therapy with short-duration chemotherapy
followed by radiation became the standard approach on the basis of a Southwest
Oncology Group trial in the late 1990s that demonstrated an OS benefit to this
approach, but recent modern studies failed to show a benefit after the use of R-CHOP.
Preliminary results have recently been presented of a phase III study with 313 patients
with nonbulky limited-stage disease who were treated with RCHOP14 for four to six
cycles ± radiation.68 The complete remission, OS, and relapse rates were similar
between the two groups suggesting that there is little benefit to radiation in nonbulky
limited-stage disease and long-term toxicities are likely. The standard therapy for
patients with bulky disease (>10 cm), however, still remains consolidative radiation
therapy despite the lack of randomized studies that clearly demonstrate it is required.
E. Primary mediastinal B-cell lymphoma
As previously mentioned, PMBL has been identified on the basis of DNA microarray
profiles to have a unique molecular profile that carries a relatively good prognosis with
current treatment strategies.69 Clinically, it has some unique features, including the fact
that it commonly affects persons of young age (classically women) and at the time of
initial presentation usually stays within the mediastinum. Bone marrow involvement and
 nodal chains below the diaphragm are very uncommon, making the Ann Arbor staging
system nondiscriminating in this disease. Thus, all patients with PMBL are treated with
advanced-stage disease principles. There are no randomized studies to guide therapy.
Retrospective studies have been done using R-CHOP, but this requires the use of
consolidative radiation, as chemotherapy alone will not cure these patients. Dose
intensity is important for the treatment of this disease. In a published prospective phase
II study of 51 patients treated with DA-EPOCH-R, the 5-year EFS was 93% and OS
97%.70 Radiation was needed in only two of the patients demonstrating that radiation
can safely be omitted in those who are PET negative at the end of chemotherapy. This
study was the first prospective study of a regimen exclusively in PMBL and has
established DA-EPOCH-R as the standard of care in most institutions for PMBL.
F. Peripheral T-cell lymphomas (PTCLs)
PTCLs are a heterogeneous group of diseases with differences in pathologic and
clinical appearances. The combination of clinical, histologic, and immunophenotype is
used to determine diagnosis. The categories can be separated into cutaneous and
systemic involvement with CTCL being more indolent and PTCL being more
aggressive. The most common nodal types of PTCL include peripheral T-cell
lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell
lymphoma, and anaplastic large-cell lymphoma (ALCL). In general, PTCL are CD20
negative and CD3 positive. CD30 and EBV are other clinically relevant associations
with PTCL.
PTCLs have a worse prognosis than that of their B-cell intermediate-grade
lymphoma counterparts, and, as a result, have a relatively poor prognosis except for the
ALK+ ALCLs. PTCLs are a heterogeneous group of lymphomas that constitute only 5%
to 7% of adult NHLs diagnosed in the United States.19 The International T-cell/NK
Lymphoma Project demonstrated that the use of an anthracycline in PTCLs does not
correlate to improved outcomes compared with non–anthracycline-based therapies,
bringing into question the conventional approach of using CHOP as initial therapy in
most cases of PTCL. Unfortunately, with the exception of CHOP for ALK+ ALCL, an
optimal therapy for PTCLs has not yet been defined, and practice patterns vary
markedly between institutions.
In younger patients eligible for ASCT, CHOP is only effective in about 25% to 30%
of cases and alternative chemotherapy regimens that include etoposide (CHOEP) has
demonstrated an improvement in PFS particularly in patients under the age of 60
years.71 Drugs with some activity as single agents in the relapsed setting are being
added to CHOP in randomized phase III studies in an attempt to improve upfront
therapy. These agents include brentuximab, romidepsin, and alemtuzumab. Results of
these studies have yet to be reported and it will be important to consider the toxicity in
relation to the efficacy. Despite the lack of randomized clinical data demonstrating clear
survival benefit, many patients with PTCL are offered an ASCT as consolidation while
in first remission (Table 23.19).
 G. Relapsed PTCL
Patients with PTCL should be encouraged to participate in well-designed clinical trials
whenever possible in order to help determine optimal first-line treatment algorithms. In
fit patients, allogeneic transplant should be discussed as a potential option. In the last 6
years, the FDA has approved four new drugs with promising activity for the treatment of
relapsed/refractory PTCL.74 Pralatrexate is a novel antifolate drug studied in patients
refractory to many previous therapeutic regimens with an ORR of 29% with a median
DOR of 10.1 months. The histone deacetylase inhibitors, romidepsin and belinostat, are
potent inducers of histone acetylation and leads to cell-cycle arrest and apoptosis. ORR
was 25% and 26% with responses being 17 and 8.3 months, respectively. Response
rates are approximately 25% to 30% universally with varied DOR, and although easily
accessible, these treatments are not curative and new therapies are still needed to
improve the mediocre outcomes. Brentuximab, an anti-CD30 monoclonal antibody, has
shown impressive results in relapsed ALCL with an ORR 86% and responses lasting
greater than 12 months. In PTCL, responses are not as significant but the results
acknowledge the potential of future therapies.

TABLE
CODOX-M/IVAC for Burkitt Lymphoma
23.19
■ Cycles 1 and 3
■ Cyclophosphamide 800 mg/m2 IV on day 1
■ Vincristine 1.5 mg/m2 (maximum 2 mg) IV on days 1 and 8
■ Doxorubicin 40 mg/m2 IV on day 1
■ Cytarabine 70 mg intrathecal on days 1 and 3
■ Cyclophosphamide 200 mg/m2 IV on days 2, 3, 4, and 5
■ Methotrexate 1,200 mg/m2 IV over 1 hour starting on day 10, followed immediately by 240 mg/m2 hourly for 23 hours
■ Leucovorin 192 mg/m2 IV at hour 36 of methotrexate therapy
■ Leucovorin 12 mg/m2 IV every 6 hours until methotrexate level is <5 × 10−8 M
■ G-CSF 5 mg/kg SC daily starting day 13
■ Methotrexate 12 mg intrathecal on day 15
■ Leucovorin 15 mg PO 24 hours after intrathecal methotrexate
■ Cycles 2 and 4
■ Etoposide 60 mg/m2 IV over 1 hour daily on days 1–5
■ Ifosfamide 1,500 mg/m2 IV over 1 hour daily on days 1–5
■ Mesna 360 mg/m2 IV with ifosfamide, then every 3 hours for seven additional doses every 24 hours
■ Cytarabine 2 g/m2 IV over 3 hours every 12 hours for four total doses on days 1 and 2
■ Methotrexate 12 mg intrathecal on day 5
■ Leucovorin 15 mg PO 24 hours after methotrexate
■ G-CSF 5 mcg/kg SC daily starting day 7

G-CSF, granulocyte colony-stimulating factor; IV, intravenously; SC, subcutaneously; PO, by mouth.

H. Rare, extranodal T-cell lymphomas

HSTCL, subcutaneous panniculitis-like T-cell lymphoma, and EATCL are rare subtypes
of PTCLs that often present with primarily extranodal disease. Despite the fact that
these tumors have distinct clinical and pathologic features, they are often diagnosed
 after significant delay. Also, the use of anthracycline-based combination chemotherapy
that is highly effective in B-cell counterparts is not effective in these disorders. The
combination of delay in diagnosis, aggressive natural history of these tumors, and
ineffective therapies has resulted in a poor prognosis in most cases. In patients who do
achieve remissions with initial therapy, consideration should be given to consolidation
with allogeneic stem-cell transplantation given the dismal prognosis, especially for
HSTCL, cutaneous γδ T-cell lymphoma, and the anaplastic variant of EATCL.

VIII. MANAGEMENT OF HIGHLY AGGRESSIVE NHL

A. Burkitt lymphoma
BL is composed of post–germinal center mature B-cells with a highly aggressive
presentation and natural history. Morphologically, Burkitt tumor cells are small
noncleaved cells arranged in a monotonous pattern and may have a “starry sky”
appearance. It is often subdivided into cases that are endemic, sporadic, and associated
with underlying HIV. All cases of BL are associated with an MYC translocation and
most commonly arise from the reciprocal t(8;14) translocation although variant
translocations of t(2;8) and t(8;22) exist.75
In the United States, BL tends to occur in younger patients and is associated with a
higher incidence of gastrointestinal disease. R-CHOP is substandard therapy for BL,
and high-intensity brief-duration regimens such as the R-Hyper-CVAD regimen
(rituximab plus hyper-cyclophosphamide, vincristine, doxorubicin, and
dexamethasone), or the cyclophosphamide, vincristine, doxorubicin, high-dose
methotrexate/ifosfamide, etoposide, high-dose cytarabine (known as CODOX-M/IVAC)
regimen (Table 23.20) have been associated with long-term DFS in almost 50% of
patients. Low-intensity therapy with DA-EPOCH-R may also be used and spares the
myelotoxicity of older Burkitt regimens.76 This regimen should be considered in
patients who are older or with a poor performance status. Patients with disease
involving the CNS or bone marrow have a worse prognosis than those patients with
limited-stage disease. The role of stem-cell transplantation as routine consolidation
following initial high-dose therapy or in relapsed disease has not been established by
clinical trials.
 TABLE
Salvage Chemotherapy Regimens in Aggressive NHL
23.20
Regimen Treatment Description
DHAP Cisplatin 100 mg/m2 by continuous IV infusion for 24 hours on day 1
Cytarabine 2,000 mg/m2 per dose IV over 3 hours every 12 hours for 2 doses on day 2
Dexamethasone 40 mg/day PO or IV for 4 days on days 1–4
Treatment is repeated every 21 days
ESHAP Etoposide 40 mg/m2/day over 1 hour IV for 4 days, days 1–4
Methylprednisolone 250–500 mg/day IV on days 1–5
Cytarabine 2,000 mg/m2 IV over 2 hours on day 5
Cisplatin 25 mg/m2/day by continuous IV infusion on days 1–4
Treatment is repeated every 21 days
ICE Ifosfamide 5,000 mg/m2 over 24 hours by continuous IV infusion starting on day 2, mixed with equal amounts of mesna
Etoposide 100 mg/m2 IV twice a day on days 1–3
Carboplatin AUC = 5 (maximum dose of 800 mg) IV on day 2
G-CSF administered at 5 μg/kg SC on days 7–14
Treatment is repeated every 14 days but if ANC <1,000 or platelets <50,000, then administer at 21-day intervals
GDP Gemcitabine 1,000 mg/m2 IV on days 1 and 8
Dexamethasone 40 mg PO on days 1–4
Cisplatin 75 mg/m2 IV on day 1
Treatment is repeated every 21 days
RGemOx Rituximab 375 mg/m2 IV on day 1
Gemcitabine 1,000 mg/m2 IV on day 2
Oxaliplatin 100 mg/m2 IV on day 2
Treatment is repeated every 15 days

ANC, absolute neutrophil count; AUC, area under the curve; IV, intravenously; NHL, non-Hodgkin lymphoma; PO, by mouth;
SC, subcutaneously.

B. Prophylaxis
1. CNS prophylaxis
Involvement of the CNS at the time of diagnosis of DLBCL is uncommon with
incidence rates of only 5%, but at the time of relapse, uncontrolled disease in the
CNS is a very poor prognostic sign.77 Thus, efforts to predict who is at risk to
develop CNS disease have focused on patients with an extranodal disease
presentation and/or an elevated LDH at diagnosis. By convention, patients with at
least two sites of extranodal involvement (including bone marrow) and an elevated
LDH as well as those with “sanctuary sites” involved at presentation (testis,
nasopharynx, orbit) are offered CNS prophylaxis with intrathecal therapy: usually
methotrexate with or without cytarabine. The addition of rituximab to chemotherapy
 has improved outcomes for patients and there may be a protective effect against
CNS relapse. More recent data suggest that patients can be stratified into groups on
the basis of risk. In addition to the above risk factors, certain extranodal sites
(kidney, breast), having an MYC rearrangement or double hit rearrangement, place
patients into a high-risk group and CNS prophylaxis should be considered. The
administration of CNS prophylaxis, however, is very much understudied and no
consensus exists. Therefore, significant variation exists in the patients selected as
well as the number and total doses of prophylaxis given.
2. Tumor lysis prophylaxis
Highly aggressive lymphomas have rapidly proliferative tumor cells with the
potential to cause spontaneous lysis of tumor cells even before the administration of
combination chemotherapy.78 When tumor cells lyse, they release intracellular
cations such as potassium, uric acid, and phosphorus, which can be toxic to renal
tubules. This potentially fatal clinical scenario is termed the tumor lysis syndrome
and is becoming increasingly common as regimens become more effective.
C. Therapy of relapsed NHL
1. Salvage chemotherapy
Up to 40% of patients with DLBCL will ultimately relapse or be refractory after
initial chemoimmunotherapy; the number is higher with MCL and PTCL, meaning
that large numbers of patients will ultimately need second-line or “salvage”
chemotherapy. Aggressive NHLs such as DLBCL that have relapsed after response
to initial chemotherapy are often treated with curative intent in younger patients. One
of the most important prognostic markers of relapsed NHL is whether it remains
chemosensitive or has become resistant to chemotherapy. Tumors that have become
chemoresistant or are primarily refractory to initial chemotherapy (defined as never
achieving CR or a DOR <6 months) have a much worse prognosis than cases that are
not chemoresistant.79
Despite the importance of salvage chemotherapy, the optimal regimen remains
a research question as comparative data is lacking. Typically, a platinum-based
regimen (Table 23.20) is administered for two to three cycles (usually with
rituximab) and patients are then offered ASCT if they demonstrate chemosensitivity.
The standard practice of taking patients to ASCT in first relapse is rooted from a
study published in the pre-rituximab era known as the PARMA study.80 In the
PARMA study, patients with aggressive lymphomas who had achieved an initial
complete response and then still achieved a response to salvage chemotherapy were
randomly assigned to receive chemotherapy with radiation or autologous transplant.
A survival advantage was demonstrated with ASCT in that group of patients.
However, it is unclear if the PARMA results are applicable to the current era
in which all patients are treated with rituximab in their initial regimen. A modern
randomized study known as the CORAL study demonstrated that patients treated with
rituximab-containing regimens had much less of a benefit to ASCT. Thus, there is
 great interest in developing novel therapies for patients with relapsed aggressive
lymphomas as most of them will not be cured with ASCT alone. Another emerging
concept is better definition of response to therapy. Some data suggest that patients
with residual 18FDG-PET positivity prior to transplant may not benefit from high-
dose therapy and should not be offered this approach.
2. Immunotherapy for relapsed NHL
Allogeneic transplantation has traditionally been reserved as a final option for select
patients with both relapsed indolent and relapsed aggressive NHLs that have failed
all other therapies.81 Even though the graft-versus-leukemia effect can be very potent
in NHL, the morbidity and mortality of the procedure have been a significant barrier
to widespread use. Nevertheless, it appears that allogeneic transplantation is a
potentially curative approach in carefully selected patients with relapsed NHL; with
the use of reduced-intensity preparative regimens, more patients are becoming
eligible for this high-risk/high-reward therapy.
The source of donors for allogeneic transplant may come from a sibling
(matched related donor or MUD) or an unrelated person (matched unrelated donor
or MUD). In cases where a matched sibling is not available, the sibling or parent
may be a haploidentical transplant. There are different risks and benefits to each
type of transplant and these must be extensively discussed; however, the intricacies
of allogeneic transplant are outside the scope of this chapter.
A novel approach to treatment of relapsed NHL includes engineering patients’
immune system to attack the tumor cells. Most of these approaches have focused on
genetically modifying a patient’s T-cells toward an antigen that is present on the
malignant lymphoma. In one example, T-cells can be modified to express a chimeric
antigen receptor against CD19 leading to activity against malignant CD19-positive
B-cells.82 Since tumor response is often cytokine driven, the most significant
toxicities observed affect the neurological system ranging from confusion to
obtundation. However, in a small study with 15 heavily pretreated DLBCL patients,
8 achieved a complete remission with durations lasting between 9 and 22 months.
These results have led to an expansion of trials investigating this approach against a
number of different target antigens.
3. Targeted agents
Numerous agents with novel mechanisms are being tested in relapsed/refractory
NHLs in an effort to address this unmet clinical need. Many of these agents are
considered “targeted” agents that attempt to selectively inhibit tumor cells in a more
selective manner than conventional DNA-damaging agents. Molecular biology has
uncovered many pathways important for proliferation and impaired apoptosis, which
are the targets of many of these agents. In addition, some novel agents are thought to
work by affecting the tumor cell’s interactions with the local microenvironment,
which may be providing protection from the effects of chemotherapy (Table 23.21).
4. Radiation therapy in NHL
 NHL is very sensitive to the tumoricidal effects of radiation therapy, and it remains
an essential treatment modality to improve local control in the management of
patients with NHL. Enthusiasm for widespread use of radiation therapy has been
somewhat tempered, however, by concerns about its inherent risks of localized
tissue destruction; premature risks of coronary artery and valvular heart disease;
secondary malignancies such as carcinomas of the breast, lung, and thyroid; and
sarcomas that frequently present 15 to 25 years after patients are cured of their NHL.
Additionally, as chemotherapeutic strategies improve and functional imaging
modalities such as PET/CT can better define tumor responses in residual nodal
masses, questions arise regarding the need for consolidative radiation.
Current indications for radiation therapy include a potential curative approach
in limited-stage indolent NHL such as FL and consolidative therapy to sites of tumor
bulk in patients with mediastinal lymphomas and primary CNS lymphoma (PCNSL).

TABLE
Targeted Agents
23.21

D. Subgroups and special considerations in NHL

1. AIDS-related lymphomas
Among patients with HIV infection, 3% to 6% will develop NHL, and this is
considered an AIDS-defining illness. The lymphoid neoplasms that are associated
with HIV include DLBCL, PCNSL, primary effusion lymphoma, plasmablastic
lymphoma of the oral cavity, and BL, and concomitant infection with HHV-8 and
EBV also appears to play a role in pathogenesis. NHL is typically a late
 manifestation of HIV, with most cases occurring when the CD4 cell count is less than
200 mm3 except for BL that can occur with any CD4 count (see Chapter 25 for
further discussion of the HIV- and AIDS-related lymphomas).
2. Posttransplant lymphoproliferative disorders (PTLDs)
Abnormal expansions of lymphoid cells (either B-cell or T-cell) in patients who
have undergone either solid organ or hematopoietic stem-cell transplantation are
defined as PTLDs. Given the broad definition, PTLDs are a clinically heterogeneous
group of disorders with marked variation in clinical behavior ranging from benign
expansions to aggressive and fatal NHL.83

TABLE
Risk Factors for PTLDs
23.22
■ Seronegative for EBV pretransplantation (HSCT recipients)
■ Age >50 years at time of transplantation
■ Use of a second transplantation
■ Less than 1 year since transplantation
■ ATG or OKT3 (anti-CD3 monoclonal antibody) as prophylaxis
■ Unrelated or mismatched HLA grafts
■ Use of a T-cell-depleted graft
■ Acute or chronic GVHD
■ Cardiac transplant > renal transplant

ATG, antithymocyte globulin; EBV, Epstein-Barr virus; GVHD, graft-verus-host disease; HLA, human leukocyte antigen;
HSCT, hematopoietic stem-cell transplantation; PTLD, posttransplant lymphoproliferative disorder.
Source: Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative
disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99:346–352.

Risk factors for the development of PTLD are listed in Table 23.22. EBV plays
a pivotal role in the development of the majority of PTLDs. In fact, many transplant
centers now routinely monitor periodic PCR for EBV and will preemptively treat
cases of a rapidly rising viral load of EBV with rituximab.
If the PTLD is limited in extent, one can employ therapy designed at increasing
the host response to EBV, such as withdrawing or decreasing immunosuppression,
administering interferon, or giving lymphocytes from individuals who have had EBV
infection. Such therapy is most effective in limited disease and in patients in whom
the lymphocytes are polyclonal.
Radiotherapy or surgery can be effective in localized and accessible disease,
but for more advanced disease and for disease in which the lymphocytes are
monoclonal, combination chemotherapy with or without rituximab or donor
lymphocyte infusions for stem-cell transplant patients is often necessary.
Unfortunately, response rates are lower for transplant-associated lymphomas than
for de novo lymphomas, and long-term survival has been disappointing.
3. Primary central nervous system lymphoma
 PCNSL is defined as a lymphoma that is confined to the CNS and rarely has systemic
involvement. PCNSL has risen more rapidly than other extranodal sites in part due to
the association with HIV, but it has risen in immunocompetent hosts as well. It is a
type of DLBCL, most commonly of the ABC subtype.84 For reasons that are not
entirely clear, it very infrequently metastasizes outside of the CNS even though very
sensitive techniques such as PCR can detect tumor cells in the peripheral blood of a
significant minority of patients with PCNSL. The diagnosis can be made with direct
tissue biopsy or demonstration of lymphoma cells on examination of the
cerebrospinal fluid (CSF). If PCNSL is considered in the differential diagnosis of
patients who present with isolated brain lesions, it is important to attempt diagnostic
studies prior to the administration of steroids as tumor cells are very sensitive to
steroids and the opportunity to accurately characterize the lymphoma may be lost.
Treatment with radiation therapy alone is generally associated with poor OS,
and radiotherapy alone is no longer recommended for patients with PCNSL who are
able to undergo more intensive therapies.85 The current standard is a multimodality
approach that utilizes chemotherapy with agents that cross the blood–brain barrier
such as high-dose methotrexate and cytarabine (with the addition of rituximab of B-
cell lineage) followed by consolidative whole-brain radiotherapy (WBRT). Such
approaches can achieve overall response rates greater than 90%, but 2-year PFS
rates are approximately 50% to 55% and relapse is a common clinical problem.
Because of concerns of both acute and long-term toxicities on both central and
peripheral neurologic function associated with WBRT, some regimens use high-dose
methotrexate-based chemotherapy, but response rates tend to be lower.
4. Testicular lymphomas
Testicular lymphomas represent the most common testicular tumor seen in men over
the age of 60 years, with DLBCL being the most common histologic type. Primary
testicular lymphoma (PTL) is a rare entity with a distinct natural history compared
with nodal DLBCL that frequently affects the contralateral testis, lung pleura, and
soft tissues.86 Recent reports suggest that the majority of these tumors are of the ABC
subtype of DLBCL with marked proliferative activity. Therapy consists of a
multimodality approach of surgical removal of the primary tumor, systemic
chemoimmunotherapy, and radiation of the contralateral testis. Additionally, as PTL
originates in an immunoprivileged site, prophylactic treatment of the CNS is
uniformly administered. Despite this approach, PTL has an inferior outcome
compared with nodal DLBCL and can be associated with late relapses.
5. Treatment of NHL in patients of advanced age
The treatment of NHL in patients of advanced age deserves special mention because
the median age at diagnosis of NHL is between 60 and 65 years, the US population
is aging, and age is consistently determined to be a prognostic marker in outcomes in
NHL despite no known biologic differences in the disease associated with age.87,88
Thus, a common clinical problem involves the selection of appropriate therapy for a
 patient with an aggressive lymphoma over the age of 70 years with significant
comorbid disease. Concerns about the potential toxicities for these patients
frequently lead to empiric dose reductions or dose delays that likely compromise the
potential for cure. Available data, however, suggest that when CHOP is used in
lower doses, remission rates decline and survival is shortened.89 In the Group
d’Etude des Lymphome d’Adulte LN 98-5 trial, 399 patients with DLBCL aged 60 to
80 years were treated with R-CHOP versus CHOP. The addition of rituximab was
associated with a 15% improvement in response rate with associated improvements
in DFS and OS. In this trial, the most common ≥G3 toxicity was infection, cardiac
toxicities ≥G3 were seen in only 8% of patients, and other toxicities were consistent
with those expected with the use of CHOP in younger populations. It is likely that,
with the use of supportive medications such as granulocyte colony-stimulating factor,
most patients over the age of 60 years can be offered standard treatments at standard
doses and experience similar toxicities as younger patients with NHL, but
identifying patients over the age of 60 years (and especially 80 years) who are at
risk for excessive toxicities remains a significant clinical challenge.

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I. INTRODUCTION
A. Types of plasma cell dyscrasias
Plasma cell dyscrasias represent a heterogeneous group of conditions characterized by
an increased number of plasma cells or by the production of a monoclonal protein.1 To
efficiently utilize the newly introduced therapeutic classes and new refined compounds
in the current classes, it is crucial to understand the diseases’ pathophysiology and their
interaction with the microenvironment. The later term is a complex cellular, humoral,
and supportive cell environment. The potency of the new compounds has resulted in
many patients achieving deep responses; unfortunately, there is a group of patients that
continue to succumb to their disease within the first 2 years of diagnosis. The term
“minimal residual disease” (MRD) has been suggested as a measure of outcome to
different regimens especially in the newly diagnosed setting where high response rates
are the norm. Minimal residual disease continues to be vaguely defined and in reality
describes the outcome of one component of the disease—a single clone. Perhaps a
better term at this stage is “minimal residual clone”—MRC. The pathophysiology of
plasma cell dyscrasia, clonal diversity, evolution, and mutation, as well as how all
these complex yet integrated components interact with the microenvironment, is beyond
the scope of this chapter but is critical in the understanding of the evolving therapeutic
field.
The following plasma cell dyscrasias will be discussed in this chapter: monoclonal
gammopathy of undetermined significance (MGUS), multiple myeloma (MM),
Waldenström macroglobulinemia (WM), amyloidosis, and solitary plasmacytomas.
Light chain deposition disease, heavy chain diseases, immunoglobulin D MM,
nonsecretory MM, osteosclerotic myeloma or POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, and primary
plasma cell leukemia are beyond the scope of this text.
B. Monoclonal protein
A monoclonal protein (M-protein) is detected in the serum, urine, or both of most
patients with plasma cell dyscrasias. The so-called M-protein is thought to be a
measure of plasma cell burden, although a correlation is not always evident. A notable
discordance between the M-protein and disease burden could be noted in heavily
pretreated patients, where the malignant cells might have dedifferentiated and have
 become less secretory or nonsecretory. This is often accompanied by an increase in the
serum lactate dehydrogenase. Exceptions aside, most plasma cell dyscrasias are best
followed by serial measurements of the M-protein and parameters of end organ
dysfunction. Current standard criteria rely on changes in the M-protein for determining
response and progression after treatment. The basic immunoglobulin (Ig) unit comprises
two identical heavy chains (G, A, M, D or E) and two identical light chains (kappa or
lambda). The serum protein electrophoresis is used to quantify the monoclonal
component of the globulin; it fails to do so, however, when the concentration of the
latter is low because of lack of secretion or when the M-protein is excreted in the urine.
If there is a high clinical suspicion for the presence of an M-protein despite a negative
serum protein electrophoresis, an immunoelectrophoresis should be performed on both
the serum and the urine, as up to 15% of patients may have a negative serum
immunofixation with positive urine immunofixation. The urinary light chain excretion
(expressed in grams per 24 hours) is used to follow the urinary M-protein. This is
calculated from the 24-hour urine protein and the percent contribution of light chain to
proteinuria on the urine protein electrophoresis. It is critical to assess the percent
contribution of the light chain to the proteinuria, especially in patients with other
comorbidities such as hypertension and diabetes mellitus, where the patient could
present with an M-protein with the proteinuria consisting mainly of albumin secondary
to the other medical processes. Newer assays for serum free light chain are becoming
increasingly used, and often result in the detection of increased free light chains in the
serum of many patients with nonsecretory MM (negative immune fixation of the serum
and urine) and amyloid light chain (AL) amyloidosis. The latter assay does not
demonstrate monoclonality of the light chain, but relies on the ratio of kappa-to-lambda
light chain or a measured excess of one of the light chains. Although some investigators
have correlated changes in the free light chain induced by therapy with outcomes and
the use of the serum free light chain test has been incorporated in the International
Myeloma Working Group (IMWG) response criteria, the precise role of these markers
beyond their contribution to the diagnosis has not been thoroughly validated. Infections,
autoimmune disorders, and poor renal function make interpretation of the free light
chain assay difficult.

II. MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE

Monoclonal gammopathy of uncertain significance (MGUS) is usually characterized by a
low M-protein (less than 3 g/dL), the absence of bone lesions, less than 10% plasma cells
on the bone marrow biopsy, and the absence of attributable end organ damage such as
anemia, hypercalcemia, and renal dysfunction. The prevalence of MGUS increases with
age and has been described in as many as 3% of all individuals over 70 years of age. The
rate of progression from MGUS to MM or other lymphoproliferative disorders depends on
several factors, the most notable of which is the level of the serum M-protein. A high serum
M-protein (≥1.5 g/dL), a higher bone marrow plasma cell burden, and possibly an
 abnormal kappa-to-lambda ratio on free light chain testing puts select patients at higher risk
of progression to MM. While patients with a lower risk of MGUS may be followed up on a
yearly or biannual basis, patients with a higher risk of progression probably benefit from
closer follow-up and may be eligible for enrollment in prevention clinical trials. In a small
number of patients, MGUS may be associated with peripheral neuropathy. The majority of
patients with MGUS and peripheral neuropathy in association with an Ig M-protein have
anti-myelin-associated glycoprotein antibodies. This group of patients responds favorably
to therapy with single-agent rituximab.

III. MULTIPLE MYELOMA

A. General considerations and aims of therapy2
1. Diagnosis
Multiple myeloma (MM) is a clonal B-cell tumor of slowly proliferating plasma
cells within the bone marrow. Table 24.1 illustrates diagnostic criteria required for
a diagnosis of MM. The Durie and Salmon staging system was initially used for the
staging of patients with MM (Table 24.2). Its use has fallen out of favor owing to
difficulties inherent to its use. A more practical staging system is the International
Staging System, which is illustrated in Table 24.3. It relies on the serum β2-
microglobulin and on serum albumin. It was found to accurately prognosticate
patient outcomes.
With the increased awareness, an increasing number of patients are being
diagnosed with monoclonal gammopathy incidentally, and the decision to monitor or
actively treat has become difficult with the old nomenclature.
a. End organ damage. The IMWG has presented the concept of MM with active or
inactive disease based on the presence or absence of end organ damage,
respectively.
b. Criteria defining end organ damage. The conventional criteria defining organ
damage are anemia, renal failure, hypercalcemia, or lytic bony disease. More
recently, the IMWG suggested that patients with 60% or greater bone marrow
plasmacytosis, a free light chain ratio of 100 or greater, and positron emission
tomography (PET) or magnetic resonance imaging (MRI)-defined lesions may
also warrant initiation of systemic therapy given the high likelihood of
progression to symptomatic myeloma, although the benefits of early treatment
initiation have not been demonstrated in this subgroup.
 TABLE
Diagnostic Criteria of MGUS and MM
24.1
MGUS Asymptomatic MM Symptomatic MM
M-protein in the serum or urine and
Serum M-protein <3 g/dL and clonal bone Serum M-protein ≥3 g/dL or clonal bone marrow
clonal bone marrow plasmacytosis or
marrow plasmacytosis <10% plasmacytosis ≥10%
plasmacytoma
No other B-cell lymphoproliferative disorder No related organ and tissue impairment Related organ and tissue impairment*
No related organ and tissue impairment

M-protein, monoclonal protein; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma.
*Related organ tissue impairment includes the following:

• Hypercalcemia
• Renal dysfunction
• Anemia: Hemoglobin 2 g/dL below the lower limit of normal
• Lytic bone lesions (solitary plasmacytoma requires >30% plasma cells)
• 60% or greater bone marrow plasmacytosis
• Serum free light chain ratio of 100 or greater
• PET- or MRI-defined lesions greater than 1 cm

TABLE
Durie-Salmon Staging System
24.2
Stage* Criteria
All of the following:
1. Hemoglobin >10 g/dL
2. Serum calcium value normal (≤12 mg/dL)
3. On radiograph, normal bone structure or solitary bone plasmacytoma only
I ■ Low M-component production rates
■ IgG value <5 g/dL
■ IgA value <3 g/dL
Urine light-chain M component on electrophoresis <4 g/24 hours
II Fitting neither stage I nor stage III
One or more of the following:
1. Hemoglobin <8.5 g/dL
2. Serum calcium value >12 mg/dL
3. Advanced lytic bone lesions
III
4. High monoclonal component production rates
■ IgG value >7 g/dL
■ IgA value >5 g/dL
■ Urine light chain M component on electrophoresis >12 g/24 hours

*Stages I, II, and III are further designated A for serum creatinine <2 and B for serum creatinine ≥2.
Source: Durie BG, Salmon SE. A clinical staging system for multiple myeloma: correlation of measured myeloma cell mass with
presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842–854.
 TABLE
ISS System for Multiple Myeloma
24.3

c. Patients without end organ damage. (MGUS or inactive myeloma) should be

monitored carefully as early intervention does not affect the outcome of the
disease. Patients with inactive MM should be considered for enrollment in
clinical trials aimed at preventing or retarding the progression to active disease.
2. Epidemiology
The annual incidence of MM is 4 per 100,000 population, with a peak incidence
between the sixth and seventh decades of life. Patients of African American descent
have an incidence of MGUS and MM approaching twice the incidence for
Caucasians in the United States. Several agents have been strongly associated with
the development of MM, ionizing radiation being the most commonly described risk
factor. Nickel, agricultural chemicals, petroleum products, and other aromatic
hydrocarbons, benzene, and silicon have been considered potential risk factors as
well. One particular note is made for Agent Orange exposure by Vietnam veterans,
which imparts an increased incidence of MM.
3. Goals of therapy3,4
Despite recent advances in the treatment of MM, the disease remains incurable.
Accordingly, therapy is aimed at improving symptoms and preventing complications
of the disease, thus improving quality of life and survival. These goals could be
achieved with different approaches: one approach is to transform the disease into a
chronic process by using frequent sequential low-morbidity therapies, while the
other approach attempts to eradicate the disease with intensive therapy. The cure-
versus-control paradigm remains a subject of considerable debate, and it remains
unclear which treatment methodology is superior. However, there is evidence that
certain subgroups of patients might benefit from either approach, and therapy aimed
at control of the myeloma may be inappropriate for patients with more aggressive
risk features. Because of these uncertainties and because standard first-line therapy
is not well defined, patients with MM, regardless of age, stage of disease, or number
of previous therapies, must be considered for enrollment in clinical trials and
 referral to a tertiary care center.
In addition to the management of the malignant plasma cell clone, particular
attention must be paid to end organ dysfunction including skeletal health, prevention
of infections, and thrombotic, neuronal, and renal complications. Accordingly,
response to therapy is based on changes to the M-protein concentration, the
percentage of plasma cells in the bone marrow, as well as monitoring end organs for
improvement in function. The cooperative oncology groups in the United States and
Europe have adopted different cutoffs to define response. Table 24.4 illustrates the
uniform response criteria as defined by the IMWG.
4. Prognostic factors5–7
Severe anemia, hypercalcemia, advanced lytic lesions, and very high M-protein are
all associated with a high tumor burden and a poor survival, and are the basis of the
Durie and Salmon staging system. Renal failure, although not clearly correlated with
disease burden, is associated with worse outcomes. Other established clinical poor
prognostic factors include the following: advanced age, poor performance status at
presentation, high serum lactate dehydrogenase level, lower platelet counts, bone
marrow with greater than 50% plasma cells, greater than 2% bone marrow
plasmablasts, high plasma cell labeling index, elevated serum β2-microglobulin, and
low serum albumin. The latter two are the basis for the Southwest Oncology Group
(SWOG) and the IMWG staging systems. The identification of cytogenetic
prognostic factors using metaphase karyotyping relies on cellular growth, which is
difficult as the MM plasma cells have a low in vitro proliferative rate, and thus,
such information is available only in 20% to 40% of the patients. The presence of
abnormalities with this method, however, is meaningful. Genomic prognostic factors
include the deletion of chromosome 13, translocation of the immunoglobulin heavy
chain [t(4;14), t(14;16)], and loss of 17p13. The t(11;14), on the other hand, is not
thought to portend a worse outcome. Recently, interphase fluorescence in situ
hybridization (FISH) has been used to detect specific cytogenetic abnormalities.
Even though FISH analysis is more sensitive at detecting certain abnormalities such
as chromosome 13, this might not be clinically meaningful without other additional
poor prognosticators. Nonhyperdiploid karyotypes are frequently associated with
immunoglobulin heavy chain rearrangements and worse clinical outcomes. More
recently, several gene expression profiling (GEP) signatures have been introduced
into the clinical arena. For instance, a commercial 70 gene GEP, MyPRS (Myeloma
Prognostic Risk Signature),8 is available in the United States and provides
information regarding the molecular subtype of myeloma as well as a prognostic
score that identifies a subset of patients with high-risk disease. Although the
prognostic utility of this test has been validated in multiple data sets, it remains
unclear whether it has predictive value and impacts treatment decisions. Patients
with high-risk disease continue to experience poor outcomes and should be
considered for clinical trials, if possible.
 TABLE
Uniform Response Criteria as Defined by the IMWG
24.4
■ Negative immunofixation on the serum and urine, and
CR ■ Disappearance of any soft tissue plasmacytomas, and
■ No more than 5% plasma cells in the bone marrow (confirmation with repeat bone marrow is not needed)
■ CR as defined above, and
■ Normal serum FLC ratio, and
Stringent CR ■ Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence, based on
a κ/λ ratio of >4:1 or <1:2, performed on a minimum of 100 plasma cells (confirmation with repeat bone
marrow is not needed)
■ Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or
Very good partial remission ■ At least 90% reduction in serum M-protein plus urine M-protein level of <100 mg/24 hours
■ At least 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%, or to
<200 mg/24 hours
■ If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference between involved
Partial remission and uninvolved FLC levels is required in place of the M-protein criteria
■ In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue
plasmacytomas is also required
Stable disease ■ Not meeting criteria for CR, very good partial remission, partial remission, or progressive disease
■ Increase of ≥25% from baseline in serum monoclonal component, and the absolute increase must be ≥0.5
g/dL. If the starting monoclonal component is ≥5 g/dL, increases ≥1 g/dL are sufficient to define relapse.
■ Increase of ≥25% from baseline in urine monoclonal component, and the absolute increase must be ≥200
mg/24 hours
■ Only in patients without measurable serum and urine M-protein levels: increase of ≥25% from baseline in
the difference between involved and uninvolved FLC levels, and the absolute difference must be >10
Progressive disease mg/dL
■ Increase of ≥25% from baseline in bone marrow plasma cell percentage, and the absolute % must be
≥10% (relapse from CR has the 5% cutoff versus 10% for other categories of relapse)
■ Definite development of new bone lesions or soft tissue plasmacytomas, or definite increase in the size
of existing bone lesions or soft tissue plasmacytomas
■ Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or >2.65 mmol/L) that can be
attributed solely to the plasma cell proliferative disorder

CR, complete remission; FLC, free light chain; IMWG, International Myeloma Working Group; M-protein, monoclonal protein.
All relapse categories require two consecutive assessments made at any time before classification as relapse or disease
progression and/or the institution of any new therapy. Measurable disease is defined as:
• Serum M-protein ≥1 g/dL (≥10 g/L)
• Urine M-protein ≥200 mg/24 hours
• Serum FLC assay: involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal.

B. Treatment—standard regimens
1. General measures
Patients with a new diagnosis of MM occasionally have associated complications
that require immediate attention, such as hypercalcemia, renal failure, severe
cytopenias, and spinal cord compression. These complications should be promptly
identified and managed either simultaneously or before the start of therapy.
Alternatively, asymptomatic patients and those with smoldering MM may be
followed without specific therapy until clear evidence of progression. Ambulation
and hydration should be maintained throughout the initial therapy. Avoidance of
nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, and intravenous
contrast agents is important for renal health. If radiologic procedures involving the
use of intravenous contrast agents are to be considered, appropriate hydration and
 the use of N-acetyl-cysteine should be considered. The use of bisphosphonates
(either zoledronic acid or pamidronate) is recommended for nearly every patient
with symptomatic myeloma with adequate renal function, particularly in those with
bony disease (see Section III. F.1). The authors recommend holding the initiation of
the bisphosphonates in the first cycle of therapy to help decrease renal
complications from the use of these agents, especially in patients with high light
chain burden or borderline renal function. In addition, because of the increased
awareness of osteonecrosis of the jaw, a rare complication of bisphosphonate
therapy, a dental evaluation prior to starting therapy should be considered when
feasible.
2. Systemic therapy for the newly diagnosed patient—approach to therapy
Although a plethora of therapeutic options for the treatment of patients with newly
diagnosed MM are available, there is no standard first-line therapy. In this text, we
will define non–high-dose therapy as traditional therapy and high-dose therapy with
stem cell rescue as intensive therapy. As therapy for MM does not result in cures,
treatment recommendations are often individualized and based on a patient’s
comorbidities, performance status, and preference, as well as disease
characteristics. For example, if high-dose therapy is considered during the course of
therapy, avoidance of agents, such as melphalan and other alkylating agents, that
impair stem cell collection is important. In the patient with significant symptoms
from the disease, the choice of highly active first-line therapy that results in rapid
responses is reasonable. Similarly, in patients with renal dysfunction at presentation,
the choice of agents with a safe renal profile is recommended (e.g., bortezomib-
based therapy).
Patients with poor prognostic factors at presentation [chromosome 13 deletion
by metaphase cytogenetics or t(4;14), deletion 17p, high β2 microglobulin, or
increased plasma cell labeling index] fare poorly with all traditional therapies.
Accordingly, these patients are best managed by enrollment in clinical trials.
Alternatively, it is intuitive, though unproven, that intensive therapy (combination
novel agent induction therapy followed by consideration of high-dose therapy and
consolidation with novel agents as well as maintenance) would result in improved
outcomes. While some reports suggest that bortezomib-based therapy overcomes the
negative implications of high-risk disease, these observations are based on small
numbers and relatively short follow-up, and other investigations did not confirm
these findings.
For patients eligible for intensive therapy, the use of dexamethasone in
combination with an immunomodulator (lenalidomide) and a proteasome inhibitor
(bortezomib) is a reasonable consideration. Alternatively, bortezomib,
cyclophosphamide and dexamethasone can be considered, especially for patients
with renal insufficiency. The randomized phase II trial noted a similarly high
response rate with either regimen. Such induction therapy is usually continued for
 four to eight cycles until a plateau phase is reached, at which time, high-dose therapy
or maintenance therapy is initiated.
Although many patients over the age of 65 years remain excellent candidates
for intensive therapy, high-dose therapy may not be appropriate for some; therapy
with lenalidomide and low-dose dexamethasone, or bortezomib and low-dose
dexamethasone can be considered standard of care. Specifically, the FIRST trial9
has demonstrated the superiority of continued lenalidomide-dexamethasone over a
fixed duration of the same therapy (18 months) or a combination of melphalan,
prednisone and thalidomide. Furthermore, the addition of melphalan or
cyclophosphamide to the lenalidomide-dexamethasone backbone did not improve
outcomes in the elderly population. In addition, there are similar outcomes with
bortezomib-dexamethasone as compared with those with bortezomib-melphalan-
prednisone or bortezomib-thalidomide-dexamethasone in this patient population. In
some circumstances, it is reasonable to consider a more intensive combination
(bortezomib-dexamethasone with either lenalidomide or cyclophosphamide) in
elderly patients with higher tumor burden.
3. Traditional chemotherapy recommendations
While numerous additional chemotherapeutic regimens have been described, only
agents commonly used in the treatment of MM are reviewed below.
a. Dexamethasone 10 is considered the standard corticosteroid for many induction
regimens for MM. The Eastern Cooperative Oncology Group study comparing
lenalidomide and low-dose dexamethasone with lenalidomide and high-dose
dexamethasone demonstrated a survival benefit in the lower dose of
dexamethasone. This was more pronounced in patients older than 65 years, but
was noted in all age groups. High-dose dexamethasone, for a few cycles, in
combination with lenalidomide remains reasonable in younger patients with high
disease burden.
High-dose dexamethasone is given at a dose of 40 mg by mouth (PO) on
days 1 to 4, 9 to 12, and 17 to 20. Cycles are repeated every 28 days. Low-dose
dexamethasone consists of 40 mg PO weekly or on days 1 to 4 of a 28-day cycle.
Significant early toxicities include hyperglycemia, dyspepsia, fatigue, and
muscle weakness. Additionally, patients often report agitation and insomnia.
Longer-term toxicities include increased infections, cataract, osteoporosis, and
avascular necrosis of femoral heads. As a single agent in patients with newly
diagnosed myeloma, responses are observed in about 50% of patients, and the
median time to response is approximately 1 month. However, the median
duration of response is only 6 months. As such, single-agent dexamethasone is
generally not the treatment of choice.
b. Melphalan and prednisone (MP)9 has fallen out of favor, with the availability
of novel agents, and combinations of thalidomide or bortezomib with MP have
resulted in superior survival than MP alone. Nonetheless, MP remains a
 reasonable option for very elderly patients with many comorbidities. MP results
in about a 50% overall response rate (ORR) in patients with newly diagnosed
myeloma, and a median time to progression of about 15 months. While a number
of different dosages and schedules for MP exist, we recommend the following:
■ Melphalan 9 mg/m2 PO on days 1 to 4, and
■ Prednisone 100 mg PO on days 1 to 4.
For reliable absorption, melphalan should be taken on an empty stomach.
Repeat the cycle every 4 to 6 weeks, depending on recovery of counts. MP is
usually given in six to nine cycles, and treatment beyond 1 year does increase
risks of myelodysplasia. Responses to MP tend to occur slower on average,
making this a less attractive regimen in patients with significant symptoms. On
the other hand, MP is well tolerated in patients with myeloma, with
myelosuppression being the most significant adverse event. MP should not be
used in patients who are candidates for intensive therapy as it may impair stem
cell collection.
c. Cyclophosphamide and prednisone (CP)11 is a forgotten alternative to MP.
Cyclophosphamide does not need dose adjustments for renal failure, making it a
useful agent in patients with a decreased performance status and/or
comorbidities. It results in a response rate of about 50% and a progression-free
survival (PFS) of 12 to 15 months in treatment-naïve patients. CP is given as
follows:
■ Cyclophosphamide 1,000 mg/m2 intravenously (IV) on day 1, and
■ Prednisone 100 mg PO on days 1 to 5
■ Cycles are repeated every 21 days.
CP is well tolerated and, in distinction to MP, does not result in significant
compromise to stem cell reserve. Furthermore, bortezomib has been added to
this backbone with demonstrated efficacy.
d. Proteasome inhibitor–based therapy
1) Bortezomib12
Bortezomib was the first proteasome inhibitor approved for MM as a single
agent or combination with MP. In addition, combination therapy with
dexamethasone or PEGylated liposomal doxorubicin or with thalidomide or
lenalidomide has shown promising results. As a single agent in relapsed and
refractory patients, it was shown to result in a response rate of about 30% to
40% and a median time to progression of 6 to 7 months. This was found to be
superior to high-dose dexamethasone. A subcutaneous (SC) dosing strategy
for bortezomib is available, and has been shown to reduce the incidence of
peripheral neuropathy without a compromise in efficacy.
■ Bortezomib is given at 1.3 mg/m2 IV over 3 to 5 seconds, or through a
SC injection, on days 1, 4, 8, and 11 on a 21-day cycle.
■ Dexamethasone 20 mg is often added on the day of and the day after
 bortezomib is given.
Treatment is continued for eight cycles. Grades 3 and 4 adverse events
of bortezomib include the following: thrombocytopenia (30%), neutropenia
(14%), anemia (10%), and neuropathy (8%). Neuropathy should be
monitored carefully, with special attention to autonomic neuropathy in the
form of paralytic ileus and delayed peripheral neuropathy after the
discontinuation of therapy. Neuropathy is often painful in nature, but is also
reversible in about two-thirds of patients after 3 to 6 months of
discontinuation of therapy. Bortezomib-based therapy is often the treatment of
choice in patients with significant renal impairment (although often in
combination with cyclophosphamide in that setting). The risk of varicella
zoster reactivation can be effectively reduced/eliminated with the use of
acyclovir prophylaxis, which is recommended for all bortezomib- and
carfilzomib-containing regimens.
2) Melphalan, prednisone, and bortezomib (VMP)13,14
Two 3-week bortezomib cycles are added to a 6-week MP cycle in standard
VMP. In addition, bortezomib is often given weekly instead of twice weekly
without evidence of a compromise in efficacy and with less neuropathy or
gastrointestinal toxicity.
a) Standard VMP
■ Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 for four
cycles followed by bortezomib 1.3 mg/m2 on days 1, 8, 22, and 29
for five cycles
■ Melphalan 9 mg/m2 on days 1 to 4
■ Prednisone 60 mg/m2 on days 1 to 4
■ Cycles are repeated every 6 weeks.
b) VMP superlite
■ Similar MP dosing with bortezomib given on days 1, 8, 22, and 29
for all nine cycles.
3) VDC modified.15 Several regimens have incorporated the addition of
cyclophosphamide to bortezomib and dexamethasone. The VDC-modified
regimen was compared with RVD in a randomized phase II trial in newly
diagnosed myeloma patients and resulted in similar outcomes.
■ Bortezomib 1.3 mg/m2 IV (or SC) days 1, 4, 8, 11
■ Cyclophosphamide 500 mg/m2 IV days 1, 8, 15
■ Dexamethasone 40 mg PO days 1, 8, 15
■ Cycles are repeated every 3 weeks.
4) Bortezomib, lenalidomide, and dexamethasone (RVD)16
The combination of lenalidomide, bortezomib, and dexamethasone was
evaluated in patients with newly diagnosed as well as previously treated
 MM. In newly diagnosed myeloma, the combination has a demonstrated high
response rate and appears to be well tolerated. An ongoing intergroup trial
compared this combination with lenalidomide and dexamethasone in newly
diagnosed patients, although results are pending and it remains unclear
whether the high response rate for this triplet will translate into improved
patient outcomes. For newly diagnosed patients, RVD is administered as
follows:
■ Lenalidomide 25 mg PO on days 1 to 14
■ Bortezomib 1.3 mg/m2 IV or SC on days 1, 4, 8, and 11
■ Dexamethasone 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12
■ Cycles are repeated every 21 days.
Supportive therapy includes acyclovir and aspirin prophylaxis for
varicella zoster virus reactivation and thromboembolic disease, respectively.
In relapsed and refractory myeloma, the RVD regimen has demonstrated
the ability to induce responses in patients refractory to both lenalidomide and
bortezomib. Because of the marrow compromise often present in patients
with relapsed and refractory myeloma, the lenalidomide starting dose is 15
mg orally on days 1 to 14 of a standard bortezomib cycle.
5) Bortezomib and PEGylated liposomal doxorubicin
Bortezomib has been combined with PEGylated liposomal doxorubicin.17,18 A
pivotal phase III trial, which led to the approval of PEGylated liposomal
doxorubicin, compared this combination with single-agent bortezomib in
patients with relapsed and refractory myeloma. The combination results in a
similar ORR to single-agent bortezomib, but the quality responses (very good
partial responses and better) were increased with combination therapy. This
translated to improved PFS. PEGylated liposomal doxorubicin (30 mg/m2)
was given on day 4 of a standard bortezomib cycle in this combination.
Notable toxicities of PEGylated liposomal doxorubicin include palmar
plantar erythrodysesthesia syndrome (hand-foot syndrome),
myelosuppression, and cardiotoxicity. In addition, dexamethasone can be
added to this regimen, and intriguing early results with this combination have
been reported.
6) Panobinostat, bortezomib, and dexamethasone (PVD)
Panobinostat is a pan histone deacetylase inhibitor that has been evaluated in
combination with bortezomib and dexamethasone for patients with relapsed
and refractory MM. For patients with bortezomib refractory disease, PVD
results in responses in about a third of the patients. Importantly, a randomized
trial (PANORAMA-1)19 reported increased efficacy (PFS) for PVD
compared with bortezomib and dexamethasone in patients with one to three
prior lines of therapy who were not bortezomib refractory. However, this
regimen was associated with high rates of thrombocytopenia and
 gastrointestinal toxicities, which makes it more suitable for patients with
advanced myeloma.
■ Panobinostat 20 mg PO on days 1, 3, 5, 8, 10, and 12
■ Bortezomib is given at 1.3 mg/m2 IV or SC on days 1, 4, 8, and 11 on a
21-day cycle
■ Dexamethasone 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day
cycles
■ After eight 3-week cycles, a “maintenance” therapy can be given using
6-week cycles in which panobinostat is given on the same days and
bortezomib is given weekly (days 1, 8, 22, 28)
7) Carfilzomib.20 Carfilzomib is an epoxy ketone that irreversibly inhibits the
proteasome and that has been evaluated in the treatment of both newly
diagnosed and relapsed and/or refractory MM. Carfilzomib is currently
approved for the treatment of patients with relapsed and refractory MM who
have received at least two prior therapies including bortezomib and an
immunomodulatory agent. Notable toxicities of carfilzomib include
myelosuppression, pneumonitis, acute renal failure, pyrexia, hypertension,
and cardiotoxicity. The approval was based on single-agent activity, 23% in
heavily pretreated patients. In the ENDEAVOR trial,21 patients that received
one to three prior lines of therapy and were not refractory to proteasome
inhibitors, a higher dose of carfilzomib in combination with dexamethasone
and compared with bortezomib with dexamethasone was given. In this study,
the median PFS was 18.7 versus 9.4 months, and ORR was 77% versus 66%
favoring carfilzomib.
■ Carfilzomib is given at 20 mg/m2 IV over 2 to 10 minutes, on days 1, 2,
8, 9, 15, and 16 of 28-day cycles. If the 20 mg/m2 is tolerated in cycle 1,
the dose can be escalated to 27 mg/m2 for subsequent cycles. In the
ENDEAVOR trial, the carfilzomib dose was 20 mg/m2 IV on days 1, 2,
and 56 mg/m2 on the same schedule thereafter.
■ Dexamethasone 20 mg PO on days 1, 2, 8, 9, 15, 16, 22, and 23 of 28-
day cycles
Supportive therapy includes acyclovir for varicella zoster virus
reactivation. It is important to note that hydration and fluid monitoring are
recommended to reduce the risk of renal toxicity and of tumor lysis
syndrome, while closely monitoring blood chemistries. Prior to and
following each dose in cycle 1, 250 to 500 mL of IV fluids should be
administered as needed. IV fluids can often be discontinued in subsequent
cycles. Carfilzomib has also been combined with cyclophosphamide or with
pomalidomide in the newly diagnosed and relapsed refractory setting,
respectively.
8) Carfilzomib, lenalidomide, and dexamethasone (KRd)
 Carfilzomib has been investigated in combination with lenalidomide and
dexamethasone for both newly diagnosed MM and in patients that have
received one or more prior therapies. The phase III ASPIRE trial22 in
patients that received one or more prior therapies demonstrated increased
efficacy with the addition of carfilzomib to lenalidomide and dexamethasone
therapy. This study included 792 patients with relapsed MM randomized to
Rd or KRd. Patients randomized to the KRd arm received up to 18 cycles of
KRd, and patients in both arms that remained progression free at cycle 18
continued to receive Rd until disease progression. An increase in ORR was
observed, 66.7% (Rd) versus 87.1% (KRd), and the median PFS improved
from 17.6 (Rd) to 26.3 months (KRd).
■ Carfilzomib is given IV over 2 to 10 minutes, on days 1, 2, 8, 9, 15, and
16 of 28-day cycles. If the 20 mg/m2 is tolerated on days 1 and 2 in
cycle 1, the dose can be escalated to 27 mg/ m2 for subsequent cycles,
up to cycle 12. For cycles 13 to 18, carfilzomib was administered on
days 1, 2, 15, and 16
■ Lenalidomide 25 mg PO on days 1 to 21
■ Dexamethasone 40 mg PO on days 1, 8, 15, and 16
■ Cycles repeat every 28 days
The adverse events associated with the KRd regimen include
myelosuppression, dyspnea, cardiac failure, ischemic heart disease,
hypertension, and acute renal failure. Patients should receive both antiviral
and antithrombotic prophylaxis with this regimen. Hydration with IV fluids
before and after carfilzomib administration should be administered in cycle
1, and can often be discontinued in subsequent cycles at the physician’s
discretion.
e. Immunomodulatory compounds–based therapy
Immunomodulatory agents include thalidomide, lenalidomide, and
pomalidomide. They have pleiotropic effects in patients with MM that are
largely mediated through targeting of cereblon.
1) Thalidomide and dexamethasone 23,24
The addition of thalidomide to dexamethasone results in an increased
response rate (about 70%) at the cost of additional toxicity (in the form of
thromboembolic events, rash, sedation, peripheral neuropathy, and
constipation). Although thalidomide was started at 200 mg daily at bedtime
on the pivotal clinical trial, our experience suggests improved patient
tolerance with a more gradual start of thalidomide.
We recommend initiating thalidomide at 50 mg daily at bedtime and
increasing the daily dose by 50 mg increments every week to a desired target
dose not exceeding 200 mg daily or as dictated by patient tolerance. It should
be noted, however, that there is no known minimal dose required for
 response: some (though rare) patients respond to dosages as low as 50 mg
three times a week.
In addition, in responding patients receiving high-dose dexamethasone,
reduction of dexamethasone to 40 mg on days 1 to 4 monthly (low-dose
dexamethasone) results in improved patient tolerance.
With the increased risks of thromboembolic events (about 17% of
patients receiving this combination), we recommend the use of prophylactic
low-dose aspirin (81 mg).25 Other investigators have used different
prophylactic strategies, which include low-molecular-weight heparin and
therapeutic anticoagulation with warfarin. A recent randomized trial of these
thromboprophylactic strategies did not demonstrate the superiority of any one
of the above regimens in patients with one or less risk factor. Given that
thalidomide use has been associated with the development of neuropathy with
long-term use, this agent has largely been replaced with lenalidomide in this
setting. This regimen may be considered in patients with significant
cytopenias or renal insufficiency with disease refractory to bortezomib.
2) Melphalan, prednisone, and thalidomide (MPT)9,11
Thalidomide has been added to MP in the MPT regimen. Similar
recommendations noted pertaining to the dosing of thalidomide can be made.
In addition, thalidomide up to 100 mg at bedtime is usually recommended. In
some studies involving MPT, thalidomide was continued for 1 year after MP
therapy was discontinued, whereas in other MPT studies, thalidomide was
discontinued at the time of stopping MP. In patients with a good tolerance to
thalidomide, continuing such therapy would be reasonable. However, given
the results of the FIRST trial,26 it is difficult to consider this regimen in
newly diagnosed patients.
3) Lenalidomide and low-dose dexamethasone (Rd)26
Lenalidomide is an immunomodulatory drug with more potent tumor necrosis
factor-α inhibition than thalidomide. In addition, lenalidomide has a different
adverse event profile than thalidomide and does not usually cause significant
sedation or neuropathy; it does result in myelosuppression. In patients with
relapsed or refractory MM, the combination of lenalidomide and
dexamethasone resulted in responses in approximately 60% of patients with a
PFS of approximately 12 months.
The combination of lenalidomide and dexamethasone was recently
approved for patients with newly diagnosed transplant-ineligible MM
(FIRST trial).26 In this patient population, continuous dosing of Rd was
compared with standard melphalan, prednisone, and thalidomide (MPT).
Continuous dosing of Rd resulted in superior PFS (median of 25.5 vs. 21.2
months), with 42% of patients progression-free at 3 years, compared with
23% of patients that received MPT. A significant overall survival benefit
 was also observed in patients that received continuous Rd.
Lenalidomide is usually started at 25 mg PO daily for 21 of 28 days.
Lower starting doses are recommended in patients with renal dysfunction as
lenalidomide is renally cleared. Lenalidomide toxicities include
thromboembolic events, myelosuppression, rash, and diarrhea.
Myelosuppression is often noted early during the course of therapy, and
febrile neutropenia is rare. Therapy should be continued until disease
progression, given the FIRST trial results. In addition, in responding patients
after 1 year of therapy, omitting dexamethasone and continuing with single-
agent lenalidomide is reasonable. Long-term lenalidomide therapy may make
stem cell collection difficult, and the use of chemotherapy in combination
with granulocyte colony-stimulating factor (G-CSF) may be needed for stem
cell collection.
4) Elotuzumab, lenalidomide, and dexamethasone (EloRd)27
This combination has been evaluated for the treatment of patients with
relapsed and refractory and newly diagnosed MM. Elotuzumab is a
monoclonal antibody targeting SLAMF7 (CS1). SLAMF7 is expressed on
both malignant plasma cells and NK cells. In patients with one to three prior
regimens, EloRd was compared with Rd in patients not refractory to prior
lenalidomide. Median PFS was 19.4 (EloRd) versus 14.9 months (Rd), with
a hazard ratio of 0.70, and improvements in both 1-year and 2-year PFS.
Response rate was higher in the EloRd arm, 79% versus 66%.
■ Elotuzumab 10 mg/kg IV on days 1, 8, 15, and 22 of cycles 1 and 2, and
on days 1 and 15 for subsequent cycles
■ Lenalidomide 25 mg PO on days 1 to 21
■ Dexamethasone 28 mg PO and 8 mg IV on weeks with elotuzumab, and
40 mg PO on weeks without elotuzumab
■ Cycles repeat every 28 days until disease progression or unacceptable
toxicity
Adverse events with EloRd include lymphocytopenia, neutropenia,
fatigue, and pneumonia. Infusion reactions were reported in 10%, were
primarily grades 1 and 2, and occurred more frequently during the first
infusion. Patients in the EloRd arm received premedication 30 to 60 minutes
before infusion that consisted of diphenhydramine (25 to 50 mg), ranitidine
(50 mg), and acetaminophen (650 to 1,000 mg), or the equivalents of these
medications. All patients received thromboprophylaxis.
5) Pomalidomide and low-dose dexamethasone (Pd)28
Pomalidomide is a next-generation immunomodulatory drug with similar
mechanisms of action as lenalidomide. In vitro assays show pomalidomide to
be a more potent tumoricidal, immune stimulatory, and antiangiogenic
compound. In preclinical models, pomalidomide inhibits the proliferation
 and survival of both lenalidomide-sensitive and lenalidomide-resistant cell
lines.
Pd was recently approved for MM patients who are refractory to
lenalidomide and proteasome inhibitor (US) or bortezomib (EU). A
randomized phase III study of pomalidomide low-dose dexamethasone versus
high-dose dexamethasone in this patient population showed a significant
clinical benefit favoring pomalidomide/low-dose dexamethasone. At the time
of the updated PFS and final overall survival analyses (median follow-up
10.0 months), the PFS data continued to show an advantage for
pomalidomide plus low-dose dexamethasone compared with the high-dose
dexamethasone group (4.0 months [95% CI, 3.6 to 4.7] vs. 1.9 months [1.9 to
2.2]; HR 0.48 [0.39 to 0.60]; p < 0.0001). Median PFS was significantly
longer with pomalidomide plus low-dose dexamethasone irrespective of
previous treatment in the subgroup analyses. In the final overall survival
analysis, median overall survival was significantly longer in the
pomalidomide plus low-dose dexamethasone group than in the high-dose
dexamethasone group (12.7 months [95% CI, 10.4 to 15.5] vs. 8.1 months
[6.9 to 10.8]; HR 0.74 [0.56 to 0.97]; p = 0.0285).
■ Pomalidomide 4 mg PO on days 1 to 21
■ Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle
■ Cycles are repeated every 28 days until progressive disease or
unacceptable toxicity
Pomalidomide is started at 4 mg PO daily for 21 of 28 days, and, unlike
lenalidomide, lower starting doses are not recommended in patients with
renal dysfunction as pomalidomide is extensively metabolized prior to renal
clearance. Pomalidomide toxicities include myelosuppression, pneumonia,
fatigue, and dyspnea. A low rate of thrombotic events was observed.
Antithrombotic prophylaxis is recommended to reduce the risk of thrombotic
events. In patients greater than 75 years of age, the dose of dexamethasone
may be reduced to 20 mg/day. Dosing of Pd is continued until disease
progression or the development of unacceptable toxicity. We recently
reported the results of a randomized phase II trial comparing pomalidomide
oral weekly cyclophosphamide and dexamethasone with standard
pomalidomide and dexamethasone. We noted an increased ORR with the
addition of oral weekly cyclophosphamide (400 mg PO days 1, 8, 15 of the
standard pomalidomide dexamethasone cycle). Carfilzomib or bortezomib
have also been combined with the pomalidomide dexamethasone backbone
with encouraging results.
f. Single-agent monoclonal antibody
1) Daratumumab29
Has been evaluated in the treatment of relapsed and refractory MM.
 Daratumumab is a monoclonal antibody targeting CD38, a protein highly
expressed on the surface of MM cells and that can also be expressed on a
lower level on normal lymphoid and myeloid cells. In a phase II study with
patients with advanced relapsed and refractory MM (median of five prior
lines of therapy), daratumumab monotherapy demonstrated single-agent
activity with an ORR of 29% and a 7.4-month median duration of response.
Median time to progression was 3.7 months. After a median follow-up of 9.4
months, 14/31 (45.2%) of responders remain on therapy. Median overall
survival has not been reached, and the estimated 1-year overall survival (OS)
rate is 65%. Therapy was well tolerated. Adverse events (AE; ≥20%) were
fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia
(25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%).
Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first
infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to
IRRs; five (4.7%) discontinued treatment because of AEs. None of these AEs
were assessed by the investigator to be daratumumab related.
■ Daratumumab 16 mg/kg IV every week for 8 weeks, every 2 weeks for
16 weeks, then every 4 weeks until progressive disease or unacceptable
toxicity
Methylprednisolone, acetaminophen, and diphenhydramine are
administered prophylactically according to the institutional standards.
Of note, SAR650984,30 another monoclonal antibody also targeting
CD38, resulted in single-agent activity in patients with advanced myeloma as
well as a response rate of about 60% in combination with lenalidomide and
dexamethasone.
4. Novel compounds and regimens in patients with relapsed or refractory MM—
summary
Despite original responses to therapy, virtually all patients develop recurrent or
refractory MM. In patients who experience a relapse more than 1 year after
receiving chemotherapy, remission can frequently be obtained using the same
regimen. Patients relapsing earlier will likely require an alternate treatment regimen.
Patients with refractory myeloma have evidence of progressive disease while
receiving active therapy or within 60 days from last therapy despite possible
original responses. This patient population has a worse outcome than relapsed
patients do. Enrollment of patients with relapsed or refractory myeloma into clinical
trials should be a first consideration in the choice of antineoplastic therapy. A
number of novel therapeutic tools are emerging in the treatment of MM. These
include combination therapies with novel immunomodulatory drugs (pomalidomide),
novel proteasome inhibitors (ixazomib), monoclonal antibodies (elotuzumab,
daratumumab), histone deacetylase inhibitors (panobinostat or ricolinostat), Kinesin
spindle protein inhibitors (Filanesib), or nuclear transport inhibitors (Selinexor).
 Many of these will likely be approved first for the treatment of relapsed or
refractory patients before gaining indication in newly diagnosed patients.
C. High-dose therapy with bone marrow or peripheral blood stem cell transplantation
The role of high-dose therapy and autologous stem cell transplantation for MM in the
era of novel agents remains poorly defined. Initial reports of high-dose therapy
generated significant enthusiasm for this approach, as it was associated with a survival
advantage over standard therapy using alkylating agents. Contemporary clinical trials
comparing high-dose therapy with conventional therapy have failed to consistently
confirm the results of initial trials, likely because of the improvement in standard
therapies and the availability of novel active salvage therapies. Despite the lack of
consistent overall survival advantage, early high-dose therapy does offer a prolongation
in the Time without Symptoms of Disease or Toxicity of Treatment, a quality-of-life
measure surrogate. With the advent of novel agents, the role of high-dose therapy and its
timing in the MM therapeutic armamentarium will require revalidation.
For patients electing to proceed to high-dose therapy, available induction therapies
include the use of lenalidomide–bortezomib–dexamethasone or bortezomib–
cyclophosphamide–dexamethasone regimens. Three-agent induction has been shown to
result in a higher rate of quality responses prior to high-dose therapy compared with
two-agent induction. While this may translate into improved posttransplant quality
responses, it remains unclear whether three-agent induction will improve survival.
Stem cells can be derived from the peripheral blood or the bone marrow. The
former can be done with the use of G-CSF with or without chemotherapy. Novel agents
to facilitate stem cell collection (plerixafor) have entered the clinical arena. Peripheral
stem cell rescue results in faster engraftment as compared with bone marrow stem cell
rescue and has accordingly supplanted the former in clinical use. High-dose therapy is
usually in the form of melphalan given at 200 mg/m2 for younger patients with intact
renal function. Total-body radiation has mostly been abandoned in this setting in view
of inferior results associated with its use. Although purging the graft of malignant cells
seems intuitively useful, it has not been shown to improve outcomes, and in vivo
purging (with systemic therapy) remains the preferred modality. High-dose therapy with
peripheral stem cell rescue has been carried out in an outpatient setting at some
transplant centers, but remains an inpatient therapy for 2 to 3 weeks at most other
centers.
D. Duration of therapy and role of maintenance therapy
The evidence to support maintenance is considerable, and such lower-intensity therapy
should be considered whenever possible. The bulk of the literature supports
maintenance therapy with immunomodulatory agents. However, a couple of reports
using bortezomib maintenance have also shown efficacy. We herein briefly summarize
the data supporting maintenance therapy in patients with MM.
Historically, a study by the SWOG has shown that maintenance therapy with
prednisone given at 50 mg every other day improves overall and PFS when compared
 with maintenance therapy with 10 mg of prednisone every other day.31 Although
interferon maintenance resulted in a prolonged PFS, overall survival was not increased,
and toxicity from interferon was notable. The use of thalidomide32 to maintain
responses observed after intensive therapy has been associated with a survival benefit
in patients, not in a very good partial response or better after high-dose therapy. On the
other hand, patients receiving continued thalidomide should be closely monitored for
peripheral neuropathy, and doses as low as 50 mg every other day are often all that
patients are able to tolerate. Thalidomide maintenance is currently not routinely
recommended for all patients post intensive therapy.
Maturing data from two double-blinded, randomized studies, the Cancer and
Leukemia Group B (CALGB)33 and the Intergroupe Francophone du Myelome (IFM),34
have evaluated maintenance with lenalidomide at a dose of 10 mg daily initiated
approximately 3 months post high-dose therapy and autologous stem cell transplant
versus placebo. Both studies reported a significant benefit to lenalidomide maintenance
on PFS. OS was significantly improved at the time of un-blinding for the CALGB study
and continued to be significant despite crossover of the patients on the placebo arm to
the active therapy arm. On the other hand, the OS in the IFM study remains not
statistically different with maintenance lenalidomide. The consideration of
lenalidomide maintenance should be individualized with discussion of risks and
benefits with the patient. Of note, a small absolute increase in second primary
malignancies was noted with lenalidomide in these studies.
Finally, the HOVON 65 trial35 compared a bortezomib-based induction, high-dose
therapy, and bortezomib maintenance with vincristine, adriamycin (doxorubicin) and
dexamethasone (VAD) induction, high-dose therapy, and thalidomide maintenance. This
trial demonstrated the superiority of the bortezomib-containing arm, although it is
unclear whether the induction or maintenance or both are responsible for these results.
In that setting, bortezomib was given at 1.3 mg/m2 every 2 weeks for a total of 2 years.
E. Role of radiotherapy36
While radiotherapy is sometimes curative in patients with solitary plasmacytomas, its
use in patients with MM is palliative and adjunctive to the use of systemic therapy.
Patients with symptomatic extraskeletal plasmacytomas, large lytic lesions threatening
fracture of long bones, spinal cord, or root compression by plasma cells, and certain
pathologic fractures are good candidates for radiotherapy. Conservative use of
radiotherapy is wise as radiation of bone marrow can impair marrow reserves and
render the patient less able to tolerate subsequent therapy.
F. Complications of disease or therapy
Notable toxicities of each chemotherapeutic agent are described in Chapter 28. In
addition, complications characteristic of MM are described here.
1. Hypercalcemia37,38
Once a very frequent complication of MM, hypercalcemia is less often noted, likely
as a result of more widespread use of bisphosphonate therapy for bone health. The
 pathophysiology of hypercalcemia in patients with MM is related to increased
osteoclast activation as a result of binding of VCAM-1 on stromal cells and α4β1
integrin on myeloma cells. Receptor activator of nuclear factor-κB (RANK)-ligand
produced by bone marrow stromal cells is the best-described cytokine mediating
this effect. Antibodies to RANK-ligand are entering the clinical arena and are
currently being tested in clinical trials in patients with MM. Symptoms of
hypercalcemia are often protean, often overlap with adverse events of thalidomide,
and require a strong index of suspicion. Symptoms include anorexia, constipation,
polyuria, and lethargy. Coma and death can be the result of untreated hypercalcemia.
Dehydration and potentially reversible renal dysfunction are frequently associated
with hypercalcemia. Treatment of hypercalcemia involves aggressive saline
hydration, use of loop diuretics once fluid overload occurs, use of corticosteroids
(such as prednisone 60 mg for 7 days or dexamethasone), and bisphosphonate
therapy. Calcitonin is sometimes used, and hemodialysis is reserved for refractory
cases. When hypercalcemia occurs in previously untreated patients, prompt
initiation of therapy for the MM in addition to the above usually results in effective,
durable control.
a. Bisphosphonates
■ Pamidronate 90 mg given as a 2-hour IV infusion that can be repeated every
30 days or
■ Zoledronic acid 4 mg IV over 15 to 30 minutes in the absence of renal
dysfunction.
b. Calcitonin 100 to 300 U SC every 8 to 12 hours for up to 2 to 3 days. Calcitonin
is usually given with prednisone 60 mg PO daily to prolong its effectiveness.
c. Hemodialysis is very effective but rarely needed.
2. Infection39
Patients with MM are at increased risk for infectious complications usually related
to capsulated microorganisms. Deficiency of normal immunoglobulins, diminished
bone marrow reserves, therapies for MM, and immobilization due to skeletal
disease are important predisposing factors. Prompt evaluation of fever or other
manifestations of infection and institution of empiric antimicrobial therapy are
essential. The prophylactic and therapeutic use of growth factors (such as G-CSF) is
often considered. Intravenous Ig is administered to patients with recurrent significant
infectious complications.
Infections in MM patients continue to represent a major threat. The effect on
infectious complications of novel drugs introduced in the treatment of MM needs to
be established, and trials on prophylactic measures are needed.
3. Hyperviscosity
This is a rare manifestation of MM and is more commonly observed in patients with
WM. It may present as central nervous system impairment (which is often subtle and
noted as difficulty concentrating, visual changes, and headaches) and occasionally
 congestive heart failure. Plasmapheresis is used for the treatment of symptomatic
hyperviscosity; however, therapy should be combined with systemic therapy
directed at the plasma cell clone, as benefits of plasmapheresis are short-lived.
4. Renal dysfunction
The possible causes of renal dysfunction in patients with MM include the following:
myeloma kidney or cast nephropathy, drugs (such as NSAIDs, bisphosphonates, and
intravenous contrast agents), hypercalcemia, hyperuricemia and urate nephropathy,
amyloid deposition, pyelonephritis and other infections, hyperviscosity syndrome,
plasma cell infiltration of both kidneys (rare), and renal tubular acidosis. In
addition, patients with MM are particularly susceptible to intravascular volume
depletion and prerenal azotemia. Adequate hydration, avoidance of possible culprit
drugs when possible, high index of suspicion, and early identification of etiology
will result in improved renal outcomes, as most of the causes of renal dysfunction
are reversible. Patients with MM with severe renal dysfunction, in whom readily
identifiable causes of renal dysfunction have been ruled out, may be assumed to have
cast nephropathy without the need for a biopsy. Plasmapheresis, in addition to
institution of chemotherapy should be considered in such selected cases. While
plasmapheresis does not impact overall survival, it may result in improved dialysis-
free survival. In patients with severe renal failure that has not improved with the
previously discussed interventions, hemodialysis should be considered if
chemotherapy offers the potential for a prolonged remission.
5. Skeletal destruction
This remains a major cause of disability, pain, and immobilization for patients with
MM. Adopting a multidisciplinary approach to the patient with bone disease cannot
be overemphasized. Bisphosphonates are best given monthly in the first 1 to 2 years,
and less frequently thereafter. They have been shown to reduce the incidence of
skeletal-related events, and the UK MRC IX study38 noted a survival benefit with
zoledronic acid compared with clodronate. Pamidronate and zoledronic acid have
both been associated with the development of osteonecrosis of the jaw. A dentist
experienced in management of this complication should promptly evaluate patients
with symptoms referable to the jaw or teeth. While no clear guidance exists for
patients who do require invasive dental procedures and have received
bisphosphonate therapy, it is reasonable to hold bisphosphonate therapy for at least
1 month prior and 2 months after the dental procedure or after confirmation of the
total healing after the procedure. Radiation therapy is often used to palliate painful
lytic lesions. Surgical intervention is used for prevention of impending fractures of
weight-bearing bones and the treatment of compression fractures causing pain and
loss of height (kyphoplasty).40
6. Anemia
Anemia is frequently observed in patients with MM. MM and its treatment are
etiologic factors in most patients. In addition, a subset of patients was found to have
 vitamin B12 and folate deficiency, and treatment with erythropoietic agents is thought
to result in decreases in iron stores. Thus, monitoring vitamin B12, folate, and iron
levels is recommended. The use of recombinant human erythropoietin results in
responses of the anemia in about 80% of patients.
7. Leukemia
Acute myeloid leukemia develops in up to 4% of patients with myeloma who have
received alkylator-based chemotherapy (melphalan). Myelodysplasia is present at
diagnosis in a subset of patients as it, like myeloma, occurs in older age groups.
Leukemia in this setting appears to be caused by the interaction of a carcinogenic
drug with a predisposed host. With the avoidance of long-term therapy with
alkylating agents, the incidence of this complication is declining. In addition,
myelodysplastic syndrome post high-dose therapy and autologous stem cell
transplant is increasingly recognized in patients with myeloma who currently enjoy
longer survival than with previous therapies.

IV. WALDENSTRÖM MACROGLOBULINEMIA (LYMPHOPLASMACYTIC

LYMPHOMA)
A. Diagnosis and presentation
Waldenström macroglobulinemia is a B-cell lymphoproliferative disorder characterized
by the production of a monoclonal Ig of the IgM subtype and by intertrabecular bone
marrow infiltration with a lymphoplasmacytic infiltrate. The second international
workshop on WM has proposed the following diagnostic criteria41: an IgM M-protein
of any concentration, bone marrow infiltration with small lymphocytes exhibiting
plasmacytoid differentiation, and with a suggestive immunophenotype (expression of
surface IgM, CD19, CD20, CD25, CD27, FMC7, and CD138 without the expression of
CD5, CD10, CD23, and CD103). In addition, a mutation in MYD88 (L265P) is noted in
the majority of patients with WM, while a CXCR4 mutation (also noted in patients with
warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis [WHIM]
syndrome) is less common.
Symptoms attributable to WM are related to tumor infiltration or to the M-protein.
The former results in constitutional symptoms (fevers, sweats, and weight loss),
cytopenias (secondary to bone marrow involvement), lymphadenopathy, and
hepatosplenomegaly. Symptoms related to the M-protein include hyperviscosity,
cryoglobulinemia, cold agglutinin, neuropathy, and amyloidosis.42
B. General considerations and aims of therapy
There is no cure for WM. Treatment is palliative and aimed at reduction of symptoms
and prevention of complications of the disease. Increasing numbers of patients without
signs or symptoms are being diagnosed with WM. Expectant observation is the
recommended approach for patients with asymptomatic WM. The level of the M-protein
should not be used as an indication for treatment. The choice of therapeutic option in a
symptomatic individual is guided by disease characteristics as well as patient
 characteristics. The available therapies include the following: oral alkylating agents,
nucleoside analogs, rituximab monotherapy, and a combination of chemotherapy,
rituximab, and autologous stem cell transplantation. Novel therapies include
thalidomide, alemtuzumab, bortezomib, and ibrutinib.43,44 Limited randomized clinical
trials have been conducted for WM, and treatment recommendations rely mostly on
phase II studies. Patients with WM are monitored by repeated measurements of one or
more of the following: the serum M-protein, the serum viscosity when that is elevated,
and by serial imaging for those with adenopathy. A complete response is defined as the
disappearance of the M-protein and by resolution of infiltration of lymph node and
visceral organs confirmed on two separate evaluations 6 weeks apart. A partial
response is defined as a greater than 50% reduction in the M-protein and a greater than
50% reduction in lymphadenopathy with the resolutions of symptoms related to WM.
Progressive disease is defined as a greater than 25% increase in the M-protein,
worsening of cytopenias, organ infiltration, or disease-related symptoms. After the
documentation of the best response, continued therapy is not clearly beneficial, although
maintenance therapy with rituximab can be considered. The median survival of patients
with WM has historically been 5 to 10 years, likely as a consequence of the older
patient population and comorbidities.
C. Treatment
1. Cytopenias in patients with WM are related to bone marrow involvement and
occasionally to hypersplenism. Anemia in patients with WM is common and often
responds to erythropoietic agents. While transfusions are generally safe, it is
generally done with caution in patients with hyperviscosity as red blood cells
contribute to whole blood viscosity. Thrombocytopenia and anemia usually are
indications to initiate treatment, and improvement in these cytopenias is often
regarded as evidence of response to therapy. Platelet transfusions are occasionally
needed, especially after chemotherapy is given to the patient with baseline
thrombocytopenia.
2. Hyperviscosity. Hyperviscosity syndrome readily responds to plasmapheresis.
Plasmapheresis should not be regarded as a long-term treatment, and consolidation
of that response with chemotherapy is ultimately needed to render patients
independent of that procedure.
3. Chemotherapy
a. Oral alkylating agents
■ Chlorambucil 2 to 6 mg PO daily, or
■ Cyclophosphamide 50 to 100 mg PO daily.
■ Prednisone 40 to 60 mg PO on days 1 to 4 every 4 weeks is often added.
While complete responses are rare with the use of alkylating agents, partial
responses approach 50% in some series. The time to response has been slow
with alkylating agents. The use of alkylating agents should be considered in
older patients in whom rapid control of the disease is not necessary.
 b. Nucleoside analog
■ Fludarabine 25 mg/m2 IV on days 1 to 5 or
■ Bendamustine IV over 30 minutes 90 mg/m2/day on days 1 and 2
■ Cycles are repeated every 28 days
■ Rituximab is frequently used in combination with nucleoside analogs
While many patients are able to tolerate this regimen, older individuals and
patients with significant cytopenias at baseline are best treated with a reduced
dose or schedule of fludarabine. Two to three days of fludarabine 25 mg/m2 in
the first two cycles are recommended; consider dose increases if the patient is
able to tolerate therapy well and responses are suboptimal. Nucleoside analogs
have been shown to result in a higher response rate than oral alkylators, but a
survival benefit has not been demonstrated. The time to response is shortened by
the use of nucleoside analogs. We recommend the use of these agents in younger
patients in whom autologous stem cell transplantation is not considered and who
require a fast tumor control.
c. Rituximab
Rituximab is a monoclonal antibody targeting CD20 on B-lymphocytes.
Response rates range from 20% to 70% in newly diagnosed patients, and around
30% in relapsed patients. Time to response to rituximab is of the order of 3
months. A flare reaction has been described in patients treated with rituximab,
and is characterized by a transient increase in the serum IgM of patients. A serum
IgM lower than 5 g is predictive of response to this agent. We recommend the
use of this agent in younger patients with minimal symptoms of their disease and
with a lower serum IgM level.
■ Rituximab 375 mg/m2 IV weekly for four doses (consider repeating for
another four doses) and consider a maintenance schedule after the response
is established as well.
d. Ibrutinib43
Ibrutinib is an orally administered, small molecule inhibitor of Bruton tyrosine
kinase (BTK) that triggers apoptosis of WM cells with MYD88L265P.
In a phase II study in symptomatic Waldenström patients who received at
least one prior regimen, the ORR was 90.5%, and the major response rate was
73.0%; these rates were highest among patients with MYD88L265P CXCR4WT
(with WT indicating wild-type) (100% ORR and 91.2% major response rate),
followed by patients with MYD88L265PCXCR4WHIM (85.7% and 61.9%,
respectively), and patients with MYD88WTCXCR4WT (71.4% and 28.6%).
The estimated 2-year PFS and overall survival rates among all patients were
69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or
higher included neutropenia (in 22% of the patients) and thrombocytopenia (in
14%), which were more common in heavily pretreated patients; postprocedural
 bleeding (in 3%); epistaxis associated with the use of fish oil supplements (in
3%); and atrial fibrillation associated with a history of arrhythmia (5%).
■ Ibrutinib is given orally at a daily dose of 420 mg until disease progression
or the development of unacceptable toxic effects.
e. High-dose therapy and autologous stem cell transplantation
Autologous stem cell transplantation has resulted in high rates of responses
(approaching 90%) and lasting responses (PFS approaching 70 months) in a
small series of patients. The small number of patients, the nonrandomized nature
of the studies, and potential for treatment-related morbidity make it difficult to
routinely recommend this approach for most patients. It should, however, be
considered in younger patients after cytoreductive treatment with rituximab.
Treatment with alkylating agents and nucleoside analogs may impair the ability
to collect stem cells and should be judiciously used in younger patients.

V. AMYLOIDOSIS45
Only AL or AH (primary) amyloidosis, with or without associated plasma cell neoplasms,
is considered in this section. In these disorders, fragments of Ig light or heavy chain
accumulate and deposit in the affected tissues. These deposits are characterized by a
pathognomonic apple green birefringence on polarized microscopy. These deposits lead to
organ dysfunction. AL amyloidosis characteristically infiltrates the tongue, heart, skin,
ligaments, and muscle, and occasionally the kidney, liver, and spleen. The diagnosis
requires biopsy of the affected organ, although occasionally, a fat pad biopsy may obviate
that need. In patients with documented lymphomas or plasma cell neoplasms, treatment is
directed at the underlying neoplasm, but the decline in the amount of amyloid deposits is
often minimal.
With primary amyloidosis without a demonstrable underlying neoplasm, treatment
with alkylator-based therapy such as MP has been used historically and is of moderate
benefit. The use of high-dose dexamethasone is often prescribed as well. High-dose
therapy with stem cell rescue is considered in only a minority of patients as most patients
are not eligible and the procedure-related mortality remains high in this patient group.
Patients with cardiac amyloidosis have dismal outcomes often measured in months if they
have concomitant heart failure. Recently, bortezomib-based therapy has been shown to
result in high hematologic responses, but long-term follow-up and organ responses have
not been clearly defined with this therapy. The addition of alkylating agents
(cyclophosphamide or melphalan) to bortezomib has been evaluated in nonrandomized
trials and may be associated with higher hematologic response rates. In addition,
immunomodulatory agents have also shown efficacy in this setting, although they have been
associated with an increase in cardiac biomarkers. Novel proteasome inhibitors
(carfilzomib and ixazomib) as well as therapies aiming at reducing the amyloid burden
(NEOD-001) are currently being investigated in that setting. Novel effective therapies are
needed and enrollment of patients onto clinical trials should be considered early.
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I. INTRODUCTION
Carcinomas of unknown primary site (CUP) are a group of heterogeneous tumors that share
the unique clinical characteristic of metastatic diseases with no identifiable origin at the
time of therapy. A CUP is defined as a histologically confirmed metastatic cancer for which
the primary site is not identified after a complete physical examination (including pelvic
and rectal examination), a histopathologic biopsy examination using immunohistochemistry,
and computed tomography (CT) of the thorax, abdomen, and pelvis. It is important to note
that patients with upfront metastatic cancer and a clear primary tumor identified after
studying a biopsy of the metastasis or after full-body imaging are not CUP patients. Despite
advances in tumor imaging and pathology, patients with CUP still account for about 3% to
5% of all cancer patients in European registries from the Netherlands (The Netherlands
Cancer Registry 2003) and Sweden (The National Board of Health and Welfare 2006), and
also in the United States, as assessed by Surveillance, Epidemiology, and End Results
(SEER) (ACS 2007). Because of a specific and unique phenotype of early and usually
aggressive metastatic dissemination with no identifiable primary tumor, CUPs are a
challenge for physicians. Patients with CUP have a poor prognosis, attaining a median of 8
to 11 months, and only 25% survive for 1-year.1–3
Patients with metastatic lesions at diagnosis must be classified into those with a
primary tumor that is revealed by the metastatic lesion and those with “true” CUP, who are
then further classified into established clinicopathologic subsets in order to orient
diagnostic approaches and to be able to offer optimal therapeutic management.4,5

II. DIAGNOSIS OF CUPS

The diagnostic workup of patients with CUP is based on three main components: a careful
clinical examination, an extensive histopathologic analysis, and the use of imaging
techniques4–7 (Table 25.1).
A. First, a full medical history and physical examination should be obtained to guide the
diagnosis of upfront metastatic cancer without an identified primary tumor. Then,
patients should undergo a full-body CT scan, and a basic blood and biochemistry
analysis with serum tumor marker analyses (prostate-specific antigen [PSA], human
chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]) in males if appropriate.
Mammography and breast magnetic resonance imaging (MRI) are recommended for
female patients with metastatic adenocarcinoma involving axillary lymph nodes. Other
 diagnostic methods could also include additional imaging studies, such as positron
emission tomography scanning and magnetic resonance scanning of the breast, as well
as particular endoscopic procedures.2,3 18F-FDG-PET scans can be useful, particularly
if the involved cervical lymph nodes of patients exhibit squamous cell carcinoma.

