Oncology Clinical Pathways

Biliary Tract Cancer

September 2024 – V3.2024

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Table of Contents
Presumptive Conditions.…………………………………………....…….……………………………………………………………………………………………………. 3

Suspected Extrahepatic Cholangiocarcinoma……………………..………………………………………………………………………………………………………....4

Suspected Intrahepatic Cholangiocarcinoma............................................................................................................................................................................... 5

Suspected or Incidental Gallbladder Cancer.………………………………………..………..…………………………………………………………………..................6

Resected………..………………………………………………………………………………………………......................................................................................... 7

Unresectable Intrahepatic Cholangiocarcinoma………………………………………………………………………………………….………………………………..... 8

Unresectable and/or Metastatic, Fit for Combination Chemotherapy, First Line……………………………………………………..………...………………………... 9

Unresectable or Metastatic, Second Line………………………………….....................................................................................................................................10

Molecular Testing.…………………………………………………………...…….………………………………………………………………………………….............. 11

Molecular Testing Table …………………………………………………...…….…………………………………………………………………………………….……... 12

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 Biliary Tract Cancer – Presumptive Conditions
VA automatically presumes that certain disabilities were caused by military service. This is because of the unique
circumstances of a specific Veteran’s military service. If a presumed condition is diagnosed in a Veteran within a
certain group, they can be awarded disability compensation.

Vietnam Veterans – Agent Orange Exposure or Specified Locations​

• Cancer of the bile duct

Gulf War and Post 9/11 Veterans

If the patient served on or after Sept. 11, 2001, in Afghanistan, Djibouti, Egypt, Jordan, Lebanon, Syria, Uzbekistan,
or Yemen or if you served in the *Southwest Asia theater of operations, or Somalia, on or after Aug. 2, 1990, specific
conditions include:
• Gastrointestinal cancer of any type

* The Southwest Asia theater of operations refers to Iraq, Kuwait, Saudi Arabia, the neutral zone between Iraq and
Saudi Arabia, Bahrain, Qatar, the United Arab Emirates, Oman, the Gulf of Aden, the Gulf of Oman, the Persian
Gulf, the Arabian Sea, the Red Sea, and the airspace above these locations.

For more information, please visit U.S. Department of Veterans Affairs - Presumptive Disability Benefits (va.gov)

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 Biliary Tract Cancer – Suspected Extrahepatic
Cholangiocarcinoma

Follow Unresectable or
Yes Tissue biopsy
Metastatic pathway

Suspected Extrahepatic
Stage IV? a Complete resection and regional Follow Completely
(including perihilar) Cholangiocarcinoma Yes
lymph node dissection b Resected pathway

No Resectable?

Follow Unresectable or
No
Metastatic pathway c

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Stage multiphase CT or MRI + contrast, CT chest, labs (CEA, CA 19-9, AFP, LFTs, viral hepatitis serologies); contrast MRI with MRCP preferred for
evaluating gallbladder masses and tumors with bile duct involvement; delayed phase imaging preferred for intrahepatic bile duct cancer
b
Resectable pancreaticoduodenectomy required for distal bile duct tumors and major hepatic resection for proximal perihilar tumors
c
Transplant Candidate if patient is a potential transplant candidate, place referral to transplant center; avoid fine needle biopsy; unresectable perihilar or
hilar cholangiocarcinomas (CCAs) ≤3 cm without metastases and nodal disease may be considered for liver transplantation

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 Biliary Tract Cancer – Suspected Intrahepatic
Cholangiocarcinoma
Neoadjuvant
chemotherapy
Multidisciplinary
Resectable
discussion
Hepatic resection and Follow Completely
portal lymphadenectomy Resected pathway

Suspected Intrahepatic Follow Unresectable Intrahepatic

Biopsy Clinical stage? a Unresectable b c
Cholangiocarcinoma Cholangiocarcinoma pathway

Follow Unresectable and/or

Stage IV
Metastatic pathway

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Clinical Stage multiphase CT or MRI + contrast, CT chest, labs (CEA, CA 19-9, AFP, LFTs, viral hepatitis serologies); contrast MRI with MRCP
preferred for evaluating gallbladder masses and tumors with bile duct involvement; delayed phase imaging preferred for intrahepatic bile duct cancer
b
Unresectable includes both anatomically unresectable or patient is not a candidate for resection
c
Transplant Candidate in highly selective patients if transplant is considered, place referral to transplant center prior to biopsy

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 Biliary Tract Cancer – Suspected or Incidental Gallbladder Cancer

Unresectable
Follow Unresectable or
Metastatic pathway
Imaging Clinical stage? a Stage IV