TABLE
Baseline Assessments for Diagnosis of CUPs
25.1
■ The baseline assessment will include:
■ A careful medical history,
■ A thorough physical examination (with pelvic and rectal examinations),
■ Immunohistochemical analysis of biopsies for organ- or tissue-specific markers (recommended stainings include pan-cytokeratine,
CK7, and CK20 in all patients, and estrogen receptors, progesterone receptors, and HER2-neu in women). Other stainings can be
considered if found appropriate.
■ Serum tumor marker (PSA, hCG, AFP) in males if appropriate,
■ Computed tomography scans of the chest, abdomen, and pelvis,
■ Mammogram in women
■ White blood cell, red blood cell, and platelet count
■ Assessment of kidney function (serum creatinine and/or creatinine clearance) and liver function (bilirubin, AST, ALT).

AFP, alpha-fetoprotein; ALT, alanine transaminase; AST, aspartate transaminase; hCG, human chorionic gonadotropin; PSA,
prostate-specific antigen.

Finally, the diagnosis of CUP requires pathologic examination of a biopsied tumor

with the tissue sample showing an epithelial cancer. A tumor biopsy is essential for
tissue examination, immunohistochemical staining, and more specific investigations
such as genetic or molecular studies.
CUP is classified into four major histologic subtypes: 50% of cases are well-
differentiated or moderately differentiated metastatic adenocarcinoma; 30% are poorly
or undifferentiated carcinoma; 15% are squamous cell carcinomas and occur in 15% of
all CUP patients; and 5% are undifferentiated neoplasms. Most of them are further
characterized by immunohistochemistry and defined as neuroendocrine tumors,
lymphomas, germ-cell tumors, melanomas, or sarcomas.
B. Immunohistochemistry
First, a standard pathologic screening is performed to identify different tumor types
(such as carcinomas, melanomas, lymphomas, and others) (Table 25.2). In the case of
carcinomas, a panel of antibodies can help to pinpoint a possible primary site. In
particular, staining for cytokeratins CK7 and CK20 is used to subtype carcinomas: CK7
is widely expressed in breast, pancreas, lung, biliary tract, and transitional epithelium,
whereas CK20 is expressed in gastrointestinal epithelium, especially in the colon, and
in transitional epithelium.1–4 Moreover, if the first screening was inconclusive, a panel
of different antibodies could be used for a carcinoma diagnosis. These include CA125,
CDX2, cytokeratins 7 and 20, estrogen receptor, gross cystic disease fluid protein 15,
lysozyme, mesothelin, PSA, and thyroid transcription factor 1 (Table 25.3).
 TABLE
Key Screening Antibodies and Immunohistochemical Markers for the
Identification of CUPs
25.2

TABLE
Cytokeratin Profile of Frequent Primary Cancers
25.3
CK20-Negative CK20-Positive
Lung cancer (TTF1-positive in 80%)
Breast cancer (ER, PR, HER2)
Pancreatic cancer
Nonmucinous ovarian cancer
Bladder cancer
CK7-positive Endometrial cancer
Gastric cancer
Thyroid cancer
Cholangiocarcinoma
Cholangiocarcinoma
Pancreatic cancer
Hepatocarcinoma
Renal cell carcinoma Colon cancer
CK7-negative
Prostate cancer Mucinous ovarian cancer
Gastric cancer

ER, estrogen receptor; HER2, receptor tyrosine-protein kinase ERBB-2; PR, progesterone receptor; TTF-1, thyroid
transcription factor 1.

C. Prognosis and CUP classification

One of the major advances in the clinical management of CUP has been the recognition
of a number of clinicopathologic subsets with a favorable prognosis and a specific
recommended treatment. The goal of the diagnostic workup is to identify specific
subgroups (<15% of all patients), who achieve a better response to systemic or local
treatment and obtain a more favorable prognosis. However, 85% of patients do not fit
into these subgroups, and survival rates of these patients are very poor.2,3
Favorable clinicopathologic CUP entities that have been defined include squamous
cell carcinoma of the cervical lymph nodes, adenocarcinoma of the axillary lymph
nodes in women, poorly differentiated carcinoma of the retroperitoneum or the
 mediastinum in young men, peritoneal serous papillary adenocarcinomatosis, poorly
differentiated carcinoma with neuroendocrine characteristics, men with bone metastases
and elevated PSA; and classically also, in young male patients, middle-line
undifferentiated carcinomas, although whether this situation is still a specific subgroup
is currently debated.4,5
Besides the recognition of subsets of CUP with a specific treatment and a better
outcome, for the majority of patients who do not fall into one of these rather favorable
categories, a number of studies with multivariate analyses have identified a poor
performance status, the presence of liver metastases, and elevated serum lactate
dehydrogenase (LDH) levels as the main indicators of recurrent adverse prognosis.1
Specifically, the French CUP Group (GEFCAPI) developed a simple prognostic index
with the combined use of performance status and serum LDH and validated a prognostic
index comprising a “nonunfavorable” group and an “unfavorable” group with median
overall survival rates of 12 and 4 months, respectively (p < 0.0001). The 1-year
survival rates were 45% and 11%, respectively.8 These prognostic factors may help
oncologists in the daily management of patients, assess the results of clinical trials, and
design more successful clinical research studies. Several other algorithms that have
been developed by other groups exist, but most have not been validated independently.
D. Therapeutic management of patients with CUP
Patients with favorable clinicopathologic CUP entities are treated on the basis of
specific recommendations4,5:
1. Extragonadal germ-cell cancer syndrome. This patient subset is characterized by a
high response to cisplatin-based combination chemotherapy, and should thus be
managed as patients with germ-cell tumors with a poor prognosis.
2. Peritoneal papillary adenocarcinoma. Comparable to ovarian cancer, the disease is
very chemosensitive, and the treatment of this subgroup should follow the guidelines
for patients with stage III ovarian cancer, with surgical cytoreduction and
chemotherapy (platinum-based and taxane-based).
3. Adenocarcinoma in axillary lymph nodes. These patients should be managed as
women with stage II–III breast cancer. A specific workup with mammography, breast
MRI, and immunohistochemical staining for the estrogen, progesterone, and HER2
receptors on biopsy specimens provides not only the diagnosis but also the
prognosis and therapeutic indication of hormonal therapies or of the administration
of trastuzumab (a monoclonal antibody against HER2).
4. Cervical squamous cell carcinoma. These patients should be treated according to
the guidelines for locally advanced head and neck cancer.
5. Neuroendocrine carcinoma. These patients should be treated with platinum-based
chemotherapy with etoposide (cisplatin or carboplatin plus etoposide), according to
the guidelines for the treatment of patients with small-cell lung cancer.
6. Blastic bone metastases and elevated PSA. This rare subset of patients with
adenocarcinoma should be considered as having metastatic prostate cancer, and
 androgen-deprivation treatment is recommended. The guidelines for the treatment of
metastatic prostate cancer involve endocrine therapies, chemotherapy when the
cancer becomes castration resistant, and treatment with bisphosphonates to prevent
complications of bone metastases.6–9
7. Other favorable patient subsets. CUP patients with a single metastatic site
(including lymph nodes, liver, lung, adrenal gland, skin, etc.) should be treated with
radical local treatment by surgical resection, radiotherapy, or both.
8. The overall outcome of patients with CUP who do not fit into these specific
subgroups is poor, and the benefit of chemotherapy over best supportive care has not
been established by a randomized trial. This group of patients is empirically treated
with chemotherapy drugs that have activity against a wide variety of primary tumors.
The optimal chemotherapy regimen to be used also remains to be determined, with
only a few randomized trials being reported.1–6 Although no evidence-based
standard therapy has been established from phase III trial data, the “Minimal
Clinical Recommendations” guidelines produced by the European Society of
Clinical Oncology (ESMO) recommend a platinum-based doublet chemotherapy
regimen with gemcitabine or taxane for CUP patients with a good performance status
(≤1).2–9
E. Future perspectives: molecular analysis in patients with CUPs
Molecular targeted therapies approved for other solid tumors are now considered for
the treatment of patients with CUP. Molecular diagnostic tools, such as DNA microarray
analysis, could help in the search for “lost” CUP origins.
The first approach is based on primary tumor molecular profiling. In recent years,
several groups have shown that cancers can be identified with a high reproducibility by
their microarray signature.12 In addition, significant therapeutic progress has been made
in a number of metastatic cancers using specific treatments (chemotherapy and/or
targeted agents), leading to improvement in progression-free survival and, in some
cases, overall survival. Therefore, it becomes more tempting to identify a primary
cancer before treating a patient with CUP so that a more specific treatment can be used.
These studies showed that almost half of the primary cancers suspected by microarray
analysis (colo-rectal cancer, hepatocarcinoma, renal cell carcinoma, breast cancer,
melanoma) would not be treated appropriately by an empiric chemotherapy regimen
like the cisplatin-gemcitabine combination. This clearly supports the study of gene
microarray analysis followed by suspected primary cancer–tailored specific therapy in
patients with CUP. Based on these promising results, the “à la carte CUP of T trial—
GEFCAPI 04” is a European randomized phase III trial comparing a molecular
analysis–oriented treatment with empiric chemotherapy in patients with CUP.
The second approach is based on the development of precision medicine, and has
effected tremendous improvements in the understanding of cancer biology as well as in
patients’ treatment. Comprehensive tumor molecular profiling has been the backbone of
precision medicine over the last few years, and multiple molecular screening
 technologies are becoming more widely available at decreasing costs. The widespread
use of high-throughput molecular techniques has allowed the identification of recurrent
and actionable molecular traits across various tumor types. Several prospective trials
are ongoing worldwide using high-throughput analysis for characterization of the
genomic alterations in cancer patients, with the aim of collecting on-purpose tumor
samples and subsequently analyzing them for targeted gene panel sequencing and CGH
(comparative genomic hybridization) in order to screen for actionable alterations and
allow matching of the targeted therapy to the patient’s tumor molecular profile.
Preliminary results confirm in a large cohort of patients the feasibility of molecular
characterization of cancer patients in routine clinical practice. Such an approach allows
the enrichment of early-phase clinical trials with specific and rare genomic alterations.
Recent studies suggest that CUP patients could be very good candidates for molecular
screening programs of this kind.15

References
1. Varadhachary GR, Raber MN. Carcinoma of unknown primary site. N Engl J Med.
2014;371(21):2040.
2. Briasoulis E, Tolis C, Bergh J, et al. ESMO minimum clinical recommendations for
diagnosis, treatment and follow-up of cancers of unknown primary site (CUP). Ann
Oncol. 2005;16(suppl 1):i75–i76.
3. Pavlidis N, Fizazi K. Carcinoma of unknown primary (CUP). Crit Rev Oncol Hematol.
2009;69:271–278.
4. Fizazi K. Treatment of patients with specific subsets of carcinoma of an unknown
primary site. Ann Oncol. 2006;17(suppl 10):x177–x180.
5. Hainsworth JD, Fizazi K. Treatment for patients with unknown primary cancer and
favorable prognostic factors. Semin Oncol. 2009;36:44–51.
6. Fizazi K, ed. Carcinoma of an unknown primary site. New York: Taylor and Francis
Group; 2006.
7. Bugat R, Bataillard A, Lesimple T, et al. Summary of the standards, options and
recommendations for the management of patients with carcinoma of unknown primary
site. Br J Cancer. 2003;89(suppl 1):S59–S66.
8. Culine S, Kramar A, Saghatchian M, et al. Development and validation of a prognostic
model to predict the length of survival in patients with carcinomas of an unknown
primary site. J Clin Oncol. 2002;20:4679–4683.
9. Culine S, Lortholary A, Voigt JJ, et al. Cisplatin in combination with either gemcitabine
or irinotecan in carcinomas of unknown primary site: results of a randomized phase II
study-trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI
01). J Clin Oncol. 2003;21:3479–3482.
10. Horlings HM, van Laar RK, Kerst JM, et al. Gene expression profiling to identify the
histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol.
 2008;26:4435–4441.
11. Varadhachary GR, Talantov D, Raber MN, et al. Molecular profiling of carcinoma of
unknown primary and correlation with clinical evaluation. J Clin Oncol. 2008;26:4442–
4448.
12. Monzon F, Lyons-Weiler M, Buturovic LJ, et al. Multi-center validation of a 1550-gene
expression profile for identifying tissue of origin. J Clin Oncol. 2009;27:2503−2508.
13. Ross JS, Wang K, Gay L, et al. Comprehensive genomic profiling of carcinoma of
unknown primary site: new routes to targeted therapies. JAMA Oncol. 2015;1(1):40–49.
14. Hollebecque A, Massard C, Soria JC. Implementing precision medicine initiatives in the
clinic: a new paradigm in drug development. Curr Opin Oncol. 2014;26(3):340–346.
15. Meric-Bernstam F, Brusco L, Shaw K, et al. Feasibility of large-scale genomic testing to
facilitate enrollment onto genomically matched clinical trials. J Clin Oncol.
2015;33(25):2753–2762.
 SECTION III: SUPPORTIVE CARE OF PATIENTS
WITH CANCER

I. INTRODUCTION
Supportive care of the patient receiving chemotherapy continues to gain recognition as an
equally important component of definitive therapy. Advances have been possible through
the study of evidence-based interventions and guideline development. Contributions to the
substantial improvements include better understanding of the pathophysiology of specific
side effects, increased knowledge and attention to risk factors, and availability of newer
agents for prevention and management of side effects. The side effects of cancer
chemotherapy can be acute or prolonged, and can be mild or severe in nature. Specific
cancer patient populations may be at higher risk for complications. The growing elderly
population is often affected by cancer, and may also have multiple comorbidities,
complicating the tolerance of treatment. Many chemotherapy regimens are complex,
especially with concurrent chemotherapy and radiation therapy, common in cancers of the
head/neck, esophagus, and lung. Treatment of patients with advanced disease is
particularly challenging, as many have existing symptom issues in addition to those caused
by treatment, increasing the need for palliative care. Although much progress has been
made, the management of side effects continues to be of utmost importance for the
tolerability of therapy and effect on overall quality of life. Inadequately controlled side
effects may also lead to increased use of health care resources and costs, and may
occasionally impact adherence to therapy. The implementation of evidence-based
interventions is critical in making appropriate clinical decisions for patient safety and the
management of side effects. Reduction of symptoms and complications is also important in
preventing hospital admissions, and may ultimately affect reimbursement.

II. INFUSION-RELATED COMPLICATIONS

A. Extravasation
Extravasation is an acute, infusion-related complication that should be considered an
oncologic emergency. Extravasation occurs when a chemotherapy agent is inadvertently
 administered into the perivascular space or subcutaneous tissue, instead of into the vein.
The severity of the extravasation damage depends on the specific type of drug, the
length of time the tissues are exposed, and the concentration and amount of drug
extravasated, the location of the extravasation, and other patient factors such as older
age, comorbidities, and impaired immunocompetence.1 Extravasation injury to the
tissues can range from local irritation to severe necrosis.
1. Classification
Chemotherapy drugs are often grouped into categories according to their potential to
cause tissue damage due to extravasation. Vesicant drugs are those capable of
causing pain, edema, erythema, and necrosis of the tissues when administered
outside the vein. Vesicants are further categorized as DNA-binding and non-DNA-
binding agents. The vesicant can bind to nucleic acids in the DNA of healthy cells in
the tissue, causing cell death or apoptosis. There is a continued cycle of tissue
damage as the agent is retained. DNA-binding vesicants include the anthracyclines
(daunorubicin, doxorubicin, idarubicin, and epirubicin). In agents that are non-DNA
binding, the tissue injury is mild to moderate and more localized, as the drug is
eventually metabolized in the tissue and neutralized.1,2 Examples of non-DNA-
binding agents include the plant alkaloids (vinblastine, vincristine, vinorelbine) and
the taxanes (docetaxel, paclitaxel, and paclitaxel protein-bound particles). One of
the difficulties in the vesicant designation of the taxanes is that there are some
recommendations against infusing vesicants peripherally for more than 30 to 60
minutes. Paclitaxel, for example, is often infused peripherally over 1 to 3 hours.
Current available literature supports the safety of the administration of the taxanes
through peripheral access at the recommended concentrations and durations.3 Further
updates are needed to clarify these practice guidelines.
Irritant drugs may cause redness and pain in the affected vein or extravasation
site, but do not often lead to tissue necrosis. Ulceration is unlikely unless a large
volume of concentrated drug has extravasated.
2. Risk factors
Risk factors for peripheral extravasation that are patient-related include small,
fragile veins, multiple previous venipunctures, prior treatment with irritating or
sclerosing drugs, diseases with impaired circulation, impaired cognition, and
communication difficulties. Procedure-related risk factors include multiple
venipuncture attempts, nonoptimal sites (antecubital fossa, back of hand, inner
wrist), and inexperienced personnel. Risk factors for extravasation from central
venous access devices include inadequate access or securing of the noncored
needle, deeply implanted ports, and lack of patency or blood return.1
Safe administration practices, implementation of policies and procedures, and
education of staff are all measures to assist in the prevention of extravasation
episodes. Patients should also be educated on the signs and symptoms of
extravasation, prior to their first treatment. Early identification of potential
 extravasation is important in preventing further exposure and prompt initiation of
antidotes. Common signs and symptoms of extravasation are pain or burning at the
intravenous (IV) site, redness, swelling, inability to obtain a blood return, and
change in the quality of the infusion. Any of these complaints or observations should
be considered a symptom of extravasation until proven otherwise. Table 26.1 lists
common actions should a peripheral or central extravasation be suspected.1,2,4

TABLE
Procedures to Manage Peripheral and Central Extravasations
26.1
1. Stop administration of the chemotherapy agent.
2. Leave the needle/catheter in place, and immobilize the extremity.
3. Attempt to aspirate any residual drug in the tubing, needle, or suspected extravasation site.
4. Remove peripheral IV or port needle.
5. Assess the suspected site of extravasation and patient symptoms.
6. Notify the physician or midlevel provider.
7. Administer the appropriate antidote, as shown in Table 26.2. This may include instillation of a drug antidote or application of heat or
cold to the site. Consideration for antidote order sets and verification of antidote accessibility is recommended prior to administration.
8. Provide the patient and/or caregiver with instructions, including the need to elevate the site for 48 hours and the continuation of
antidote measures as appropriate.
9. Discuss the need for further intervention with the physician, and photograph if indicated.
10. Document extravasation occurrence according to institutional guidelines.
11. Continued monitoring of extravasation site at 24 hours, 1 week, 2 weeks, and additionally as guideline recommends. Secondary
complications such as infection and pain may occur. Follow-up photographs at these time periods, if possible, are helpful in
monitoring extent of injury and progress in healing.
12. Other imaging may be done for central extravasation (chest X-ray, CT scan, venography).
13. Surgical consultation (vascular and/or plastic surgery) may be done for central extravasations or in any extravasation that may require
further interventions.

Source: Polovich M, Olsen M, LeFebvre KB. Chemotherapy and biotherapy guidelines and recommendations for
practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014 and Boulanger J, Ducharme A, Dufour A, et al. Management of
the extravasation of anti-neoplastic agents. Support Care Cancer. 2015;23:1459–1471.

3. Management strategies
There is very little evidence-based data on management of extravasation and
antidote use. Currently, dexrazoxane has the most data in treating anthracycline
extravasation, with greater than 98% efficacy.1,2 The only US Food and Drug
Administration (FDA)–approved product for the treatment of anthracycline
extravasation, Totect, has not been commercially available from the manufacturer,
with time of availability unknown. In the interim, generic dexrazoxane, or Zinecard,
is an option for use. Much of the data on the other antidotes and surgical
interventions for central extravasations such as lavage are anecdotal or based on
case reports. Surgical lavage within 12 hours of a central extravasation may have
some benefit; however, the outcomes may be less favorable for extravasations
greater than 50 mL and the nature of the extravasated agent.5 See Table 26.2 for
common chemotherapy agents and management guidelines.
4. Administration practice change: vincristine
 Guidelines for the administration of vincristine via mini-bags have been
recommended by several national and international organizations, such as the World
Health Organization (WHO), Institute for Safe Medication Practices (ISMP), and
The Joint Commission (TJC). While it is often common practice to administer
vesicants via syringe as an IV sidearm push, the use of mini-bags is essential in the
prevention of inadvertent intrathecal administration of vincristine.
Although there may have been initial resistance to the adoption of this
guideline, many organizations adhere to this practice. The concern for risk of
extravasation has been found to be minimal, and the mini-bag use has been found to
be safe, practical, and feasible.6
B. Infusion reactions: anaphylaxis, hypersensitivity reactions (HSRs), and cytokine-
release reactions

TABLE
Common Vesicant and Irritant Drugs and Potential Antidotes
26.2

Infusion reactions are considered an oncologic emergency associated with

chemotherapy administration. Specific drugs with the potential for hypersensitivity with
or without an anaphylactic response should be administered under the constant
supervision of a competent and experienced nurse and with a physician or midlevel
provider readily available, preferably during the daytime hours. Important
preassessment data to be documented include the patient’s allergy history, though this
information may not predict an allergic reaction to chemotherapy. Patients who are
currently prescribed beta blockers and angiotensin-converting enzyme inhibitors may
have increased severity of an anaphylactic reaction and may have difficulty responding
to effective anaphylactic treatments.7 Furthermore, cardiovascular and pulmonary
disorders may also complicate the patient’s ability to tolerate a HSR. Other risk factors
 include previous exposure to the agent and failure to administer effective prophylactic
medications. Chemotherapy drugs with the highest risk of HSRs are asparaginase, the
taxanes (e.g., paclitaxel and docetaxel), and platinum compounds (e.g., cisplatin,
carboplatin, and oxaliplatin). Carboplatin is the agent with the most reported HSRs in
patients with ovarian cancer. In patients receiving more than seven cycles, the incidence
of HSRs is 27%. BRCA carriers are at greatest risk, and up to 40% of BRCA+ ovarian
cancer patients can be sensitized after 10 exposures.8 Drugs with a low to moderate risk
include the anthracyclines, bleomycin, IV melphalan, etoposide, and humanized (e.g.,
trastuzumab) or chimeric (e.g., rituximab) monoclonal antibodies.
1. Types of reactions
Type 1 HSRs (which may or may not be immune-mediated) are the most common
chemotherapy-induced type of reactions. These reactions characteristically occur
within 1 hour of receiving the drug; however, with paclitaxel, the HSRs often occur
within the first 10 minutes of the start of the infusion. Common manifestations of a
grade 1 or 2 type I reaction include flushing, urticaria, fever, chills, rigors, dyspnea,
and mild hypotension. Grade 3 and 4 reactions may involve bronchospasm,
hypotension requiring treatment, angioedema, or symptoms requiring hospitalization.
Less common signs and symptoms of infusion reactions include back or abdominal
pain, nausea, vomiting, and diarrhea, incontinence, and anxiety. With appropriate
premedication, the incidence of the HSRs has markedly decreased. Commonly used
premedications include dexamethasone, diphenhydramine, and an H2-histamine
antagonist such as cimetidine, ranitidine, or famotidine. Emergency equipment
should be immediately accessible, including oxygen. The following parenteral drugs
should also be stocked in the treatment area: epinephrine 1:10,000 solution,
diphenhydramine 25 to 50 mg, methylprednisolone 125 mg, and dexamethasone 20
mg.1 The development of a clinical guideline for HSRs, with or without true
anaphylaxis, may be helpful in preparing for a potential reaction, reducing delays in
response time to a reaction, and standardizing the management of a reaction with
standing orders. Table 26.3 is an example of a HSR standing order guideline.
2. Cytokine-release reactions, which are commonly referred to as infusion reactions,
are a symptom complex that occurs most frequently when monoclonal antibodies are
administered. This type of reaction is believed to be primarily related to the release
of cytokines from targeted cells and other immune cells. Most monoclonal
antibodies have the potential to cause this syndrome, and the appearance may be
similar to the type I HSR. In contrast, however, the cytokine-release reactions may
be managed by short-term cessation of the infusion, administration of histamine
blockers, and restarting the infusion at a slower rate, that is, 50% after resolution of
symptoms. Table 26.4 compares the differences between chemotherapy and
biotherapy infusion reactions.1,7–9
 TABLE
Sample Standing Orders for Hypersensitivity Reactions to Chemotherapy Agents
26.3
Have the following medications available:
■ Diphenhydramine 50 IV
■ Methylprednisolone 125 mg IV or equivalent hydrocortisone
■ Epinephrine (1:10,000 solution)
1. If signs/symptoms of hypersensitivity occur (such as urticaria [hives], respiratory distress, bronchospasm, hypotension,
angioedema, flushing, chest/back pain, anxiety), stop infusion of chemotherapy/biotherapy agent.
2. Maintain IV access with IV normal saline at 200 mL/hour until blood pressure stabilizes.
3. Administer oxygen at 2–4 L/minute, and measure pulse oximetry.
4. Administer methylprednisolone 125 mg IV push.
5. Administer diphenhydramine (Benadryl) 50 mg IV push.
6. Continuously monitor blood pressure, pulse, and oxygen saturation.
7. Notify physician immediately for further orders.
8. If symptoms do not resolve or worsen, administer epinephrine as directed by physician.
9. Initiate a code if airway patency is not maintained or cardiopulmonary arrest occurs.

IV, intravenous.
Source: Polovich M, Olsen M, LeFebvre KB. Chemotherapy and biotherapy guidelines and recommendations for
practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014 and Vogel WH. Hypersensitivity reactions to antineoplastic drugs.
In: Yarbro CH, Wujcik D, Gobel BH, eds. Cancer symptom management. 4th ed. Burlington: Jones & Bartlett Learning;
2014:115–130.

3. Risk stratification testing

Test doses or skin tests may be performed if there is an increased suspicion for
hypersensitivity. Standardized testing has not been established, and different testing
concentrations have been reported. It is recommended to wait at least 2 to 4 weeks
following the initial reaction to test dose, to ensure that the skin test is not falsely
negative. This is most commonly done for platinum agents. Carboplatin skin testing
sensitivity has been reported at 85.7%, with an 8% to 8.5% false-negative rate.
Repeated skin testing has been recommended for risk stratification, as patients with
a negative skin test could convert to a positive skin test result with subsequent
testing.8,10 A skin testing protocol for carboplatin skin testing is shown in Table
26.5.
 TABLE
Infusion Reactions: The Comparison of Chemotherapy and Biotherapy Agents
26.4
Characteristic Chemotherapy Biotherapy
Reaction type Type I hypersensitivity Cytokine release
Platinum: after multiple cycles (Carboplatin >7
Timing of reaction Most monoclonal antibodies: first infusion
cycles)
Taxanes: first or second infusion Rituximab: any infusion
Prevention Premedication Premedication
■ Dependent on grade
■ Grade 1 or 2: premedication—reinitiate
■ Interruption
Management/rechallenge infusion at slower rate
■ Premedication
■ Grade 3 or 4: not likely to rechallenge
■ Reinitiate at slower rate
■ 1: Mild reaction: No infusion interruption
■ 1: Transient flushing/rash/fever >38°C ■ 2: Infusion interruption; responds promptly to
■ 2: Rash; flushing; urticaria, dyspnea, fever symptomatic treatment (drugs, fluids);
>38°C prophylactic medications indicated for ≤24
■ 3: Symptomatic bronchospasm, with/without hours
Grading urticaria; parenteral medications indicated; ■ 3: Prolonged/recurrences of symptoms after
allergy-related angioedema; hypotension initial improvement; hospitalization indicated
■ 4: Anaphylaxis ■ 4: Life-threatening; pressors or ventilator
■ 5: Death needed
■ 5: Death

Source: Polovich M, Olsen M, LeFebvre KB. Chemotherapy and biotherapy guidelines and recommendations for
practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014; Vogel WH. Hypersensitivity reactions to antineoplastic drugs. In:
Yarbro CH, Wujcik D, Gobel BH, eds. Cancer symptom management. 4th ed. Burlington: Jones & Bartlett Learning;
2014:115–130; Castells MC. Anaphylaxis to chemotherapy and monoclonal antibodies. Immunol Allergy Clin North Am.
2015;35:335–348; and National Cancer Institute Cancer Therapy Evaluation Program. Common terminology criteria for adverse
events (CTCAE) (Version 4.03); 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf

Tryptase is a protease that is present in all human mast cells. Tryptase is

released from mast cell granules during allergic and anaphylactic reactions, within
30 to 60 minutes from the onset of symptoms. An elevated tryptase level (>11
ng/mL) drawn at the time of the reaction may be helpful in determining the indication
for desensitization. If the serum tryptase level is elevated, a subsequent level is
needed to screen for mastocytosis.8,11
 TABLE
Sample Carboplatin Skin Testing Protocol
26.5
1. All patients receiving their sixth and subsequent doses of carboplatin will have skin test dosing.
2. The planned carboplatin dose is diluted in 50 mL of 0.9% sodium chloride. A 0.02-mL aliquot is withdrawn and administered
intradermally.
3. Following the intradermal injection, the injection site is examined at 5, 15, and 30 minutes.
4. A positive skin test is a wheal of ≥5 mm in diameter, with surrounding redness. A strongly positive skin test was one with ≥1 cm in
diameter. If a patient develops a positive skin test, the physician is notified.
5. If the skin test is negative, the patient is then pretreated for the carboplatin with antiemetics, dexamethasone, diphenhydramine, and
famotidine. Thirty minutes after the premedications are given, the carboplatin is given.

Source: Patil SU, Long AA, Ling M, et al. A protocol for risk stratification of patients with carboplatin-induced hypersensitivity
reactions. J Allergy Clin Immunol. 2012;129(2):443–447; Calado J, Picard M. Diagnostic tools for hypersensitivity to platinum
drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators. Curr Allergy Asthma Rep. 2014;14:451; and
Blatman KS, Castells MC. Desensitizations for chemotherapy and monoclonal antibodies: indications and outcomes. Curr
Allergy Rep. 2014;14:453.

4. Desensitization procedures
Desensitization procedures for specific agents may be utilized in patients in which
there is considerable benefit to the continuation of therapy. Desensitization may be
utilized after HSRs to paclitaxel, platinum agents (cisplatin, carboplatin,
oxaliplatin), and rituximab, and is documented in the literature; however, planning
for the desensitization is necessary. Regimens including dexamethasone 20 mg orally
at 36 and 12 hours before chemotherapy and the morning of chemotherapy have been
studied. Other regimens have included loratadine or cetirizine 10 mg for days and
hours preceding the desensitization. Other premedications such as oral
acetylsalicylic acid 325 mg may be used, if the reaction included flushing. A full 30
minutes before the chemotherapy, other IV premedications such as dexamethasone 20
mg, diphenhydramine 50 mg, and a H2-histamine antagonist are given. For
paclitaxel, the desensitization procedure continues with administration of a test dose
of 2 mg in 100 mL of normal saline over 30 minutes. If there is no reaction, 10 mg in
100 mL of normal saline is given over 30 minutes, followed by the remaining full
dose in 500 mL of normal saline over 3 hours if there is still no reaction.12 If a
reaction is experienced, the usual diphenhydramine and methylprednisolone
medications are given.
C. Chemotherapy-induced nausea and vomiting (CINV)
Nausea and vomiting continue to be some of the most feared side effects of
chemotherapy. Nausea and vomiting can be distressing enough to the patient to cause
extreme physiologic and psychological discomfort, culminating in withdrawal from
therapy. With the advent of more effective antiemetic regimens in the last 20 years,
many improvements in the prevention and control of nausea and vomiting have led to a
better quality of life for patients receiving chemotherapy. The goal of therapy is to
prevent the three phases of nausea and vomiting: that which occurs before the treatment
is administered (anticipatory), that which follows within the first 24 hours after the
 treatment (acute), and that which occurs more than 24 hours after the treatment
(delayed). It is also important to assess nausea and vomiting separately because they
are different events and may have different causes. Factors related to the chemotherapy
that can affect the likelihood and severity of symptoms include the specific agents used,
the doses of the drugs, and the schedule and route of administration. Other patient
characteristics that may affect emesis include history of poor emetic control, history of
alcoholism, age, gender, anxiety level, and history of motion sickness.1,13
1. Emetic potential
To plan an effective approach to control nausea and vomiting, the chemotherapeutic
agents are grouped according to their emetic potential (Table 26.6).14,15 This type of
categorization is helpful in making decisions regarding possible antiemetics to be
used and how aggressive the antiemetic regimen should be for patients receiving
chemotherapy for the first time or in subsequent treatments. It is important to select
appropriate antiemetics from the outset with the first cycle of therapy. Failure to
control nausea and/or vomiting may result in a conditioned response and subsequent
anticipatory nausea and vomiting.
2. Antiemetic drugs
Agents that have been effective in preventing and treating nausea and vomiting
(Table 26.7) come from various pharmacologic classes. They work through different
mechanisms that may relate to the pathophysiologic processes causing nausea and
vomiting. Within the last 20 years, it was discovered that agents that block
predominately the serotonin 5-hydroxytryptamine subtype 3 (5-HT3) receptors,
rather than the dopamine receptors, have greater efficacy in the prevention of nausea
and vomiting. More recent research indicates that the tachykinins, including a
peptide called substance P, play an important role in emesis. Substance P binds to
the neurokinin type 1 (NK-1) receptor. Thus, the NK-1 receptor antagonists are now
validated in their role in inhibiting nausea and vomiting with moderately and highly
emetogenic chemotherapy. NK-1 receptor antagonists are thought to improve acute
nausea and vomiting associated with chemotherapy when combined with standard
regimens (i.e., dexamethasone and 5-HT3 receptor antagonists) and to have
additional effect during the period of delayed nausea and vomiting, alone or in
combination with dexamethasone. Netupitant is a new fixed-dose oral agent that
combines netupitant, a new highly selective NK-1 receptor antagonist, and
palonosetron, a serotonin 5-hydroxytryptamine receptor antagonist. This provides an
oral option for CINV associated with highly and moderately emetogenic
chemotherapy.16 Olanzapine has recently been incorporated into clinical practice
guidelines, not only for breakthrough nausea and vomiting, but for the prevention of
acute and delayed emesis. Olanzapine has been studied in combination with
palonosetron and dexamethasone.15,17–20
 TABLE
Emetogenic Potential for Commonly Used Intravenous and Oral
Chemotherapeutic Agents*
26.6
Highly Emetogenic Agents Moderately Emetogenic Agents Mildly Emetogenic agents
(≥75% Potential for Nausea, (50%–75% Potential for (25%–50% Potential for
Vomiting, or Both) Nausea, Vomiting, or Both) Nausea, Vomiting, or Both)
■ Ado-trastuzumab emtansine
■ Asparaginase
■ Bevacizumab
■ IV: ■ Bleomycin
■ Arsenic trioxide ■ Bortezomib
■ IV:
■ Azacitidine ■ Capecitabine
■ Carmustine
■ Bendamustine ■ Cetuximab
■ Cisplatin
■ Carboplatin ■ Cyclophosphamide (<200 mg/m2)
■ Cyclophosphamide (>1 g/m2) ■ Clofarabine
■ Cytarabine (>1 g/m2) ■ Cytarabine (<200 mg/m2)
■ Cyclophosphamide (200 mg/m2–1 g/m2) ■ Decitabine
■ Dacarbazine
■ Cytarabine (200 mg/m2–1 g/m2) ■ Docetaxel
■ Doxorubicin (≥60 mg/m2) ■ Daunorubicin
■ Epirubicin ■ Fludarabine
■ Doxorubicin (<60 mg/m2) ■ Fluorouracil
■ Ifosfamide (>1.2 g/m2) ■ Etoposide ■ Gemcitabine
■ Methotrexate (>1 g/m2) ■ Idarubicin ■ Ixabepilone
■ Mitomycin (>15 mg/m2) ■ Ifosfamide (<1.2 g/m2) ■ Liposomal doxorubicin
■ Oxaliplatin ■ Irinotecan ■ Methotrexate (<50 mg/m2)
■ Oral: 2 2
■ Methotrexate (50 mg/m –1 g/m ) ■ Paclitaxel
■ Lomustine ■ Pemetrexed
■ Mitomycin (<15 mg/m2)
■ Procarbazine ■ Pertuzumab
■ Oral:
■ Temozolomide ■ Rituximab
■ Cyclophosphamide
■ Etoposide ■ Trastuzumab
■ Vinblastine
■ Vincristine
■ Vinorelbine

*High-dose therapy requiring progenitor cell support is not included in this table.

Source: Polovich M, Olsen M, LeFebvre KB. Chemotherapy and biotherapy guidelines and recommendations for
practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014; Tipton J. Nausea and vomiting. In: Yarbro CH, Wujcik, D, Gobel
BH, eds. Cancer symptom management. 4th ed. Burlington: Jones & Bartlett Learning; 2014:213–239; Jordan K, Gralla R,
Jahn F, et al. International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and
implementation in daily routine practice. Eur J Pharmacol. 2014;722:197–202; National Comprehensive Cancer Network.
Clinical guidelines in oncology: antiemesis (Version 1); 2015. Retrieved June 21, 2015, from
http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf; and Irwin M, Johnson LA. Putting evidence into
practice: a pocket guide to cancer symptom management. Pittsburgh: Oncology Nursing Society; 2014.

TABLE
Agents Used for Chemotherapy-Induced Nausea and Vomiting
26.7
 3. Combination antiemetic therapy
Several antiemetic regimens are effective, but their design should be based on two
general principles:
■ Combinations of antiemetics are more effective than single agents.
■ Preemptive treatment and scheduled administration are more effective than
reactive therapy to prevent nausea and vomiting early in therapy and to
manage potential delayed nausea and vomiting in the days following
treatment.
Table 26.8 shows examples of antiemetic regimens that may be used when the
chemotherapy has a high, moderate, and low emetic potential.
4. Multiday chemotherapy
 The prevention of nausea in multiday chemotherapy regimens is challenging, and
little data is known on the best pharmacologic intervention. Consensus guidelines
indicate that including dexamethasone on all days of chemotherapy is recommended,
as well as a 5-HT3 receptor antagonist. If palonosetron is used, repeat dosing is
likely to be safe, according to the evidence.15
5. Nonpharmacologic interventions
Patients who are likely to experience or who have experienced anticipatory nausea
and vomiting related to chemotherapy may benefit from the use of nonpharmacologic
interventions in addition to the pharmacologic agents taken. The use of systematic
desensitization, hypnosis, acupuncture, acupressure, guided imagery, music therapy,
and progressive muscle relaxation is being studied in this setting.21 Many of these
are forms of distraction that assist patients in maintaining a feeling of control over
their treatment effects. Massage therapy, hypnosis, exercise, ginger, and
acustimulation with wristband devices have insufficient data, and further studies are
needed to support their use as interventions. With increasing attention to
complementary therapies, it is hoped that more clinical studies will determine their
value in patient care. Patients who are able to have little or no nausea and vomiting
with their first chemotherapy treatment often assert that positive thinking is helpful
as well. Patients may also prepare for their chemotherapy treatments by eating foods
that do not have offensive odors or spicy tastes. Clear liquids, foods served at room
temperature, soda crackers, and carbonated beverages are sometimes good
suggestions. Following chemotherapy, smaller, more-frequent meals are less likely
to promote the development of nausea and vomiting.
 TABLE
Examples of Regimens for Antiemetic Prevention and Management of
Chemotherapy-Induced Nausea and Vomiting
26.8
Level I: patients receiving a mildly emetogenic agent
■ Dexamethasone 12 mg PO/IV before chemotherapy
■ with or without
■ Prochlorperazine 10 mg PO before chemotherapy, then 10 mg PO every 4–6 hours when necessary, or
■ Lorazepam 1 mg PO every 4–6 hours when necessary, or both

Level II: patients receiving a moderately emetogenic agent or patients receiving a mildly
emetogenic agent who have failed to respond to or are intolerant of at least two level I
regimens
■ Fosaprepitant 150 mg IV before chemotherapy and
■ Palonosetron* 0.25 mg IV before chemotherapy, and
■ Dexamethasone 10–12 mg IV/PO before chemotherapy, then 8 mg PO daily on days 2–4
■ with or without
■ Lorazepam 1 mg PO or IV before chemotherapy every 4–6 hours when necessary or
■ Prochlorperazine 10 mg PO every 4–6 hours when necessary, or both

Level III: patients receiving a highly emetogenic agent or patients receiving two or more
moderately emetogenic agents or patients who have failed a level II regimen
■ Fosaprepitant 150 mg IV before chemotherapy and
■ Palonosetron † 0.25 mg IV before chemotherapy and
■ Dexamethasone 10–12 mg PO/IV before chemotherapy, then 8 mg PO on days 2–4, and
■ Lorazepam 1 mg PO or IV before chemotherapy, then every 4–6 hours when necessary
■ In addition, for delayed nausea and vomiting:
■ Metoclopramide 40 mg PO every 6 hours × 4 days, and
■ Give antiemetics 20–30 minutes prior to chemotherapy when using the IV route and 1 hour prior to chemotherapy when using the PO
route. Given in this fashion, oral medication is usually as effective as the same medication IV, and the cost is considerably less

IV, intravenous; PO, by mouth.

*Alternatives (5-HT3): ondansetron 16–24 mg IV × 1 before chemotherapy, dolasetron 100 mg PO, or granisetron 1 mg PO or
IV before chemotherapy.
†Alternatives (5-HT antagonists): ondansetron 16–24 mg IV before chemotherapy; dolasetron 100 mg PO, or granisetron 1 mg
3
PO or IV before chemotherapy.
Source: Polovich M, Olsen M, LeFebvre KB. Chemotherapy and biotherapy guidelines and recommendations for
practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014; Tipton J. Nausea and vomiting. In: Yarbro CH, Wujcik, D, Gobel
BH, eds. Cancer symptom management. 4th ed. Burlington: Jones & Bartlett Learning; 2014:213–239; Jordan K, Gralla R,
Jahn F, et al. International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and
implementation in daily routine practice. Eur J Pharmacol. 2014;722:197–202; National Comprehensive Cancer Network.
Clinical guidelines in oncology: antiemesis (Version 1); 2015. Retrieved June 21, 2015, from
http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf; and Irwin M, Johnson LA. Putting evidence into
practice: a pocket guide to cancer symptom management. Pittsburgh: Oncology Nursing Society; 2014.

III. OTHER SHORT-TERM COMPLICATIONS RELATED TO CANCER

CHEMOTHERAPY
A. Mucositis and other oral complications
The oral mucosa is vulnerable to the effects of chemotherapy and radiotherapy because
of its rapid growth and cell turnover rate. Radiotherapy also interferes with the
production of saliva, and may increase oral complications because of a consequent
reduction in the protective effect of the saliva. It is crucial to manage oral
 complications effectively because patients may experience considerable discomfort or
develop secondary infections from the disruption of the oral mucosa. The likelihood of
the development of mucositis from a drug is dependent on the agent, the dose, and the
schedule of administration.1,22
1. Specific chemotherapy agents causing mucositis
■ Antimetabolites: methotrexate, fluorouracil, capecitabine, cytarabine, irinotecan
■ Antitumor antibiotics: doxorubicin, idarubicin, dactinomycin, mitomycin,
bleomycin
■ Plant alkaloids: vincristine, vinblastine, vinorelbine
■ Taxanes: docetaxel, paclitaxel
■ Alkylating agents: high doses of busulfan, cyclophosphamide
■ Mammalian target of rapamycin inhibitors: everolimus, temsirolimus
2. Prevention and early detection
If oral complications are anticipated, it is important to implement a good oral
hygiene program before the initiation of therapy. Dental consultation is
recommended for all, and mandatory for those at increased risk, including those with
stem-cell transplant, leukemia, or head and neck malignancies. Maintaining good
nutrition and dental hygiene are also primary preventive measures. Establishing an
oral care protocol is fundamental to the prevention and treatment of mucositis.
Avoiding agents with alcohol is recommended, and sodium bicarbonate mouth rinses
are recommended. For patients receiving bolus fluorouracil, it is recommended that
patients perform oral cryotherapy. This involves holding ice chips in the mouth,
starting 5 minutes prior to the bolus of fluorouracil and for 30 minutes after the
administration of the drug.1,22,23 This intervention is effective for bolus
administration only and should not be done when oxaliplatin is also given, owing to
the potential for increase in acute neurotoxicity. Systematic oral assessments should
be integrated into the physical examination at regular intervals. Special attention
should be given to the tongue, the gingiva, the buccal mucosa, the soft palate, and the
lips. It is also important to assess the patient for soreness, functional ability to
swallow, and any effects on eating.
3. Management of oral complications
Although the primary goal is prevention, once oral complications develop, the focus
of care should shift to the continuation of good oral hygiene and treatment of
symptoms. Agents used for oral care are categorized according to function:
cleansing agents, lubricating agents, analgesic agents, and preventive agents.
Commercial mouthwashes and lemon glycerin swabs are not recommended for use
because of their irritating and drying effects. If painful ulcerations do develop,
topical relief may be best obtained by using single-agent topical analgesics.
Compounded analgesic mouth rinses such as “magic mouthwash” consisting of
various components such as lidocaine, diphenhydramine, antacids, and/or sodium
bicarbonate may be helpful, but do not have clear evidence of benefit. Systemic pain
 control measures such as oral or parenteral narcotics should be implemented if
topical analgesics are ineffective.1,22,23
B. Taste alterations
Taste alterations are reported in 45% to 84% of patients receiving chemotherapy. The
changes have been described as the absence of taste, a decreased or increased taste
sensitivity, or a distorted taste.24 A broad range of chemotherapy drugs can cause taste
alterations, including cyclophosphamide, doxorubicin, fluorouracil, and the platinum-
based regimens. The onset and timing of the taste changes have been reported within a
few minutes of the start of administration, lasting several days to weeks. While it is a
commonly observed symptom problem, little is known about the mechanisms that cause
it and interventions to prevent or manage it. Taste alterations can impact quality of life,
appetite, and oral intake.
1. Interventions
The use of plastic silverware instead of metal silverware is a strategy to make food
more palatable. There are pilot data suggesting that zinc supplementation may be
promising in improving taste perception during chemotherapy.24,25 Cancer patients
have also reported that eating cold foods, and the use of herbs and spices and
flavored gum, mints, and candies may be helpful. Other anecdotal recommendations
include the use of lemon, lime, or orange to overcome metallic taste changes.
C. Fatigue
Cancer treatment–related fatigue has become an increasingly reported side effect of
cancer therapy, and it can be the most distressing. An estimated 25% to 99% of patients
experience fatigue.26 Cancer treatment–related fatigue is a subjective feeling of
tiredness that is disproportionate to the level of exertion. This symptom often interferes
with activities of daily living and can be part of a symptom cluster, which can be
debilitating if left untreated. Any chemotherapy or biotherapy agent may cause fatigue,
and all patients should be screened for potential etiologic factors and appropriate
management.27
Interventions recommended for fatigue include exercise, education, energy
conservation and activity management, measures to optimize sleep quality, massage, and
behavioral therapies such as relaxation and healing touch. The strongest and most
cumulative evidence is cited in support of exercise as an intervention for fatigue.1,23
Exercise interventions should be individualized and based on the patient’s specific
disease and treatment. Medical management may have some benefit, particularly
psychostimulants such as methylphenidate and modafinil, and antidepressants if
depression is a causal factor.1,23,28 While erythropoiesis-stimulating agents should be
used with caution, they may have some benefit in correcting fatigue associated with
anemia.
D. Diarrhea
Among the many causes of diarrhea in patients with cancer are chemotherapy,
radiotherapy, the cancer itself, medications, supplemental feedings, and anxiety.
 Chemotherapy may result in osmotic diarrhea or secretory diarrhea, and is often
associated with the destruction of actively dividing epithelial cells of the
gastrointestinal (GI) tract. Secretory diarrhea also may result from infectious causes
(e.g., Clostridium difficile or other enterocolitis-causing bacteria), with or without
concurrent neutropenia. Prolonged diarrhea can lead to discomfort, severe electrolyte
imbalances and dehydration, altered social life, and poor quality of life. In the past,
little attention has been paid to the prompt evaluation and management of diarrhea, but
with increasing use of agents such as irinotecan, the observation of severe and
potentially life-threatening problems has heightened awareness of this side effect. The
elderly, in particular, may be at increased risk for treatment-related diarrhea and may
require close monitoring.
1. Chemotherapy and biologic agents
Agents that contribute to the development of diarrhea most commonly include the
antimetabolites such as fluorouracil, capecitabine, methotrexate, cytarabine, and
irinotecan. In addition, agents such as dactinomycin, hydroxyurea, idarubicin, the
nitrosoureas, and paclitaxel may cause diarrhea. When diarrhea from fluorouracil or
irinotecan is present while on therapy, it is a sign of toxicity that must be monitored
closely because it can escalate rapidly to severe levels at which the drug must be
held or discontinued. Diarrhea has also been noted with biotherapy agents such as
interferons and interleukin. The targeted agent ipilumumab has been associated with
diarrhea, approximately 32%, with all grades. Gastrointestinal symptoms such as
abdominal pain, mucous or blood in the stool, and immune-mediated enterocolitis
are associated symptoms and require different management with corticosteroids.
Oral small molecule targeted therapies, such as lapatinib, erlotinib, sorafenib, and
sunitinib, can also cause diarrhea, but it is manageable with proper education and
reporting.1 High-dose chemotherapy regimens used in stem cell transplantation may
also be associated with severe diarrhea, and may be caused by acute graft-versus-
host disease.
2. Assessment
Assessment of a patient experiencing diarrhea should begin with a baseline history
of usual elimination patterns, pattern of symptoms, and concurrent medications. The
duration of the diarrhea and frequency of stool passage should be noted with
reference to a stool diary if indicated. The physical examination may disclose
abdominal tenderness, signs of dehydration, and disruption in perianal or peristomal
skin integrity. Laboratory data may be obtained to assess serum chemistries,
complete blood count, and stool samples for C. difficile toxin and other enteropathic
bacteria.
3. Management
Treatment-related diarrhea management is often symptomatic and requires little or no
alteration in cancer therapy. Agents that decrease bowel motility should not be used
for longer than 24 hours unless significant infections have been excluded. In the
 absence of obvious inflammation and infection, it is appropriate to treat most
patients with nonspecific treatment for diarrhea, including opioids (loperamide,
diphenoxylate, and codeine), anticholinergics (atropine and scopolamine), or both.
Octreotide is often effective in controlling chemotherapy-related diarrhea as well as
diarrhea associated with the carcinoid syndrome. As previously discussed,
management of diarrhea and related symptoms with ipilumumab requires
management with corticosteroids.1,23 Table 26.9 lists common agents used to treat
diarrhea. Nonpharmacologic measures that may also assist in the prevention and
management of diarrhea are a low-residue diet and increased fluids. If the diarrhea
is severe, IV hydration is necessary to prevent serious hypovolemia, electrolyte
disturbances, and shock. In patients who experience severe irinotecan-associated
diarrhea, antibiotic therapy such as ciprofloxacin is recommended because of a high
incidence of an infectious contribution to GI problems, which may include a
functional ileus.
E. Constipation
In patients whose cancer has resulted in debility or immobility or in those who require
narcotic analgesics, constipation can be a particular problem. Constipation may also
develop in patients who have received neurotoxic chemotherapy agents including the
vinca alkaloids, etoposide, and cisplatin, each of which may cause autonomic
dysfunction. Targeted agents including thalidomide, lenalidomide, and bortezomib are
known to cause constipation. Decreased bowel motility due to intra-abdominal disease,
hypercalcemia, dehydration, and antiemetic use can also contribute to constipation.
Chronic constipation in patients with cancer is a problem that is more easily prevented
than treated. A diet high in bulk fiber, fresh fruits, and vegetables, as well as adequate
fluid intake, may help to minimize constipation. Patients started on narcotic analgesics
should also begin a bowel regimen, first with mild stool softeners and bulk laxatives,
and then proceeding to stimulants or osmotic laxatives if the milder regimen is not
effective. Methylnaltrexone is an agent approved for use with opioid-induced
constipation and has clear evidence-based benefit. An example of a bowel regimen for
a patient at risk for constipation is as follows:
 TABLE
Pharmacologic Management Strategies for Diarrhea
26.9
Agent Comments
Kaolin pectin (Kaopectate) 30–60 mL PO after each loose stool
Two capsules (4 mg) PO 4 hours initially, then add 1 capsule (2 mg)
Loperamide (Imodium)
after each loose stool; should not exceed 16 capsules daily
1–2 tablets PO 4 hours; should not exceed eight tablets daily; there
Diphenoxylate hydrochloride, with atropine sulfate (Lomotil)
may be anticholinergic effects due to atropine
Used with early-onset cholinergic diarrhea (i.e., irinotecan) 0.25–1 mg
Atropine
PO or SC
May be useful for fluorouracil-induced diarrhea; starting dose: 0.05–
Octreotide 0.1 mg SC twice a day; may be increased to 1.8 mg/day in refracfftory
diarrhea
Sandostatin LAR Depot is indicated for carcinoid and VIPomas. It is

a slow-release drug that is dosed at 20–30 mg every 4 weeks
Moderate enterocolitis: 0.5 mg/kg/day of prednisone or equivalent (if
4–6 stools over baseline/day and symptoms ongoing >7 days)
Dexamethasone (for use with ipilumumab or nivolumab) Severe enterocolitis: 1–2 mg/kg/day of prednisone or equivalent (if
stools ≥7 stools over baseline/day with peritoneal signs of bowel
perforation, fever, ileus)

PO, by mouth; SC, subcutaneously; VIPoma, vasoactive intestinal peptide tumor.

1. Docusate sodium 100 mg twice a day alone or with casanthranol one capsule twice a
day.
2. If no bowel movement, add:
■ Senna at bedtime (dose varies with the preparation) or
■ Milk of magnesia 30 mL at bedtime.
3. If no bowel movement with the above, may add:
■ Bisacodyl one to three tablets or one 10-mg suppository at bedtime or
■ Lactulose one to four tablespoons daily or
■ Polyethylene glycol (PEG) 17 g daily.
4. Other more aggressive alternatives, if there is no impaction, include:
■ Fleet enema
■ Magnesium citrate 1 bottle
■ Tap-water enema.
5. Prokinetic agents, such as metoclopramide (10 to 20 mg every 6 hours) may be used
to promote upper GI motility, gastric emptying, and intestinal transit time.
F. Neurotoxicity
The incidence of neurotoxicity associated with chemotherapy is increasing, potentially
because of the greater use of high-dose chemotherapy and newer drugs causing
neurotoxicity used in combination. In many cases, early detection and treatment of
neurotoxicity (i.e., reduction of drug dose or discontinuation) allow for the reversal of
symptoms. The neurotoxic symptoms may manifest as altered level of consciousness or
 coma, cerebellar dysfunction, ototoxicity, or peripheral neuropathy, which may be
temporary but can cause significant changes in functional ability that persist as a long-
term effect. It is also important to assess renal function because poor renal function may
reduce clearance of the chemotherapy agent, leading to increased neurotoxicity.
1. Chemotherapy and biologic agents
Agents with known potential for neurotoxicity include high-dose cytarabine, high-
dose methotrexate, vincristine, vinblastine, vinorelbine, ifosfamide, cisplatin,
carboplatin, oxaliplatin, paclitaxel, docetaxel, ixabepilone, procarbazine,
bortezomib, thalidomide, interleukin-2, and the interferons.
2. Prevention and early detection
Close monitoring for neurotoxicity is key to the prevention of permanent neurologic
damage. Assessment of symptoms of neurotoxicity should be documented on a
routine basis. In certain treatment regimens, altering the drug sequence can markedly
decrease the symptoms.
3. Management
Management of peripheral neurotoxicity is being studied, with the goal of slowing,
halting, and reversing the neuropathy. Dose reduction of the suspect agent,
particularly with the microtubule inhibitors and epothilones, may be warranted,
depending on the grade and duration of neuropathy. There is very little evidence to
support specific interventions for peripheral neuropathy. Anecdotally, B complex
vitamins such as pyroxidine or vitamin B6 may be used, 100 mg twice a day, in an
attempt to minimize the peripheral neuropathy. Glutamine, anticonvulsants
(gabapentin, pregabalin, or carbamazepine), or tricyclic antidepressants
(amitriptyline) have been studied in phase II trials and may be considered. Topical
analgesics and opioids may also be effective. Conventional nondrug interventions
with some report of effectiveness include exercise, physical therapy, massage, and
transcutaneous electrical nerve stimulation. Patient safety is critical and patient
education on self-care measures is recommended.
G. Palmar plantar erythrodysesthesia (PPE) (hand-foot syndrome)
PPE is dose-limiting and is the most common cumulative toxicity associated with
continuous-infusion fluorouracil in the past, but has recently captured attention with
newer chemotherapy drugs such as capecitabine and liposomal doxorubicin. Biologic
and targeted therapies may cause a hand-foot skin reaction. Multikinase inhibitors such
as sorafenib, sunitinib, axitinib, and lapatinib may cause the hand-foot skin reaction in
approximately 9% to 62% of patients, typically occurring within the first 2 to 4 weeks
of therapy. PPE is a toxic drug reaction that begins as a cutaneous eruption of the
integument on the palms of the hands and plantar surfaces of the feet. It has been
postulated that PPE occurs because of drug extravasation in the microcapillaries of the
hands and feet due to local everyday trauma or by drug concentration and accumulation
in sweat glands found in the palms and soles with resultant tissue damage. PPE is time
exposure–dependent and occurs with protracted, chronic exposure over long periods
 (i.e., more than 3 to 4 weeks).
Prevention or minimization of PPE has been observed through regional cooling
during the infusion of PEGylated liposomal doxorubicin by having patients keep ice
packs around the wrists and ankles, and consume iced liquids. These interventions were
continued for 24 hours after completion of the chemotherapy. While regional cooling
decreased the frequency and severity of PPE in patients in the intervention group, data
are not sufficient to support routine use in clinical practice. This intervention appears
promising, and the minimal cost, relatively simple procedure, and well-tolerated
intervention may be helpful. Other preventive interventions that have few studies or
case report support include oral corticosteroids, supportive care with topical wound
care, and patient education.28,29
1. Clinical findings
PPE may present as tingling, numbness, pain, dryness, erythema, swelling, rash,
blister formation, and pruritus of the hands and feet. Clinical knowledge of the
potential for PPE and early assessment are imperative for adjustments of dose or
withholding of therapy.
2. Management of PPE
Prompt identification of symptoms allows for early treatment. The grading scale for
PPE is shown in Table 26.10.29 At the first sign of PPE, the drug should be stopped,
the interval between doses should be increased, or the drug dose should be reduced.
If identified at grade 2 toxicity, symptoms typically improve within a few days of
stopping the drug. If untreated, grade 2 side effects may quickly progress to grade 3,
requiring more intense medical concern and intervention. Depending on the drug
used, recommendations are available for dose modifications. In situations where
PPE is likely, education on preventative measures should be given to patients before
beginning the drug. Patients should be counseled to avoid tight-fitting shoes and
rings or repetitive rubbing pressure to the hands or feet. Other precautionary
measures include avoiding excessive pressure and heat on the skin for 3 to 5 days
after treatment, avoidance of hot baths, showers, or hot tubs (hot water for 24 hours
prior to and 72 hours after treatment), and friction-causing activities such as
exercise for 3 to 5 days after treatment. Patients should also be advised to use
emollients such as Bag Balm (Dairy Association Co., Lyndonville, VT), Udderly
Smooth (Redex Industries, Salem, OH), or other petroleum- or lanolin-containing
creams liberally and frequently. Pyroxidine supplementation has been studied for
prophylaxis and management of PPE; however, there is no clinical evidence to
support this use.28,29 Patients should also be instructed to notify their health care
providers at the first signs or symptoms of PPE. If the grade of toxicity worsens,
supportive care related to analgesia and prevention of infection is important. Further
studies need to be done to evaluate which interventions are helpful for PPE and do
not exacerbate the skin toxicity.
 TABLE
Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia) Grading Scale
26.10
Grade 1 Grade 2 Grade 3
Minimal skin changes or dermatitis Skin changes (peeling, blisters, bleeding, Severe skin changes (peeling, blisters,
(erythema, edema, or hyperkeratosis) edema, or hyperkeratosis) with pain; limiting bleeding, edema, or hyperkeratosis) with pain,
without pain instrumental activities of daily living limiting self-care activities of daily living

Source: National Cancer Institute Cancer Therapy Evaluation Program. Common terminology criteria for adverse events
(CTCAE) (Version 4.03); 2010. Retrieved June 28, 2015, from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf

H. Skin reactions
With the advent of epidermal growth factor receptor (EGFR) antagonist drugs and
small-molecule targeted therapies, dermatologic toxicities have become relevant to
patients and oncology health care providers. The dermatologic toxicities can vary in
their type, time of onset, severity, duration, and response to therapeutic interventions.
Reactions can include dry skin, rashes, pruritus, blistering, and desquamation. While
such reactions do not often lead to alteration in therapy, they do pose a new challenge
for symptomatic treatment.
Biologic agents and small-molecule targeted agents known to cause skin reactions
include cetuximab, panitumumab, erlotinib, lapatinib, sunitinib, and sorafenib.
1. Clinical findings
EGFR skin reactions are primarily a pustulopapular rash that is often mild to
moderate in severity. The rash can cause pruritus and some discomfort, and patients
may have difficulty coping with the appearance and body image changes. The rash
often appears 8 to 10 days after the start of therapy, peaks about 2 weeks after
initiation of therapy, and diminishes after 4 to 6 weeks. The rash is often noted on
the scalp, face, upper chest, and back. While often not severe in nature, the rash may
contribute to the development of secondary infections.
2. Management of skin reactions
Consensus guidelines emphasize the importance of utilizing an interdisciplinary
approach to management, involving specialists in oncology and dermatology.
Important to any skin reaction is the understanding of the etiology and aggravating
factors. As more data become available, particular agents to avoid as well as
therapeutic options are critical in supportive care. For example, traditional acne
medications and retinoids may actually enhance inflammation and exacerbate the
rash, and alcohol-based gels and lotions may irritate the skin and exacerbate xerosis.
A proactive, stepwise intervention strategy based on rash severity may be helpful for
prophylaxis and prevention. Topical agents such as hydrocortisone 1%, skin
moisturizers, and sunscreen are also preventative approaches. Minocycline or
doxycycline are recommended agents for treatment. For a localized and minimally
 symptomatic rash, no intervention or topical hydrocortisone 1% or 2.5% cream
and/or clindamycin 1% gel may be used. Reassessment by a health care professional
or patient self-report within a few weeks is recommended if the reaction worsens or
does not improve. For a moderate reaction, where there is a more generalized rash
with some mild symptoms such as pruritus, options may include hydrocortisone
cream 2.5%, clindamycin 1% gel, in addition to doxycycline 100 mg by mouth twice
a day or minocycline 100 mg by mouth twice a day.1 If the rash continues to worsen,
symptoms are severe and impact functional status, and the potential for
superinfection is present, a corticoid dose pack may need to be added to the
moderate reaction interventions.

References
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recommendations for practice. 4th ed. Pittsburgh: Oncology Nursing Society; 2014.
2. Boulanger J, Ducharme A, Dufour A, et al. Management of the extravasation of anti-
neoplastic agents. Support Care Cancer. 2015;23:1459–1471.
3. Barbee MS, Owonikoko TK, Harvey RD. Taxanes: vesicants, irritants, or just irritating?
Ther Adv Med Oncol. 2014:6(1):16–20.
4. O’Leary C, Catania, K. Extravasation. In Yarbro CH, Wujcik D, Gobel BH, eds. Cancer
symptom management. 4th ed. Burlington: Jones & Bartlett Learning; 2014:541–554.
5. Azais H, Bresson L, Bassil A, et al. Chemotherapy drug extravasation in totally
implantable venous access port systems: how effective is early surgical lavage? J Vasc
Access. 2015;16(1):31–37.
6. Nurgat ZA, Smythe M, Al-Jedai A, et al. Introduction of vincristine mini-bags and an
assessment of the subsequent risk of extravasation. J Oncol Pharm Pract.
2015;21(5):339–347.
7. Vogel WH. Hypersensitivity reactions to antineoplastic drugs. In: Yarbro CH, Wujcik D,
Gobel BH, eds. Cancer symptom management. 4th ed. Burlington: Jones & Bartlett
Learning; 2014:115–130.
8. Castells MC. Anaphylaxis to chemotherapy and monoclonal antibodies. Immunol Allergy
Clin North Am. 2015;35:335–348.
9. National Cancer Institute Cancer Therapy Evaluation Program. Common terminology
criteria for adverse events (CTCAE) (Version 4.03); 2010. Retrieved from
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
10. Patil SU, Long AA, Ling M, et al. A protocol for risk stratification of patients with
carboplatin-induced hypersensitivity reactions. J Allergy Clin Immunol. 2012;129(2):
443–447.
11. Calado, J, Picard M. Diagnostic tools for hypersensitivity to platinum drugs and taxanes:
skin testing, specific IgE, and mast cell/basophil mediators. Curr Allergy Asthma Rep.
 2014;14:451.
12. Blatman KS, Castells MC. Desensitizations for chemotherapy and monoclonal
antibodies: indications and outcomes. Curr Allergy Asthma Rep. 2014:14:453.
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symptom management. 4th ed. Burlington: Jones & Bartlett Learning; 2014:213–239.
14. Jordan K, Gralla R, Jahn F, et al. International antiemetic guidelines on chemotherapy
induced nausea and vomiting (CINV): content and implementation in daily routine
practice. Eur J Pharmacol. 2014;722:197–202.
15. National Comprehensive Cancer Network. Clinical guidelines in oncology: antiemesis
(Version 1); 2015. Retrieved June 21, 2015, from
http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
16. Gralla RJ, Bosnjak SM, Hontsa A, et al. A phase III study evaluating the safety and
efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for
prevention of chemotherapy-induced nausea and vomting over repeated cycles of
chemotherapy. Ann Oncol. 2014;25:1333–1339.
17. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of
netupitant and palonosetron, for prevention of chemotherapy-induced nausea and
vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal
study. Ann Oncol. 2014;25:1340–1346.
18. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy
and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for
prevention of chemotherapy-induced nausea and vomiting following moderately
emetogenic chemotherapy. Ann Oncol. 2014;25:1328–1333.
19. Navari R. Management of chemotherapy-induced nausea and vomiting. Drugs.
2013;73:249–262.
20. Hocking CM, Kichenadasse G. Olanzapine for chemotherapy-induced nausea and
vomiting: a systematic review. Support Care Cancer. 2014;22:1143–1151.
21. Kamen C, Tejani MA, Chandwani K, et al. Anticipatory nausea and vomiting due to
chemotherapy. Eur J Pharmacol. 2014;722:172–179.
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symptom management. Pittsburgh: Oncology Nursing Society; 2014.
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related mucositis: putting evidence into practice. Clin J Oncol Nurs. 2014;18(6,
suppl):80–96.
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chemotherapy. Cancer Treat Rev. 2015;41,179–186.
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alterations in chemotherapy patients. A systematic review. J Pain Symptom Manage.
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27. Mitchell SA. Cancer-related fatigue: state of the science. PM R. 2010;2:364–383.
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nail changes: a review clinical presentation, etiology, pathogenesis, and management. J
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29. Jo SJ. Shin J, Kwon O, et al. Prophylactic and therapeutic efficacy of pyroxidine
supplements in the management of hand-foot syndrome during chemotherapy: a meta-
analysis. Clin Exp Dermatol. 2015;40(3):260–270.
I. INTRODUCTION
The toxicity profile of immune-based therapies has in the past typically been related to the
dose and schedule of the administered therapy. Toxicity increased as the dose and
frequency of administration increased and, in general, resolved upon withdrawal of
treatment in hours to days without additional intervention. This pattern is seen with
interferon-α (IFN-α) approved for the treatment of hairy cell leukemia at low doses (3
million international units [IU] three times weekly) and for the adjuvant therapy of high-
risk melanoma at high doses (20 million IU daily five times for 4 weeks). Interleukin 2 (IL-
2) is approved for the treatment of metastatic melanoma and renal cell cancer. Other
members of the interleukin and cytokine families including the unapproved agents—tumor
necrosis factor (TNF), interleukin 1 (IL-1), interleukin 21 (IL-21), and interleukin 15 (IL-
15)—show similar toxicity patterns. In contrast, the new class of immune therapy agents
produce side effect profiles that are more idiosyncratic in nature, frequently require
administration of immunosuppressive agents for resolution, and can take weeks or even
months for resolution. Irreversible damage with the need for lifelong hormone replacement
therapy beyond thyroid hormone is observed. These agents show significant therapeutic
activity and predominantly consist of monoclonal antibodies directed at cell surface
signaling molecules such as CTLA-4, PD-1, and PD-L1. The toxicities of immune-based
therapy will be discussed in this chapter with a focus on the organ affected.

II. SYSTEMIC EFFECTS

IFN-α produces side effects that can be divided into acute and chronic categories.1 The
acute toxicities include flu-like symptoms with fever, chills, myalgias, headache, anorexia,
nausea, vomiting, diarrhea, and fatigue. These typically occur within hours of
administration of the initial dose, and most abate despite continued administration, a
phenomenon termed tachyphylaxis. Their severity is related to the dose and schedule of
treatment. Systemic symptoms can be managed with nonsteroidal anti-inflammatory drugs
(acetaminophen should be avoided due to its potential for complicating hepatic toxicity),
antiemetics, and fluid hydration either orally or intravenously. With continued
administration of IFN-α, a spectrum of chronic dose-limiting fatigue and anorexia occur
usually in association with depression. Weight loss is frequently observed with the high-
dose IFN-α regimen. IL-2 produces a similar side effect profile with fever and chills that
may require meperidine for control, nausea, vomiting, diarrhea, and fatigue. High-dose IL-
 2 should be administered by experienced practitioners in an inpatient setting with access to
cardiac monitoring and the ability to deliver hemodynamic support.2 IL-2 causes a
capillary leak syndrome due to endothelial cell injury. This increased vascular
permeability results in fluid overload with the development of ascites, pulmonary edema
and pleural effusions, and renal dysfunction. Systemic side effects are unusual with
immunomodulatory monoclonal antibody therapy, but as they are foreign proteins, they can
produce allergic reactions that will prevent further therapy. These tend to be rare. More
commonly, infusion reactions will occur as with other therapeutic antibodies such as
rituximab. Infusion reactions are rare with ipilimumab, nivolumab, and pembrolizumab, but
occur commonly with the unapproved antibodies directed at PD-L1. Pretreatment with
diphenhydramine and acetaminophen is recommended to prevent or ameliorate these
effects.

III. CARDIAC EFFECTS

Cardiac events, with the exception of hypotension, are unusual with IFN-α therapy but can
produce cardiac ischemia in those who are susceptible. Intravenous fluid administration
during the high-dose IV phase of the induction regimen for melanoma therapy should be
used. Hypotension is frequently a dose-limiting toxicity of IL-2 and is managed by
judicious use of intravenous fluids. We tended to avoid its use because of the associated
capillary leak syndrome that minimized its effectiveness. We instead managed patients with
pressors to avoid weight gain, edema, and pulmonary toxicity that can be associated with
IV fluids. Because of the ability of β-agonists to precipitate cardiac arrhythmias, α-
adrenergic agonists are recommended for the management of hypotension. It is advisable to
perform cardiac stress testing in any patient over the age of 50 years to identify patients
who are poor candidates for the therapy. Myocarditis can occur during or following
discontinuation of IL-2 and can be fatal.3 Cardiac events are rare with agents that target
CTLA-4 and PD-1, but cardiomyopathy and myocarditis have been reported.4 Interestingly,
the PD-1 knockout mouse develops cardiomyopathy in a strain-specific manner owing to
the development of antibodies to troponin I.5

IV. HEMATOLOGIC TOXICITY

Reduction in blood counts is almost universally seen with high-dose IFN-α with high-grade
toxicity in 25% to 60% of patients. Granulocytopenia is the most common reason for dose
reduction. Neutropenia is rarely associated with fever, but should be managed as with any
febrile neutropenic patient. Hematologic toxicity is responsive to dose reductions and
administration of filgrastim. Rare cases of thrombotic thrombocytopenic purpura have been
observed and require permanent discontinuation.6,7 IL-2 produces thrombocytopenia and
anemia, which may be dilutional in origin, but decreased production is also a likely
mechanism. Granulocyte migration defects occur during IL-2 therapy and are associated
with infectious complications.8 The use of antibiotic prophylaxis significantly reduced the
incidence of catheter-related sepsis but antibiotics may participate in the coagulopathy that
 sometimes accompanies IL-2 administration by eliminating vitamin K–producing bacteria.
Use of vitamin K supplementation, particularly in patients who are eating very little, may
be warranted. Hematologic toxicity is rare with the antibodies directed at cell surface
signaling molecules, but autoimmune hemolytic anemia, thrombocytopenia, and
granulocytopenia have been reported.

V. HEPATIC TOXICITY
Hepatic toxicity associated with high-dose IFN-α can be lethal if therapy is not interrupted
when liver damage occurs, and it is critical that liver function tests (LFTs) be followed
closely while on therapy. Similarly, IL-21 produces hepatic toxicity that can be fatal. This
represents a major obstacle to the clinical development of IL-21 where treatment has been
restricted to patients with normal LFTs and is interrupted for grade 2 (greater than three
times the ULN values) transaminitis. The standard IFN-α regimen for adjuvant melanoma
treatment consists of a 1-month induction with 20 million IU (MIU)/m2 administered
intravenously 5 days weekly for 4 weeks followed by 10 MIU/m2 administered three times
weekly for 11 months, for a total of 1 year of therapy. The majority of patients are unable to
complete the regimen as initiated. Elevated transaminases occurred in over half of patients
and 14% to 29% developed grade 3 or higher transaminitis.92 IFN-α should be held for
grade 3 transaminitis and the dose reduced for continued treatment. The mechanism of
hepatic damage due to IFN-α may be related to the induced downstream cytokine signaling
with a complex array of cytokines and interleukins interacting to produce toxicity.
Liver function test abnormalities occur almost universally in patients treated with
high-dose IL-2 (600,000 IU IV q8 hours for up to 15 doses), with about 40% of patients
developing grade 3 (five times ULN) or greater transaminase elevation with 20% showing
fivefold to tenfold or greater elevation of bilirubin levels.13,14 IL-2 is typically
administered without dose interruption despite grade 3 elevations of transaminase levels
even in conjunction with significant bilirubin elevation. Decreased hepatic synthesis
contributes to the drop in albumin and clotting factor levels that can produce a
coagulopathy. As with most other IL-2 toxicities, hepatic toxicity resolves completely upon
therapy discontinuation. Liver biopsy findings in patients treated with IL-2 are rare due to
its almost universal resolution without intervention. In the one reported case, acute
multifocal hepatitis with necrosis and acute pericholangitis was observed.15 The effects of
IL-2 in man predominantly produce cholestatic changes rather than cytotoxic effects, in
contrast to rodents, in which a cytotoxic effect is primarily observed.16,17 The potential
mechanisms for toxicity in man include endothelial cell injury with induction of capillary
leak and bile stasis, induction of cytokines in response to IL-2 administration, or direct
effect of activated lymphocyte populations on hepatocytes. IL-2 produces hepatic toxicity
that is atypical when compared with that induced by other immunotherapy agents in its
complete reversibility.
Hepatitis is relatively rare with the new class of cell surface–signaling molecules
ipilimumab,18 tremelimumab,19 nivolumab,20 and pembrolizumab.21 Liver function tests
 should be monitored before administration of every dose of these therapies, and is
typically held for grade 2 elevations of the transaminases. Ipilimumab and tremelimumab
target CTLA-4, and the former is FDA-approved for the treatment of metastatic melanoma
at a dose of 3 mg/kg administered at 3-week intervals for four doses. At this dose, 2% of
patients developed severe, life-threatening, or fatal hepatitis in the pivotal approval study
of ipilimumab, and tremelimumab had a 1% incidence of severe hepatic toxicity. It most
frequently occurs at 8 to 12 weeks after initiation of therapy, but can occur at any time
following initiation of therapy. Imaging studies and pathology specimens are available in
only a small number of cases.22,23 Imaging studies were normal or showed mild
hepatomegaly, periportal edema, and periportal lymphadenopathy. Pathology specimens
may show either injury to hepatocytes (acute hepatitis pattern) or injury to the bile ducts
(biliary pattern). The histologic changes observed with ipilimumab-related hepatitis are
similar to those with acute viral and autoimmune hepatitis, and distinguishing these can be
difficult for the latter. Recurrence of hepatitis is highly likely with reexposure to
ipilimumab, occurs rapidly upon retreatment, and should therefore be avoided. Whether
administration of agents targeting PD-1/PD-L1 interaction is safe in this setting is unknown
at this time. Hepatitis usually presents as asymptomatic elevation of the transaminases with
or without bilirubin elevation, but can be associated with fever. Hepatitis occurs more
frequently when ipilimumab is combined with other agents and can produce dose-limiting
toxicities in these combinations. With the addition of dacarbazine, severe hepatic toxicity
increased in frequency and occurred in 20% of patients. The number of doses of
ipilimumab administered were reduced in this trial.24 Hepatic toxicity was also markedly
increased in frequency when combined with vemurafenib25 and ended attempts to combine
these agents. Both pembrolizumab and nivolumab have been associated with hepatitis, but
its frequency is lower than that observed with ipilimumab, and hepatitis requiring therapy
is lower and may respond more rapidly to intervention. Hepatitis caused by these agents
should be distinguished from other causes of liver inflammation, particularly viral hepatitis
and other liver disorders, and is managed with steroid therapy. Hepatitis may be steroid
refractory but has been responsive to treatment with mycophenolate mofetil (CellCept:
Genentech, South San Francisco, CA). Infliximab should be avoided because of its risk for
hepatotoxicity. The time course of resolution of hepatitis can be prolonged despite steroid
and CellCept therapy, sometimes for months.

VI. DIARRHEA/COLITIS
Diarrhea is common in patients treated with monoclonal antibodies targeting CTLA-4 and
PD-1/PD-L1. The incidence of diarrhea is much higher with CTLA-4-targeted therapy than
PD-1/PD-L1, and this is true of most other immune-related adverse events. Diarrhea most
commonly occurs following two doses of therapy, but can occur at any time, and patients
must be cautioned about this side effect because if left untreated, it may progress and
produce bowel perforation, which has caused deaths. Gastrointestinal toxicity appears to
be dose-related with ipilimumab, whereas it is not with nivolumab. In a phase II
 randomized trial of three dose levels of ipilimumab, 10, 3, and 0.3 mg/kg, there were 11/73
(15%), 2/72(3%), and 0/72 (0%) patients with grade 3 to 4 gastrointestinal toxicities,
respectively.26 In contrast, diarrhea of any grade associated with nivolumab with doses
ranging from 0.1 to 10 mg/kg was similar in frequency, ranging from 6% to 19%, with 2%
of patients experiencing grade 3/4 diarrhea both at the highest dose level.20 It is important
to rule out other etiologies for diarrhea, particularly Clostridium difficile or other
pathogens. Steroid therapy is the mainstay of management and is usually effective, but
requires a slow taper to prevent recurrences. When oral steroid therapy is ineffective,
patients should be hospitalized and treated with intravenous methylprednisolone at a dose
of 2 mg/kg twice daily. If diarrhea is still not controlled, infliximab (Remicade; Janssen
Biotech, Horsham, PA) at a dose of 5 mg/kg should be given and is usually rapidly
effective.27,28 Infliximab can be repeated every 2 weeks. Although colonoscopy was used
in the early years of ipilimumab development, it is now used only in instances where the
diagnosis is unclear.

VII. ENDOCRINE SIDE EFFECTS

Thyroid dysfunction was recognized as toxicity associated with both IFN-α and IL-2 early
on in their clinical development, and was noted to be correlated with tumor regression.22
The most common pattern associated with IFN-α therapy is a period of hyperthyroidism
followed by hypothyroidism. Preexisting autoimmune thyroid dysfunction or baseline
serological evidence of antithyroid antibodies predispose to this complication. The
existence of such antibodies provides a 60% risk of developing clinical thyroid disease,
and thyroid dysfunction occurs in 8% to 20% of patients receiving IFN-α. Occasional
cases of Graves disease have been reported. Similarly, IL-2 therapy has been associated
with the development of hypothyroidism in up to 47% of patients. Hyperthyroidism does
not usually require therapy but beta-blockers may need to be used in unresponsive thyroid
disease, and hypothyroidism is managed with replacement therapy that is usually lifelong.
In addition to the thyroid gland, CTLA-4 and PD-1 targeted therapies also affect the
pituitary and adrenal glands.20,21,33,34 The incidence of these effects is about 10% to 15%
and is likely dependent upon the underlying autoimmune predisposition of the subject as is
the case for IL-2 and IFN-α. While thyroid dysfunction is usually an indolent process,
inflammation of the pituitary or adrenal gland is a medical emergency that requires urgent
adrenal steroid replacement therapy. The symptoms of hypophysitis are nonspecific, and it
is important to have a high index of suspicion. Some patients present with headaches and
will have an enlarged sella turcica on MRI scan, but not all have this prodromal syndrome.
There may be selective loss of pituitary hormones—thyroid-stimulating hormone (TSH),
follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH),
prolactin, or adrenocorticotropic hormone (ACTH). Measurements of these levels are
helpful in diagnosing hypophysitis. It is also important that hypophysitis be recognized
early as a course of high-dose steroids may alleviate the inflammation and preserve
pituitary gland function and decrease the need for lifelong hormone replacement therapy. It
 is standard to measure thyroid function tests every cycle with ipilimumab and will be
helpful in detecting autoimmune disease. It is important to distinguish primary (low free T4
and high TSH) and secondary (low free T4 and low TSH) hypothyroidism.

VIII. OCULAR TOXICITY

Ocular toxicity with interferon presents as blurred vision or visual loss and is usually
reversible. Ophthalmoscopic examination shows cotton wool exudates and intraretinal
hemorrhages. Rare severe toxicities including retinal artery and vein thrombosis, epiretinal
membrane development, optic disc edema, and macular edema have been reported.
Although this is a rare complication, it is a reason for permanent discontinuation of
therapy.35 Ipilimumab has been associated with uveitis, conjunctivitis, episcleritis,
bilateral choroidal membrane development, and granulomatous panuveitis with serous
retinal detachment. This latter case also developed neurologic and auditory defects
associated with the Vogt-Koyanagi-Harada syndrome.36–38 An ophthalmologist should be
consulted, and treatment with topical or oral steroids may be helpful. PD-1 targeted
therapies can also cause uveitis, but remains uncommon.

IX. NEUROLOGIC TOXICITY

Neuropsychiatric effects are common with long-term IFN-α, with depression being the
most common event that requires dose reduction or discontinuation. Therefore, IFN-α
should be used with caution in patients with a history of depression. It is significantly less
common with the low-dose regimen used for hairy cell leukemia (3 MIU three times
weekly). Antidepressants showed benefit in a small randomized trial in patients undergoing
treatment with high-dose IFN-α,39 but was associated with three cases of retinal
hemorrhage in the paroxetine-treated group. IL-2 also produces neurologic toxicity and can
be a costly medical expense if additional doses of IL-2 are given inappropriately. Patients
may require respiratory support for lengthy periods when neurologic toxicity progresses to
coma. This is one of the reasons that high-dose IL-2 should be administered only by those
familiar with its spectrum of toxicities. Subjects with signs of lethargy, confusion, or
agitation should be observed closely, and it is reasonable to withhold a dose of therapy to
confirm that therapy can safely be continued. If severe somnolence, disorientation, severe
paresthesiae, or motor weakness develops, therapy should be discontinued. A variety of
neurologic toxicities have been observed with administration of checkpoint antibodies.40,41
These include antibody-mediated disorders such as myasthenia gravis and Guillain-Barré
syndrome that are responsive to plasmapheresis to encephalopathy and aseptic meningitis.
These are rare events most likely produced as the result of genetic predispositions or
environmental exposures that produce cross-reactive immune responses.

X. PULMONARY TOXICITY
IFN-α is rarely associated with pulmonary toxicity, but interstitial pneumonitis and
bronchiolitis obliterans have been reported42 and may be more common in patients treated
 for hepatitis than malignancy. IL-2-related pulmonary toxicity is primarily related to
capillary leak syndrome and volume overload that frequently accompany its administration.
Restricting fluid administration and management of hypotension with pressors help to limit
this toxicity. Pulmonary infiltrates are rare with ipilimumab, and sarcoidosis should be
considered in patients who present with this finding.43 Pneumonitis is seen with nivolumab
and pembrolizumab, and without early intervention with immunosuppression and
withdrawal of therapy, may be fatal.20,21 An early finding is asymptomatic pulmonary
infiltrates on X-ray or computerized chest tomography, but patients may present with cough,
shortness of breath, and hemoptysis. These latter patients should be evaluated with
bronchoscopy with lavage for infectious complications before institution of
immunosuppressive therapy. High-dose steroid therapy such as methylprednisolone should
be used when infiltrates are associated with symptoms. Other immunosuppressive agents
such as infliximab, mycophenolate mofetil, cyclophosphamide, or T-cell directed lytic
antibodies such as alemtuzumab (Campath:Teva) could be considered in refractory cases.

XI. OTHER ORGANS

Ipilimumab has been associated with inflammatory infiltrates in almost every body system.
These events are rare but must be considered in the differential diagnosis when using these
therapies. Hematologic complications have included factor VIII inhibitors, neutropenia,
and red blood cell aplasia. Steroid therapy remains the initial immunosuppression of
choice. Renal impairment has been observed and both interstitial nephritis and
membranous glomerulonephropathy have been seen. PD-1-targeted therapy has also been
associated with this toxicity. Pancreatic inflammation occurs infrequently and routine
monitoring of lipase and amylase is not recommended for either CTLA-4 or PD-1-targeted
therapies. There is a relatively high rate of asymptomatic elevation of these enzymes and
therapy should not be held in the absence of symptoms. The amylase and lipase should be
checked and withheld with the proper clinical presentation.

XII. COMBINATION STUDIES OF IPILIMUMAB AND NIVOLUMAB

As anticipated, the occurrence of grade 3/4 events occurs more frequently with the
combination of these antibodies but is associated with a higher and more rapid onset
response rate as well as deeper level of response. These events should be managed in a
similar fashion to that for toxicities observed with single agents.

XIII. SUMMARY
Toxicity with immunotherapy if responsive to withdrawal of the offending agent but
hepatitis, colitis, and other inflammatory conditions induced by checkpoint inhibitors may
require steroids for control. Depending on the clinical situation, oral or intravenous
steroids may be warranted. Most resolve with steroid therapy but a long slow period of
tapering may be required before it can be withdrawn. Colitis unresponsive to steroids
should be managed with infliximab but it should be avoided in hepatic inflammation.
Instead these patients should be managed with mycophenolate mofetil.
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tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
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PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
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Clin Oncol. 2005;23:6043–6053.
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 SECTION IV: CHEMOTHERAPEUTIC AND
MOLECULAR TARGETED AGENTS AND THEIR
USE

I. CLASSES OF DRUGS
Chemotherapeutic agents, whether classical or molecular targeted, are customarily divided
into several classes. For two of the classes, the alkylating agents and the antimetabolites,
the names indicate the mechanism of cytotoxic action of the drugs in their class. For the
hormonal agents, the name designates the physiologic action of the drug, and for the
natural products, the name reflects the source of the agents. The biologic response
modifiers include agents that mimic, stimulate, enhance, inhibit, or otherwise alter the host
responses to the cancer. Molecular targeted agents affect defined and putative
abnormalities in the cancer cell and its environment, and in many cases can also be
designated as biologic response modifiers. Drugs that do not fit easily into other categories
are grouped together as miscellaneous agents. Summary information on mechanism of
action, primary indications, usual dosage and schedule, special precautions, and
toxicity for individual agents are given in Section III of this chapter.
Within each class are several types of agents (Table 28.1). As with the criteria for
separating into class, the types are also grouped according to the mechanism of action,
biochemical structure or derivation, physiologic action, or molecular target. In some
instances, these groupings into classes and types are arbitrary, and some drugs seem to fit
into either more than one category or none. While this knowledge was helpful in planning
therapy with classical chemotherapy, this classification is less helpful in planning therapy
in the targeted therapy era, as treatment selection is now commonly based on known altered
molecular characteristics and pathways of a tumor type or individual tumors.

TABLE
 Classification of Classical and Molecular Targeted Agents
28.1
 A. Alkylating agents
The alkylating agents are a diverse group of chemical compounds capable of forming
molecular bonds with nucleic acids, proteins, and many molecules of low molecular
weight. The compounds either are electrophiles or generate electrophiles in vivo to
produce polarized molecules with positively charged regions. These polarized
molecules can then interact with electron-rich regions of most cellular molecules. The
cytotoxic effect of the alkylating agents appears to relate primarily to the interaction
between the electrophiles and the DNA. This interaction may result in substitution
reactions, cross-linking reactions, or strand-breaking reactions. The net effect of the
alkylating agent’s interaction with DNA is to alter the information coded in the DNA
molecule. This alteration results in inhibition or inaccurate replication of DNA, with
resultant mutation or cell death. One implication of the mutagenic capability of
alkylating agents is the possibility that they are teratogenic and carcinogenic. Because
they interact with preformed DNA, RNA, and protein, the alkylating agents are not
phase-specific, and at least some are cell cycle–nonspecific.
B. Antimetabolites
The antimetabolites are a group of low-molecular-weight compounds that exert their
effect by virtue of their structural or functional similarity to naturally occurring
metabolites involved in nucleic acid synthesis. Because they are mistaken by the cell
for normal metabolites, they either inhibit critical enzymes involved in nucleic acid
 synthesis or become incorporated into the nucleic acid and produce incorrect codes.
Both mechanisms result in inhibition of DNA synthesis and ultimate cell death. Because
of their primary effect on DNA synthesis, the antimetabolites are most active in cells
that are actively growing and are largely cell cycle phase–specific.
C. Natural products
The natural products are grouped together not on the basis of activity but because they
are derived from natural sources. The clinically useful drugs include plant products,
fermentation products of various species of the soil fungus Streptomyces, and bacterial
products.
D. Hormones and hormone antagonists
1. General description. The hormones and hormone antagonists that are clinically
active against cancer include steroid estrogens, progestins, androgens, corticoids
and their synthetic derivatives, nonsteroidal synthetic compounds with steroid or
steroid-antagonist activity, aromatase inhibitors, hypothalamic-pituitary analogs, and
thyroid hormones. Each agent has diverse effects. Some effects are mediated directly
at the cellular level by the drug binding to specific cytoplasmic receptors or by
inhibition or stimulation of the production or action of the hormones. These agents
may also act by stimulating or inhibiting natural autocrine and paracrine growth
factors (e.g., epidermal growth factor, transforming growth factors [TGFs]-α and -
β). The relative roles of the various actions of hormones and hormone antagonists
are only partially understood and probably vary among tumor types. For selective
estrogen receptor modulators such as tamoxifen, which, when bound to the estrogen
receptor, ultimately controls the promoter region of genes that affect cell growth,
there are a host of modulating factors including some 20 receptor-interacting
proteins and 50 transcription-activating factors as well as many response elements.
Other effects are mediated through indirect effects on the hypothalamus and its
anterior pituitary–regulating hormones. The final common pathway in most
circumstances appears to lead to the malignant cell, which retains some sensitivity
to direct or indirect hormonal control of its growth. An exception to this mechanism
is the effect of corticosteroids on leukemias and lymphomas, in which the steroids
appear to have direct lytic effects on abnormal lymphoid cells that have high
numbers of glucocorticoid receptors.
E. Molecularly targeted agents
1. General. This classification is a relatively recent one in oncology that has become
possible because of maturation of knowledge about the molecular events that are
responsible for the development of cancer. Understanding of the genetic changes in
the cancer cell, the downstream molecular events that follow as a consequence, and
the mechanisms by which these events regulate cell growth and death has led to a
host of possibilities for the control of cancer growth.
2. Tyrosine kinase and multikinase inhibitors. The first clinical example of this was
the signal transduction inhibitor imatinib mesylate, which inactivates the
 constitutively active fusion product tyrosine kinase arising from the Philadelphia
chromosome (Ph) found in chronic myelogenous leukemia (CML), Bcr-Abl, as well
as c-KIT kinase, which is overexpressed in (GI) stromal tumors. There are now a
large number of small molecule inhibitors of intracellular kinase activity (receptor
and nonreceptor molecules) in clinical use, with demonstrated clinical efficacy in
nearly every cancer type.
3. Monoclonal antibodies have emerged over the last 15 to 20 years as useful adjuncts
to the medical oncologist’s armamentarium. These agents, which may be directed at
growth factors or their receptors, may have varying levels of humanization
(chimerism), and may be unconjugated (alemtuzumab, bevacizumab, cetuximab,
ofatumumab, rituximab, trastuzumab) or conjugated with radionuclides (ibritumomab
tiuxetan, tositumomab) or another toxic moiety (ado-trastuzumab emtansine,
brentuximab vedotin, gemtuzumab). Several molecular targeted agents, such as the
immune checkpoint inhibitors, are biologic response modifiers.
4. Other agents. Other agents affect nuclear activity, such as the binding of all-trans-
retinoic acid with cytoplasmic proteins, which in turn interact with nuclear retinoic
acid receptors (RARs) that affect expression of genes that control cell growth and
differentiation; inhibit proteasomes, which mediate protein degradation and play an
essential role in intracellular protein regulation and consequent cellular signal
transduction pathways and cellular homeostasis; or perturb other critical pathways.
F. Miscellaneous agents
These are listed in Table 28.1 and include biologic response modifiers, which may
have multiple biologic effects (like the interferons or thalidomide-like agents) or may
be more specific in activity (like the monoclonal immune checkpoint inhibitors), and
other miscellaneous agents.
Descriptions of specific agents are found in Section III.

II. CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND

MOLECULARTARGETED AGENTS
Section III of this chapter contains an alphabetically arranged compendium that contains a
description of the chemotherapeutic, biologic, and molecular targeted agents that are
recognized to be clinically useful. Each drug is listed by its generic name, with other
common names or trade names included. A brief description is given of the probable
mechanism of action, clinical uses, recommended doses and schedules, precautions, and
side effects.
A. Recommended doses: CAUTION
Although every effort has been made to ensure that the drug dosages and schedules
given here are accurate and in accord with published standards, readers are advised to
check the product information sheet included in the package of each U.S. Food and Drug
Administration (FDA)–approved drug. For drugs or indications not yet approved for
general use, active protocol guidelines and any current medical literature should be
 used to verify recommended dosages, contraindications, and precautions and to review
potential toxicity.
B. Dose selection and designation
The doses are listed using body surface area (square meters) as the base for all agents
when this is appropriate. Because many of the drugs are given in combination with
other agents, doses most commonly used in popular combinations may also be
indicated. These data should not be used as the sole source of information for any of
the drugs but rather should be used as a guide to confirm and compare dose ranges and
schedules and to identify potential problems. For some agents, the area under the curve
(AUC) method of dose calculation seems to be most reliable for achieving the most
accurate dosing and balance between efficacy and toxicity; when that is the standard,
the AUC dose is used.
C. Drug toxicity: frequency designation
The designation of the frequency of toxic side effects is indicated as follows
(probability of occurrence equals percentage of patients who may be expected to
experience the toxic effect):
■ Universal (90% to 100%)
■ Common (15% to 90%)
■ Occasional (5% to 15%)
■ Uncommon (1% to 5%)
■ Rare (<1%)
These designations are meant only to be guides, and the likelihood of a side effect in
each patient depends on that patient’s physical status, including comorbidities, treatment
history, dose, schedule, and route of drug administration, as well as other concurrent
treatment. For some toxicities, an actual percentage of observed frequency is also
listed.
D. Dose modification
1. Philosophy. The optimal dose and schedule of a drug are those that give the
maximum benefit with tolerable toxicity. Most classical chemotherapeutic agents
(and some of the targeted agents) have a steep dose-response curve; therefore, if no
toxicity is seen, as a rule, a higher dose (dose escalation) of most of the classical
chemotherapeutic agents should be given to get the best possible therapeutic benefit.
If toxicity is great, however, the patient’s life may be threatened, or the patient may
decide that the treatment is worse than the disease and refuse further therapy. How
much toxicity the patient and the physician are willing to tolerate depends on the
likelihood that more intensive treatment will make a major therapeutic difference
(e.g., cure vs. no cure) and on the patient’s physical and psychological tolerance for
adverse effects.
The general grading scheme for all toxicity is as follows:
■ 0: None
■ 1: Mild
 ■ 2: Moderate
■ 3: Severe
■ 4: Life-threatening
2. Guidelines
a. Nonhematologic toxicity
1) Acute effects. Acute drug toxicity that is limited to 1 to 2 days and is not
cumulative is not usually a cause of dose modification unless it is of grade 3
or 4, that is, severe or life-threatening. (For individual toxicities, see the
Common Terminology Criteria for Adverse Events v4.0, available on the
Internet at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
or downloaded in the latest version from
http://evs.nci.nih.gov/ftp1/CTCAE/About.html).1 Occasionally, repeating a
dose that caused intractable nausea and vomiting, a temperature higher than
40°C (104°F), or an acute infusion reaction is warranted, but for most other
grade 3 or 4 toxicities, the subsequent doses should be reduced by 25% to
50%, assuming that the toxicity is believed to be dose-related. If the acute
drug effects (e.g., severe paresthesias or abnormalities of renal or liver
function) last longer than 48 hours, the subsequent doses should be reduced
by 35% to 50%. A recurrence of the grade 3 or 4 side effects at the reduced
doses would be an indication either to reduce by another 25% to 50% or to
discontinue the drug altogether. Non–dose-related toxicity such as
anaphylaxis usually is an indication to discontinue the offending drug, unless
there is a reliable and safe way to desensitize the patient. Lesser degrees of
hypersensitivity can often be dealt with effectively by increasing the dose of
protective agents (like dexamethasone or diphenhydramine), desensitization
(e.g., carboplatin), or slowing the rate of infusion (e.g., rituximab). For some
biologic agents, such as trastuzumab, physiologic effects that look like
immunologic hypersensitivity reactions are probably related to cytokine
release, occur primarily on first or second infusions, and diminish with
continued treatment.
2) Chronic effects. Chronic or cumulative toxicity such as pulmonary function
changes with bleomycin or decreased cardiac function with doxorubicin is
nearly always an indication to discontinue the responsible agent. Chronic or
cumulative neurotoxicity due to vincristine, cisplatin, paclitaxel, or other
agents may require no dose change, reduction, or discontinuation, depending
on the severity of the resultant neurologic dysfunction and the patient’s ability
to tolerate it.
b. Hematologic toxicity
The degree of myelosuppression and attendant risk of infection and bleeding that
are acceptable depend on the cancer, the duration of the myelosuppression, the
 goals of therapy, and the general health of the patient. In addition, one must
consider the relative benefit of less aggressive or more aggressive therapy. For
example, with acute nonlymphocytic leukemia, remission is unlikely unless
sufficient therapy is given to cause profound pancytopenia for at least 1 week.
Because there is little benefit with lesser treatment, grade 4 leukopenia and
thrombocytopenia are acceptable toxicities in this circumstance. Grade 4
myelosuppression is also acceptable when the goal is cure of a cancer that does
not involve the marrow, such as testicular carcinoma. With breast cancer, on the
other hand, responses are seen with less aggressive treatment, and prolonged
pancytopenia may not be acceptable, particularly if chemotherapy is being used
palliatively or in an adjuvant setting in which the proportion of patients expected
to benefit from chemotherapy is relatively small and excessive toxicity would
pose an unacceptable risk.
With these caveats in mind, the dose modification scheme shown in Table
28.2 can serve as a guide to reasonable dose changes for drugs whose major
toxicity is myelosuppression with a blood count nadir of 7 to 14 days.
c. Dosing for the obese patient
In general, patients who are overweight (body mass index [BMI], 25 to 29.9) and
those who are obese (BMI, 30 to 34.9) should be treated with full doses of
chemotherapy, based on the body surface area calculated from their actual
weight, particularly when therapy is given with curative intent. Whether this is
true for those who are very obese (BMI, 35 to 39.9) or extremely obese (BMI
>40) is not clear, owing to a lack of sufficient data. While some clinicians
would limit the dose, using a maximum weight based on a BMI of 35 (maximum
treatment weight (kg) = 35 × [height (m)]2), it is clear that basing treatment on
ideal weight or an average of actual and ideal weight results in undertreatment if
used for patients with a BMI of 35 or less.2,3
 TABLE
Dose Modifications for Myelosuppressive Drugs With a Nadir* at Less than 3
Weeks
28.2

III. DATA FOR CLINICALLY USEFUL CHEMOTHERAPEUTIC, BIOLOGIC, AND

MOLECULAR TARGETED AGENTS1
Agents or uses that have not yet been approved by the FDA may be included because they
either have shown preliminary efficacy in clinical trials or are currently being investigated
and show promise of benefit. As their efficacy and toxicity are more firmly established, it
is expected that some will be approved by the FDA for general use, whereas others will
remain investigational or be dropped from further study.

ABIRATERONE ACETATE
Other name. Zytiga.
Mechanism of action. An androgen biosynthesis inhibitor. It inhibits 17 alpha-hyroxylase/C
17, 20-lyase (CYP 17), which results in decreased formation of dehydroepiandrosterone
(DHEA) and androstenedione and increased mineralocorticoid production by the adrenal
glands.
Primary indication. In combination with prednisone in the treatment of metastatic castration-
resistant prostate cancer.
Usual dosage and schedule. 1,000 mg (four 250 mg tablets) orally once daily in combination
with prednisone 5 mg orally twice daily. Abiraterone must be taken on an empty stomach, at
least 2 hours after or 1 hour before a meal. Recommended starting dose in patients with
moderate hepatic impairment (Child-Pugh B) is 250 mg orally once daily. Use with caution
with strong CYP3A4 inhibitors or inducers. Dose reduction may be required when used with
substrates of CYP2D6 with narrow therapeutic index.
Special precautions
1. Abiraterone can cause fetal harms if administered to pregnant women.
2. Hypertension, hypokalemia, and fluid retention may occur as a result of increased
mineralocorticoid production. However, severe reactions are uncommon, and the
coadministration of prednisone leads to decreased ACTH secretion and thus reduces the
incidence and severity of these reactions.
Toxicity
1. Myelosuppression and other hematologic effects. Lymphopenia is common and
occasionally severe.
2. Nausea, vomiting, and other GI effects. Diarrhea and constipation are common, and
dyspepsia is occasional.
3. Mucocutaneous effects. Skin rash is occasional, but rarely severe.
4. Immunologic effects and infusion reactions. Urinary and upper respiratory tracts
infections can occasionally occur.
5. Miscellaneous effects
a. General. Fatigue is common. Pyrexia is occasional.
b. Respiratory. Cough is occasional. Dyspnea is occasional.
c. Cardiovascular. Edema and hot flashes are common. Hypertension is occasional. Chest
pain is uncommon. Cardiac failure (asymptomatic and symptomatic) is uncommon, but
can be rarely severe and lead to death. Cardiac arrhythmias including tachy- and brady-
arrhythmias are occasional and not usually severe, but can be fatal.
d. Metabolic. Hypertriglyceridemia, hypokalemia, and hypophosphatemia are common.
e. Hepatic. Increased AST and ALT are common. Hyperbilirubinemia is occasional. Liver
function tests should be checked at baselines, every 2 weeks for the first 3 months and
monthly thereafter. If grade 3 or greater toxicity develops (AST and or ALT greater than
five times ULN or total bilirubin greater than three times ULN), dose interruption is
recommended until toxicity improves to grade 1 or less, upon which treatment can be
restarted at a reduced dose. In patients with moderate hepatic impairment (Child-Pugh
B) who develop grade 3 or higher toxicity, permanent discontinuation of treatment is
recommended.
f. Endocrine. Adrenal insufficiency is rare, and the risk is higher during infections, stress,
withdrawal from prednisone, and during prednisone dose reductions. Increased dose of
steroids may be indicated before, during, and after stressful situations.
g. Genitourinary. Urinary frequency, nocturia and hematuria are occasional.
h. Musculoskeletal and connective tissue. Arthralgia, myalgia, joints swelling, joints
stiffness, and muscle spasms are common, but usually not severe.
i. Psychiatric. Insomnia is occasional.

ADO-TRASTUZUMAB EMTANSINE
Other name. Kadcyla.
Mechanism of action. HER2-targeted antibody-drug conjugate (ADC) combining the
humanized anti-HER2 IgG1, trastuzumab with the small molecule microtubule inhibitor, DM1.
Upon binding to the subdomain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes
receptor-mediated internalization and subsequent lysosomal degradation, resulting in
intracellular release of DM1-containing cytotoxic catabolites.
Primary indication. Metastatic HER2-positive carcinoma of the breast in patients who
previously received trastuzumab and a taxane, separately or in combination, and either
received prior therapy for advanced disease or developed disease recurrence during or within
6 months of completing adjuvant treatment.
Usual dosage and schedule. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks. The first
infusion is given over 90 minutes, and patients are monitored for infusion-related reactions up
to 90 minutes after the infusion. Subsequent infusions are given over 30 minutes. It should not
be given concurrently with trastuzumab or pertuzumab. The infusion rate should be slowed or
interrupted if the patient develops infusion-related reactions. Permanent discontinuation is
recommended for severe reactions. Dose adjustment/interruptions or permanent
discontinuation may be required for increased serum transaminases, hyperbilirubinemia, left
ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy. The
dose must not be reescalated after a dose reduction is made.
Special precautions
1. Pulmonary toxicity. Cases of severe, and sometimes fatal, pneumonitis and interstitial lung
disease leading to acute respiratory distress syndrome have been reported in up to 1.2% of
patients. Permanent discontinuation is recommended if diagnosis is confirmed or strongly
suspected after exclusion of other possible causes.
2. Infusion-related and hypersensitivity reactions manifested by fever, chills, flushing,
dyspnea, hypotension, bronchospasms, wheezing, and tachycardia can occur in 1.4% of
patients. Although these cases are usually mild and resolve with rate slowing or treatment
interruption with appropriate medical management, some cases can be severe and fatal.
Treatment discontinuation is recommended in patients who develop severe, anaphylactic-
like reaction. Extravasation reactions (erythema, tenderness, skin irritation, pain and/or
swelling) can occur usually within 24 hours of infusion. These reactions are usually mild,
and general supportive care is recommended as there is no specific treatment.
3. Bleeding (including epistaxis, CNS, respiratory, and GI) is common (32.2%). Severe
hemorrhagic reactions are uncommon, but can be fatal. Coadministration of medications
known to increase the risk of bleeding should be taken with caution.
4. Embryo-fetal toxicity. Verification of pregnancy status prior to initiation of therapy in
women of childbearing age and the use of effective birth control measures during and up to
6 months after the last dose of treatment is recommended.
5. Ado-trastuzumab emtansine can cause left ventricular dysfunction, although it is uncommon.
Assessment at base line, as well as every 3 months while on treatment, with
 echocardiogram or multigated acquisition (MUGA) scan is recommended. If the left
ventricular ejection fraction (LVEF) is <40% or 40% to 45% with >10% decrease in the
absolute value, treatment interruption and reassessment in 3 weeks is recommended, and
permanent discontinuation is warranted if the LVEF does not improve or declines further.
6. Severe, and sometimes fatal, hepatotoxicity and hepatic failure can occur. Periodic
monitoring of liver function tests is recommended. Dose reduction/interruption may be
required for elevated transaminases and/or total bilirubin. However, permanent
discontinuation is recommended if the AST or ALT is >three times ULN concomitantly with
total bilirubin >two times ULN. Do not treat if active hepatitis B or C. Nodular
regenerative hyperplasia and portal hypertension were rarely described and warrant
permanent discontinuation of treatment.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and anemia are common,
but rarely severe. Thrombocytopenia is common and occasionally severe. The incidence of
thrombocytopenia is higher in the Asian population.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea,
xerostomia, and constipation are common. Dyspepsia is occasional.
3. Mucocutaneous effects. Stomatitis is occasional. Rash and pruritus are occasional.
4. Immunologic effects and infusion reactions. See Special Precautions.
5. Miscellaneous effects
a. General. Fatigue, asthenia, and pyrexia are common.
b. Respiratory. Dyspnea is occasional. Cough and epistaxis are common.
c. Cardiovascular. Peripheral edema is occasional. Hypertension is occasional.
d. Metabolic. Hypokalemia is occasional.
e. Neurologic. Dysgeusia and dizziness are occasional. Headache is common. Peripheral
sensory neuropathy is common and mostly mild. Grade 3 or greater is uncommon, but
treatment interruption is recommended until it resolves to grade 2 or less.
f. Hepatic. Increased AST/ALT and/or total bilirubin is common and occasionally severe.
g. Musculoskeletal and connective tissue. Arthralgia and musculoskeletal pain are
common. Myalgia is occasional.
h. Psychiatric. Insomnia is occasional.
i. Ophthalmic. Blurred vision, conjunctivitis, dry eyes, and increased lacrimation are
uncommon.

AFATINIB
Other name. Gilotrif.
Mechanism of action. Tyrosine kinase inhibitor; afatinib binds covalently to the kinase
domains of ErbB1(EGFR), ErbB2(HER2), and ErbB4(HER4) and inhibits tyrosine kinase
autophosphorylation, irreversibly resulting in downregulation of ErbB signaling.
Primary indications. Metastatic non–small cell lung cancer (NSCLC) tumors that harbor
epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution
mutations.
Usual dosage and schedule. 40 mg orally daily until disease progression or unacceptable
toxicity. Dose to be taken at least 1 hour before or 2 hours after a meal. Missed doses must not
be taken within 12 hours of the next scheduled dose. Reduced doses are indicated following
temporary discontinuation for adverse drug reactions and may be needed for patients who are
concurrently taking P-glycoprotein inhibitors.
Special precautions. Afatinib can cause fetal harm when administered to a pregnant woman.
Fatal cases of severe hepatic toxicity, interstitial lung disease, and diarrhea can occur.
Discontinue treatment in patients who develop life-threatening bullous, blistering, or
exfoliating lesions, and in any confirmed case of interstitial lung disease or severe keratitis.
Must not be used with vinorelbine in HER2-positive metastatic breast cancer.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported. However, paronychia is
common, and cystitis is occasional.
2. Nausea, vomiting, and other GI effects. Diarrhea is universal, with severe cases (grade 3
or greater) occurring in 15% of cases in the first 6 weeks of treatment, and can result in
severe, and rarely fatal, dehydration with or without renal impairment. Abnormalities in
liver function tests are occasional and rarely fatal.
3. Mucocutaneous effects. Cutaneous reactions consisting of rash, erythema, and acneiform
rash are universal. Grade 3 reactions can occur in 16% of cases. The incidence of grade 1
to 3 palmar-plantar erythrodysesthesia syndrome in clinical trials was 7%. Severe bullous
and exfoliating dermatitis is rare. Stomatitis is common and occasionally grade 3 or higher.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects.
a. Renal impairment as a result of diarrhea is occasional and uncommonly severe.
b. Conjunctivitis is uncommon, and severe cases that progress to ulcerative keratitis are
rare.
c. Interstitial lung disease or reactions that mimic this occur in up to 20% and may be fatal.
d. Ventricular dysfunction is uncommon.
e. Fever, weight loss, pruritis, and hypokalemia are occasional.

ALTRETAMINE
Other names. Hexamethylmelamine, Hexalen, HXM.
Mechanism of action. Unknown. Although it structurally resembles the known alkylating agent
triethylenemelamine, it has some antimetabolite characteristics.
Primary indication. Carcinoma of the ovary, persistent or recurrent after first-line therapy.
Usual dosage and schedule
1. 260 mg/m2 PO daily in three or four divided doses after meals and at bedtime for 14 or 21
days every 4 weeks when used as a single agent.
2. 150 to 200 mg/m2 PO daily in three or four divided doses for 2 out of 3 or 4 weeks when
used in combination.
Special precautions. Concurrent altretamine and antidepressants of the monoamine oxidase
(MAO) inhibitor class may cause severe orthostatic hypotension. Cimetidine may increase
toxicity.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and
thrombocytopenia are uncommon, though lesser degrees are common. Anemia is common.
2. Nausea, vomiting, and other GI effects. Mild-to-moderate nausea, vomiting, and other GI
effects occur in about 30% of patients and are rarely severe. Diarrhea is occasional.
Tolerance may develop.
3. Mucocutaneous effects. Alopecia, skin rash, and pruritus are rare.
4. Miscellaneous effects
a. Peripheral sensory neuropathies are common and may be ameliorated by pyridoxine, but
tumor response may be compromised.
b. Central nervous system (CNS) effects, including agitation, confusion, hallucinations,
depression, and Parkinsonian-like symptoms are uncommon with recommended
intermittent schedule.
c. Decreased renal function is occasional.
d. Increased alkaline phosphatase level is occasional.

ANAGRELIDE
Other names. Imidazo(2,1-b)quinazolin-2-one, Agrelin.
Mechanism of action. Mechanism for thrombocytopenia unknown, but may be due to impaired
megakaryocyte function. Inhibitor of platelet aggregation, but not at usual therapeutic doses.
Primary indication. Uncontrolled thrombocytosis in chronic myeloproliferative disorders,
such as essential thrombocythemia, chronic granulocytic leukemia, and polycythemia rubra
vera.
Usual dosage and schedule. (Supplied as 0.5-mg and 1-mg capsules.)
1. 0.5 mg PO q.i.d. or 1 mg PO b.i.d. Increase by 0.5 mg/day every 5 to 7 days if no response.
Maximum daily dose is 10 mg/day. Maximum single dose is 2.5 mg. Higher doses cause
postural hypotension.
2. Alternate dosing schedules:
a. Elderly: 0.5 mg PO daily, increase by 0.5 mg each week.
b. Abnormal renal or hepatic function: 0.5 mg PO b.i.d.
Special precautions. Contraindicated in pregnancy and in patients with severe hepatic
impairment. Use with caution in patients with heart disease. Tachycardia and forceful heartbeat
may be exacerbated by caffeine; consumption of caffeine should be avoided for 1 hour before
and after anagrelide is taken. Use other drugs that inhibit platelet aggregation (such as
nonsteroidal anti-inflammatory drugs (NSAIDs)) with caution. Monitor platelet count every
few days during the first week, then weekly until the maintenance dose is reached.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia is rare. Anemia is common
but mild. Thrombocytopenic hemorrhage is uncommon.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are occasional. Diarrhea,
gas and abdominal pain are common; pancreatitis is rare. Lactase supplementation
eliminates diarrhea (anagrelide formulated with lactose). Hepatic enzyme elevation is rare,
but caution is recommended when there is evidence of hepatic dysfunction.
3. Mucocutaneous. Rash, including urticaria, is occasional (8%). Hyperpigmentation is rare.
Sun sensitivity is possible.
4. Miscellaneous effects
a. Cardiovascular. Palpitations, forceful heartbeat, and tachycardia are common.
Congestive heart failure is uncommon, but fluid retention or edema is common.
Tachyarrhythmias (including atrial fibrillation and premature atrial beats) are
occasional. Angina, cardiomyopathy, or other severe cardiovascular effects are rare,
although there are somewhat more frequent (8%) episodes of chest pain. Drinking
alcoholic beverages may cause flushing. Higher than recommended single doses cause
postural hypotension. Cardiovascular effects appear to result from vasodilation,
positive inotropy, and decreased renal blood flow.
b. Neurologic. Headaches are common and occasionally are severe; they usually diminish
in about 2 weeks. Weakness (asthenia) is common. Dizziness is occasional.
c. Pulmonary. Infiltrates are rare, but are a reason to stop anagrelide and treat with
steroids.

ANASTROZOLE
Other name. Arimidex.
Mechanism of action. Decreases estrogen biosynthesis by selective inhibition of aromatase
(estrogen synthetase).
Primary indications
1. Carcinoma of the breast as adjuvant treatment in postmenopausal women with positive
hormone receptors.
2. Carcinoma of the breast that is advanced or metastatic as first therapy in postmenopausal
women with positive or unknown hormone receptors, alone or in combination with
Fluvestrant.
3. Carcinoma of the breast that is advanced or metastatic as second therapy in postmenopausal
women with progression following initial response to tamoxifen.
4. Prevention of breast cancer in women at high risk, including prior ductal carcinoma in situ
(DCIS), who have contraindications to tamoxifen.
Usual dosage and schedule. 1 mg PO daily.
Special precautions. Potential hazard to fetus if given during pregnancy. In women with
preexisting ischemic heart disease, an increased incidence of ischemic cardiovascular events
occurred with anastrozole use compared with tamoxifen use. Consider obtaining bone mineral
density testing prior to initiation of anastrozole and treating as clinically indicated.
Toxicity
1. Myelosuppression and other hematologic effects. No dose-related myelosuppression.
Thromboembolic events are uncommon (3%).
2. Nausea and vomiting, other GI effects. Nausea, diarrhea, and constipation are
occasional. Vomiting is uncommon.
3. Mucocutaneous effects. Rash is occasional. Hot flushes are common (35%). Vaginal
dryness and leukorrhea are uncommon.
4. Miscellaneous effects
a. Asthenia is common. Headache and dizziness are occasional.
b. Musculoskeletal pain is occasional. Arthralgia is occasional.
c. Peripheral edema and weight gain are occasional (lower than with megestrol).
d. Dyspnea and cough are occasional.
e. Cataracts are occasional (6%).
f. Decreased bone mineral density with osteoporosis is occasional (11%), and there is
increased risk of fractures (10%).
g. Vaginal bleeding is uncommon, and endometrial cancer is rare (0.2%).

ARSENIC TRIOXIDE
Other name. Trisenox.
Mechanism of action. Although the mechanism is incompletely understood, effects of arsenic
trioxide include morphologic changes and DNA fragmentation characteristic of apoptosis and
alteration of the fusion protein PML-RAR alpha.
Primary indication
Acute promyelocytic leukemia that is refractory to, or has relapsed from, retinoid and
anthracycline therapy and has t(15;17) translocation or PML/RAR alpha gene expression.
Usual dosage and schedule
1. Induction. 0.15 mg/kg IV daily until marrow remission. Maximum of 60 doses.
2. Consolidation. 0.15 mg/kg IV daily for 25 doses over a period of up to 5 weeks.
 Consolidation is started 3 to 6 weeks after completion of induction therapy.
Special Precautions
Cardiovascular. Tachycardia and prolonged QT interval are common. This may lead to
complete AV block with fatal ventricular arrhythmia. Electrolyte (including magnesium)
abnormalities should be corrected prior to initiation of therapy, and patients with prolonged
QT intervals should have measures taken to reduce this prolongation prior to treatment with
arsenic trioxide. A QT value >500 msec during therapy is an indication to suspend arsenic
trioxide treatment and to initiate measures to correct other risk factors that may be contributing
to the prolongation of the QT.
Acute promyelocytic leukemic differentiation syndrome, similar to that seen with retinoic
acid, may be seen and is potentially fatal. This syndrome consists of fever, dyspnea, weight
gain, pulmonary infiltrates, and pleural or pericardial effusions with or without leukocytosis.
High-dose corticosteroids (e.g., dexamethasone, 10 mg b.i.d) should be started at the first signs
of this syndrome and continued until it has subsided.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, thrombocytopenia, and
neutropenia are occasional. Leukocytosis is common. Disseminated intravascular
coagulation is occasional and may be severe. Infections and neutropenic fever are
occasional.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and abdominal pain
are common (>50%). GI bleeding, with or without diarrhea, is occasional (8%).
Constipation, anorexia, and other abdominal distress are occasional.
3. Mucocutaneous effects. Sore throat is common (40%). Dermatitis, pruritis, and
ecchymosis are also common. More severe mucocutaneous reactions including local
exfoliation, urticaria, and oral blistering are occasional to uncommon. Epistaxis is common
(25%). Eye irritation and injection are occasional.
4. Miscellaneous effects
a. Cardiovascular. Tachycardia and prolonged QT interval are common. This may lead to
complete AV block with fatal ventricular arrhythmia.
b. Acute promyelocytic leukemic differentiation syndrome, similar to that seen with
retinoic acid, may be seen. This consists of fever, dyspnea, weight gain, pulmonary
infiltrates, and pleural or pericardial effusions with or without leukocytosis. This
syndrome may be fatal.
c. General and administration site. Headache and insomnia are common. Edema and
pleural effusion are common (though not commonly serious), and general weight gain is
occasional. Drug hypersensitivity is uncommon. Injection site edema, erythema, and pain
are occasional.
d. Metabolic. Hypokalemia, hypomagnesemia, and hyperglycemia are common (45% to
50%). Hyperkalemia is occasional to common (18%), as are elevated transaminases,
hypocalcemia, and hypoglycemia.
 e. Pulmonary. Cough and dyspnea are common (>50%). Pleural effusion, hypoxia,
wheezing, and asymptomatic auscultatory findings are occasional to common (8% to
20%).
f. Renal. Renal failure is occasional.

ASPARAGINASE
Other names. L-Asparaginase, Elspar, Kidrolase, pegaspargase, Oncaspar, Erwinaze
(asparaginase Erwinia chrysanthemi).
Mechanism of action. Hydrolysis of serum asparagine occurs, which deprives leukemia cells
of the required amino acid and inhibits protein synthesis. Normal cells are spared because they
generally have the ability to synthesize their own asparagine. Pegaspargase is a chemically
modified formulation of asparaginase in which the L-asparaginase is covalently conjugated
with monomethoxy polyethylene glycol (PEG). This modification increases its half-life in the
plasma by a factor of 4 to about 5.7 days and reduces its recognition by the immune system,
which allows the drug to be used in patients previously hypersensitive to native L-
asparaginase.
Primary indication. Acute lymphocytic leukemia, primarily for induction therapy.
Usual dosage and schedule. All schedules are used in combination with other drugs. The
schedules listed are only a few of many acceptable dosing schedules.
1. L-asparaginase. 6,000 IU/m2 SC on days 5, 8, 11, 15, and 22 of the treatment period.
2. L-asparaginase. 10,000 IU IV daily for 10 successive days beginning on day 17 of the
treatment period.
3. Pegaspargase. 2,500 IU/m2 intramuscular (IM; or IV) once every 14 days, either for first-
line acute lymphocytic leukemia or in patients who have developed hypersensitivity to
native forms of asparaginase. For IM use, limit volume at single injection site to 2 mL. For
IV administration, give over 1 to 2 hours in saline or normal saline with 5% dextrose.
Special precautions. Asparaginase is contraindicated in patients with pancreatitis or a history
of pancreatitis. Asparaginase is contraindicated in patients who have had significant
hemorrhagic events associated with prior L-asparaginase therapy. Pegaspargase is also
contraindicated in patients who have had previous serious allergic reactions, such as
generalized urticaria, bronchospasm, laryngeal edema, hypotension, or other unacceptable
adverse reactions to prior pegaspargase.
Be prepared to treat anaphylaxis at each administration of the drug. Epinephrine,
antihistamines, corticosteroids, and life-support equipment should be readily available.
Giving concurrently with or immediately before vincristine may increase vincristine
toxicity.
The IM route is preferred for pegaspargase, because of a lower incidence of
hepatotoxicity, coagulopathy, and GI and renal disorders compared with the IV route of
administration.
Toxicity
1. Myelosuppression and other hematologic effects. Occasional myelosuppression. CNS
thrombosis and other coagulopathies are uncommon.
2. Nausea, vomiting, and other GI effects. Occasional and usually mild. (see below for
liver and pancreas effects.)
3. Mucocutaneous effects. No toxicity occurs except as a sign of hypersensitivity.
4. Anaphylaxis. Mild-to-severe hypersensitivity reactions, including anaphylaxis, occur in
20% to 30% of patients. Such reaction is less likely to occur during the first few days of
treatment. It is particularly common with intermittent schedules or repeat cycles. If the
patient develops hypersensitivity to the Escherichia coli–derived enzyme (Elspar),
Erwinia-derived asparaginase may be safely substituted because the two enzyme
preparations are not cross-reactive. Note that hypersensitivity may also develop to
Erwinia-derived asparaginase, and continued preparedness to treat anaphylaxis must be
maintained.
If given IM, asparaginase should be given in an extremity so that a tourniquet can be
applied to slow the systemic release of asparaginase should anaphylaxis occur.
Approximately 30% of patients previously sensitive to L-asparaginase will have a
hypersensitivity reaction to pegaspargase, while only 10% of those who were not
hypersensitive to the native form will have a hypersensitivity reaction to the PEG-modified
drug.
1. Miscellaneous effects
a. Mild fever and malaise are common and occasionally progress to severe chills and
malignant hyperthermia.
b. Hepatotoxicity is common and occasionally severe. Abnormalities observed include
elevations of serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase,
and bilirubin; depressed levels of hepatic-derived clotting factors and albumin; and
hepatocellular fatty metamorphosis.
c. Renal failure is rare.
d. Pancreatic endocrine and exocrine dysfunction, often with manifestations of pancreatitis,
occasionally occurs. Nonketotic hyperglycemia is uncommon.
e. CNS effects (depression, somnolence, fatigue, confusion, agitation, hallucinations, or
coma) are seen occasionally. They are usually reversible following discontinuation of
the drug.

AXITINIB
Other name. Inlyta.
Mechanism of action. Multi-receptor tyrosine kinases inhibitor, including vascular endothelial
growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, which results in decreased
angiogenesis, tumor growth, and cancer progression.
Primary indications. Advanced renal cell carcinoma (RCC) after failure of one prior systemic
therapy.
Usual dosage and schedule. 5 mg orally every 12 hours. A dose escalation to 7 mg twice
daily may be used if treatment is well tolerated for at least 2 consecutive weeks with no grade
2 or higher adverse events and if patients remain normotensive and not receiving
antihypertension medications. A second dose escalation to 10 mg twice daily under the same
criteria can be done. The concomitant use of strong CYP3A4/5 inhibitors should be avoided.
Starting dose should be decreased to 50% in patients with moderate (Child-Pugh B) hepatic
impairment, while treatment should be avoided in patients with severe (Child-Pugh C) hepatic
impairment.
Special precautions
1. Axitinib can cause fetal harm if administered to a pregnant woman.
2. As with other agents with antiangiogenic effect, wound healing complications can occur,
and thus, treatment should be held at least 24 hours prior to scheduled surgery. The decision
to resume therapy after surgery should be based on clinical judgment of adequate wound
healing.
3. GI fistula formation and perforations have been reported and can be fatal.
4. Hemorrhagic events including cerebral hemorrhage, hematuria, hemoptysis, lower GI
hemorrhage, and melena are common, but severe reactions are rare and can be fatal.
5. Axitinib has not been studied in patients who have evidence of untreated brain metastasis.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are
occasional. Anemia and lymphopenia are common. Polycythemia is rare.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe.
Nausea, vomiting, and constipation are common. Stomatitis, dysgeusia, dyspepsia, and
abdominal pain are occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome is common and
occasionally severe. Rash, pruritus, dry skin, and mucosal inflammation are occasional.
Alopecia and erythema are uncommon.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Fatigue, asthenia, and decreased appetite are common. Tinnitus is uncommon.
b. Respiratory. Dysphonia is common. Cough and dyspnea are occasional.
c. Cardiovascular. Treatment-related hypertension is common with median onset of 1 to 4
weeks. It can be severe in up to 16% of cases and rarely lead to hypertensive crisis.
Arterial thromboembolic events including transient ischemic attacks, cerebrovascular
accidents, myocardial infarctions, and retinal artery occlusions are uncommon, but can
be fatal. Venous thromboembolic events including pulmonary embolism, deep vein
thrombosis, retinal vein occlusion, and retinal vein thrombosis are uncommon and can
 be fatal.
d. Metabolic. Hypocalcemia, hyperglycemia, hypernatremia, and increase in lipase and
amylase are common. Hyperkalemia, hypophosphatemia, hyponatremia, and
hypoglycemia are occasional.
e. Hepatic. Elevation in ALT, AST, or both are common, and periodic monitoring of liver
function is recommended.
f. Neurologic. Reversible posterior leukoencephalopathy syndrome (RPLS), which can
present with headache, seizure, lethargy, confusion, blindness, and other visual and
neurologic disturbances, and is diagnosed by MRI, is rare. Headache and dizziness are
occasional.
g. Endocrine. Hypothyroidism is common, while hyperthyroidism is rare. Monitoring of
thyroid function should be done at baseline and periodically during treatment.
h. Genitourinary. Proteinuria is occasional and uncommonly severe. Creatinine increase is
common and rarely severe.
i. Musculoskeletal and connective tissue. Arthralgia, myalgia, and pain in extremities are
occasional.

AZACITIDINE
Other name. Vidaza.
Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing
hypomethylation of DNA and thus, it is believed, results in cellular differentiation or
apoptosis. May restore normal function of genes that are critical for the control of cellular
differentiation and proliferation. Nonproliferating cells are relatively insensitive to
azacitidine.
Primary indication. Myelodysplastic syndrome (MDS).
Usual dosage and schedule. 75 mg/m2 SC or IV daily for 7 days, repeated every 4 weeks.
Dose may be increased to 100 mg/m2 if no toxicity other than nausea and vomiting. Therapy
may be continued so long as the patient has improved from the drug.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and
anemia are common. Febrile neutropenia is four times as common as in patients receiving
supportive care. Petechiae or ecchymosis are occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea or
constipation are common. Abdominal pain is occasional.
3. Mucocutaneous effects. Pharyngitis and stomatitis—occasional. Skin rash is occasional,
urticaria is occasional. Injection site pain is common.
4. Neurotoxicity. Insomnia is common. Lethargy, dizziness, or confusional state are
occasional.
5. Miscellaneous effects
a. Cardiorespiratory. Cough and dyspnea are common. Pulmonary edema—uncommon.
Edema is occasional. Tachycardia or other more serious cardiac disorders—uncommon.
b. Fever is common.
c. Fatigue and weakness—common.
d. Arthralgias and back pain are occasional.
e. Hypokalemia—occasional.

BELINOSTAT
Other name. Beleodaq.
Mechanism of action. Histone deacetylase (HDAC) inhibitor. It causes accumulation of
acetylated histones and other proteins, including cell cycle arrest and/or apoptosis of some
transformed cells. It has preferential cytotoxicity toward tumor cells compared with normal
cells.
Primary indications. Relapsed or refractory peripheral T-cell lymphoma (PTCL).
Usual dosage and schedule. The recommended dose is 1,000 mg/m2 IV on days 1 to 5 of each
21-day cycle. Cycles are continued until disease progression or intolerable toxicity. Dose
modifications may be required for neutropenia and/or thrombocytopenia. All nonhematologic
toxicities need to be of grade 2 or less prior to each treatment cycle. The starting dose should
be reduced to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele.
Special precautions. Belinostat can cause teratogenicity and/or embryo-fetal lethality. Patients
with moderate-to-severe hepatic impairment (total bilirubin >1.5 times the ULN) were
excluded from clinical trials and there is insufficient evidence to recommend a dose for those
patients. Hepatic failure, tumor lysis syndrome in patients with bulky disease, ventricular
fibrillation, and pneumonia can occur.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common. Thrombocytopenia
is occasional. Leukopenia (neutropenia and lymphopenia) with serious or fatal infections
including pneumonia and sepsis can also occur.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are
common.
3. Mucocutaneous effects. Rash and pruritus are common. Abdominal pain is occasional.
4. Immunologic effects and infusion reactions. Infusion site pain can occur in up to 14% of
patients.
5. Miscellaneous effects
a. Hepatic. Fatal hepatotoxicity and liver function abnormalities can occur.
b. Pyrexia and fatigue are common.
c. Neurologic. Headache and dizziness are occasional.
 d. Respiratory. Cough and dyspnea are common.
e. Cardiovascular. Peripheral edema is common. Prolonged QT interval and fatal
ventricular fibrillation can occur.

BENDAMUSTINE
Other names. Treanda, bendamustine hydrochloride.
Mechanism of action. Bendamustine is an alkylating agent that is a bifunctional
mechlorethamine derivative containing a purine-like benzimidazole ring. It forms interstrand
DNA crosslinks that lead to cell death in both resting and dividing cells, though the exact
mechanism of cell death is not clear.
Primary indications
1. Chronic lymphocytic leukemia (CLL)
2. Indolent B-cell non-Hodgkin lymphoma
Usual dosage and schedule
1. CLL. 90 to 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6
cycles.
2. Non-Hodgkin lymphoma. 120 mg/m2 IV over 30 minutes on days 1 and 2 of a 21-day
cycle, up to 8 cycles.
Initiation of successive cycles of therapy is usually delayed until there is an absolute
neutrophil count (ANC) ≥1 × 109/L and a platelet count ≥75 × 109/L. Dose reductions of
50% to 75% should be initiated for grade 3 to 4 hematologic or nonhematologic toxicity.
Special precautions. Infusion reactions consisting of fever, chills, pruritis, and rash are
common. Severe anaphylactic or anaphylactoid reactions, particularly in the second or
subsequent cycles of therapy, may rarely occur. Antihistamines (e.g., diphenhydramine and
cimetidine) and corticosteroids are commonly used to minimize the severity of infusion
reactions. Tumor lysis syndrome has been observed, particularly in the first cycle of therapy.
Toxic epidermal necrolysis has rarely occurred when bendamustine was given with rituximab.
Stevens–Johnson syndrome has rarely occurred when bendamustine was administered
concomitantly with allopurinol. The relationship of these severe reactions to bendamustine is
not known. If severe skin reactions occur, bendamustine should be withheld or discontinued.
Do not give if known hypersensitivity to bendamustine or mannitol. Bendamustine can cause
fetal harm and must not be administered to pregnant women.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is common and in
the higher dosage ranges is universal. Grade 3 to 4 leukopenia (both neutrophils and
lymphocytes) is common. Grade 3 to 4 anemia and thrombocytopenia are occasional.
Infections overall are occasional. Pneumonia and neutropenic sepsis are uncommon, but
may be fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are occasional to
common and dose dependent, but rarely severe. Anorexia, dyspepsia, gastroesophageal
reflux, upper abdominal pain, and distension are occasional.
3. Mucocutaneous effects. Skin rash and pruritis are occasional, including toxic skin
reactions and bullous exanthema.
4. Immunologic effects and infusion reactions. Infusion reactions consisting of fever, chills,
pruritis, and rash are common. Severe anaphylactic or anaphylactoid reactions, particularly
in the second or subsequent cycles of therapy, are rare. Preventive measures, including
antihistamines, and corticosteroids, should be given if grade 1 or 2 infusion reactions were
experienced in a prior cycle. Bendamustine should generally not be repeated if patients
have had a prior grade 3 or 4 infusion reaction.
5. Miscellaneous effects
a. Fever (occasionally with chills) and fatigue are common; weakness and weight loss are
occasional.
b. Tumor lysis syndrome, including hyperuricemia, may occur, primarily with the first
cycle of therapy, and lead to acute renal failure. With concomitant allopurinol, watch
closely for severe skin reactions.
c. Hypokalemia is only occasional, but may be severe.
d. Cough, dyspnea, throat pain, wheezing, and nasal congestion are occasional to common.
e. Hypotension is occasional.

BEVACIZUMAB
Other name. Avastin.
Mechanism of action. Binds VGEF and prevents interaction of VEGF with its receptors on the
surface of endothelial cells. This in turn impairs endothelial cell proliferation and new blood
vessel formation, impeding tumor growth and metastasis.
Primary indications
1. Breast, colon, kidney, rectum, and nonsquamous NSCLC, usually with other agents.
2. Glioblastoma, alone or with other agents.
3. Ovarian, fallopian tube, or primary peritoneal cancer in the recurrent, platinum resistant
setting.
4. Cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan in
persistent, recurrent or metastatic disease.
Usual dosage and schedule
1. 5 to 10 mg/kg IV once every 2 weeks.
2. 15 mg/kg IV once every 3 weeks.
Special precautions. GI perforation occurs in up to 4% of patients, and may have a fatal
outcome. Impaired wound healing may rarely lead to anastomotic dehiscence. Bevacizumab
should not be initiated for at least 28 days following major surgery. The interval between
termination of bevacizumab and subsequent surgery should take into account the accumulation
ratio of 2.8 (with every 2-week dosing) and the half-life of approximately 20 days. Blood
pressure monitoring is recommended every 2 to 3 weeks because of the risk of hypertension.
RPLS has been reported rarely; if it occurs, therapy must be discontinued immediately and
treatment for hypertension initiated if it is present. Urinary protein should be evaluated prior to
each treatment with a urine dipstick, and if 2+ or greater, the patient should undergo further
assessment to rule out severe proteinuria, such as with a urine protein-creatinine (UPC) ratio.
Hold therapy if UPC >3.5.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia is common, but associated
primarily with the cytotoxic agents used together with bevacizumab. Thrombocytopenia is
uncommon. Minor bleeding, such as epistaxis, is common; severe hemorrhage is not, except
for hemoptysis in patients with squamous cell carcinomas of the lung. Serious, and in some
cases fatal, hemoptysis has occurred in NSCLC, with the highest risk appearing in patients
with squamous cell histology; other severe or fatal hemorrhage, including CNS bleeding
has occurred. Thromboembolic events are occasional and may be severe.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and constipation are
common. Diarrhea is common, particularly when used with fluorouracil and irinotecan
chemotherapy. Abdominal pain is common. GI hemorrhage is occasional; perforation is
uncommon.
3. Mucocutaneous effects. Dry skin, skin discoloration, stomatitis, and exfoliative dermatitis
are occasional to common. Alopecia, skin ulcers, and nail changes are uncommon.
4. Immunologic effects and infusion reactions. Infusion reactions with hypertension,
wheezing, stridor, desaturation, chest pain, headaches, and diaphoresis are uncommon.
Severe reactions are rare (0.2%).
5. Miscellaneous effects
a. Fatigue, weakness, and headache—common
b. Cardiovascular and respiratory—Hypertension is common and occasionally is severe
(>200/110 mm Hg). Blood pressure >160/100 or rise of >30 mm Hg requires holding
therapy, at least temporarily. Hypotension is occasional. Dyspnea is occasional.
Congestive heart failure is uncommon, but risk with anthracyclines is increased (14%).
Venous thromboembolic events are increased by about 15% compared with
chemotherapy not containing bevacizumab.
c. Neurologic—Dizziness is common. RPLS has been reported rarely (<0.1%); if it occurs,
therapy must be discontinued immediately and treatment for hypertension initiated if it is
present.
d. Metabolic—Proteinuria is common, but severe proteinuria (>3.5 g/24 hours) is
uncommon and rarely leads to nephrotic syndrome (<1%), but requires holding
bevacizumab and rechecking prior to next cycle.
e. Osteonecrosis of the jaw.
BEXAROTENE (Capsules)
Other name. Targretin.
Mechanism of action. A member of the subclass of retinoids (rexinoid) that selectively
activates retinoid X receptors (RXRs). These receptors are distinct from RARs, but also act as
transcription factors that regulate the expression of genes that control cellular differentiation
and proliferation. The exact mechanism in cutaneous T-cell lymphoma (CTCL) is unknown.
Primary indication. Cutaneous manifestations of CTCL in patients refractory to at least one
prior systemic therapy.
Usual dosage and schedule. 300 mg/m2/day to start as a single oral daily dose taken with a
meal. Dosage is adjusted downward by 100 mg/m2/day decrements for toxicity, or upward to
400 mg/m2/day if there has been no response and good tolerability after 8 weeks of treatment.
Treatment may be continued for up to 2 years.
Special precautions. Avoid use in pregnant women because of marked teratogenic potential.
Toxicity
1. Myelosuppression and other hematologic effects. Mild-to-moderate leukopenia is
occasional to common with a time of onset of 4 to 8 weeks. Severe or worse leukopenia is
occasional.
2. Nausea, vomiting, and other GI effects. Mild nausea, abdominal pain, and diarrhea are
occasional. Vomiting and anorexia are uncommon. Inflammatory bowel disease and
pancreatitis (associated with hypertriglyceridemia) are rare.
3. Mucocutaneous effects. Skin reactions are occasional to common. They include redness,
dryness, and pruritus of the skin and mucous membranes; possible vesicle formation;
exfoliative dermatitis; cheilitis; and conjunctivitis. There also may be increased skin
photosensitivity (e.g., to sun) and the nails may become brittle. Alopecia is uncommon.
4. Miscellaneous effects
a. Cataracts and corneal ulcerations or opacities are uncommon.
b. Systemic. Arthralgias, bone pain, muscle aches are occasional. Fever, chills, and
headache (flu syndrome) are occasional.
c. Hypertriglyceridemia (80%) and hypercholesterolemia (35% to 40%) are common.
Hypertriglyceridemia is usually more severe. These are reversible with discontinuation
of therapy and may be reduced by antilipemic therapy.
d. Neurologic. Headache is common. Lethargy, fatigue, confusion, and mental depression
are uncommon; pseudotumor cerebri is rare.
e. Hepatotoxicity with increased LDH, SGOT, serum glutamic pyruvic transaminase
(SGPT), gamma-glutamyl transpeptidase (GGTP), alkaline phosphatase is occasional.
f. Hypothyroidism—Common, with decreased T4 and thyroid stimulating hormone (TSH).
g. Peripheral edema—Occasional.
h. Hypernatremia is rare.
BICALUTAMIDE
Other name. Casodex.
Mechanism of action. A nonsteroidal antiandrogen that is a competitive inhibitor of androgens
at the cellular androgen receptor in target tissues, such as the prostate.
Primary indication. Carcinoma of the prostate.
Usual dosage and schedule. 50 mg daily in combination with LHRH analog.
Special precautions. Rare cases of severe liver injury have been reported. Bicalutamide
should be used with caution in patients with moderate-to-severe hepatic impairment.
Toxicity
1. Myelosuppression and other hematologic effects. No myelosuppression. May interact
with warfarin and increase INR.
2. Nausea, vomiting, and other GI effects. Nausea, diarrhea, flatulence, and constipation are
occasional; vomiting is uncommon.
3. Mucocutaneous effects. Mild skin rash is occasional.
4. Miscellaneous effects
a. Secondary pharmacologic effects, including breast tenderness, breast swelling, hot
flashes, impotence, and loss of libido are common but reversible after cessation of
therapy.
b. Elevated liver function tests are uncommon, but severe hepatic failure has been
observed only rarely.
c. Dyspnea and cough are seen occasionally.
d. Adverse cardiovascular events are similar to those seen with orchiectomy.
e. Dizziness or vertigo is occasional.

BLEOMYCIN
Other name. Blenoxane.
Mechanism of action. Bleomycin binds to DNA, causes single- and double-strand scission,
and inhibits further DNA, RNA, and protein synthesis.
Primary indications
Testis, head and neck, penis, cervix, vulva, anus, and skin carcinomas.
Hodgkin and non-Hodgkin lymphomas.
Pleural effusions—used as sclerosing agent.
Usual dosage and schedule
1. 10 to 20 U/m2 IV or IM once or twice a week or
2. 30 U IV push weekly for 9 to 12 weeks in combination with other drugs for testis cancer.
3. 60 U in 50 mL of normal saline instilled intrapleurally.
Special precautions
1. In patients with lymphoma, a test dose of 1 or 2 U should be given IM prior to the first dose
of bleomycin because of the possibility of anaphylactoid, acute pulmonary, or severe
hyperpyretic responses. If no acute reaction occurs within 4 hours, regular dosing may
begin.
2. Reduce dose for renal failure.

Serum Creatinine % of Full Dose

2.5–4 25
4–6 20
6–10 10

3. The cumulative lifetime dose should not exceed 400 U because of the dose-related
incidence of severe pulmonary fibrosis. Smaller limits may be appropriate for older
patients or those with preexisting pulmonary disease. Frequent evaluation of pulmonary
status, including symptoms of cough or dyspnea, rales, infiltrates on chest X-ray film, and
pulmonary function studies are recommended to avert serious pulmonary sequelae.
4. Glass containers are recommended for continuous infusion to minimize drug instability.
5. High Fio2 (fraction of inspired oxygen) (such as might be used during surgery) should be
avoided as it exacerbates lung injury, sometimes acutely.
Toxicity
1. Myelosuppression and other hematologic effects. Significant depression of counts is
uncommon. This factor permits bleomycin to be used in full doses with myelosuppressive
drugs.
2. Nausea, vomiting, and other GI effects. Occasional and self-limiting.
3. Mucocutaneous effects. Alopecia, stomatitis, erythema, edema, thickening of nail bed, and
hyperpigmentation and desquamation of skin are common.
4. Pulmonary effects
a. Acute anaphylactoid or pulmonary edema–like response is occasional in patients with
lymphoma (see Special Precautions above).
b. Dose-related pneumonitis with cough, dyspnea, rales, and infiltrates, progressing to
pulmonary fibrosis.
5. Fever. Common. Occasionally severe hyperpyrexia, diaphoresis, dehydration, and
hypotension have occurred and resulted in renal failure and death. Antipyretics help control
fever.
6. Miscellaneous effects
a. Lethargy, headache, joint swelling is rare.
b. IM or SQ injection may cause pain at injection site.

BLINATUMOMAB
Other name. Blincyto.
Mechanism of action. A bispecific CD19-directed CD3 T-cell engager. It activates
endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on
benign and malignant B cells. By mediating the formation of synapse between T cells and
tumor cells, upregulation of cell adhesion molecules, production of cytolytic proteins, release
of inflammatory cytokines and proliferation of T-cells, it causes redirected lysis of CD19+
cells.
Primary indications. Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell
precursor acute lymphoblastic leukemia (ALL).
Usual dosage and schedule. Treatment course consists of up to two cycles of induction
followed by three additional consolidation cycles (up to a total of five cycles). A single cycle
consists of 4 weeks of continuous IV infusion via a pump followed by 2 weeks treatment-free
interval. For patients at least 45 kg in weight:
■ Cycle 1: 9 μg/day on days 1 to 7 followed by 28 μg/day on days 8 to 28.
■ For subsequent cycles: 28 μg/day on days 1 to 28.
Hospitalization is recommended for the first 9 days of cycle 1 and the first 2 days of the
subsequent cycles. Dexamethasone 20 mg IV should be given 1 hour prior to the first dose
of each cycle, prior to a step dose (cycle 1 day 8) and when restarting an infusion after an
interruption of 4 hours or more. A new cycle should be started if infusion interruption after
an adverse event is longer than 7 days, whereas for less than a 7-day-long interruption, the
same cycle can be continued for a total of 28 days, including the days before and after the
interruption.
Special precautions
1. Blinatumomab can cause fetal harms if administered to a pregnant woman based on its
mechanism of action. Since there is no adequate evidence in pregnant women, it should be
used in this patient population only if benefits justify potential risks to the fetus.
2. Initiation of treatment causes transient release of cytokines that may suppress CYP450
enzymes, especially during the first 9 days of the first cycle and during the first 2 days of
subsequent cycles. Dose adjustment and close monitoring of CYP450 substrates (like
warfarin and cyclosporine) are warranted.
3. Life-threatening and fatal cytokine release syndrome, seizures, tumor lysis syndrome, and
infections can occur.
4. Special caution must be used during preparation and administration as errors in both have
occurred resulting in under- or overdosing.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and thrombocytopenia are
occasional. Anemia and neutropenia are common and occasionally severe. Febrile
neutropenia is common and can be life-threatening. Leukocytosis and lymphopenia are
uncommon.
2. Nausea, vomiting, and other GI effects. Nausea, constipation, and diarrhea are common
but rarely severe. Abdominal pain and vomiting are occasional.
3. Mucocutaneous effects. Rash (popular, maculopapular, and vesicular) is common but
uncommonly severe.
4. Immunologic effects and infusion reactions. Cytokines release syndrome (CRS), which
may be indistinguishable from infusion reactions, can occur and rarely be fatal. Signs and
symptoms can include: pyrexia, hypotension, bronchospasm, headaches, nausea,
hyperbilirubinemia, and elevation in ALT and/or AST. Cases of disseminated intravascular
coagulation (DIC) and hemophagocytic lymphohistiocytosis (HLH) have also been
described. Hypogammaglobulinemia is occasional. Increased risk of bacterial, fungal, and
viral infections has been reported, with severe infections occurring in up to 25% of cases.
These infections can be life-threatening, and administration of prophylactic antibiotics may
be indicated on a case-by-case basis.
5. Miscellaneous effects
a. General. Pyrexia is common and occasionally severe. Fatigue is common and chills are
occasional.
b. Respiratory. Cough and dyspnea are common, but uncommonly severe.
c. Cardiovascular. Tachycardia is occasional. Peripheral edema is common. Capillary
leak syndrome is rare.
d. Metabolic. Hypokalemia is common. Hypomagnesemia, hypophosphatemia, and
hyperglycemia are occasional.
e. Hepatic. Elevated liver enzymes is occasional especially during the first 2 weeks of
treatment, but rarely results in discontinuation of treatment.
f. Neurologic. Headaches and tremor are common. Dizziness is occasional. Convulsions,
speech disorders, disturbances in consciousness, confusion and disorientation, and
coordination and balance disorders are uncommon, but can be severe in 15% of cases.
Due to these potential toxicities, patients should refrain from driving and engaging in
hazardous occupations or activities such as heavy or potentially dangerous machines
while treatment is being administered. Although leukoencephalopathic changes on
cranial MRI can occur especially in patients with history of prior cranial irradiation
and/or antileukemic chemotherapy, the clinical significance of such changes is unknown.
g. Musculoskeletal and connective tissue. Arthralgia, back pain, pain in extremities, and
bone pain are occasional.
h. Psychiatric. Insomnia is occasional.

BORTEZOMIB
Other name. Velcade.
Mechanism of action. A reversible inhibitor of the chymotrypsin-like activity of the 26S
proteasome, which mediates ubiquitinated protein degradation and plays an essential role in
intracellular protein regulation and consequent cellular signal transduction pathways and
cellular homeostasis. Disruption of these homeostatic mechanisms can lead to cell death.
Bortezomib is metabolized by liver enzymes.
Primary indications
1. Multiple myeloma
2. Mantle cell lymphoma
Usual dosage and schedule
1. Multiple myeloma. 1.3 mg/m2 SC (preferred) or IV bolus twice weekly (days 1, 4, 8, 11,
22, 25, 29, and 32), often together with oral melphalan and oral prednisone (days 1 to 4
every 6 weeks) for four 6-week treatment cycles. Then once weekly (days 1, 8, 22, and 29)
together with oral melphalan and oral prednisone (days 1 to 4 every 6 weeks) for five more
6-week treatment cycles. The intensity may be modified by giving the twice-weekly
component for one cycle only followed by eight cycles of the weekly schedule; or by using
the weekly schedule for all nine cycles. Weekly dose may be increased to 1.5 mg/m2.
Similar schedules used in combination with other agents.
2. Mantle cell lymphoma. 1.3 mg/m2 SC or IV bolus twice weekly (days 1, 4, 8, 11 every 3
weeks for up to eight cycles. Frequency may be reduced to weekly, 3 weeks out of 4 for
maintenance.
3. Reduce each dose to 0.7 mg/m2 in the first cycle for patients with moderate or severe liver
function impairment (bilirubin > 1.5 ULN). Consider dose escalation to 1.0 mg/m2 or
further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Special precautions. Cardiogenic shock, congestive heart failure, and respiratory insufficiency
have been rarely observed. Anaphylaxis has also been observed. Patients with hepatic
impairment should be monitored closely, as bortezomib is metabolized by liver enzymes.
Consider acyclovir 400 mg b.i.d for Herpes zoster prophylaxis.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and
thrombocytopenia are common; neutropenia is only occasionally severe (grade 3 or 4).
Thrombocytopenia is severe in 30% of patients. Disseminated intravascular coagulation
has been observed (rare to uncommon).
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, diarrhea, and
constipation are common. Dehydration is a concern because of vomiting and diarrhea and
may be seen occasionally.
3. Mucocutaneous effects. Rash is common (20%).
4. Neurotoxicity. Peripheral neuropathy is common, and occasionally (7%) severe. This is
frequently manifest by paresthesias and dysesthesias. Headache is common. Neurotoxicity
is often less with SC rather than IV administration.
5. Immunologic effects and infusion reactions. Hypersensitivity reactions have been seen,
including anaphylactic reactions and immune complex mediated hypersensitivity (rare).
 Tumor lysis syndrome may be seen in patients with a high tumor burden. Increased
incidence of H. zoster compared with controls—occasional.
6. Miscellaneous effects
a. Fatigue and weakness are common.
b. Arthralgias, muscle cramps, and back pain are occasional.
c. Fever is common.
d. Cardiovascular. Hypotension is occasional, is seen throughout therapy, and may be
orthostatic or not. Peripheral edema is common. Other cardiovascular events during
treatment have included severe congestive heart failure, AV block, angina, atrial
fibrillation, and flutter—these are probably uncommon to rare as a consequence of the
drug.
e. Infiltrative pulmonary disease—rare, but may be severe or fatal.
f. Hepatitis and pancreatitis have been observed—probably rare.

BOSUTINIB
Other name. Bosulif.
Mechanism of action. A tyrosine kinase inhibitor that inhibits the Bcr-Abl kinase (including
imatinib-resistant forms of Bcr-Abl) and the Src-family kinases including Src, Lyn, and Hck.
Primary indications. Chronic, accelerated, or blast phase Philadelphia chromosome-positive
(Ph+) CML with resistance or intolerance to prior therapy.
Usual dosage and schedule. 500 mg orally once daily with food. If a dose is missed beyond
12 hours, the patient should skip the dose and take the usual prescribed dose on the following
day. Dose escalation to 600 mg once daily can be considered in patients who do not reach
complete hematologic response (CHR) by week 8 or a complete cytogenetic response (CCyR)
by week 12, who did not have grade 3 or higher adverse reactions. Concomitant use of strong
or moderate CYP3A inhibitors, strong or moderate CYP3A inducers, and/or P-gp substrates
should be avoided. In patients with preexisting mild, moderate, and severe hepatic impairment,
the recommended dose of Bosulif is 200 mg daily.
Special precautions
1. Bosutinib can cause fetal harm if administered to a pregnant woman.
2. Fluid retention that may manifest as pericardial effusion, pleural effusion, pulmonary
edema, and/or peripheral edema is common, but uncommonly severe and can be fatal,
requiring dose interruptions, modifications, or even permanent discontinuation.
3. Hypersensitivity reactions have been reported in less than 10% of patients and anaphylactic
shock occurred in less than 0.2% of treated patients.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and
thrombocytopenia are common and can be severe. Febrile neutropenia can occur in less
 than 10% of cases. CBC monitoring should be done at baseline, weekly for the first month
and monthly thereafter.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, and diarrhea
are common. Diarrhea can be occasionally severe. These reactions can be managed using
standards of care. Dose interruptions/adjustments may be indicated for severe reactions.
Gastritis is occasional. Pancreatitis and GI hemorrhage are rare.
3. Mucocutaneous effects. Skin rash is common and occasionally severe. Pruritus is
occasional. Erythema multiforme is rare.
4. Immunologic effects and infusion reactions. Upper and lower respiratory tract infections
are occasional but rarely severe.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are common. Asthenia is occasional. Tinnitus has been
reported in less than 10% of patients.
b. Respiratory. Cough is common and dyspnea is occasional.
c. Cardiovascular. QTc prolongation to more than 500 msec is rare, but caution should be
used in patients with underlying cardiovascular disease and other risk factors for QTc
prolongation.
d. Metabolic. Hypophosphatemia and elevation in lipase level are occasional.
Hyperkalemia as well as elevation in creatinine level and acute renal failure have been
reported in less than 10% of patients, the latter of which may be related to dehydration
rather than direct drug-related toxicity.
e. Hepatic. Drug-induced liver injury is rare. Moderate elevations in ALT or AST (<3 ×
ULN) are common and may require dose interruption/modification. Monitoring of liver
function tests should be done on a monthly basis or as clinically indicated.
f. Neurologic. Headache is common, and dizziness is occasional.
g. Musculoskeletal and connective tissue. Arthralgia, myalgia, and back pain are
occasional.

BRENTUXIMAB VEDOTIN
Other name. Adcetris.
Mechanism of action. Brentuximab vedotin is an ADC, which is a chimeric IgG1 directed
against CD30 that is covalently attached to the small molecule, MMAE (monomethyl auristatin
E), a microtubule disrupting agent via a linker. The binding of the ADC to CD30-expressing
cells results in internalization of the ADC-CD30 complex, and the release of MMAE via
proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the
cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.
Primary indications
1. Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after
failure of at least two prior multiagent chemotherapy regimens in patients who are not
 ASCT candidates.
2. Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior
multiagent chemotherapy regimen.
3. Classical HL as consolidation treatment for patients at high risk of relapse or progression
post autologous hematopoietic stem cell transplantation.
Usual dosage and schedule. 1.8 mg/kg administered as an IV infusion over 30 minutes every 3
weeks (maximum of 16 cycles). Coadministration with strong CYP3A4 inhibitors and inducers
results in increase and decrease in the ADC exposure, respectively, with the former potentially
increasing toxicity. Dose interruptions/modifications may be required for peripheral
neuropathy and neutropenia.
Special precautions
1. Brentuximab vedotin can cause fetal harm if administered to a pregnant woman.
2. A fatal case of progressive multifocal leukoencephalopathy (PML) has been reported.
3. Tumor lysis syndrome may occur especially in patients with rapidly proliferating tumor and
high tumor burden.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are
common and occasionally severe. Lymphadenopathy is occasional but rarely severe.
Neutropenia is common and occasionally severe. It can also be prolonged (>1 week).
Cases of upper respiratory tract infections were reported in 47% of patients, all of which
were mild. Cases of urinary tract infection, pyelonephritis, and septic shock were
uncommonly reported.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea, and
constipation are common but uncommonly severe.
3. Mucocutaneous effects. Rash and pruritus are common. Alopecia is occasional. Dry skin
is uncommon.
4. Immunologic effects and infusion reactions. Infusion-related reactions (including chills,
nausea, dyspnea, pruritus, pyrexia, cough, and anaphylaxis) have occurred. If an infusion-
related reaction occurs, the infusion should be interrupted and appropriate medical
management instituted. Premedication for subsequent infusions with acetaminophen, an
antihistamine and a corticosteroid is recommended. Transient and persistent antibodies to
the ADC can develop in 30% and 7%, respectively. A higher incidence of infusion-related
reactions was observed in patients who developed persistently positive antibodies.
Stevens–Johnson syndrome has been reported.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are common. Chills and night sweats are occasional.
b. Respiratory. Cough is common. Dyspnea and oropharyngeal pain are occasional. Cases
of pneumonitis, pulmonary embolism, and pneumothorax were reported in 2% of
patients.
c. Cardiovascular. Peripheral edema is uncommon. Supraventricular tachycardia was
 reported in 3% of patients.
d. Metabolic. Decreased weight and appetite are occasional.
e. Neurologic. ADC-induced peripheral sensory and motor neuropathy is common and is
cumulative. This can persist even after discontinuation of treatment. Headache is
common and dizziness is occasional.
f. Musculoskeletal and connective tissue. Arthralgia and myalgia are common. Back pain,
pain in extremity, and muscle spasms are occasional.
g. Psychiatric. Insomnia is occasional.

CABAZITAXEL
Other name. Jevtana.
Mechanism of action. Microtubule inhibitor binds to tubulin, which leads to the stabilization
of microtubules, and the inhibition of mitotic and interphase cellular functions.
Primary indication. Carcinoma of the prostate, metastatic, previously treated with a
docetaxel-containing regimen.
Usual dosage and schedule. 25 mg/m2 IV over 1 hour every 3 weeks in combination with
prednisone 10 mg daily. Reduce dose to 20 mg/m2 if the patient experiences prolonged grade 3
or higher neutropenia, febrile neutropenia, or severe or persistent diarrhea.
Special precautions. Hypersensitivity reactions can occur, and therefore patients should be
premedicated with corticosteroids and histamine H1 and H2 antagonists. Should not be given to
patients with hepatic impairment. Patients aged 65 years and older are more likely to
experience adverse effects from cabazitaxel treatment. Because cabazitaxel is metabolized
primarily through CYP3A, coadministration with strong CYP3A inhibitors should be avoided.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, anemia, and
thrombocytopenia are common. Grade 3 to 4 febrile neutropenia is occasional, but may be
fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, anorexia, diarrhea, and
constipation are common, but infrequently (2% to 6%) severe.
3. Mucocutaneous effects. Alopecia is occasional.
4. Immunologic effects and infusion reactions. Hypersensitivity reactions are uncommon,
but may occur within a few minutes following initiation of therapy; they may be associated
with rash, erythema, hypotension, and bronchospasm.
5. Miscellaneous effects
a. Fatigue and weakness are common. Fever is occasional.
b. Renal failure is uncommon, but may be fatal (rare). Hematuria is occasional.
c. Peripheral edema—occasional.
 d. Cardiac arrhythmias and hypotension are uncommon.
e. Back pain and arthralgias are occasional.
f. Peripheral neuropathy and headache are occasional.
g. Dyspnea and cough are occasional.

CABOZANTINIB
Other name. Cometriq.
Mechanism of action. Inhibits the tyrosine kinase activity of RET, MET, VEGFR-1 and 2,
KIT, TRKB, FLT-3, AXL, and TIE-2, which are involved in oncogenesis, metastasis, tumor
angiogenesis, and maintaining tumor microenvironment.
Primary indications. Progressive, metastatic medullary thyroid cancer.
Usual dosage and schedule. 140 mg orally daily. To be taken at least 2 hours after or 1 hour
before a meal. Certain foods (grapefruit, grapefruits) or nutritional supplements known to
inhibit cytochrome P450 should not be taken during treatment period. Missed doses can be
taken up to 12 hours before the next dose.
Special precautions. Cabozantinib can cause fetal harm if administered to a pregnant woman
and can cause male infertility. Coadministration with substrates of P-glycoprotein can increase
the plasma concentration of the latter. It is recommended not to coadminister cabozantinib with
strong CYP3A4 inhibitors and/or inducers. If the use of a strong CYP3A4 inhibitor is required,
the dose of cabozantinib should be decreased by 40 mg prior to initiation until 2 or 3 days after
discontinuation of the strong inhibitor. If the use of a strong CYP3A4 inducer is required, the
dose of cabozantinib should be increased by 40 mg prior to initiation until 2 or 3 days after
discontinuation of the strong inducer. Moderate and severe hepatic impairment should preclude
the use of cabozantinib. Dose interruptions are recommended for grade 4 hematologic
toxicities, grade 3 or higher nonhematologic toxicities, and for intolerable grade 2 adverse
reactions. Permanent discontinuation is required for: visceral perforations, fistulas formation,
severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, malignant
hypertension and hypertensive crisis, osteonecrosis of the jaw, and RPLS.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are
common, mostly grade 1 and 2. Lymphopenia is common with grade 3 toxicity occurring in
up to 16% of patients. The incidence of serious (grade 3 or higher) hemorrhagic events was
observed in 3% of patients treated with cabozantinib. These reactions can be fatal and
permanent discontinuation of treatment is indicated. Cabozantinib can impair wound healing
and cause healing complications. Withholding treatment at least 28 days prior to scheduled
surgeries is recommended, and treatment resumption postsurgery is indicated after adequate
wound healing.
2. Nausea, vomiting, and other GI effects. Serious GI perforations and fistulas (including
 esophageal) and non-GI (tracheal) fistulas formation can occur in 3%, 1%, and 4%,
respectively, and can be fatal. Abdominal pain, stomatitis, nausea, vomiting, diarrhea, and
constipation are common. Diarrhea can be grade 3 or greater in 16% of cases. Dysphagia
and dyspepsia are occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome (PPES) can occur in
up to 50% of patients, with grade 3 or higher reported in 13% of cases. Rash, dry skin, and
alopecia are common. Hyperkeratosis is occasional. Hair color changes
(depigmentation/graying) can occur in up to 34% of patients.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Decreased appetite, fatigue, asthenia, and weight loss are common.
b. Respiratory. Dysphonia was reported in 20% of patients, all grade 1 or 2.
c. Cardiovascular. Elevation in blood pressure is universal with most cases being pre- or
stage I hypertension. Stage I or II hypertension can occur in up to 61% of patients. Mild
cases can be managed with antihypertensive medications. More severe cases or those
that are not adequately controlled with medications may require dose
reduction/interruption and/or permanent discontinuation. Increased risk of both venous
and arterial thromboembolic events have been reported; 6% and 2%, respectively.
Permanent discontinuation is recommended in patients who develop treatment-related
acute myocardial infarction or other serious thromboembolic complications. Although
10 to 15 msec increase in QTc interval was observed at 4 weeks after initiation of
treatment, changes in wave form morphology or new rhythms were not observed and no
patients had a QTc interval >500 msec.
d. Metabolic. Electrolytes disturbances, including hypocalcemia, hyponatremia,
hypokalemia, and hypophosphatemia are common. Grade 3 or higher hypocalcemia was
observed in 12% of patients.
e. Hepatic. Increase in AST, ALT, ALP, and total bilirubin is common but grade 3 or higher
are uncommon.
f. Neurologic. Dysgeusia and headache are common. Peripheral neuropathy is occasional.
Although RPLS is rare (occurred in one patient across clinical trials), clinical suspicion
is warranted in patients presenting with seizures, headache, visual disturbances,
confusion, or altered mental status, and evaluation with MRI is indicated to make the
diagnosis. Permanent discontinuation of cabozantinib is recommended if the diagnosis is
confirmed.
g. Genitourinary. Nephrotic range proteinuria and nephrotic syndrome can occur. Regular
monitoring of urine protein is recommended and permanent discontinuation is warranted
in patients who develop nephrotic syndrome.
h. Musculoskeletal and connective tissue. Musculoskeletal chest pain, arthralgia, and
muscle spasms are occasional. Osteonecrosis of the jaw (ONJ) can occur and manifests
as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection,
gingival ulceration or erosion, or slow healing after dental surgery. Periodic oral
 examination is recommended. Treatment should be held for at least 28 days prior to
scheduled surgery, if possible.
i. Psychiatric. Grade 1 or 2 anxiety was reported in 9% of patients taking cabozantinib
versus 2% of patients taking placebo.

CAPECITABINE
Other name. Xeloda.
Mechanism of action. An orally administered prodrug that is converted to fluorouracil
intracellularly. When this is converted to the active nucleotide, 5-fluoro-2-deoxyuridine
monophosphate, it inhibits the enzyme thymidylate synthetase and blocks DNA synthesis. The
triphosphate may also be mistakenly incorporated into RNA, which interferes with RNA
processing and protein synthesis.
Primary indications
1. Metastatic breast cancer that is resistant to anthracycline- and paclitaxel-containing
chemotherapy regimens. May also be used in patients in whom anthracyclines are
contraindicated.
2. Colorectal (adjuvant or metastatic), small bowel, stomach, pancreas, and biliary
carcinomas.
Usual dosage and schedule. Generally taken with water, twice daily (about 12 hours between
doses) within 30 minutes after a meal. Dose reductions are commonly required, by reducing
the daily dose, the number of consecutive daily treatments, or both.
1. 1,000 to 1,250 mg/m2 orally twice daily for 2 weeks as a single agent, followed by a 1-
week rest, given as 3-week cycles.
2. 850 to 1,250 mg/m2 orally twice daily for 2 weeks when used in combination with other
drugs, followed by a 1-week rest, given as 3-week cycles.
3. 800 mg/m2 orally twice daily 5 days per week during radiotherapy as a radiosensitizer.
Special precautions. Increase in prothrombin time (PT) and International Normalized Ratio
(INR) may be seen in patients previously stable on oral anticoagulants. Monitor PT/INR more
frequently when patient is on capecitabine. Patients with moderate renal impairment (CCr 30
to 50 mL/minutes) require a 25% dosage reduction: Diarrhea may be severe and require fluid
and electrolyte replacement. Incidence and severity may be worse in patients 80 years of age
or older. Therapy may need to be interrupted and subsequent doses decreased for severe or
repeated toxicity. Phenytoin levels should be monitored, as elevated levels may occur.
Toxicity
1. Myelosuppression and other hematologic effects. Common, but when used as a single
agent, these usually are mild to moderate with anemia predominating. Neutropenia is
common when used in combination and may be associated with neutropenic fever.
2. Nausea, vomiting, and other GI effects. Both nausea (45%) and vomiting (35%) are
 common, but usually not severe. Diarrhea is common (55%); in up to 15% of patients, it is
severe to life-threatening. GI motility disorders, including ileus, may be seen, and
necrotizing enterocolitis has been reported. Abdominal pain is occasional to common.
Anorexia is occasional to common (26%).
3. Mucocutaneous effects. Hand-and-foot syndrome is common (54%) and may be severe.
Dermatitis is also common (27%), as is stomatitis, but it is uncommon that these are severe.
Eye irritation and increased lacrimation are occasional.
4. Miscellaneous effects
a. Fatigue is common.
b. Paresthesias are occasional.
c. Hyperbilirubinemia is common (48%), but only occasionally severe or life-threatening.
d. Fever is occasional.
e. Headache or dizziness is occasional.
f. Cardiotoxicity is possible as with any fluorinated pyrimidine.

CARBOPLATIN
Other names. Paraplatin, CBDCA.
Mechanism of action. Covalent binding to DNA.
Primary indications. Ovarian, endometrial, breast, bladder, and lung cancers, and other
cancers in which cisplatin is active.
Usual dosage and schedule. AUC (area under the curve) dosing (Calvert formula) is generally
preferred.
1. Target AUC is commonly 4 to 6, depending on previous treatment and other drugs to be
used. Administration dose (mg) = (target AUC) × ([creatinine clearance] + 25).
Administration dose is given by IV infusion over 15 to 60 minutes, and repeated every 4
weeks.
2. Higher doses up to 1,600 mg/m2 divided over several days have been used followed by
stem cell rescue.
Special precautions
Much less renal toxicity than cisplatin, so there is no need for a vigorous hydration schedule or
forced diuresis. If AUC dosing is not used, reduce dose to 250 mg/m2 for creatinine clearance
of 41 to 59 mL/minute, reduce to 200 mg/m2 for clearance of 16 to 40 mL/minute.
Anaphylactic-like reactions to carboplatin have been reported and may occur within
minutes of carboplatin administration. Infusion reactions generally develop after several
months of drug tolerance. Epinephrine, corticosteroids, antihistamines, and fluid administration
for hypotension have been employed to alleviate symptoms.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, granulocytopenia, and
 thrombocytopenia are common and dose-limiting. Red blood cell transfusions or epoetin
may be required. Thrombocytopenia may be delayed (days 18 to 28).
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but vomiting
(65%) is not as frequent or as severe as with cisplatin and can be controlled with
combination antiemetic regimens. Liver function abnormalities are common. GI pain is
occasional.
3. Mucocutaneous effects. Alopecia is uncommon. Mucositis is rare.
4. Immunologic effects and infusion reactions. Infusion reactions are occasional, but may be
severe. These may include rash, urticaria, pruritus, and rarely bronchospasm and
hypotension. Desensitization protocols may allow continued therapy with carboplatin, but
should be carried out under close observation. See Special Precautions above.
5. Miscellaneous effects
a. Peripheral neuropathies or central neurotoxicity are uncommon.
b. Cardiovascular (cardiac failure, embolism, cerebrovascular accidents) are uncommon.
c. Hemolytic-uremic syndrome is rare.
d. Renal tubular abnormalities. Elevation in serum creatinine or blood urea nitrogen occurs
occasionally. More common is electrolyte loss with decreases in serum sodium,
potassium, calcium, and magnesium.

CARFILZOMIB
Other name. Kyprolis.
Mechanism of action. Irreversibly binds to the N-terminal threonine-containing active sites of
the 20S proteasome, the proteolytic core particle within the 26S proteasome that mediates
ubiquitinated protein degradation and plays an essential role in intracellular protein regulation
and consequent cellular signal transduction pathways and cellular homeostasis.
Primary indications
1. Multiple myeloma in combination with lenalidomide and dexamethasone in patients who
have received one to three prior lines of prior therapy.
2. Multiple myeloma after receiving at least two prior therapies including an
immunomodulatory agent and bortezomib, and have demonstrated disease progression on or
within 60 days of the completion of the last therapy.
Usual dosage and schedule
1. Cycle 1: 20 mg/m2 (maximum BSA of 2.2 m2) IV over 2 to 10 minutes on days 1, 2, 8, 9, 15,
and 16 of each 28-day cycle.
2. If tolerated, the dose should be escalated to a target dose of 27 mg/m2 (maximum BSA of
2.2 m2) starting day 8 of cycle 1 and during the subsequent cycles.
Hydrate prior to and subsequent to each dose to reduce risk of renal failure and tumor
lysis syndrome. Premedicate with dexamethasone prior to all cycle 1 doses, during first
 cycle of dose escalation, and if infusion reactions develop or reappear.
Dose adjustments do not need to be made for weight changes of equal or less than
20%.
Special precautions
1. No safe dose has been determined in patients with baseline hepatic impairment.
2. Can cause fetal harm if administered to a pregnant woman.
3. Cases of cardiac arrest, cardiogenic shock, congestive heart failure, pulmonary edema,
pulmonary hypertension, and fatal hepatic failure have been observed. Anaphylaxis has also
been observed. Consider acyclovir 400 mg b.i.d for H. zoster prophylaxis. Tumor lysis
syndrome can rarely occur, especially in patients with high tumor burden.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and lymphopenia
are common and occasionally severe. Thrombocytopenia is common and can be grade 4 in
10% of patients. Upper respiratory tract bacterial infections are common but mostly mild.
Pneumonia is occasional and rarely fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are
common and can be rarely severe.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Infusion reactions, characterized by a
spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing,
facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest
tightness, or angina. These reactions may happen immediately following or up to 24 hours
after administration. Administer dexamethasone prior to each treatment to reduce the
incidence and severity of reactions. H. zoster reactivation is uncommon but antiviral
prophylaxis should be considered.
5. Miscellaneous effects.
a. General. Fatigue, peripheral edema, and pyrexia are common. Chills and anorexia are
occasional.
b. Respiratory. Pulmonary arterial hypertension was reported in 2% of patients (grade 3 or
greater in less than 1%). Dyspnea is common and rarely severe/fatal. Cough is common.
c. Cardiovascular. Cardiac failure events (congestive heart failure, pulmonary edema, and
decrease in ejection fraction) were reported in 7% of patients. Patients with New York
Heart Association Class III and IV heart failure, myocardial infarction in the preceding
6 months, and conduction abnormalities uncontrolled by medications were excluded
from the clinical trials. These patients may be at greater risk for cardiac complications.
Hypertension is occasional and uncommonly severe.
d. Metabolic. Hyponatremia, hypophosphatemia, hypercalcemia, hyperglycemia,
hypokalemia, and hypomagnesemia are occasional.
e. Hepatic. Elevation in AST/ALT and/or bilirubin levels is occasional. Dose
adjustments/interruption may be recommended.
 f. Neurologic. Peripheral sensory and motor neuropathy occurred in 14% of patients.
Grade 3 or 4 toxicity is rare. Dizziness is occasional. Headache is common.
g. Genitourinary. Increase in blood creatinine is common. Renal failure is occasional.
These events are occasionally severe and rarely life-threatening.
h. Musculoskeletal and connective tissue. Back pain and arthralgia are common. Muscle
spasms, chest wall pain, and pain in extremity are occasional.
i. Psychiatric. Insomnia is occasional.