Resection of liver segments IVB/V with en bloc Follow Completely

Resectable
gallbladder if present and portal lymphadenectomy Resected pathway
Suspected or Incidental
Mode of discovery? T1a (positive margins)
Gallbladder Cancer
or >T1b
Neoadjuvant Resection of liver segments IVB/V with en bloc Follow
chemotherapy gallbladder if present and portal lymphadenectomy Resected pathway
Pathology after Cystic duct Post-operative Multidisciplinary
cholecystectomy node positive staging b discussion
Follow Unresectable
and/or Metastatic pathway
T1a
No further treatment
(negative margins)

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Clinical Stage multiphase CT or MRI + contrast, CT chest, labs (CEA, CA 19-9, AFP, LFTs, viral hepatitis serologies), fine needle aspiration/core biopsy; contrast
MRI with MRCP preferred for evaluating gallbladder masses and tumors with bile duct involvement; delayed phase imaging preferred for intrahepatic bile duct cancer

b
Post-Op Staging includes multiphasic CT abdomen/pelvis, contrast MRI, chest CT, CEA, CA 19-9

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 Biliary Tract Cancer – Resected
Capecitabine (4 months)
Yes
and chemoRT d
Candidate for
High
capecitabine? c
Chemotherapy (4 months)
No
and chemoRT d e

Patient
preference after Capecitabine
Resected DPYD testing a Risk status? b Standard
shared decision (6 months) c
making?

Low Observation

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Perform DPYD Testing If Not Already Performed if DPYD PGx results return predicted phenotypes of either intermediate or poor metabolizer, please consult your local PGx pharmacist or submit an
IFC Pharmacogenomics e-consult for assistance with therapeutic recommendation; a clinician may proceed without DPYD results if withholding chemotherapy for 2-3 weeks may gravely endanger
patient's life; for example, if the disease burden is very high and it involves a large portion of vital organs such as liver, etc.
b
Risk Status patients with R1 (positive margins); lymph node disease will be considered high risk; T1NO gallbladder cancers will be considered low risk; all other patients will be considered standard risk

c
Candidate for Capecitabine avoid capecitabine if adherence issues, unable to self-report toxicity or severe renal impairment (CrCl < 30 min/ml)

d
ChemoRT if R1 resection, consider capecitabine and RT or protracted infusion 5-fluorouracil and RT before systemic capecitabine; should consider protracted infusion 5-fluorouracil and RT

e
Chemotherapy consider gemcitabine-based chemotherapy regimen

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 Biliary Tract Cancer – Unresectable Intrahepatic
Cholangiocarcinoma

Follow Resected
Yes Refer to Surgery c
pathway
Ablative or Multidisciplinary
Yes Resectable?
radiotherapy techniques a discussion b Yes
Follow Unresectable
Unresectable Intrahepatic Multidisciplinary Liver-directed and/or Metastatic pathway
Cholangiocarcinoma discussion therapy preferred? No Progression?
No Follow Stage IV pathway
No Continue surveillance

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Ablative or Radiotherapy Techniques include external beam radiation, thermal ablation with microwave or RFA, radiation segmentectomy (y90), irreversible electroporation,
transarterial chemoembolization, or histotripsy based on multidisciplinary discussion and availability
b
Multidisciplinary Discussion perform at time of restaging
c
Surgery referral to hepato-biliary surgery if available

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 Biliary Tract Cancer – Unresectable and/or Metastatic, Fit for
Combination Chemotherapy, First Line

Durvalumab, gemcitabine, Continue until

Yes Yes
and cisplatin b progression
Unresectable and/or Metastatic, Fit for Candidate for Refer to appropriate
Restaging d Stage IV? Yes
Combination Chemotherapy, First Line immunotherapy? a specialty
No Gemcitabine and cisplatin c
Multidisciplinary Local treatment
No
discussion preferred?
Continue until
No
progression
Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Candidate for Immunotherapy prior recipients of solid organ transplant or those with uncontrolled autoimmune/inflammatory condition should not be offered immunotherapy
b
Durvalumab, Gemcitabine, and Cisplatin recommend continuation of chemotherapy for up to 8 cycles provided clinical tolerance followed by durvalumab maintenance for
up to 2 years
c
Gemcitabine and Cisplatin recommend continuation of chemotherapy for up to 8 cycles provided clinical tolerance
d
Restaging as per institutional standards

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 Biliary Tract Cancer – Unresectable or Metastatic, Second Line
FGFR2 fusion/
Pemigatinib
rearrangement