CARMUSTINE
Other names. BCNU, BiCNU, Gliadel wafer (surgically implantable, biodegradable polymer
wafer that releases impregnated carmustine from the hydrophobic matrix after implantation.)
Mechanism of action. Alkylation and carbamylation by carmustine metabolites interfere with
the synthesis and function of DNA, RNA, and proteins. Carmustine is lipid soluble and easily
enters the brain.
Primary indications
A. Systemic therapy:
1. Brain tumors
2. Hodgkin and non-Hodgkin lymphomas
3. Melanoma
B. Implantable carmustine-impregnated wafer. Glioblastoma multiforme
Usual dosage and schedule
C. Systemic therapy:
1. 200 to 240 mg/m2 IV as a 30- to 45-minute infusion every 6 to 8 weeks. Dose often is
divided and given over 2 to 3 days. Some recommend limiting the cumulative dose to
1,000 mg/m2 to limit pulmonary and renal toxicity.
2. Higher doses of up to 600 mg/m2 have been used with stem cell rescue (e.g., bone
marrow or peripheral blood stem cell transplantation).
D. Implantable carmustine-impregnated wafer. Up to 8 wafers, each containing 7.7 mg of
carmustine, are applied to the resection cavity surface after removal of the tumor.
Special precautions (systemic therapy). Because of delayed myelosuppression (3 to 6
weeks), do not administer drug more often than every 6 weeks. Await a return of normal
platelet and granulocyte counts before repeating therapy. Amphotericin B may enhance the
potential for renal toxicity, bronchospasm, and hypotension.
Toxicity
A. Systemic therapy:
1. Myelosuppression and other hematologic effects. Delayed and often biphasic, with
the nadir at 3 to 6 weeks; it may be cumulative with successive doses. Recovery may be
protracted for several months. High-dose therapy requires stem cell rescue.
 2. Nausea, vomiting, and other GI effects. Begins 2 hours after therapy and lasts 4 to 6
hours—common.
3. Mucocutaneous effects
a. Facial flushing and a burning sensation at the IV site may be due to alcohol used to
reconstitute the drug; this is common with rapid injection.
b. Hyperpigmentation of skin after accidental contact is common.
4. Miscellaneous effects
a. Hepatotoxicity is uncommon but can be severe.
b. Pulmonary fibrosis is uncommon at low doses, but its frequency increases at doses
higher than 1,000 mg/m2.
c. Secondary neoplasia is possible.
d. Renal toxicity is uncommon at doses of less than 1,000 mg/m2.
e. With high-dose therapy, encephalopathy, hepatotoxicity, and pulmonary toxicity are
common and dose limiting. Hepatic veno-occlusive disease also occurs
(occasional).
B. Implantable carmustine-impregnated wafer: Limited toxicity beyond that expected from
craniotomy is seen. Serious intracranial infection was seen in 4% of patients, compared
with 1% of placebo-treated patients. Brain edema not responsive to steroids may also be
seen in a similar percentage of patients. Abnormal wound healing may occur. Remnants of
the wafer may be seen for many months after implantation.

CERITINIB
Other name. Zykadia.
Mechanism of action. Inhibitor of receptor tyrosine kinases including ALK, insulin-like
growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib
is most active against ALK. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated
phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-
dependent cancer cells.
Primary indications. Locally advanced or metastatic anaplastic lymphoma kinase (ALK)-
positive NSCLC in patients who have progressed on or are intolerant of crizotinib.
Usual dosage and schedule. 750 mg orally once daily on an empty stomach (i.e., do not
administer within 2 hours of a meal). A recommended dose has not been determined for
patients with moderate-to-severe hepatic impairment. Missed doses can be taken up to 12
hours before the next scheduled dose. Dose modifications/interruptions and/or permanent
discontinuation may be warranted in hepatic dysfunction, pneumonitis and interstitial lung
disease (ILD), QTc prolongation, and bradycardia.
Special precautions
1. Concurrent use of strong CYP3A inhibitors should be avoided. If concomitant use of a
 strong CYP3A inhibitor is unavoidable, reduce the dose by approximately one-third,
rounded to the nearest 150-mg dosage strength. After discontinuation of a strong CYP3A
inhibitor, resume treatment at the dose that was taken prior to initiating the strong CYP3A4
inhibitor.
2. Ceritinib can cause fetal harm if administered to a pregnant woman.
3. Cases of severe/fatal ILD/pneumonitis have been observed.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common and occasionally
severe.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, vomiting, constipation,
abdominal pain, and esophageal disorder are common and occasionally severe, requiring
dose interruptions/modifications and symptomatic management.
3. Mucocutaneous effects. Rash is common but rarely severe.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Decreased appetite is common.
b. Respiratory. ILD or pneumonitis has been reported in 4% of patients and was severe in
3%. Permanent discontinuation is recommended upon diagnosis of any grade treatment-
related pneumonitis.
c. Cardiovascular. QTc interval prolongation can uncommonly occur and is concentration
dependent. Periodic monitoring with electrocardiograms (ECGs) is recommended in
patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or
those who are taking medications that are known to prolong the QTc interval. Treatment
interruption is indicated in patients who develop a QTc interval greater than 500 msec
on at least two separate ECGs until the QTc interval is less than 481 msec or recovery
to baseline if the QTc interval is greater than or equal to 481 msec. Dose resumption
should be at a reduced dose. Permanent discontinuation is recommended in patients who
develop QTc interval prolongation in combination with torsade de pointes or
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmias.
Bradycardia is uncommon. In cases of symptomatic bradycardia that is not life-
threatening, withhold treatment until recovery to asymptomatic bradycardia or to a heart
rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the
dose. Permanent discontinuation is indicated for life-threatening bradycardia if no
contributing concomitant medication is identified; however, if associated with a
concomitant medication known to cause bradycardia or hypotension, withhold ceritinib
until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if
the concomitant medication can be adjusted or discontinued, resume at a reduced dose
upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with
frequent monitoring.
d. Elevations in ALT/AST and or bilirubin levels are common and can be severe in up to
27% of patients requiring dose interruptions/modifications. Regular monitoring of
 hepatic function is recommended once a month and as clinically indicated.
e. Neurologic. Neuropathy syndromes (comprised of paresthesia, muscular weakness, gait
disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy,
dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy) can
occur in up to 17% of patients.
f. Endocrine. Hyperglycemia is common and occasionally severe. Hypophosphatemia and
elevation in lipase level are common and occasionally severe.
g. Genitourinary. Increase in creatinine level is common but uncommonly severe.
h. Ophthalmic vision disorders (comprised of vision impairment, blurred vision,
photopsia, accommodation disorder, presbyopia, or reduced visual acuity) can occur in
9% of patients.

CETUXIMAB
Other names. EGFR antibody, C225, Erbitux.
Mechanism of action. EGFR antibody that blocks the ligand-binding site and inhibits
proliferation of cells. It is thought potentially most useful in those tumors that overexpress
EGFR, but correlation with percent of positive cells or intensity of EGFR expression is weak.
Primary indications
1. Carcinoma of head and neck, in combination with radiation therapy or as first-line therapy
with platin-based therapy plus fluorouracil for recurrent locoregional advanced or
metastatic disease, or after failure of platinum-based therapy.
2. Colon cancer when KRAS is wild-type either as
a. First-line therapy in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin),
or
b. After failure of irinotecan and oxaliplatin-based regimens. Often-in combination with
irinotecan or other cytotoxic regimens.
3. Lung cancer if EGFR amplification.
Usual dosage and schedule. 400 mg/m2 IV loading dose administered over 2 hours on day 1.
Then 250 mg/m2 IV maintenance doses administered over 1 hour weekly thereafter. May be
administered in combination with other agents.
Special precautions. Serious infusion reactions, some fatal, may occur (3% of patients). One-
hour observation period is recommended following a cetuximab infusion. Cardiopulmonary
arrest or sudden death has occurred in 2% of patients receiving cetuximab in combination with
radiation therapy. Severe hypomagnesemia is seen in 10% to 15% of patients, and all patients
should have magnesium levels monitored throughout the persistence of cetuximab (8 weeks).
All patients with metastatic colorectal cancer who might be candidates for cetuximab
should have their tumor tested for KRAS mutations. If KRAS mutation in codon 12 or 13 is
detected, cetuximab should not be given, as the patient is unlikely to benefit.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, diarrhea, and
constipation are occasional. Abdominal pain is common.
3. Mucocutaneous effects. Acne-like rash is common (76%). Stomatitis is occasional when
used alone, but universal when used in combination with radiation therapy. Severe
radiation dermatitis may be seen when used concurrently with radiation therapy.
4. Miscellaneous effects
a. Asthenia is common; headache and back pain are occasional.
b. Weight loss, peripheral edema, and dehydration are occasional.
c. Infusion reactions with allergic or hypersensitivity reactions, fever, chills, or dyspnea
are occasional to common (approximately 20%), but may be severe.
d. Human antichimeric antibodies (HACAs) are uncommon.
e. Electrolyte depletion, particularly hypomagnesemia, occurs commonly.
Hypomagnesemia is occasionally severe.

CHLORAMBUCIL
Other name. Leukeran.
Mechanism of action. Classic alkylating agent, with primary effect on preformed DNA.
Primary indications
1. CLL
2. Low-grade non-Hodgkin lymphoma
Usual dosage and schedule
1. Initially, 3 to 4 mg/m2 PO daily until a response is seen or cytopenias occur; then, if
necessary, maintain with 1 to 2 mg/m2 PO daily.
2. 30 mg/m2 PO once every 2 weeks (with or without prednisone 80 mg/m2 PO on days 1 to
5).
Special precautions. Increased toxicity may occur with prior barbiturate use.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting and may be prolonged.
2. Nausea, vomiting, and other GI effects. May be seen with higher doses, but are
uncommon.
3. Mucocutaneous effects. Rash is uncommon.
4. Miscellaneous effects
a. Liver function abnormalities is rare.
b. Secondary neoplasia is possible.
c. Amenorrhea and azoospermia is common.
d. Drug fever is uncommon.
 e. Pulmonary fibrosis is rare.
f. CNS effects including seizure and coma may be seen at very high doses (>100 mg/m2).

CISPLATIN
Other names. cis-Diamminedichloroplatinum (II), DDP, CDDP, Platinol.
Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking
strands of DNA.
Primary indications. Usually used in combination with other cytotoxic drugs.
1. Testis, ovary, endometrial, cervical, bladder, head and neck, GI, and lung carcinomas.
2. Soft tissue and bone sarcomas.
3. Non-Hodgkin lymphoma.
Usual dosage and schedule
1. 40 to 120 mg/m2 IV on day 1 as infusion every 3 weeks.
2. 15 to 20 mg/m2 IV on days 1 to 5 as infusion every 3 to 4 weeks.
3. 30 to 50 mg/m2 IV days 1, 8 every 4 weeks (in combination with other therapy).
Special precautions. Do not administer if serum creatinine level is more than 1.5 mg/dL.
Irreversible renal tubular damage may occur if vigorous diuresis is not maintained, particularly
with higher doses (>40 mg/m2) and with additional concurrent nephrotoxic drugs, such as the
aminoglycosides. At higher doses, diuresis with mannitol with or without furosemide plus
vigorous hydration is mandatory.
1. An acceptable method for hydration in patients without cardiovascular impairment for
cisplatin doses up to 80 mg/m2 is as follows.
a. Have patient void, and begin infusion of 5% dextrose in half-normal saline with
potassium chloride (KCl) 20 mEq/L and magnesium sulfate (MgSO4) 1 g/L (8 mEq/L);
run at 500 mL/hour for 1.5 to 2.0 L.
b. After 1 hour of infusion, give 12.5 g of mannitol by IV push.
c. Immediately thereafter, start the cisplatin (mixed in normal saline at 1 mg/mL) and infuse
over 1 hour through the sidearm of the IV, while continuing the hydration.
d. Give additional mannitol (12.5 to 50.0 g) by IV push if necessary to maintain urinary
output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L
behind on urinary output or signs or symptoms of congestive heart failure develop, 40
mg of furosemide may be given.
2. For doses of more than 80 mg/m2, a more vigorous hydration is recommended.
a. Have patient void, and begin infusion of 5% dextrose in half-normal saline with KCl 20
mEq/L and MgSO4 1 g/L (8 mEq/L); run at 500 mL/hour for 2.5 to 3.0 L.
b. After 1 hour of infusion, give 25 g of mannitol by IV push.
c. Continue hydration.
 d. After 2 hours of hydration, if urinary output is at least 250 mL/hour, start the cisplatin
(mixed in normal saline at 1 mg/mL) and infuse over 1 to 2 hours (1 mg/m2/minute)
through the sidearm of the IV, while continuing the hydration.
e. Give additional mannitol (12.5 to 50 g by IV push) if necessary to maintain urinary
output of 250 mL/hour over the duration of the hydration. If patient gets more than 1 L
behind on urinary output or signs or symptoms of congestive heart failure develop, 40
mg of furosemide may be given.
3. For patients with known or suspected cardiovascular impairment (ejection fraction <45%),
a less vigorous rate of hydration may be used, provided the dose of cisplatin is limited
(e.g., <60 mg/m2). An alternative is to give carboplatin.
Toxicity
1. Myelosuppression and other hematologic effects. Mild to moderate, depending on the
dose. Relative lack of myelosuppression and other hematologic allows cisplatin to be used
in full doses with more myelosuppressive drugs. Anemia is common and may have a
hemolytic component. Anemia often is amenable to epoetin therapy.
2. Nausea, vomiting, and other GI effects. Severe and often intractable vomiting regularly
begins within 1 hour of starting cisplatin and lasts 8 to 12 hours. Prolonged nausea,
vomiting, and other GI occur occasionally. Nausea, vomiting, and other GI may be
minimized by the use of a combination antiemetic regimen.
3. Mucocutaneous effects. None.
4. Renal tubular damage. Acute reversible and occasionally irreversible nephrotoxicity may
occur, particularly if adequate attention is not given to achieving sufficient hydration and
diuresis. Nephrotoxic antibiotics increase risk of acute renal failure.
5. Ototoxicity. High-tone hearing loss is common, but significant hearing loss at vocal
frequencies occurs only occasionally. Tinnitus is uncommon.
6. Severe electrolyte abnormalities. These abnormalities, for example, marked
hyponatremia, hypomagnesemia, hypocalcemia, and hypokalemia, may be seen up to
several days after treatment.
7. Anaphylaxis. May occur after several doses. Responds to epinephrine, antihistamines, and
corticosteroids.
8. Miscellaneous effects
a. Peripheral neuropathies are clinically significant signs and symptoms are common at
cumulative doses more than 300 mg/m2.
b. Hyperuricemia is uncommon, parallels renal failure.
c. Autonomic dysfunction with symptomatic postural hypotension is occasional.

CLADRIBINE
Other names. 2-Chlorodeoxyadenosine, Leustatin.
Mechanism of action. Deoxyadenosine analog with high cellular specificity for lymphoid
cells. Resistant to effect of adenosine deaminase. Accumulates in cells as triphosphate, is
incorporated into DNA, and inhibits DNA repair enzymes and RNA synthesis. Also results in
NAD depletion. Effect is independent of cell division.
Primary indications. Hairy-cell leukemia, CLL, Waldenström macroglobulinemia, and
possibly other lymphoid neoplasms.
Usual dosage and schedule
1. 0.09 mg/kg (3.33 mg/m2) IV daily as a continuous 7-day infusion.
2. 0.14 mg/kg (5.2 mg/m2) IV as a 2-hour infusion daily for 5 days.
3. 0.14 mg/kg (5.2 mg/m2) SC daily for 5 days.
4. 0.12 mg/kg IV daily × 3 together with cyclophosphamide 250 mg/m2 IV daily × 3 every 28
days up to 6 cycles (For CLL without TP53 (17p13) gene deletion).
Special precautions. Give allopurinol, 300 mg daily, as prophylaxis against hyperuricemia.
Opportunistic infections occur occasionally and should be watched for closely.
Toxicity
1. Myelosuppression and other hematologic effects. Moderate granulocyte suppression is
common. Marrow suppression with leukopenia and thrombocytopenia may be prolonged for
over a year. Serious infection is common. Profound suppression of CD4 and CD8 counts is
common and often prolonged for over 1 year. Opportunistic infections, including herpes,
fungus, and pneumocystis infection, may occur and should be watched for. Some routinely
use prophylaxis against one or more of these infections, to include acyclovir 400 mg b.i.d
and trimethoprim-sulfamethoxazole, 1 double-strength tablet twice daily on 2 or 3 days a
week. Autoimmune hemolytic anemia and immune thrombocytopenic purpura occur
occasionally; pure red cell aplasia rarely.
2. Nausea, vomiting, and other GI effects. Mild nausea with decrease in appetite is
common, but no vomiting is expected. Mild reversible increase in liver function tests may
be seen.
3. Mucocutaneous effects. Rash is common. Injection site reactions are occasional.
4. Miscellaneous effects
a. Fever, possibly due to release of pyrogens from tumor cells, is common.
b. Fatigue is common. Headache, dizziness, insomnia, myalgia, and arthralgia are
occasional.
c. Edema and tachycardia are occasional.
d. Cough, shortness of breath, and abnormal breath sounds are occasional.

CLOFARABINE
Other name. Clolar.
Mechanism of action. Clofarabine is a nucleoside analog (an adenine derivative), which is a
potent inhibitor of ribonucleotide reductase. Also inhibits DNA polymerases and DNA
synthesis. Increases intracellular ara-CTP when used with cytarabine.
Primary indications
1. Acute lymphoblastic leukemia in children (age 1 to 21) who have relapsed or are refractory
to other therapy.
2. ALL or acute myelogenous leukemia (AML) in adults.
Usual dosage and schedule
1. 52 mg/m2 IV over 2 hours daily for 5 consecutive days. May be repeated in 2 to 6 weeks.
2. 40 mg/m2 IV over 1 hour (days 2 to 6), followed in 4 hours by cytarabine 1 g/m2 IV as a 2-
hour infusion (days 1 to 5) in AML in adults. (day 1—only cytarabine; day 6—only
clofarabine.)
3. 30 mg/m2 IV over 1 hour daily for 5 days in older adults with AML and unfavorable
prognostic factors. For reinduction (day 29) or consolidation (on recovery of counts), dose
reduced to 20 mg/m2 IV daily for 5 days (six cycles maximum).
Special precautions. Capillary leak syndrome and systemic inflammatory response syndrome
(SIRS) have been observed with clofarabine administration.
Toxicity
1. Myelosuppression and other hematologic effects. Pancytopenia is common. Febrile
neutropenia and documented infections are common.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and abdominal pain
are common. Elevation of transaminases is common and may be severe (grade 3 to 4);
jaundice is occasional. Anorexia is common.
3. Mucocutaneous effects. Nonspecific dermatitis and pruritis are common. Palmar-plantar
erythrodysesthesia is occasional.
4. Miscellaneous effects
a. Arthralgia and back pain are occasional.
b. Creatinine elevations are uncommon to occasional.
c. Fatigue is common. Lethargy is occasional.
d. Flushing and hypotension are occasional to common.

COBIMETINIB
Other name. Cotellic.
Mechanism of action. Reversible inhibitor of mitogen-activated extracellular signal-regulated
kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. Combined
use with the BRAF inhibitor, Vemurafenib, results in greater and prolonged growth inhibition
of the BRAF V600 mutation positive melanoma cells compared with either drug alone.
Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF
tumor cells.
Primary indications
In combination with vemurafenib in BRAFV600E or BRAFV600K mutation-positive unresectable
or metastatic melanoma.
Usual dosage and schedule
60 mg orally once daily on days 1 to 21 of every 28-day cycle, until disease progression or
intolerable toxicity. Concomitant use with strong CYP3A inducers and/or inhibitors should be
avoided. If concurrent short-term (14 days or less) use of moderate CYP3A inhibitors
including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable, reduce
cobimetinib dose to 20 mg. While the appropriate dose has not been established for patients
with moderate-to-severe hepatic impairment and for those with severe renal impairment (GFR
less than 30 mL/minutes/1.73 m2), no dose adjustments are recommended for patients with
mild hepatic impairment (normal total bilirubin and AST higher than ULN or any AST and
total bilirubin up to 1.0 to 1.5 times the ULN) or for those with mild-to-moderate renal
impairment.
Special precautions
1. Cobimetinib is teratogenic and can cause fetal harm if administered to a pregnant woman. It
can also impair fertility in men.
2. Cases of hemorrhage were occasionally reported but uncommonly severe. Cerebral
hemorrhage is rare.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, lymphopenia, and
thrombocytopenia are common but uncommonly severe except for lymphopenia, which can
be occasionally severe.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, and vomiting are common.
Stomatitis is occasional.
3. Mucocutaneous effects. Moderate-to-severe rash can occasionally occur and may result in
hospitalization. Photosensitivity is common but uncommonly severe. Patients should avoid
sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and
lip balm (SPF ≥30) when outdoors. Acneiform dermatitis is common but uncommonly
severe.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Pyrexia is common, and chills are occasional.
b. Cardiovascular. Cardiomyopathy, defined as cardiac failure, left ventricular
dysfunction, or decreased LVEF, can occur. Assessment of LVEF by echocardiogram or
MUGA scan before initiating the treatment is recommended. Monitoring with either
modality is recommended 1 month after starting treatment and every 2 to 3 months
thereafter while on treatment. Of note, the safety of cobimetinib has not been established
 in patients with baseline LVEF that is either below institutional lower limit of normal
(LLN) or below 50%. Hypertension occurred in 15% of patients and 4% of cases were
grade 3 or greater.
c. Ophthalmic. Serious retinopathy occurred in 26% of patients, and retinal vein occlusion
is rare. Periodic eye examination is warranted. Blurry vision is occasional.
d. Musculoskeletal and connective tissue. Cases of rhabdomyolysis have been described
in less than 5% of patients.
e. Metabolic. Increased creatinine is universal but uncommonly severe. Increased AST,
ALT, alkaline phosphatase, and creatine kinase are common and occasionally severe.
Hypophosphatemia and hyponatremia are common and occasionally severe.
Hypoalbuminemia, hyperkalemia, and hypokalemia are common but uncommonly
severe. Hypocalcemia is common and rarely severe.
f. Secondary malignancies. Secondary cutaneous malignant or premalignant conditions can
occasionally occur. Regular skin examination is warranted until 6 months after the last
dose, and local treatment for those lesions is indicated with no dose modifications of
cobimetinib.

CRIZOTINIB
Other name. Xalkori.
Mechanism of action. Inhibitor of receptor tyrosine kinases including ALK, hepatocyte growth
factor receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations
affecting the ALK gene result in the expression of oncogenic fusion proteins that leads to
increased cell proliferation and survival in tumors expressing these proteins.
Primary indications. Locally advanced or metastatic anaplastic lymphoma kinase (ALK)-
positive NSCLC.
Usual dosage and schedule. 250 mg orally twice daily with or without food. Missed dose can
be taken up to 6 hours before the next scheduled dose to maintain a twice-daily regimen. Avoid
use with strong CYP3A inhibitors or inducers. Grapefruit or grapefruit juices may also
increase plasma concentration of crizotinib and should be avoided.
Special precautions. Crizotinib can cause fetal harm if administered to a pregnant woman.
Caution should be undertaken in patients with hepatic impairment as clinical studies excluded
patients with baseline AST or ALT greater than 2.5 times the ULN, as well as those with
baseline total bilirubin of greater than 1.5 times the ULN. Although no dose adjustment is
needed for patients with mild-to-moderate renal impairment, the data about a starting dose for
those with severe renal impairment (creatinine clearance [Ccr] < 30 mL/minute) is lacking.
Severe, and sometimes fatal, cases of pneumonitis, QTc prolongation, and hepatic toxicity can
occur and may warrant permanent discontinuation.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and
thrombocytopenia can occur, and dose modification/interruption is recommended for severe
(grade 3 or greater) reactions. Treatment-related upper respiratory tract infections are
uncommon. Severe and sometimes life-threatening pneumonitis can occur in 1% to 2% of
patients. Permanent discontinuation is recommended if treatment-related diagnosis is
confirmed or suspected after exclusion of other potential causes.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are
common. Abdominal pain, esophagitis, esophageal ulceration, odynophagia, and dysphagia
are occasional.
3. Mucocutaneous effects. Stomatitis is occasional. Rash is occasional.
4. Immunologic effects and infusion reactions. Interstitial lung disease (ILD) and/or
pneumonitis occurred in 2.9% of patients. Permanent discontinuation upon diagnosis is
warranted.
5. Miscellaneous effects
a. General. Fatigue, decreased appetite, and peripheral edema are common. Fever is rare.
b. Respiratory. Dyspnea and cough are uncommon.
c. Cardiovascular. Bradycardia was reported in 5% of patients, and all cases were grade 1
or 2. QTc prolongation is uncommon. Periodic ECG and electrolytes monitoring is
recommended in patients with risk factors for or taking medications known to prolong
QTc. Permanent discontinuation is warranted for grade 4 toxicity while dose
interruption is recommended for grade 3 until recovery to less than or equal to grade 1
with resumption at a one level dose reduction. Use should be avoided in patients with
congenital long QT syndrome.
d. Hepatic. Elevation in ALT and/or AST is occasional and uncommonly severe. Liver
function tests should be monitored once a month while on treatment or more frequently if
toxicity develops.
e. Neurologic. Dizziness is common. Headache is uncommon and dysgeusia is occasional.
Peripheral motor and sensory neuropathy is occasional and mostly grade 1 or 2.
f. Genitourinary. Complex renal cysts occurred in 1% of patients but without renal
impairment.
g. Ophthalmic. Vision disorders including visual impairment, blurry vision, photopsia,
vitreous floaters, photophobia, and diplopia were reported in 62% of patients.
However, none were grade 3 or greater.
h. Musculoskeletal and connective tissue. Arthralgia is uncommon.
i. Psychiatric. Insomnia is uncommon.

CYCLOPHOSPHAMIDE
Other names. CTX, Cytoxan, Neosar.
Mechanism of action. Metabolism of cyclophosphamide by hepatic microsomal enzymes
produces active alkylating metabolites. Cyclophosphamide’s primary effect is probably on
DNA.
Primary indications
1. Breast, lung, ovary, testis, and bladder carcinomas.
2. Bone and soft tissue sarcomas.
3. Hodgkin and non-Hodgkin lymphomas.
4. ALL and CLL.
5. Waldenström macroglobulinemia.
6. Neuroblastoma and Wilms tumor of childhood.
7. Gestational trophoblastic neoplasms.
8. Multiple myeloma.
Usual dosage and schedule
1. 1,000 to 1,500 mg/m2 IV every 3 to 4 weeks or
2. 400 mg/m2 PO days 1 to 5 every 3 to 4 weeks or
3. 60 to 120 mg/m2 PO daily
4. High-dose regimens (4 to 7 g/m2 divided over 4 days) are investigational and should be
used only with stem cell rescue and mesna bladder protection.
Special precautions. Give dose in the morning, maintain ample fluid intake, and have patient
empty bladder several times daily to diminish the likelihood of cystitis.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting. Platelets are relatively
spared. Nadir is reached about 10 to 14 days after IV dose with recovery by day 21.
2. Nausea, vomiting, and other GI effects. Frequent with large IV doses; less common after
oral doses. Symptoms begin several hours after treatment and are usually over by the next
day.
3. Mucocutaneous effects. Reversible alopecia is common, usually starting after 2 to 3
weeks. Skin and nails may become darker. Mucositis is uncommon.
4. Bladder damage. Hemorrhagic or nonhemorrhagic cystitis may occur in 5% to 10% of
patients treated. It is usually reversible with discontinuation of the drug, but it may persist
and lead to fibrosis or death. Frequency is diminished by ample fluid intake and morning
administration of the drug. Mesna will protect from this effect.
5. Miscellaneous effects
a. Immunosuppression is common.
b. Amenorrhea and azoospermia is common.
c. Inhibition of antidiuretic hormone is only of significance with very large doses.
d. Interstitial pulmonary fibrosis is rare.
e. Secondary neoplasia is possible.
f. Acute and potentially fatal cardiotoxicity occurs with high-dose therapy. Abnormalities
include pericardial effusion, congestive heart failure, decreased electrocardiographic
 (ECG) voltage, and fibrin microthrombi in cardiac capillaries with endothelial injury
and hemorrhagic necrosis.

CYTARABINE
Other names. Cytosine arabinoside, ara-C, Cytosar-U, DepoCyt (cytarabine, liposomal for
intrathecal use only).
Mechanism of action. A pyrimidine analog antimetabolite that, when phosphorylated to
arabinosyl-cytosinetriphosphate (ara-CTP), is a competitive inhibitor of DNA polymerase.
Primary indications
1. AML
2. Non-Hodgkin lymphoma
3. Meningeal lymphoma or leukemia.
Usual dosage and schedule
1. Induction. 100 mg/m2 IV daily as a continuous infusion for 5 to 7 days (in combination with
other drugs).
2. Maintenance. 100 mg/m2 SQ every 12 hours for 4 or 5 days every 4 weeks (with other
drugs).
3. Intrathecally:
a. 40 to 50 mg/m2 of cytarabine, unencapsulated, every 4 days in preservative-free
buffered isotonic diluent.
b. 50 mg of cytarabine, liposomal, repeated in 14 to 28 days.
1. High dose:
a. Induction: 2 to 3 g/m2 IV over 1 to 2 hours every 12 hours for up to 12 doses.
b. Consolidation: 3 g/m2 IV over 3 hours every 12 hours on days 1, 3, and 5.
Special precautions. None for standard doses. High dose, to be given in 1 to 3 hour infusions.
Longer infusion enhances toxicity. CNS toxicity is increased in patients with a decreased
creatinine clearance. Cytarabine, liposomal (DepoCyt) should be used only intrathecally.
Toxicity (standard dose only)
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and
thrombocytopenia occur, with nadir at 7 to 10 days after treatment has ended and with
recovery during the following 2 weeks, depending on the degree of suppression.
Megaloblastosis is common.
2. Nausea, vomiting, and other GI effects. Common, particularly if the drug is given as a
push or rapid infusion.
3. Mucocutaneous effects. Stomatitis is seen occasionally.
4. Miscellaneous effects
a. Flulike syndrome with fever, arthralgia, and sometimes a rash is occasional.
 b. Transient mild hepatic dysfunction is occasional.
Toxicity (high dose)
1. Myelosuppression and other hematologic effects. Universal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
3. Mucocutaneous effects. Occasional to common mucositis. Keratoconjunctivitis is
common; glucocorticoid eyedrops may ameliorate or prevent in some patients.
4. Neurotoxicity. Cerebellar toxicity is common, particularly in the elderly, but is usually
mild and reversible. However, on occasion it has been severe and permanent or fatal.
5. Hepatic toxicity with cholestatic jaundice. Uncommon.

DABRAFENIB
Other name. Tafinlar.
Mechanism of action. Inhibitor of the V600 mutations of the BRAF kinase seen in some
melanoma cells as well as other kinases. By this mechanism, it inhibits tumor cells
proliferation that is dependent on the constitutive activation of the BRAF proteins, which
results from mutations in the BRAF gene. Combined use with the MEK inhibitor, trametinib,
results in greater and prolonged growth inhibition of the BRAF V600 mutation-positive
melanoma cells compared with either drug alone.
Primary indications
1. As a single agent in BRAFV600E mutation-positive unresectable or metastatic melanoma.
2. In combination with trametinib in BRAFV600E or BRAFV600K mutation-positive unresectable
or metastatic melanoma.
Usual dosage and schedule
■ 150 mg oral twice daily, 12 hours apart, as a single agent
■ 150 mg oral twice daily, 12 hours apart, in combination with trametinib taken 2 mg oral
once daily.
To be taken 1 hour before or 2 hours after a meal. Missed doses can be taken up to 6 hours
prior to the next dose, maintaining twice-daily regimen. Concomitant use with strong CYP3A4
inducers or inhibitors and with strong CYP2C8 inducers or inhibitors should be avoided.
Special precautions
1. New primary malignancies
a. Cutaneous malignancies. Increased incidence of cutaneous squamous cell carcinomas
(cuSCC) and keratocanthoma has been reported (19% in patients receiving dabrafenib
alone and 7% in patients receiving the combination with trametinib) with median time to
develop first cuSCC of 9 weeks. New primary melanoma was reported in 2% of
patients receiving dabrafenib alone and in none of the patients receiving the combination
with trametinib. New basal cell carcinoma can occur in up to 9% of patients receiving
dabrafenib alone and 2% of those receiving the combination with trametinib.
 Dermatologic examination should be performed prior to initiation of therapy and every 2
months while on treatment, and for up to 6 months after discontinuation. No dose
modifications or interruptions are required in patients who develop new primary
cutaneous malignancies.
b. Noncutaneous malignancies. Dabrafenib can cause paradoxical activation of the MAP-
kinase signaling pathway, through RAS activation, in exposed BRAF–wild-type cells
and promote the growth and development of malignancies. Cases of pancreatic
adenocarcinoma, colorectal carcinoma, head and neck carcinoma, and glioblastoma
have been reported. Permanent discontinuation of dabrafenib is indicated in such cases,
while no dose modifications of trametinib are warranted when the combination is used.
2. Dabrafenib is teratogenic and can cause fetal harm if administered to a pregnant woman. It
can also impair fertility in men.
Toxicity
1. Myelosuppression and other hematologic effects. Cases of nasopharyngitis can occur in
up to 10% of patients, most of which are grade 1 or 2. Potential risk of hemolytic anemia in
patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Deep venous
thrombosis and pulmonary embolus are occasional when used in combination with
trametinib. Bleeding is occasional when used with trametinib; uncommon when used as a
single agent.
2. Nausea, vomiting, and other GI effects. Constipation is occasional. Pancreatitis is
occasional.
3. Mucocutaneous effects. Rash, alopecia, hyperkeratosis, and palmar-plantar
erythrodysesthesia are common. Skin papillomas are occasional. Hypersensitivity
manifesting as bullous rash has been described in less than 10% of patients.
4. Miscellaneous effects
a. General. Pyrexia is common. Serious febrile reactions (defined as grade 3 or higher or
any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure)
in the absence of other identifiable causes (like infection) can occur in up to 3.7% of
patients. Dose interruptions/reductions or permanent discontinuation may be indicated
depending on the severity of the reaction. Mild cases can be managed with antipyretic
agents. Sometimes, prophylactic antipyretic or corticosteroid may be required.
b. Respiratory. Cough is occasional.
c. Cardiac. Occasional cardiomyopathy when used in combination with trametinib. Assess
LVEF prior to therapy, after 1 month, and every 2 to 3 months thereafter.
d. Metabolic. Hyperglycemia is common, but grade 3 or higher is uncommon. Close
monitoring of blood glucose in patients with diabetes mellitus and dose modifications of
antidiabetic medications may be required. Hyponatremia is occasional.
Hypophosphatemia is common.
e. Neurologic. Headache is common.
f. Genitourinary. Cases of interstitial nephritis have been described in less than 10% of
patients.
 g. Eye. Retinal pigment epithelial detachment when used with trametinib is uncommon.
Uveitis and iritis are rare. Treatment with steroid and mydriatic ophthalmic drops may
be required to manage uveitis.
h. Musculoskeletal and connective tissue. Arthralgia is common. Myalgia is occasional.

DACARBAZINE
Other names. Imidazole carboxamide, DIC, DTIC-Dome.
Mechanism of action. Uncertain but probably interacts with preformed macromolecules by
alkylation. Inhibits DNA, RNA, and protein synthesis.
Primary indications
1. Melanoma.
2. Soft tissue sarcomas.
3. Hodgkin lymphoma.
Usual dosage and schedule
1. 150 to 250 mg/m2 IV push or rapid infusion on days 1 to 5 every 3 to 4 weeks or
2. 400 to 500 mg/m2 IV push or rapid infusion on days 1 and 2 every 3 to 4 weeks or
3. 200 mg/m2 IV daily as a continuous 96-hour infusion.
Special precautions
1. Administer cautiously to avoid extravasation, as tissue damage may occur.
2. Venous pain along the injection site may be reduced by diluting dacarbazine in 100 to 200
mL of 5% dextrose in water and infusing over 30 minutes rather than injecting rapidly. Ice
application may also reduce pain.
Toxicity
1. Myelosuppression and other hematologic effects. Mild to moderate. This factor allows
dacarbazine to be used in full doses with other myelosuppressive drugs.
2. Nausea, vomiting, and other GI effects. Common and severe but decrease in intensity
with each subsequent daily dose. Onset is within 1 to 3 hours, with duration up to 12 hours.
3. Mucocutaneous effects. Moderately severe tissue damage if extravasation occurs.
Alopecia is uncommon. Erythematous or urticarial rash is uncommon.
4. Miscellaneous effects
a. Flulike syndrome with fever, myalgia, and malaise lasting several days is uncommon.
b. Hepatic toxicity is uncommon.

DACTINOMYCIN
Other names. Actinomycin D, act-D, Cosmegen.
Mechanism of action. Binds to DNA and inhibits DNA-dependent RNA synthesis. Inhibition
of topoisomerase II.
Primary indications
1. Gestational trophoblastic neoplasms.
2. Wilms tumor, childhood rhabdomyosarcoma, and Ewing sarcoma.
Usual dosage and schedule
1. Children. 0.40 to 0.45 mg/m2 (up to a maximum of 0.5 mg) IV daily for 5 days every 3 to 5
weeks.
2. Adults
a. 0.40 to 0.45 mg/m2 IV on days 1 to 5 every 2 to 3 weeks.
b. 0.5 mg IV daily for 5 days every 3 to 5 weeks.
Special precautions
1. Administer by slow IV push through the sidearm of a running IV infusion, being careful to
avoid extravasation, which causes severe soft tissue damage.
2. If given at or about the time of infection with chicken pox or H. zoster, a severe generalized
disease may occur that sometimes results in death.
Toxicity
1. Myelosuppression and other hematologic effects. Cytopenias may be dose-limiting and
severe. They begin within the first week of treatment, but the nadir may not be reached for
21 days.
2. Nausea, vomiting, and other GI effects. Severe vomiting often occurs during the first few
hours after drug administration and lasts up to 24 hours.
3. Mucocutaneous effects. Erythema, hyperpigmentation, and desquamation of the skin with
potentiation by previous or concurrent radiotherapy are common. Oropharyngeal mucositis
is potentiated by previous or concurrent radiotherapy. Alopecia is common. Moderately
severe tissue damage occurs with extravasation.
4. Miscellaneous effects
a. Mental depression is rare.
b. Hepatic veno-occlusive disease, worse with higher doses and shorter schedules; for
example, single dose of 2.5 mg versus 5 days at 0.5 mg/day.

DARATUMUMAB
Other name. Darzalex.
Mechanism of action. IgG1κ human monoclonal antibody (mAb) that binds to CD38 and
inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through Fc-
mediated cross-linking as well as by immune-mediated tumor cell lysis through complement-
dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and
antibody-dependent cellular phagocytosis (ADCP).
Primary indications. Patients with multiple myeloma who have received at least three prior
lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who
are double-refractory to a PI and an immunomodulatory agent.
Usual dosage and schedule. 16 mg/kg administered as IV infusion according to the following
schedule:
■ Weekly from weeks 1 to 8. Diluted in 1,000 mL at a rate of 50 mL/hour. The rate can be
increased by 50 mL every hour, provided the patient does not develop infusion-related
reactions, to a maximum rate of 200 mL/hour.
■ Every 2 weeks from weeks 9 to 24. Diluted in 500 mL at a rate of 50 mL/hour. The rate
can be increased by 50 mL every hour, provided the patient does not develop infusion-
related reactions, to a maximum rate of 200 mL/hour.
■ Every 4 weeks from weeks 25 until disease progression or intolerable toxicity. Diluted
in 500 mL at a rate of 100 mL/hour. The rate can be increased by 50 mL every hour,
provided the patient does not develop infusion-related reactions, to a maximum rate of 200
mL/hour.
Preinfusion medications should be administered 1 hour prior to the infusion as follows:
IV methylprednisolone 100 mg or equivalent, oral acetaminophen 650 to 1,000 mg, and
oral or IV diphenhydramine 25 to 50 mg. Following the second infusion, the dose of
corticosteroids can be reduced to 60 mg of IV methylprednisolone or equivalent. On the
first and second days after all infusions, a dose of oral corticosteroids (20 mg
methylprednisolone or equivalent) should be given. Short- and long-acting bronchodilators
as well as inhaled corticosteroids are recommended post infusion in patients with history
of obstructive pulmonary disorders. Following the first four infusions, if the patient
experiences no major infusion reactions, these additional inhaled postinfusion medications
may be discontinued. Antiviral prophylaxis to prevent H. zoster reactivation should be
started within 1 week of starting therapy and continued for 3 months following treatment.
Special precautions
■ Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect
antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test
may persist for up to 6 months after the last daratumumab infusion.
■ Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the
serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical
monitoring of endogenous M-protein. This interference can impact the determination of
complete response and of disease progression in some patients with IgG kappa myeloma
protein.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, lymphopenia,
and thrombocytopenia are common and commonly severe.
2. Nausea, vomiting, and other GI effects. Nausea, diarrhea, and constipation are common,
but rarely severe. Vomiting is occasional.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Infusion-related reactions can occur in up to
one half of patients. These are mostly mild and uncommonly severe. Signs and symptoms
may include respiratory symptoms, such as cough, wheezing, larynx, and throat tightness
and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis.
Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea,
vomiting, and chills. These reactions mostly occur during the first infusion, but they can
also occur with subsequent infusions, although less frequently. Nearly all reactions
occurred during infusion or within 4 hours of completion. However, they can develop up to
48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia,
dyspnea, and hypertension. Upon development of infusion-related reactions, treatment
interruption and symptomatic and supportive care is recommended. For grade 1 to 2 (mild
to moderate): once reaction symptoms resolve, resume the infusion at no more than half the
rate at which the reaction occurred. If the patient does not experience any further reaction
symptoms, infusion rate escalation may resume at increments and intervals as appropriate.
For grade 3 (severe): If the intensity of the reaction decreases to grade 2 or lower, consider
restarting the infusion at no more than half the rate at which the reaction occurred. If the
patient does not experience additional symptoms, resume infusion rate escalation at
increments and intervals as appropriate. Repeat the procedure above in the event of
recurrence of grade 3 symptoms. Permanently discontinue therapy upon the third occurrence
of a grade 3 or greater infusion reaction. For grade 4 (life-threatening): permanently
discontinue treatment. Upper respiratory infections are common, but rarely severe.
Pneumonia was reported in 17% of patients and was severe in 6% of cases.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are common, but uncommonly severe. Decreased appetite
is occasional.
b. Respiratory. Cough and dyspnea are common, but rarely severe.
c. Cardiovascular. Hypertension is occasional.
d. Neurologic. Headache is occasional, but rarely severe.
e. Musculoskeletal and connective tissue. Back pain and arthralgia are common, but
rarely severe. Musculoskeletal chest pain is occasional.

DASATINIB
Other name. SPRYCEL.
Mechanism of action. Inhibition of multiple receptor tyrosine kinases (RTKs), including
BCR-ABL and the SRC family. Believed to bind to multiple conformations of the ABL kinase.
Primary indications
1. Chronic myelogenous leukemia (CML) in the chronic, accelerated, or blast phase (myeloid
or lymphoid) with resistance or intolerance to prior therapy including imatinib.
2. CML in chronic phase newly diagnosed disease.
3. ALL that is Philadelphia chromosome positive and refractory to prior therapy.
4. ALL that is Philadelphia chromosome positive, newly diagnosed, in combination with
chemotherapy (investigational).
Usual dosage and schedule
1. Chronic-phase CML 100 mg PO daily. Doses are adjusted up or down in 20-mg increments
as needed.
2. Accelerated phase CML, blast phase CML, or Ph+ ALL—100 to 140 mg PO daily.
Special precautions. Should not be administered to patients who have or are at risk for
prolonged QT interval.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and
anemia are common in all patients. Bleeding is common and occasionally is severe, but
they are seen primarily in the accelerated or blastic phases. Use with caution in patients
requiring platelet inhibitors or anticoagulants. Febrile neutropenia is uncommon.
2. Nausea and vomiting and other GI effects. Nausea and vomiting are occasional, but
rarely severe. Diarrhea is common, but severe diarrhea uncommon. Abdominal pain is
common. Constipation is occasional.
3. Mucocutaneous effects. Stomatitis is occasional. Various skin maladies are occasional.
4. Miscellaneous effects
a. Cardiovascular. Fluid retention is common and occasionally severe. Pleural effusions
are occasional. Pericardial effusions are uncommon. Severe pulmonary edema is rare.
Prolonged cardiac ventricular repolarization (QT prolongation) is uncommon and rarely
severe.
b. Respiratory. Dyspnea, cough, and upper respiratory infections are common.
c. Neurologic. Peripheral neuropathy is occasional. Headache is common.
d. Musculoskeletal pain and myalgia are occasional to common.
e. Fever is uncommon; fatigue is common.
f. Hypophosphatemia is occasional. Hypokalemia and hypocalcemia are uncommon.
Abnormal transaminases or elevated bilirubin are rare.

DAUNORUBICIN
Other names. Daunomycin, rubidomycin, DNR, Cerubidine.
Mechanism of action. DNA strand breakage mediated by anthracycline effects on
topoisomerase II; DNA intercalation; DNA polymerase inhibition.
Primary indications. AML, ALL.
Usual dosage and schedule
1. 45 to 90 mg/m2 IV push on days 1, 2, and 3 in combination with other drugs as induction-
therapy AML. Second cycle may be given at 45 mg/m2 if blasts not gone by day 15.
2. 45 to 60 mg/m2 IV push in various schedules in combination with other drugs as induction
therapy in ALL.
Special precautions
1. Administer over several minutes into the sidearm of a running IV infusion, taking
precautions to avoid extravasation. Severe local tissue damage may progress to skin
ulceration, and necrosis may occur with subcutaneous extravasation.
2. Do not give if patient has significantly impaired cardiac function (ejection fraction <45%),
angina pectoris, cardiac arrhythmia, or recent myocardial infarction.
3. Do not exceed cumulative dosage of 550 mg/m2 (400 mg/m2 if given previous radiation
therapy that has encompassed the heart).
4. Reduce dose if patient has impaired liver or renal function.

Serum Bilirubin (mg/dL) Serum Creatinine (mg/dL) % of Full Dose

1.2–3.0 — 75
>3.0 or >3.0 50

Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting pancytopenia with nadir
at 1 to 2 weeks.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting occur on the day of
administration in one-half of patients.
3. Mucocutaneous effects. Alopecia is common, but stomatitis is rare. Severe local tissue
damage may progress to skin ulceration, and necrosis may occur with subcutaneous
extravasation.
4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to
cardiomyopathy. The incidence is highly dependent on the lifetime cumulative dose, which
should not exceed 550 mg/m2 (400 mg/m2 if patient was given previous radiotherapy that
encompassed the heart). Discontinue drug if there is clinical congestive heart failure or if
the ejection fraction falls on the radionuclide angiogram,
a. To less than 45% or
b. To less than 50% if the total decrease is 10% or more (e.g., falls from 59% to 49%).
If repeat ejection fraction determination shows return of function, drug may be
cautiously restarted, but ejection fraction should be measured before each dose. Transient
ECG changes are common and are not usually serious.
5. Miscellaneous effects
a. Red urine caused by the drug and its metabolites is common.
b. Chemical phlebitis and phlebothrombosis of veins used for injection is common.
DAUNORUBICIN, LIPOSOMAL
Other name. DaunoXome.
Mechanism of action. Daunorubicin, liposomal, which is designed to be protected from
removal by the reticuloendothelial system, has a prolonged circulation time compared with
unprotected drug. The agent penetrates tumor tissue and releases the active ingredient
daunorubicin.
Primary indication. Kaposi sarcoma, advanced, human immunodeficiency virus (HIV)
associated.
Usual dosage and schedule. 40 mg/m2 IV over 60 minutes every 2 weeks.
Special precautions
1. Must be diluted to a concentration of 1 mg/mL with 5% dextrose for injection. Liposomal
daunorubicin should be considered an irritant, and care should be taken to avoid
extravasation.
2. Do not give if the patient has significantly impaired cardiac function.
3. Do not exceed a lifetime cumulative dose of 550 mg/m2 (400 mg/m2 if the patient was given
prior chest radiotherapy). Patients with HIV may experience a decrease in left ventricular
ejection fraction and congestive heart failure at lower doses than those without.
4. Reduce or hold dose in patients with impairment of liver function. A 25% dose reduction is
recommended if the serum bilirubin is 1.2 to 3 mg/dL. One-half the normal dose is
recommended in patients with serum bilirubin concentration greater than 3 mg/dL.
Toxicity
Effects that are a result of the liposomal daunorubicin have been somewhat difficult to
determine with certainty, because most patients have been on several other agents that can
result in other drugs that may cause marrow or other toxicity.
1. Myelosuppression and other hematologic effects. Common and dose related. May be
severe.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
3. Mucocutaneous effects. Alopecia is occasional. Stomatitis is occasional.
4. Immunologic effects and infusion reactions. Acute infusion-associated reactions with
back pain, flushing, and tightness in the chest and throat, alone or in combination, occur
occasionally. They usually occur with the first infusion, and are not likely to occur later if
the first infusion is given without a reaction. They generally occur during the first 5 minutes
of the infusion and subside with interruption of the infusion. Some patients tolerate
restarting at a lower rate of infusion. Most patients are able to continue therapy.
5. Miscellaneous effects
a. Cardiac events, including cardiomyopathy or congestive heart failure may occur and are
dose dependent. (see Special Precautions.)
b. Fatigue, fever, and headache are common.
 c. Pain at the injection site is likely after extravasation.
d. Neuropathy is occasional.

DECITABINE
Other name. Dacogen.
Mechanism of action. Pyrimidine analog that inhibits methyltransferase, causing
hypomethylation of DNA and thus, it is believed, results in cellular differentiation or
apoptosis. May restore normal function of genes that are critical for the control of cellular
differentiation and proliferation.
Primary indications
1. MDS.
2. AML in the elderly.
Usual dosage and schedule
1. MDS
a. 20 mg/m2 IV over 1 hour daily for 5 days every 4 weeks.
b. 15 mg/m2 continuous IV infusion over 3 hours, repeated every 8 hours for 3 days. This
cycle is repeated every 6 weeks for a minimum of 4 cycles (older schedule).
Therapy may be continued so long as the patient is improved from the drug.
2. AML. 20 mg/m2 IV days 1 to 10 of a 4-week cycle for induction. May be repeated if
persistent AML. 20 mg/m2 daily for 3 to 5 days for maintenance.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and
anemia are common. Febrile neutropenia is five times as common as in patients receiving
supportive care.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea or constipation
occur in about one-third of patients. Abdominal pain may be associated.
3. Mucocutaneous effects. Stomatitis is occasional. Skin rash is occasional, alopecia is
occasional, urticaria is uncommon.
4. Neurotoxicity. Insomnia is common. Lethargy or confusional state are occasional.
5. Miscellaneous effects
a. Cardiovascular. Pulmonary edema is uncommon. Peripheral edema is occasional.
b. Blurred vision. Uncommon.
c. Fever is common; infections are occasional.
d. Arthralgias and back pain are occasional.
e. Hypomagnesemia, hypokalemia, hyperglycemia, hyponatremia, and hypoalbuminemia
occur in 20% to 25% of patients.
f. Abnormal liver function tests. Occasional.
DEGARELIX
Other name. Firmagon.
Mechanism of action. Gonadotropin-releasing hormone receptor antagonist that causes a
decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and
subsequently, testosterone.
Primary indications
1. Carcinoma of the prostate
Usual dosage and schedule. 240 mg as two 120-mg subcutaneous injections in the abdominal
region, followed by a single injection of 80 mg every 28 days.
Special precautions. May prolong QT interval, as does other androgen depletion.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Nausea, diarrhea, constipation are uncommon.
3. Mucocutaneous effects. Injection site erythema, swelling, induration are common.
4. Miscellaneous effects
a. Weight increase, fatigue, chills, asthenia are occasional to uncommon.
b. Hot flushes are common.
c. Hypertension is occasional.
d. Musculoskeletal—occasional arthralgias.
e. Increase in transaminases is occasional.
f. Dizziness, headache, insomnia are uncommon.
g. Erectile dysfunction, gynecomastia, testicular atrophy are reported, but frequency above
baseline not established.

DENILEUKIN DIFTITOX
Other name. Ontak.
Mechanism of action. Denileukin diftitox is produced by genetically fusing protein from the
diphtheria toxin to interleukin-2 (IL-2). This stable, fusion protein targets cells with receptors
for IL-2 on their surfaces, including malignant cells and some normal lymphocytes, resulting in
cell death. Efficacy in patients without the CD25 receptor is not known.
Primary indication. Persistent or recurrent cutaneous T-cell lymphoma that expresses the
CD25 component of IL-2 receptor. (Confirm that patient’s malignant cells express CD25 prior
to treatment.)
Usual dosage and schedule. 9 or 18 µg/kg/day (350 to 700 mg/m2/day) IV over 30 to 60
minutes for 5 consecutive days every 21 days for 8 cycles.
Special precautions. Acute hypersensitivity reactions occur commonly. Loss of visual acuity,
usually with loss of color vision, usually resulting in permanent visual impairment.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and lymphopenia are common.
Thrombocytopenia is occasional. Thrombotic events are occasional.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
Dehydration as a consequence is occasional.
3. Mucocutaneous effects. Rashes—including generalized macropapular, petechial,
vesicular bullous, urticarial, and eczematous—may be seen, with both acute and delayed
onset.
4. Immunologic effects and infusion reactions. Mild infusion reactions are common. Severe
acute infusion reactions occur occasionally (8%), including hypotension, back pain,
dyspnea, vasodilation, rash, chest pain or tightness, and tachycardia. Syncope is uncommon;
anaphylaxis is rare. Fever is common. Neutralizing antibodies develop in most patients by
three cycles of treatment.
5. Miscellaneous effects
a. Cardiovascular effects, including hypotension, vasodilation, fluid retention, and
tachycardia are occasional.
b. Respiratory reactions of dyspnea, increase in cough, and pharyngitis are occasional.
c. Capillary leak syndrome is common and is often delayed.
d. Metabolic changes that include hypoalbuminemia, transaminase increase, and
hypocalcemia are common.
e. Arterial and venous thromboses are uncommon.
f. Flulike symptoms with chills, fever, headache, and weakness are common. Myalgias and
arthralgias are occasional.
g. Visual changes, including loss of visual acuity, which may be persistent, are uncommon.

DOCETAXEL
Other name. Taxotere.
Mechanism of action. Enhanced formation and stabilization of microtubules. Antineoplastic
effect may result from nonfunctional tubules or altered tubulin-microtubule equilibrium.
Mitotic arrest is seen and is associated with accumulated polymerized microtubules.
Primary indications. Carcinomas of the breast, stomach, head and neck, lung, ovary, and
prostate.
Usual dosage and schedule
75 mg/m2 as a 1-hour infusion every 3 weeks, alone or in combination with other agents. Dose
from 60 to 100 mg/m2 may be used, depending on tolerance.
Dexamethasone, 8 mg PO b.i.d. for 3 days starting 1 day before docetaxel, should be given
before each course of docetaxel to limit the frequency and severity of hypersensitivity
reactions and to reduce the severity of fluid retention.
Special precautions. Severe hypersensitivity reactions with flushing and hypotension with or
without dyspnea occur in about 1% of patients (even when premedication is used). Should be
used with caution in patients with bilirubin above upper limit of normal (ULN) or other
abnormal liver function tests (>1.5 ULN), because of more profound neutropenia.
Toxicity
1. Myelosuppression and other hematologic effects. Severe (grade 4) neutropenia is
common and dose related. Many patients have neutropenic fever.
2. Nausea, vomiting, and other GI effects. Common, but brief; severe episodes are
uncommon.
3. Mucocutaneous effects. Mild mucositis is common; severe mucositis is uncommon.
Alopecia is common. Mild-to-moderate cutaneous reactions such as maculopapular
eruptions are common; severe reactions, which may be associated with desquamation or
bullous eruptions, occur only occasionally if systemic prophylaxis is used. Mild-to-
moderate nail changes are common, but severe onycholysis is uncommon.
4. Immunologic effects and infusion reactions. Mild-to-moderate hypersensitivity reactions
with flushing, hypotension (or rarely hypertension) with or without dyspnea, and drug fever
are occasional with use of the prophylactic regimen recommended. Severe hypersensitivity
reactions are uncommon.
5. Miscellaneous effects
a. Fluid retention syndrome is common and cumulative (more commonly after four
courses); can be reduced to occasional frequency (6%) by prophylactic steroids; may
limit continuing therapy. May be associated with both pleural and pericardial effusions
b. Neurologic. Mild and reversible dysesthesias or paresthesias are common; more severe
sensory neuropathies are uncommon.
c. Hepatic. Reversible increases in transaminase, alkaline phosphatase, and bilirubin.
d. Local reactions. Reversible peripheral phlebitis.
e. Mild diarrhea is common; severe diarrhea is rare.
f. Fatigue, weakness (asthenia), and myalgia are common; arthralgia is occasional.

DOXORUBICIN
Other names. ADR, Adriamycin, Rubex, hydroxydaunorubicin.
Mechanism of action. DNA strand breakage mediated by anthracycline effects on
topoisomerase II; DNA intercalation; DNA polymerase inhibition.
Primary indications
1. Breast, bladder, liver, lung, prostate, stomach, and thyroid carcinomas.
2. Bone and soft tissue sarcomas.
3. Hodgkin and non-Hodgkin lymphomas.
4. Multiple myeloma
5. Wilms tumor, neuroblastoma, and rhabdomyosarcoma of childhood.
Usual dosage and schedule
1. 60 to 75 mg/m2 IV every 3 weeks. (Or as 96-hour continuous infusion.)
2. 30 mg/m2 IV on days 1 and 8 every 4 weeks (in combination with other drugs).
3. 9 mg/m2 IV daily for 4 days as a continuous infusion (in myeloma).
4. 15 to 20 mg/m2 IV weekly.
5. 50 to 60 mg instilled into the bladder weekly for 4 weeks, then every 4 weeks for 6 cycles.
Special precautions
1. Administer over several minutes into the sidearm of a running IV infusion (except when
given as a continuous infusion), taking care to avoid extravasation.
2. Do not give if patient has significantly impaired cardiac function (ejection fraction <45%),
angina pectoris, cardiac arrhythmia, or recent myocardial infarction.
3. Do not exceed a lifetime cumulative dose of 550 mg/m2 (450 mg/m2 if patient was given
prior chest radiotherapy or concomitant cyclophosphamide) unless there are known risk
modifiers, such as continuous infusion, weekly dosing, or cardioprotective dexrazoxane,
and serial measurements of cardiac ejection fraction show minimal change and adequate
function.
4. Reduce or hold dose if patient has impaired liver function.
a. For serum bilirubin of 1.2 to 3.0 mg/dL, give one-half the normal dose.
b. For serum bilirubin of more than 3.0 mg/dL, give one-fourth the normal dose.
Toxicity
1. Myelosuppression and other hematologic. Dose-limiting for most patients. Nadir white
blood cell (WBC) and platelet counts occur at 10 to 14 days; recovery by day 21.
2. Nausea, vomiting, and other GI. Mild to moderate in about one-half of patients.
3. Mucocutaneous effects. Stomatitis that is dose-dependent. Alopecia beginning 2 to 5
weeks from start of therapy with recovery following completion of therapy is common.
Recall of skin reaction due to prior radiotherapy is common. Severe local tissue damage
possibly progressing to skin ulceration and necrosis if subcutaneous extravasation occurs is
common. Hyperpigmentation of skin overlying veins used for drug injection in which
chemical phlebitis has occurred is common.
4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to
cardiomyopathy. The incidence is highly dependent on the lifetime cumulative dose, which
should not exceed 550 mg/m2. This limit is lower (450 mg/m2) if patient has received prior
chest radiotherapy or is taking cyclophosphamide concomitantly. Weekly schedule and 96-
hour infusions are less cardiotoxic, and higher cumulative doses may be tolerable.
Congestive heart failure may be predicted by serial measurement of left ventricular function
or endomyocardial biopsy. Discontinue drug if there is clinical congestive heart failure or if
 the ejection fraction falls on the radionuclide angiogram
a. To less than 45% or
b. To less than 50% if the total decrease is 10% or more (e.g., falls from 59% to 49%).
If repeat ejection fraction determination shows return of function, drug may be
cautiously restarted, but ejection fraction determination should be done before each dose.
Transient ECG changes are common and are not usually serious.
5. Miscellaneous effects
a. Red urine caused by drug and its metabolites is common.
b. Chemical phlebitis and phlebosclerosis of veins used for injection are common,
particularly if a vein is used repeatedly.
c. Fever, chills, and urticaria are uncommon.

DOXORUBICIN, LIPOSOMAL
Other name. Doxil.
Mechanism of action. Doxorubicin, liposomal, which is designed to be protected from
removal by the reticuloendothelial system, has a prolonged circulation time compared with
unprotected drug. The agent penetrates tumor tissue and releases the active ingredient
doxorubicin.
Primary indications
1. Kaposi sarcoma, advanced, HIV associated.
2. Ovarian and breast carcinomas.
3. Multiple myeloma.
Usual dosage and schedule
1. 20 mg/m2 IV infusion at a rate of 1 mg/minute for the first dose, then over 30 minutes for
subsequent doses every 3 weeks for Kaposi sarcoma.
2. 40 to 50 mg/m2 IV infusion at a rate of 1 mg/minute for the first dose, then over 1 hour every
4 weeks for ovarian or breast carcinoma when used as a single agent.
3. 40 mg/m2 IV infusion at a rate of 1 mg/minute for the first dose, then over 1 hour every 4
weeks for multiple myeloma, together with vincristine and dexamethasone.
4. 30 mg/m2 IV infusion on day 1 or 4 in combination with bortezomib in relapsed and
refractory multiple myeloma.
Special precautions. Must be diluted in 250 mL of 5% dextrose for injection. Liposomal
doxorubicin is not a vesicant but should be considered an irritant. Initial doses should be given
at a rate of 1 mg/minute to avoid infusion reactions.
Toxicity. Effects that are a result of the liposomal doxorubicin have been somewhat difficult to
determine with certainty, because most patients have been on several other agents that can
result in other drugs that may cause marrow or other toxicity.
1. Myelosuppression and other hematologic effects. Common and dose related. May be
severe.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common at the higher
doses. Constipation is occasional. Diarrhea is occasional. Anorexia is occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia is common at the higher doses
and is occasionally severe. Stomatitis is common. Alopecia is occasional. Rash is
occasional to common.
4. Immunologic effects and infusion reactions. Acute infusion-associated reactions with
flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the
chest and throat, or hypotension, alone or in combination, have occurred in approximately
7% of patients treated with liposomal doxorubicin. They usually occur with the first
infusion, and are not likely to occur later if the first infusion is given without a reaction.
Most resolve over the course of several hours to a day.
5. Miscellaneous effects
a. Cardiac events, including cardiomyopathy or congestive heart failure occur in 5% to
10% of patients treated. This is dose dependent, and not really adequately tested with
liposomal doxorubicin.
b. Asthenia is occasional.
c. Fever is occasional.
d. Pain at the injection site is likely after extravasation.

ELOTUZUMAB
Other name. Empliciti.
Mechanism of action. A humanized immunoglobulin G1 immunostimulatory monoclonal
antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), a
glycoprotein expressed on myeloma and natural killer (NK) cells but not on normal tissues.
Primary indications. In combination with lenalidomide and dexamethasone in patients with
multiple myeloma who have received one to three previous therapies.
Usual dosage and schedule
1. For cycles 1 and 2: 10 mg/kg IV infusion on days 1, 8, 15, and 22 of each 28-day cycle.
2. For cycles 3 and beyond: 10 mg/kg IV infusion on days 1 and 15 of each 28-day cycle.
Dexamethasone is given at a dose of 40 mg orally weekly except on days of elotuzumab
administration when it is given 8 mg IV between 45 and 90 minutes prior, plus 28 mg orally
between 3 and 24 hours prior to infusion.
Premedication regimen given 30 to 90 minutes prior to the infusion includes:
1. Diphenhydramine 25 to 50 mg IV or its equivalent.
2. Ranitidine 50 mg IV or its equivalent.
3. Acetaminophen 650 to 1,000 mg orally or its equivalent.
Special precautions
1. Rates of secondary primary hematologic malignancies, secondary solid tumors, and
nonmelanoma skin cancers were reported in 2%, 3%, and 3.1% of patients, respectively.
This is most likely related to the coadministration of lenalidomide rather than a direct effect
of elotuzumab therapy.
2. Elotuzumab can be detected on both the SPEP and IFE assays used for the clinical
monitoring of endogenous M-protein.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, thrombocytopenia,
lymphopenia, and neutropenia are common and commonly severe.
2. Nausea, vomiting, and other GI effects. Diarrhea and constipation are common but
uncommonly severe. Hepatotoxicity is occasional but rarely severe warranting treatment
discontinuation. Vomiting is occasional but rarely severe.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Infusion reactions, including pyrexia, chills,
hypertension, hypotension, and bradycardia are occasional but rarely severe. These
reactions most commonly occur with the first infusion. Treatment interruption may be
necessary and general medical management of these reactions is done on a case-by-case
basis. Nasopharyngitis is common (25%) and is usually mild to moderate. There is slight
increase in the rate of infections, including pneumonia and opportunistic infections with the
addition of elotuzumab to lenalidomide-dexamethasone compared with lenalidomide-
dexamethasone alone.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Pyrexia and insomnia are common
but uncommonly severe.
b. Respiratory. Cough is common but rarely severe.
c. Cardiovascular. Peripheral edema is common but uncommonly severe.
d. Metabolic. Hyperglycemia is common and commonly severe. Hypocalcemia and
hyperkalemia are common and occasionally severe.
e. Neurologic. Peripheral, sensory, and motor, is common but uncommonly severe.
Headache is common.
f. Musculoskeletal and connective tissue. Muscle spasms are common but rarely severe.
Back pain is common.
g. Ophthalmic. Cataracts are occasional and about half may be severe.

ENZALUTAMIDE
Other name. Xtandi.
Mechanism of action. Competitive inhibitor of the androgen receptor leading to decreased
proliferation and apoptosis of prostate cancer cells.
Primary indications. Metastatic castration-resistant prostate cancer.
Usual dosage and schedule. 160 mg orally once daily with or without food. Dose
modifications and/or interruptions are indicated for grade 3 or higher, or intolerable grade 2
toxicities. Concomitant use with strong CYP2C8 inhibitors should be avoided, but in cases
where patients must receive a strong CYP2C8 inhibitor, the dose of enzalutamide should be
decreased to 80 mg orally once daily until the inhibitor is discontinued after which the dose
can be reescalated to what it was before the inhibitor was given. The use with strong CYP3A4
inducers should be avoided as they may decrease the plasma exposure of enzalutamide.
Special precautions. Enzalutamide can cause fetal harms if administered to a pregnant woman.
There is increased risk of seizures (0.9% of patients in clinical trials) and permanent
discontinuation is recommended. The safety in patients with risk factors for seizures (history of
prior seizures, underlying brain injury with loss of consciousness, cerebral vascular accidents,
transient ischemic attack within the past 12 months, brain metastasis, brain arteriovenous
malformation, or the concomitant use of medications known to lower seizure threshold) is
unknown since those patients were excluded from clinical trials. Although no dose adjustment
is needed for patients with mild-to-moderate hepatic or renal impairment, the use in those with
severe hepatic or renal impairment has not been studied, and caution should be used when
administering enzalutamide to this population.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia is occasional but it is not
usually severe. Although there is increased risk of mostly mild, upper, and lower
respiratory infections in patients receiving enzalutamide, these cases can be rarely fatal.
Thrombocytopenia can occur, but is rarely severe. Epistaxis is uncommon.
2. Nausea, vomiting, and other GI effects. Diarrhea is common. Grade 1 and 2 elevation in
alanine transaminase (ALT) and/or aspartate transaminase (AST) is occasional. Grade 1
elevation in total bilirubin is uncommon.
3. Mucocutaneous effects. Pruritus and dry skin are uncommon.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. General. Asthenia and fatigue are common. Hot flashes are common.
b. Cardiovascular. Peripheral edema is occasional. Hypertension is occasional to
uncommon.
c. Neurologic. Headache, dizziness, and paresthesia are occasional, whereas memory and
cognitive impairment are uncommon.
d. Genitourinary. Hematuria is occasional, and urinary frequency is uncommon.
e. Musculoskeletal and connective tissue. Musculoskeletal pain and weakness are
common and occasional, respectively. There may be some increase in the risk of falls.
f. Psychiatric. Insomnia and anxiety are occasional. Grade 1 and 2 visual, tactile, or
undefined hallucinations were described in 1% to 2% of patients.
EPIRUBICIN
Other names. Ellence, 4´Epi-doxorubicin, EPI.
Mechanism of action. DNA strand breakage, mediated by anthracycline effects on
topoisomerase II.
Primary indications
1. Carcinomas of the breast, esophagus, and stomach.
2. Hodgkin and non-Hodgkin lymphoma.
Usual dosage and schedule
1. 100 mg/m2 IV through the sidearm of a freely flowing IV infusion, repeated every 3 weeks
administered, or
2. 60 mg/m2 IV days 1 and 8 repeated every 3 weeks.
Special precautions
1. Take care to avoid extravasation.
2. Do not exceed a lifetime cumulative dose of 900 mg/m2. (Use a lesser dose for patients
with prior chest radiotherapy or prior anthracycline or anthracenedione therapy. 720 mg/m2
was the maximum cumulative dose in adjuvant studies.)
3. Reduce or hold dose if patient has impaired liver function.
a. For serum bilirubin of 1.2 to 3 mg/dL, give one-half the normal dose.
b. For serum bilirubin of more than 3 mg/dL, give one-fourth the normal dose.
Toxicity
1. Myelosuppression and other hematologic. Dose-limiting leukopenia with recovery by day
21.
2. Nausea, vomiting, and other GI. Nausea and vomiting are common. Diarrhea and
abdominal pain are occasional.
3. Mucocutaneous effects
a. Stomatitis that is dose-dependent.
b. Alopecia beginning approximately 10 days after the first treatment with regrowth when
cessation of drug treatment occurs is common, but not universal (25% to 50%).
c. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to
irradiated skin (radiation-recall reaction) have been observed.
d. Severe local tissue damage possibly progressing to skin ulceration and necrosis if
subcutaneous extravasation occurs is common.
4. Cardiac effects. Potentially irreversible congestive heart failure may occur owing to
cardiomyopathy. The incidence depends on the lifetime dose, which should not exceed 900
mg/m2. This limit is lower if patient has received prior chest radiotherapy or prior
anthracycline or anthracenedione therapy. Congestive heart failure may be predicted by
serial measurement of left ventricular function or endomyocardial biopsy. Transient ECG
changes are similar in type and frequency to those observed after doxorubicin.
5. Miscellaneous effects
a. Red-orange urine for 24 hours after injection owing to drugs and its metabolites is
common.
b. Urticaria and anaphylaxis have been reported in patients treated with epirubicin; signs
and symptoms of these reactions may vary from skin rash and pruritus to fever, chills,
and shock.
c. Secondary AML and MDS are rare.

ERIBULIN MESYLATE
Other name. Halaven.
Mechanism of action. Microtubule inhibitor.
Primary indications. Metastatic breast cancer in patients who have previously received at
least two chemotherapeutic regimens including an anthracycline and a taxane.
Usual dosage and schedule. 1.4 mg/m2 administered IV over 2 to 5 minutes on days 1 and 8 of
a 21-day cycle. The dose should be reduced to 1.1 mg/m2 for patients with mild hepatic
impairment (Child-Pugh A), to 0.7 mg/m2 for moderate hepatic impairment (Child-Pugh B),
and to 1.1 mg/m2 for moderate renal impairment (creatinine clearance 30 to 50 mL/minute).
Special precautions
1. Eribulin can cause fetal harms if administered to a pregnant woman.
2. QTc prolongation can occur, and baseline assessment with ECG should be done in patients
with underlying cardiac disease or other risk factors for QTc prolongation. Correction of
underlying electrolytes abnormalities is also recommended before starting therapy.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common. Neutropenia is
common and can severe. Febrile neutropenia has been reported in 5% of patients and can
be severe and result in fatal complications.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are
common but uncommonly severe. Abdominal pain, dyspepsia, stomatitis, and dry mouth are
occasional.
3. Mucocutaneous effects. Mucositis and skin rash are occasional. Alopecia is common.
4. Immunologic effects and infusion reactions. Upper respiratory and urinary tracts
infections are occasional.
5. Miscellaneous effects
a. General. Fatigue, asthenia, and pyrexia are common. Anorexia and weight loss are
common.
b. Respiratory. Cough and dyspnea are occasional.
c. Cardiovascular. Peripheral edema is occasional.
 d. Metabolic. Hypokalemia is occasional.
e. Hepatic. Grade 2 elevation in ALT and/or AST can occur in up to 18% of patients. It
usually resolves with dose interruption.
f. Neurologic. Peripheral neuropathy is common and occasionally severe. It can lead to
drug discontinuation in 5% of patients and sometimes last for more than a year.
Dysgeusia and dizziness are occasional. Headache is common.
g. Musculoskeletal and connective tissue. Muscle spasms and weakness are occasional.
Arthralgia, myalgia, and back pain are common. Bone pain and pain in extremity are
occasional.
h. Psychiatric. Insomnia and depression are occasional.
i. Ophthalmic. Increased lacrimation is occasional.

ERLOTINIB
Other name. Tarceva.
Mechanism of action. Inhibits intracellular phosphorylation of the tyrosine kinase associated
with epidermal growth factor receptor (EGFR).
Primary indications
1. Non–small cell lung cancer
a. Locally advanced after failure of one prior regimen.
b. Maintenance treatment after four cycles of platinum-based chemotherapy.
c. First-line treatment of metastatic non–small cell lung cancer (NSCLC) patients whose
tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.
2. Pancreatic cancer (with gemcitabine)
Usual dosage and schedule. Give at least 1 hour before or 2 hours after food.
1. 150 mg PO daily for lung cancer.
2. 100 mg PO daily for pancreatic cancer.
Special precautions. May be associated with interstitial lung disease–like events, manifest by
unexplained dyspnea, cough, and fever. If this occurs, erlotinib therapy should be discontinued
and management of the pulmonary condition instituted. GI perforation; bullous, blistering, and
exfoliative skin conditions, suggestive of toxic epidermal necrolysis (TEN); and ocular
disorders, including corneal perforation or ulceration, have been reported.
CYP3A4 inhibitors such as ketoconazole increase erlotinib AUC, while inducers such as
rifampicin decrease erlotinib AUC, resulting in potential increase in toxicity or reduction in
efficacy, respectively. Monitor closely for International Normalized Ratio (INR) elevation in
patients taking concomitant warfarin. Give with extreme caution if liver impairment (bilirubin
> 3 × ULN); monitor those with less liver impairment closely.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is not an effect of
 erlotinib. Deep venous thrombosis—uncommon. Unexpected INR elevation may occur in
patients taking warfarin. Microangiopathic hemolytic anemia with thrombocytopenia is
rare.
2. Nausea, vomiting, and other GI effects. Anorexia, dyspepsia, nausea, vomiting, diarrhea
(second most common reason for dose interruption), constipation, and abdominal pain are
common.
3. Mucocutaneous effects. Rash is common (75%) and the most common reason for dose
interruption; stomatitis is occasional to common (17%). Keratoconjunctivitis is occasional.
4. Miscellaneous effects
a. Systemic. Fatigue, weight loss, edema are common; fever is common, occasionally with
rigors.
b. Hepatic. Transaminase elevations are common, and occasionally associated with
increased bilirubin, but they are rarely life-threatening.
c. Bone pain and myalgia are common.
d. Dyspnea is common, cough is occasional.
e. Anxiety, depression, headache, and neuropathy are occasional.
f. Myocardial ischemia or infarction is uncommon.
g. Cerebrovascular accidents are uncommon.

ETOPOSIDE
Other names. Epipodophyllotoxin, VP-16, VP-16-213, VePesid, Etopophos (etoposide
phosphate).
Mechanism of action. Interaction with topoisomerase II produces single-strand breaks in
DNA. Arrests cells in late S phase or G2 phase.
Primary indications
1. Small cell anaplastic and NSCLC.
2. Stomach carcinoma.
3. Germ cell cancers.
4. Lymphomas.
5. Acute leukemia.
6. Neuroblastoma.
Usual dosage and schedule
1. 120 mg/m2 IV on days 1 to 3 every 3 weeks.
2. 50 to 100 mg/m2 IV on days 1 to 5 every 2 to 4 weeks.
3. 125 to 140 mg/m2 IV on days 1, 3, and 5 every 3 to 5 weeks.
4. High-dose therapy (750 to 2,400 mg/m2) is investigational and should only be used with
progenitor cell rescue (e.g., bone marrow or peripheral blood stem cell transplantation).
Special precautions
1. Administer etoposide as a 30- to 60-minute infusion to avoid severe hypotension. Monitor
blood pressure during infusion. Etoposide phosphate may be administered as a 5-minute
bolus infusion.
2. Take care to avoid extravasation.
3. Etoposide must be diluted in 20 to 50 volumes (100 to 250 mL) of isotonic saline before
use. Etoposide phosphate vials (100 mg) may be reconstituted in 5 to 10 mL (water, saline,
or dextrose) to a concentration of 10 or 20 mg/mL.
4. Decrease dose by 50% for bilirubin levels of 1.5 to 3 mg/dL; decrease by 75% for
bilirubin levels of 3 to 5 mg/dL; discontinue drug if bilirubin level is more than 5 mg/dL.
5. Decrease dose by 25% for creatinine clearance rate of less than 30 mL/minute.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting leukopenia and less
severe thrombocytopenia have a nadir at 16 days with recovery by days 20 to 22.
2. Nausea, vomiting, and other GI effects. Usually mild-to-moderate nausea and vomiting in
about one-third of patients receiving standard doses; common with high-dose therapy.
Anorexia is common. Diarrhea is uncommon.
3. Mucocutaneous effects
a. Alopecia is common.
b. Stomatitis is uncommon with standard doses; common with high-dose therapy.
c. Painful rash may occur with high-dose therapy.
d. Chemical phlebitis is occasional.
4. Miscellaneous effects
a. Hepatotoxicity is rare.
b. Peripheral neurotoxicity is rare.
c. Allergic reaction is rare.
d. Hemorrhagic cystitis may occur with high-dose therapy.

EVEROLIMUS
Other name. Afinitor.
Mechanism of action. Everolimus, after complexing with an intracellular protein, FKBP-12,
is an inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase, the
pathway of which is dysregulated in several human cancers. It also inhibits the expression of
hypoxia-inducible factor (HIF-1) and the expression of vascular endothelial growth factor
(VEGF). Mechanism is similar, if not identical, to temsirolimus.
Primary indications
1. Advanced renal cell carcinoma.
2. In combination with exemestane in metastatic hormone receptor–positive breast cancer in
postmenopausal women after failure of nonsteroidal aromatase inhibitors.
3. Subependymal giant cell astrocytoma (SEGA) in adults and children, which cannot be
 totally resected.
4. Unresectable, locally advanced or metastatic pancreatic neuroendocrine tumors in adults.
5. Renal angiomyolipomas, associated with tuberous sclerosis complex, that do not require
immediate surgery.
Usual dosage and schedule
1. 10 mg PO once daily.
2. Reduce dose to 5 mg PO once daily for patients with Child-Pugh class B hepatic
impairment or as needed to manage adverse drug reactions.
3. If strong inducers of CYP3A4 are required, increase daily dose in 5-mg increments to a
maximum of 20 mg once daily.
Special precautions. Coadministration of everolimus with strong or moderate inhibitors of
CYP3A4 or the multidrug efflux pump PgP, such as ketoconazole, increases the AUC of
everolimus by up to 15-fold and should be avoided. CYP3A4 inducers may decrease
everolimus AUC, and increased doses may be required.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and lymphopenia are common
and occasionally severe. Thrombocytopenia and neutropenia occur only occasionally, and
are rarely grade 3 or 4. Hemorrhage is uncommon.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, and vomiting are common, but
rarely severe. Abdominal pain is occasional.
3. Mucocutaneous effects. Mucositis is common (44%), but grade 3 or 4 ulceration is
uncommon. Rash is common; pruritis and dry skin are occasional. Hand-foot syndrome is
uncommon as are nail disorders and acneiform dermatitis.
4. Miscellaneous effects
a. Noninfectious pneumonitis (a class effect of rapamycin derivatives) is occasional, but
grade 3 or 4 reaction is uncommon.
b. Infections, particularly with opportunistic infections are common, and may occasionally
be severe.
c. Metabolic changes. Elevations in lipids, glucose, creatinine, and transaminases and
decreased phosphate are common. Except for glucose elevation, which is occasional,
severe (grade 3 or 4) abnormalities of the other changes are uncommon to rare.
d. Asthenia, fatigue, peripheral edema, fever, headache, cough, and dyspnea are common
(15% to 30%), but severe episodes are uncommon to rare. Decreased weight is
occasional.
e. Cardiovascular. Hypertension, tachycardia, chest pain are uncommon, and congestive
heart failure is rare.
f. Nervous system. Insomnia, dizziness, and paresthesias are occasional to uncommon.
g. Acute renal failure is rare.
EXEMESTANE
Other name. Aromasin.
Mechanism of action. Exemestane is an irreversible, steroidal aromatase inactivator that
decreases estrogen biosynthesis by selective inhibition of aromatase (estrogen synthetase) in
peripheral tissues.
Primary indications
1. Carcinoma of the breast in postmenopausal women that has progressed following tamoxifen
therapy.
2. Carcinoma of the breast as adjuvant treatment in postmenopausal women with estrogen-
receptor positive breast cancer.
Usual dosage and schedule. 25 mg PO once daily after meal.
Special precautions. Potential hazard to fetus if given during pregnancy.
Toxicity
1. Myelosuppression and other hematologic. No dose-related effect. Thromboembolic
events are uncommon to rare.
2. Nausea, vomiting, and other GI. Nausea, vomiting, constipation, diarrhea are uncommon
to occasional.
3. Mucocutaneous effects. Rash is uncommon.
4. Miscellaneous effects
a. Fatigue is occasional.
b. Musculoskeletal pain (arthralgia or bone) is occasional to common.
c. Headache is occasional.
d. Peripheral edema, weight gain are occasional (lower than with megestrol).
e. Dyspnea and cough are uncommon to occasional.
f. Hot flushes are occasional.
g. Decreased bone mineral density with osteoporosis is occasional, and there is increased
risk for fractures.
h. Hypertension is occasional.

FLUDARABINE
Other names. FAMP, Fludara, Oforta.
Mechanism of action. A purine analog that causes inhibition of DNA polymerase alpha,
ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis.
Primary indications
1. CLL (B-cell).
2. Macroglobulinemia.
3. Indolent lymphomas.
4. Acute leukemia (in combination).
Usual dosage and schedule
1. 25 mg/m2 IV as a 30-minute infusion daily for 5 days. (Fludara). Other dose schedules,
usually less intensive, have been used, often in combinations with other drugs. Repeat every
4 weeks.
2. 40 mg/m2 PO daily for 5 days. Repeat every 4 weeks. (Oforta).
Special precautions. If there is the potential for tumor lysis syndrome, administer allopurinol
and ensure good hydration and close clinical monitoring. Transfusion-associated graft versus
host disease may be seen. Therefore, prior irradiation of blood products for transfusion in
patients at risk is recommended. Sometimes fatal cases of autoimmune hemolytic anemia have
been reported, and patients should be closely monitored for hemolysis, particularly if there is a
prior history of autoimmune hemolysis or immune thrombocytopenia related to the CLL. Not
recommended for use in combination with pentostatin because of high incidence of pulmonary
toxicity. Adult patients with moderate impairment of renal function (creatinine clearance 30 to
70 mL/minute/1.73 m2) should have a 20% dose reduction of fludarabine. It should not be
given to patients with severely impaired renal function (creatinine clearance less than 30
mL/minute/1.73 m2).
Toxicity
1. Myelosuppression and other hematologic effects. Granulocytopenia and
thrombocytopenia are common but appear to become less common in patients whose
disease is responding. May progress to trilineage marrow hypoplasia. Infection,
particularly pneumonia, is common during early courses and uncommon after the sixth
course. Autoimmune hemolytic anemia and immune thrombocytopenia have been observed
(probably rare).
2. Nausea, vomiting, and other GI effects. Nausea is occasional to common but not usually
severe. Diarrhea is occasional.
3. Mucocutaneous effects. Occasional mucositis, rash, no alopecia.
4. Neurotoxicity. Uncommon at usual dosage. Somnolence or fatigue, paresthesias, and
twitching of extremities may be seen. Severe neurologic symptoms, including visual
disturbances, have been common at higher doses than those recommended.
5. Immune suppression. Common. Usually seen as a depression in CD4 and CD8 lymphocyte
counts. Opportunistic infections may result, and many recommend pneumocystis pneumonia
prophylaxis with trimethoprim-sulfamethoxazole until the CD4 lymphopenia resolves.
6. Miscellaneous effects
a. Abnormal liver or renal function is rare.
b. Cough, dyspnea, upper respiratory infections are occasional.
c. Fever, infection, diaphoresis, headache are occasional.
d. Allergic pneumonitis is occasional to uncommon.
e. Edema is occasional.
 f. Tumor lysis syndrome is uncommon.

FLUOROURACIL
Other names. 5-FU, Adrucil, Efudex, Fluoroplex, 5-fluorouracil.
Mechanism of action. A pyrimidine antimetabolite that, when converted to the active
nucleotide, inhibits the enzyme thymidylate synthetase and thereby blocks DNA synthesis.
Primary indications
1. Breast, colorectal, anal, stomach, pancreas, esophagus, liver, head and neck, and bladder
carcinomas.
2. Actinic keratosis; basal and squamous cell carcinomas of skin (topically).
Usual dosage and schedule
1. Systemic options (alternatives). Other schedules when in combinations, particularly with
leucovorin.
a. 500 mg/m2 IV on days 1 to 5 every 4 weeks.
b. 450 to 600 mg/m2 IV weekly.
c. 200 to 400 mg/m2 daily as a continuous IV infusion.
d. 1,000 mg/m2 daily for 4 days as a continuous IV infusion every 3 to 4 weeks.
2. Intracavitary. 500 to 1,000 mg for pericardial effusion; 2,000 to 3,000 mg for pleural or
peritoneal effusions.
3. Topically. Apply solution or cream twice daily. Use only 5% strength for carcinomas.
Special precautions
1. Reduce dose in patients with compromised liver function.
2. Precipitation may occur if leucovorin and fluorouracil are mixed in the same bag.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting with a nadir at 10 to 14
days after the last dose and recovery by 21 days.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting may occur, but are not
usually severe. Diarrhea is common with higher doses, continuous infusion, or when used in
combination with leucovorin and irinotecan. Esophagitis and proctitis may also occur.
3. Mucocutaneous effects
a. Stomatitis is an early sign of severe toxicity. It progresses from soreness and erythema to
frank ulceration, which becomes hemorrhagic in a small number of patients.
b. Partial alopecia is uncommon.
c. Hyperpigmentation of skin over face, hands, and the veins used for infusion is
occasional.
d. Maculopapular rash is uncommon.
e. Sun exposure tends to increase skin reactions.
 f. “Hand-foot syndrome” with painful, erythematous desquamation and fissures of palms
and soles is common with continuous infusion, occasional with other schedules or
combinations.
4. Miscellaneous effects
a. Neurotoxicity, including headache, minor visual disturbances, and cerebellar ataxia is
rare.
b. Increased lacrimation is uncommon.
c. Cardiac toxicity, including arrhythmias, angina, ischemia, and sudden death is rare. May
be more common with continuous infusion and previous history of coronary artery
disease.

FLUTAMIDE
Other name. Eulexin.
Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in
the prostate cancer cells.
Primary indication. Carcinoma of the prostate, most often in combination with LHRH
agonists.
Usual dosage and schedule. 250 mg PO every 8 hours.
Special precautions. Serum transaminase levels should be measured prior to starting treatment
with flutamide. Flutamide is not recommended in patients whose serum transaminase values
exceed twice the ULN.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are uncommon to
occasional. Diarrhea, flatulence, and mild abdominal pain are occasional.
3. Mucocutaneous effects. Mild skin rash is occasional.
4. Miscellaneous effects
a. Endocrine. Secondary pharmacologic effects, including breast tenderness, breast
swelling, hot flashes, impotence, and loss of libido, are common but reversible after
cessation of therapy.
b. Hepatic. Elevated liver function tests are uncommon; liver failure is rare, but may be
preceded by flulike symptoms or right upper quadrant pain and tenderness.
c. Hypertension is occasional.
d. Adverse cardiovascular events are similar to those seen with orchiectomy.

FULVESTRANT
Other name. Faslodex.
Mechanism of action. An estrogen receptor antagonist that binds to the estrogen receptor in a
competitive manner. It downregulates the estrogen receptor protein in human breast cancer
cells. In vitro there is reversible inhibition the growth of tamoxifen-resistant as well as
estrogen-sensitive human breast cancer cell lines.
Primary indications
Hormone receptor–positive metastatic breast cancer in postmenopausal women with disease
progression following antiestrogen therapy. (There are no efficacy data for premenopausal
women with advanced breast cancer.)
Hormone receptor–positive metastatic breast cancer in postmenopausal women with
disease progression following therapy with a third-generation aromatase inhibitor.
Usual dosage and schedule
1. 500 mg IM as two concurrent 5-mL injections (50 mg/mL) into each buttock, repeated once
monthly after loading on days 1, 15, and 29.
2. Reduce dose to 250 mg in patients with moderate hepatic impairment (Child-Pugh class B),
using the same schedule as above.
Special precautions. Safety has not been evaluated in patients with severe hepatic impairment.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is rare.
2. Nausea, vomiting, and other GI effects. Nausea is common; vomiting, constipation,
diarrhea, and anorexia are occasional.
3. Mucocutaneous effects. Rash and increased sweating are occasional.
4. Miscellaneous effects
a. For the body as a whole, headache, back pain, abdominal pain, injection site pain, and
pelvic pain are occasional. Occasional patients also experience a flulike syndrome or
fever.
b. Vasodilation and edema are occasional.
c. Dizziness, insomnia, paresthesias, depression, and anxiety are uncommon to occasional.
d. Pharyngitis, dyspnea, and increased cough are occasional.
Gefitinib
Other names. Iressa, ZD1839.
Mechanism of action. Selectively inhibits tyrosine kinase activity of the EGFR. Epidermal
growth factor receptor tyrosine kinase inhibition by gefitinib impairs epidermal growth factor–
stimulated autophosphorylation and thus blocks growth signals within the cell.
Primary indications
1. Advanced NSCLC that is EGFR mutation positive for exon 19 deletions or exon 21
substitution mutations.
2. Carcinoma of the lung as monotherapy for the continued treatment of patients with locally
advanced or metastatic NSCLC after failure of both platinum-based and docetaxel
 chemotherapies who are benefiting or have benefited from its use.
Usual dosage and schedule. 250 mg daily. (May require interruption for diarrhea or skin
reactions.)
Special precautions. Diarrhea or hepatic function abnormalities may be dose limiting and
require discontinuation of the drug.
Toxicity
1. Myelosuppression and other hematologic effects. Uncommon, except for anemia, which
is occasional and not dose related.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
Diarrhea may be dose limiting. Anorexia, constipation, and abdominal pain are also
common but usually not severe.
3. Mucocutaneous effects. Acne-like or folliculitis-type rash is common, usually appearing
by day 14; frequency and severity are dose related. May be associated with dry skin and
itching. Rash usually does not worsen with continued treatment and resolves within a week
of discontinuation of the drug. Dry mouth and conjunctivitis are occasional.
4. Miscellaneous effects
a. Dyspnea is occasional to common.
b. Asthenia is common.
c. Headache and somnolence are occasional.
d. Hepatic: Elevated transaminases are occasional but may be severe (grade 3 or 4).

GEMCITABINE
Other name. Gemzar.
Mechanism of action. After being metabolized intracellularly to the active diphosphate and
triphosphate nucleotides, gemcitabine, a cytidine analog, inhibits ribonucleotide reductase and
competes with deoxycytidine triphosphate for incorporation into DNA.
Primary indications
1. Carcinoma of the pancreas, locally advanced or metastatic.
2. Non–small cell carcinomas of the lung.
3. Carcinomas breast, biliary tract, bladder, and ovary.
4. Non-Hodgkin lymphoma.
5. Soft tissue sarcoma.
Usual dosage and schedule
1. 1,000 mg/m2 IV over 30 minutes once weekly for up to 7 weeks when used as a single
agent. After 1 week of rest, subsequent cycles are given once weekly for 3 consecutive
weeks out of 4.
2. 1,000 to 1,250 mg/m2 IV over 30 minutes once weekly for 2 or 3 successive weeks during
 each 3- to 4-week cycle, when used in combination regimens.
Special precautions. Prolongation of infusion time beyond 60 minutes increases toxicity.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-related and common. Overt
hemolytic-uremic syndrome is rare, but milder cases with renal insufficiency may be more
common.
2. Nausea and vomiting and other GI effects. Nausea and vomiting are common, but only
occasionally severe. Diarrhea and constipation are occasional to common.
3. Mucocutaneous effects. Rash, alopecia, and mucositis are occasional.
4. Miscellaneous effects
a. Hepatic. Transient elevations of serum transaminases and alkaline phosphatase are
common. Serious hepatotoxicity is rare.
b. Mild proteinuria and hematuria are common.
c. Fever without documented infection is common.
d. Neurotoxicity. Mild paresthesias are occasional.
e. Dyspnea is occasional.

GLUCARPIDASE
Other name. Voraxaze.
Mechanism of action. A recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal
glutamate residue from folic acid and classical antifolates such as methotrexate. It converts
methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA)
and glutamate providing an alternative nonrenal pathway for methotrexate elimination in
patients with renal dysfunction during high-dose methotrexate treatment.
Primary indications. The treatment of toxic plasma methotrexate concentrations (>1 µmol/L)
in patients with delayed methotrexate clearance due to impaired renal function.
Usual dosage and schedule. Single IV bolus injection of 50 U/kg over 5 minutes. Patients with
preglucarpidase methotrexate concentrations >100 µmol/L could receive a second dose 48
hours after the first dose.
Special precautions
1. Methotrexate concentrations within 48 hours following administration can only be reliably
measured by a chromatographic method as DAMPA interferes with the measurement of
methotrexate concentration using immunoassays resulting in an erroneous measurement,
which overestimates the methotrexate concentration.
2. Leucovorin should not be administered within 2 hours before or after a dose of
glucarpidase because leucovorin is a substrate for glucarpidase. The leucovorin dose
should remain the same for the first 48 hours after the glucarpidase dose. Beyond 48 hours,
 leucovorin dose is based on the measured methotrexate concentration and continued until
the methotrexate concentration has been maintained below the leucovorin treatment
threshold for a minimum of 3 days.
Toxicity
Allergic reactions to the infusion that could include parethesias, flushing, hypotension, nausea
and vomiting, tremor, headaches, blurry vision, diarrhea, throat irritation, and rash are all
uncommon and mostly grade 1 or 2. Severe reactions are rare.

GONADOTROPIN-RELEASING HORMONE ANALOGS

Other names. LHRH analogs, leuprolide (Eligard, Lupron, Lupron depot), goserelin (Zoladex
depot), triptorelin pamoate (Trelstar depot).
Mechanism of action. Initial release of FSH and LH from the anterior pituitary, followed by
diminution of gonadotropin secretion owing to desensitization of the pituitary to gonadotropin-
releasing hormone (GnRH) and consequent decrease in the respective gonadal hormones. May
also have direct effects on cancer cells, at least in cancer of the breast, in which GnRH-
binding sites have been demonstrated.
Primary indications
1. Metastatic prostate carcinoma.
2. Breast carcinoma in premenopausal and perimenopausal women with metastatic disease
(goserelin).
Usual dosage and schedule
1. Leuprolide depot, 7.5 mg IM monthly, 22.5 mg IM every 3 months, or 30 mg IM every 4
months.
2. Goserelin depot, 3.6 mg SC every 4 weeks or 10.8 mg SC every 12 weeks. Use only 3.6 mg
implant for breast carcinoma.
3. Triptorelin depot 3.75 mg IM monthly; triptorelin depot 22.5 mg IM every 6 months.
Special precautions. Worsening of symptoms may occur during the first few weeks.
Toxicity
1. Myelosuppression and other hematologic. Rare, if at all.
2. Nausea, vomiting, and other GI. Anorexia, nausea, vomiting, and constipation are
uncommon.
3. Mucocutaneous effects. Erythema and ecchymosis at the injection site, rash, hair loss, and
itching are uncommon.
4. Cardiovascular effects. Congestive heart failure, hypertension, and thrombotic episodes
are uncommon. Peripheral edema is occasional.
5. Miscellaneous effects
a. Central nervous system: dizziness, pain, headache, and paresthesias are uncommon.
 b. Endocrine: hot flashes are common; decreased libido is common; gynecomastia with or
without tenderness is uncommon; impotence is occasional to common.
c. Bone pain, or “flare,” is common on initiation of therapy in patients with bony
metastasis. This can be minimized by pretreating with flutamide or another androgen
antagonist in men with prostate cancer.
d. Hypersensitivity reactions with rare angioneurotic edema and anaphylaxis have been
reported.

HYDROXYUREA
Other names. Hydrea, Droxia.
Mechanism of action. Interferes with DNA synthesis, at least in part by inhibiting the
enzymatic conversion of ribonucleotides to deoxyribonucleotides.
Primary indications
1. Head and neck carcinomas.
2. CML
3. ALL and AML with high blast counts.
4. Essential thrombocythemia.
5. Polycythemia rubra vera.
6. Prevention of retinoic acid syndrome in acute promyelocytic leukemia.
7. Sickle cell anemia with frequent painful crises.
Usual dosage and schedule
1. 800 to 2,000 mg/m2 PO as a single or divided daily dose. Dose is adjusted up or down,
depending on efficacy and tolerability.
2. 3,200 mg/m2 PO as a single dose every third day (not for leukemias).
3. Starting dose in sickle cell anemia is 15 mg/kg/day, with increments of 5 mg/kg every 12
weeks, so long as ANC is >2,000 cells/μL and platelets >80,000/μL.
Special precautions. The daily dose must be adjusted for blood count trends. Be careful not to
change dose too often, because there is a delay in response. Severe cutaneous vasculitic
toxicities, including ulcers and gangrene, have been seen, particularly in association with
current or prior interferon therapy. Toxic reactions may be greater in patients with impaired
renal function, such as may be seen in elderly patients. Reduce doses by 50% if creatinine
clearance less than 60 mL/minute.
Toxicity
1. Myelosuppression and other hematologic. Occurs at doses of more than 1,600 mg/m2
daily by day 10. Recovery is usually prompt. Increased RBC mean corpuscular volume
(MCV) is common.
2. Nausea, vomiting, and other GI. Nausea is common at high doses. Other GI symptoms are
uncommon. Pancreatitis may be seen in patients with HIV disease being treated with
 didanosine and other antiviral agents.
3. Mucocutaneous effects. Stomatitis is rare. Maculopapular rash may be seen. Inflammation
of mucous membranes caused by radiation may be exaggerated.
4. Miscellaneous effects
a. Temporary renal function impairment or dysuria is uncommon.
b. CNS disturbances are rare.
c. May be leukemogenic or teratogenic.

IBRUTINIB
Other name. Imbruvica.
Mechanism of action. Inhibitor of Bruton tyrosine kinase, which results in inhibition of
signaling pathways necessary to malignant B-cells proliferation and survival.
Primary indications
1. Mantle cell lymphoma (MCL) in patients who received at least one prior therapy.
2. CLL in patients who received at least one prior therapy.
3. CLL in patients who carry a deletion in chromosome 17 (17p del).
4. Waldenström macroglobulinemia (WM).
Usual dosage and schedule
1. MCL—560 mg PO daily for MCL.
2. CLL and WM—420 mg PO daily.
The dose is to be taken approximately at the same time daily with water. Dose
interruption and/or reduction is indicated for grade 3 or greater hematologic and
nonhematologic toxicities, and also for concomitant use of CYP3A inhibitors. Concomitant
use with strong CYP3A inhibitors/inducers should be avoided. If a dose is missed, it can be
taken as soon as possible with return to the same schedule the next day.
Special precautions. Ibrutinib can cause fetal harm if administered to a pregnant woman. Use
in patients with baseline impairment in liver function should be avoided as those with serum
AST or ALT ≥3 times upper normal limit were excluded from clinical trials of ibrutinib.
Grade 3 or higher bleeding events can occur in up to 5% with the dose of 560 mg daily.
Withholding ibrutinib 3 to 7 days pre- and postsurgical procedures may be warranted,
depending on the bleeding risk.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are
common. Anemia is occasional. Bleeding events, including bruising, of any grade can occur
in up to 48% of patients taking the 560 mg oral daily dose. Ibrutinib-induced lymphocytosis
can result from redistribution of tissue-resident CLL cells into the blood with rapid
shrinkage of the lymph nodes. This effect is transient in most patients lasting for about 8
months but can be prolonged for up to more than 12 months in some cases. This, however,
 does not imply drug inactivity, and close monitoring for expected recovery should be
undertaken unless other signs of disease progression are present. Grade 3 or greater
infections can occur in up to 25% of patients and some cases can be fatal. Upper
respiratory tract infections are more common. However, skin infections, urinary tract
infections, and pneumonia can also occur.
2. Nausea, vomiting, and other GI effects. Diarrhea, constipation, nausea, vomiting, and
abdominal pain are common. Dyspepsia is occasional.
3. Mucocutaneous effects. Rash is common. Stomatitis is occasional.
4. Immunologic effects and infusion reactions. Not applicable.
5. Miscellaneous effects
a. Pyrexia is occasional. Peripheral edema is common.
b. Neurologic. Peripheral sensory neuropathy is uncommon. Dizziness and headache are
occasional.
c. Renal toxicity. Increase in creatinine levels of up to 1.5 times the ULN—67%; 1.5 to 3
times the ULN 9%.
d. Second primary malignancies. In patients with MCL treated with ibrutinib, other
malignancies occurred in 5% of patients, including skin cancers (4%) and other
carcinomas (1%).
e. Musculoskeletal and connective tissue. Musculoskeletal pain is common. Muscles
spasms and arthralgia are occasional.
f. Respiratory. Dyspnea is common and cough is occasional.
g. Cardiovascular. Increased risk of atrial fibrillation has been observed in 3% to 5% of
patients.

IDARUBICIN
Other names. 4-Demethoxydaunorubicin, IDA, Idamycin.
Mechanism of action. DNA strand breakage mediated by anthracycline effects on
topoisomerase II or free radicals; DNA intercalation; DNA polymerase inhibition.
Primary indications
1. AML.
2. Blast crisis of CML.
3. ALL.
Usual dosage and schedule. 12 to 13 mg/m2 IV daily for 3 days (usually in a combination with
cytarabine) during induction; 10 to 12 mg/m2 IV daily for 2 days during consolidation.
Special precautions. Administer over several minutes into the sidearm of a running IV
infusion, taking care to avoid extravasation. Cardiac toxicity may be less than that with
daunorubicin. Maximum dose not yet established. Cumulative doses >150 mg/m2 have been
associated with decreased cardiac ejection fraction.
Toxicity
1. Myelosuppression and other hematologic effects. Universal and dose-limiting.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and anorexia, are common.
Diarrhea is occasional to common.
3. Mucocutaneous effects. Alopecia is common; mucositis is common but usually not severe.
4. Miscellaneous effects
a. Hepatic dysfunction. Common but usually not severe and not clearly due to the
idarubicin.
b. Renal effects. Common but usually not clinically significant.
c. Cardiac effects. Uncommon during induction and consolidation (1% to 5%).
d. Tissue damage is probable if infiltration occurs.
e. Neurologic effects. Occasional.

IDELALISIB
Other name. Zydelig.
Mechanism of action. Inhibitor of PI3K-delta kinase. It induces apoptosis and inhibits
proliferation in cell lines derived from malignant B cells and in primary tumor cells.
Primary indications
1. Relapsed CLL, in combination with rituximab, in patients for whom rituximab alone would
be considered appropriate therapy due to other comorbidities.
2. Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least
two prior systemic therapies.
3. Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two
prior systemic therapies.
Usual dosage and schedule. 150 mg oral twice a day. Can be taken with or without food.
Dose reduction and/or interruption may be indicated for severe or life-threatening adverse
events. Permanent discontinuation is indicated with reoccurrence of severe or life-threatening
adverse events and in patients with symptomatic pneumonitis of any severity. Should not be
used with strong CYP3A inducers or with drugs that may cause liver toxicity. Close monitoring
for toxicity is warranted when used with strong CYP3A inhibitors. This is also critical in
patients with baseline hepatic impairment as those with serum AST or ALT greater than 2.5
ULN or bilirubin greater than 1.5 ULN were excluded from clinical studies.
Special precautions. Idelalisib can cause fetal harm if administered to a pregnant woman.
Fatal and/or serious hepatotoxicity, colitis, pneumonitis, and intestinal perforation can occur
(up to 15% of patients), warrant special caution, and may require dose interruption or
permanent discontinuation.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are
 common. Neutropenia is common, with grade 3 or higher occurring in up to 31% of cases.
Pneumonia was reported in 25% of cases. Other infections can occur, including upper
respiratory tract and urinary tract infections.
2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are common. Vomiting is
occasional. Grade 3 or higher diarrhea or colitis can occur in up to 14% of cases and
responds poorly to antimotility agents. This may warrant dose interruption and in some
cases, corticosteroids use. Intestinal perforation can occur and warrants permanent
discontinuation.
3. Mucocutaneous effects. Stomatitis is occasional. Rash is common. Severe (grade 3 or
greater) cutaneous manifestations including rash, dermatitis, and even TEN are rare and
warrant discontinuation of treatment.
4. Immunologic effects and infusion reactions. Serious allergic reactions including
anaphylaxis are rare but warrant discontinuation of treatment and supportive care.
5. Miscellaneous effects
a. Hepatic. Fatal and/or serious hepatotoxicity can occur in up to 14% of patients
generally within the first 12 weeks and is reversible with dose interruption. Recurrent
hepatotoxicity warrants permanent discontinuation. Monitor AST and ALT every 2
weeks for the first 3 months, then every 4 weeks for the next 3 months, then every 1 to 3
months thereafter. Monitor weekly if the ALT or AST rises above three times ULN until
resolves, and withhold idelalisib if the ALT or AST rises above five times ULN, and
continue to monitor the ALT/AST weekly until resolved.
b. Pyrexia is occasional. Peripheral edema is common. Asthenia is occasional.
c. Neurologic. Headache is occasional.
d. Musculoskeletal and connective tissue. Arthralgia is occasional.
e. Respiratory. Cough and dyspnea are common. Fatal and serious pneumonitis can occur.
Patients with symptomatic pneumonitis secondary to idelalisib are treated with
discontinuation of therapy and corticosteroids.
f. Psychiatric. Insomnia is occasional.

IFOSFAMIDE
Other name. Ifex.
Mechanism of action. Metabolic activation by microsomal liver enzymes produces
biologically active intermediates that attack nucleophilic sites, particularly on DNA.
Primary indications
1. Testicular and lung cancers.
2. Bone and soft tissue sarcomas.
3. Lymphoma.
Usual dosage and schedule
1. 1.2 g/m2 IV over 30 minutes or more daily for 5 consecutive days every 3 or 4 weeks,
 usually with other agents. Mesna 120 mg/m2 is given just before ifosfamide, then mesna
1,200 mg/m2 as a daily continuous infusion is given until 16 hours after the last dose of
ifosfamide.
2. 3.6 g/m2 IV daily as a 4-hour infusion for 2 consecutive days, usually with other agents.
Mesna is given at a dose of 750 mg/m2 IV just prior to and at 4 and 8 hours after the start of
the ifosfamide.
Higher dosage schedules have been used experimentally with up to 14 g/m2 being
used per course over a 6-day period, with equal or greater doses of mesna.
Special precautions. Must be used with mesna to prevent hemorrhagic cystitis. Mesna dose is
at least 20% of the ifosfamide dose (on a weight basis), administered just prior to (or mixed
with) the ifosfamide dose and again at 4 and 8 hours after the ifosfamide to detoxify the urinary
metabolites that cause the hemorrhagic cystitis. Higher doses of ifosfamide may require higher
doses and longer durations of mesna. Neither mesna nor its only metabolite, mesna disulfide,
affect ifosfamide or its antineoplastic metabolites. Mesna disulfide is reduced in the kidney to
a free thiol compound, which then reacts chemically with urotoxic metabolites resulting in their
detoxification. Vigorous hydration is also required with a minimum of 2 L of oral or IV
hydration daily. Administer as a slow IV infusion over a period of at least 30 minutes.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is dose-limiting.
Platelets are relatively spared. Granulocyte nadirs are commonly reached at 10 to 14 days,
and recovery is seen by day 21. Thrombocytopenia may be seen with higher doses.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common without
standard antiemetics.
3. Mucocutaneous effects. Alopecia is common; mucositis is rarely seen at standard doses;
dermatitis is rare.
4. Hemorrhagic cystitis. Common and dose-limiting unless a uroprotective agent such as
mesna is used. With mesna, the incidence of hemorrhagic cystitis is 5% to 10%, and gross
hematuria is uncommon. Increasing the duration of mesna may alleviate the problem during
subsequent cycles.
5. Miscellaneous effects
a. CNS toxicity (somnolence, confusion, depressive psychosis, hallucinations,
disorientation, and uncommonly seizures, cranial nerve dysfunction, or coma) is
occasional with doses in lower range, more common with larger doses.
b. Infertility is common in men and women, as with other alkylating agents.
c. Renal impairment is occasional to common. Fanconi syndrome dependent on dose. May
be severe acidosis.
d. Liver dysfunction is uncommon.
e. Phlebitis is uncommon.
f. Fever is rare.
g. Peripheral neuropathy with high-dose therapy is uncommon.
IMATINIB MESYLATE
Other names. Gleevec, STI-571 (signal transduction inhibitor 571).
Mechanism of action. Inhibitor of the constitutively activated Bcr-Abl tyrosine kinase that is
created as a consequence of the (9;22) chromosomal translocation and is required for the
transforming function and excess proliferation seen in CML. It also inhibits the RTKs for
platelet-derived growth factor (PDGF), stem cell factor, and c-KIT, the latter of which is
activated in gastrointestinal stromal tumors (GISTs).
Primary indications
1. CML in chronic phase, accelerated or blast phase of the disease.
2. ALL, Philadelphia chromosome positive (Ph+).
3. GIST that is KIT+ (CD117), adjuvant and metastatic disease.
4. MDS or myeloproliferative diseases (MPD) with PDGF receptor gene rearrangements
5. Aggressive systemic mastocytosis (ASM) without D816V c-KIT mutation or with cKIT
mutation status unknown.
6. Hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) with the
FIP1L1-PDGFRα fusion kinase (CHIC2 deletion) (and also if fusion kinase negative or
unknown.)
7. Dermatofibrosarcoma protuberans (DFSP).
Usual dosage and schedule
1. 400 mg PO daily in the chronic phase of CML; MDS or MPD; or GISTs. Reduce to 300
mg/day with severe liver impairment or moderate renal impairment.
2. 600 mg PO daily in the accelerated phase or blast crisis of CML or Ph+ ALL.
3. 100 to 400 mg PO daily in ASM, HES, or CEL.
4. 800 mg PO daily in DFSP.
Special precautions
Use caution when giving to patients with cardiac disease, who have an increased likelihood of
developing severe congestive heart failure, edema, and severe fluid retention. Risk particularly
high in patients with high eosinophil counts who may develop cardiogenic shock. GI
perforations have been reported, as have bullous dermatologic reactions. Patients who require
anticoagulation should not receive warfarin. Imatinib is an inhibitor of and primarily
metabolized by CYP3A4.
Toxicity
1. Myelosuppression and other hematologic effects. Moderate neutropenia and
thrombocytopenia are common in all phases, but severe neutropenia or thrombocytopenia is
uncommon unless patients are in the accelerated phase or blast crisis of CML.
2. Nausea, vomiting and other GI effects. Nausea, vomiting, abdominal pain, and diarrhea
are common, but it is uncommon that they are severe.
3. Mucocutaneous effects. Skin rash and nasopharyngitis are common; pruritis and petechiae
 are occasional. Erythema multiforme and Stevens–Johnson syndrome have been reported.
4. Miscellaneous effects
a. Fluid retention and edema are common. Pleural effusion and ascites are occasional.
b. Musculoskeletal pain or cramps, arthralgia, headache, fever, and fatigue are common,
but it is uncommon that they are severe or life-threatening.
c. Dyspnea and cough are occasional.
d. Hepatic. Elevated liver function tests are occasional. Rare cases of severe
hepatotoxicity have been seen.
e. Rise in serum creatinine and hypokalemia are occasional but rarely severe.
f. Congestive heart failure is uncommon, but may lead to pulmonary edema and rarely
pericardial effusion. It may be related to imatinib inhibition of Abl, which in turn may
be related to mitochondrial function in the heart.
g. Monitor TSH levels during imatinib treatment in patients who have had thyroidectomy
and are on levothyroxine.

INTERFERON ALPHA
Other names. Roferon-A (interferon α2a, recombinant alpha-A interferon), Intron A (interferon
α2b, recombinant alpha-2 interferon), Sylatron (peginterferon α2b).
Mechanism of action. Believed to involve direct inhibition of tumor cell growth and
modulation of the immune response of the host, including activation of NK cells, modulation of
antibody production, and induction of major histocompatibility antigens.
Primary indications
1. Melanoma (both as adjuvant and metastatic disease therapy).
2. Renal cell carcinoma.
3. Multiple myeloma.
4. Kaposi sarcoma, HIV associated.
5. Non-Hodgkin lymphoma (low grade), mycosis fungoides.
6. Condyloma acuminatum (intralesional).
7. Chronic hepatitis B and C.
Usual dosage and schedule
1. 3 to 10 million IU IM or SQ in various schedules. Daily dosing is often used for several
weeks or months, followed by three times a week dosing.
2. As adjuvant therapy for high-risk melanoma, 20 million IU/m2 IV 5 consecutive days
weekly for 4 weeks, then 10 million IU/m2 SQ three times weekly for 48 weeks.
3. For HIV-related Kaposi sarcoma, 1 to 5 million IU SC daily, with dose modifications based
upon toxicity.
4. Investigationally, doses have been higher (up to 50 million IU/m2 per dose), usually IV at
doses higher than 10 million IU/m2.
5. Peginterferon α2b—6 μg/kg/week SC for 8 weeks followed by 3 μg/kg/week SC for up to 5
years as adjuvant therapy for node positive melanoma after surgical resection.
Special precautions
May cause or aggravate life-threatening or fatal neuropsychiatric, autoimmune, ischemic, and
infectious disorders. Patients with persistently severe or worsening signs or symptoms of these
conditions should be withdrawn from therapy.
Toxicity
1. Myelosuppression and other hematologic effects. Common but usually mild to moderate
and transient, even with continued therapy. Higher doses may be associated (25% of
patients receiving the recommended adjuvant therapy for melanoma) with granulocyte
counts of <750/μL and consequent increased risk for infection. Exacerbation of herpetic
eruptions and nonherpetic cold sores is uncommon. Coagulation disorders are uncommon.
2. Nausea and vomiting and other GI effects. Anorexia and nausea are common, occurring
in up to two-thirds of all patients, but vomiting is only occasional. Diarrhea or loose stools
are occasional to common.
3. Mucocutaneous effects. Rash, dryness, or inflammation of the oropharynx, dry skin or
pruritus, and partial alopecia is occasional to common. Urticaria is uncommon.
4. Miscellaneous effects
a. Flulike syndrome with fatigue, fever, chills, sweating, myalgias, arthralgias, and
headache is common to universal, with greater severity at higher doses. Tends to
diminish with continuing therapy and acetaminophen.
b. Neurologic. Occasional paresthesias or numbness. CNS toxicity is uncommon at lower
doses, but with higher doses there is an increased likelihood of problems, including
headache, dizziness, somnolence, anxiety, depression (including suicidal behavior),
confusion, hallucinations, cerebellar dysfunction, and emotional lability.
c. General. Fatigue, anorexia, fatigue, and weight loss are common with chronic
administration.
d. Cardiovascular. Mild hypotension is common but rarely symptomatic. Rarely to
uncommonly seen are hypertension, chest pain, arrhythmias, or other cardiovascular
disorders.
e. Respiratory. Dyspnea and cough are occasional at higher doses.
f. Neurologic. Leg cramps, insomnia, hot flashes, are uncommon. Visual problems,
including blurring, diplopia, dry eyes, nystagmus, and photophobia, are uncommon.
g. Metabolic. Elevated liver enzymes are common. Mild proteinuria, increase in serum
creatinine is occasional. Hypercalcemia is occasional. Hypothyroidism and
hyperthyroidism with or without antithyroid antibodies. Hypertriglyceridemia is rare.
h. Immunologic. Antibody development (binding and neutralizing) occurs more readily
with interferon α2a than with interferon α2b. The significance of this is not clear, though it
may be associated with the development of clinical resistance in some patients.
IPILIMUMAB
Other names. Yervoy, MDX-CTLA 4.
Mechanism of action. Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T
lymphocyte-associated antigen-4 (CTLA-4), a negative regulator of the immune system.
Primary indications
1. Melanoma, unresectable or metastatic.
2. Melanoma as adjuvant treatment of patients with >1 mm pathologic involvement of lymph
nodes that have been resected.
Usual dosage and schedule. 3 mg/kg IV over 90 minutes every 3 weeks × 4 doses.
Discontinue if unable to complete full treatment course within 16 weeks from administration of
first dose.
Special precautions. Ipilimumab can result in severe and fatal immune-mediated adverse
reactions due to T-cell activation and proliferation. These immune-mediated reactions may
involve any organ system; however, the most common severe immune-mediated adverse
reactions are enterocolitis, hepatitis, dermatitis (including TEN), neuropathy, and
endocrinopathy. The majority of these immune-mediated reactions initially manifest during
treatment but may occur weeks to months after discontinuation of ipilimumab.
Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy
for severe immune-mediated reactions. Assess patients for signs and symptoms of
enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests and thyroid function tests at baseline and before each dose.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and lymphopenia
are common, but only occasionally grade 3 or more. Venous thrombosis is uncommon.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but usually not
severe. Diarrhea is also common and occasionally severe (grade 3) and may be associated
with colitis.
3. Mucocutaneous effects. Pruritis is common (>40%), as is skin rash. TEN—rare.
4. Immunologic effects and infusion reactions. Many of nonhematologic effects, particularly
skin and GI, but also hepatic, neurologic, ocular (uveitis), endocrine, and other organ
system reactions may be immunologic in etiology and require emergent treatment with
corticosteroids.
5. Miscellaneous effects
a. Fatigue is common and occasionally severe.
b. Increased transaminases are common and occasionally (8%) grade 3 to 4. Significant
rise in bilirubin may also be seen as well as pancreatitis.
c. Endocrine: Adrenal insufficiency, hypothyroidism, and hypopituitarism are rare to
uncommon, but may require emergent therapy.
 d. Dyspnea is common.
e. Pain is common.
f. Confusion is occasional.

IRINOTECAN
Other names. Camptosar, CPT-11, Onivyde (liposome formation).
Mechanism of action. Irinotecan, a semisynthetic water soluble derivative of camptothecin, is
a prodrug for the lipophilic metabolite SN-38, a potent inhibitor of topoisomerase I, an enzyme
essential for effective replication and transcription. It binds to the topoisomerase I—DNA
cleavable complex, preventing re-ligation after cleavage by topoisomerase I. The liposome
form is irinotecan encapsulated in a lipid bilayer.
Primary indications
1. Carcinoma of the colon or rectum, esophagus, or stomach.
2. Carcinoma of the lung.
3. Glioblastoma multiforme.
4. Pancreatic adenocarcinoma.
Usual dosage and schedule
1. 80 to 125 mg/m2 IV over 90 minutes weekly for 4 weeks followed by a 2-week rest to
complete one cycle when used either as a single agent or in combination with fluorouracil
and leucovorin.
2. 180 mg/m2 IV over 90 minutes every 2 weeks when used with leucovorin (over 2 hours)
plus bolus fluorouracil followed by a 22-hour infusion of fluorouracil.
3. The dose of the liposome injection is 70 mg/m2 IV infusion over 90 minutes every 2 weeks,
and in those who are homozygous for the UGT1A1*28 allele, 50 mg/m2 IV infusion over 90
minutes every 2 weeks. It is to be given in combination with fluorouracil and leucovorin.
(Pancreatic adenocarcinoma.)
In patients being concurrently treated with enzyme-inducing antiepileptic drugs (EIAEDS),
doses must be increased approximately fourfold.
For severe or worse diarrhea (≥7 stools over pretreatment), doses should be held. When
the diarrhea has improved (≤7 stools over pretreatment), treatment may be restarted with doses
modified downward by 25 to 30 mg/m2 during the current and subsequent cycles if there was
an increase in stools of 7/day to 9/day, and by 50 to 60 mg/m2 if there was an increase in stools
of 10 or more. Doses are also held during treatment and reduced in the same and subsequent
cycles for severe neutropenia (absolute neutrophil count [ANC] <1,000).
Special precautions
1. Both early and late diarrhea may occur. That which occurs within 24 hours (a cholinergic
effect) should be treated with atropine, 0.25 to 1 mg IV. Late diarrhea should be treated
promptly with loperamide (up to 2 mg every 2 hours until the patient is diarrhea-free for 12
 hours) and prompt fluid and electrolyte replacement as indicated, if the diarrhea becomes
severe (increase of 7 or more stools per day) or there is dehydration or postural
hypotension. Consideration should be given to antibiotic therapy, such as with an oral
fluoroquinolone, particularly if the patient is neutropenic.
2. A vascular syndrome characterized by sudden unexpected thromboembolic events has also
been described.
3. Dose must be reduced in patients who are homozygous for the UGT1A1*28 allele, a
variation of a uridine diphosphate glucuronosyltransferase gene and its corresponding
enzyme (UGT1A1), which is responsible for glucuronidation of bilirubin and involved in
deactivation of irinotecan’s toxic active metabolite SN-38. Testing may be done by the
Invader UGT1A1 Molecular Assay (Third Wave Technologies).
4. Severe and life-threatening neutropenia occurred in 20% of patients receiving the liposomal
formation. Life-threatening neutropenic fever or sepsis occurred in 3% of cases.
5. Cases of interstitial lung disease were described with the liposomal formation.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia common and often severe,
particularly in combination therapy; anemia and thrombocytopenia are common, but
uncommonly severe, unless homozygous for UGT1A1*28.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common and are
occasionally severe. Early diarrhea is common, but is not usually severe. Late diarrhea is
common (85%) and is occasionally severe (15%) to life-threatening (5% to 10%). Severe
diarrhea may be more common if homozygous for UGT1A1*28. Abdominal cramping is
common, occasionally severe. Anorexia is common. Constipation and dyspepsia are
occasional. Ileus, colitis, or toxic megacolon are seen rarely.
3. Mucocutaneous effects. Alopecia and mucositis are common. Rash and sweating occur
occasionally.
4. Miscellaneous effects
a. Fever is common, rarely severe.
b. Headache, back pain, chills, and edema are occasional.
c. Grade 1 to 2 increases in liver function tests are common; it is uncommon for liver
function abnormalities to be severe, except in patients with known liver metastasis.
d. Dyspnea, cough, or rhinitis is occasional to common, but usually not severe.
e. Insomnia or dizziness is occasional.
f. Flushing is occasional.
g. Anaphylactic reactions are rare.

IXABEPILONE
Other name. Ixempra.
Mechanism of action. Ixabepilone is an analog of epothilone B that binds to β-tubulin subunits
on microtubules, leading to suppression of microtubule dynamics, blocks the cell in mitosis,
leading to cell death.
Primary indications
1. Carcinoma of the breast, usually after failure with anthracyclines and taxanes. Often given
in combination with capecitabine.
Usual dosage and schedule. 40 mg/m2 IV over 3 hours every 3 weeks. All patients should be
pretreated with both an H1 and an H2 histamine receptor antagonist.
Special precautions. Patients with a history of hypersensitivity reactions to ixabepilone or
other agents containing Cremophor must be pretreated with dexamethasone. If the reactions are
severe, do not treat. Coadministration with potent inhibitors of CYP3A4 such as ketoconazole
increases ixabepilone AUC, and dose reduction should be considered. Strong inducers of
CYP3A4, such as dexamethasone or phenytoin, may decrease ixabepilone concentrations. Do
not give in combination with capecitabine in patients with AST or ALT > 2.5 ULN or bilirubin
> 1 × ULN. Dose reductions required in patients with moderate hepatic impairment (AST or
ALT > 2.5 ULN or bilirubin > 1.5 ULN).
Toxicity
1. Myelosuppression and other hematologic effects. Severe (grade 3 to 4) neutropenia is
common. Severe anemia and thrombocytopenia are only occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea are
common, but it is uncommon that they are severe. Constipation and abdominal pain are
occasional, but rarely severe.
3. Mucocutaneous effects. Mucositis is common, but it is uncommon that it is severe.
Alopecia is common. Skin rash, nail disorders, palmar-plantar erythrodysesthesia, and
pruritis are occasional. Hyperpigmentation and skin exfoliation are uncommon.
4. Immunologic effects and infusion reactions. 1% of patients may have hypersensitivity
reactions.
5. Miscellaneous effects
a. Neurologic. Peripheral neuropathy is common and cumulative and occasionally severe
(grade 3 to 4). It is the most frequent toxicity responsible for drug discontinuation.
Headache, dizziness, insomnia, and altered taste are occasional.
b. Musculoskeletal. Myalgia and arthralgia are common.
c. Fatigue and asthenia are common. Edema and fever are occasional.
d. Cardiorespiratory. Use of ixabepilone in combination with capecitabine may increase
cardiac adverse reactions such as myocardial ischemia or ventricular dysfunction (1%
to 2%). Cough and dyspnea are occasional.

IXAZOMIB
Other name. Ninlaro.
Mechanism of action. Reversible PI. It preferentially binds and inhibits the chymotrypsin-like
activity of the β5 subunit of the 20S proteasome.
Primary indications. In combination with lenalidomide and dexamethasone for the treatment of
patients with multiple myeloma who have received at least one prior therapy.
Usual dosage and schedule. 4 mg orally on days 1, 8, 15, of a 28-day cycle, at least 1 hour
before or 2 hours after a meal. A missed dose should not be taken within 72 hours of the next
scheduled dose and a double dose should not be taken to make up for the missed dose. Starting
dose should be reduced to 3 mg in patients with moderate-to-severe hepatic impairment as
well as in those with severe renal impairment and end stage renal disease (ESRD) requiring
dialysis.
Special precautions
1. Concomitant use with strong CYP3A inducers should be avoided.
2. Ixazomib can cause fetal harm if administered to a pregnant woman.
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia and neutropenia are
common and can be severe in up to 26% of cases.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe.
Nausea, vomiting, and constipation are common, but uncommonly severe.
3. Mucocutaneous effects. Macular and maculopapular rash is common, but mostly mild.
4. Immunologic effects and infusion reactions. Upper respiratory tract infections occurred in
19% of patients and were rarely severe.
5. Miscellaneous effects
a. Cardiovascular. Peripheral edema is common and mostly grade 1 or 2.
b. Neurologic. Peripheral neuropathy, mainly sensory, is common but uncommonly severe.
c. Musculoskeletal and connective tissue. Back pain is common, but rarely severe.
d. Ophthalmic. Blurry vision, dry eyes, and conjunctivitis are occasional, but uncommonly
severe.
e. Other. The following serious adverse reactions have each been reported at a frequency
of <1%: acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens–Johnson
syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor
lysis syndrome, and thrombotic thrombocytopenic purpura.

LAPATINIB
Other name. Tykerb.
Mechanism of action. Lapatinib is a dual tyrosine kinase inhibitor with specificity for EGFR
and human epidermal receptor type 2 (HER2).
Primary indications. Advanced or metastatic carcinoma of breast that overexpresses the
HER2 receptor in combination with:
■ Capecitabine in women who have received prior therapy including an anthracycline, a
taxane, and trastuzumab.
■ Letrozole in postmenopausal women with receptor-positive metastatic breast cancer.
■ Trastuzumab in women who have progressed on this drug (may be effective because of
different mechanism of action on HER2).
Usual dosage and schedule. 1,250 mg PO daily with capecitabine. 1,500 mg PO daily with
letrozole.
Special precautions. Confirm left ventricular ejection fraction before starting therapy. Monitor
liver function tests before and every 4 to 6 weeks during therapy. Reduce dose for severe
hepatic impairment (Child-Pugh class C). Discontinue therapy for severe pulmonary symptoms.
Avoid strong CYP3A4 inhibitors, which will increase plasma concentrations of lapatinib.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is not an effect of
lapatinib. May potentiate warfarin and cause unexpected rise in INR.
2. Nausea and vomiting and other GI effects. Nausea and diarrhea are common; diarrhea
may be severe; vomiting and anorexia are occasional.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia (with capecitabine) and rash
(with letrozole) are common. Dry skin, alopecia, pruritis, nail disorder are occasional.
Epistaxis is occasional.
4. Miscellaneous effects
a. Left ventricular ejection fraction decrease is uncommon and rarely severe. Prolongation
of QT interval is uncommon.
b. Interstitial lung disease is rare to uncommon.
c. Asthenia, fatigue, and headache are occasional to common.
d. Hepatic: Commonly associated with transaminase elevations and occasionally with
increased bilirubin, but severe elevations (grade 3 to 4) are uncommon.

LENALIDOMIDE
Other name. Revlimid.
Mechanism of action. Multiple potential mechanisms, including immunomodulatory and
antiangiogenic effects. Precise mechanism not delineated.
Primary malignancy indications
1. MDS, low or intermediate-1 risk, associated with deletion of 5q31 (del 5q). Also effective
in some patients without 5q deletion.
2. Multiple myeloma.
3. Mantle cell lymphoma in patients whose disease has relapsed or progressed after two prior
therapies, one of which included bortezomib.
Usual dosage and schedule
MDS: 10 mg PO daily, with dosing interruptions and subsequent dose reduction to 5 mg daily
as determined by cytopenias or other toxicity.
Multiple myeloma:
1. 25 mg PO daily for 21 of 28 days. Renal insufficiency is associated with decreased
clearance and need for reduced starting doses.
2. 10 to 15 mg PO daily as maintenance, such as after autologous stem cell transplant.
Special precautions. Severe and life-threatening birth defects, primarily phocomelia, may be
caused by this analog of thalidomide, a known human teratogen. For this reason, special
precautions must be taken to assure that female patients are not pregnant when the drug is
started, and that both female and male patients practice strict birth control measures.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia and thrombocytopenia are
common and dose limiting. Febrile neutropenia is uncommon. Anemia is occasional, and
may be autoimmune in nature (uncommon). Hypercoagulability with thromboembolic
events, including pulmonary emboli (2% to 3%), have been seen in patients treated with
lenalidomide combination therapy—uncommon to occasional. Relative benefit of
prophylactic anticoagulation or antiplatelet therapy uncertain, but some form of prophylaxis
generally recommended, particularly in patients with myeloma or others receiving
concurrent corticosteroids.
2. Nausea, vomiting, and other GI effects. Diarrhea is common; constipation is common, but
less often than diarrhea. Nausea is common, but vomiting only occasional. Abdominal pain
is occasional.
3. Mucocutaneous effects. Macular rash, dryness of the skin, increased sweating, and
pruritis are common. Urticaria is occasional.
4. Miscellaneous effects
a. Cough, nasopharyngitis, dyspnea, and bronchitis are occasional.
b. Myalgia, arthralgia, muscle cramps, or limb pain are occasional.
c. Fatigue and fever common, but rigors are uncommon.
d. Headache and dizziness are occasional. Peripheral neuropathy is uncommon (5%).
Insomnia and depression are occasional.
e. Hypothyroidism is occasional.
f. Palpitations, hypertension, chest pain, and peripheral edema are occasional.
g. Hypokalemia and hypomagnesemia are occasional.
h. Birth defects. (see Special Precautions above.)

LENVATINIB
Other name. Lenvima.
Mechanism of action. RTK inhibitor that inhibits the kinase activities of VEGF receptors
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs
that have been implicated in pathogenic angiogenesis and tumor growth including fibroblast
growth factor (FGF) receptors FGFR1, 2, 3, and 4; and the platelet-derived growth factor
receptor alpha (PDGFRα), KIT, and RET.
Primary indications. Locally recurrent or metastatic, progressive, radioactive iodine-
refractory differentiated thyroid cancer (DTC).
Usual dosage and schedule
1. 24 mg PO taken once daily with or without food at the same time each day. If a dose is
missed and cannot be taken within 12 hours, it is to be skipped.
2. 14 mg PO once daily in patients with severe renal impairment (creatinine clearance less
than 30 mL/minute) or severe hepatic impairment (Child-Pugh C).
Special precautions
1. Lenvatinib can cause fetal harm if administered to a pregnant woman. Also, women should
be advised to stop breast-feeding while on treatment since lenvatinib and its metabolites
are excreted in milk at concentrations higher than in maternal plasma, according to studies
in rats.
2. Fatal cases of hepatotoxicity, pulmonary emboli, and intracranial hemorrhage have been
reported.
Toxicity
1. Myelosuppression and other hematologic effects. Severe cases of thrombocytopenia are
uncommon. Hemorrhagic events, mostly epistaxis, are common but usually not severe, but
have been fatal.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe.
Stomatitis, nausea, vomiting, constipation, abdominal pain, oral pain, and dry mouth are
common but uncommonly severe. Dyspepsia is occasional, but rarely severe. Events of GI
perforation or fistula were reported in 2% of patients.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia is common, but uncommonly
severe. Alopecia and hyperkeratosis are occasional with all cases being mild (grade 1 and
2). Macular or maculopapular rash is common, but rarely severe.
4. Immunologic effects and infusion reactions. Dental, oral, and urinary tract infections are
occasional.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe.
b. Respiratory. Dysphonia and cough are common, but rarely severe. Epistaxis is
occasional.
c. Cardiovascular. Hypertension is common and can be severe in up to 44% of cases.
Good blood pressure control prior to and periodic monitoring during treatment is
recommended. Cardiac dysfunction, defined as decreased left or right ventricular
function, cardiac failure, or pulmonary edema, was reported in 7% of patients (2%
grade 3 or greater). Arterial thromboembolic events can occur in 5% of patients and be
 severe in 3% of cases. QT/QTc interval prolongation can occur in 9% of patients and
serial monitoring with electrocardiograms is recommended for patients known to have
congenital QT prolongation, risk factors for QT prolongation such as arrhythmias and
congestive heart failure, and/or taking medicines known to prolong the QT/QTc interval.
Peripheral edema is common but rarely severe. Hypotension is occasional.
d. Metabolic. Severe hypocalcemia is occasional and in most cases responds to
replacement therapy without dose interruptions or modifications. Decreased appetite
and weight loss are common and occasionally severe. Severe cases of hypokalemia
were reported in 4% of patients. Hypomagnesemia, hypoglycemia, hypercalcemia,
hypercholesterolemia, increased serum amylase, and hyperkalemia can also occur.
e. Hepatic. Hypoalbuminemia, increased transaminases are occasional. Increase in ALT
and AST that was grade 3 or greater is uncommon, but rarely acute and fatal hepatic
failure may occur.
f. Neurologic. Headache is common and uncommonly severe. Dysgeusia is common but
rarely severe and dizziness is occasional and rarely severe. Cases reversible posterior
leukoencephalopathy syndrome (RPLS) were rarely reported. Discontinuation until full
recovery is recommended.
g. Musculoskeletal and connective tissue. Arthralgia/myalgia are common, but
uncommonly severe.
h. Endocrine. Subclinical or clinical hypothyroidism was reported in 57% of patients.
Monthly monitoring of TSH levels is recommended.
i. Renal. Proteinuria is common and occasionally severe. Cases of renal failure were
occasionally reported but uncommonly severe, with the primary risk factor for such
events being dehydration/hypovolemia secondary to vomiting and/or diarrhea.
j. Psychiatric. Insomnia is occasional, but rarely severe.

LETROZOLE
Other name. Femara.
Mechanism of action. Decreases estrogen biosynthesis by selective, competitive inhibition of
the aromatase enzyme in peripheral tissues, thereby reducing the conversion of the adrenal
androgens testosterone and androstenedione to estradiol and estrone, respectively.
Primary indications
1. Carcinoma of the breast, advanced or metastatic, that is hormone receptor positive or
unknown in postmenopausal women as first-line treatment; or in hormone responsive
postmenopausal women with progression following antiestrogen therapy.
2. Carcinoma of the breast as adjuvant therapy in hormone receptor-positive postmenopausal
women.
Usual dosage and schedule. 2.5 mg PO daily.
Special precautions. Potential hazard to fetus if given during pregnancy. Because of the
potential fracture risk, calcium and vitamin D with or without bisphosphonates are often used.
Toxicity
1. Myelosuppression and other hematologic effects. No dose-related effect.
Thromboembolic events are uncommon to rare and less than with tamoxifen.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, diarrhea are
uncommon to occasional.
3. Mucocutaneous effects. Rash is uncommon.
4. Miscellaneous effects
a. Hot flushes are common and night sweats are occasional.
b. Musculoskeletal pain (arthralgia or bone) is occasional to common.
c. Weight increase is occasional.
d. Fatigue is occasional.
e. Acceleration of osteoporosis (occasional) and increase in fracture risk (uncommon).
f. Headache is uncommon.
g. Peripheral edema, weight gain is occasional (lower than with megestrol).
h. Dyspnea and cough are uncommon to occasional.
i. Hypercalcemia is rare.
j. Endometrial cancer is rare (0.2%) and less likely that with tamoxifen.

LOMUSTINE
Other names. CCNU, CeeNU.
Mechanism of action. Alkylation and carbamylation by lomustine metabolites interfere with
the synthesis and function of DNA, RNA, and proteins. Lomustine is lipid-soluble and easily
enters the brain.
Primary indication. Malignant brain tumors.
Usual dosage and schedule. 100 to 130 mg/m2 PO once every 6 to 8 weeks (lower dose used
for patients with compromised bone marrow function). Limit cumulative dose to 1,000 mg/m2
to limit pulmonary and renal toxicity.
Special precautions. Because of delayed myelosuppression (3 to 6 weeks), do not treat more
often than every 6 weeks. Await a return of normal platelet and granulocyte counts before
repeating therapy.
Toxicity
1. Myelosuppression and other hematologic effects. Universal and dose-limiting.
Leukopenia and thrombocytopenia are delayed 3 to 6 weeks after therapy begins and may
be cumulative with successive doses.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting may begin 3 to 6 hours after
 therapy and last up to 24 hours.
3. Mucocutaneous effects. Stomatitis and alopecia are rare.
4. Miscellaneous effects
a. Confusion, lethargy, and ataxia are rare.
b. Mild hepatotoxicity is infrequent.
c. Secondary neoplasia is possible.
d. Pulmonary fibrosis is uncommon at doses of less than 1,000 mg/m2.
e. Renal toxicity is uncommon at doses of less than 1,000 mg/m2.

MECHLORETHAMINE
Other names. Nitrogen mustard, HN2, Mustargen.
Mechanism of action. Mechlorethamine is a prototype alkylating agent. Its action involves
transfer of the alkyl group to amino, carboxyl, hydroxyl, imidazole, phosphate, and sulfhydryl
groups within the cell, altering structure and function of DNA (primarily), RNA, and proteins.
Primary indications
1. Hodgkin lymphoma.
2. Malignant pleural and, less commonly, peritoneal, or pericardial effusions.
3. Cutaneous T-cell lymphomas (topically).
Usual dosage and schedule
1. 6 mg/m2 IV on days 1 and 8 every 4 weeks (in MOPP regimen for Hodgkin lymphoma).
2. 8 to 16 mg/m2 by intracavitary injection.
3. 10 mg in 60 mL of tap water applied to entire body surface (avoid eyes).
Special precautions
1. Administer over several minutes into the sidearm of a running IV infusion, taking care to
avoid extravasation.
2. Because mechlorethamine is a potent vesicant, extreme care must be exercised while
preparing and administering the drug. Gloves and eye glasses are recommended to protect
the preparer. If accidental eye contact should occur, institute copious irrigation with normal
saline and follow by prompt ophthalmologic consultation. If accidental skin contact occurs,
irrigate the affected part immediately with water for at least 15 minutes and follow by 2.6%
sodium thiosulfate solution (1/6 M).
3. Mechlorethamine should be used soon after preparation (15 to 30 minutes) as it
decomposes on standing. It must not be mixed in the same syringe with any other drug.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting, with the nadir at about 1
week and recovery by 3 weeks.
2. Nausea, vomiting, and other GI effects. Universal. They usually begin within the first 3
 hours and last 4 to 8 hours.
3. Mucocutaneous effects. Severe painful inflammation and necrosis are likely if
extravasation occurs. May be ameliorated with sodium thiosulfate. Maculopapular rash is
uncommon.
4. Miscellaneous effects
a. Phlebitis, thrombosis, or both of the veins used for the injection are common.
b. Amenorrhea and azoospermia are common.
c. Hyperuricemia with rapid tumor destruction.
d. Weakness, sleepiness, and headache are uncommon.
e. Severe allergic reactions, including anaphylaxis are rare.
f. Secondary neoplasms, including myelodysplasia, acute leukemia, and carcinomas are
possible.

MELPHALAN
Other names. Phenylalanine mustard, L-sarcolysin, L-PAM, Alkeran.
Mechanism of action. Alkylating agent with primary effect on DNA. Amino acid–type
structure may result in cellular transport that is different from other alkylating agents.
Primary indications
1. Multiple myeloma.
2. Stem cell preparative regimens.
Usual dosage and schedule
1. 8 mg/m2 PO on days 1 to 4 every 4 weeks or
2. 10 mg/m2 PO on days 1 to 4 every 6 weeks or
3. 3 to 4 mg/m2 PO daily for 2 to 3 weeks, then 1 to 2 mg/m2 PO daily for maintenance.
4. High-dose regimens of 140 to 200 mg/m2 IV have been used, followed by stem cell rescue.
Special precautions
1. Myelosuppression may be delayed and prolonged to 4 to 6 weeks. Reduce IV dose by 50%
for creatinine >1.5 × normal.
2. Use in early myeloma may preclude harvest of sufficient numbers of peripheral stem cells
for autologous transplantation.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-limiting; nadir at days 14 to 21.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are uncommon at
standard doses, but common with high-dose regimens.
3. Mucocutaneous effects. Alopecia, dermatitis, and stomatitis are uncommon at standard
doses; alopecia and mucositis are common with high-dose regimens.
4. Miscellaneous effects
 a. AML and MDS are rare, but well documented.
b. Pulmonary fibrosis is rare.

MERCAPTOPURINE
Other names. 6-Mercaptopurine, 6-MP, Purinethol.
Mechanism of action. A purine antimetabolite that, when converted to the nucleotide, inhibits
the formation of nucleotides necessary for DNA and RNA synthesis.
Primary indication. ALL
Usual dosage and schedule
1. 100 mg/m2 PO daily if used alone.
2. 50 to 90 mg/m2 PO daily if used with methotrexate or other cytotoxic drugs.
Special precautions
1. Decrease dose by 75% when used concurrently with allopurinol.
2. Increase interval between doses or reduce dose in patients with renal failure.
Toxicity
1. Myelosuppression and other hematologic effects. Common but mild at recommended
doses.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are uncommon. Diarrhea is
rare.
3. Mucocutaneous effects. Stomatitis may be seen with very large doses. Dry, scaling rash is
uncommon.
4. Miscellaneous effects
a. Intrahepatic cholestasis and mild focal centrilobular necrosis with jaundice are
uncommon.
b. Hyperuricemia with rapid leukemia cell lysis is common.
c. Fever is uncommon.

MESNA
Other name. Mesnex.
Mechanism of action. Mesna disulfide is reduced in the kidney to a free thiol compound,
which then reacts chemically with urotoxic metabolites of ifosfamide or cyclophosphamide
resulting in their detoxification.
Primary indication. Prophylaxis for ifosfamide (or high-dose cyclophosphamide)-induced
hemorrhagic cystitis.
Usual dosage and schedule. Mesna dose is at least 20% of the ifosfamide dose (on a weight
[mg] basis), administered just prior to (or mixed with) the ifosfamide dose and again at 4 and 8
hours after the ifosfamide to detoxify the urinary metabolites that cause the hemorrhagic
cystitis. Higher doses of ifosfamide may require higher doses and longer durations of mesna.
Special precautions. Contraindicated if patient is sensitive to thiol compounds. Does not
prevent or ameliorate any adverse effects of ifosfamide or cyclophosphamide other than
hemorrhagic cystitis. Neither mesna nor its only metabolite, mesna disulfide, affects
ifosfamide, cyclophosphamide, or their antineoplastic metabolites.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are occasional.
Nausea and vomiting more commonly from ifosfamide.
3. Mucocutaneous effects. Bad taste in the mouth is common.
4. Miscellaneous effects
a. Headache, fatigue, limb pain are occasional.
b. Hypotension or allergic reactions are uncommon to rare.
c. Gives false-positive test for urinary ketones.

METHOTREXATE
Other names. Amethopterin, MTX, Mexate, Folex, Trexall.
Mechanism of action. Inhibition of dihydrofolate reductase, which results in a block of the
reduction of dihydrofolate to tetrahydrofolate. This blockage in turn inhibits the formation of
thymidylate and purines, and arrests DNA (predominantly), RNA, and protein synthesis.
Primary indications
1. Breast, head and neck, gastric, and gestational trophoblastic carcinomas.
2. Osteosarcomas (high-dose methotrexate).
3. ALL.
4. Meningeal leukemia or carcinomatosis.
5. Non-Hodgkin lymphoma.
Usual dosage and schedule
1. Gestational trophoblastic carcinoma. 15 to 30 mg PO or IM on days 1 to 5 every 2 weeks.
2. Other carcinomas. 40 to 80 mg/m2 IV or PO two to four times monthly with a 7- to 14-day
interval between doses.
3. ALL. 15 to 20 mg/m2 PO or IV weekly (together with mercaptopurine).
4. Osteosarcoma. Up to 12 g/m2 with leucovorin rescue (high-dose methotrexate). This usage
requires on-site monitoring of methotrexate levels and a high degree of expertise to
administer safely.
5. Intrathecally. 12 mg/m2 (not >20 mg) twice weekly.
Special precautions
1. High-dose methotrexate (>80 mg/m2) should be administered only by individuals
experienced in its use and at institutions where serum methotrexate levels can be readily
measured.
2. Intrathecal methotrexate must be mixed in buffered physiologic solution containing no
preservative.
3. Avoid, aspirin, sulfonamides, tetracycline, phenytoin, and other protein-bound drugs that
may displace methotrexate and cause an increase in free drug.
4. Oral anticoagulants, for example, warfarin, may be potentiated by methotrexate; therefore,
prothrombin times should be followed carefully.
5. Oral antibiotics may decrease methotrexate absorption; penicillin and NSAIDs decrease
clearance of methotrexate.
6. Concomitant use of proton pump inhibitors with high-dose methotrexate may elevate and
prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, leading to
methotrexate toxicities.
7. Monitor use with theophylline.
8. In patients with renal insufficiency it may be necessary to markedly reduce the dose or
discontinue methotrexate therapy.
9. Do not give if patient has a significant effusion, because of “reservoir” effect.
Toxicity
1. Myelosuppression and other hematologic effects. Occurs commonly, with nadir at 6 to 10
days after a single IV dose. Recovery is rapid.
2. Nausea, vomiting, and other GI effects. Occasional at standard doses.
3. Mucocutaneous effects
a. Mild stomatitis is common and a sign that a maximum tolerated dose has been reached.
Higher doses may result in confluent or hemorrhagic stomal ulcers and bloody diarrhea.
This requires prompt leucovorin therapy to limit duration and severity.
b. Erythematous rashes, urticaria, and skin pigment changes are uncommon.
c. Mild alopecia is frequent.
1. Miscellaneous effects
a. Acute hepatocellular injury is uncommon at standard doses. Hepatic fibrosis is
uncommon but seen at low chronic doses.
b. Pneumonitis is rare. Polyserositis is rare.
c. Renal tubular necrosis is rare at standard doses.
d. Convulsions and a Guillain-Barré–like syndrome following intrathecal therapy are
uncommon.

MITOMYCIN
Other names. Mitomycin C, Mutamycin.
Mechanism of action. Alkylation and cross-linking by mitomycin metabolites interfere with
structure and function of DNA.
Primary indications. Bladder (intravesical), esophagus, stomach, anal, and pancreas
carcinomas.
Usual dosage and schedule
1. 20 mg/m2 IV on day 1 every 4 to 6 weeks or
2. 2 mg/m2 IV on days 1 to 5 and 8 to 12 every 4 to 6 weeks.
3. 10 mg/m2 IV on day 1 every 8 weeks in combination with fluorouracil and doxorubicin for
stomach and pancreatic carcinomas.
4. 30 to 40 mg instilled into the bladder weekly for 4 to 8 weeks, then monthly for 6 months.
Special precautions. Administer as slow push or rapid infusion through the sidearm of a
rapidly running IV infusion, taking care to avoid extravasation. Pulmonary, renal, and
hematologic toxicity (microangiopathic anemia and thrombocytopenia) may result from
endothelial cell damage.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is serious,
cumulative, and dose-limiting. Nadir is reached usually by 4 weeks but may be delayed.
Recovery is often prolonged over many weeks, and occasionally the cytopenia never
disappears. Hemolytic-uremic syndrome—rare, but when it occurs, may be poorly
responsive to plasmapheresis and other therapies.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common at higher
doses, but severity is usually mild to moderate.
3. Mucocutaneous effects. Stomatitis and alopecia are common.
4. Miscellaneous effects
a. Renal toxicity is uncommon. Hemolytic-uremic syndrome is rare.
b. Pulmonary toxicity is uncommon, but may be severe.
c. Fever is uncommon.
d. Cellulitis at injection site if extravasation occurs is common.
e. Secondary neoplasia is possible.

MITOTANE
Other names. o, p’-DDD, Lysodren.
Mechanism of action. Suppresses adrenal steroid production, modifies peripheral steroid
metabolism, and is cytotoxic to adrenal cortical cells.
Primary indication. Adrenocortical carcinoma.
Usual dosage and schedule. Begin with 2 to 6 g PO daily in three or four divided doses and
build to a maximum tolerated daily dose that is usually 8 to 10 g, although it may range from 2
to 16 g. Glucocorticoid and mineralocorticoid replacements during mitotane therapy are
necessary to prevent hypoadrenalism. Cortisone acetate (25 mg PO in the a.m. and 12.5 mg PO
in the p.m.) and fludrocortisone acetate (0.1 mg PO in the a.m.) are recommended.
Special precautions. Patients who experience severe trauma, infection, or shock should be
treated with supplemental corticosteroids. Because of the effect of mitotane on peripheral
steroid metabolism, larger than usual replacement doses may be necessary.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and anorexia are common and
may be dose-limiting. Diarrhea is occasional.
3. Mucocutaneous effects. Skin rash occurs occasionally.
4. CNS effects. Lethargy, sedation, vertigo, or dizziness in up to 40% of patients; may be
dose-limiting.
5. Miscellaneous effects. Albuminuria, hemorrhagic cystitis, hypertension, orthostatic
hypotension, and visual disturbances are uncommon.

MITOXANTRONE
Other names. Novantrone, dihydroxyanthracenedione, DHAD, DHAQ.
Mechanism of action. DNA strand breakage mediated by anthracenedione effects on
topoisomerase II.
Primary indications
1. AML.
2. Carcinoma of the breast or ovary.
3. Non-Hodgkin and Hodgkin lymphoma.
Usual dosage and schedule
1. 12 to 14 mg/m2 IV as a 5- to 30-minute infusion once every 3 weeks for solid tumors.
2. 12 mg/m2 IV as a 5- to 30-minute infusion daily for 3 days for acute nonlymphocytic
leukemia.
Special precautions. Rarely causes extravasation injury if infiltrated. Cardiotoxicity probably
less than with doxorubicin; but prior anthracycline, chest irradiation, or underlying cardiac
disease increases the risk.
Toxicity
1. Myelosuppression and other hematologic effects. Universal.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common, but less
frequent and less severe than with doxorubicin. Diarrhea is uncommon.
3. Mucocutaneous effects. Alopecia is common, but its frequency and severity are less than
with doxorubicin. Mucositis is occasional.
4. Miscellaneous effects
a. Cardiac toxicity. Probably less than with doxorubicin; there is no clear maximum dose,
though the risk appears to increase at 125 mg/m2 cumulative dose.
b. Local erythema and swelling with transient blue discoloration if extravasated, but rarely
leads to severe skin damage.
c. Green or blue discoloration of urine.
d. Phlebitis is uncommon.

NECITUMUMAB
Other name. Portrazza.
Mechanism of action. A recombinant human IgG1 monoclonal antibody that binds to the
human EGFR and blocks the binding of EGFR to its ligands.
Primary indications. In combination with gemcitabine and cisplatin, for first-line treatment of
patients with metastatic squamous NSCLC.
Usual dosage and schedule. 800 mg administered as an IV infusion over 60 minutes on days 1
and 8 of each 3-week cycle prior to gemcitabine (days 1 and 8) and cisplatin (day 1) infusion.
For patients who have experienced a previous grade 1 or 2 infusion-related reaction,
premedicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent
infusions. For patients who have experienced a second occurrence, premedicate for all
subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or
equivalent), and dexamethasone (or equivalent) prior to each infusion.
Special precautions
1. Cardiopulmonary arrest and sudden death was reported in 3% of patients. Severe
electrolytes abnormalities can increase the risk. Close monitoring of serum electrolytes
including magnesium, potassium, and calcium is critical prior to each infusion and
correction of electrolytes abnormalities, if abnormal, is recommended until improved to
grade 2 or less. Special attention needs to be directed toward patients with underlying
coronary artery disease and other cardiopulmonary risk factors.
2. Venous and/or arterial thrombotic events including deep venous thrombosis and pulmonary
emboli were occasionally reported. These are uncommonly severe but can be rarely fatal.
3. Necitumumab can cause fetal harm if administered to a pregnant woman.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported.
2. Nausea, vomiting, and other GI effects. Vomiting and diarrhea are common, but
uncommonly severe. Stomatitis is occasional and uncommonly severe.
3. Mucocutaneous effects. Rash and dermatitis acneiform are common and occasionally
severe. Dry skin and pruritus are occasionally, but rarely, severe. Withhold treatment for
grade 3 rash or acneiform rash until symptoms resolve to grade ≤2, then resume at reduced
 dose of 400 mg for at least one treatment cycle. If symptoms do not worsen, may increase
dose to 600 mg and 800 mg in subsequent cycles. Permanently discontinue therapy if grade
3 rash or acneiform rash does not resolve to grade ≤2 within 6 weeks, reactions worsen or
become intolerable at a dose of 400 mg, patient experiences grade 3 skin
induration/fibrosis or grade 4 dermatologic toxicity. Paronychia are occasional but rarely
severe.
4. Immunologic effects and infusion reactions. Infusion-related reactions are uncommon and
rarely severe.
5. Miscellaneous effects
a. Respiratory. Hemoptysis is occasional, but uncommonly severe.
b. Metabolic. Hypomagnesemia is common and commonly severe. Hypokalemia,
hypocalcemia, and hypophosphatemia are common and may be severe.
c. Musculoskeletal and connective tissue. Muscle spasms are uncommon.
d. Ophthalmic. Conjunctivitis is occasional, but rarely severe.

NELARABINE
Other name. Arranon.
Mechanism of action. Nelarabine is a prodrug of arabinofuranosylguanine (ara-G), a
cytotoxic analog of deoxyguanosine. When converted to triphosphorylated ara-G, it is
incorporated into DNA (preferentially into T cells), inducing fragmentation and apoptosis.
Primary indications
T-cell ALL and T-cell lymphoblastic lymphoma that have relapsed or are refractory to at least
two prior chemotherapy regimens.
Usual dosage and schedule
Adults—1,500 mg/m2 IV over 2 hours on days 1, 3, and 5, repeated every 21 days.
Children—650 mg/m2 IV over 1 hour daily for 5 consecutive days, repeated every 21 days.
Special precautions. Close monitoring for neurologic events is recommended, owing to the
possibility of severe neurologic complications of therapy. Prophylaxis against tumor lysis
syndrome recommended.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and
thrombocytopenia are common. Febrile neutropenia is occasional.
2. Nausea and vomiting and other GI effects. Nausea, vomiting, diarrhea, and constipation
are common, but usually low grade. Abdominal pain is occasional.
3. Mucocutaneous effects. Stomatitis is occasional.
4. Neurologic effects
a. Headache is occasional.
b. Somnolence and confusion are occasional.
 c. Peripheral neuropathy is occasional. May range from numbness and paresthesias to
motor weakness and paralysis.
d. Ataxia is occasional.
e. Insomnia is occasional.
f. Convulsions and coma are rare.
g. Leukoencephalopathy and demyelination and ascending peripheral neuropathy are rare.
5. Miscellaneous effects
a. Fatigue, weakness, and fever (occasionally with rigors) are common.
b. Cough, dyspnea, pleural effusion are common to occasional.
c. Abnormal liver function tests are occasional.
d. Hypokalemia, hypomagnesemia, hypocalcemia, increased creatinine are occasional.
e. Edema is occasional.
f. Sinus tachycardia is occasional.
g. Musculoskeletal pain is occasional.

NILOTINIB
Other names. Tasigna, AMNI07.
Mechanism of action. Selective inhibitor of the constitutively activated Bcr-Abl tyrosine
kinase that is created as a consequence of the (9;22) chromosomal translocation and is
required for the transforming function and excess proliferation seen in CML. In vitro, nilotinib
is active against many Bcr-Abl mutations associated with imatinib resistance.
Primary indications
1. CML (Philadelphia chromosome positive [Ph+])—in chronic, accelerated, or blastic phase
—in newly diagnosed patients and in those resistant or intolerant of imatinib.
2. Investigational
a. Ph+ ALL
b. GI stromal tumor
Usual dosage and schedule.
1. Newly diagnosed Ph+ CML-Chronic Phase: 300 mg orally twice daily.
2. Resistant or intolerant Ph+ CML-Chronic Phase and CML—Accelerated Phase: 400 mg
orally twice daily.
Lower doses recommended for hepatic impairment or for toxicity.
Special precautions. Do not use in patients with hypokalemia, hypomagnesemia, or long QT
syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be
avoided. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and
periodically thereafter. Do not give if QTc >480 minutes/second.
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia and neutropenia are
common. Anemia is occasional.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are occasional.
3. Mucocutaneous effects. Skin rash is common; alopecia, dry skin, and pruritis are
occasional.
4. Miscellaneous effects.
a. Abnormal liver function tests, including elevations in bilirubin (primarily unconjugated)
are occasional.
b. Increase in the corrected QT interval by 5 to 15 minutes/second has been seen and may
result in sudden death—rare.
c. Increase in lipase and amylase are uncommon.
d. Grade 3 or 4 hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and
hyponatremia are occasional to uncommon.
e. Arthralgia, myalgia, muscle spasms, and bone pain are occasional.
f. Fatigue and insomnia are common; fever and weakness are occasional.
g. Peripheral edema is occasional.
h. Cough and dyspnea are occasional.

NILUTAMIDE
Other name. Nilandron.
Mechanism of action. Competitive inhibitor of androgens at the cellular androgen receptor in
prostate cancer cells. Complements surgical castration.
Primary indications. Metastatic carcinoma of the prostate, in combination with surgical
castration or LHRH agonist.
Usual dosage and schedule. 300 mg PO once daily for 30 days, followed by 150 mg PO once
daily thereafter.
Special precautions. Should be restricted to patients with normal liver function test values.
Because interstitial pneumonitis may occur, a routine chest radiograph should be obtained
before therapy and any time that the patient reports new exertional dyspnea or worsening of
preexisting dyspnea. Inhibits activity of liver cytochrome P450 isoenzymes and may delay
elimination of drugs such as warfarin, phenytoin, and theophylline.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Nausea, constipation, and anorexia are
occasional to common. Vomiting is uncommon.
3. Mucocutaneous effects. Rash, dry skin, and sweating are uncommon.
4. Miscellaneous effects
a. Hepatitis is rare (1%). Increased liver function test values are uncommon.
 b. Interstitial pneumonitis with dyspnea is uncommon (2%). May be higher in patients with
Asian ancestry.
c. Inhibits activity of liver cytochrome P450 isoenzymes and may delay elimination of
drugs such as warfarin, phenytoin, and theophylline.
d. Hot flashes are common.
e. Impaired adaptation to dark is common (57%).
f. Cardiac and other lung disorders are uncommon.

NIVOLUMAB
Other name. Opdivo.
Mechanism of action. A fully human monoclonal IgG4 antibody that binds to the programmed
death-1 (PD-1) receptor on T cells and blocks its interaction with its ligands PD-L1 and PD-
L2, both of which are upregulated in several tumor types and responsible for immune response
inhibition.
Primary indications
1. Alone or in combination with ipilimumab in patients with unresectable or metastatic
melanoma with wild-type BRAF V600 mutation.
2. Unresectable or metastatic melanoma following progression on ipilimumab therapy or
BRAF inhibitors (in tumors that harbor the BRAF V600 mutations).
3. Metastatic NSCLC for patients who have had tumor progression during or after treatment
with platinum-based chemotherapy.
4. Metastatic renal cell carcinoma in patients who received prior antiangiogenic therapy.
Usual dosage and schedule
1. 1 mg/kg IV over 60 minutes followed by ipilimumab on the same day, every 3 weeks for
four doses. After four doses of the combination, give 3 mg/kg IV over 60 minutes every 2
weeks as a single agent until disease progression or unacceptable toxicity.
2. 3 mg/kg administered as an IV infusion over 60 minutes every 2 weeks until disease
progression or intolerable toxicity.
Special precautions. Nivolumab can cause fetal harm if administered to a pregnant woman.
Immune-related adverse events (irAEs) including colitis, pneumonitis, hepatitis, hypophysitis,
nephritis, thyroiditis, uveitis, optic neuritis, hemolytic anemia, pancreatitis, dermatitis, partial
seizures, myositis, and arthritis can occur and require close monitoring and occasionally
withholding treatment and steroid therapy (see below). Rare cases of autoimmune encephalitis
as well as TEN have been described.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported.
2. Nausea, vomiting, and other GI effects. Not reported.
3. Mucocutaneous effects. Rash and pruritus are common, but rarely severe. Exfoliative
 dermatitis, erythema multiforme, vitiligo, and psoriasis were reported in less than 10% of
cases.
4. Immunologic effects and infusion reactions. Upper respiratory tract infections are
occasional.
a. Immune-mediated pneumonitis, which is defined as requiring the use of corticosteroids
and no clear alternate etiology and can manifest with dyspnea, cough, or chest pain, has
been reported in 3% to 4% of patients. For grade 2 reactions, withholding therapy in
addition to administering systemic steroids (greater or equal to 40 mg of prednisone or
equivalent per day followed by a taper for at least a month) is indicated until
improvement to grade 1 or less. Permanent discontinuation is indicated for grade 3 or 4
reactions. Some cases can be fatal.
b. Immune-mediated colitis, which is defined as requiring the use of corticosteroids and no
clear alternate etiology and can present with abdominal pain, diarrhea, and/or
hematochezia, occurs in 2% to 3% of patients. For grade 2 and 3 reactions, withholding
therapy in addition to administering systemic steroids (greater or equal to 40 mg of
prednisone or equivalent per day followed by a taper for at least a month) is indicated
until improvement to grade 1 or less. Permanent discontinuation is indicated for grade 4
reactions.
c. Immune-mediated hepatitis, which is defined as requiring the use of corticosteroids and
no clear alternate etiology, was reported in about 1% of patients. For grade 2 or higher
reactions, treatment with systemic steroids is indicated. Dose interruption and
permanent discontinuation may be indicated for more severe reactions.
d. Immune-mediated nephritis including autoimmune nephritis and interstitial nephritis with
renal failure occurred in <1% of patients. Management of these reactions follows the
general rules for other irAEs.
e. Immune-mediated hyperthyroidism and hypothyroidism occurred in 3% and 8% of
patients, respectively. Dose interruption and treatment with systemic steroids are
indicated for grade 3 reactions. Permanent discontinuation is recommended for grade 4
reactions.
f. Immune-mediated diabetes mellitus possibly with ketoacidosis and anion gap as well as
hyperglycemia in up to 3% of patients.
5. Miscellaneous effects
a. Respiratory. Cough is common.
b. Cardiovascular. Ventricular arrhythmias were reported in less than 10% of cases.
Peripheral edema is occasional.
c. Metabolic. Hyponatremia is common. Hyperkalemia is occasional. Increased levels of
amylase and/or lipase can occur in less than 10% of cases.
d. Hepatic. Increased AST/ALT and alkaline phosphatase are common but mostly mild.
e. Neurologic. Immune-mediated peripheral and autonomic neuropathies can occur and
require dose interruption and possibly corticosteroids therapy, depending on the
severity. Cases of myasthenia gravis and Guillain-Barré syndrome were reported as
 well as cases of facial and abducens nerve paresis.
f. Ophthalmic. Iridocyclitis was reported in less than 10% of patients.

OBINUTUZUMAB
Other name. Gazyva.
Mechanism of action. Obinutuzumab is a humanized glycoengineered type II anti-CD20
monoclonal antibody. The CD20 antigen is expressed on the surface of pre B- and mature B-
lymphocytes; upon binding to CD20, obinutuzumab activates CDC, ADCC, and ADCP,
resulting in cell death.
Primary indications. CLL in combination with chlorambucil in previously untreated patients.
Usual dosage and schedule
To minimize infusion reactions, obinutuzumab is to be administered over six 28-day cycles as
an IV infusion according to the following schedule:
■ 100 mg on day 1 cycle 1
■ 900 mg on day 2 cycle 1
■ 1,000 mg on day 8 and day 15 of cycle 1
■ 1,000 mg on day 1 of cycles 2 to 6
Infuse cycle 1/day 1 over 4 hours. Cycle 1/day 2 may be started at 50 mg/hour; if
hypersensitivity or other infusion-related events do not occur, the rate can be increased by
50 mg/hour increments every 30 minutes to a maximum rate of 400 mg/hour. Cycle 1/days
8 and 15 may be administered initially at 100 mg/hour; if hypersensitivity or other
infusion-related events do not occur, the rate can be increased by 100 mg/hour increments
to a maximum rate of 400 mg/hour. For cycles 2 to 6, administer initially at 100 mg/hour; if
hypersensitivity or other infusion-related events do not occur, the rate can be increased by
100 mg/hour increments to a maximum rate of 400 mg/hour. Premedication with
acetaminophen, diphenhydramine, and IV glucocorticoid is recommended to reduce the
risk of infusion reactions.
Special precautions
1. An infusion-related set of symptoms occurs commonly during the first infusion and can
occur in subsequent infusions. These can include fever and chills, with or without true
rigors, nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of
tongue or throat swelling, rhinitis, vomiting, hypotension, flushing, and pain at disease sites.
Rarely, infusion-related events result in a fatal outcome. Hypersensitivity reactions
generally start within 30 to 120 minutes of starting the infusion but can occur up to 24 hours
after the infusion. Most will resolve with slowing or interruption of the infusion and with
supportive care, including IV saline, diphenhydramine, acetaminophen, and
glucocorticoids. Severe reactions will additionally require aggressive cardiorespiratory
support including oxygen, epinephrine, vasopressors, corticosteroids, and bronchodilators,
 and may preclude additional treatment with obinutuzumab. Premedication with
acetaminophen, diphenhydramine, and IV glucocorticoid is recommended to reduce the risk
of infusion reactions. Withholding antihypertensive medications 12 hours prior to, during
each infusion, and up to 1 hour after infusion until blood pressure is stable is recommended.
For patients at risk for hypertensive crisis, risk versus benefit of holding antihypertensive
medications should be considered.
2. Hepatitis B reactivation with related fulminant hepatitis, hepatic failure, and even death can
occur. Hepatitis B virus reactivation has been reported in patients with hepatitis B surface
antigen (HBsAg) positive and also in those with HBsAg negative but are hepatitis B core
antibody (anti-HBc) positive. Obtaining a hepatitis B panel is recommended and
consultation with physicians with expertise in managing hepatitis B may be warranted
regarding monitoring and consideration for antiviral therapy.
3. Progressive multifocal leukoencephalopathy has been observed and may be fatal.
Discontinuation of obinutuzumab and consideration for discontinuation or reduction of any
concomitant chemotherapy or immunosuppressive therapy is warranted.
4. Tumor lysis syndrome can occur within 12 to 24 hours after the first infusion. Patients with
higher tumor burden and/or high circulating lymphocytes count (>25 × 109/L) are at higher
risk and require appropriate prophylaxis with antihyperuricemic agents and hydration
beginning 12 to 24 hours prior to the infusion of obinutuzumab.
5. The use in patients with creatinine clearance of <30 mL/minute has not been studied.
6. Immunization: Obinutuzumab in combination with chlorambucil resulted in lymphopenia in
80% of patients. Immunization with live viral vaccines is not recommended during
treatment and until B-cell recovery.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia is common, with grade 3
or 4 occurring in 34% of patients in the obinutuzumab plus chlorambucil arm and in 16% of
patients in the chlorambucil alone arm. It can be of late onset (occurring more than 28 days
after completion of treatment) and/or prolonged (lasting longer than 28 days). Prophylactic
antimicrobials, antivirals, and antifungals should be considered in patients with
neutropenia. Obinutuzumab did not seem to increase the incidence of infections when added
to chlorambucil. Thrombocytopenia and anemia are occasional. Acute thrombocytopenia
(within 24 hours of treatment) can occur. Fatal hemorrhagic events can occur, especially
during the first cycle. Dose reduction and/or interruption may be required for
thrombocytopenia.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting as part of infusion-related
hypersensitivity reactions.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Infusion-related hypersensitivity reactions
(may include fever, chills, headache, myalgia, weakness, nausea, urticaria, pruritus, throat
irritation, rhinitis, dizziness, and hypo- or hypertension) can occur in up to 69% of patients
with the first infusion, with grade 3 or higher reported in up to 21%. The incidence of
 reactions with subsequent infusions is less (reported in 3% of patients receiving the second
1,000 mg dose and <1% thereafter). They usually resolve with interrupting or slowing the
rate of the infusion and administration of supportive therapy; see Special Precautions
above.
5. Miscellaneous effects
a. Pyrexia is occasional.
b. Metabolic. Hypocalcemia, hyperkalemia, and hyponatremia are common, but only
occasionally severe. Hypokalemia is occasional.
c. Hepatic. Liver function abnormalities, including increased transaminases and alkaline
phosphatase, are common, but rarely severe. Hypoalbuminemia is common.
d. Respiratory. Cough is occasional.
e. Cardiac. Worsening of preexisting cardiac conditions and fatal cardiac events can occur.

OFATUMUMAB
Other name. Arzerra.
Mechanism of action. Ofatumumab is a recombinant human monoclonal antibody that binds to
extracellular loops of the CD20 molecule, resulting in B-cell lysis, possibly through both
complement-dependent and cell-mediated cytotoxicity.
Primary indication
1. CLL, refractory to fludarabine and alemtuzumab.
2. In combination with chlorambucil in patients with previously untreated CLL for whom
fludarabine-based therapy is considered inappropriate.
3. As maintenance treatment in patients with recurrent or progressive chronic lymphocytic
leukemia who are in complete or partial response after at least two lines of therapy.
Usual dosage and schedule
1. For refractory CLL. 12 doses administered as follows:
■ 300 mg initial dose, followed 1 week later by
■ 2,000 mg weekly for 7 doses, followed 4 weeks later by
■ 2,000 mg every 4 weeks for 4 doses.
2. For patients with untreated CLL. Maximum of 12 doses administered as follows:
■ 300 mg initial dose, followed 1 week later by
■ 1,000 mg on day 8 followed 4 weeks later by
■ 1,000 mg every 4 weeks for 10 doses
3. As maintenance treatment in CLL.
■ 300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years.
Special precautions. For refractory disease: dose 1 should be infused at an initial rate of 3.6
mg/hour, dose 2 at an initial rate of 24 mg/hour, and doses 3 to 12 at an initial rate of 50
mg/hour. In the absence of infusion reactions, the infusion rate may be doubled every 30
minutes for a maximum of four doublings. For treatment, naïve CLL: dose 1 should be infused
at an initial rate of 3.6 mg/hour, remaining doses at an initial rate of 25 mg/hour. In the absence
of infusion reactions, the infusion rate may be doubled every 30 minutes for a maximum of four
doublings. Premedication with acetaminophen, an H1 histamine receptor antagonist and
corticosteroid is required. Hepatitis B reactivation can occur owing to CD20 cytolytic effect,
and patients should have pretreatment determination of hepatitis B immune status with HBsAg
and anti-HBc. Progressive multifocal leukoencephalopathy (PML) also may occur.
Toxicity
1. Myelosuppression and other hematologic effects. Grade 3 or 4 neutropenia is common
and may persist for over 1 week. Anemia is occasional to common. 70% of patients in one
trial developed bacterial, viral, or fungal infections, which were fatal in 12% of patients
treated.
2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are occasional.
3. Mucocutaneous effects. Rash and urticaria are occasional.
4. Immunologic effects and infusion reactions. Infusion reactions occur in 44% on the first
day of infusion, 29% on the second day, and less frequently during subsequent infusions.
5. Miscellaneous effects
a. Neurologic. Progressive multifocal leukoencephalopathy, including a fatal case, has
occurred with ofatumumab, but is rare. Insomnia is occasional. Headache is occasional.
b. Infections. Hepatitis B reactivation is possible as with other anti-CD20 antibodies.
Pneumonia is occasional to common; bronchitis, sepsis, nasopharyngitis, H. zoster are
occasional.
c. Fever and chills, fatigue, headache, and peripheral edema are occasional.
d. Respiratory. Cough and dyspnea are occasional.
e. Cardiovascular. Hypertension, hypotension, and tachycardia are uncommon.