IDH-1 mutation Ivosidenib

Fam-trastuzumab
Yes
deruxtecan-nxki
Unresectable or Metastatic, Molecular ERBB2 amplification based on
HER2 IHC 3+?
Second Line a alteration subtype? DNA copy number
Precision Oncology
No
consult
Dabrafenib
BRAF V600E
and trametinib

NTRK fusion Entrectinib

Gemcitabine and
Yes
cisplatin
Prior
No targetable alterations
5-fluorouracil?
No DPYD testing b mFOLFOX6

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Second Line prior progression on first line chemotherapy or relapse within 6 versus 12 months of completion of adjuvant treatment
b
Perform DPYD Testing If Not Already Performed if DPYD PGx results return predicted phenotypes of either intermediate or poor metabolizer, please consult your local
PGx pharmacist or submit an IFC Pharmacogenomics e-consult for assistance with therapeutic recommendation; a clinician may proceed without DPYD results if withholding
chemotherapy for 2-3 weeks may gravely endanger patient's life; for example, if the disease burden is very high and it involves a large portion of vital organs such as liver, etc.

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 Biliary Tract Cancer – Molecular Testing
<50 Obtain germline testing b

Germline Testing a Age at diagnosis?

If indicated based on personal and/or family history,

>50
consider genetic consultation or referral to genetics c

Perform CGP, MMR, and

Yes
HER2 status by IHC d
Adequate tumor
Yes
tissue available? Rebiopsy of primary Perform CGP, MMR, and
Yes
or metastatic site HER2 status by IHC d
Locally
No Rebiopsy feasible?
Somatic Testing a unresectable or
metastatic?
No Liquid biopsy
Assess tumor MMR status by IHC
No
and/or MSI by PCR

Clinical trial(s) always considered on pathway. For assistance finding a clinical trial, email [email protected].
a
Molecular Testing perform for all pathologically confirmed biliary tract cancers
b
Germline Testing for bile duct cancer should include at minimum the following genes: BRCA1, BRCA2, BAP1, PALB2, EPCAM (deletion), MLH1, MSH2, MSH6, PMS2
c
Personal and Family History consider germline testing if there is a personal history of other cancers (e.g., breast, ovarian, pancreas, colorectal, gastric, endometrial) or family history of a close
relative with bile duct cancer or multiple relatives with other cancers
d
CGP with platform that uses DNA and RNA based testing or DNA and RNA based CGP

CGP Comprehensive Genomic Profiling

IHC Immunohistochemistry
MMR Mismatch Repair
MSI Microsatellite Instability
PCR Polymerase Chain Reaction

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 Biliary Tract Cancer – Molecular Testing Table

Eligibility Test Category Test Type Recommended Vendors NPOP Coverage Specimen Type
IHC* MLH1, MSH2, MSH6, PMS2 Local VA or locally contracted vendor No Tumor Tissue
Localized, Resectable Disease Tumor Tissue and
PCR* Microsatellite instability (MSI) status by PCR Regional Testing Center (GLA) Yes
Normal Tissue or Blood
Somatic NGS** CGP using both DNA and RNA based methodology Tempus Yes Tumor Tissue***, Blood
Metastatic or Unresectable Cholangiocarcinoma
IHC** MLH1, MSH2, MSH6, and PMS2 Tempus Yes (when ordered with CGP) Tumor Tissue
Fulgent Yes
Age <50 Germline NGS*** Germline NGS panel Saliva, Blood
Prevention Genetics Yes
Personal or Family History of Other Bile Duct Cancers, Fulgent Yes
Germline NGS*** Germline NGS panel Saliva, Blood
Multiple Cancers, or Other Lynch-Associated Cancers Prevention Genetics Yes
If full germline testing not performed, perform Germline Lynch testing if:
1) MSH2 or MSH6 loss by IHC or Fulgent Yes
Deficient MMR or MSI-H Tumor Germline NGS*** Saliva, Blood
2) MLH1 or PMS2 loss by IHC and MLH1 unmethylated or Prevention Genetics Yes
3) MSI-H without IHC testing and MLH1 unmethylated
* Localized, resectable disease needs either IHC or PCR to assess MMR status
** Metastatic or unresectable disease should perform BOTH IHC and NGS for MMR status
*** Tissue testing strongly preferred because it is the only method for RNA based testing. Liquid testing is suboptimal but acceptable only if adequate tissue cannot be obtained
**** Germline testing should include at a minimum BRCA1, BRCA2, BAP1, PALB2, EPCAM (deletion), MLH1, MSH2, MSH6, and PMS2; Alternatively, the VA Common Hereditary POC panel can be performed; For genetic online ordering, refer to
CCGS page for further details

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