OLAPARIB
Other name. Lynparza.
Mechanism of action. Inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes and also
increases formation of PARP-DNA complexes, resulting in disruption of cellular homeostasis
and cell death.
Primary indications
1. Advanced ovarian cancer in patients with deleterious or suspected deleterious germ-line
mutated BRCA who have been treated with three or more prior lines of chemotherapy.
2. Triple negative breast cancer.
3. Pancreatic or prostate cancer in patients who are carriers BRCA1/2 germ line or selected
DNA repair gene mutations.
Usual dosage and schedule. 400 mg PO twice daily. Concomitant use of strong and moderate
CYP3A inhibitors/inducers. If the inhibitor cannot be avoided, dose should be reduced, and if
a moderate CYP3A inducer cannot be avoided, there will be a potential for decreased efficacy.
Special precautions
1. Olaparib can cause fetal harm if administered to a pregnant woman.
2. Severe and fatal cases of pneumonitis and MDSs/AML have been described. These
conditions require permanent discontinuation of therapy.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common and can be severe
in 18% of cases. Neutropenia, thrombocytopenia, and lymphopenia are common. Increase
in MCV can be seen in 57% of cases. There is an increased risk of upper respiratory
infections and urinary tract infections, which can result in severe sepsis syndrome.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common but
uncommonly are they severe. Abdominal pain is common and occasionally severe.
Dyspepsia is common but rarely severe. Constipation is occasional. Rare cases of intestinal
perforation were described.
3. Mucocutaneous effects. Rash and dermatitis are common but rarely severe.
4. Immunologic effects and infusion reactions. N/A
5. Miscellaneous effects
a. General. Decreased appetite is common. Fatigue and asthenia are common. Pyrexia is
uncommon.
b. Respiratory. Cough is common but rarely severe. Dyspnea is occasional.
c. Cardiovascular. Hypertension is occasional. Venous thromboembolism and pulmonary
embolus are uncommon. Peripheral edema is occasional.
d. Metabolic. Hyperglycemia and hypomagnesemia are uncommon. Increase in creatinine
level is common but uncommonly severe.
e. Neurologic. Headache is common but rarely severe. Dizziness is occasional. Peripheral
neuropathy is uncommon.
f. Musculoskeletal and connective tissue. Arthralgia and myalgia are common but rarely
severe.
g. Psychiatric. Anxiety, depression, and insomnia are uncommon.
h. Secondary malignancies. MDSs and AML have been seen in 2% of patients. Most cases
were fatal, and all developed in patients who received previous chemotherapy with
platinum agents and/or other DNA damaging agents. The duration of therapy before
development of MDS/AML varied between less than 6 months and more than 2 years.

OMACETAXINE MEPESUCCINATE
Other name. Synribo.
Mechanism of action. The exact mechanism of action is not fully understood. It includes the
inhibition of protein synthesis irrespective of direct Bcr-Abl binding, and results in decreased
protein levels of the Bcr-Abl onco-protein and Mcl-1, an anti-apoptotic Bcl-2 family member.
The drug is active against wild-type and T315I-mutated Bcr-Abl CML.
Primary indications. Chronic or accelerated phase CML with resistance and/or intolerance to
two or more tyrosine kinase inhibitors (TKIs).
Usual dosage and schedule
1. Induction schedule. 1.25 mg/m2 subcutaneously twice daily for 14 days every 28 days
cycle until hematologic response.
2. Maintenance schedule. 1.25 mg/m2 subcutaneously twice daily for 7 days every 28 days
cycle.
Treatment interruption and dose modification may be required for neutropenia,
thrombocytopenia, and other severe nonhematologic toxicities.
Special precautions
1. Fetal harm can occur if administered to a pregnant woman.
2. Severe fatal bleeding events, including cerebral and GI bleeds, can occur mostly as a
consequence of severe thrombocytopenia.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and
thrombocytopenia are common and mostly severe (grade 3 or higher). Febrile neutropenia
occurred in 6% of patients with chronic phase and in 18% of patients with accelerated
phase disease. This resulted in increased incidence of bacterial, viral, and fungal
infections. Severe thrombocytopenia can result in fatal bleeding events.
2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are common but
uncommonly severe. Constipation, abdominal pain and vomiting are occasional, and
gastritis, dysphagia, and dyspepsia were reported in less than 10% of patients.
3. Mucocutaneous effects. Rash, alopecia, stomatitis, and gingivitis are occasional.
4. Immunologic effects and infusion reactions. Infusion and injection site–related reactions
are common but rarely severe.
5. Miscellaneous effects
a. General. Fatigue, pyrexia, and asthenia are common. Chills are occasional. Ear pain and
tinnitus were reported in less than 10% of patients.
b. Respiratory. Cough is common but rarely severe. Dyspnea is occasional.
c. Cardiovascular. Peripheral edema is occasional. Tachycardia, bradycardia, angina
pectoris, and acute coronary syndromes were reported in less than 10% of patients.
d. Metabolic. Hyperuricemia is common; increased creatinine, hyperglycemia, and
hypoglycemia are occasional. Grade 3 or 4 hyperglycemia occurred in 11% of patients.
e. Hepatic. Hyperbilirubinemia and increased ALT are occasional.
f. Neurologic. Headache is common. Paresthesia, dysgeusia, tremor, and dizziness are seen
in less than 10% of patients.
g. Genitourinary. Dysuria is occasional.
 h. Musculoskeletal and connective tissue. Arthralgia is common. Back pain and pain in
extremity are occasional.
i. Psychiatric. Insomnia is occasional. Anxiety, depression, confusion, and altered mental
status are occasional.
j. Ophthalmic. Dry eyes, diplopia, increased lacrimation, blurry vision, conjunctival
bleed, eyelid edema, and eye pain are occasional.

OSIMERTINIB
Other name. Tagrisso.
Mechanism of action. A kinase inhibitor of the EGFR, which binds irreversibly to certain
mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately ninefold
lower concentrations than wild-type.
Primary indications. Treatment of patients with metastatic EGFR T790M mutation-positive
NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI
therapy.
Usual dosage and schedule. 80 mg orally daily, with or without food. Missed doses should
not be made up for and the next dose should be taken as scheduled.
Special precautions
1. Interstitial lung disease/pneumonitis has been reported in 3.3% of patients. Permanent
discontinuation is recommended if the diagnosis is confirmed.
2. Osimertinib can cause fetal harm if administered to a pregnant woman.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, lymphopenia, and
thrombocytopenia are common but uncommonly severe. Anemia is common but rarely
severe.
2. Nausea, vomiting, and other GI effects. Diarrhea and nausea are common but rarely
severe. Constipation and stomatitis are occasional and rarely severe. Pruritus is occasional
and mostly mild.
3. Mucocutaneous effects. Rash, dry skin, and nail toxicity are common, but rarely severe.
4. Immunologic effects and infusion reactions. Cases of pneumonia were reported in 4% of
patients, but were mostly mild.
5. Miscellaneous effects
a. General. Fatigue is occasional.
b. Respiratory. Cough is occasional and rarely severe.
c. Cardiovascular. QTc prolongation can uncommonly occur. Patients with baseline QTc
of 470 msec or greater were excluded for trials. Close and periodic monitoring of
electrocardiogram and serum electrolytes is warranted. Cardiomyopathy (defined as
cardiac failure, pulmonary edema, ejection fraction decreased or stress
 cardiomyopathy) occurs rarely (1.4%). Baseline and periodic assessment (every 3
months while on treatment) of ejection fraction is recommended. Venous
thromboembolism including deep vein thrombosis, jugular venous thrombosis, and
pulmonary embolism is occasional (7%) and may be severe (2.4%).
d. Metabolic. Hyponatremia and hypomagnesemia are common.
e. Neurologic. Headache is occasional.
f. Musculoskeletal and connective tissue. Back pain is occasional, but rarely severe.
g. Ophthalmic. Eye disorders, including dry eye, blurry vision, keratitis, cataract, eye
irritation, blepharitis, eye pain, increased lacrimation, and floaters are occasional
(18%). However, these are rarely severe.

OXALIPLATIN
Other name. Eloxatin.
Mechanism of action. Similar to alkylating agents with respect to binding and cross-linking
strands of DNA, forming DNA adducts, and thereby inhibiting DNA replication and
transcription.
Primary indications
1. Carcinomas of the colon and rectum, stomach, pancreas, and biliary tract.
Usual dosage and schedule
1. Combination therapy. 85 to 100 mg/m2 as a 2-hour infusion every 2 weeks in combination
with fluorouracil (often as a continuous infusion)
2. Single agent. 130 mg/m2 as a 2-hour infusion every 3 weeks or 85 mg/m2 as a 3-hour
infusion every 2 weeks.
Special precautions. Acute neurosensory and neuromotor symptoms may develop with the
infusion. Laryngospasm may be minimized by avoiding cold drinks or food for a few days
following treatment. Chronic neurosensory symptoms are dose limiting. Must never be diluted
with or administered with sodium chloride or other chloride containing solutions.
Toxicity
1. Myelosuppression and other hematologic effects. Low-grade myelosuppression is
common, but grade 3 or 4 neutropenia, thrombocytopenia, or anemia is uncommon (about
5%) when used as single agent. Its use with fluorouracil and leucovorin increases the
neutropenia and its severity. Hemolytic anemia is rare.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
Severe diarrhea may lead to hypokalemia. May be worsening of cholinergic syndrome
when given with irinotecan.
3. Mucocutaneous effects. Alopecia is uncommon. Stomatitis is increased when used with
fluorouracil.
4. Miscellaneous effects
 a. Neurotoxicity, consisting of paresthesias and cold-induced dysesthesias in the stocking
glove or perioral distribution are common as acute transient changes that begin with the
infusion and last for less than 1 week. Chronic sensory neuropathy, fine motor
disturbance, or ataxia is occasional to common with cumulative dosing (cumulative
dose-dependent), and may last for months. It is occasionally grade 3 to 4, and not
improved by calcium or magnesium infusions.
b. Laryngospasm may develop during or within 2 hours of the infusion and can last up to 5
days. Cold temperatures may induce; warm liquids or a hot-pack may ameliorate.
c. Hepatotoxicity is common with oxaliplatin, in some cases associated with fibrosis or
severe veno-occlusive lesions, but grade 3 to 4 toxicity is uncommon.
d. Fever is common.
e. Nephrotoxicity is uncommon.
f. Ototoxicity is rare.
g. Allergic reactions are occasional. High-grade reactions or anaphylaxis are uncommon to
rare.

PACLITAXEL
Other names. Taxol, Onxol.
Mechanism of action. Enhanced formation and stabilization of microtubules. Antineoplastic
effect may result from nonfunctional tubules or altered tubulin—microtubule equilibrium.
Mitotic arrest is seen and is associated with accumulated polymerized microtubules.
Primary indications
1. Carcinomas of the ovary, breast, lung, head and neck, bladder, and cervix.
2. Melanoma.
3. Kaposi sarcoma, acquired immunodeficiency syndrome (AIDS) related.
Usual dosage and schedule
1. 135 to 225 mg/m2 as a 3-hour infusion every 3 weeks.
2. 135 to 200 mg/m2 as a 24-hour infusion every 3 weeks.
3. 100 to 135 mg/m2 as a 3-hour infusion every 2 to 3 weeks for the treatment of AIDS-related
Kaposi sarcoma.
4. 80 to 100 mg/m2 as a 1-hour weekly infusion.
5. 45 mg/m2 (together with carboplatin) weekly during radiotherapy.
Special precautions. Anaphylactoid reactions with dyspnea, hypotension (or occasionally
hypertension), bronchospasm, urticaria, and erythematous rashes may occur as a result of the
paclitaxel itself or the Cremophor vehicle required to make paclitaxel water soluble. Such
reaction is minimized but not totally prevented by pretreatment with antihistamines and
corticosteroids and by prolonging the infusion rate (to 24 hours). Paclitaxel must be filtered
with a 0.2-micron in-line filter.
Standard pretreatment regimen
1. Dexamethasone, 20 mg IV for doses >100 mg/m2 and 10 mg IV for doses ≤100 mg/m2, 30 to
60 minutes before treatment.
2. Diphenhydramine, 50 mg IV 30 to 60 minutes before treatment.
3. Histamine H2-receptor antagonist, IV 30 to 60 minutes before treatment (e.g., Cimetidine,
300 mg.)
Toxicity
1. Myelosuppression and other hematologic effects. Granulocytopenia is universal and
dose limiting; thrombocytopenia is common; anemia is occasional.
2. Nausea, vomiting, and other GI effects. Common, but usually not severe.
3. Mucocutaneous effects. Alopecia is universal; mucositis is occasional at recommended
doses.
4. Immunologic effects and infusion reactions. Dyspnea, hypotension (or occasionally
hypertension), bronchospasm, urticaria, and erythematous rashes are occasionally seen,
despite precautions.
5. Miscellaneous effects
a. Sensory neuropathy is common (30% to 35%), and may be progressively worse with
time. Recovery may take months to years.
b. Hepatic dysfunction is uncommon.
c. Diarrhea is occasional and mild.
d. Myalgias and arthralgias are common (25%).
e. Seizures are rare.
f. Abnormal electrocardiogram is occasional. If clinically significant bradycardia, stop
drug. Restart at slower rate when stable.

PACLITAXEL, PROTEIN-BOUND
Other names. Nanometer albumin-bound paclitaxel (nab-paclitaxel), Abraxane.
Mechanism of action. Albumin binding circumvents the requirement for Cremophor vehicle
for paclitaxel and its associated toxicity, and exploits albumin receptor–mediated endothelial
transport. As with parent compound, intratumor paclitaxel results in enhanced formation and
stabilization of microtubules. Antineoplastic effect may result from nonfunctional tubules or
altered tubulin-microtubule equilibrium. Mitotic arrest is seen and is associated with
accumulated polymerized microtubules.
Primary indications
1. Metastatic carcinoma of the breast
2. In combination with carboplatin for the initial treatment of patients with locally advanced
or metastatic non–small cell lung cancer (NSCLC) who are not candidates for curative
surgery or radiation therapy.
3. In combination with gemcitabine for the first-line treatment of patients with metastatic
adenocarcinoma of the pancreas.
Usual dosage and schedule
260 mg/m2 IV over 30 minutes every 3 weeks.
Special precautions. Hypersensitivity reactions may occur during the infusion of nab-
paclitaxel, but are rare. Premedication, as is used with paclitaxel with Cremophor, is not
required.
Toxicity
1. Myelosuppression and other hematologic effects. Granulocytopenia is common and dose
limiting; anemia is common as well, but rarely severe. Thrombocytopenia is uncommon.
Febrile neutropenia is rare.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are occasional to common,
but usually not severe. Diarrhea is common, but rarely severe.
3. Mucocutaneous effects. Alopecia is universal; mucositis is occasional.
4. Hypersensitivity reactions. Uncommon and rarely severe.
5. Miscellaneous effects
a. Cardiovascular events during the infusion, including hypotension or bradycardia, are
uncommon to rare. Late cardiovascular effects are also uncommon. Abnormal ECGs are
common, but not associated with symptoms and usually require no intervention. Edema
is occasional.
b. Sensory neuropathy is common and may be progressively worse with time. Recovery
may take months to years.
c. Asthenia is common.
d. Ocular or visual disturbances are occasional.
e. Cough and dyspnea are occasional.
f. Abnormal liver function tests are common, and occasionally severe.
g. Myalgias and arthralgias are common.
h. Seizures are rare.

PALBOCICLIB
Other name. Ibrance.
Mechanism of action. Inhibitor of cyclin-dependent kinase 4 and 6, which are downstream of
signaling pathways that lead to cellular proliferation.
Primary indications. In combination with letrozole for the treatment of postmenopausal
women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2
(HER2)–negative advanced breast cancer in the first-line setting.
Usual dosage and schedule. 125 mg PO once daily for 21 consecutive days followed by 7
days every 4 weeks. It should preferably be taken at the same time each day. Dose
modifications and/or interruption may be required for grade 3/4 hematologic and
nonhematologic adverse events.
Special precautions
1. Concomitant use with strong CYP3A inhibitors and moderate or strong CYP3A inducers
should be avoided. If a patient needs to be on a CYP3A inhibitor, then the starting dose of
palbociclib should be 75 mg daily. Also, the coadministration with midazolam may
increase the plasma exposure of the latter by 61%.
2. Palbociclib can cause fetal harm if administered to a pregnant woman.
3. Severe cases of infections, neutropenia, and pulmonary emboli can occur.
4. There are no safety or efficacy data regarding the use in patients with moderate-to-severe
hepatic impairment or in those with severe renal impairment.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia is common and can be
severe in 19% of cases. Anemia and thrombocytopenia are common and occasionally
severe. Neutropenia is common and can be severe in up to 60% of patients with a median
duration of 7 days or longer. Epistaxis is occasional.
2. Nausea, vomiting, and other GI effects. Stomatitis is common, but not severe. Nausea and
diarrhea are common, but uncommonly are they severe. Vomiting is occasional.
3. Mucocutaneous effects. Alopecia is common, but mostly grade 1.
4. Immunologic effects and infusion reactions. Infections are common, but mostly involve
the upper respiratory tract; severe infections are uncommon.
5. Miscellaneous effects
a. General. Fatigue and decreased appetite are common, but uncommonly are they severe.
Asthenia is occasional.
b. Cardiovascular. Pulmonary embolism has been reported at a higher rate in patients
treated with palbociclib plus letrozole (5%) compared with letrozole alone
c. Neurologic. Peripheral sensory neuropathy is occasional.

PANITUMUMAB
Other names. Vectibix, epidermal growth factor receptor (EGFR) antibody, rHuMAb-EGFR.
Mechanism of action. Fully humanized EGFR antibody that blocks the ligand-binding site and
inhibits proliferation of cells. It is thought potentially most useful in those tumors that
overexpress EGFR, but correlation with percentage of positive cells or intensity of EGFR
expression is lacking.
Primary indication
1. Colorectal cancer (CRC); in tumors that do not harbor KRAS-mutations (KRAS-wild type).
Usual dosage and schedule. 6 mg/kg (approximately 220 mg/m2) IV over 60 to 90 minutes
every 14 days.
Special precautions. Antipanitumumab antibodies have not been seen, but are possible.
Severe hypomagnesemia may be seen, and all patients should have magnesium levels
monitored throughout the persistence of cetuximab (8 weeks).
All patients with metastatic CRC who might be candidates for panitumumab should have
their tumor tested for KRAS mutations. If KRAS mutation in codon 12 or 13 is detected,
panitumumab should not be given, as the patient is unlikely to benefit.
Toxicity
1. Myelosuppression and other hematologic effects. Leukopenia and anemia are occasional.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, vomiting, and diarrhea are
occasional to common but high-grade effects are uncommon. Abdominal pain is common.
3. Mucocutaneous effects. Acne-like rash and other skin changes are universal and
occasionally high grade. Exposure to sunlight may exacerbate. Pruritis, erythema, nail
changes, and fissures are common. Irritation of the eyes is occasional. Growth of the
eyelashes is occasional. Stomatitis is occasional.
4. Immunologic effects and infusion reactions. Infusion reactions with allergic or
hypersensitivity reactions, fever, chills, or dyspnea are uncommon and rarely high grade
(1%). Binding antibodies develop in 1% to 5% of patients, but there has been no effect on
the pharmacokinetic or toxicity profile.
5. Miscellaneous effects
a. Fatigue, headache, and back pain are common to occasional.
b. Weight loss, peripheral edema, and dehydration are occasional
c. Electrolyte depletion, particularly hypomagnesemia, occurs commonly.
Hypomagnesemia is occasionally severe.
d. Pulmonary fibrosis is rare.

PANOBINOSTAT
Other name. Farydak.
Mechanism of action. Histone deacetylase (HDAC) inhibitor.
Primary indications. In combination with bortezomib and dexamethasone for the treatment of
patients with multiple myeloma who have received at least two prior regimens, including
bortezomib and an immunomodulatory agent.
Usual dosage and schedule
1. Treatment phase I. 20 mg orally once daily on days 1, 3, 5, 8, 10, 12 per 3-week cycle for
8 cycles (24 weeks), together with bortezomib and dexamethasone.
2. Treatment phase II. Patients achieving clinical benefit (defined as a response category of
“No Change,” PR, MR, nCR, or CR) without unresolved severe or medically significant
toxicity may be considered for another eight cycles of therapy with modified dosing of
 bortezomib and dexamethasone.
Starting dose is 15 mg in patients with mild hepatic impairment (bilirubin ≤1 × ULN
and AST >1 × ULN, or bilirubin >1.0 to 1.5 × ULN and any AST) and 10 mg in patients
with moderate hepatic impairment (bilirubin > 1.5 to 3.0 × ULN, any AST). Should not be
used in patients with severe hepatic impairment. Starting dose is 10 mg in patients using
strong CYP3A inhibitors.
Special precautions
1. Should not be used concomitantly with strong CYP3A inducers, sensitive CYP2D6
substrates, or antiarrhythmic drugs/QT-prolonging drug.
2. Panobinostat can cause fetal harm if administered to a pregnant woman.
3. Severe diarrhea, and severe and fatal cardiac events including ischemia and arrhythmias
can occur and can be exacerbated by electrolytes abnormalities. Baseline ECG and serum
electrolytes, including potassium and magnesium, should be checked and monitored
periodically during treatment. Electrolytes abnormalities are to be corrected as indicated
prior to and during therapy.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, neutropenia, and
lymphopenia are common and can be severe. Use of granulocyte-colony stimulating factor
(G-CSF) may be warranted, especially in patients older than 65. Thrombocytopenia is
universal and can be severe in two-thirds of patients. Fatal hemorrhage associated with
grade 3 to 4 thrombocytopenia has occurred during treatment. Grade 3/4 hemorrhage has
been reported in 4% of patients.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and can be severe in 25% of
cases. Nausea and vomiting are common and occasionally severe. Abdominal pain,
dyspepsia, gastritis, abdominal distension, flatulence, and colitis have been reported in less
than 10% of cases.
3. Mucocutaneous effects. Rash, erythema, cheilitis, and dry mouth are occasional.
4. Immunologic effects and infusion reactions. Serious infections are common, including
pneumonia, bacterial infections, invasive fungal infections, and viral infections. Hepatitis B
infection has been seen in less than 10% of patients.
5. Miscellaneous effects
a. General. Fatigue and asthenia are common. Asthenia can be severe in up to 25% of
patients. Pyrexia is common but uncommonly severe. Decrease or loss of appetite is
common, but mostly mild.
b. Respiratory. Cough, dyspnea, respiratory failure, rales, and wheezing were reported in
less than 10% of cases.
c. Cardiovascular. Arrhythmias occurred in 12% of patients, while cardiac ischemic
events occurred in 4%. Treatment should not be initiated in patients with history of
recent myocardial infarction or unstable angina. Electrocardiographic abnormalities
such as ST-segment depression, T-wave abnormalities, or QT/QTc prolongation
 occurred in 22% of patients. Treatment should not be started in patients with a QTc of
>450 msec or clinically significant baseline ST-segment or T-wave abnormalities.
Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment, the
QTc increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities.
If QT prolongation does not resolve, permanently discontinue treatment. Peripheral
edema is common, but uncommonly severe. Hypertension and orthostatic hypotension
were reported in less than 10% of patients.
d. Metabolic. Hypokalemia and hypophosphatemia are common and can be severe in up to
20% of cases. Hyponatremia is common and occasionally severe. Hypermagnesemia,
hyperphosphatemia, hypocalcemia are common, but uncommonly severe. Increased
blood creatinine level is common, but uncommonly severe. Increased serum alkaline
phosphatase can occur in less than 10% of patients. Cases of hypothyroidism were
described in less than 10% of patients. Hyperglycemia, hyperuricemia, and
hypomagnesemia can occur in less than 10% of cases.
e. Hepatic. Elevations in aminotransferases, hypoalbuminemia, and increased total
bilirubin are uncommon.
f. Neurologic. Dizziness, headache, syncope, tremor, and dysgeusia can occur in less than
10% of patients.
g. Musculoskeletal and connective tissue. Joints swelling can occur in less than 10% of
cases.
h. Renal. Renal failure and urinary incontinence can occur in less than 10% of cases.

PAZOPANIB
Other name. Votrient.
Mechanism of action. An oral multitargeted receptor tyrosine kinase inhibitor of VEGFR,
PDGFR, fibroblast growth factor receptor, and c-KIT that blocks tumor growth and inhibits
angiogenesis. Metabolized primarily by CYP3A4 and excreted in the stool.
Primary indication
1. Advanced renal cell carcinoma.
2. Advanced soft tissue sarcoma with prior chemotherapy.
3. Carcinoma of the ovary.
Usual dosage and schedule
1. 800 mg PO daily without food.
2. 200 mg PO daily without food, if moderate hepatic impairment.
3. 400 mg or less PO if strong inhibitors of CYP3A4 cannot be avoided.
Special precautions. May cause severe liver toxicity; therefore, liver function tests should be
monitored closely before and during treatment. Do not give pazopanib if severe hepatic
impairment. Fatal hemorrhagic events have been seen, and use in patients with history of GI
hemorrhage, hemoptysis, or cerebral hemorrhage should be avoided. If possible, avoid use of
strong inhibitors of CYP3A4, which may increase concentration of pazopanib. CYP3A4
inducers may decrease pazopanib concentrations.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, thrombocytopenia, and
lymphocytopenia are common, but rarely severe. Arterial thrombotic events have been
observed and can be fatal. Fatal hemorrhagic events have also been observed.
2. Nausea, vomiting, and other GI effects. Diarrhea is common, as are nausea, vomiting,
and anorexia. GI perforation has been observed, but is probably rare. Abdominal pain is
occasional.
3. Mucocutaneous effects. Hair color change (de-pigmentation) is common. Hand-foot
syndrome is occasional. Skin depigmentation is uncommon.
4. Immunologic effects and infusion reactions. None.
5. Miscellaneous effects
a. Systemic effects. Fatigue, asthenia, and headache are occasional to common.
b. Hepatic. ALT and AST elevations are common and occasionally (12%) severe.
c. Cardiovascular. Hypertension is common, but grade 3 or 4 hypertension is uncommon.
Prolonged QT intervals and torsades de pointes have been observed, but are rare. Chest
pain is uncommon.
d. Hyponatremia, hypomagnesemia, and hypophosphatemia. Occasional.
e. Hypothyroidism. Occasional.
f. Proteinuria. Occasional, but rarely severe.

PEMBROLIZUMAB
Other name. Keytruda.
Mechanism of action. A humanized monoclonal IgG4 antibody that binds to the programmed
death-1 (PD-1) receptor on T cells and blocks its interaction with its ligands PD-L1 and PD-
L2, both of which are upregulated in several tumors and responsible for immune response
inhibition.
Primary indications
1. Unresectable or metastatic melanoma.
2. Metastatic NSCLC in patients whose tumors express programmed death ligand 1 (PD-L1)
as determined by an FDA-approved test and who have had progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor alterations
should have disease progression on and FDA-approved therapy for these aberrations prior
to receiving pembrolizumab.
Usual dosage and schedule. 2 mg/kg administered as an IV infusion over 30 minutes every 3
weeks until disease progression or intolerable toxicity.
Special precautions. Pembrolizumab can cause fetal harm if administered to a pregnant
woman. Immune-related adverse events (irAEs) including colitis, pneumonitis, hepatitis,
hypophysitis, nephritis, thyroiditis, uveitis, optic neuritis, hemolytic anemia, pancreatitis,
dermatitis, partial seizures, myositis, and arthritis can occur, and require close monitoring and
occasionally withholding treatment and steroids therapy (see below).
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common and occasionally
severe. Upper respiratory tract infections are occasional.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, constipation, and diarrhea are
common and mostly mild. Abdominal pain is occasional.
3. Mucocutaneous effects. Rash and pruritus are common. Vitiligo is occasional.
4. Immunologic effects and infusion reactions. Upper respiratory tract infections are
occasional; sepsis is uncommon to occasional.
a. Immune-mediated pneumonitis is seen in 2% to 3% of patients. For grade 2 reactions,
withholding therapy in addition to administering systemic steroids (greater than or equal
to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is
indicated until improvement to grade 1 or less. Permanent discontinuation is indicated
for grade 3 or 4 reactions.
b. Immune-mediated colitis occurred in 1% of patients. For grade 2 and 3 reactions,
withholding therapy in addition to administering systemic steroids (greater than or equal
to 40 mg of prednisone or equivalent per day followed by a taper for at least a month) is
indicated until improvement to grade 1 or less. Permanent discontinuation is indicated
for grade 4 reactions.
c. Immune-mediated hepatitis is rare (<0.5%). For grade 2 or higher reactions, treatment
with systemic steroids is indicated. Dose interruption and permanent discontinuation
may be indicated for more severe reactions.
d. Immune-mediated hypophysitis is rare (0.5%). Dose interruption and treatment with
systemic steroids is indicated for grade 2 and 3 reactions. Permanent discontinuation is
recommended for grade 4 reactions.
e. Immune-mediated nephritis including autoimmune nephritis and interstitial nephritis with
renal failure is rare (<1%). Management of these reactions follows the general rules for
other irAEs.
f. Immune-mediated hyperthyroidism and hypothyroidism occurs in 1% and 8% of patients,
respectively. Dose interruption and treatment with systemic steroids are indicated for
grade 3 reactions. Permanent discontinuation is recommended for grade 4 reactions.
Monitor all patients for thyroid function.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Pyrexia and chills are occasional.
b. Respiratory. Cough and dyspnea are occasional but uncommonly severe.
c. Cardiovascular. Peripheral edema is common.
d. Metabolic. Hyperglycemia and increased AST are common and can be severe.
 Hyponatremia and hypertriglyceridemia are common.
e. Neurologic. Headache is common. Dizziness is occasional.
f. Musculoskeletal and connective tissue. Arthralgia and pain in extremity are common.
Myalgia and back pain are occasional.
g. Psychiatric. Insomnia is occasional.

PEMETREXED
Other name. Alimta.
Mechanism of action. Interference with folate-dependent metabolic processes, including
inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide
formyltransferase, largely after being converted to polyglutamate forms.
Primary indications
1. Malignant pleural mesothelioma that is unresectable or not amenable to curative surgery.
Given in combination with cisplatin.
2. Nonsquamous, NSCLC, as first- or second-line therapy and as maintenance after remission
induction.
3. Carcinoma of the ovary.
Usual dosage and schedule
1. 500 mg/m2 IV over 10 minutes on day 1 of each 21-day cycle. For mesothelioma, it is
followed in one-half hour by cisplatin 75 mg/m2 over 2 hours.
Special precautions
1. Folic acid, 1 to 2 mg PO daily in divided doses, starting 7 days prior to pemetrexed and
continuing for 21 days after the last dose; and vitamin B12 1,000 μg IM during the week
prior to pemetrexed and every three cycles thereafter must be taken as a prophylactic
measure to reduce treatment-related hematologic and GI toxicity.
2. Dexamethasone 4 mg PO twice daily the day before, the day of, and the day after
pemetrexed should be given to reduce skin rash.
3. If creatinine clearance is <45 mL/min, give with caution and avoid NSAIDs.
Toxicity
1. Myelosuppression. Anemia and neutropenia are common when used with cisplatin, only
occasional when used as a single agent; severe episodes are only occasional;
thrombocytopenia is occasional.
2. GI effects. Anorexia, nausea, vomiting, and diarrhea are occasional. Liver function
abnormalities are occasional.
3. Mucocutaneous effects. Rash and pruritis are occasional. Stomatitis and pharyngitis are
common. Alopecia is occasional. Taste disturbances are occasional. Conjunctivitis is
uncommon.
4. Miscellaneous effects
a. Fever. Uncommon.
b. Serum creatinine elevation is occasional, renal failure is rare.
c. Fatigue is common. Myalgia and arthralgia are occasional. Sensory neuropathy is
occasional.
d. Hypersensitivity reactions are occasional, but rarely severe.
e. Supraventricular arrhythmias are rare.

PENTOSTATIN
Other names. 2´-Deoxycoformycin, Nipent.
Mechanism of action. Inhibition of adenosine deaminase, particularly in the presence of
adenosine or deoxyadenosine leads to cytotoxicity. Is associated with block of DNA synthesis
through inhibition of ribonucleotide reductase. Other effects that may contribute to cytotoxicity
include inhibition of RNA synthesis and increased DNA damage.
Primary indication. Hairy-cell leukemia.
Usual dosage and schedule. 4 mg/m2 IV push over 1 to 2 minutes or diluted in a larger volume
over 20 to 30 minutes. Patients should be given hydration with 500 to 1,000 mL of 5% dextrose
in 0.5 N saline or equivalent before pentostatin administration and 500 mL after the drug is
given. Repeat every 2 weeks.
Special precautions
Hydration required to ensure urine output of 2 L daily on the day pentostatin is administered.
Patients often are hospitalized for their first drug administration. Allopurinol 300 mg b.i.d is
recommended initially in patients with a large tumor mass. Sedative and hypnotic drugs should
be used with caution or not at all because CNS toxicity may be potentiated. Dose reduction or
discontinuation needed for renal impairment (creatinine clearance <50 mL/minute).
Should not be used in combination with fludarabine because of a high probability of severe
or fatal pulmonary toxicity.
Toxicity
1. Myelosuppression and other hematologic effects. Common but severity variable.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common but usually not
severe. Diarrhea is occasional. Hepatic dysfunction is occasional at recommended doses.
3. Mucocutaneous effects. Mucositis is rare; skin rashes and pruritis are occasional to
common.
4. Miscellaneous effects
a. Fatigue is common.
b. Cough is common and dyspnea is occasional. Higher doses or use in combination of
fludarabine may lead to severe pulmonary toxicity.
c. Chills and fever are common.
 d. Infections, probably related to both myelosuppression and lymphocytopenia, are
occasional.
e. Renal insufficiency is rare at usual doses.
f. Neuropsychiatric effects. High doses may cause serious neurologic and psychiatric
symptoms, including seizures, mental confusion, irritability, and coma.

PERTUZUMAB
Other name. Perjeta.
Mechanism of action. A recombinant humanized monoclonal antibody that targets the
extracellular dimerization domain (subdomain II) of the human epidermal growth factor
receptor protein, HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2
with other HER family members.
Primary indications. Carcinoma of the breast that has overexpression of HER2 (c-erbB-2) in
combination with trastuzumab and docetaxel either in the first line for advanced disease or as
neoadjuvant therapy.
Usual dosage and schedule. Initial dose of 840 mg as a 60-minute IV infusion followed every
3 weeks by a dose of 420 mg IV infusion over 30 to 60 minutes until disease progression or
intolerable toxicity in the metastatic setting, and during administration of chemotherapy in the
neoadjuvant setting. For delayed or missed doses, if the time between two sequential doses is
less than 6 weeks, the dose of 420 mg can be administered, whereas if the time between two
sequential doses is more than 6 weeks, the initial dose of 840 mg should be administered
followed by 420 mg every 3 weeks.
Special precautions
1. Embryo-fetal toxicity. Verification of pregnancy status prior to initiation of therapy in
women in childbearing age and the use of effective birth control measures during and up to
6 months after the last dose of treatment is recommended.
2. During the first infusion, and occasionally during later infusions, a systemic symptom
complex similar to that seen with other human monoclonal antibodies is common. Severe
hypersensitivity reactions and pulmonary adverse events are rare. These events include
anaphylaxis, angioedema, bronchospasm, hypotension, hypoxia, dyspnea, pulmonary
infiltrates, pleural effusions, noncardiogenic pulmonary edema, and acute respiratory
distress syndrome. A more common symptom complex, occurring occasionally, consists of
mild-to-moderate chills, fever, asthenia, pain, nausea, vomiting, and headache. These latter
symptoms are generally well managed by temporary slowing or interruption of the infusion
and administration of acetaminophen, diphenhydramine, and corticoids.
3. Cardiac dysfunction. Pertuzumab in combination with trastuzumab and docetaxel was not
associated with increased incidence of symptomatic or asymptomatic decrease in left
ventricular ejection fraction (LVEF) compared with placebo in combination with
 trastuzumab and docetaxel. Baseline assessment, as well as every 3 months while on
treatment, with echocardiogram or MUGA scan is recommended. If the LVEF is <40% or
40% to 45% with greater than 10% decrease in the absolute value, treatment interruption
and reassessment in 3 weeks is recommended. Severe disability or death from cardiac
dysfunction can occur, and extreme caution should be exercised in treating patients with
preexisting cardiac dysfunction.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia, anemia and
thrombocytopenia are common. Upper respiratory infections and febrile neutropenia are
occasional but the latter may be severe and rarely fatal.
2. Nausea, vomiting, and other GI effects. Diarrhea is common.
3. Mucocutaneous effects. Mucositis is common, but most cases were mild. Dry skin and
pruritus are occasional. Rash is common. Paronychiae are occasional.
4. Immunologic effects and infusion reactions. See Special Precautions.
5. Miscellaneous effects
a. General. Fever is common; headache and fatigue are occasional.
b. Neurologic. Headache and dysgeusia are common.

POMALIDOMIDE
Other name. Pomalyst.
Mechanism of action. Immunomodulatory agent with several mechanisms of action. It
enhances T-cell and NK cell-mediated immunity, inhibits production of proinflammatory
cytokines (e.g., TNF-α, IL-6) by monocytes and has antiangiogenesis activity. It also inhibits
proliferation of lenalidomide-resistant myeloma cell lines.
Primary indications. Multiple myeloma after receiving at least two prior therapies including
lenalidomide and bortezomib.
Usual dosage and schedule. 4 mg orally once daily, on days 1 to 21 of repeated 28-day
cycles, at least 2 hours before or after a meal. It may be given in combination with
dexamethasone. Coadministration with strong CYP1A2 should be avoided. Smoking can
reduce pomalidomide exposure due to CYP1A2 induction.
Special precautions
1. Pomalidomide is teratogenic and can cause fetal harm if administered to a pregnant woman.
Two negative pregnancy tests must be obtained prior to treatment initiation. Females of
reproductive age must abstain from sexual intercourse or use two reliable birth control
methods beginning 4 weeks before and continuing for 4 weeks following discontinuation of
therapy. Males must use latex or synthetic condoms during any sexual contact with females
with reproductive potential during and for 4 weeks following discontinuation of treatment
even if they had vasectomies. Blood or sperm donation must be avoided during and for 4
 weeks following discontinuation of treatment.
2. Venous thromboembolic events were reported in 3% of patients and can be severe/fatal. All
the patients should receive prophylaxis or anti-thrombotic treatment after assessment of
underlying risk factors.
3. Tumor lysis syndrome can develop in those with high tumor burden.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia is common and is
commonly severe (grade 3). Febrile neutropenia is uncommon. There is increased risk of
upper respiratory tract infections, pneumonia, urinary tract infections, and sepsis. These
events can be occasionally severe. Pneumocystis jirovecii pneumonia and respiratory
syncytial virus infections has been reported. Anemia and thrombocytopenia are common
and commonly severe. Epistaxis is occasional. Lymphopenia is occasional and can be
severe especially in the combination with low-dose dexamethasone.
2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are common. Vomiting is
occasional. Constipation is common and uncommonly severe.
3. Mucocutaneous effects. Hyperhidrosis and rash are common. Dry skin and pruritus are
occasional.
4. Immunologic effects and infusion reactions. Patients with prior history of hypersensitivity
reactions to thalidomide or lenalidomide were excluded from the clinical trial and may be
at higher risk of developing these events.
5. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Pyrexia is common and
uncommonly severe. Peripheral edema is common. Chills, night sweats, and weight loss
are occasional.
b. Respiratory. Cough is occasional. Dyspnea is common and occasionally severe. Cases
of interstitial lung disease (ILD) were also reported.
c. Cardiovascular. Atrial fibrillation is uncommon. Congestive heart failure can rarely
occur in patients receiving pomalidomide with low-dose dexamethasone.
d. Metabolic. Hyperglycemia, hypocalcemia, and hyponatremia are occasional.
Hypercalcemia is common and occasionally severe. Hyperkalemia is occasional.
e. Hepatic. Increased ALT and hyperbilirubinemia are uncommon.
f. Neurologic. While dizziness is common and confusion is occasional, they are
uncommonly severe. Peripheral neuropathy is occasional and mostly grade 1 or 2.
Headaches and tremor are occasional.
g. Genitourinary. Renal failure is occasional and can be severe. Dose interruption is only
required for grade 3 or greater events. Cases of urinary retention were also reported.
h. Secondary neoplasms/malignancies. AML has been reported.
i. Musculoskeletal and connective tissue. Musculoskeletal chest pain, arthralgia, and
muscle spasms are common. Musculoskeletal pain, pain in extremity, and bone pain are
occasional. Back pain and muscular weakness are common and occasionally severe.
j. Psychiatric. Insomnia and anxiety are occasional.
PONATINIB
Other name. Iclusig.
Mechanism of action. Inhibits the tyrosine kinase activity of native or mutant BCR-ABL,
including T315I.
Primary indications
1. Chronic, accelerated, or blast phase CML (Philadelphia chromosome positive [Ph+]) that is
resistant or intolerant to prior tyrosine kinase inhibitor therapy.
2. Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
Usual dosage and schedule. 45 mg orally once a day, with or without food. Coadministration
of strong CYP3A inducers, CYP3A inhibitors, or drugs that elevate gastric pH (H2 blockers,
proton pump inhibitors, or antacids) should be avoided unless benefits outweigh risks. When
administered with a strong CYP3A inhibitor, ponatinib dose should be decreased to 30 mg
orally once daily.
Special precautions
1. Ponatinib can cause embryo-fetal toxicity if administered to a pregnant woman.
2. Thrombosis and thromboembolism:
a. Arterial thrombosis reactions were reported in 11% of patients. These include
cardiovascular, cerebrovascular, and peripheral arterial disease. Severe (grade 3 or
greater) events are occasional, may require revascularization interventions, or
amputation and may be fatal.
b. Venous thromboembolic events including deep venous thrombosis, pulmonary embolism,
portal vein thrombosis, and retinal vein thrombosis are uncommon, but may be severe
and rarely fatal.
3. Because ponatinib can cause wound healing impairment, withholding treatment at least 1
week prior to surgery is recommended.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and
thrombocytopenia are common, and commonly severe. Febrile neutropenia is common in
Ph+ ALL, occasional in accelerated phase-CML and blast phase-CML and rare in chronic-
phase CML. Increased risk of sepsis, pneumonia, urinary tract infections, upper respiratory
tract infections, nasopharyngitis, and cellulitis was reported, but these cases are
uncommonly severe. Hemorrhagic reactions are common up to 24% of patients, mostly in
those with grade 4 thrombocytopenia. These events, including GI and cerebral events, can
be severe, and rarely fatal.
2. Nausea, vomiting, and other GI effects. Abdominal pain is common and occasionally
severe. Nausea, vomiting, diarrhea, and constipation are common.
3. Mucocutaneous effects. Rash is common and occasionally severe. Dry skin is common.
Oral mucositis is common.
4. Miscellaneous effects
a. General. Fatigue and pyrexia are common. Chills are occasional.
b. Respiratory. Cough and dyspnea are common.
c. Cardiovascular. Hypertension is common and can be serious in up to 39% of cases.
Symptomatic bradyarrhythmias, including complete heart block, sick sinus syndrome,
and atrial fibrillation with bradycardia requiring pacemaker implantation are rare.
Congestive heart failure is occasional (11%), with 4% being severe. Peripheral edema,
pericardial effusion, pleural effusion, pulmonary edema, ascites and cerebral edema are
occasional to common.
d. Metabolic. Hyperglycemia, hypoglycemia, hypophosphatemia, hypocalcemia,
hypokalemia are common. Hyperkalemia, hypernatremia, and increased creatinine are
occasional. Hypertriglyceridemia is uncommon.
e. Hepatic and pancreatic. Clinical pancreatitis is occasional with most cases resolving
within 2 weeks of treatment interruption. Increased lipase is common and occasionally
severe. Increased AST and/or ALT and hyperbilirubinemia are common. Severe
hepatotoxicity resulting in fulminant hepatic failure and death can rarely occur.
f. Neurologic. Headache is common. Peripheral neuropathy and dizziness are occasional.
Insomnia is occasional.
g. Musculoskeletal and connective tissue. Arthralgia and myalgia are common. Muscle
spasms are occasional.
h. Tumor lysis syndrome is rare.

PRALATREXATE
Other name. Folotyn.
Mechanism of action. Pralatrexate is a folate analog that competitively inhibits dihydrofolate
reductase. It is also an inhibitor for polyglutamylation by folylpolyglutamyl synthetase.
Primary indication. Relapsed or refractory peripheral T-cell lymphoma.
Usual dosage and schedule. 30 mg/m2 IV push over 3 to 5 minutes weekly for 6 weeks in 7-
week cycles.
Patients should take 1 to 1.25 mg oral folic acid daily starting 10 days prior to the first
dose of pralatrexate as well as 1 mg of vitamin B12 IM, which should be administered every 8
to 10 weeks during treatment.
Special precautions. Omitting a dose, with or without subsequent dose modifications, is
required for mucositis >grade 1 and significant cytopenias (ANC <1,000/µL, platelets
<50,000/µL).
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia, anemia, and
neutropenia are common. Grade 3 or 4 thrombocytopenia is common, but grade 3 or 4
 neutropenia is less frequent (approximately 20%).
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common, but
it is rare to uncommon that they are severe. Constipation is common. Anorexia and
abdominal pain are occasional.
3. Mucocutaneous effects. Mucositis is very common (70%) and may be associated with a
sore throat; grade 3 to 4 mucositis occurs about 20% of the time. Epistaxis is common.
Rash and pruritis are occasional.
4. Immunologic effects and infusion reactions. Not reported.
5. Miscellaneous effects
a. Fatigue and fever are common.
b. Cardiorespiratory effects. Cough, dyspnea, and edema are common. Tachycardia is
occasional.
c. Hypokalemia and elevated transaminases are occasional.

PROCARBAZINE
Other names. Matulane, Natulan.
Mechanism of action. Uncertain but appears to affect preformed DNA, RNA, and protein.
Primary indications
1. Hodgkin and non-Hodgkin lymphomas.
2. Brain tumors
3. Melanoma
Usual dosage and schedule. 60 to 100 mg/m2 PO daily for 7 to 14 days every 4 weeks (in
combination with other drugs).
Special precautions. Many food and drug interactions are possible, although their clinical
significance may be low.

Drug or Food Possible Result

Disulfiram-like reactions: nausea, vomiting, visual disturbances,
Ethanol
headache
Sympathomimetics, tricyclic antidepressants, tyramine-rich foods
Hypertensive crisis, tremors, excitation, angina, cardiac palpitations
(cheese, wine, bananas)
CNS depressants Additive depression

CNS, central nervous system.

Toxicity
1. Myelosuppression and other hematologic effects. Pancytopenia is dose-limiting.
Recovery may be delayed.
2. Nausea, vomiting, and other GI effects. Nausea is frequent during first few days until
 tolerance develops. Diarrhea is uncommon.
3. Mucocutaneous effects. Stomatitis is uncommon. Alopecia, pruritus, and drug rash are
uncommon.
4. CNS effects. Paresthesias, neuropathies, headache, dizziness, depression, apprehension,
nervousness, insomnia, nightmares, hallucinations, ataxia, confusion, convulsions, and coma
have been reported with varying frequency.
5. Miscellaneous effects
a. Secondary neoplasia is possible.
b. Visual disturbances are rare.
c. Postural hypotension is rare.
d. Hypersensitivity reactions are rare.
e. Teratogenesis is strong potential.

PROGESTINS
Other names. Medroxyprogesterone acetate (Provera, Depo-Provera), hydroxyprogesterone
caproate (Delalutin), megestrol acetate (Megace).
Mechanism of action. Mechanisms of antitumor effects or for appetite stimulation are not
clear.
Primary indications. Endometrial carcinoma.
Usual dosage and schedule
1. Megestrol acetate 80 to 320 mg PO daily.
2. Medroxyprogesterone acetate 1,000 to 1,500 mg IM weekly or 400 to 800 mg PO twice
weekly.
3. Hydroxyprogesterone caproate 1,000 to 1,500 mg IM weekly.
Special precautions
Acute local hypersensitivity or dyspnea due to oil in IM preparations is uncommon.
Hypercalcemia with initial therapy is occasional, particularly in patients with bone
metastasis.
Toxicity
1. Myelosuppression and other hematologic effects. None.
2. Nausea, vomiting, and other GI effects. Rare. Is an appetite stimulant (800 mg PO daily).
3. Mucocutaneous effects. Mild alopecia or skin rash are uncommon.
4. Miscellaneous effects
a. Mild fluid retention is occasional to common.
b. Mild liver function abnormalities are occasional; intrahepatic cholestasis may occur.
c. Menstrual irregularities are common.
d. Increased appetite and weight gain are common.
RALOXIFENE
Other name. Evista.
Mechanism of action. A selective ER modulator that inhibits estrogen effects by competing
with estrogen for binding on the cytosol ER protein in normal and cancer cells. The receptor-
hormone complex ultimately controls the promoter region of genes that affect cell growth.
Effects may manifest as estrogen agonistic (bone) or antagonistic (breast and uterus),
depending on the tissue and other modifying factors.
Primary indications
1. Prevention of osteoporosis in postmenopausal women.
2. Prevention of invasive breast cancer in postmenopausal women at increased risk. (No
apparent decrease in ductal or lobular in situ carcinomas.)
Usual dosage and schedule. 60 mg PO daily.
Special precautions. Contraindicated in women with active or past history of venous
thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein
thrombosis. May cause fetal harm if administered to a pregnant woman.
Toxicity
1. Myelosuppression and other hematologic effects. Uncommon and mild.
2. Nausea, vomiting, and other GI effects. Uncommon.
3. Mucocutaneous effects. Rash, sweating, and vaginitis are uncommon.
4. Miscellaneous effects
a. Thromboembolic events, including deep vein thrombosis, pulmonary embolism, and
retinal vein thrombosis, are rare. Lower risk than with tamoxifen.
b. Leg cramps are uncommon to occasional.
c. Hot flashes are common.
d. Lowers total cholesterol and low-density lipoprotein cholesterol.
5. Carcinogenesis. Risk for endometrial carcinoma is rare (0.5%) and lower than tamoxifen
(0.75%).

RAMUCIRUMAB
Other name. Cyramza.
Mechanism of action. A recombinant human monoclonal IgG1 antibody that binds to the
human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of
VEGF-R2 to its ligands VEGF-A, VEGF-C, and VEGF-D. As a result, it inhibits ligand-
stimulated activation of VEGF-R2, thereby inhibiting ligand-induced proliferation, and
migration of human endothelial cells.
Primary indications
1. Advanced or metastatic gastric or gastroesophageal junction tumors in patients who have
received prior fluoropyrimidine- or platinum-containing chemotherapy either as a single
agent or in combination with paclitaxel.
2. Non–small cell lung cancer: in combination with docetaxel for patients who have had tumor
progression during or after treatment with platinum-based chemotherapy, and should be
used with docetaxel.
3. In combination with FOLFIRI (leucovorin, fluorouracil, irinotecan) for the treatment of
patients with metastatic CRC whose disease has progressed on a first-line bevacizumab,
oxaliplatin, and fluoropyrimidine-containing regimen.
Usual dosage and schedule
1. Gastric, gastroesophageal junction and colorectal tumors: 8 mg/kg IV infusion over 60
minutes every 2 weeks. (Prior to FOLFIRI in colorectal carcinoma.)
2. Non–small cell lung cancer: 10 mg/kg IV infusion every 3 weeks.
Premedication with diphenhydramine is recommended. In patients who develop grade 1 or
2 infusion-related reactions (IRRs), premedication with corticosteroids and acetaminophen
prior to each infusion is also indicated.
Special precautions
1. Severe and fatal hemorrhagic events can uncommonly occur. Coadministration of NSAIDs
in patients with gastric cancer should be taken with extreme caution. Permanent
discontinuation for grade 3 or 4 events is recommended.
2. Severe and fatal arterial thromboembolic events (including myocardial infarction, cardiac
arrest, cerebrovascular accident, and cerebral ischemia) have been uncommonly observed.
GI perforations/obstructions have also been rarely reported.
3. Ramucirumab can impair wound healing and cause healing complications. Withholding
treatment at least 28 days prior to scheduled surgeries is recommended, and treatment
resumption post surgery is indicated after adequate wound healing.
4. Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or
hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis. Use in
patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are
judged to outweigh the risks of clinical deterioration.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported.
2. Nausea, vomiting, and other GI effects. Diarrhea is occasional.
3. Mucocutaneous effects. Not reported.
4. Immunologic effects and infusion reactions. Prior to the institution of premedication
recommendations across clinical trials, IRRs occurred in 16% of patients. The majority of
IRRs occur during or following a first or second infusion. Symptoms include
rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea,
wheezing, hypoxia, and paresthesias. In severe cases, symptoms include bronchospasm,
supraventricular tachycardia, and hypotension. Permanent discontinuation is indicated for
 grade 3 or 4 reactions.
5. Miscellaneous effects
a. Cardiovascular. Hypertension is occasional and can be grade 3 or 4 in 8% of cases.
b. Metabolic. Hyponatremia is occasional.
c. Neurologic. Headache is occasional. Reversible posterior leukoencephalopathy
syndrome (RPLS) is rare, and although symptoms may resolve within days, some cases
can be severe and fatal.
d. Genitourinary. Proteinuria can occur in 8% of patients. Interrupt treatment for urine
protein levels ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours,
treatment reinitiation at a reduced dose of 6 mg/kg every 2 weeks is indicated. If the
protein level ≥2 g/24 hours reoccurs, interrupt treatment and reduce the dose to 5 mg/kg
every 2 weeks once the urine protein level returns to <2 g/24 hours. Permanently
discontinue therapy for urine protein level >3 g/24 hours or in the setting of nephrotic
syndrome.
e. Endocrine. Hypothyroidism was reported in 2.6% of patients based on thyroid
monitoring in patients with metastatic CRC.

REGORAFENIB
Other name. Stivarga.
Mechanism of action. Inhibitor of multiple kinases including VEGFR1, 2, and 3. These
kinases are involved in angiogenesis, oncogenesis, and maintenance of tumor
microenvironment.
Primary indications. Treatment of patients with metastatic CRC who have been previously
treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF
therapy, and, if KRAS wild-type, an anti-EGFR therapy.
Usual dosage and schedule. 160 mg (four 40 mg tablets) taken orally once daily for the first
21 days of each 28-day cycle. To be taken at the same time every day with a meal that contains
less than 30% fat. Dose modifications/interruptions may be required for hepatotoxicity, hand-
foot skin reaction (HFSR), hypertension, and other grade 3 or 4 adverse reactions.
Concomitant use with strong CYP3A4 inducers or inhibitors is not recommended. Avoid use in
patients with severe hepatic (Child-Pugh class C) or renal impairment (CLcr <30
mL/min/1.73m2).
Special precautions
1. Regorafenib can cause fetal harm if administered to a pregnant woman.
2. Severe/fatal cases of hepatotoxicity and hemorrhage as well as cases of GI perforations and
fistulas formation have been observed.
3. As with other VEGFR inhibitors, there is a risk of wound healing complications. Thus,
treatment should be stopped at least 2 weeks prior to scheduled surgery. The decision to
 resume therapy after surgery should be based on clinical judgment of adequate wound
healing.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, lymphopenia, and
thrombocytopenia are common and occasionally severe. Neutropenia is uncommon.
Hemorrhagic events are common, but rarely severe or fatal. Increase in International
Normalized Ratio (INR) is common, and 4% may have grade 3 toxicity. Close monitoring
of INR for patients taking warfarin is recommended.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally severe.
Mucositis is common but uncommonly severe. GI perforations/fistulas are rare and require
permanent discontinuation.
3. Mucocutaneous effects. Xerostomia was reported in less than 10% of patients. Rash is
common and occasionally severe. HFSR is common and can be severe in 17% of patients
requiring dose interruptions/modifications.
4. Immunologic effects and infusion reactions. Infections are common, but rarely severe.
5. Miscellaneous effects
a. General. Alopecia was reported in less than 10% of patients. Weight loss and lack of
appetite are common. Fatigue is common and occasionally severe. Fever is common.
b. Respiratory. Dysphonia is common.
c. Cardiovascular. Hypertension is common, but rarely severe. Increased risk of acute
coronary syndromes can be uncommonly observed.
d. Metabolic. Hypocalcemia, hypokalemia, and hyponatremia are common.
Hypophosphatemia is common and commonly severe.
e. Hepatic. Increase in ALT/AST and/or total bilirubin is common and occasionally
severe. Increase in amylase and/or lipase is common can be severe. Fatal hepatotoxicity
has been reported in 1% to 2% of patients, all of whom had hepatic metastasis. Liver
functions test should be obtained at baseline, every 2 weeks during the first 2 months
and monthly thereafter.
f. Neurologic. Dysgeusia was reported in less than 10% of patients. RPLS is rare and
requires permanent discontinuation of treatment. Headache is occasional.
g. Endocrine. Hypothyroidism was reported in less than 10% of patients.
h. Genitourinary. Proteinuria is common, but rarely severe.
i. Musculoskeletal and connective tissue. Musculoskeletal stiffness was reported in less
than 10% of patients.

RITUXIMAB
Other name. Rituxan.
Mechanism of action. Rituximab is a genetically engineered chimeric (murine and human)
monoclonal antibody directed against the CD20 antigen found on the surface of normal cells
and in high copy number on malignant B-lymphocytes (but not stem cells). The Fab domain of
rituximab binds to the CD20 antigen on B-lymphocytes and B-cell non-Hodgkin lymphomas,
and the Fc domain recruits immune effector functions to mediate B-cell lysis.
Primary indications
1. Non-Hodgkin B-cell lymphoma that is low grade or follicular, CD20 positive, as a single
agent or in combination or sequence with cytotoxic chemotherapy.
2. Non-Hodgkin lymphoma, diffuse large B-cell, CD20 positive, in combination or sequence
with cytotoxic chemotherapy.
3. Other B-cell non-Hodgkin lymphomas.
4. CLL (CLL), usually in combination or sequence with fludarabine, cyclophosphamide, or
both.
Usual dosage and schedule
1. 375 mg/m2 given as a slow IV infusion, initially at a rate of 50 mg/hour. If hypersensitivity
or other infusion-related events do not occur, escalate in 50 mg/hour increments to a
maximum of 400 mg/hour. Usually takes 4 to 6 hours to infuse initial therapy. Interrupt or
slow the infusion rate for infusion-related events. As a single agent, often given once
weekly for four to eight doses; in combination with cytotoxic chemotherapy, often given on
day 1 or 2 of each cycle of chemotherapy. Premedication with acetaminophen and
diphenhydramine may attenuate infusion-related symptoms. Corticosteroids should not be
used for premedication.
2. For CLL when used with fludarabine and cyclophosphamide (FC):
■ 375 mg/m2 given as a slow IV infusion (as above) on the day prior to the first cycle of
FC then 500 mg/m2 as an IV infusion on day 1 of each subsequent 28-day cycles.
Special precautions
1. An infusion-related set of symptoms consisting of fever and chills, with or without true
rigors, occurs commonly during the first infusion. Other hypersensitivity symptoms
including nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation
of tongue or throat swelling, rhinitis, vomiting, hypotension, flushing, and pain at disease
sites may also be seen. Rarely infusion-related events result in a fatal outcome. Fatal
reactions have followed a symptom complex that includes hypoxia, pulmonary infiltrates,
acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and
cardiogenic shock. Hypersensitivity reactions generally start within 30 to 120 minutes of
starting the infusion. Most will resolve with slowing or interruption of the infusion and with
supportive care, including IV saline, diphenhydramine, and acetaminophen. Severe
reactions will additionally require aggressive cardiorespiratory support including oxygen,
epinephrine, vasopressors, corticosteroids, and bronchodilators and may preclude
additional treatment with rituximab. The rate of infusion events decreases from 80% during
the first infusion to 40% during subsequent infusions.
2. Abdominal pain, bowel obstruction and perforation have been seen in patients receiving
rituximab in combination with chemotherapy.
3. Hepatitis B reactivation with related fulminant hepatitis and other viral infections including
parvovirus B19, varicella-zoster. Cytomegalovirus and herpes simplex virus has been
reported. Obtaining a hepatitis panel (A, B, and C) is recommended. Hepatitis B surface
antigen positivity is a particular reason to monitor liver function closely.
Toxicity
1. Myelosuppression and other hematologic effects. Uncommon. However, B-cell depletion
occurs in 70% to 80% of patients, with decreased immunoglobulins in a minority of
patients. Infectious events occur in about 30% of patients treated with rituximab, but only
uncommonly are they severe.
2. Nausea, vomiting, and other GI effects. Nausea is common (23%) but rarely severe.
Vomiting and diarrhea are occasional. Bowel obstruction and perforation is rare.
3. Mucocutaneous effects. Pruritus, rash, urticaria, and night sweats are occasional. Severe
mucocutaneous reactions including Stevens–Johnson syndrome, lichenoid dermatitis,
vesiculobullous dermatitis, and toxic epidermal necrolysis are rare but have been reported
from 1 to 13 weeks following rituximab exposure.
4. Immunologic effects and infusion reactions. Infusion-related hypersensitivity reaction
(may include fever, chills, headache, myalgia, weakness, nausea, urticaria, pruritus, throat
irritation, rhinitis, dizziness, and hypertension) is common, but usually resolves with
interrupting or slowing the rate of the infusion and administration of supportive therapy; see
Special Precautions above.
5. Miscellaneous effects
a. Myalgia and arthralgia are occasional. Rarely, a serum sickness-like reaction may be
seen that requires corticosteroid therapy.
b. Hypotension is occasional but rarely severe. Chest pain, bronchospasm, tachycardia,
increased cough, edema, and postural hypotension are uncommon. Severe, though
potentially fatal, cardiac events, including angioedema, arrhythmia, and angina are rare.
c. Renal failure, possibly requiring dialysis, has been seen, particularly in association with
tumor lysis syndrome in patients with high tumor cell burden. Also may be seen if used
in combination with cisplatin.
d. Hepatitis B reactivation with related fulminant hepatitis is rare.
e. Dizziness and anxiety are occasional.
f. Progressive multifocal leukoencephalopathy has been observed in patients with
rheumatoid arthritis treated with rituximab.

ROMIDEPSIN
Other name. Istodax.
Mechanism of action. Inhibits HDACs, enzymes that catalyze the removal of acetyl groups
from lysine residues in histone and thereby modulate gene expression. In some cancer cell
lines, this inhibition allows the accumulation of acetylated histones and induces cell cycle
arrest and apoptosis.
Primary indications. Cutaneous T-cell lymphoma (CTCL) in patients who have received at
least one prior systemic therapy.
Usual dosage and schedule. 14 mg/m2 IV over 4 hours on days 1, 8, and 15 of a 28-day cycle.
Special precautions. There is a risk of QT prolongation; be sure that potassium and
magnesium are within the normal range before administration. Because romidepsin is
metabolized by CYP3A4, avoid coadministration with strong inhibitors or inducers of
CYP3A4 if possible.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, lymphopenia,
and thrombocytopenia are common. Infections are common, and may be fatal.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and anorexia are common.
Constipation is occasional to common.
3. Mucocutaneous effects. Dermatitis, including exfoliative dermatitis and pruritis, are
occasional to common.
4. Miscellaneous effects
a. Fatigue and fever are common.
b. ECG T-wave and ST-segment changes are common, but of uncertain significance.
Supraventricular arrhythmias and ventricular arrhythmias have been observed. There is
risk of QT prolongation, particularly in those with a history of congenital long QT
syndrome, significant cardiovascular disease, or taking medications that lead to
significant QT prolongation. Monitoring of electrolytes and ECG at baseline and during
treatment is recommended. Hypotension is occasional.
c. Hypomagnesemia, hypokalemia, hypocalcemia, and hyperuricemia are occasional to
common, but only rarely severe.
d. Hepatic. Elevated transaminases are occasional to common, but only rarely severe.
However, use caution when using warfarin (Coumadin) or warfarin derivatives.

RUXOLITINIB
Other name. Jakafi.
Mechanism of action. A kinase inhibitor of the Janus-associated kinases (JAKs) JAK1 and
JAK2, the signaling of which is believed to be dysregulated in polycythemia vera (PV) and
myelofibrosis (MF).
Primary indications
1. Intermediate or high-risk primary MF, post-polycythemia MF, and post-essential
thrombocythemia MF.
2. Polycythemia vera in patients who have had inadequate response to or are intolerant of
 hydroxyurea.
Usual dosage and schedule
1. MF dosing:
■ For platelet count of greater than 200 × 109/L: 20 mg orally twice daily.
■ For platelet count between 100 × 109/L and 200 × 109/L: 15 mg orally twice daily.
■ For platelet count between 50 × 109/L and 100 × 109/L: 5 mg orally twice daily.
2. Polycythemia vera dosing: 10 mg orally twice daily.
Dose adjustments and/or interruptions for hematologic toxicity may be required based
on each starting dose. Dose escalation for inadequate response can be done after the first 4
weeks of therapy and not more frequent than every 2 weeks by 5 mg daily increments for a
maximum total dose of 25 mg twice daily. Dose modification is also required when used
with strong CYP3A4 inhibitors or fluconazole in doses equal to or less than 200 mg daily.
Concomitant use of fluconazole doses of greater than 200 mg daily should be avoided.
Starting dose modification is also required for patients with renal and/or hepatic
impairment.
Special precautions
1. Ruxolitinib can cause fetal harm if administered to a pregnant woman based on its
mechanism of action. Since there is no adequate evidence in pregnant women, it should be
used in this patient population only if benefits justify potential risks to the fetus.
2. Treatment should be interrupted for any clinical bleeding requiring intervention regardless
of the platelet count. If the bleeding and the underlying cause are controlled, treatment can
be resumed at the same dose. If the bleeding is controlled but the underlying cause persists,
treatment should be resumed at one level dose reduction.
3. Symptoms of MF may return to pretreatment level over 1 week after discontinuation of
therapy. Some patients may also develop fever, DIC, respiratory distress, hypotension or
multiorgan failure. Gradual tapering of the dose is recommended rather than abrupt
discontinuation except for cases of neutropenia and/or thrombocytopenia.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common with median time
to onset of 6 weeks and nadir occurring after 8 to 12 weeks. Neutropenia is common but
rarely severe, usually reversible with dose interruption, and rarely requires discontinuation
of treatment. Thrombocytopenia is common with median time to onset of 8 weeks,
occasionally resulting in epistaxis and/or skin bruising.
2. Nausea, vomiting, and other GI effects. Nausea, diarrhea, constipation, and abdominal
pain are occasional and rarely severe. Increase in ALT/AST levels is common but rarely
severe.
3. Mucocutaneous effects. Pruritus is occasional. Cases of nonmelanoma skin cancers have
been reported, and periodic skin examination is recommended.
4. Immunologic effects and infusion reactions. Tuberculosis (TB) infections have been
reported. Patients should be assessed for TB risk factors prior to initiation of treatment and
 managed accordingly. The decision to continue ruxolitinib during TB treatment should be
based on risk-benefit determination. H. zoster reactivation is uncommon. Urinary tract
infections are occasional, but rarely severe.
5. Miscellaneous effects
a. General. Weight gain and fatigue are occasional.
b. Respiratory. Dyspnea, cough, and nasopharyngitis are occasional, but rarely severe.
c. Cardiovascular. Peripheral edema is occasional, but rarely severe.
d. Metabolic: Hypercholesterolemia and hypertriglyceridemia are common, but rarely
severe.
e. Neurologic. Headache is occasional. Dizziness is common. Cases of progressive
multifocal leukoencephalopathy are rare.
f. Musculoskeletal and connective tissue. Arthralgia and muscle spasms are occasional.

SILTUXIMAB
Other name. Sylvant.
Mechanism of action. Binds to human IL-6 and inhibits its binding to its soluble and
membrane bound receptors.
Primary indications. Multicentric Castleman disease, which is human immunodeficiency virus
(HIV) negative and human herpes virus-8 (HHV-8) negative.
Usual dosage and schedule. 11 mg/kg as an IV infusion over 1 hour given every 3 weeks.
Hematology laboratory tests should be monitored prior to each dose for the first 12 months,
then every three dosing cycles. There are no data to recommend an appropriate dose for
patients with baseline severe hepatic impairment as such patients were excluded from the
clinical trials.
Special precautions
1. Siltuximab can cause fetal harm if administered to a pregnant woman.
2. Patients with infections should be fully treated before treatment is started/reinitiated as
siltuximab can mask signs and symptoms of acute inflammation.
3. Live vaccinations should not be administered to patients receiving siltuximab treatment.
4. Treatment-related GI perforations can occur.
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia is occasional.
2. Nausea, vomiting, and other GI effects. Constipation is occasional. Abdominal pain and
distension are occasional.
3. Mucocutaneous effects. Rash and pruritus are common. Cases of eczema, psoriasis, and
dry skin were uncommonly observed and mostly mild.
4. Immunologic effects and infusion reactions. Infusion-related reactions can occur and can
be severe (including cases of anaphylaxis). These reactions may require infusion
 interruption and slower rate of infusion, in addition to general medical management.
Premedication with acetaminophen, antihistamines, and corticosteroids is recommended
prior to subsequent infusions in patients who develop such reactions. Upper respiratory
tract infections are common, and lower respiratory tract infections are occasional.
5. Miscellaneous effects
a. General. Weight loss is common.
b. Respiratory. Oropharyngeal pain is occasional.
c. Cardiovascular. Generalized and localized edema is common and occasionally severe.
Hypotension is occasional and rarely severe.
d. Metabolic. Hyperuricemia is occasional and uncommonly severe. Hypercholesterolemia
and hypertriglyceridemia are occasional.
e. Neurologic. Headache is occasional.
f. Genitourinary. Renal impairment is occasional and rarely severe.

SOMATOSTAIN ANALOGS
Other names. Octreotide, Sandostatin, Sandostatin LAR depot. (Other related analogs are
pasireotide and lanreotide.)
Mechanism of action. Somatostatin analog that inhibits release of polypeptide hormones,
particularly in the pancreas and gut. Slows GI transit time. Promotes water and electrolyte
absorption, reflecting change from overall secretory to absorptive state.
Primary indications
1. Carcinoid tumors.
2. Vasoactive intestinal peptide tumors and other amine precursor uptake and decarboxylation
tumors.
3. Chemotherapy-induced diarrhea.
4. Acromegaly.
Usual dosage and schedule. 100 to 1,500 µg/day SC of the nondepot preparation, in two to
four divided doses. Doses are usually started at the lower end and titrated upward to the best
symptomatic improvement. If patients respond favorably to the rapid-acting SC injections, they
may be maintained on 10 to 40 mg IM of the depot preparation by intragluteal injection every 4
weeks. Caution should be used in treating >3 months.
Special precautions. Lower doses indicated if severe renal dysfunction (creatinine > 5
mg/dL).
Toxicity
1. Myelosuppression and other hematologic. None.
2. Nausea, vomiting, and other GI. Nausea abdominal discomfort, bloating, and diarrhea are
common, particularly early in early therapy. Vomiting is only occasionally seen.
3. Mucocutaneous effects. Local site reactions are occasional; other effects are rare.
4. Miscellaneous effects
a. Hypoglycemia or hyperglycemia is uncommon; hypothalamic-pituitary dysfunction is
rare.
b. Bradycardia and other conduction abnormalities occur in up to 25% of patients with
acromegaly who are treated with octreotide.
c. Biliary: Decreased gall bladder contractility and decreased bile secretion may result in
biliary abnormalities. Gallstones develop in less than 2% if treatment is for 1 month or
less but can be 25% if treatment is for 1 year or more. Ascending cholangitis and
pancreatitis are uncommon to rare.

SONIDEGIB
Other name. Odomzo.
Mechanism of action. Inhibitor of the Hedgehog pathway.
Primary indications. Treatment of locally advanced basal cell carcinoma (BCC) that has
recurred following surgery or radiation therapy. It is also indicated in patients who are not
candidates for surgery or radiation therapy.
Usual dosage and schedule. 200 mg taken orally once daily on an empty stomach, at least 1
hour before or 2 hours after a meal. Dose interruption and permanent discontinuation might be
indicated in moderate-to-severe cases of elevation in creatine kinase (CK), renal dysfunction,
and musculoskeletal adverse reactions.
Special precautions
1. Sonidegib can cause fetal harm if administered to a pregnant woman.
2. Musculoskeletal adverse reactions, which may be accompanied by serum CK (CK)
elevations, renal dysfunction, and rhabdomyolysis (defined as serum CK increase of more
than 10 times the baseline value with a concurrent 1.5-fold or greater increase in serum
creatinine above baseline value) may occur and result in dose interruption and permanent
discontinuation depending on the severity.
3. Use should be avoided with strong and moderate CYP3A inducers or inhibitors.
4. Although no dose adjustment is recommended for patients with mild hepatic impairment
(total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >
ULN or total bilirubin > 1.0 to 1.5 times ULN), sonidegib has not been studied in patients
with moderate or severe hepatic impairment.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common, but rarely severe.
Lymphopenia is common and uncommonly severe.
2. Nausea, vomiting, and other GI effects. Nausea and diarrhea are common, but
uncommonly severe. Abdominal pain is common and rarely severe. Vomiting is occasional
and mostly mild.
3. Mucocutaneous effects. Alopecia and pruritus are common, but rarely severe.
4. Immunologic effects and infusion reactions. None reported.
5. Miscellaneous effects
a. General. Fatigue is common but rarely severe. Decreased weight and appetite are
common, but uncommonly severe.
b. Metabolic. Hyperglycemia, increased alanine aminotransferase (ALT), increased AST,
and increased amylase are common, but uncommonly severe. Increased serum CK and
increased lipase are common and occasionally severe.
c. Neurologic. Dysgeusia is common, but rarely severe. Headache is occasional, but
uncommonly severe.
d. Musculoskeletal and connective tissue. Muscle spasm and musculoskeletal pain are
common and occasionally severe. Increased serum CK is common and occasionally
severe. This is mostly preceded by the former musculoskeletal reactions mentioned.
Obtaining serum CK and creatinine levels at least weekly is recommended in patients
with other musculoskeletal symptoms.

SORAFENIB
Other name. Nexavar.
Mechanism of action. Inhibition of multiple tyrosine kinases and serine/threonine kinases
within tumor cells and tumor vasculature resulting in decreased tumor cell proliferation and
reduction of tumor angiogenesis.
Primary indications
1. Renal cell carcinoma.
2. Hepatocellular carcinoma.
3. Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to
radioactive iodine treatment.
4. GI stromal tumors with prior imatinib or sunitinib treatment.
Usual dosage and schedule. 400 mg PO twice daily either without food or with a moderate fat
meal.
Special precautions. Increased risk of bleeding compared with placebo. In patients also taking
warfarin, sorafenib may increase the prothrombin time and INR, resulting in increased risk of
bleeding. May increase AUC of compounds metabolized by UGT1A1 pathway (e.g.,
irinotecan). Also increases AUC of docetaxel, doxorubicin, and in some patients, fluorouracil.
Toxicity
1. Myelosuppression and other hematologic effects. Lymphopenia is common; anemia,
neutropenia, and thrombocytopenia are occasional; various bleeding events (including
epistaxis, GI hemorrhage, respiratory tract hemorrhage, hematomas) are common but only
rarely life-threatening.
2. Nausea, vomiting, and other GI effects. Diarrhea is common (33%); nausea and vomiting
are occasional to common (10% to 20%); anorexia and constipation are occasional.
Increased amylase and lipase are common, and transient increases in transaminases are
occasional. Clinical pancreatitis is uncommon. GI perforation is rare.
3. Mucocutaneous effects. HFSR is common (27%). Alopecia is common (23%). Pruritis is
occasional to common (17%). Other skin changes are rare to uncommon.
4. Miscellaneous effects
a. Hypertension, usually mild to moderate, is occasional. Hypertensive crisis is rare.
b. Fatigue is common.
c. Sensory neuropathy is occasional (10%).
d. Hypophosphatemia is common (41%) (Unknown etiology.)
e. Cardiac ischemia or infarction is uncommon.

STREPTOZOCIN
Other names. Streptozotocin, Zanosar.
Mechanism of action. Inhibition of DNA synthesis, possibly by interference with pyridine
nucleotide synthesis. Streptozocin appears to have some specificity for neoplastic pancreatic
endocrine cells. Glucose moiety attached to nitrosourea appears to diminish myelotoxicity.
Primary indications
1. Pancreatic islet cell and pancreatic exocrine carcinomas.
2. Carcinoid tumors.
Usual dosage and schedule
1. 1.0 to 1.5 g/m2 IV weekly for 6 weeks followed by 4 weeks of observation.
2. 1 g/m2 IV days 1 and 8 in combination with fluorouracil and mitomycin. Repeat every 4
weeks.
3. 500 mg/m2 IV on days 1 to 5 every 6 weeks.
Special precautions
1. A 30- to 60-minute infusion is recommended to reduce local pain and burning around the
vein during treatment.
2. Avoid extravasation.
3. Have 50% glucose available to treat sudden hypoglycemia.
Toxicity
1. Myelosuppression and other hematologic effects. Uncommon and mild.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are common and severe.
May become progressively worse over 5-day course of therapy.
3. Mucocutaneous effects. Uncommon.
4. Miscellaneous effects
a. Renal toxicity is common. Although it is not clearly dose-related, it may limit continued
 drug use in individual patients. Proteinuria, glucosuria, azotemia, and
hypophosphatemia, if persistent or severe, are indications to discontinue therapy.
Hydration may ameliorate the problem.
b. Hypoglycemia. In patients with insulinoma, hypoglycemia may be severe (although
transient) owing to a burst of insulin release.
c. Hyperglycemia is uncommon in normal or diabetic patients, as normal β cells are usually
insensitive to the effect of streptozocin.
d. Transient mild hepatotoxicity is occasional.
e. Second malignancies are possible.

SUNITINIB
Other names. Sutent, Sunitinib malate.
Mechanism of action. Inhibition of multiple receptor tyrosine kinases (RTK), including
platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and
several forms of the mutation-activated stem cell factor receptor (KIT) with consequent
inhibition of tumor cells expressing dysregulated target RTKs and tumor angiogenesis.
Metabolized primarily by the cytochrome P450 enzyme allele, CYP34A.
Primary indications
1. GI stromal tumor that has shown progression during prior treatment with imatinib or in
patients who are intolerant to imatinib.
2. Advanced renal cell carcinoma.
3. Neuroendocrine tumors of the pancreas.
4. Angiosarcoma.
5. Metastatic papillary, medullary, follicular, and Hürthle cell thyroid carcinoma.
Usual dosage and schedule. 50 mg PO daily for 4 weeks followed by a 2-week rest, with
incremental dose reductions or increase (12.5 mg/day) based upon tolerability.
Special precautions. Dose reduction should be considered when administered concurrently
with strong CYP3A4 inhibitors. Dose increase should be considered when administered
concurrently with strong CYP3A4 inducers. Prolonged QT intervals and torsade de pointes
have been observed. Use with caution in patients at higher risk for developing QT interval
prolongation.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression and lymphopenia
are common, but it is uncommon to rare for them to be high grade (3 or 4). Bleeding is
occasional, with possible tumor-related hemorrhage. Venous thromboembolic events are
uncommon.
2. Nausea, vomiting, and other GI effects. Diarrhea, nausea, vomiting, anorexia, and
abdominal pain are common. Rare fatal GI complications, including perforation have been
 seen. Hepatic and pancreatic enzyme elevations and other liver function abnormalities are
occasional to common.
3. Mucocutaneous effects. Stomatitis is common. Skin discoloration is common. Rash and
hand-foot syndrome are occasional. Alopecia is uncommon.
4. Miscellaneous effects
a. Congestive heart failure with decrease in LVEF to below the lower limit of normal is
occasional (15%).
b. Hypertension. Occasional, but severe hypertension is uncommon.
c. Adrenal insufficiency. Possible, based on animal studies.
d. Asthenia, headache, arthralgia, myalgia, oral pain, and back pain are occasional.
e. Cough and dyspnea are occasional.
f. Renal function abnormalities (low grade) are occasional. Hypo- and hyperkalemia,
hypo- and hypernatremia, and hypophosphatemia are occasional.
g. Hypothyroidism is uncommon.
h. Edema is occasional.

TAMOXIFEN
Other name. Nolvadex.
Mechanism of action. Tamoxifen is a selective ER modulator that inhibits estrogen effects by
competing with estrogen for binding on the cytosol ER protein in cancer cells. This complex is
probably transported into the nucleus, where it affects nucleic acid function. It also has effects
on cellular growth factors, epidermal growth factors, and TGF-α and TGF-β.
Primary indications
1. Breast carcinoma.
a. Metastatic tumors in postmenopausal or premenopausal women with estrogen-receptor
positive (or unknown) tumors.
b. Adjuvant therapy in women with estrogen-receptor positive (or progesterone-receptor
positive) tumors after primary therapy. Optimal duration of therapy for most
premenopausal women is 5 years. For postmenopausal women, aromatase inhibitors are
substituted after 2 to 3 years of tamoxifen or given instead of tamoxifen.
c. Breast cancer prevention in very high-risk women, including women with carcinoma in
situ of the breast after primary therapy.
Usual dosage and schedule. 20 mg PO as single daily dose.
Special precautions. Hypercalcemia may be seen during initial therapy. Use of selective
serotonin reuptake inhibitors (except citalopram, and escitalopram and the SNRI venlafaxine)
with tamoxifen decreases formation of endoxifen, the active metabolite of tamoxifen, by
inhibition of CYP2D6, and should be avoided, if possible.
Toxicity
1. Myelosuppression and other hematologic effects. Myelosuppression is uncommon and
mild. Thromboembolic phenomena are rare, unless prior thromboembolic disease.
2. Nausea, vomiting, and other GI effects. Nausea occurs early in the course of therapy in
up to 20% of patients but abates rapidly as therapy is continued. Diarrhea is occasional.
3. Mucocutaneous effects. Cataracts and other eye toxicities have been observed, but effects
due to drug are uncommon. Skin rash and pruritus vulvae are uncommon. May cause
increase or marked decrease in vaginal secretions and result in difficult or painful
intercourse.
4. Miscellaneous effects
a. Thromboembolism and strokes are rare but increased among women taking tamoxifen.
b. Hot flashes are common.
c. Vaginal bleeding and menstrual irregularity are uncommon to occasional.
d. Lassitude, headache, leg cramps, and dizziness are uncommon.
e. Peripheral edema is occasional.
f. Increased bone pain, tumor pain, and local disease flare (associated both with good
tumor response as well as with tumor progression) are occasional.
g. Slowed progression of osteoporosis.
h. Reduction in serum cholesterol with favorable changes in lipid profile.
i. Liver function test abnormalities are occasional.
5. Uterine carcinomas are rare (two to four times the predicted incidence in adjuvant trials).

TEMOZOLOMIDE
Other name. Temodar.
Mechanism of action. Undergoes rapid conversion to the reactive substituted imidazole
carboxamide, MTIC. This compound is believed to be active primarily through alkylation
(methylation) of DNA at the O6 and N7 positions of guanine.
Primary indications
1. Glioblastoma, concurrently with radiotherapy and as maintenance after radiotherapy.
2. Anaplastic astrocytoma that is refractory to nitrosoureas.
3. Melanoma.
4. Metastatic carcinomas to the brain.
Usual dosage and schedule
1. 150 to 200 mg/m2 PO on an empty stomach daily for 5 days every 28 days.
2. 75 mg/m2 PO on an empty stomach daily during radiation therapy for up to 7 weeks.
Special precautions. Contraindicated in patients with a hypersensitivity to dacarbazine
(DTIC), since both drugs are metabolized to MTIC. Preventive treatment for pneumocystis
jirovecii pneumonia is required when temozolomide is administered with radiotherapy.
Toxicity
1. Myelosuppression and other hematologic. Myelosuppression with anemia,
thrombocytopenia, and neutropenia, is common and dose dependent, but only occasionally
is it severe.
2. Nausea, vomiting, and other GI. Nausea and constipation are common, but usually not
severe. Vomiting is occasional as is anorexia. Abdominal pain is uncommon.
3. Mucocutaneous effects. Rash and pruritis are occasional. Alopecia is common.
4. Miscellaneous effects
a. Headache, fatigue, asthenia, and fever are common (20% to 65%).
b. Peripheral edema is occasional.
c. Neurologic symptoms are common on temozolomide, but it is difficult to distinguish
whether the symptoms are from the drug or the disease. Common findings are
convulsions, hemiparesis, dizziness, abnormal coordination, amnesia, or insomnia.
Occasional findings are paresthesias, somnolence, paresis, incontinence, ataxia,
dysphasia, gait abnormality, myalgias, and confusion. Diplopia or other visual
abnormalities are occasional.
d. Anxiety and depression are occasional.
e. Upper respiratory and urinary tract infections are occasional.
f. MDS, acute leukemia, and other secondary malignancies have been observed.

TEMSIROLIMUS
Other names. Torisel, CCI-779.
Mechanism of action. After temsirolimus complexes with the immunophilin FKBP12, the
complex inhibits mTOR (mammalian Target Of Rapamycin) kinase activity. mTOR, as a master
regulator of cell physiology, is involved in regulation of cell growth and angiogenesis, and
changes that are induced downstream from mTOR as a consequence of the temsirolimus
inhibition lead to cell cycle arrest at the G1 phase.
Primary indications. Renal cell carcinoma.
Usual dosage and schedule
1. 25 mg IV over a 30- to 60-minute period weekly.
2. Reduce dose to 12.5 mg/week if patients must be coadministered a strong CYP3A4
inhibitor.
3. An increase from 25 mg/week up to 50 mg/week should be considered if patients must be
coadministered a strong CYP3A4 inducer.
Special precautions. The concomitant use of strong CYP3A4 inhibitors or inducers should be
avoided, if possible. Not recommended in combination with sunitinib. Avoid live vaccines.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia and thrombocytopenia are
common. Venous thrombosis and embolism are uncommon.
2. Nausea and vomiting and other GI effects. Anorexia, nausea, and vomiting are common.
Diarrhea and abdominal pain are common. Bowel perforation may occur rarely.
3. Mucocutaneous effects. Mucositis is common. Maculopapular rash or acne is common.
Nail disorders are common. Wound healing may be impaired.
4. Immunologic effects and infusion reactions. Hypersensitivity reactions manifested by
symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have
been observed occasionally.
5. Miscellaneous effects
a. Asthenia, edema, and fever are common
b. Dyspnea and cough are common
c. Increased liver transaminases and alkaline phosphatase are common; increased bilirubin
is occasional.
d. Back pain, arthralgia, myalgia are occasional.
e. Headache, chills and chest pain are occasional.
f. Hyperglycemia is common and occasionally severe.
g. Hypophosphatemia is occasional and may be severe.
h. Hypertriglyceridemia is common and may be severe.
i. ILD is uncommon.
j. Creatinine is commonly increased, but renal failure is rare.
k. Taste perversion is common.

THALIDOMIDE
Other name. Thalomid.
Mechanism of action. Multiple potential mechanisms, including inhibition of vascular
endothelial growth factor, inhibition of TNF-α, direct inhibition of G1 growth and promotion
of apoptosis, and expansion of NK cells, and co-stimulation of T cells.
Primary indications
1. Multiple myeloma.
2. MDS.
3. Primary MF.
Usual dosage and schedule. A starting dose of 50 to 100 mg PO once daily in the evening. The
dose is escalated weekly by 50 to 100 mg until the maximum dose specified, commonly 400
mg daily.
Special precautions. Severe and life-threatening birth defects, primarily phocomelia, can be
caused by taking even a single 50 mg dose. For this reason, special precautions must be taken
to assure that female patients are not pregnant when the drug is started, and that both female
and male patients practice strict birth control measures. Prophylactic anticoagulation or aspirin
may diminish frequency of thromboembolism.
Toxicity
1. Myelosuppression and other hematologic effects. Minimal myelosuppression in most
patients. Hypercoagulability with deep venous thrombosis is common (22%) in patients
receiving in combination with dexamethasone.
2. Nausea, vomiting, and other GI effects. Constipation is common.
3. Mucocutaneous effects. Macular rash, usually involving trunk, is common. Alopecia is
uncommon. Rare severe or life-threatening epidermal damage.
4. Miscellaneous effects
a. Dose-dependent somnolence and dizziness are common. Tolerance usually develops to
the sedative effects. Dizziness may be related to hypotension and can be minimized by
adequate hydration and avoidance of rapid postural changes.
b. Peripheral neuropathy is common (25%) with chronic therapy. Occasional patients
develop myalgia, tremor, or muscle spasms.
c. Fatigue is common.
d. Headache is occasional.
e. Edema is occasional to common.
f. Hypothyroidism is occasional.
g. Birth defects (see Special Precautions above).

THIOTEPA
Other names. Triethylenethiophosphoramide, Thioplex.
Mechanism of action. Alkylating agent similar to mechlorethamine.
Primary indications
1. Superficial papillary carcinoma of urinary bladder.
2. Malignant peritoneal, pleural, or pericardial effusions.
3. Neoplastic meningeal infiltrates.
Usual dosage and schedule
1. 30 to 60 mg in 40 to 50 mL water instilled into the bladder and retained for 1 hour. Dose is
repeated weekly for 3 to 6 weeks, then every 3 weeks for 5 cycles.
2. 25 to 30 mg/m2 in 50 to 100 mL saline solution as a single intracavitary injection. Dose may
be repeated as tolerated by blood counts.
3. 10 to 15 mg intrathecally.
Special precautions. Dose should be reduced in patients with impaired renal function, as the
drug is primarily excreted in the urine.
Toxicity
1. Myelosuppression and other hematologic. Dose-limiting. Pancytopenia and sepsis may
follow intravesical or intracavitary administration. Nadir counts are reached in 1 to 2
weeks; recovery by 4 weeks is usual.
2. Nausea, vomiting, and other GI. Uncommon.
3. Mucocutaneous effects. Uncommon. Thiotepa is not a vesicant. Hyperpigmentation of skin
occurs at high doses.
4. Miscellaneous effects
a. Local pain, dizziness, headache, and fever are uncommon.
b. Secondary neoplasms are possible.
c. Amenorrhea and azoospermia is common.
d. CNS effects with high-dose therapy.

TOPOTECAN
Other name. Hycamtin.
Mechanism of action. Topotecan, a semisynthetic derivative of camptothecin, is a potent
inhibitor of topoisomerase I, an enzyme essential for effective replication and transcription. It
binds to the topoisomerase I—DNA cleavable complex, preventing religation after cleavage
by topoisomerase I.
Primary indications
1. Ovarian carcinoma.
2. Carcinoma of the cervix.
3. Small cell and non–small cell carcinoma of the lung.
Usual dosage and schedule
1. As a single agent, 1.5 mg/m2 IV as a 30-minute infusion daily times five every 3 weeks.
2. In combination with cisplatin, 0.75 mg.m2 IV as a 30-minute infusion daily times three
every 3 weeks.
Special precautions. None.
Toxicity
1. Myelosuppression and other hematologic. Leukopenia is universal and dose limiting.
Anemia and thrombocytopenia are common and occasionally severe. Febrile neutropenia is
occasional to common.
2. Nausea, vomiting, and other GI. Nausea and vomiting and diarrhea are common, but
usually mild. Other GI symptoms, including constipation and abdominal pain, occur
occasionally.
3. Mucocutaneous effects. Alopecia is common; stomatitis is occasional but usually mild;
skin rash is rare.
4. Miscellaneous effects
a. Fever, headache, fatigue, and weakness are common (15% to 25%), but rarely severe.
b. Microscopic hematuria is occasional.
c. Dyspnea occurs occasionally, but it is uncommon for it to be severe.
d. Infection as a consequence of severe leukopenia is common.
TOREMIFENE
Other name. Fareston.
Mechanism of action. A selective ER modulator that inhibits estrogen effects by competing
with estrogen for binding on the cytosol ER protein in cancer cells. The receptor:hormone
complex ultimately controls the promoter region of genes that affect cell growth.
Primary indications. Metastatic carcinoma of the breast in postmenopausal women with ER–
positive (or unknown) tumors.
Usual dosage and schedule. 60 mg PO daily.
Special precautions. Uncertain whether it has any carcinogenic effect on endometrium as has
been observed with tamoxifen. May result in increased prothrombin time in patients taking
warfarin (Coumadin). Cytochrome P450 3A4 enzyme inhibitors, such as phenobarbital,
phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the
concentration in the serum.
Toxicity
1. Myelosuppression and other hematologic. Uncommon and mild. Thromboembolic
phenomena are rare.
2. Nausea, vomiting, and other GI. Minimal nausea is common early in treatment; vomiting
is uncommon.
3. Mucocutaneous effects. Dry eyes, cataracts are rare. May cause an increase or decrease
in vaginal secretions; which may result in difficult or painful intercourse.
4. Miscellaneous effects
a. Hot flashes are common.
b. Dizziness is occasional.
c. Sweating is occasional.
d. Vaginal discharge, bleeding, and menstrual irregularity are occasional.
e. Hypercalcemia is uncommon.
f. Occasional elevation of liver function tests.

TRABECTEDIN
Other name. Yondelis.
Mechanism of action. Alkylating agent that binds guanine residues in the minor groove of
DNA, forming adducts and resulting in a cascade of events that lead to cell cycle arrest and
cell death.
Primary indications. Unresectable or metastatic liposarcoma or leiomyosarcoma after a prior
anthracycline-containing regimen.
Usual dosage and schedule. 1.5 mg/m2 as IV infusion over 24 hours every 21 days until
disease progression or intolerable toxicity. Dexamethasone 20 mg IV is administered prior to
each infusion.
Special precautions
1. Fatal cases of neutropenic sepsis have been reported but uncommon.
2. Trabectedin can cause fetal harm if administered to a pregnant woman.
3. Concomitant use of strong CYP3A inducers and/or inhibitors should be avoided.
4. Fatal cases of rhabdomyolysis were reported but rare.
5. Extravasation resulting in tissue necrosis, requiring debridement, can occur.
6. Trabectedin was not adequately studied in patients with serum bilirubin higher than normal
and serum AST/ALT above 2.5 ULN.
Toxicity
1. Myelosuppression and other hematologic effects. Neutropenia is common, commonly
severe, and could result in fatal sepsis. Anemia and thrombocytopenia are common and
commonly severe.
2. Nausea, vomiting, and other GI effects. Not reported.
3. Immunologic effects and infusion reactions. Not reported.
4. Miscellaneous effects
a. General. Fatigue is common and occasionally severe. Decreased appetite is common.
b. Respiratory. Dyspnea is common, but uncommonly severe.
c. Cardiovascular. Cardiomyopathy including congestive heart failure, ejection fraction
decreased, diastolic dysfunction, or right ventricular dysfunction is occasional,
uncommonly severe, and rarely fatal. Peripheral edema is common and rarely severe.
d. Metabolic. Elevated liver function tests are common and commonly severe.
e. Neurologic. Headache is common, but rarely severe.
f. Musculoskeletal and connective tissue. Arthralgia is common, and myalgia is
occasional but those are rarely severe.
g. Renal. Increased creatinine is common, but uncommonly severe.
h. Psychiatric. Insomnia is occasional and rarely severe.

TRAMETINIB
Other name. Mekinist.
Mechanism of action. Reversible inhibitor of mitogen-activated extracellular signal-regulated
kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. This
mechanism results in inhibition of cell growth and proliferation in BRAF V600 mutation–
positive melanoma cells. Combined use with the BRAF inhibitor, dabrafenib, results in greater
and prolonged growth inhibition of the BRAF V600 mutation–positive melanoma cells
compared with either drug alone.
Primary indications
1. BRAFV600E or BRAFV600K mutation–positive unresectable or metastatic melanoma alone or
in combination with dabrafenib.
Usual dosage and schedule
■ 2 mg orally daily as a single agent until disease progression or unacceptable toxicity.
■ 2 mg orally daily in combination with dabrafenib 150 mg orally taken twice daily.
To be taken 1 hour before or 2 hours after a meal. Missed doses can be taken up to 12 hours
prior to the next dose. When taken with dabrafenib, the dose should be taken at the same time
daily with either the morning or the evening dose of dabrafenib. Dose
modifications/interruptions and/or permanent discontinuation may be indicated for cutaneous,
cardiac, pulmonary, and ocular toxicities (see Special Precautions section). While the
appropriate dose has not been established for patients with moderate-to-severe hepatic
impairment and for those with severe renal impairment (GFR less than 30 mL/min/1.73 m2), no
dose adjustments are recommended for patients with mild hepatic impairment (normal total
bilirubin and AST higher than ULN or any AST and total bilirubin up to 1.0 to 1.5 times the
ULN) and for those with mild-to-moderate renal impairment.
Special precautions
1. Trametinib is teratogenic and can cause fetal harm if administered to a pregnant woman. It
can also impair fertility in men.
2. Cardiomyopathy, defined as cardiac failure, left ventricular dysfunction, or decreased
LVEF, can occur in up to 11% of patients. Assessment of LVEF by echocardiogram or
MUGA scan before initiating the treatment is recommended. Monitoring with either
modality is recommended 1 month after starting treatment and every 2 to 3 months thereafter
while on treatment. Dose interruption is indicated if the LVEF decreases by 10% or more
from pretreatment values. Reassess LVEF in 4 weeks, and if it is back to baseline, resume
treatment with dose reduction. Permanent discontinuation is warranted for symptomatic
cardiomyopathy or persistent, asymptomatic LVEF dysfunction that does not resolve within
4 weeks of holding treatment. Of note, patients with history of acute coronary syndrome
within 6 months, evidence of class II NYHA or greater congestive heart failure or abnormal
LVEF at baseline were excluded from the clinical trial of trametinib.
3. Ocular toxicities. Retinal pigment epithelial detachment resulting in decreased visual
acuity can occur. However, the incidence is low, approximately 0.8%, and usually resolves
within a median of 12 days after treatment interruption. Abnormalities on ocular coherence
tomography can persist beyond a month. Ophthalmologic evaluation is recommended before
initiating treatment and at any time a patient reports visual disturbances. Hold trametinib if
retinal pigment epithelial detachment is diagnosed. If resolution on a repeat ophthalmologic
exam within 3 weeks is documented, resume treatment at a one level dose reduction.
Retinal vein occlusion leading to macular edema, decreased visual functions,
neovascularization, and glaucoma can also occur, but the incidence is rare, approximately
0.2%. Permanent discontinuation of treatment is recommended for any severity of treatment-
related retinal vein occlusion.
4. Interstitial lung disease or pneumonitis can occur in 1.8% of patients. Signs and symptoms
include dyspnea, cough, hypoxia, pleural effusions, and infiltrates. Permanent
discontinuation of treatment is recommended for any severity of treatment-related ILD or
pneumonitis.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia is common. Cases of
hemorrhage (including epistaxis, gingival bleeding, hematochezia, conjunctival hemorrhage,
vaginal hemorrhage, hemorrhoids hemorrhage, and hematuria) can occur in up to 13% of
patients. Most of these events are grade 1 or 2 (less than 1% grade 3 or greater).
2. Nausea, vomiting, and other GI effects. Diarrhea is common. Abdominal pain is
occasional.
3. Mucocutaneous effects. Xerostomia and stomatitis are occasional. Rash, including
acneiform, is common. Paronychia and pruritus are occasional. Folliculitis, cellulitis, and
pustular rash are occasional.
4. Miscellaneous effects
a. Cardiovascular. Bradycardia can occur in less than 10% of patients. Peripheral edema
is common in 32% of patients. Hypertension occurred in 15% of patients, and 12% of
cases were grade 3 or greater. See Special Precautions for other cardiac toxicities.
b. Hepatic. Increases in ALT, AST, and/or alkaline phosphatase are common, but grade 3
or 4 are uncommon.
c. Ophthalmic. Blurry vision and dry eyes can occur in less than 10% of patients. See
Special Precautions for other ophthalmic toxicities.
d. Neurologic. Dizziness and dysgeusia can occur in less than 10% of patients.
e. Musculoskeletal and connective tissue. Cases of rhabdomyolysis have been described
in less than 10% of patients.

TRASTUZUMAB
Other names. Humanized anti-HER2 antibody, Herceptin.
Mechanism of action. A recombinant humanized monoclonal antibody that targets the
extracellular domain of the human epidermal growth factor receptor protein, HER2.
(p185HER2).
Primary indications
1. Carcinoma of the breast that has overexpression of HER2 (c-erbB-2), either in advanced
disease or as adjuvant therapy.
2. Metastatic gastric or gastroesophageal junction adenocarcinoma and other carcinomas that
exhibit overexpression of HER2.
Usual dosage and schedule
1. Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV
 infusion every 3 weeks for 52 weeks (adjuvant breast cancer), or
2. Initial dose of 4 mg/kg IV over 90 minutes, then 2 mg/kg IV over 30 minutes weekly.
In advanced breast cancer or other cancers, continue treatment until disease progression or
intolerable toxicity.
Special precautions
1. During the first infusion, and occasionally during later infusions, a systemic symptom
complex similar to that seen with other human monoclonal antibodies is common. Severe
hypersensitivity reactions and pulmonary adverse events have been reported, but are
uncommon to rare. These events include anaphylaxis, angioedema, bronchospasm,
hypotension, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, noncardiogenic
pulmonary edema, and acute respiratory distress syndrome. A more common symptom
complex consists of mild-to-moderate chills, fever, asthenia, pain, nausea, vomiting, and
headache. These latter symptoms are generally well managed by temporary slowing or
interruption of the infusion and administration of acetaminophen, diphenhydramine, and
meperidine.
2. Cardiac dysfunction (cardiac symptoms or an asymptomatic decrease in ejection fraction of
10% or greater) occurs in about 7% of patients treated with trastuzumab alone, but in 28%
of patients treated with trastuzumab plus anthracycline and in 11% of patients treated with
trastuzumab plus paclitaxel. In most cases, this improves with symptomatic therapy. Severe
disability or death from cardiac dysfunction occurs in about 1% of patients. Extreme
caution should be exercised in treating patients with preexisting cardiac dysfunction.
Toxicity
1. Myelosuppression. Uncommon.
2. Nausea, vomiting, and other GI. Nausea and vomiting are common with the first infusion.
Diarrhea is also common.
3. Mucocutaneous effects. A rash is occasional to common, and may be associated with
urticaria or pruritus.
4. Miscellaneous effects
a. Mild-to-moderate chills, fever, asthenia, pain, and headache are common, primarily
during the first infusion.
b. Cardiac dysfunction occurs in about 7% of patients treated with trastuzumab alone, but
28% of patients treated with trastuzumab plus anthracycline and in 11% of patients
treated with trastuzumab plus paclitaxel. In most cases, this improves with symptomatic
therapy.
c. Chest pain, back pain, dyspnea, and cough are occasional to common.
d. Peripheral edema is occasional.

TRETINOIN
Other names. All-trans-retinoic acid, t-RNA, ATRA, Vesanoid, Retin-A.
Mechanism of action. Binds to cytoplasmic retinoic acid–binding proteins and then is
transported to the nucleus, where it interacts with nuclear retinoic acid receptors. These then
affect expression of the genes that control cell growth and differentiation. In acute
promyelocytic leukemia (APL), which characteristically has a chromosomal translocation,
t(15:17), abnormal mRNA transcripts are seen for RAR-α, the gene for which is on
chromosome 17.
Primary indication. Acute promyelocytic leukemia for induction of remission.
Usual dosage and schedule. 45 mg/m2 PO daily (divided into two doses in the morning and 6
hours later) until 30 days after complete remission is documented, up to a maximum of 90 days.
Therapy usually initiated concurrently with anthracycline.
Special precautions. Avoid use in pregnant women because of marked teratogenic potential.
Advise patient to avoid pregnancy by using two reliable contraceptive methods simultaneously.
Retinoic acid acute promyelocytic (RA-APL) syndrome (see below) may require mechanical
ventilation and dexamethasone 10 mg every 12 hours at the first signs of fever with respiratory
distress until resolution of the acute symptoms (often several days). Continuation of retinoid
therapy is controversial.
Toxicity
1. Myelosuppression and other hematologic. Myelosuppression is rare. 40% of patients
develop leukocytosis, which increases the risk of RA-APL syndrome. Disseminated
intravascular coagulation is common (26%).
2. Nausea, vomiting, and other GI. Nausea and vomiting, abdominal pain, diarrhea,
anorexia, and constipation are common, but usually not severe. GI hemorrhage is
occasional to common and may be severe. Inflammatory bowel disease is rare.
3. Mucocutaneous effects. Universal, particularly at doses at higher end of range. They
include redness, dryness, and pruritus of the skin and mucous membranes; increased
sweating; possible vesicle formation; peeling of the skin of the palms and soles; cheilitis;
and conjunctivitis. There also may be increased skin photosensitivity (e.g., to sun) and the
nails may become brittle. Alopecia is uncommon.
4. Retinoic acid syndrome. High fever, respiratory distress, weight gain, diffuse pulmonary
infiltrates, pleural or pericardial effusions with the possibility of impaired myocardial
contractility, and hypotension, with or without concomitant leukocytosis, are common in
patients with acute promyelocytic leukemia (25%) (see Chapter 18).
5. Miscellaneous effects
a. Cardiovascular. Arrhythmias, flushing, hypotension, hypertension, and phlebitis are
occasional. Cardiac failure, cardiac arrest, pulmonary hypertension, and other more
severe cardiovascular problems are uncommon.
b. Cataracts and corneal ulcerations or opacities are uncommon.
c. Musculoskeletal. Arthralgias, bone pain, muscle aches are occasional to common;
skeletal hyperostosis is common at higher doses (80 mg/m2/day).
 d. Hypertriglyceridemia. Mild-to-moderate elevations are common; marked elevations
(>5 times normal) are uncommon; hypercholesterolemia occurs to a lesser degree.
e. Neurologic. Headache is common; paresthesias, dizziness, and visual disturbances are
occasional; lethargy, fatigue, and mental depression are uncommon; pseudotumor cerebri
is rare.
f. Hepatotoxicity with increased LDH, SGOT, SGPT, GGTP, alkaline phosphatase is
common.
g. Hyperhistaminemia with shock is rare.
h. Renal insufficiency is occasional.
i. Fever, malaise, shivering, and edema are common.

TRIFLURIDINE/TIPIRACIL
Other names. Lonsurf, TAS-102.
Mechanism of action. An orally administered combination of a thymidine-based nucleic acid
analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride.
Trifluridine is the active cytotoxic component with its triphosphate form incorporated into
DNA resulting in its antitumor effects. Tipiracil hydrochloride is a potent inhibitor of
thymidine phosphorylase and, when combined with trifluridine to form TAS-102, prevents the
rapid degradation of the trifluridine, allowing for the maintenance of adequate plasma levels of
the active drug.
Primary indications. Metastatic CRC (mCRC) after at least two prior regimens of standard
chemotherapies including a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for
patients with KRAS wild-type tumors — cetuximab or panitumumab.
Usual dosage and schedule. 35 mg per square meter orally twice daily, after morning and
evening meals on days 1 through 5 and 8 through 12 of each 28-day cycle. Doses can be
reduced by a maximum of three decrements of 5 mg/square meter.
Special precautions. Although rare, cases of septic shock, secondary to febrile neutropenia,
resulting in death have been reported. Lonsurf can cause fetal harm if administered to a
pregnant woman.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, leukopenia, and neutropenia
are common and commonly severe. However, febrile neutropenia is uncommon.
Thrombocytopenia is common and occasionally severe.
2. Nausea, vomiting, and other GI effects. Abdominal pain, nausea, vomiting, diarrhea, and
decreased appetite are common but uncommonly severe.
3. Mucocutaneous effects. Hand-foot syndrome is uncommon and rarely severe. Stomatitis is
occasional and rarely severe. Alopecia is occasional.
4. Miscellaneous effects
 a. General. Fatigue, fever, and asthenia are common but uncommonly severe.
b. Cardiovascular. Cardiac ischemic events including myocardial infarction, angina
pectoris, and myocardial ischemia were rarely reported in both the TAS-102 and
placebo groups.
c. Metabolic. Increase in ALT and AST is common, but uncommonly severe. Increase in
total bilirubin and alkaline phosphatase is common and occasionally severe.
d. Renal. Increase in creatinine level is occasional and rarely severe.

VANDETANIB
Other name. Caprelsa ZD6474.
Mechanism of action. An oral multitargeted receptor tyrosine kinase inhibitor of EGFR and
VEGFR, and the RET proto-oncogene receptor tyrosine kinase, which is associated with both
hereditary and sporadic medullary thyroid cancer, blocking both tumor growth and inhibiting
tumor angiogenesis.
Primary indication. Medullary thyroid carcinoma, symptomatic or progressive and
unresectable.
Usual dosage and schedule. 300 mg PO daily with food. Reduce to 200 mg PO daily if
moderate or severe renal impairment.
Special precautions. Do not use in patients with hypokalemia, hypomagnesemia, or long QT
syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be
avoided. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and
periodically thereafter. Do not give if QTc >480 msec.
Toxicity
1. Myelosuppression and other hematologic effects.
2. Nausea, vomiting, and other GI effects. Diarrhea is common and occasionally grade 3 to
4. Nausea is common, but vomiting is only occasional and usually not severe. Constipation
is occasional to common. Anorexia is common, but usually only grade 1 to 2.
3. Mucocutaneous effects. Rash is common, but high-grade dermatologic abnormalities are
uncommon.
4. Miscellaneous effects
a. Fatigue is common and occasionally grade 3 to 4. Weight loss is occasional.
b. Headache is common.
c. QTc interval prolongation is occasional (about 15%).
d. Hypertension is occasional and may be high grade (rise of >30 mm Hg systolic), but
usually easily controlled.
e. Hypothyroidism in about half of patients.
VEMURAFENIB
Other name. Zelboraf.
Mechanism of action. Oral low molecular weight kinase inhibitor of BRAF mutations,
including the BRAFV600E. Through this mechanism, it inhibits tumor cells proliferation that is
dependent on the constitutive activation of the BRAF proteins, which results from mutations in
the BRAF gene.
Primary indications. Unresectable or metastatic melanoma with BRAFV600E mutation in
treatment naïve or pretreated patients.
Usual dosage and schedule. 960 mg PO twice a day, with or without a meal. The two doses
are to be taken approximately 12 hours apart. Missed doses can be taken up to 4 hours prior to
the next dose, maintaining twice-daily regimen.
Special precautions. Vemurafenib can cause fetal harm if administered to a pregnant woman. It
can increase the AUC of S-warfarin and close monitoring of INR during concomitant use is
warranted. Should be used with caution with strong CYP3A4 inhibitors or inducers. Dose
reductions/interruptions or even permanent discontinuation may be required for QTc
prolongation. Uveitis, iritis, and photophobia has been described. Treatment with steroid and
mydriatic ophthalmic drops may be required to manage uveitis. New malignant melanomas
were reported in eight patients across clinical trials. These cases were managed with local
excision and patients continued treatment without dose adjustment.
Toxicity
1. Myelosuppression and other hematologic effects. Folliculitis can occur in less than 10%
of patients.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, and diarrhea are common.
Constipation is occasional.
3. Mucocutaneous effects. Mild-to-severe photosensitivity is common. Rash, pruritus,
alopecia, hyperkeratosis are common. Actinic keratosis is occasional. Sunburn can occur in
10% of cases. Palmar-plantar erythrodysesthesia reported in <10% of patients treated with
vemurafenib. Severe dermatologic reactions are rare, but require permanent discontinuation
of treatment.
4. Immunologic effects and infusion reactions. Serious hypersensitivity reactions, including
generalized rash, erythema, and even anaphylaxis, can occur. Severe hypersensitivity
adverse events require permanent discontinuation of therapy.
5. Miscellaneous effects
a. General. Fatigue, peripheral edema, and pyrexia are common.
b. Respiratory. Cough is occasional.
c. Cardiovascular. QTc prolongation with resultant ventricular arrhythmias can occur
especially in patients with risk factors (like electrolytes abnormalities and/or in those
who are taking medicinal products known to cause prolonged QTc). ECG and
 electrolytes, including potassium, magnesium, and calcium, should be monitored 15 days
after treatment initiation, then monthly for 3 months, and every 3 months thereafter.
Initiation of vemurafenib is not recommended for QTc >500 msec. If during treatment,
the QTc exceeds 500 msec (grade 3 or greater), treatment interruption is indicated with
correction/control of the underlying cause. Restart treatment at a lower dose once the
QTc decreases below 500 msec. Permanent discontinuation of treatment is indicated if
after correction of associated risk factors, the QTc continues to be >500 msec and >60
msec change from pretreatment values.
d. Hepatic. Elevations in ALT/AST, alkaline phosphatase, and/or bilirubin are uncommon,
but monitoring of liver function is recommended during treatment.
e. Neurologic. Headache is common. Dysgeusia is occasional. Peripheral sensory
neuropathy and VIIth nerve palsy reported in <10% of patients.
f. Secondary neoplasms/malignancies. Skin papilloma occurred in 21% to 30% of
patients. Seborrheic keratosis is occasional. Cutaneous squamous cell reactions
(including SCCs of the skin and keratoacanthomas) can occur in up to 24% of patients,
usually within the first 7 to 8 weeks of treatment. These are usually treated with local
excision, and no dose reductions/interruptions are recommended. Frequent occurrences
can happen.
g. Musculoskeletal and connective tissue. Arthralgia is common. Myalgia is occasional.

VINBLASTINE
Other names. VLB, Velban.
Mechanism of action. Mitotic inhibition with reversible metaphase arrest due to action on
microtubular and spindle contractile proteins.
Primary indications
1. Hodgkin and non-Hodgkin lymphomas.
2. Testicular, gestational trophoblastic carcinomas.
Usual dosage and schedule
1. 6 mg/m2 IV on days 1 and 15 in combination with doxorubicin, bleomycin, and dacarbazine
for lymphomas.
2. 4 to 18 mg/m2 IV weekly.
Special precautions. Administer as a slow push, taking care to avoid extravasation.
Toxicity
1. Myelosuppression and other hematologic effects. Dose-related leukopenia occurs with a
nadir at 4 to 10 days and recovery in 7 to 10 days. Severe thrombocytopenia is uncommon.
2. Nausea, vomiting, and other GI effects. Common but not usually severe.
3. Mucocutaneous effects. Extravasation may lead to severe inflammation, pain, and tissue
damage. Local infiltration with 1 to 6 mL of hyaluronidase (150 U/mL) may help (see Table
 26.1). Mild alopecia is common. Stomatitis is occasionally severe.
4. Miscellaneous effects
a. Neurotoxicity manifested by (1) constipation, adynamic ileus, and abdominal pain if
very high doses are used; or (2) paresthesias, peripheral neuropathy, and jaw pain with
lower doses. Neurotoxicity is less frequent with vinblastine than with vincristine.
b. Transient hepatitis is uncommon.
c. Depression, headache, convulsions, and orthostatic hypotension are rare.

VINCRISTINE
Other names. VCR, Oncovin, Vincasar.
Mechanism of action. Mitotic inhibition with reversible metaphase arrest due to drug action
on microtubular and spindle contractile proteins.
Primary indications
1. Hodgkin and non-Hodgkin lymphomas.
2. ALL.
3. Multiple myeloma.
4. Wilms tumor, neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma of childhood.
Usual dosage and schedule
1. 1 to 2 mg/m2 (maximum 2.0 to 2.4 mg, except in Hodgkin lymphoma) IV weekly.
2. 0.4 mg/day as a continuous IV infusion on days 1 to 4.
Special precautions
1. Administer as a slow IV push, taking care to avoid extravasation.
2. Because neurotoxicity is cumulative, neurologic evaluation should be done before each
dose and therapy withheld if severe paresthesias, motor weakness, or other severe
abnormalities occur. Underlying neurologic problems accentuate the effect of vincristine.
3. Reduce dose if liver disease is significant.
4. Stool softeners or high-fiber or bulk diets may avert severe constipation.
Toxicity
1. Myelosuppression and other hematologic effects. Mild and rarely of clinical
significance.
2. Nausea, vomiting, and other GI effects. Nausea and vomiting are not seen unless
paralytic ileus occurs. Constipation is common.
3. Mucocutaneous effects. Severe local inflammation if extravasation occurs. Alopecia is
common.
4. Miscellaneous effects
a. Neurotoxicity. Dose-dependent and dose-limiting. Mild paresthesias and decreased
deep tendon reflexes are to be expected. More extensive peripheral neuropathies, severe
constipation, or ileus are indications to reduce or hold therapy. Autonomic dysfunction
 with orthostatic hypotension or urinary retention may be seen.
b. Uric acid nephropathy due to rapid tumor cell lysis and release of uric acid is always a
potential problem when therapy is first given.
c. Syndrome of inappropriate antidiuretic hormone is rare.
d. Jaw pain is uncommon.

VINCRISTINE SULFATE LIPOSOME

Other name. Marqibo.
Mechanism of action. This is a sphingomyelin/cholesterol liposome encapsulated formulation
of vincristine sulfate, which acts through binding to tubulin, altering the tubulin polymerization
equilibrium and stabilizes the spindle apparatus, preventing chromosome aggregation,
triggering metaphase arrest and inhibition of mitosis.
Primary indications. Philadelphia chromosome-negative (Ph−) ALL in second or greater
relapse or after progression on two or more antileukemic therapies.
Usual dosage and schedule. 2.25 mg/m2 IV over 1 hour once every 7 days through secure and
free-flowing venous access line. Coadministration with strong CYP3A inhibitors or inducers
as well as potent P-glycoprotein (P-gp) inhibitors or inducers should be avoided. Concomitant
use of phenytoin may result in decreased blood level of phenytoin and increased risk of
seizures.
Special precautions
1. Contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth
syndrome.
2. Contraindicated for intrathecal administration!
3. Can cause fetal harm if administered to a pregnant woman.
4. Risk of tumor lysis syndrome when treatment is first given especially with high disease
burden, which may lead to urate nephropathy.
Toxicity
1. Myelosuppression and other hematologic effects. Anemia, neutropenia, and
thrombocytopenia are common. Febrile neutropenia is common (31.3%).
2. Nausea, vomiting, and other GI effects. Ileus, constipation, colonic pseudo-obstruction,
and bowel obstruction are occasional. Prophylactic bowel regimen including adequate
dietary fiber intake, hydration, and routine use of stool softeners is recommended. Increased
AST is occasional.
3. Mucocutaneous effects. None.
4. Immunologic effects and infusion reactions. Vincristine liposome is a vesicant, and there
is a risk of extravasation. If extravasation occurs, immediately discontinue the infusion, and
apply local treatment measures. Cases of pneumonia, septic shock, and staphylococcal
bacteremia were occasionally reported.
5. Miscellaneous effects
a. General. Fatigue and pyrexia are occasional.
b. Respiratory. Respiratory distress is occasional.
c. Cardiovascular. Orthostatic hypotension is occasional and may be related to autonomic
neuropathy. Five cases of cardiac arrest were reported.
d. Neurologic. Peripheral sensory and motor neuropathy is common. Mental status changes
are uncommon.
e. Musculoskeletal and connective tissue. Muscle weakness is uncommon.

VINORELBINE
Other name. Navelbine.
Mechanism of action. Binds to tubulin, depolymerizes microtubules causing mitotic inhibition,
similar to other vinca alkaloids. Lower affinity for axonal microtubules associated with lower
neurotoxicity.
Primary indications
1. Metastatic carcinoma of the breast.
2. Non–small cell carcinoma of the lung.
Usual dosage and schedule
1. 30 mg/m2 IV as 6- to 10-minute rapid infusion weekly when used with a single agent or
with cisplatin.
2. 20 to 25 mg/m2 IV as a 6- to 10-minute rapid infusion in various schedules, when used with
other myelotoxic agents.
Special precautions. Administer infusion through the side arm of a freely flowing IV, taking
care to avoid extravasation. Reduce dose by 50% for serum bilirubin levels of 2.1 to 3 mg/dL;
by 75% for bilirubin levels of more than 3 mg/dL.
Toxicity
1. Myelosuppression and other hematologic. Granulocytopenia is common and dose
limiting, with nadir at 7 to 10 days. Thrombocytopenia is uncommon. Anemia is occasional
to common.
2. Nausea, vomiting, and other GI. Nausea and vomiting are common, but usually mild to
moderate. Diarrhea occurs occasionally.
3. Mucocutaneous effects. Alopecia, mild diarrhea, and stomatitis are occasional. Severe
local inflammation can occur with extravasation.
4. Miscellaneous effects
a. Neurotoxicity. Cumulative but reversible constipation and decreased deep tendon
reflexes are occasional; paresthesias are uncommon.
Erythema, pain, and skin discoloration at injection site are common; phlebitis at injection site
is occasional.
VISMODEGIB
Other name. Erivedge.
Mechanism of action. Inhibitor of the hedgehog pathway. It binds to and inhibits Smoothened,
a transmembrane protein involved in Hedgehog signal transduction.
Primary indications. Locally advanced and metastatic BCC.
Usual dosage and schedule. 150 mg orally once daily, with or without food. If a dose is
missed, resumed dosing with next schedule dose is recommended.
Special precautions
1. Increased systemic exposure and adverse events may be observed when administered with
P-gp inhibitors.
2. Embryo-fetal toxicity. Verification of pregnancy status prior to initiation of therapy in
women in childbearing age and the use of effective birth control measures during and up to
6 months after the last dose of treatment is recommended.
3. Donation of blood or blood product is not recommended during and up to 7 months after the
last dose of therapy.
4. The safety and efficacy of vismodegib have not been established in patients with hepatic or
renal impairment.
Toxicity
1. Myelosuppression and other hematologic effects. Not reported.
2. Nausea, vomiting, and other GI effects. Nausea, vomiting, diarrhea, and constipation are
common but rarely severe.
3. Mucocutaneous effects. Alopecia is common.
4. Miscellaneous effects
a. General. Fatigue is common. Weight loss is common and occasionally severe.
b. Metabolic. Hyponatremia and hypokalemia are uncommon.
c. Neurologic. Dysgeusia is common. Ageusia is occasional.
d. Genitourinary. Amenorrhea is common.
e. Musculoskeletal and connective tissue. Muscle spasms and arthralgia are common.

VORINOSTAT
Other name. Zolinza.
Mechanism of action. Inhibits HDACs, which are overexpressed in some cancer cells.
Accumulation of acetylated histones following vorinostat exposure induces cell cycle arrest or
apoptosis in some transformed cells in vitro.
Primary indication. CTCL with progressive, persistent, or recurrent skin disease after two
other systemic therapies.
Usual dosage and schedule. 400 mg PO daily with food. May be reduced to 300 mg daily or 5
days weekly if the higher dose is not tolerated.
Special precautions. Patients should drink at least 2 L of fluid daily to prevent dehydration
from vomiting and diarrhea. Deep venous thrombosis and pulmonary embolism (5%) have
been reported. Serum chemistries (including potassium, magnesium, calcium, glucose, and
creatinine) and platelets should be monitored every 2 weeks during the first 2 months of
treatment. Severe thrombocytopenia and GI bleeding may occur with concomitant use with
other HDAC inhibitors, such as valproic acid.
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia is common; anemia
and neutropenia are occasional. Increased prothrombin time and INR may be seen with
concomitant use of warfarin with vorinostat.
2. Nausea, vomiting, and other GI effects. Anorexia, nausea, and diarrhea are common.
Vomiting, constipation, and weight loss are occasional.
3. Mucocutaneous effects. Alopecia is occasional to common.
4. Miscellaneous effects
a. Blood chemistry abnormalities. Hypercholesterolemia, hypertriglyceridemia,
hyperglycemia, and increased creatinine are common and may be severe (grade 3 or
higher).
b. Cardiovascular. QTc prolongation on the electrocardiogram is uncommon. Pulmonary
embolism and deep venous thrombosis are uncommon.
c. Edema is occasional.
d. Neuromuscular. Fatigue is common. Headache, muscle spasms, and dizziness are
occasional.
e. Neoplastic. Squamous cell carcinoma is uncommon.

ZIV-AFILBERCEPT
Other name. Zaltrap.
Mechanism of action. An antiangiogenic that acts by binding to human ligands VEGF-A,
VEGF-B, and PlGF, which results in inhibition of the binding and activation of their cognate
receptors. This inhibition can result in decreased neovascularization and decreased vascular
permeability.
Primary indications. Metastatic colorectal cancer that is resistant to or has progressed
following an oxaliplatin-containing regimen.
Usual dosage and schedule. 4 mg/kg as an IV infusion over 1 hour every 2 weeks in
combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI). There are no data
available to recommend an appropriate dose for patients with severe hepatic impairment.
Special precautions
1. Potential fetal harm if administered to a pregnant woman.
2. Hemorrhagic events including GI hemorrhage, hematuria, intracranial hemorrhage,
pulmonary hemorrhage/hemoptysis, and post-procedural hemorrhage can occur in up 38%
of patients. These events can be severe in 3% of cases and rarely fatal.
3. Cases of GI perforations as well as GI and nonGI fistula formation have been described.
4. As with other antiangiogenic agents, there is a risk of wound healing complications. Thus,
treatment should be stopped at least 4 weeks prior to scheduled surgery. The decision to
resume therapy after surgery should be based on clinical judgment of adequate wound
healing.
Toxicity
1. Myelosuppression and other hematologic effects. Thrombocytopenia and leukopenia are
common. Neutropenia is common. Severe cases of neutropenia, febrile neutropenia, and
neutropenia infections/sepsis occurred in 37%, 4%, and 1.5%, respectively. Infectious
adverse events (including urinary tract infection, nasopharyngitis, upper respiratory tract
infection, pneumonia, catheter site infection, and tooth infection) are common and
occasionally severe.
2. Nausea, vomiting, and other GI effects. Stomatitis is common. Diarrhea is common and
can be severe in up to 19% of cases and lead to dehydration. Abdominal pain is common.
Increased AST/ALT is common, but not usually severe.
3. Mucocutaneous effects. Palmar-plantar erythrodysesthesia syndrome and skin
hyperpigmentation are uncommon.
4. Immunologic effects and infusion reactions. Severe hypersensitivity reactions have been
rarely reported (0.3%).
5. Miscellaneous effects
a. General. Fatigue is common. Weight loss is occasional.
b. Respiratory. Epistaxis, dysphonia, rhinorrhea, and oropharyngeal pain are uncommon.
Dyspnea is occasional.
c. Cardiovascular. Hypertension is common and occasionally severe. Arterial
thromboembolic events, including transient ischemic attack, cerebrovascular accident,
and angina pectoris are uncommon but require permanent discontinuation of therapy.
Venous thromboembolic events, consisting primarily of deep venous thrombosis and
pulmonary embolism, occurred in 9% of patients.
d. Neurologic. RPLS is rare and requires permanent discontinuation of treatment.
Headache is occasional.
e. Genitourinary. Proteinuria is common and occasionally severe. Increased serum
creatinine is common, but rarely severe. Cases of nephrotic syndrome and thrombotic
microangiopathy were rarely described.

References
 1. National Cancer Institute Cancer Therapy Evaluation Program. Common terminology
criteria for adverse events v4.0. Retrieved from
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm or
downloaded in the latest version from http://evs.nci.nih.gov/ftp1/CTCAE/About.html
2. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese
adult patients with cancer: American Society of Clinical Oncology clinical practice
guideline. J Clin Oncol. 2012;30:1553–1561.
3. Rosner GL, Hargis JB, Hollis DR, et al. Relationship between toxicity and obesity in
women receiving adjuvant chemotherapy for breast cancer: results from cancer and
leukemia group B study 8541. J Clin Oncol. 1996;14:3000–3008.
 INDEX

Note: Page numbers followed by “f” indicate figures; those followed by “t” indicate tables.

A
abiraterone, prostate cancer, 302
abiraterone acetate (Zytiga)
mechanism of action, 677
primary indication, 677
special precautions, 677
toxicity, 677 -678
usual dosage and schedule, 677
absolute neutrophil count (ANC), 439, 690
ABT-199 (Venetoclax), 45
CLL, 497–498
ABT-263. See Navitoclax
ABVD regimen, Hodgkin lymphoma, 545–547, 545t
AC regimen, breast cancer, 232
ACC. See adrenocortical carcinoma
accelerated phase (AP), chronic myelogenous leukemia, 481, 482t
acetaminophen, MM, 612
acetylsalicylic acid. See aspirin
aclarubicin, acute leukemias, 440
acquired immune deficiency syndrome (AIDS). See also human immunodeficiency virus (HIV)
lymphomas and, 586
acquired resistance, 13
ACTH. See adrenocorticotropic hormone
actinomycin D (ACT-D). See dactinomycin
active surveillance (AS), prostate cancer, 298–299
acute leukemias, 426–477
of ambiguous lineage, 434
general features
clinical, laboratory features, 427, 428t
diagnosis, classification, prognostic features, 427–434
epidemiology, 426
etiology, risk factors, 427
initial support
birth control, fertility and, 437
blood product support, 436
coagulopathy correction, 436
fever, infection, 436–437
HLA typing, 436
hydration, electrolyte imbalance, 435
hyperleukocytosis, leukostasis, leukapheresis, 434–435
menses suppression, 437
psychosocial support, 437
uric acid nephropathy prevention, 435
vascular access, 437
therapy
aim of, 438
 definition of response, 439
induction chemotherapy, 438
postremission chemotherapy, 438–439
acute lymphoblastic leukemia (ALL)
adult, therapy and, 460–477
CNS disease, 468–470
consolidation (intensification) therapy, 461
induction, 461
maintenance, 462
mature (Burkitt) B-cell, 467
minimal residual disease (MRD), 468
pre–B-, T-cell lineage, 462–467
classification, 432, 432t
clinical, laboratory features, 428t
epidemiology, 426
etiology, risk factors, 427
hematopoietic stem cell transplantation, 475–477
immunophenotypes of, 432t
novel, investigational strategies, therapy, 475
older adults, 470–471
Ph+ and, therapy for, 471–472
prognostic factors, 433
salvage therapy, 472–475
acute myelogenous leukemia, 92–93
acute myeloid leukemia (AML)
adult AML therapy, 439
induction therapy, 439–441, 440t
postremission therapy, 442–444
primary refractory AML, 444
relapsed AML, 444–448, 445t
residual disease, 441
classification, 427–430, 429t
clinical, laboratory features, 428t
cytarabine dose intensification, 440–441
epidemiology, 426
etiology, risk factors, 427
induction therapy, 439–441, 440t
myeloma and, 618
older adults and
background, 448–449
induction therapy, 449–450
postremission therapy, 450–451
RIC (mini)-HCST, 451
postremission therapy, 442–444
pregnancy and, 452
primary refractory, 444
prognostic factors, 430, 431t
regimens, 441
relapsed, 444–448, 445t
residual disease, 441
therapy-related
background, 451
therapy, 451–452
acute promyelocytic leukemia (APL), 452–460
clinical, laboratory features, 428t
 coagulopathy, 436
coagulopathy management, 453, 454t
cytogenetic abnormalities, prognostic factors and, 452–453, 453t
differentiation syndrome, 458
early death rate, 459–460
epidemiology, 426
postremission chemotherapy, 438–439
relapsed, 458–459
ATO, 458–459
HSCT, 459t, 460
therapy, 453–458, 454–455t
consolidation, 456–457
HSCT, 457
induction, 453, 456
maintenance, 458
vascular access, 437
acute undifferentiated leukemia (AUL), 434
acyclovir
herpes zoster prophylaxis, 698
varicella zoster prophylaxis, 605
ADCC. See antibody-dependent cellular cytotoxicity
Adcetris. See brentuximab vedotin
adenocarcinoma. See esophageal adenocarcinoma; metastatic adenocarcinoma; pancreatic cancer; peritoneal papillary
adenocarcinoma; small intestine cancer
adjuvant chemotherapy, 332–333
cervical cancer, 255
DTC, 332–333
endometrial cancer, 263
kidney cancer, 322–323
pancreatic neuroendocrine tumors, 206
response to, 82–83
soft-tissue sarcomas, 402
Adjuvant! Online tool, 230
ado-trastuzumab emtansine (T-DM1 or Kadcyla), 59
mechanism of action, 678
primary indication, 678
special precautions, 678–679
toxicity, 679–680
usual dosage and schedule, 678
adrenocortical carcinoma (ACC), 337–344
biopsy, role of, 338
clinical manifestations, 337
etiology, 337
evaluation and workup, 337–338
incidence, 337
management, 339–343
hormonal excess and deficiency, 343
interventional radiology, as treatment modality, 342–343
mitotane use, 340–341
multidisciplinary approach, 343
radiation therapy, 342
surgical resection, 339–340
systemic chemotherapy, 341–342
pathology, 338
adrenocorticotropic hormone (ACTH), 662
Adriamycin. See doxorubicin
ADT. See androgen deprivation therapy
advanced age patients, NHL, 588–589
adverse-risk AML, postremission therapy, 443–444
afatinib (Gilotrif), 36
mechanism of action, 680
NSCLC, 124, 135t, 141
primary indication, 680
special precautions, 680
toxicity, 680–681
usual dosage and schedule, 680
Afinitor. See everolimus
Aflibercept, colon cancer, 177
AFP. See α-fetoprotein
AGS-003, kidney cancer, 322
AIDS. See acquired immune deficiency syndrome
AIs. See aromatase inhibitors
ALCL. See anaplastic large-cell lymphoma
aldesleukin. See Interleukin 2 (IL-2)
alectinib, 41
alemtuzumab (Campath), 57–58
myelodysplastic syndrome, 529, 533–534
Waldenström macroglobulinemia, 619
algenpantucel-L, adenocarcinoma of pancreas, 197
alisertib, 49–50
ALK. See anaplastic lymphoma kinase
alkylating agents
EV, 517
general description, 668t, 670–671
ALL. See acute lymphoblastic leukemia
all-trans retinoic acid (ATRA)
APL, 453–460, 454–455t, 459t
allo-HSCT. See allogeneic hematopoietic stem cell transplant
allogeneic bone marrow transplantation, graft-versus-tumor effect in, 63
allogeneic hemapoietic stem cell transplantation (allo-HSCT)
ALL, 471–473, 475–477
AML, 443, 444, 447, 452
APL, 460
CML, 489, 490t
myelodysplastic syndrome, 532, 533
NHL, 584
Ph+ ALL, 472
PMF, 520, 521
allopurinol
acute leukemias, 435
hyperuricemia, 514, 716
Stevens-Johnson syndrome, 691
toxicity, 91
tumor lysis syndrome, 691
uric acid nephropathy, 435
α-fetoprotein (AFP), 283
altretamine
dosage, schedule, 681
mechanism of action, 681
primary indications, 681
 special precautions, 681
toxicity, 681–682
alveolar soft part sarcomas, 403
aminocaproic acid, myelodysplastic syndrome, 537
aminoglycosides, 601
toxicity, 91
AML. See acute myeloid leukemia
amphotericin, 710
toxicity, 91
amsacrine, acute leukemias, 440
A-MVAC regimen, muscle-invasive bladder cancer, 295t
amyloidosis, 621–622
anagrelide
dosage, schedule, 682
EV, 517
mechanism of action, 682
primary indications, 682
PV, 513
special precautions, 682
toxicity, 682–683
anal cancer, 183–185
local disease, 184
metastatic disease, 184–185
anaplastic large-cell lymphoma (ALCL), 579
anaplastic lymphoma kinase (ALK), 40–41
inhibitors NSCLC, 142–143
anaplastic thyroid cancer (ATC), 329
prognosis, 329
treatment
radiotherapy, 336
surgery, 336
systemic therapies, 336–337
anastrozole
breast cancer, 238, 239, 241
dosage, schedule, 683
mechanism of action, 683
primary indications, 683
special precautions, 683
toxicity, 683–684
ANC. See absolute neutrophil count
androgen ablation, 300
LHRH agonists, 300–301
orchiectomy, 300
androgen deprivation therapy (ADT)
bilateral orchiectomy, 300
intermittent, 301
LHRH agonists, 300–301
LHRH antagonists, 301
prostate cancer, 300–301
anemia
MDS, 536
MM, 618
PMF, 521
angiogenesis, 137–138
angiogenesis inhibitors, gastric carcinoma, 165–166
angiogenesis-targeted therapy, 54–55
Ann Arbor Staging System, 542, 542t, 560–561, 561t
anthracenediones
acute leukemias, 440, 441
toxicity, 89
anthracyclines
AML, 440, 441, 446
ATC, 336
breast cancer, 232
cancers of the head and neck, 114
toxicity, 89
anti-CTLA-4, 70
adenocarcinoma, 72
adverse interactions, 73
combined with anti-PD-1, 73
metastatic melanoma, 68, 72, 74
renal or marrow allografts, 72
response kinetics, 68, 69–70
squamous cell carcinoma of the lung, 72
toxicity, 66
anti-GD-2/GM-CSF/IL-2, 72
anti-PD-1, 70
combined with anti-CTLA-4, 73
metastatic melanoma, 72
metastatic non–small-cell lung cancer, 72
renal or marrow allografts, 72
response kinetics, 68, 69, 70
toxicity, 66
anti-PD-L1, and cancers of head and neck, 115
anti-PD-L2, and cancers of head and neck, 115
antibiotics, 7, 668t, 718, 777
antitumor, 647
infections, 67, 536
side effects, 183, 406, 659, 697, 715
antibody-dependent cellular cytotoxicity (ADCC), 65, 71, 73
anticancer immune responses, 63–65
anticonvulsants therapy, metastatic brain disease, 390
antiemetic drugs, 641–645, 643–644t
antigen-presenting cells (APCs), 63, 64
antimetabolites, general description, 671
antineoplastic agents
resistance to, 12–13
biochemical causes, 13–14
cell kinetics and, 13
nonselectivity and, 15
pharmacologic causes, 14–15
antithrombotic therapy, PV, 510–511
antithymocyte globulin (ATG), 529, 533
Anzemet. See dolasetron
AP. See accelerated phase
Apatinib, gastric carcinoma, 166
APCs. See antigen-presenting cells
APL. See acute promyelocytic leukemia
apoptosis, 2–3, 2f
intrinsic rate, 4
aprepitant (Emend), 644t
ara-C. See cytarabine
aromatase inhibitors (AIs), breast cancer, 221, 225, 228, 231, 238–241, 239f
arsenic trioxide (ATO), 458–459
APL therapy, 456–459
dosage, schedule, 684
mechanism of action, 684
arsenic trioxide (ATO), 458–459 (continued)
primary indications, 684
relapsed APL, 458–459
special precautions, 684
toxicity, 684–685
Arzerra. See ofatumumab
arzoxifene, breast cancer, 221
AS. See active surveillance
ASCT. See autologous stem cell transplantation
asparaginase
dosage, schedule, 685–686
mechanism of action, 685
primary indications, 685
special precautions, 686
toxicity, 89, 686–687
Aspergillus species, 493
aspiration, cancers of the head and neck therapy and, 117–118
aspirin (acetylsalicylic acid)
ET, 517–518
kidney cancer, 315
MM, 609
PV, 509, 510–511
astrocytomas, pilocytic, 375
ATC. See anaplastic thyroid cancer
ATG. See antithymocyte globulin
Ativan. See lorazepam
ATO. See arsenic trioxide
ATRA. See all-trans retinoic acid
atropine, 651t
AUL. See acute undifferentiated leukemia
aurora kinase, 49–50
auto-HSCT. See autologous hematopoietic stem cell transplantation
autologous hematopoietic stem cell transplantation (auto-HSCT)
ALL, 471, 475
AML
adult, 442
adverse-risk, 444
older adults, 450–451
relapsed, 447
therapy-related, 452
APL, 460
autologous stem cell transplantation (ASCT), 540
testicular cancer, 309
Avastin. See bevacizumab
Axillary lymph nodes, adenocarcinoma in, 628–629
axitinib (Inlyta), 32
ATC, 337
kidney cancer, 320, 323
 mechanism of action, 687
metastatic renal cell carcinoma, 324t
primary indication, 687
special precautions, 687
toxicity, 688
usual dosage and schedule, 687
AZA. See azacitidine
azacitidine (AZA)
AML, in older adults, 450
MDS, 529, 531, 534–536
mechanism of action, 688
primary indications, 689
toxicity, 689
usual dosage and schedule, 689
azoospermia, 94

B
B-cells, T-cell/CD19 administration on, 67
Bacillus Calmette–Guérin (BCG) vaccine, 293, 362
Barrett esophagitis, 155
basal cell carcinoma (BCC), 364
diagnosis, 365
local treatment, 365–366
metastatic disease treatment, 366–367
baseline lesions, 84
BCC. See basal cell carcinoma
BCDT regimen, melanoma, 361t
BCG vaccine. See Bacillus Calmette–Guérin vaccine
BCNU. See carmustine
Bcr-Abl tyrosine kinase, 42–45
BCR-ABL1-negative MPNs, 506–522
essential thrombocythemia, 515–518
polycythemia vera, 507–515
primary myelofibrosis, 518–522
BEACOPP regimen, Hodgkin lymphoma, 546
Beleodaq. See belinostat
belinostat (Beleodaq)
mechanism of action, 689
primary indication, 689
special precautions, 689
toxicity, 690
usual dosage and schedule, 689
Benadryl. See diphenhydramine
bendamustine
CLL, 494–495
dosage, schedule, 690
indolent lymphoma, 567, 568t
mechanism of action, 690
primary indication, 690
special precautions, 690–691
toxicity, 691
WM, 620
Berlin-Frankfurt-Muenster (BFM)-like regimens (MRC/ECOG), 462–464
CNS treatment, prophylaxis, 463
 consolidation therapy, 463–464
induction, 462–463
intensification therapy, 463
maintenance therapy, 464
Bessel-Hagen disease, 412
β-agonists, 658
β-blockers
paraganglioma, 345
pheochromocytoma, 345
β-hCG. See β-human chorionic gonadotropin
β-human chorionic gonadotropin (β-hCG), 437
bevacizumab (Avastin), 32
carcinoid tumors, 171
cervical cancer, 256, 256t
colon cancer, 174, 175–176
colorectal cancer, 175, 180–181
dosage, schedule, 692
gastric carcinoma, 165
glioblastoma multiforme, 382, 382t
grade III and IV gliomas, 380
kidney cancer, 319, 323
mechanism of action, 691
metastatic disease, 201
NSCLC, 125, 134t, 135, 136, 137–138
ovarian cancer, 273t, 274–275
pancreatic neuroendocrine tumors, 208
primary indications, 692
side effects, 31, 183
special precautions, 692
toxicity, 692–693
VEGF-targeted therapy, 30–31
bexarotene (capsules), 368, 369
dosage, schedule, 693
mechanism of action, 693
primary indications, 693
special precautions, 693
toxicity, 693–694
bexarotene gel, MF, 368, 369
Bexxar. See iodine-131 (131I)-tositumomab
bicalutamide
dosage, schedule, 694
mechanism of action, 694
primary indications, 694
special precautions, 694
toxicity, 694
bilateral orchiectomy, prostate cancer, 300
binimetinib (MEK-162), 48
biochemotherapy, melanoma, 361–362, 361t
biologic response modifiers, 3–4, 98–99
classification, 667, 670t
biomarkers to immunotherapy, predictive, 70–72
biopsy
ACC, 338
bone marrow, 544
core-needle, 103
 fine needle aspiration, 103, 192–193, 330–331
soft-tissue sarcomas, 400
birth control, acute leukemias, 437
bisphosphonates
breast cancer, 242
MM, 601, 616
toxicity, 91
BL. See Burkitt lymphoma
bladder cancer
approach to therapy, 293–294
bladder-sparing therapy, 295–296
general considerations, 292–293
neoadjuvant chemotherapy, 294–295
bladder-sparing therapy, 295–296
muscle-invasive bladder cancer, 295–296
blast phase (BP), chronic myelogenous leukemia, 481–482, 482t
blastic bone metastases, therapeutic management, 629
bleeding, MDS, 536–537
bleomycin
cancers of the head and neck, 114, 115t
cervical cancer, 255
dosage, schedule, 695
esophageal carcinoma, 158, 159
mechanism of action, 695
ovarian germ cell tumors, 283
penile cancer, 310
primary indications, 695
special precautions, 695
testicular cancer, 308
toxicity, 89, 695–696
vulvar cancer, 282
blinatumomab (Blincyto), 58
ALL, 474
mechanism of action, 696
primary indication, 696
special precautions, 696–697
toxicity, 697–698
usual dosage and schedule, 696
Blincyto. See blinatumomab
blood product support, 436
bone marrow biopsy, 544
bone marrow transplantation
MM, 613–614
osteosarcoma, 417
bone sarcomas, 411–423
chondrosarcoma, 417–418
chordomas, 423
clinical symptoms, 413–414
diagnosis, 413–414, 414f
Ewing sarcoma, 418–421
chemotherapy, 419–421
outcome after first-line treatment, 421
treatment strategy, 419
of ulna, 418, 419f
giant cell tumor of the bones, 422–423
 histologic subtypes, 421–422
incidence, 411–412
nosology, 411–412
osteosarcoma, 415–417
cytotoxic chemotherapy, 416–417
recurrence and treatment of refractory disease, 417
treatment strategy, 416
predisposing factors, 412–413
radiotherapy and, 413
staging, 414–415
bone scan, esophageal carcinoma, 156
borderline resectable pancreatic cancer, 198
bortezomib (Velcade), 53, 55
amyloidosis, 622
dosage, schedule, 698
mechanism of action, 698
MM, 602–607, 614, 615
primary indications, 698
special precautions, 698
toxicity, 91, 698–699
WM, 619
Bosulif. See bosutinib
bosutinib (Bosulif), 45
CML, 485
mechanism of action, 699
primary indication, 699
special precautions, 700
toxicity, 700
usual dosage and schedule, 699
BP. See blast phase
BRAF inhibitors, melanoma, 358–360
brain metastases. See metastatic brain disease
brain tumors, primary, 374–389
epidemiology, 374
malignant gliomas, 374–383, 382t
grade I glioma, 375
grade II glioma, 375–378
grade III glioma, 378–383
grade IV glioma, 378–383
medulloblastomas, 384–385
pineal region tumors, 383–384
primary CNS lymphoma, in immunocompetent patients, 385–387, 387t
risk factors, 374
sellar and parasellar tumors, 387–389
craniopharyngiomas, 388–389
pituitary adenomas, 387–388
survival, 374
breast cancer
cytotoxic therapy, 230–238
advanced disease treatment, 236–238
early disease treatment, 231–235
response to, 231
diagnostic evaluation, 223–224
endocrine therapy, 238
advanced disease treatment, 240–241
 early disease treatment, 238–240
ovarian suppression, 240
epidemiology, risk factors, 218–220
histology, 224
prevention, 220–221
prognosis, 228, 232t
estrogen, progesterone receptors, 229
gene profiling, 229–230
HER2/neu gene, 229
online tools, 230
other factors, 230
stage, 228–229
screening, 221–222
signs, symptoms, 222–223
staging, 223
therapy, approach to, 224–228
Adjuvant! Online tool, 230
advanced (metastatic) disease, 226
consultation, 224–225
early-stage invasive disease, 225
endocrine therapy, 228
locally advanced disease, 225–226
radiation therapy, 227
surgery, 226–227
systemic therapy, 227–228
therapy goals, 225
therapy complications, 241–242
TNM classification, 223
brentuximab vedotin (Adcetris), 59–60
mechanism of action, 700–701
primary indication, 701
special precautions, 701
toxicity, 701–702
usual dosage and schedule, 701
brivanib, 33
bronchioloalveolar cancer, 126
bronchoscopy, esophageal carcinoma, 156
Bruton agammaglobulinemia, 39
Bruton tyrosine kinase (BTK), 39–40
inhibitors
CLL, 498
BTK. See Bruton tyrosine kinase
buparlisib, 52
Burkitt lymphoma (BL), 574–575, 582t
busulfan
EV, 517
PV, 513

C
C225. See cetuximab
cabazitaxel
dosage, schedule, 702
mechanism of action, 702
primary indications, 702
 prostate cancer, 303
special precautions, 702
toxicity, 702–703
cabozantinib (Cometriq), 38
kidney cancer, 320
lung cancer, 124
mechanism of action, 703
metastatic renal cell carcinoma, 324t
MTC, 335–336
primary indication, 703
special precautions, 703
toxicity, 704–705
usual dosage and schedule, 703
calcitonin
hypercalcemia, 616
MM, 616
CALGB 8811, ALL, 464–465
Campath. See alemtuzumab
cancer immunotherapy, principles of, 63–74
anticancer immune responses, 63–65
clinical activity and application, 72–74
predictive biomarkers and patient selection, 70–72
response kinetics, 67–70
toxicity and management of toxicity, 66–67
cancer of large intestine, 172
adjuvant chemotherapy
colon cancer, 173–175
rectal cancer, 182–183
resected hepatic metastases, 181
advanced colon cancer, treatment for, 175–181
complications, 182–183
follow-up, 182
serum CEA, 173
staging, 172–173
treatment, advanced disease, 175–181
cancer of small intestine
adenocarcinomas, 172
NETs, 169
carcinoid syndrome, 169–170
treatment, 170–172
cancer treatment
choice of modality
biologic response modifiers, MTT and, 98–99
chemotherapy, 98
combined-modality therapy, 99
radiotherapy, 97–98
surgery, 97
goals, setting
medical perspective, 96–97
patient perspective, 96
late physical effects. See cancer treatment, late physical effects
palliative care, 99–101
cancer treatment, late physical effects
late organ toxicities
cardiac toxicity, 90–91
 hematologic, immunologic impairment, 92
nephrotoxicity, 91
neurotoxicity, 91–92
pulmonary toxicity, 91
other sequelae
endocrine problems, 93
gonadal failure, dysfunction, 94
musculoskeletal system, 94
premature menopause, 93–94
psychological, social concerns, 94
second malignancies
acute myelogenous leukemia, 92–93
solid tumors, other malignancies, 93
cancers of head and neck (HNCs), 102–120
anatomy, 102, 103f
chemotherapy agents, 112–114
evaluation, 103–104
new agents, 114–115, 115t
palliative/supportive care, 115–120
pathology, 104
presenting symptoms, 102–103
staging, 104–105
treatment
HPV-associated oropharyngeal carcinoma, 111–112
localized disease, 105–106
locoregional disease, 106–109
metastatic and/or recurrent disease, 109–110
nasopharyngeal carcinoma, 110–111
organ preservation, 112
pretreatment assessment, 105
Candida species, 493
capecitabine
adenocarcinoma of the pancreas, 196, 197
breast cancer, 29, 236–238
cancers of the head and neck, 114
cholangiocarcinoma, 212
colon cancer, 174, 175
colorectal cancer, 180
dosage, schedule, 705
esophageal carcinoma, 159
gallbladder carcinoma, 212
gastric carcinoma, 163, 164, 165, 166–167, 169
mechanism of action, 705
metastatic disease, 200–201, 203
pancreatic neuroendocrine tumors, 208
primary indications, 705
rectal cancer, 181, 182
special precautions, 705–706
toxicity, 706
unresectable pancreatic carcinoma, localized, 199
carboplatin
ACC, 342
breast cancer, 233
cancers of the head and neck, 108, 112–113, 115t
cervical cancer, 256
 dosage, schedule, 706
endometrial cancer, 263, 263t, 264
esophageal carcinoma, 157, 158, 159
gastric carcinoma, 164
glioblastoma multiforme, 382
HL, 548t
lung cancer
NSCLC, 129, 132, 132t, 133, 134t, 135, 138, 139, 140, 141, 143
SCLC, 145, 145t
mechanism of action, 706
melanoma, 360, 361
NSCLC, 30
ovarian cancer, 272–278, 273t, 274, 277
ovarian germ cell tumors, 278
pancreatic neuroendocrine tumors, 207
primary indications, 706
SCCHN, 27
skin testing protocol, 640t
special precautions, 707
toxicity, 707
carcinoid syndrome, 169–170
carcinoma of bile ducts
chemotherapy, 210–212
current recommendations, 212
epidemiology, 209–210
natural history, 210
pathogenesis, 210
presentation, 209–210
carcinoma of lung. See lung carcinoma
carcinomatous meningitis. See leptomeningeal carcinomatosis (LMC)
cardiac effects, immune therapy, 658
cardiac toxicity, 90–91
carfilzomib (Kyprolis), 55–56
amyloidosis, 622
mechanism of action, 707
MM, 607–608
primary indication, 707–708
special precautions, 708
toxicity, 708–709
usual dosage and schedule, 708
carmustine (BCNU), 381–382, 382t
dosage, schedule, 709
mechanism of action, 709
primary indications, 709
special precautions, 710
toxicity, 710
CBC. See complete blood cell count
CCNU, medulloblastomas, 385
CDC. See complement-dependent cytolysis
CDDP, bone sarcomas, 422
CDX-110. See rindopepimut
cediranib, 33
grade III and IV gliomas, 380
cell cycle, 4–5, 5f
nonspecific drugs, 8, 8t
 specific drugs, 7, 8t
specificity, phase and, 5–8, 6t
time, 4, 5f
cell death. See apoptosis
cell signaling–targeted therapy, 18, 26–54
EGFR family, 26
IGF1R, 34
intracellular signaling proteins, inhibition of, 41
ligand-receptor binding, blocking, 26
receptor kinases, inhibition of, 41
RTKs, inhibition of, 34–35
VEGF, 30–34
cell surface ligands, 63
cellular therapy, melanoma, 364
cellular toxin-conjugated antibodies, 59–60
central nervous system (CNS), 15
DLBCL, 583
ceritinib (Zykadia)
lung cancer, 124
mechanism of action, 710
primary indication, 710
special precautions, 711
toxicity, 711–712
usual dosage and schedule, 711
cervical cancer, 250
clinical presentation, 251–252
diagnosis, 252
histology, 250
prognostic factors, 252
screening, 250–251
staging, 252
treatment
adenocarcinoma, 255
dysplasia, in situ carcinoma, 253
early stage disease, 253–254
locally advanced disease, 254–255
neoadjuvant chemotherapy, 255
novel biologics, 256
palliative care, 257
recurrent and advanced-stage disease, 255–256
cervical squamous cell carcinoma, therapeutic management, 629
cetuximab (Erbitux; C225)
anal cancer, 185
cancers of the head and neck, 108, 113, 114, 115, 115t
cholangiocarcinoma, 211
colon cancer, 175–176
colorectal cancer, 181
dosage, schedule, 712–713
gallbladder carcinoma, 211
mechanism of action, 712
metastatic colorectal carcinoma, 28
metastatic disease, 201
NSCLC, 136, 141
primary indications, 712
SCCHN, 27–28
 side effects, 183
special precautions, 713
toxicity, 713
CGH. See comparative genomic hybridization
chelation therapy, MDS, 536
chemoimmunotherapy, CLL, 494–495
chemokines, 70
chemotherapeutic agents, 673
dose modification, 674–676, 676t
dose recommendation, 673
dose selection and designation, 673
drug toxicity, 673–674
drugs, classes of, 667, 668–670t
alkylating agents, 670–671
antimetabolites, 671
hormones, hormone antagonists, 671–672
molecularly target agents, 672
natural products, 671
chemotherapy, 98
cholangiocarcinoma, 210–212
classic agents, 1–3
combination, 115, 115t
concurrent, 107, 108, 109, 112, 114, 115, 117
cytotoxic. See cytotoxic chemotherapy
Ewing sarcoma, 419–421
gallbladder carcinoma, 210–212
grade III and IV gliomas, 379–381, 381t
induction. See induction chemotherapy
metastatic brain disease, 392
for metastatic disease, 199–204
metastatic disease, 200
neoadjuvant. See neoadjuvant chemotherapy
pancreatic neuroendocrine tumors, 207–208
paraganglioma, 345–346
PCNSL, 386
pheochromocytoma, 345–346
pineal region tumors, 384
radiosensitizing, 114–115
second-line therapy, 115
second-line. See second-line chemotherapy
side effects
anaphylaxis, 635–640
carboplatin skin testing, 640t
constipation, 650–652
cytokine-release reactions, 635–640
diarrhea, 649–650, 651t
extravasation, 632–635, 634t
fatigue, 648–649
hypersensitivity, 638t
hypersensitivity reactions (HSRs), 635–640
infusion reactions, 635–640, 639t
nausea and vomiting, 640–646, 642t, 643–644t, 646t
neurotoxicity, 652–653
oral complications, 647–648
PPE, 653–654, 654t
 skin reactions, 654–655
chest irradiation, SCLC, 146–147
chlorambucil
CLL, 494–496
dosage, schedule, 713
mechanism of action, 713
primary indications, 713
special precautions, 714
toxicity, 714
WM, 620
cholangiocarcinoma
chemotherapy, 210–212
current recommendations, 212
epidemiology, 209–210
natural history, 210
pathogenesis, 210
presentation, 209–210
chondrosarcoma, 417–418
incidence, 411
CHOP regimen
DLBCL, 575
NHL, in advanced age patients, 589
phenotype directed–targeted therapy, 18, 57
chordomas, 423
incidence, 412
chronic lymphocytic leukemia (CLL), 479, 489–499, 566
complications of
autoimmunity, 493
malignancies, 493
recurrent infections, 493–494
diagnosis, 490–491
prognosis, 491–493, 492t
staging, 491–493, 491t, 492t
therapy, 494–499
bendamustine, 494–495
chemoimmunotherapy, 494–495
monoclonal antibody-based, 495–496, 499t
novel therapies, 497–498
response assessment, 498–499, 499t, 500t
small-molecule inhibitors, 496–497
stem cell transplantation, 498
chronic myelogenous leukemia (CML), 479–489
classification
accelerated phase (AP), 481, 482t
blast phase (BP), 481–482, 482t
chronic phase (CP), 481
diagnosis, 480–481
prognosis, 482–483
therapy, 483–489
allo-HSCT, 489, 490t
dasatinib, 484
disease monitoring during TKI therapy, 486
imatinib, 483–484, 486t
milestones, 487t
nilotinib, 485
 omacetaxine, 489
response criteria, 486–487t
TKI, 485–489
chronic phase (CP), chronic myelogenous leukemia, 481
cisplatin
ACC, 341–342
anal cancer, 184, 185
cancers of the head and neck, 105, 112, 114, 115, 115t
cervical cancer, 254–256
cholangiocarcinoma, 210–211, 212
dosage, schedule, 714
endometrial cancer, 263–265, 263t
esophageal carcinoma, 156, 158, 159
gallbladder carcinoma, 210–211, 212
gastric carcinoma, 162, 163, 164, 166–169
GTN, 287t, 288
HL, 548t
lung cancer
NSCLC, 127, 128t, 129–130, 132, 134t, 135, 136, 141, 143
SCLC, 145, 145t, 147
mechanism of action, 714
medulloblastomas, 385
melanoma, 360, 368
metastatic colorectal carcinoma, 28
metastatic disease, 201
metastatic urothelial cancers, 296
osteosarcoma, 416, 417
ovarian cancer, 273t, 274
ovarian germ cell tumors, 283
pancreatic neuroendocrine tumors, 207–208
penile cancer, 310
primary indications, 714
SCCHN, 27
special precautions, 714–715
testicular cancer, 308–309
toxicity, 89, 91, 715–716
unresectable pancreatic carcinoma, localized, 198
vulvar cancer, 282
cixutumumab, 34
cladribine
B-cell leukemias, 500–501
dosage, schedule, 716
hematologic, immunologic impairment, 92
mechanism of action, 716
primary indications, 716
special precautions, 716
toxicity, 89, 716–717
classic chemotherapy agents, 1–3
Classical HL, 541
CLL. See chronic lymphocytic leukemia
Clodronate, MM, 617
clofarabine
ALL, 475
dosage, schedule, 717
MDS, 535
 mechanism of action, 717
primary indications, 717
relapsed AML, 447
special precautions, 717
toxicity, 717
Clostridium difficile, 661
C-met, hepatocellular carcinoma, 216
CMF regime, breast cancer, 231–232
CML. See chronic myelogenous leukemia
CMV. See cytomegalovirus
CMV regimen, muscle-invasive bladder cancer, 294
CNS. See central nervous system
CNS disease, ALL, 468–470
CNS prophylaxis, 448
ALL, 463, 464
relapsed AML, 448
CNS toxicity, of ifosfamide, 407, 760
coagulopathy management
acute leukemias, 436
acute promyelocytic leukemia, 453, 454t
cobimetinib (Cotellic)
mechanism of action, 718
primary indication, 718
special precautions, 718
toxicity, 718–719
usual dosage and schedule, 718
CODOX-M/IVAC regimen, 580t, 582
colitis, immune therapy, 661
colon cancer, 173–181
adjuvant chemotherapy, 173–175
advanced, treatment for, 175–181
colorectal cancer, 172
adjuvant chemotherapy
colon cancer, 173–175
rectal cancer, 181–182
resected hepatic metastases, 181
complications, 182–183
follow-up, 182
serum CEA, 173
staging, 172–173
treatment, advanced disease, 175–181
colorectal carcinoma, metastatic, 27
colposcopy, cervical cancer, 252–253
combination chemotherapy
agent selection, principles of, 11–12
cancers of the head and neck, 114–115, 115t
clinical effectiveness, 12
effectiveness, reasons for, 9–11
metastatic disease, 200–202
combined-modality therapy, 99
adenocarcinoma of the pancreas, 194–199
Cometriq. See cabozantinib
Common Toxicity Criteria, 90
comparative genomic hybridization (CGH), 630
Compazine. See prochlorperazine
complement-dependent cytolysis (CDC), 65
complete blood cell count (CBC), 293
complete response (CR)
acute leukemias, 438–439
definition, 84
computed tomography (CT)
ACC, 337
adenocarcinoma of the pancreas, 192–193
baseline lesions, 84
bladder cancer, 293
bone sarcomas, 413, 422
cancers of the head and neck, 104, 106, 109
cervical cancer, 252, 253, 254
esophageal carcinoma, 155, 156, 157
gastric carcinoma, 161
hepatocellular carcinoma, 214
large intestine cancer, 173
lung cancer screening, 124–125
melanoma, 351–352
NHL, 561
small-cell lung cancer, 144
soft-tissue sarcomas, 400
spiral, 124
of thorax, 625
thyroid carcinoma, 331
tumor size, baseline, 84
concurrent chemotherapy, cancers of the head and neck, 107, 108, 109, 112, 114, 115, 117
conjugated antibodies
cellular toxin-conjugated antibodies, 59–60
radioimmunoconjugate antibodies, 60–61
consolidation therapy
acute leukemia, 438
ALL, adult, 463–464, 470
APL, 454t, 456–457
constipation, 650–652
core-needle biopsy, cancers of the head and neck, 103
corticosteroids
breast cancer, 228
PMF, 521
Cotellic. See cobimetinib
Cotswold staging system, 542, 542t
CP. See chronic phase
CR. See complete response
cranial spinal irradiation (CSI)
medulloblastomas, 384
pineal region tumors, 384
craniopharyngiomas, 388–389
management algorithm, 389
C-reactive protein, 70
crenolanib, relapsed AML, 448t
crizotinib (Xalkori), 40–41
mechanism of action, 719
NSCLC, 124, 135t, 142–143
primary indication, 719
special precautions, 719
 toxicity, 720
usual dosage and schedule, 719
cryoablation, ACC, 342, 343
CSI. See cranial spinal irradiation
CT. See computed tomography
CTCL. See cutaneous T-cell lymphomas
CTLA-4. See cytotoxic T-lymphocyte–associated protein 4
cutaneous T-cell lymphomas (CTCL; mycosis fungoides), 569–570, 570t
CVD regimen, melanoma, 361t
CyberKnife stereotactic therapy
paraganglioma, 345
pheochromocytoma, 345
cyclophosphamide
acute myelogenous leukemia, 93
ALL, 463, 464, 466
amyloidosis, 622
bladder cancer, 93
breast cancer, 231–232, 232t, 233, 235, 236
CLL, 495
DLBCL, 576t
dosage, schedule, 721
Ewing sarcoma, 420
GTN, 287t, 288
indolent lymphoma, 568t, 572–573
mechanism of action, 720
medulloblastomas, 385
melanoma, 361t, 368, 369
MM, 602–605, 613
paraganglioma, 345–346
pheochromocytoma, 345–346
primary indications, 721
relapsed AML, 447
SCLC, 146
soft-tissue sarcomas, 404–405, 407
special precautions, 721
toxicity, 89, 721
WM, 620
cyclosporine A, MDS, 529
cyproheptadine
carcinoid tumors, 172
PV, 514
Cyramza. See ramucirumab
cytarabine (ara-C), 6–7
ALL, 454t, 462–467, 469, 473–474
AML
in adults, 440–441, 440t, 445–447
in older adults, 450, 451
relapsed, 445–447
APL, 454t, 456–457
dosage, schedule, 722
MDS, 535
mechanism of action, 722
metabolic inactivation, reduced, 10
PCNSL, 387t
primary indications, 722
 special precautions, 722
t-AML, 451
toxicity, 722–723
cytarabine liposomal (Depocyt), LMC, 392, 392t
cytokeratin profile, primary cancers, 626, 627t
cytokine-release reactions, 637–638
cytokines, 32, 64
-induced toxicity, 66
anti-CTLA-4. See anti-CTLA-4
anti-PD-1. See anti-PD-1
multiple soluble, 63
response kinetics, 67–70
cytomegalovirus (CMV), 493
cytopenias, 619
cytoreductive nephrectomy, kidney cancer, 317
cytoreductive surgery, ovarian cancer, 271–272
cytotoxic chemotherapy
hepatocellular carcinoma, 215
kidney cancer, 321
osteosarcoma
MAP protocol, 416–417
MAP/MAPIE regimen, 417
cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), 138
cytotoxic therapy, 230–231
advanced disease treatment, 236–238
early disease treatment, 231–235
favorable-risk AML, 443
kidney cancer, 321
response to, 231
cytotoxicity, to resting and dividing cells, 10

D
dabrafenib (Tafinlar), 48
mechanism of action, 723
melanoma, 358–359
noncutaneous malignancies, 93
primary indication, 723
special precautions, 723–724
squamous cell carcinomas of the skin, 93
toxicity, 724–725
usual dosage and schedule, 723
dacarbazine
carcinoid tumors, 170, 171, 172
dosage, schedule, 725
mechanism of action, 725
melanoma, 360, 361
paraganglioma, 345–346
pheochromocytoma, 345–346
primary indications, 725
soft-tissue sarcomas, 403
special precautions, 725
toxicity, 725
Dacogen. See decitabine
dacomitinib, 38–39
dactinomycin
antidotes, 636t
dosage, schedule, 726
Ewing sarcoma, 420
GTN, 287–288
mechanism of action, 725
primary indications, 726
soft-tissue sarcomas, 404
special precautions, 726
toxicity, 726
danazol, PMF, 521
daratumumab (Darzalex)
mechanism of action, 726
MM, 612–613
primary indication, 726
special precautions, 727
toxicity, 727–728
usual dosage and schedule, 727
Darbepoetin, MDS, 530
Darzalex. See daratumumab
dasatinib (Sprycel), 43–44
CML, 484
dosage, schedule, 729
mechanism of action, 728
Ph+ ALL, 472
primary indications, 728–729
special precautions, 729
toxicity, 729
daunorubicin
adult ALL, 465–466
adult AML, 440, 440t
ALL, salvage therapy, 473
AML, in older adults, 449–450
antidotes, 636t
APL, 455t
dosage, schedule, 729
liposomal. See daunorubicin, liposomal
mechanism of action, 729
primary indications, 729
special precautions, 730
toxicity, 730
daunorubicin, liposomal
dosage, schedule, 731
mechanism of action, 730
primary indication, 731
special precautions, 731
toxicity, 731
DCVax, kidney cancer, 322
DDT, ACC, 340
Decadron. See dexamethasone
decitabine (Dacogen)
AML, in older adults, 450
dosage, schedule, 732
MDS, 529, 531, 534
mechanism of action, 731
 primary indications, 732
relapsed AML, 450
toxicity, 732
deferasirox (Exjade), MDS, 536
deferoxamine (Desferal), MDS, 536
degarelix
dosage, schedule, 732
mechanism of action, 732
primary indications, 732
special precautions, 732
toxicity, 733
dendritic cells. See antigen-presenting cells (APCs)
denileukin diftitox (Ontak), 61
dosage, schedule, 733
mechanism of action, 733
MF, 369
primary indications, 733
special precautions, 733
toxicity, 733–734
denosumab
bone sarcomas, 423
breast cancer, 242
prostate cancer, 304–305
Depo-Provera. See medroxyprogesterone
Depocyt. See cytarabine liposomal
Desferal. See deferoxamine
dexamethasone (Decadron), 53, 643t
ALL, 463, 465, 466, 473
older adults, 470, 471
amyloidosis, 622
DLBCL, 575
gastric carcinoma, 166
melanoma, 363
metastatic brain disease, 390
MM, 602, 603, 605–606, 608–612, 613
side effects, 183
DFS. See disease-free survival
DHAP regimen, non-Hodgkin lymphoma, 582t
diarrhea, 649–650, 651t
immune therapy, 661
diazoxide, pancreatic neuroendocrine tumors, 205
differentiated thyroid cancer (DTC), 328
prognosis, 329–330
treatment
adjuvant therapy, 332–333
radiotherapy, 332–334
RAI, 332–333
surgery, 331–332
systemic therapies, 334–335
TSH suppression, 332
diffuse large B-cell lymphoma (DLBCL), 574–575, 576t
diffusing capacity of carbon monoxide (DLCO), 544
diphenhydramine, MM, 612
diphenoxylate, side effects, 182
disease-free survival (DFS), 83, 541
DLBCL. See diffuse large B-cell lymphoma
DLCO. See diffusing capacity of carbon monoxide
docetaxel, 32
adenocarcinoma, 72
antidotes, 636t
breast cancer, 29, 233, 235–238
cancers of head and neck, 113, 115t
dosage, schedule, 734
esophageal carcinoma, 158
gastric carcinoma, 164, 166, 168
mechanism of action, 734
NSCLC, 130, 133, 134t, 135t, 136, 137
ovarian cancer, 277
primary indications, 734
prostate cancer, 300, 303
soft-tissue sarcomas, 404, 405, 407
special precautions, 734
squamous cell carcinoma of the lung, 72
toxicity, 734–735
dolasetron (Anzemet), 644t
dovitnib, 33–34
doxazosin
paraganglioma, 345
pheochromocytoma, 345
doxorubicin (Adriamycin)
ACC, 341–342
acute myelogenous leukemia, 93
ALL, 465, 466, 473
antidotes, 636t
ATC, 336
bone sarcomas, 422
breast cancer, 232–236, 232t
cancers of the head and neck, 114
carcinoid tumors, 170
DLBCL, 576t
dosage, schedule, 735
endometrial cancer, 263–265, 263t
esophageal carcinoma, 158
Ewing sarcoma, 420
gastric carcinoma, 164
HL, 544, 546, 548t
liposomal. See doxorubicin, liposomal
mechanism of action, 735
MF, 368, 369
MM, 604, 606
osteosarcoma, 416, 417
pancreatic neuroendocrine tumors, 207
primary indications, 735
SCLC, 146
soft-tissue sarcomas, 402–405, 408
special precautions, 735–736
toxicity, 736
vulvar cancer, 282
doxorubicin, liposomal
dosage, schedule, 737
 mechanism of action, 737
MM, 606
primary indications, 737
special precautions, 737
toxicity, 737–738
dronabinol (Marinol), 644t
DTC. See differentiated thyroid cancer
dysphagia, cancers of the head and neck therapy and, 117–118

E
EAC. See esophageal adenocarcinoma
Eastern Cooperative Oncology Group (ECOG), 352
EATCL. See enteropathy-associated T-cell lymphoma
E-BEACOPP regimen, Hodgkin lymphoma, 545t
EBV. See Epstein-Barr virus
ECOG. See Eastern Cooperative Oncology Group
ECOG/WHO/Zubrod Performance Status Scale, 80–81, 82t
EGFR. See epidermal growth factor receptor
EGFR1-targeted therapy, 27–28
electrical field therapy
glioblastoma multiforme, 382–383
grade III and IV gliomas, 381
elotuzumab (Empliciti), 58–59
mechanism of action, 738
MM, 610–611, 613
primary indication, 738
special precautions, 738
toxicity, 738–739
usual dosage and schedule, 738
EMA-CO regimen, GTN, 287t, 288
EMA-EP regimen, GTN, 287t
Emend. See aprepitant
emetic potential, 641, 642t
Empliciti. See elotuzumab
endobronchial stents, SCLC, 147
endocrine cancers, 327–346
adrenocortical carcinoma, 337–344
paraganglioma, 344–346
pheochromocytoma, 344–346
thyroid carcinoma, 327–337
endocrine (hormonal) therapy
breast cancer, 228, 238–241, 239f
endometrial cancer, 262–263
endocrine problems, 93
endocrine side effects, immune therapy, 661–662
endometrial cancer, 257–265
clinical presentation, 258
diagnosis, 258
histology, 257
prognostic factors, 259
screening, 257–258
staging, 259–261
treatment
chemotherapy, 263–264, 263t
 endocrine therapy, 262–263
follow-up, 265
multimodality therapy, 265
novel biologics, 264
radiotherapy, 261–262
surgery, 261
uterine papillary serous carcinoma, 264
endometrial stromal sarcoma (ESS), 265–266
endoscopic esophageal ultrasound (EUS), carcinoma of esophagus, 155, 156
enteropathy-associated T-cell lymphoma (EATCL), 555
enzalutamide (Xtandi)
mechanism of action, 739
primary indication, 739
prostate cancer, 302–303
special precautions, 739–740
toxicity, 740
usual dosage and schedule, 739
epidermal growth factor receptor (EGFR), 654–655
colon cancer, 175–176
endometrial cancer, 259
family, 26
inhibitors, toxicity, 89
lung cancer, 124, 138–139
monoclonal antibodies, 141–142
tyrosine kinase inhibitors (TKIs), 135–136, 140–141
epipodophyllotoxins, toxicity, 91
epirubicin
antidotes, 636t
breast cancer, 233, 235
dosage, schedule, 741
esophageal carcinoma, 159
gastric carcinoma, 162, 163, 164, 166, 167
mechanism of action, 740
primary indications, 740
special precautions, 741
toxicity, 741
EPO. See erythropoietin
EPOCH regimen, DLBCL, 575, 578
epratuzumab, 58
Epstein-Barr virus (EBV), 541
squamous cell carcinoma of the head and neck, 102
Erbitux. See cetuximab
eribulin, breast cancer, 236
eribulin mesylate
dosage, schedule, 742
mechanism of action, 742
primary indications, 742
special precautions, 742
toxicity, 742–743
erismodegib. See sonidegib
Erivedge. See vismodegib
erlotinib (Tarceva), 35–36
adenocarcinoma of the pancreas, 195, 196
and cancers of head and neck, 115
dosage, schedule, 743
 mechanism of action, 743
metastatic disease, 201–202, 203
NSCLC, 124, 135t, 136, 140–141
primary indications, 743
resectable pancreatic adenocarcinoma, 198
special precautions, 743
toxicity, 743–744
erythropoietin (EPO)
myelodysplastic syndrome, 529–532
PMF, 521
ES. See Ewing sarcoma
ESCC. See esophageal squamous cell carcinoma
ESHAP regimen
Hodgkin lymphoma, 548, 548t
non-Hodgkin lymphoma, 582t
esophageal adenocarcinoma (EAC), 154–155, 158
esophageal squamous cell carcinoma (ESCC), 154–155, 158
esophagus carcinoma
advanced disease treatment, 158–159
clinical manifestations, 155–156
combined-modality treatment, 156
epidemiology, 154–155
follow-up studies, 160
preoperative chemoradiation, 157–158
preoperative chemotherapy, 156–157
pretreatment evaluation, 155–156
radiation therapy, 158
supportive care, 160
treatment, prognosis, 156–160
ESS. See endometrial stromal sarcoma
essential thrombocythemia (ET), 515–518
diagnosis, 515–516
evolution, outcome, 518
treatment regimens, 516–517
estrogen receptors, breast cancer, 229–230
ET. See essential thrombocythemia
etoposide
ACC, 341–342
acute leukemias, 441
ALL, 463, 464, 473
cholangiocarcinoma, 210
DLBCL, 576t
dosage, schedule, 744
Ewing sarcoma, 420
gallbladder carcinoma, 210
gastric carcinoma, 164
GTN, 287t, 288
HL, 545t, 548t
mechanism of action, 744
medulloblastomas, 385
melanoma, 368
NSCLC, 128t, 132t, 133
ovarian cancer, 273t
ovarian germ cell tumors, 283
pancreatic neuroendocrine tumors, 207–208
 pineal region tumors, 384
primary indications, 744
relapsed AML, 445–447
SCLC, 145, 145t, 146, 147
soft-tissue sarcomas, 404, 405
special precautions, 744
testicular cancer, 308
toxicity, 745
EuroEwing regimen
Ewing sarcoma, 420
EUS. See endoscopic esophageal ultrasound
evaluable disease, 86
everolimus (Afinitor), 50–51
carcinoid tumors, 171
dosage, schedule, 745
kidney cancer, 320
mechanism of action, 745
metastatic renal cell carcinoma, 324t
non–clear cell carcinoma, 323
pancreatic neuroendocrine tumors, 208
primary indication, 745
special precautions, 745–746
toxicity, 746
Ewing sarcoma (ES), 418
chemotherapy, 419–421
EuroEwing regimen, 420
IE regimen, 420
VAC regimen, 420
VAI regimen, 420
VDC regimen, 420
VIDE regimen, 420
clinical symptoms, 413–414
incidence, 411
outcome after first-line treatment
high-dose chemotherapy with stem cell transplantation, 421
second-line chemotherapy, 421
treatment strategy, 419
of ulna, 418, 419f
exemestane
breast cancer, 238, 241
dosage, schedule, 746
mechanism of action, 746
primary indications, 746
special precautions, 746
toxicity, 747
Exjade. See deferasirox
exome sequencing. See whole exome sequencing
external beam radiotherapy
DTC, 334
MTC, 335
extracorporeal photopheresis, MF, 368
extragonadal germ-cell cancer syndrome, therapeutic management, 628–629
EXTREME trial, 114, 115
F
FAB classification. See French-American-British classification
Fareston. See toremifene
Farydak. See panobinostat
fatigue, 648–649
favorable-risk AML, postremission therapy, 443
FDA. See Food and Drug Administration
FDG-PET. See 18F-fluorodeoxyglucose positron emission tomography
FEC regimen, breast cancer, 235
fertility, acute leukemias, 437
fever, 436–437
fibrosis, cancers of the head and neck therapy and, 119
Filanesib, MM, 613
filgrastim
myelodysplastic syndrome, 531
SCLC, 148
fine needle aspiration (FNA)
adenocarcinoma of the pancreas, 192–193
cancers of the head and neck, 103
thyroid carcinoma, 330–331
FISH analysis. See fluorescence in-situ hybridization analysis
FL. See follicular lymphoma
FLAG-IDA regimen
ALL, 473–474
AML, 446
FLIPI. See follicular lymphoma international prognostic index
FLO regimen
colon cancer, 174–175
colorectal cancer, 174–175
FLT-3 gene, 430–431
FLT-3-ITD gene, 430–431
fludarabine
ALL, 473, 474
CLL, 493–496
dosage, schedule, 747
hematologic, immunologic impairment, 92
mechanism of action, 747
MF, 369
primary indication, 747
relapsed AML, 445, 446
special precautions, 747–748
toxicity, 89, 748
Waldenström macroglobulinemia, 620
fludrocortisone, ACC, 341
fluorescence in-situ hybridization (FISH) analysis, 480
18F-fluorodeoxyglucose positron emission tomography (FDG-PET)
ACC, 337–338
NHL, 561, 565
NSCLC, 126
PCNSL, 386
progressive disease, 84
squamous cell carcinoma, 626
fluoropyrimidine
cholangiocarcinoma, 211
 gallbladder carcinoma, 211
gastric carcinoma, 168
fluoroquinolone, 183
5-fluorouracil (5-FU), 31, 32
adenocarcinoma of the pancreas, 194, 195, 196, 197
anal cancer, 184, 185
breast cancer, 29, 232, 232t, 233, 235
cancers of head and neck, 105, 108, 113–114, 115, 115t
carcinoid tumors, 170, 171
cervical cancer, 254, 255
cholangiocarcinoma, 210, 211, 212
colon cancer, 173–180, 176, 178–179
colorectal cancer, 172
dosage, schedule, 748–749
esophageal carcinoma, 156, 157, 158, 159
gallbladder carcinoma, 210, 211, 212
gastric carcinoma, 162, 163–164, 166–168
mechanism of action, 748
metastatic colorectal carcinoma, 27, 28
metastatic disease, 200, 202, 203–204
nonmelanoma skin cancer, 366
pancreatic neuroendocrine tumors, 207
primary indications, 748
rectal cancer, 180, 182
SCCHN, 27, 28
side effects, 183
special precautions, 749
toxicity, 113–114
unresectable pancreatic carcinoma, localized, 198
vulvar cancer, 282
flutamide
dosage, schedule, 749
mechanism of action, 749
primary indications, 749
special precautions, 749
toxicity, 750
FNA. See fine needle aspiration
FOLFIRI regimen, 19t, 20t, 712, 812, 845
colon cancer, 175, 176, 177, 179, 180
colorectal cancer, 27, 28, 30, 32, 179, 180
gastric carcinoma, 164
FOLFIRINOX regimen, adenocarcinoma of the pancreas, 196, 199, 202, 204
FOLFOX4 regimen
colon cancer, 173, 174
colorectal cancer, 180
FOLFOXIRI regimen
colon cancer, 175
colorectal cancer, 180
folinic acid, metastatic colorectal carcinoma, 27
follicle-stimulating hormone (FSH), 662
follicular lymphoma (FL), 566
pathology, 566
prognostic index scores, 564t
Follicular Lymphoma International Prognostic Index (FLIPI), 563, 564t
follicular thyroid cancer (FTC), 328
 prognosis, 329
Folotyn. See pralatrexate
Food and Drug Administration (FDA), 17
foretinib, 49
fosaprepitant, 644t, 646t
fosbretabulin, ATC, 336
fractionated radiotherapy, 127
French-American-British (FAB) classification, 427
FSH. See follicle-stimulating hormone
FTC. See follicular thyroid cancer
5-FU. See 5-fluorouracil
fulvestrant
breast cancer, 241
dosage, schedule, 750
mechanism of action, 750
primary indications, 750
special precautions, 750
toxicity, 750–751
function-directed therapy, 18
angiogenesis-targeted therapy, 54–55
cell signaling–targeted therapy, 18, 26–57
intracellular signaling proteins, inhibition of, 41
ligand-receptor binding, blocking, 26
RTKs, inhibition of, 35–36
protein degradation–targeted therapy, 55–56

G
gallbladder carcinoma
chemotherapy, 210–212
current recommendations, 212
epidemiology, 209–210
natural history, 210
pathogenesis, 210
presentation, 209–210
Gamma Knife Stereotactic Radiosurgery (GK-SRS)
metastatic brain disease, 391–392
paraganglioma, 345
pheochromocytoma, 345
ganitumab, 34
gastric carcinoma
adjuvant chemoradiation, 162–163
adjuvant chemotherapy, 162, 163
clinical manifestations, evaluation, 161
epidemiology, 160–161
follow-up studies, 169
perioperative chemotherapy, 162, 163
postoperative adjuvant combined modality regimen, 163–164
treatment, advanced disease, 164–166
treatment, prognosis, 161–169
gastroesophageal reflux disease (GERD), 155
gastrointestinal (GI) tract carcinomas, 154–184
gastrointestinal stromal tumors (GISTs), 396
Gazyva. See obinutuzumab
GBM. See glioblastoma multiforme
GC regimen, muscle-invasive bladder cancer, 294–296, 295t
G-CSF
ALL, 474
myelodysplastic syndrome, 531
relapsed AML, 446
GCTB. See giant cell tumor of the bones
GCTs. See germ cell tumors; granulosa cell tumors
GDP regimen, non-Hodgkin lymphoma, 582t
gefitinib (Iressa), 36
ATC, 337
cancers of head and neck, 115
dosage, schedule, 751
mechanism of action, 751
NSCLC, 124, 139–141
primary indications, 751
special precautions, 751
toxicity, 751
gemcitabine
adenocarcinoma of the pancreas, 195, 196, 197
borderline resectable pancreatic cancer, 198, 199
breast cancer, 236, 238
cancers of the head and neck, 114, 115t
cervical cancer, 255, 256
cholangiocarcinoma, 210–211, 212
dosage, schedule, 752
esophageal carcinoma, 158
gallbladder carcinoma, 210–211, 212
HL, 548t
mechanism of action, 752
metastatic cancer of unknown origin, 629
metastatic disease, 200–201, 202, 203
MF, 369
NSCLC, 130, 133, 134t, 136, 141
ovarian cancer, 273t
primary indications, 752
resectable pancreatic adenocarcinoma, 198
SCLC, 146
soft-tissue sarcomas, 403, 404, 405–406
special precautions, 752
toxicity, 752
uterine sarcomas, 266
GemDTIC regimen, soft-tissue sarcomas, 405, 406
GemOx. See oxaliplatin
GemTax regimen, soft-tissue sarcomas, 405–406
gemtuzumab ozogamicin (Mylotarg), 59
AML, in older adults, 441
gene expression profiling (GEP), 563–564
breast cancer, 229–230
GEP. See gene expression profiling
GERD. See gastroesophageal reflux disease
germ cell tumors (GCTs), 305
gestational trophoblastic neoplasm (GTN)
clinical presentation, 285
diagnosis, 285–286
histology, 285
 prognostic factors, 286, 286t
screening, 285
staging, 286
treatment, 287–289, 287t
GH. See growth hormone
GI tract carcinomas. See gastrointestinal tract carcinomas
giant cell tumor of the bones (GCTB), 422–423
incidence, 412
Gilotrif. See afatinib
GISTs. See gastrointestinal stromal tumors
GK-SRS. See Gamma Knife Stereotactic Radiosurgery
Gleevec. See imatinib; imatinib mesylate
glioblastoma multiforme (GBM), 375, 378
electrical field therapy, 382–383
multicentric, 379
multifocal, 379
regimens, recurrent, 381–383, 382t
gliomas, 374–383, 382t
grade I, 375
grade II, 375–378
grade III and IV, 378–383
chemotherapy, 379–381, 381t
electrical field therapy, 381
postoperative management, 379
prognostic factors, 379
radiation therapy, 379–381
regimens, recurrent GMB, 381–383, 382t
surgical resection, newly diagnosed malignant, 378–379
glucarpidase (Voraxaze), 11
mechanism of action, 752
primary indication, 753
special precautions, 753
toxicity, 753
usual dosage and schedule, 753
GM-CSF. See granulocyte-macrophage colony-stimulating factor
gonadal failure, dysfunction, 94
gonadotropin-releasing hormone analogs
dosage, schedule, 753
mechanism of action, 753
primary indication, 753
special precautions, 754
toxicity, 754
goserelin, breast cancer, 241
GPI. See Graded Prognostic Index
Graded Prognostic Index (GPI), 390, 391
graft-versus-host disease (GVHD), 436
graft-versus-leukemia effect, 65
graft-versus-tumor effect, in allogeneic bone marrow transplantation, 63
granisetron (Kytril), 644t
granulocyte-macrophage colony-stimulating factor (GM-CSF), 65
neuroblastoma following autologous bone marrow transplant, 72
granulosa cell tumors (GCTs), 284
clinical presentation, 284
histology, 284
prognostic factors, 284
 staging, 284
treatment, 284–285
growth hormone (GH), 662
GTN. See gestational trophoblastic neoplasm
GVHD. See graft-versus-host disease
gynecologic cancer, 250–289. See also specific cancers

H
HACAs. See human anti-chimeric antibodies
Haemophilus influenza, CLL, 493
hairy cell leukemia (HCL), 500
Haldol. See haloperidol
haloperidol (Haldol), 643t
HAMAs. See human anti-mouse antibodies
hand-foot syndrome. See palmar plantar erythrodysesthesia (PPE)
HCC. See hepatocellular carcinoma
hCG. See human chorionic gonadotropin
HCL. See hairy cell leukemia
HDACs. See histone deacetylases
head and neck cancers. See cancers of head and neck (HNCs)
hedgehog signaling pathway, 52
Helicobacter pylori
adenocarcinoma of the pancreas, 191
gastric carcinoma, 160
hematologic impairment, 92
hematologic toxicity
dose modification, 675
immune therapy, 658–659
hematopoietic stem cell transplantation (HSCT). See also allogeneic hemapoietic stem cell transplantation
ALL, 475–477
APL, 457, 460
hemorrhagic cystitis
cyclophosphamide therapy and, 407, 721
ifosfamide and, 759
heparin, MM, 609
hepatic toxicity, immune therapy, 659–661
hepatitis, 660
hepatocellular carcinoma (HCC)
advanced HCC, therapy of, 215–216
current recommendations, 216
diagnostic evaluation and screening, 213–214
epidemiology, 212
etiology, 212–213
laboratory tests, 214
preoperative evaluation, 214–215
presenting signs and symptoms, 213
primary therapy, 215
risk factors, 212–213
staging, 214
hepatosplenic T-cell lymphoma (HSTCL), 555
HER-2-neu (HER2, erbB2)
breast cancer, 229, 232t
-targeted therapy, 28–30
Herceptin. See trastuzumab
hereditary multiple exostosis. See Bessel-Hagen disease
hereditary renal cell carcinoma syndromes, 314t
hereditary retinoblastoma, 412
5-HIAA. See 5-hydroxyindoleacetic acid
HiDAC regimens
acute leukemias, 441
AML, in older adults, 450–451
older adults, 450, 451
relapsed AML, 446
histone deacetylases (HDACs), 53–54
HIV. See human immunodeficiency virus
HL. See Hodgkin lymphoma
HLA typing, acute leukemias, 436
HNCs. See cancers of head and neck
Hodgkin lymphoma (HL), 93, 540–541
chemotherapy, ABVD, 545–547
follow-up and survivorship, 549–550
initial treatment, by stage of disease, 547–548
pathology of, 541
refractory, 548–549
relapsed, 548–549
staging and diagnosis
Cotswold staging system, 542, 542t
procedures, 543
prognostic score, advanced HL, 542–543
treatment of, 544–547
chemotherapy, 545–546, 545t
combined modality, 546–547
response-adapted therapy, 547
RT, 544–545
salvage regimens in, 548t
hormonal excess and deficiency, management of, 343
hormonal therapy, kidney cancer, 321
hormone antagonists, 671–672
general description, 671–672
hormone replacement therapy (HRT)
breast cancer, 218
hormones, 671–672
general description, 671–672
hospice, 100
HPV. See human papillomavirus
HRT. See hormone replacement therapy
HSCT. See hematopoietic stem cell transplantation
HSTCL. See hepatosplenic T-cell lymphoma
human anti-chimeric antibodies (HACAs), 26
human anti-mouse antibodies (HAMAs), 26
human chorionic gonadotropin (hCG), 283, 305
human immunodeficiency virus (HIV), 586
human papillomavirus (HPV)
-associated oropharyngeal carcinoma, 102
treatment, 111–112
cervical cancer, 250–251
Hürthle cell cancer, 327
Hydrocortisone, ACC, 341
5-hydroxyindoleacetic acid (5-HIAA), 170
hydroxyurea
dosage, schedule, 754
EV, 517
gastric carcinoma, 164
mechanism of action, 754
PMF, 522
primary indications, 754
PV, 512
special precautions, 754–755
toxicity, 755
hyper-CVAD regimen
ALL, 466–467, 474
CNS disease, 469
mature (Burkitt) B-cell ALL, 467
Ph+ ALL, 472
hypercalcemia, MM, 615–616
hyperkalemia, acute leukemias, 435
hyperleukocytosis, 434–435
hyperphosphatemia, 435
hyperthyroidism, 662
hyperuricemia
acute leukemias, 435
uric acid nephropathy, 435
hyperviscosity, 616, 619
hypocalcemia, acute leukemias, 435
hypofractionated radiotherapy
grade II glioma, 378
grade III and IV gliomas, 380
hypogammaglobulinemia, 493
hypomethylating agents, relapsed AML, 450

I
Ibrance. See palbociclib
Ibritumomab tiuxetan (Zevalin, IDEC-Y2B8), 60–61
ibrutinib (Imbruvica), 39–40
CLL, 496–497
dosage, schedule, 755
mechanism of action, 755
primary indications, 755
special precautions, 755–756
toxicity, 756
Waldenström macroglobulinemia, 619, 621
ICE regimen
Hodgkin lymphoma, 548, 548t
non-Hodgkin lymphoma, 582t
Iclusig. See ponatinib
idarubicin
ALL, 473, 474
AML
adult, 440, 440t
in older adults, 450
in pregnancy, 456, 457
relapsed, 446
antidotes, 636t
 APL, 454–455t, 456, 457
dosage, schedule, 757
mechanism of action, 756
primary indications, 756
relapsed AML, 446
special precautions, 757
toxicity, 757
IDEC-Y2B8. See ibritumomab tiuxetan
idelalisib (Zydelig), 51
CLL, 497
mechanism of action, 757
primary indication, 757
special precautions, 758
toxicity, 758
usual dosage and schedule, 757–758
IE regimen, Ewing sarcoma, 420
IFN. See interferon
IFN-α. See interferon alpha
IFN-γ. See interferon-γ
ifosfamide
bone sarcomas, 422
cancers of head and neck, 114
cervical cancer, 266
dosage, schedule, 759
Ewing sarcoma, 420
HL, 548t
lung cancer
NSCLC, 137
SCLC, 147
mechanism of action, 759
primary indications, 759
soft-tissue sarcomas, 403, 404, 405, 407–408
special precautions, 759
testicular cancer, 309
toxicity, 89, 759–760
uterine sarcomas, 266
IGF. See insulin-like growth factor
IGF1R. See insulin-like growth factor type 1 receptor
IHC techniques. See immunohistochemical techniques
IL-1. See interleukin 1
IL-6. See interleukin 6
IL-11. See interleukin 11
IL-15. See interleukin 15
IL-21. See interleukin 21
imatinib (Gleevec)
CML, 483, 486t
resistance, 484
soft-tissue sarcomas, 402, 404, 406
imatinib mesylate (Gleevec), 42–43
dosage, schedule, 760
mechanism of action, 760
Ph+ ALL, 471
primary indications, 760
special precautions, 761
toxicity, 761
Imbruvica. See ibrutinib
123I-MIBG scintigraphy

paraganglioma, 345
pheochromocytoma, 345
131I-MIBG scintigraphy

paraganglioma, 345
pheochromocytoma, 345
IMiDs. See immunomodulatory agents
immune checkpoint inhibitors
adverse events, 66
clinical activity and application, 73
glioblastoma multiforme, 383
metastatic brain disease, 392
predictive biomarkers, 70, 71, 72
response kinetics, 68, 69
immune-related adverse events (irAEs), 66, 67, 73
immune therapy, side effects of, 657–664
cardiac effects, 658
diarrhea/colitis, 661
endocrine side effects, 661–662
hematologic toxicity, 658–659
hepatic toxicity, 659–661
ipilimumab and nivolumab, combination studies of, 664
neurologic toxicity, 662–663
ocular toxicity, 662
pulmonary toxicity, 663
systemic effects, 657–658
immunohistochemical (IHC) techniques, breast cancer, 223
immunohistochemistry, metastatic cancer of unknown origin, 626–627, 627t
immunologic impairment, 92
immunomodulatory agents (IMiDs), 522
PMF, 522
immunotherapy
kidney cancer, 317–318
myelodysplastic syndrome, 533–534
NSCLC, 138–139
immunotherapy response criteria (iRC), 69
immunotoxins, 61
Imodium. See loperamide
IMRT. See intensity-modulated radiation therapy
indolent lymphoma. See indolent non-Hodgkin lymphoma (NHL)
indolent non-Hodgkin lymphoma (NHL), 566
extended-duration therapy, 568–569
FL pathology, 566
frontline treatment principles, 566
initial treatment, 568t
maintenance in, 568–569
induction chemotherapy
acute leukemias, 439–441, 440t
AML, in older adults, 449–450
cancers of head and neck, 109
infections
acute leukemias, 436
CLL, 493–494
MM, 616
 myelodysplastic syndrome, 536
infliximab, 661
iniparib, 53
Inlyta. See axitinib
inotuzumab ozogamicin, 60
insulin-like growth factor (IGF), 34
insulin-like growth factor type 1 receptor (IGF1R), 34
intensity-modulated radiation therapy (IMRT), cancers of the head and neck, 106
intensive chemotherapy, myelodysplastic syndrome, 532–533
interferon (IFN), melanoma, 357–358
interferon alpha (IFN-α), 657, 658, 659, 661
carcinoid tumors, 171, 172
dosage, schedule, 762
EV, 517
kidney cancer, 318, 323
mechanism of action, 761
primary indications, 762
PV, 512–513, 515
resected primary and regional melanoma, 72
special precautions, 762
toxicity, 762–763
interferon-γ (IFN-γ), 64
toxicity, 66
interleukin 1 (IL-1), 657
interleukin 2 (IL-2), 65, 657, 658, 659, 661
kidney cancer, 317, 318, 323
melanoma, 69, 71, 357, 361t, 362, 364
metastatic, 72
neuroblastoma following autologous bone marrow transplant, 72
renal cell carcinoma, 69, 72
renal or marrow allografts, 72
response kinetics, 67, 68
toxicity, 66
interleukin 6 (IL-6)
toxicity, 67
interleukin 11 (IL-11)
myelodysplastic syndrome, 537
interleukin 15 (IL-15), 657
interleukin 21 (IL-21), 657
intermediate-risk AML, postremission therapy, 443
internal tandem duplication (ITD), 430
International Prognostic Index (IPI), 562–563, 562t, 563t
International Prognostic Scoring System (IPSS), 542–543
myelodysplastic syndrome, 525–526, 526t
International Workshop on CLL (IWCLL), 498
interventional radiology, as treatment modality
ACC, 342–343
intraperitoneal chemotherapy, ovarian cancer, 274
iodine-131 (131I)-tositumomab (Bexxar), 61
IPI. See International Prognostic Index
IPI-926 (Saridegib), 52
ipilimumab, 662
adenocarcinoma, 72
combination studies of, 664
dosage, schedule, 763
 mechanism of action, 763
melanoma, 72, 355–356, 357
NSCLC, 138–139
primary indications, 763
special precautions, 763–764
squamous cell carcinoma of the lung, 72
toxicity, 66, 89, 764
IPSS. See International Prognostic Scoring System
IPSS-R. See Revised International Prognostic Scoring System
irAEs. See immune-related adverse events
iRC. See immunotherapy response criteria
Iressa. See gefitinib
irinotecan
colon cancer, 174, 175, 176, 178, 179
colorectal cancer, 172
dosage, schedule, 764–765
esophageal carcinoma, 158, 159
gastric carcinoma, 164, 168
mechanism of action, 764
metastatic colorectal carcinoma, 27
metastatic disease, 200, 202, 204
NSCLC, 30
primary indications, 764
rectal cancer, 183
SCLC, 146
side effects, 183
special precautions, 765
toxicity, 765–766
iron overload, myelodysplastic syndrome, 536
ISIS-481464, 46
islet cell tumors
locally advanced or metastatic, management of, 206–207
Istodax. See romidepsin
ITD. See internal tandem duplication
IWCLL. See International Workshop on CLL
ixabepilone
breast cancer, 236
dosage, schedule, 766
mechanism of action, 766
primary indications, 766
special precautions, 766
toxicity, 91, 766–767
ixazomib (Ninlaro)
amyloidosis, 622
mechanism of action, 767
MM, 613
primary indication, 767
special precautions, 767
toxicity, 767–768
usual dosage and schedule, 768

J
JAK2 inhibitors, for PMF, 521–522
Jakafi. See ruxolitinib
Janus kinase, 46–47

K
Kadcyla. See ado-trastuzumab emtansine
Kaolin pectin (Kaopectate), 651t
Kaopectate. See Kaolin pectin
Karnofsky Performance Status Scale, 80, 81t
Keppra. See levetiracetam
ketoconazole, ACC and, 342
Keytruda. See pembrolizumab
kidney cancer
adjuvant therapy, 322–323
adoptive cellular therapy, 322
clinical characteristics, 315
combination therapy, 323
cytotoxic chemotherapy/hormonal therapy, 321
epidemiology, 314
genetic alterations, 313–314
histopathology, 313
risk factors, 315, 316t
staging, 315–316, 316t
systemic therapy, 317–321
treatment considerations, 316–317
vaccines, 321–322
Kinavet. See masitinib
Klinefelter syndrome, 309
Kyprolis. See carfilzomib
Kytril. See granisetron

L
L-Asp
ALL, 464, 465, 474
older adults, 470, 471
CNS disease, 468
lactate dehydrogenase (LDH), 70, 71
lanreotide
carcinoid tumors, 171
islet cell tumors, locally advanced or metastatic, 206
lansoprazole, pancreatic neuroendocrine tumors, 205
LAP score. See leukocyte alkaline phosphatase score
laparoscopy
esophageal carcinoma, 156
gastric carcinoma, 161
lapatinib
breast cancer, 234, 236, 238
cancers of head and neck, 115
lapatinib ditosylate (Tykerb), 37–38
breast cancer, 238
dosage, schedule, 768
mechanism of action, 768
primary indications, 768
special precautions, 768
toxicity, 768–769
large intestine cancer, 172
adjuvant chemotherapy
colon cancer, 173–175
rectal cancer, 182–183
resected hepatic metastases, 181
advanced colon cancer, treatment for, 175–181
advanced disease treatment, 175–181
complications, 182–183
follow-up, 182
serum CEA, 173
staging, 172–173
lasofoxifene, breast cancer, 221
LDH. See lactate dehydrogenase
leiomyosarcoma, 412
lenalidomide (Revlimid), 56
CLL, 497
dosage, schedule, 769
MDS, 529, 532, 534–535
mechanism of action, 769
MM, 602, 603, 605–606, 608, 609–611, 613, 614, 615
PMF, 520
primary indications, 769
special precautions, 769
toxicity, 769–770
lenvatinib (Lenvima), 33
DTC, 334–335
kidney cancer, 321
mechanism of action, 770
metastatic renal cell carcinoma, 324t
primary indication, 770
special precautions, 770
toxicity, 770–771
usual dosage and schedule, 770
Lenvima. See lenvatinib
leptomeningeal carcinomatosis (LMC), 392
chemotherapy regimens, 392t
lesions, melanoma, 349–350
letrozole
breast cancer, 238, 239, 241
dosage, schedule, 772
mechanism of action, 772
primary indications, 772
special precautions, 772
toxicity, 772
leucovorin
adenocarcinoma of pancreas, 195, 196
ALL, 463, 466
older adults, 471
cholangiocarcinoma, 210, 212
colon cancer, 173–175, 178–179
colorectal cancer, 172
cooperative inhibition, 11
esophageal carcinoma, 159
gallbladder carcinoma, 210, 212
gastric carcinoma, 162, 163–164, 168
 GTN, 287t
metastatic disease, 202, 203–204
osteosarcoma, 416, 417
rectal cancer, 180, 182
rescue, 11
leukapheresis, 434–435
leukemia, acute myelogenous, 92–93
leukocyte alkaline phosphatase (LAP) score, 480
leukostasis, 434–435
leuprolide, breast cancer, 241
levetiracetam (Keppra), 390
LFTs. See liver function tests
LH. See luteinizing hormone
LHRH. See luteinizing hormone-releasing hormone
Li-Fraumeni syndrome, 412
ligand-receptor binding, blocking, 26
LINAC-based radiosurgery, metastatic brain disease, 391
linifanib, 49
linsitinib, 34
liposomal vincristine, ALL, 474
Listeria, CLL, 493
liver function tests (LFTs), 659
liver metastases, localized treatment of, 171
liver transplantation, hepatocellular carcinoma, 215
LMC. See leptomeningeal carcinomatosis
lobectomy, 127
localized disease, cancers of the head and neck, 105–106
locoregional disease, cancers of the head and neck, 106–109
locoregionally advanced (LRA) disease, cancers of the head and neck, 106, 107, 108
lomustine
dosage, schedule, 773
glioblastoma multiforme, 382, 382t
mechanism of action, 772
primary indication, 772
special precautions, 773
toxicity, 773
Lonsurf. See trifluridine/tipiracil
loperamide (Imodium), 651t
side effects, 182, 183
lorazepam (Ativan), 643t, 646t
LRA. See locoregionally advanced disease
lumpectomy, breast cancer, 226
lung carcinoma, 123. See also metastatic non–small-cell lung cancer; non–small-cell lung cancer (NSCLC); small-cell lung
cancer (SCLC)
etiology, 123
molecular biology, 123–124
palliation
colony-stimulating factors, 148
endobronchial stents, 147
pleural effusions, 147
radiotherapy, 147
PD-1/PD-L1 antagonists for, 71
screening, 124–125
Lung Screening Study, 124–125
luspatercept, MDS, 535
luteinizing hormone (LH), 662
luteinizing hormone-releasing hormone (LHRH)
agonists, prostate cancer, 300–301
antagonists, prostate cancer, 301
lymphadenectomy, cervical cancer, 254
lymphedema, cancers of head and neck therapy and, 119
lymphodepletion, with chemotherapy prior to cell transfer, 73
lymphoma, thyroid, 329
lymphoplasmacytic lymphoma. See Waldenström macroglobulinemia (WM)
Lynparza. See olaparib
Lysodren. See mitotane

M
MACIS scoring system, 330, 330t, 331
MACOP-B regimen, non-Hodgkin lymphoma, 575
macromolecular synthesis or function, 1
MAGIC trial, 162
magnetic resonance imaging (MRI)
ACC, 337
bone sarcomas, 413
breast cancer, 221
screening, 221
cancers of head and neck, 104, 109
cervical cancer, 252, 253, 254
grade II glioma, 375
grade III and IV gliomas, 380
hepatocellular carcinoma, 214
medulloblastomas, 384
metastatic adenocarcinoma, 626
NSCLC, 126
pineal region tumors, 384
pituitary adenomas, 388
SCLC, 144, 147
soft-tissue sarcomas, 400
maintenance therapy, 69
acute leukemia, 439
major histocompatibility complex (MHC), 63, 64
malignant fibrous histiocytoma (MFH), 397
bone, 411
MALT lymphoma, 569
mammalian target of rapamycin (mTOR) inhibitors, 320
MammaPrint test, 230, 232t
mammography, 221, 222
metastatic adenocarcinoma, 626
mantle cell lymphoma (MCL), 570–574, 571t, 572–573t, 574t
MAP protocol, osteosarcoma, 416–417
MAP/MAPIE regimen, osteosarcoma, 417
marginal zone lymphomas (MZLs), 569
Marinol. See dronabinol
Marqibo. See vincristine sulfate liposome
MART-1, in melanoma, 63
masitinib (Kinavet), 39
mastectomy, breast cancer, 226
mature (Burkitt) B-cell ALL, 467
matuzumab, 39
M-BACOD regimen, non-Hodgkin lymphoma, 575
MCL. See mantle cell lymphoma
MCL 2 regimen, 572t
mCRPC. See metastatic castration-resistant prostate cancer
MD Anderson Scoring System, MDS, 526, 527t
MDR. See multidrug resistance
MDS. See myelodysplastic syndrome
MEC regimen, acute myeloid leukemia, 446
mechlorethamine, 8, 369, 517
dosage, schedule, 773
EV, 517
mechanism of action, 773
primary indications, 773
special precautions, 773–774
toxicity, 774
median survival time, 83
medical perspective, treatment goals, setting, 96–97
medroxyprogesterone (Provera, Depo- Provera), 437
medullary thyroid cancer (MTC), 328–329
prognosis, 329
treatment
radiotherapy, 335
surgery, 335
systemic therapies, 335–336
medulloblastomas, 384–385
megestrol acetate
breast cancer, 241, 242
endometrial cancer, 262, 263t
side effects of, 242
MEK-162. See binimetinib
MEK inhibitors, melanoma, 359–360
Mekinist. See trametinib
melanoma
adjuvant therapy, 352–354
IL-2 for, 69
MART-1 in, 63
metastatic. See metastatic melanoma
natural history
etiology and epidemiology, 348–349
metastases, patterns of, 351
ocular melanoma, 351
precursor lesions, genetics, familial melanoma, 349
primary lesions, types and appearance of, 349–350, 350t
PD-1/PD-L1 antagonists for, 71
resected primary and regional, 72
staging, 350t, 351–352
surgical treatment, 352
survival, 355t
therapy of metastases
biochemotherapy, 361–362
biologic agents, 355–360
chemotherapy, 360–364
experimental and future therapies, 363–364
regional therapy, 362–363
 systemic therapy, 354–355, 355t
melphalan
amyloidosis, 622
dosage, schedule, 774
mechanism of action, 774
MM, 602, 603–604, 605, 609, 618
PMF, 521
primary indications, 774
special precautions, 774
toxicity, 774–775
Memorial Sloan-Kettering Cancer Center (MSKCC), 315
menses suppression, acute leukemias, 437
6-mercaptopurine
ALL, 463–465, 467, 473
older adults, 471
dosage, schedule, 775
mechanism of action, 775
primary indication, 775
special precautions, 775
toxicity, 775
Merkel cell carcinoma
clinical features, 367
etiology and epidemiology, 367
treatment, 367–368
mesna
ALL, 466
dosage, schedule, 776
mechanism of action, 775
primary indications, 776
soft-tissue sarcomas, 404–405
special precautions, 776
toxicity, 776
metabolic abnormalities, cancers of head and neck therapy and, 119
metastatic adenocarcinoma, 626
metastatic brain disease
chemotherapy, 392
incidence, 389
management algorithm, 389–390
radiation therapy, 391–392
steroids and anticonvulsants therapy, 390
surgical management, 390–391
metastatic cancer of unknown origin, 625–630
classification, 627–628
diagnosis, 625–630
baseline assessments, 626t
cytokeratin profile, 626, 627t
immunohistochemistry, 626–627, 627t
molecular analysis, 629–630
prognosis, 627–628
therapeutic management, 628–629
metastatic castration-resistant prostate cancer (mCRPC), 300, 301–302
metastatic disease
androgen ablation and, 300–301
chemotherapy for, 199–204
combination chemotherapy, 200–202
 current recommendations, 202–203
second-line chemotherapy, 203–204
single agents, 199
evaluation of response, 305
treatment, 109–110
metastatic hormone-resistant prostate cancer, 72
metastatic melanoma
anti-CTLA-4 for, 68, 72
anti-PD-1 for, 72
IL-2 for, 69, 72
talimogene laherparepvec for, 71
metastatic non–small-cell lung cancer, anti-PD-1, 72
metastatic renal cell carcinoma, 323, 324t
metastatic urothelial cancers, 296
methotrexate (MTX), 11
ALL, 463–467, 473
older adults, 470, 471
bone sarcomas, 422
breast cancer, 232, 236
cancers of head and neck, 113, 115t
CNS disease, 468, 469
DLBCL, 576t
dosage, schedule, 776
esophageal carcinoma, 158
GTN, 287–288, 287t
LMC, 392t
mechanism of action, 776
osteosarcoma, 416–417
PCNSL, 386, 387t
penile cancer, 310
primary indications, 776
relapsed AML, 445
special precautions, 777
toxicity, 777
vulvar cancer, 282
methylprednisolone, 612
methysergide, carcinoid tumors, 172
metoclopramide (Reglan), 643t
MF. See mycosis fungoides
MFH. See malignant fibrous histiocytoma
mFOLFOX6 regimen. See modified FOLFOX6 regimen
MGUS. See monoclonal gammopathy of undetermined significance
MHC. See major histocompatibility complex
β2-microglobulin, multiple myeloma, 596, 598t
Micromonospora echinospora ssp. calichensis, 59
midostaurin, 39
minimal residual clone (MRC), 594
minimal residual disease (MRD), 594
ALL, 468
mitomycin
anal cancer, 184
antidotes, 636t
dosage, schedule, 778
esophageal carcinoma, 158
gastric carcinoma, 164
 mechanism of action, 777
primary indications, 778
special precautions, 778
toxicity, 89, 778
mitomycin C, vulvar cancer, 282
mitotane (Lysodren)
ACC, 340–341, 342
dosage, schedule, 778
mechanism of action, 778
primary indications, 778
special precautions, 778–779
toxicity, 779
mitoxantrone
ALL, 461, 473
AML
adult, 440, 440t
relapsed, 445–447
APL, 455t
cancers of head and neck, 114
dosage, schedule, 779
mechanism of action, 779
primary indications, 779
prostate cancer, 303
relapsed AML, 445, 446
special precautions, 779
toxicity, 779
MK2206, 52
MM. See multiple myeloma
MoAbs. See monoclonal antibodies
mocetinostat, 54
modified FOLFOX6 (mFOLFOX6) regimen
colon cancer, 174, 176, 179–180
rectal cancer, 182
Mohs micrographic surgery, nonmelanoma skin cancer, 366
molecular analysis, metastatic cancer of unknown origin, 629–630
molecular targeted therapy (MTT), 3–4, 98–99
angiogenesis-targeted therapy, 54–55
cell signaling–targeted therapy
intracellular signaling proteins, 41
ligand-receptor binding, blocking, 26
RTKs, inhibition of, 35–36
characteristics of, 17
classification and type of, 17–18, 19–25t
nonspecific immunomodulators, 56–57
phenotype directed–targeted therapy, 18, 57
immunotoxins, 61
protein degradation–targeted therapy, 55–56
molecularly targeted agents
dose modification, 674–676, 676t
dose recommendation, 673
dose selection and designation, 673
drug toxicity, 673–674
general description, 672
monoclonal antibodies, 672
other agents, 672
 tyrosine kinase and multikinase inhibitors, 672
monoclonal antibodies (MoAbs), 26, 672
toxicity, 89
monoclonal gammopathy of undetermined significance (MGUS), 595–596
monoclonal protein (M-protein), 594–595
MPDL 3280A, melanoma, 357
MPNs. See myeloproliferative neoplasms
M-protein. See monoclonal protein
MPT regimen, MM, 609
MRC. See minimal residual clone
MRC/ECOG. See Berlin-Frankfurt-Muenster (BFM)-like regimens
MRD. See minimal residual disease
MRI. See magnetic resonance imaging
MSKCC. See Memorial Sloan-Kettering Cancer Center
MTC. See medullary thyroid cancer
mTOR pathway. See mammalian target of rapamycin inhibitors
MTT. See molecular targeted therapy
MTX. See methotrexate
mucositis, 647–648
cancers of head and neck therapy and, 117
soft-tissue sarcomas, chemotherapy and, 407
multidrug resistance (MDR), 10, 13–14
multikinase inhibitors, 672
multiple myeloma (MM)
bone marrow transplantation, 613–614
complications, 615–618
diagnosis, 596–598, 597t
duration of therapy, 614–615
epidemiology, 598
M-protein, 594–595
maintenance therapy, role of, 614–615
MGUS, 595–596
prognostic factors, 599, 601
radiotherapy, 615
staging, 597t, 598t
stem cell transplantation, 613–614
therapy, goals of, 598–599, 600t
treatment, 601–613
muscle-invasive bladder cancer, 294–296
musculoskeletal system toxicity, 94
MVAC regimen, muscle-invasive bladder cancer, 294–296, 295t
mycosis fungoides (MF), 569–570
clinical features, 368
etiology and epidemiology, 368
treatment, 368–369
myelodysplastic syndrome (MDS), 523–537
classification, 524–525, 524t, 525t
diagnosis, 523–524
prognosis, 525–529, 526t, 527t, 528t
therapy
clinical trials, 534–536
general approach, 528t, 529
growth factors, 527t, 530–531
immunotherapy, 533–534
intensive chemotherapy, 532–533
 other agents, 534
specific agents, 531–532
supportive care, 536–537
myeloid-derived suppressor cells, 64, 65
myeloproliferative neoplasms (MPNs)
BCR-ABL1-negative, 506–522
ET, 515–518
diagnosis, 515–516
evolution, outcome, 518
treatment regimens, 516–517
MDS, 523
classification, 524–525, 524t, 525t
diagnosis, 523–524
prognosis, 525–529, 526t, 527t, 528t
PMF
conventional drug therapy, 522
diagnosis, 518–520
novel therapies, 521–522
treatment regimens, 520–521
PV, 507–515
ancillary treatments, 514–515
antithrombotic therapy, 510–511
diagnosis, 507–509, 510f
evolution, outcome, 515
myelosuppressive agents, 511–514
phlebotomy, 510
therapy, aims of, 509–510, 511f
therapy, 527t, 528t, 529–537
myelosuppressive agents, 511–514
Mylotarg. See gemtuzumab ozogamicin
MZLs. See marginal zone lymphomas

N
nab-paclitaxel, breast cancer, 238
NACT-IDS. See neoadjuvant chemotherapy, with interval debulking surgery
nanoparticle albumin-bound paclitaxel (nab-paclitaxel). See also paclitaxel
adenocarcinoma of the pancreas, 196
metastatic disease, 202, 203
nasopharyngeal carcinoma (NPC)
classification of, 111
prevalence, 110–111
National Cancer Institute (NCI), 124
Cancer Therapy Evaluation Program, 90
natural killer (NK) cells, 65, 553, 559t
natural products, 671
natural resistance, 13
nausea, 640–646, 642t, 643–644t, 646t
Navitoclax (ABT-263), 45
NCI. See National Cancer Institute
necitumumab (Portrazza)
mechanism of action, 780
primary indication, 780
special precautions, 780
toxicity, 780–781
 usual dosage and schedule, 780
nelarabine
ALL, 475
dosage, schedule, 781
mechanism of action, 781
primary indications, 781
special precautions, 781
toxicity, 781–782
neoadjuvant chemotherapy
cervical cancer, 255
with interval debulking surgery (NACT-IDS), 271–272
muscle-invasive bladder cancer, 294–295
resectable pancreatic adenocarcinoma, 197–198
response to, 82–83
soft-tissue sarcomas, 402
neoantigens, 63
nephrotoxicity, 91
NETs. See neuroendocrine tumors
netupitant, 644t
neuroblastoma, 65
neuroendocrine tumors (NETs), 169
carcinoid syndrome, 169–170
pancreatic
epidemiology, 204
presentation, 204–205
primary treatment, 205–209
therapeutic management, 629
treatment, 170–172
neurologic toxicity, immune therapy, 662–663
neurotoxicity, 91–92
side effects, cancer chemotherapy, 652–653
Nexavar. See sorafenib
NHL. See non-Hodgkin lymphoma
nilotinib (Tasigna), 44
CML, 485
dosage, schedule, 782
mechanism of action, 782
Ph+ ALL, 472
primary indications, 782
special precautions, 782
toxicity, 782–783
nilutamide
dosage, schedule, 783
mechanism of action, 783
primary indications, 783
special precautions, 783
toxicity, 783
Ninlaro. See ixazomib
nintedanib (Ofev), 33
niraparib, 53
ovarian cancer, 276–277
nitrogen mustards. See also mechlorethamine
nitrosoureas, 8
gastric carcinoma, 164
glioblastoma multiforme, 382
 melanoma, 360
nivolumab (Opdivo), 70
combination studies of, 664
kidney cancer, 318
nivolumab (Opdivo) (continued)
mechanism of action, 783
melanoma, 356, 357
metastatic renal cell carcinoma, 324t
NSCLC, 139
primary indication, 784
special precautions, 784
toxicity, 66, 784–785
usual dosage and schedule, 784
NK cell. See natural killer cells
NLPHL. See Nodular Lymphocyte-predominant HL
Nodular Lymphocyte-predominant HL (NLPHL), 541
non–clear cell carcinoma, treatment for, 323–324
non-Hodgkin lymphoma (NHL), 93, 553
aggressive NHL, management of
DLBCL, 574–575
initial treatment, advanced stage, 575, 577t, 578
initial treatment, localized form, 578–579
MCL, 570–574, 571t, 572–573t, 574t
PMBL, 579
PTCLs, 579–580
rare, extranodal T-cell lymphoma, 581
relapsed PTCL, 580–581
classification, 557, 558–559t
epidemiology, 553–554, 554t
high-grade form, BL, 581–583
highly aggressive NHL, management of
BL, 580t, 582t
CNS prophylaxis, 583
tumor lysis prophylaxis, 583
prognosis of
GEP, prognostic tools, 563–564
interim imaging scans, 565
IPI, 562–563, 562t, 563t, 564t
response assessment at end of therapy, 565–566
radiation therapy, 585–586
relapsed, therapy of
allogeneic transplantation, 584
immunotherapy, 584–585
salvage chemotherapy, 582t, 583–584
targeted agents, 585
risk factors, 554–556, 555t, 556t
staging of
Ann Arbor staging, 560–561, 561t
diagnosis, 557, 560
workup, imaging, 560, 560t
subgroups, special considerations
advanced age patients, 588–589
AIDS-related lymphomas, 586
PCNSL, 587–588
PTLDs, 586–587, 587t
 testicular lymphomas, 588
non-steroidal anti-inflammatory drugs (NSAIDs)
MM, 601
soft-tissue sarcomas, 407
nonhematologic toxicity, dose modification, 674–675
nonmelanoma skin cancer
diagnosis and clinical features, 365–367
etiology and epidemiology, 364–365
non–muscle invasive bladder cancer, 293–294
nonseminoma
BEP, 308
postchemotherapy management, 308
stage I disease, 306–307
stage II disease, 307
stage III disease, 307–308
non–small-cell lung cancer (NSCLC), 123
histology, 125
locally advanced disease, 130
bulky stage IIIA (N2), no pleural effusion, 131–133, 132t
bulky stage IIIB, no pleural effusion, 131–133, 132t
nonbulky stage IIIA, 131
pretreatment evaluation, 126–127
second-line cytotoxic chemotherapy, 137
stage I disease, 127–129, 128t
stage II disease, 129–130
stage IV disease, 133
angiogenesis inhibition, 137–138
chemotherapy, choice of, 133–135, 134t
EGFR inhibition, 139–140
first-line chemotherapy, 133
non-platinum-based regimens, 136
oligometastatic disease, 136–137
poor performance status, patients and, 136
therapy/maintenance duration, 135–136
staging, 125–126
nonspecific immunomodulators, 56–57
NovoTTF-100A System, 381, 382
NPC. See nasopharyngeal carcinoma
NSAIDs. See non-steroidal anti-inflammatory drugs
NSCLC. See non–small-cell lung cancer
nucleoside analog, 620
nutrition, cancers of head and neck, 116–117
NY-ESO-1, 63
kidney cancer, 322

O
obesity, dose modification, 675–676
obinutuzumab (Gazyva)
CLL, 496
mechanism of action, 785
primary indication, 785
special precautions, 786–787
toxicity, 787–788
usual dosage and schedule, 786
objective response, measures
evaluable disease, 86
performance status changes, 86
tumor products, 86
tumor size, 83–86
OBP-31121, 46
octreotide, 651t
islet cell tumors, locally advanced or metastatic, 206–207
pancreatic neuroendocrine tumors, 205–206
octreotide acetate (Sandostatin)
carcinoid tumors, 170, 171, 172
diarrhea, 182, 183
ocular melanoma, 351
ocular toxicity, immune therapy, 662
OD. See ollier disease
Odomzo. See sonidegib
ofatumumab (Arzerra), 58
CLL, 496
dosage, schedule, 788
mechanism of action, 788
primary indications, 788
special precautions, 788
toxicity, 788–789
Ofev. See nintedanib
olaparib (Lynparza), 53
dosage, schedule, 789
mechanism of action, 789
ovarian cancer, 276
primary indications, 789
special precautions, 789
toxicity, 789–790
older adults
ALL, 470–471
AML
auto-HSCT, 450–451
azacitidine, 450
background, 448–449
cytarabine, 450–451
daunorubicin, 449–450
decitabine, 450
HDAC, 450–451
idarubicin, 450
induction therapy, 449–450
postremission therapy, 450–451
RIC (mini)-HCST, 451
oligometastatic disease, 136–137
ollier disease (OD), 412
omacetaxine mepesuccinate (Synribo)
CML, 489
mechanism of action, 790
primary indication, 790
special precautions, 790
toxicity, 791
usual dosage and schedule, 790
omeprazole, pancreatic neuroendocrine tumors, 205
oncocytic thyroid cancer. See Hürthle cell cancer (HCC)
OncotypeDx, 230, 231, 232t, 239f
ondansetron (Zofran), 643t
Ontak. See denileukin diftitox
oophorectomy, breast cancer, 241
Opdivo. See nivolumab
oprelvekin, MDS, 537
oral care, cancers of head and neck therapy and, 118–119
orchiectomy, metastatic disease, 300
organ preservation, cancers of head and neck, 112
oropharyngeal carcinoma
HPV-associated, 102
treatment, 111–112
osimertinib (Tagrisso)
mechanism of action, 791
primary indication, 791
special precautions, 792
toxicity, 792
usual dosage and schedule, 792
osteosarcoma, 415–417
clinical symptoms, 413
cytotoxic chemotherapy
MAP protocol, 416–417
MAP/MAPIE regimen, 417
incidence, 411
of lower extremity of femur, 414f
refractory disease, recurrence and treatment of, 417
treatment strategy, 416
ovarian cancer, 266–279
clinical presentation, diagnosis, 269–270
histology, 267
prognostic factors, 270–271
screening, 267–269
staging, 271
treatment
advanced-stage disease, 272, 273t
cytoreductive surgery, 271–272
early-stage disease, 272
intraperitoneal chemotherapy, 274
maintenance, 275
palliative care, 279
PARP inhibition, 276–277
platinum-based first-line chemotherapy, 272–274
platinum-resistant disease, 278–279
platinum-sensitive disease, 278
recurrent disease, 277–278
ovarian germ cell tumors, 282–284
clinical presentation, diagnosis, 282–283
histology, 282
prognostic factors, 283
screening, 282
staging, 283
treatment, 283–284
ovarian suppression, 240
overall survival rate, 83, 541
oxaliplatin, 32
antidotes, 636t
cholangiocarcinoma, 210, 212
colon cancer, 175, 178
colorectal cancer, 172, 180
dosage, schedule, 793
esophageal carcinoma, 158, 159
gallbladder carcinoma, 210, 212
gastric carcinoma, 164, 166–167, 168
mechanism of action, 792
metastatic colorectal carcinoma, 27
metastatic disease, 202, 203–204
primary indications, 793
rectal cancer, 182
resectable pancreatic adenocarcinoma, 198
oxaliplatin (continued)
side effects, 183
special precautions, 793
toxicity, 91, 793
oxyphilic thyroid cancer. See Hürthle cell cancer (HCC)

P
paclitaxel
ATC, 336
breast cancer, 233–238, 234
cancers of head and neck, 108, 113, 115t
cervical cancer, 255, 256
dosage, schedule, 794
endometrial cancer, 263t, 264
esophageal carcinoma, 157, 158, 159, 160
gastric carcinoma, 164, 165–166, 168, 169
mechanism of action, 794
NSCLC, 30, 128t, 129, 132, 132t, 133, 134t, 139, 140
ovarian cancer, 272–279, 273t, 275–276
pancreatic neuroendocrine tumors, 207
primary indications, 794
protein-bound
dosage, schedule, 795
mechanism of action, 795
primary indications, 795
special precautions, 795
toxicity, 795–796
side effects, cancer chemotherapy, 633, 636t, 637, 640, 647, 649
soft-tissue sarcomas, 403
special precautions, 794
standard pretreatment regimen, 794
testicular cancer, 309
toxicity, 89, 794–795
uterine sarcomas, 264
vulvar cancer, 282
pacritinib, 46–47
Paget disease of bone, 412–413
palbociclib (Ibrance)
mechanism of action, 796
 primary indication, 796
special precautions, 796
toxicity, 796–797
usual dosage and schedule, 796
palliative care, 99–101
cancers of head and neck, 115–120
definition of, 116
ovarian cancer, 279
palmar plantar erythrodysesthesia (PPE), 653–654, 654t
palonosetron, 644t, 646t
pamidronate
breast cancer, 242
MM, 616, 617
Pancoast tumors, 130
pancreatic cancer, 191–204
diagnostic evaluation, 192–193
epidemiology, 191
etiology, 191
laboratory tests, 193
metastatic disease, chemotherapy for, 199–204
combination, 200–202
current recommendations, 202–203
second-line, 203–204
single agents, 200
preoperative evaluation, 193
presenting signs and symptoms, 192
primary therapy, 193–199
staging, 193
pancreatic neuroendocrine tumors (PNETs), 204–209
epidemiology, 204
presentation, 204–205
primary treatment, 205–209
locally advanced or metastatic islet cell tumors, management of, 206–207
radionuclides, 208–209
standard chemotherapy, 207–208
targeted therapies, 208
panitumumab (Vectibix)
colon cancer, 175, 176
dosage, schedule, 797
head and neck cancer, 114
large intestine cancer, 181
mechanism of action, 797
metastatic colorectal carcinoma, 28
NSCLC, 28
primary indications, 797
renal cancer, 28
side effects, 183
special precautions, 797
toxicity, 797–798
panobinostat (Farydak), 54–55
mechanism of action, 798
MM, 606–607, 613
PMF, 522
primary indication, 798
special precautions, 798
 toxicity, 798–799
usual dosage and schedule, 798
Pap test, 250
papillary thyroid cancer (PTC), 328
prognosis, 329
paraganglioma, 344–346
diagnosis, 344–345
management of
chemotherapy, 345–346
radiation therapy, 345
surgery, 345
parasellar tumors, 387–389
craniopharyngiomas, 388–389
pituitary adenomas, 387–388
paroxetine, PV, 515
PARPs. See poly (ADP-ribose) polymerase
partial response
acute leukemias, 439
definition, 84
pasireotide, 820
islet cell tumors, locally advanced or metastatic, 206
patient perspective, treatment goals, setting, 96
patient selection, for immunotherapy, 70–72
pazopanib (Votrient), 38
carcinoid tumors, 171
dosage, schedule, 800
kidney cancer, 319
mechanism of action, 800
metastatic renal cell carcinoma, 324t
primary indications, 800
soft-tissue sarcomas, 403, 406
special precautions, 800
toxicity, 800
PBMCs. See peripheral blood mononuclear cells
PBSCT. See peripheral blood stem cell transplantation
PBT. See primary brain tumors
PCNSL. See primary central nervous system lymphoma
PCTs. See proximal convoluted tubules
PCV regimen, 377
PD. See progressive disease
PD-L1. See programmed death ligand 1
PD-L2. See programmed death ligand 2
pegfilgrastim, soft-tissue sarcomas, 404
peginterferon, 353
PEGylated liposomal doxorubicin, 606
pembrolizumab (Keytruda), 70
kidney cancer, 321
mechanism of action, 801
melanoma, 356
NSCLC, 139
primary indication, 801
special precautions, 801
toxicity, 801–802
usual dosage and schedule, 801
pemetrexed
 dosage, schedule, 803
lung cancer, NSCLC, 125, 130, 133, 134t, 135–138, 137, 141
mechanism of action, 802
primary indications, 802
special precautions, 803
toxicity, 803
penile cancer, 309–310
pentostatin
B-cell leukemias, 500
dosage, schedule, 803
hematologic, immunologic impairment, 92
mechanism of action, 803
MF, 369
primary indications, 803
special precautions, 804
toxicity, 89, 804
performance status
changes, 86
quality of life, 82
treatment and, 81
types of scales, 80–81, 81t, 82t
peripheral blood mononuclear cells (PBMCs), 70
peripheral blood stem cell transplantation (PBSCT), 613–614
peripheral T-cell lymphomas (PTCLs), 579–580
peritoneal papillary adenocarcinoma, therapeutic management, 628–629
Perjeta. See pertuzumab
pertuzumab (Perjeta)
breast cancer, 29, 225, 234–237
mechanism of action, 804
primary indication, 804
side effects, 29–30
special precautions, 805
toxicity, 805
usual dosage and schedule, 804–805
PET. See positron emission tomography
PF regimen, 109
PFS. See progression-free survival
P-glycoprotein, 14
Ph+ ALL, 471–472
phase and cell cycle specificity, 5–8, 6t, 8t
phase-nonspecific drugs, 7
phase-specific drugs, 5–7, 6t
cytarabine, 6–7
implications of, 5–6
phenacetin, kidney cancer, 315
phenazopyridine, dysuria, 182
phenotype directed–targeted therapy, 18, 57
conjugated antibodies, 59–61
immunotoxins, 61
unconjugated antibodies, 57–59
phenoxybenzamine
paraganglioma, 345
pheochromocytoma, 345
pheochromocytoma, 344–346
diagnosis, 344–345
 management of
chemotherapy, 345–346
radiation therapy, 345
surgery, 345
phlebotomy, PV, 509, 510
PI3K inhibitors, CLL, 498
PI3K/Akt/mTOR pathway inhibitors, 50–52
pilocytic astrocytomas, 375
pimasertib, 49
pineal region tumors, 383–384
management algorithm, 384
pathology, 383
surgical treatment, 384
pituitary adenomas, 387–388
anatomic considerations, 387
hormonal considerations, 387–388
management algorithm, 388
surgical and postoperative management, 388
plasma cell dyscrasias, types of, 594
pleiotropic drug resistance, 13–14. See also multidrug resistance (MDR)
plerixafor, 614
pleural effusions, SCLC, 147
PLL. See prolymphocytic leukemia
PMBL. See primary mediastinal B-cell lymphoma
PMF. See primary myelofibrosis
PNETs. See pancreatic neuroendocrine tumors
Pneumocystis, CLL, 493
Pneumocystis jiroveci (carinii), 495
poly (ADP-ribose) polymerase (PARPs), 52–53
inhibition, ovarian cancer, 276–277
polycythemia vera (PV), 507–515
diagnosis, 507–509, 510f
evolution, outcome, 515
therapy, aims of, 509–510, 511f
treatment regimens
ancillary treatments, 514–515
antithrombotic therapy, 510–511
myelosuppressive agents, 511–514
phlebotomy, 510
polyglutamated paclitaxel (Xyotax), 275
pomalidomide (Pomalyst), 56–57, 611–612, 613
mechanism of action, 806
PMF, 522
primary indication, 806
special precautions, 806
toxicity, 806–807
usual dosage and schedule, 806
Pomalyst. See pomalidomide
ponatinib (Iclusig), 44–45
CML, 485
mechanism of action, 807
Ph+ ALL, 472
primary indication, 807
special precautions, 808
toxicity, 808–809
 usual dosage and schedule, 807
Portrazza. See necitumumab
positron emission tomography (PET)
cancers of head and neck, 104, 106, 109
cervical cancer, 252, 253, 254
esophageal carcinoma, 155, 156
18F-fluorodeoxyglucose. See 18F-fluorodeoxyglucose positron emission tomography
gastric carcinoma, 161
HL, 543, 547
large intestine cancer, 173
NHL, 561, 565, 567, 585
NSCLC, 126
thyroid carcinoma, 331
posttransplant lymphoproliferative disorders (PTLDs), 586–587, 587t
PPE. See palmar plantar erythrodysesthesia
PR. See partial response
pracinostat, MDS, 534
pralatrexate (Folotyn)
mechanism of action, 809
primary indication, 809
special precautions, 809
toxicity, 809
usual dosage and schedule, 809
prednisone
ALL, 464, 465, 466
DLBCL, 576t
FL, 568t, 572–573t
MF, 369
MM, 603–604, 605, 609
PMF, 521
prostate cancer, 303
WM, 620
pregnancy, acute myeloid leukemia, 452
premature menopause, 93–94
primary brain tumors (PBT). See brain tumors, primary
primary carcinoma of liver
advanced HCC, therapy of, 215–216
current recommendations, 216
diagnostic evaluation and screening, 213–214
epidemiology, 212
etiology, 212–213
laboratory tests, 214
preoperative evaluation, 214–215
presenting signs and symptoms, 213
primary therapy, 215
risk factors, 212–213
staging, 214
primary central nervous system lymphoma (PCNSL), 587–588
in immunocompetent patients, 385–387, 387t
management algorithm, 386–387
primary mediastinal B-cell lymphoma (PMBL), 564, 579
primary myelofibrosis (PMF), 518–522
diagnosis, 518–520
novel therapies, 521–522
treatment regimens, 520–521
 anemia, 521
conventional drug therapy, 522
curative intent, 521
splenomegaly, 521
primary refractory AML, 444
primary testicular lymphoma (PTL), 588
primitive neuroectodermal tumor, 384
Pro-MACE-CytaBOM regimen, 575
procarbazine
dosage, schedule, 810
mechanism of action, 809
PCNSL, 387t
primary indications, 810
special precautions, 810
toxicity, 89, 810
prochlorperazine (Compazine), 643t, 646t
side effects, 183
progesterone receptors, breast cancer, 229
progestins
dosage, schedule, 811
endometrial cancer, 263
mechanism of action, 810
primary indications, 810
special precautions, 811
toxicity, 811
programmed death ligand 1 (PD-L1), 64, 65, 66, 138, 139, 317, 318
clinical activity and application, 72, 74
head and neck cancer, 114
lung cancer, 71
melanoma, 71, 72
programmed death ligand 2 (PD-L2), 318
head and neck cancer, 114
progression-free survival (PFS), 73–74, 83
progressive disease (PD), 84
prolactin, 662
prolymphocytic leukemia (PLL), 499–500
prophylactic cranial irradiation, SCLC, 147
prostate cancer
androgen deprivation therapy, 300–301
bone-targeted supportive therapy, 304–305
castration-resistant metastatic disease, 301–304
clinically organ-confined disease, 298–299
evaluation of response, 305
general considerations, staging, 297–298
metastatic hormone-resistant, 72
protein degradation–targeted therapy, 55–56
proteins, intracellular signaling, inhibition of, 41
Provera. See medroxyprogesterone
proximal convoluted tubules (PCTs), 313
psoralen and ultraviolet radiation (PUVA), MF, 368, 369
psychosocial support, acute leukemias, 437
PTC. See papillary thyroid cancer
PTCLs. See peripheral T-cell lymphomas
PTL. See primary testicular lymphoma
PTLDs. See posttransplant lymphoproliferative disorders
pulmonary function testing, NSCLC, 126–127
pulmonary toxicity, 91
immune therapy, 663
PUVA. See psoralen and ultraviolet radiation
PV. See polycythemia vera
PVD regimen, MM, 606–607
pyridoxine, MDS, 534

Q
QOL. See quality of life
Quality of life (QOL), 82, 100
considerations, subjective change and, 86–87
quizartinib, 45
relapsed AML, 448t

R
R-CHOP regimen
DLBCL, 575, 578
indolent lymphoma, 567–568
MCL, 571
R-hyper-CVAD regimen, ALL, 467
R-hyper-CVAD/MA cycles regimen
BL, 581–582
mantle cell lymphoma, 572t
radiation therapy (RT)
ACC, 342
anal cancer, 184
ATC, 336
bone sarcomas, 413
breast cancer, 227
cancers of head and neck, 106
DTC, 332–334
endometrial cancer, 259–260
esophagus carcinoma, 158
external beam, 334
grade II glioma, 376–377
grade III and IV gliomas, 379–381
HL, 542t, 544–545
hypofractionated. See hypofractionated radiotherapy
intensity-modulated. See intensity-modulated radiation therapy
melanoma, 363
metastatic brain disease, 391–392
MM, 615
MTC, 335
NHL, 585–586
paraganglioma, 345
pheochromocytoma, 345
pineal region tumors, 384
PMF, 520
prostate cancer, 299
SCCHN, 27
SCLC, 147
soft-tissue sarcomas, 401–402
 stereotactic body. See stereotactic body radiation therapy
unresectable pancreatic carcinoma, localized, 198, 199
whole brain. See whole brain radiotherapy
radical prostatectomy, prostate cancer, 299
radioactive iodine (RAI), 332–333
radioactive phosphorus (32P), 513
EV, 517
PV, 513
radioactive remnant ablation (RRA), DTC, 332
radiofrequency ablation (RFA)
ACC, 342, 343
hepatocellular carcinoma, 216
radioimmunoconjugate antibodies, 60–61
radionuclides
bone scan, thyroid carcinoma, 331
pancreatic neuroendocrine tumors, 208–209
radiosensitizing chemotherapy, cancers of head and neck, 114–115
radiotherapy. See radiation therapy
radium-223, prostate cancer, 304
RAF/MAP kinase pathway, 47–49
RAI. See radioactive iodine
raloxifene
breast cancer, 221, 238
dosage, schedule, 811
mechanism of action, 811
primary indications, 811
special precautions, 811
toxicity, 811–812
ramucirumab (Cyramza), 31–32
colon cancer, 177, 179, 181
esophageal carcinoma, 159, 160
gastric carcinoma, 165–166, 169
mechanism of action, 812
NSCLC, 125, 138
primary indication, 812
special precautions, 812–813
toxicity, 813
usual dosage and schedule, 812
RAS. See retinoic acid syndrome
rasburicase, acute leukemias, 435
RCC. See renal cell carcinoma
receptor tyrosine kinases (RTKs), 26, 35–36
RECIST. See Response Evaluation Criteria in Solid Tumors criteria
rectal cancer
postoperative chemotherapy, 182
preoperative chemoradiation, 181–182
recurrent disease, treatment, 109–110
recursive partitioning analysis (RPA), metastatic brain disease, 390, 391
reduced intensity conditioning (RIC) (mini)-HCST, 451
AML, older adults, 451
Reed-Sternberg (RS) cells, 541
refametinib, 49
Reglan. See metoclopramide
regorafenib (Stivarga), 48–49
colon cancer, 176–177
 hepatocellular carcinoma, 216
kidney cancer, 321
mechanism of action, 813
primary indication, 814
soft-tissue sarcomas, 404, 406
special precautions, 814
toxicity, 814–815
usual dosage and schedule, 814
regulatory T-cells (Tregs), 64, 65
relapsed AML
interventions on relapse, 445
CNS prophylaxis, 448
investigational strategies, novel agents, 447, 448t
prognostic factors, 444, 445t
second postremission with HSCT, 447
standard chemotherapy, 445–447
HiDAC regimens, 446
non-HiDAC regimens, 447
renal cell carcinoma (RCC)
adjuvant therapy, 322–323
adoptive cellular therapy, 322
clinical characteristics, 315
combination therapy, 323
cytotoxic chemotherapy/hormonal therapy, 321
epidemiology, 314
histopathology, 313
IL-2 for, 69, 72
risk factors, 315, 316t
staging, 315–316
systemic therapy, 317–321
treatment considerations, 316–317
vaccines, 321–322
renal dysfunction, MM, 617
renal failure, soft-tissue sarcomas, 407
renal pelvis urothelial cancers, 296
resectable disease, 193
resected carcinomas
combined modality therapy, 194–197
resectable pancreatic adenocarcinoma, neoadjuvant chemotherapy for, 197–198
resected hepatic metastases, 181
resected primary and regional melanoma, 72
resistance, antineoplastic agents, 12–13
biochemical causes, 13–14
cell kinetics and, 13
nonselectivity and, 15
pharmacologic causes, 14–15
Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 68, 69, 73
response kinetics, 67–70
response to therapy
considerations, 83
definitions, 83
objective response, 83–86
subjective change, QOL considerations and, 86–87
survival, 82–83
retinoic acid syndrome (RAS). See acute promyelocytic leukemia (APL), differentiation syndrome
retroperitoneal lymph node dissection (RPLND), 306–307
Revised International Prognostic Scoring System (IPSS-R), MDS, 526–527, 528t
Revlimid. See lenalidomide
RFA. See radiofrequency ablation
RGemOx regimen, non-Hodgkin lymphoma, 582t
RIC (mini)-HCST. See reduced intensity conditioning (RIC) (mini)-HCST
ricolinostat, MM, 613
rindopepimut (Rintega, CDX-110), glioblastoma multiforme, 383
Rintega. See rindopepimut
Rituxan. See rituximab
rituximab (Rituxan), 57, 65
ALL, 467
B-cell leukemias, 501
DLBCL, 575
dosage, schedule, 815–816
FL, 566–570, 568t, 572–573t
hematologic, immunologic impairment, 92
indolent lymphoma, 568–569
mature (Burkitt) B-cell ALL, 467
mechanism of action, 815
PCNSL, 386, 387t
primary indications, 815
special precautions, 816
toxicity, 89, 816–817
WM, 619, 620
romidepsin (Istodax), 54
dosage, schedule, 817
mechanism of action, 817
primary indications, 817
special precautions, 817
toxicity, 817–818
RPA. See recursive partitioning analysis
RPLND. See retroperitoneal lymph node dissection
RRA. See radioactive remnant ablation
RS. See Reed-Sternberg cells
RT. See radiation therapy
RTKs. See receptor tyrosine kinases
rucaparib, ovarian cancer, 277
ruxolitinib (Jakafi), 46
mechanism of action, 818
PMF, 522
primary indication, 818
PV, 513–514
special precautions, 818–819
toxicity, 819
usual dosage and schedule, 818
RVD regimen, 605–606

S
salvage therapy
ALL, 472–475
urothelial cancer, 297
Sandostatin. See octreotide acetate
sapacitabine, relapsed AML, 448t
sarcoma, thyroid, 329
sargramostim, SCLC, 148
Saridegib. See IPI-926
SBRT. See stereotactic body radiation therapy
SCA. See squamous cell carcinoma
scintigraphy
DTC, 333
paraganglioma, 345
pheochromocytoma, 345
SCLC. See small-cell lung cancer
SCT. See stem cell transplantation
SD. See stable disease
second-line chemotherapy
Ewing sarcoma, 421
metastatic disease, 203–204
second malignancies
acute myelogenous leukemia, 92–93
solid tumors, 93
secondary cancer prevention, of head and neck, 119
selective estrogen receptor modulators (SERMs), breast cancer, 220–221, 228
Selinexor, MM, 613
sellar tumors, 387–389
craniopharyngiomas, 388–389
pituitary adenomas, 387–388
seminoma
clinical stage I, 306
clinical stage II, 306
SERMs. See selective estrogen receptor modulators
serum carcinoembryonic antigen (CEA), 173
“7 + 3” regimen
ALL, 473
relapsed AML, 446
SGI-110, MDS, 536
SIB. See simultaneous integrated boost technique
signal transduction and activator of transcription (STAT) proteins, 45–46
siltuximab (Sylvant)
mechanism of action, 819
primary indication, 819
special precautions, 820
toxicity, 820
usual dosage and schedule, 820
simultaneous integrated boost (SIB) technique, 106
sipuleucel-T, 70
metastatic hormone-resistant prostate cancer, 72
progression-free survival, 74
prostate cancer, 302
skeletal destruction, multiple myeloma, 617
SLL. See small lymphocytic lymphoma
SLPs. See speech and language pathologists
sLV5FU2 regimen
colon cancer, 174, 179, 180
rectal cancer, 182
small-cell lung cancer (SCLC), 123, 143–148
chemotherapy, chest irradiation, 146–147
pretreatment evaluation, 144
 prognostic factors, 144
prophylactic cranial irradiation, 147
staging, 143–144
therapy
combination chemotherapeutic regimens, 144–145, 145t
dose intensity, 145
duration, 145
second-line, 145–146
small intestine cancer
adenocarcinomas, 172
NETs, 169
carcinoid syndrome, 169–170
treatment, 170–172
small lymphocytic lymphoma (SLL), 566
soft-tissue sarcomas, 396–408
biopsy, 400
chemotherapy, 403–408
complications of, 406–407
first-line, 404–405
GIST, targeted treatment of, 406
second-line, 405–406
special precautions, 407–408
classification, epidemiology, 396–397
clinical presentation, 398–399
grading, 399
histologic classification, 400
imaging, 400
molecular classification, 397–398, 397t
primary treatment, 400–402
staging, 399–400
tumor progression, 399
solumedrol, toxicity, 67
somatostain analogs
dosage, schedule, 821
islet cell tumors, locally advanced or metastatic, 206–207
mechanism of action, 820
primary indications, 821
special precautions, 821
toxicity, 821
sonidegib (Odomzo; erismodegib)
mechanism of action, 821
primary indication, 821
special precautions, 822
toxicity, 822
usual dosage and schedule, 821
sorafenib (Nexavar), 47
ATC, 337
carcinoid tumors, 171
dosage, schedule, 823
DTC, 334
hepatocellular carcinoma, 216
kidney cancer, 319, 322–323
mechanism of action, 822
metastatic renal cell carcinoma, 324t
primary indications, 823
 relapsed AML, 448t
special precautions, 823
toxicity, 823
SPECTRUM trial, 114
speech and language pathologists (SLPs), 118
spiral computed tomography (CT), 124
splenectomy, PMF, 520, 521
splenomegaly, 521
Sprycel. See dasatinib
squamous cell carcinoma (SCA), 626. See also cancers of head and neck
cervical, 629
diagnosis, 365
etiology and epidemiology, 364–365
local treatment, 365–366
lung
anti-PD-1, 72
docetaxel, 72
ipilimumab, 72
of the head and neck, Epstein-Barr virus and, 102
of thyroid, 329
treatment, 367–368
SRS. See stereotactic radiosurgery
SRT. See stereotactic radiotherapy
stable disease (SD), 84
staging
system criteria, 79–80
therapy decisions and, 80
Stanford V regimen, Hodgkin lymphoma, 545t
Staphylococcus aureus, 493
STAT. See signal transduction and activator of transcription proteins
stem cell transplantation (SCT)
CLL, 498
high-dose chemotherapy with
Ewing sarcoma, 421
testicular cancer, 309
WM, 621
stereotactic body radiation therapy (SBRT)
cancers of head and neck, 106
hepatocellular carcinoma, 216
NSCLC, 127
stereotactic radiosurgery (SRS)
craniopharyngiomas, 389
glioblastoma multiforme, 382
grade II glioma, 378
metastatic brain disease, 391
pituitary adenomas, 388
stereotactic radiotherapy (SRT)
craniopharyngiomas, 389
glioblastoma multiforme, 382
pituitary adenomas, 388
steroid-refractory toxicity, 66–67
steroids, 139
metastatic brain disease, 390
Stivarga. See regorafenib
Streptococcus pneumonia, 493
streptozocin
ACC, 341, 342
carcinoid tumors, 170–171
dosage, schedule, 824
mechanism of action, 823
pancreatic neuroendocrine tumors, 207
primary indications, 823
special precautions, 824
toxicity, 824
stromal cells, 64
stromal or granulosa cell tumors (GCTs), 284
clinical presentation, 284
histology, 284
prognostic factors, 284
staging, 284
treatment, 284–285
Stupp regimen, grade III and IV gliomas, 380
subjective change, 86–87
sunitinib (Sutent), 32, 36–37
and cancers of head and neck, 115
carcinoid tumors, 171
dosage, schedule, 825
kidney cancer, 319, 322–323
mechanism of action, 824
metastatic renal cell carcinoma, 324t
non–clear cell carcinoma, 323, 324
pancreatic neuroendocrine tumors, 208
primary indications, 824
soft-tissue sarcomas, 404, 406
special precautions, 825
toxicity, 825
surgery, 97
ACC, 339–340
adenocarcinoma of the pancreas, 192–193
ATC, 336
breast cancer, 226–227
chordomas, 423
DTC, 331–332
endometrial cancer, 259
esophageal carcinoma, 156
grade III and IV gliomas, 378–379
melanoma, 363
metastatic brain disease, 390–391
MTC, 335
paraganglioma, 345
pheochromocytoma, 345
pineal region tumors, 384
pituitary adenomas, 388
Surveillance, Epidemiology and End Results database, 172
survival curves, 85–86
survivorship, cancers of head and neck, 119
Sutent. See sunitinib
Syk (spleen tyrosine kinase) inhibitors, CLL, 498
Sylvant. See siltuximab
Synribo. See omacetaxine mepesuccinate
systemic chemotherapy, ACC, 341–342
systemic effects, immune therapy, 657–658
systemic therapies
ATC, 336–337
DTC, 334–335
MTC, 335–336

T
T-AML. See therapy-related AML
T-cell receptors (TCRs), 63, 64, 70
T-cells
anticancer responses, 64–65
exhaustion of, 64
lymphoma, 581
naïve, 63
regulatory, 64, 65
tumor-infiltrating, 64
T-DM1. See ado-trastuzumab emtansine
TAC regimen, breast cancer, 235
Tafinlar. See dabrafenib
Tagrisso. See osimertinib
talimogene laherparepvec, metastatic melanoma, 71
tamoxifen
breast cancer, 220–221, 225, 231, 238–241, 239f
dosage, schedule, 826
endometrial cancer, 263
mechanism of action, 825
primary indications, 825–826
side effects of, 242
special precautions, 826
toxicity, 826
Tarceva. See erlotinib
TAS-102. See trifluridine/tipiracil
Tasigna. See nilotinib
taxanes
ATC, 336
breast cancer, 233, 235
cancers of head and neck, 105, 114, 115
gastric carcinoma, 164
lung cancer
NSCLC, 136
SCLC, 146
melanoma, 360
metastatic cancer of unknown origin, 629
toxicity, 91
Taxotere, breast cancer, 233
TCC. See transitional cell carcinoma
TCRs. See T-cell receptors
telatinib, 33
temozolomide (TMZ)
dosage, schedule, 827
grade II glioma, 377
grade III and IV gliomas, 380, 381, 381t
mechanism of action, 826–827
 melanoma, 360, 361
NSCLC, 30
pancreatic neuroendocrine tumors, 207, 208
primary indications, 827
SCLC, 146
special precautions, 827
toxicity, 89, 827
temsirolimus (Torisel), 32, 51
dosage, schedule, 828
kidney cancer, 320
mechanism of action, 827–828
metastatic renal cell carcinoma, 324t
primary indications, 828
special precautions, 828
toxicity, 828
testicular cancer (germ cell tumors)
complications of therapy, 309
general approach to therapy
nonseminoma, 306–308
seminoma, 306
general considerations, staging, 305–306
mediastinal, other midline germ cell tumors, 309
overview, 305
recurrent disease, management of, 308–309
testicular lymphomas, 588
thalidomide
dosage, schedule, 829
mechanism of action, 828–829
MM, 603, 604, 608–609, 614
PMF, 521
primary indications, 829
special precautions, 829
toxicity, 829
WM, 619
therapy-related AML (t-AML), 451–452
6-thioguanine
acute leukemias, 441
ALL, 464, 465
thiotepa
dosage, schedule, 830
mechanism of action, 829
primary indications, 829
special precautions, 830
toxicity, 830
thyroid carcinoma, 327–337
diagnosis, 330–331, 330t
etiology, 327–328
histologic types, 328–329
incidence, 327
prevention, 327–328
prognosis, 329–330
staging, 330–331
treatment, ATC
radiotherapy, 336
surgery, 336
 systemic therapies, 336–337
treatment, DTC
adjuvant therapy, 332–333
radiotherapy, 332–334
RAI, 332–333
surgery, 331–332
systemic therapies, 334–335
TSH suppression, 332
treatment, MTC
radiotherapy, 335
surgery, 335
systemic therapies, 335–336
thyroid lymphoma, 329
thyroid sarcoma, 329
thyroid stimulating hormone (TSH), 330, 662
suppression
differentiated thyroid cancer, 332
time to progression, 85
tivantinib, 49
TKI. See tyrosine kinase inhibitor
TMZ. See temozolomide
TNM Committee of the International Union Against Cancer, 80
topotecan
cervical cancer, 256
dosage, schedule, 830
endometrial cancer, 263t
MDS, 532–533
mechanism of action, 830
ovarian cancer, 273t
primary indications, 830
relapsed AML, 446
toxicity, 830–831
toremifene (Fareston)
breast cancer, 238
mechanism of action, 831
primary indications, 831
special precautions, 831
toxicity, 831
usual dosage and schedule, 831
Torisel. See temsirolimus
total thyroidectomy
DTC, 331
MTC, 335
toxicity
acute management, 90
common acute toxicities, 89
drugs for, clinical testing of, 88
evaluation, 90
factors affecting, 88
late organ
cardiac toxicity, 90–91
hematologic, immunologic impairment, 92
nephrotoxicity, 91
neurotoxicity, 91–92
pulmonary toxicity, 91
 management of, 66–67
recognition, 90
selective toxicities, 89
TPF regimen, 109
trabectedin (Yondelis)
mechanism of action, 831
primary indication, 832
soft-tissue sarcomas, 403, 405–406, 408
special precautions, 832
toxicity, 832
usual dosage and schedule, 832
trametinib (Mekinist), 47–48
mechanism of action, 832
primary indication, 833
special precautions, 833–834
toxicity, 834
usual dosage and schedule, 833
transarterial chemoembolization (TACE), hepatocellular carcinoma, 216
transitional cell carcinoma (TCC), 292
transoral laser microsurgery (TOLM), 107
transoral robotic surgery (TORS), 106, 107
transurethral resection (TUR), bladder cancer, 293
trastuzumab (Herceptin), 28–29, 65
breast cancer, 29, 225, 231, 233–238
dosage, schedule, 835
esophageal carcinoma, 158
gastric carcinoma, 164–165, 167
lung cancer, 124
mechanism of action, 834
primary indications, 834
side effects, 29
special precautions, 835
toxicity, 89, 835
trastuzumab emtansine (T-DM1), 237
trebananib, 54–55
Tregs. See regulatory T-cells
tretinoin
dosage, schedule, 836
mechanism of action, 836
primary indication, 836
special precautions, 836
toxicity, 836–837
trifluridine/tipiracil (Lonsurf, TAS-102)
mechanism of action, 837
primary indication, 837
special precautions, 837
toxicity, 837–838
usual dosage and schedule, 837
TSH. See thyroid stimulating hormone
tumor cell kinetics, chemotherapy and, 4
cell cycle, 4–5, 5f
growth rate and effectiveness, 9
phase and cell cycle specificity, 5–8, 6t, 8t
therapy implications, 8–9
tumor growth, 4
tumor growth, 4
stages of, 8–9
lag phase, 8
log phase, 8
plateau phase, 9
tumor-infiltrating lymphocytes (TILs), 73, 322
tumor lysis prophylaxis, 583
tumor necrosis factor (TNF), 657
tumor products, 86
tumor size, 83–84
baseline lesions, 84
response categories, 84–85
survival curves, 85–86
time to progression, 85
TUR. See transurethral resection
Tykerb. See lapatinib ditosylate
tyrosine kinase inhibitor (TKI), 358–360, 672
ATC, 337
cessation, 488–489
choice of, 488
CML, 485–489, 486–487t

U
UISS. See University of California, Los Angeles, integrated staging system
unclassified sarcomas, 396–397
unconjugated antibodies, 57–59
unilateral lobectomy with en bloc resection, DTC, 331
University of California, Los Angeles, integrated staging system (UISS), 315
unresectable pancreatic carcinoma, localized, 198–199
uric acid nephropathy, 435
urothelial cancer, 292–297
general considerations, staging, 292–293
metastatic urothelial cancers, 296
muscle-invasive bladder cancer, 294–296
non–muscle invasive bladder cancer, 293–294
nontransitional cell histologies, 297
renal pelvis urothelial cancers, 296
systemic therapy, 296–297
U.S. Gastrointestinal Intergroup, 162
uterine leiomyosarcomas, 265
uterine sarcomas, 264, 265
uterine papillary serous carcinoma, 264
uterine sarcomas
histology, 265
prognostic factors, 266
staging, 266
treatment, 266

V
VAC regimen, Ewing sarcoma, 420
vaccines, 64, 65
glioblastoma multiforme, 383
kidney cancer, 321–322
 melanoma, 363–364
VAdriaC regimen, soft-tissue sarcomas, 404
Vagifem, 242
VAI regimen, Ewing sarcoma, 420
vandetanib (Zactima), 38
dosage, schedule, 838
mechanism of action, 838
MTC, 335
primary indications, 838
special precautions, 838
toxicity, 838
vascular access, acute leukemias, 437
vascular endothelial growth factor (VEGF), 30–34, 328, 380
colon cancer, 176–177
kidney cancer, 314, 319–320
toxicity, 89
VDC regimen, Ewing sarcoma, 420
Vectibix. See panitumumab
VEGF. See vascular endothelial growth factor
Velcade. See bortezomib
vemurafenib (Zelboraf), 48
adverse interactions, 73
lung cancer, 124
mechanism of action, 839
melanoma, 358, 359
metastatic brain disease, 392
primary indication, 839
special precautions, 839
toxicity, 839–840
usual dosage and schedule, 839
Venetoclax. See ABT-199
venlafaxine, 242
VHL gene. See Von Hippel-Lindau gene
VIDE regimen, Ewing sarcoma, 420
vinblastine
antidotes, 636t
dosage, schedule, 840
mechanism of action, 840
NSCLC, 128t, 132
primary indications, 840
special precautions, 840
testicular cancer, 308
toxicity, 840–841
vinca alkaloids
melanoma, 360
toxicity, 89, 91
vincristine
ALL, 462–466, 473
older adults, 470, 471
antidotes, 636t
cervical cancer, 255
DLBCL, 576t
dosage, schedule, 841
Ewing sarcoma, 420
FL, 568t, 572t
 GTN, 252, 287t
mechanism of action, 841
medulloblastomas, 385
MF, 368, 369
paraganglioma, 345–346
PCNSL, 387t
pheochromocytoma, 345–346
primary indications, 841
SCLC, 146
soft-tissue sarcomas, 404–405
special precautions, 841
toxicity, 841–842
vincristine sulfate liposome (Marqibo)
mechanism of action, 842
primary indication, 842
special precautions, 842
toxicity, 842–843
usual dosage and schedule, 842
vindesine, NSCLC, 128t
vinorelbine
antidotes, 636t
breast cancer, 236–238
cervical cancer, 255, 256
dosage, schedule, 843
esophageal carcinoma, 158
HL, 548t
lung cancer
NSCLC, 128t, 133, 134t, 136, 137, 141
SCLC, 146
mechanism of action, 843
primary indications, 843
special precautions, 843
toxicity, 843
vismodegib (Erivedge), 52
mechanism of action, 844
nonmelanoma skin cancer, 366–367
primary indication, 844
vismodegib (Erivedge) (continued)
special precautions, 844
toxicity, 844
usual dosage and schedule, 844
VMP regimen, 605
Vogt-Koyanagi-Harada syndrome, 662
volasertib, relapsed AML, 448t
vomiting, 640–646, 642t, 643–644t, 646t
Von Hippel-Lindau (VHL) gene, 313
Voraxaze. See glucarpidase
vorinostat (Zolinza), 54
dosage, schedule, 844
MDS, 535
mechanism of action, 844
primary indication, 844
special precautions, 845
toxicity, 845
Votrient. See pazopanib
vulvar cancer, 279–282
clinical presentation, diagnosis, 280
histology, 280
prognostic factors, 280
screening, 280
staging, 280, 281

W
Waldenström macroglobulinemia (WM), 594
diagnosis, presentation, 618
general considerations, therapy, 618–619
treatment, 619–621
Warburg effect, 561
warfarin, MM, 609
WBRT. See whole brain radiotherapy
Weiss criteria, ACC, 338
WHO classification. See World Health Organization classification
whole brain radiotherapy (WBRT), 588
grade III and IV gliomas, 380
metastatic brain disease, 391
PCNSL, 386
whole exome sequencing, 70
WM. See Waldenström macroglobulinemia
workup and imaging, 560, 560t
World Health Organization (WHO) classification, 427

X
Xalkori. See crizotinib
XELOX regimen, 180
colorectal cancer, 180
xerostomia, cancers of head and neck therapy and, 118–119
XL147 inhibitor, 51
XL765 inhibitor, 51–52
Xtandi. See enzalutamide
Xyotax. See polyglutamated paclitaxel

Y
Yondelis. See trabectedin

Z
Zactima. See vandetanib
Zaltrap. See ziv-aflibercept
Zelboraf. See vemurafenib
Zevalin. See Ibritumomab tiuxetan
ziv-afilbercept (Zaltrap), 32
mechanism of action, 845
primary indication, 845
special precautions, 845–846
toxicity, 846
usual dosage and schedule, 845
Zofran. See ondansetron
zoledronic acid
breast cancer, 242
MM, 616, 617
prostate cancer, 304–305
Zolinza. See vorinostat
Zydelig. See idelalisib
Zykadia. See ceritinib
Zytiga. See abiraterone acetate