Seminars in Pediatric Surgery 25 (2016) 318–322

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Seminars in Pediatric Surgery

journal homepage: www.elsevier.com/locate/sempedsurg

Fertility considerations and the pediatric oncology patient

Lara Raffoul, MDa,1, Carmen Capito, MD, PhDa,1, Sabine Sarnacki, MD, PhDa,b,n
a
Department of Pediatric Surgery, APHP, Necker Enfants Malades Hospital, Paris, France
b
Paris Descartes University, Sorbonne Paris Cité, Paris, France

a r t i c l e in f o abstract

Recent years have witnessed marked improvement in cytotoxic treatments with a parallel increase in
Keywords: patient survival. Despite efforts done to minimize long-term side effects of these treatment regimens, it
Fertility is estimated that 40% of survivors of pediatric cancer will suffer from those. Some will be mild whereas
Childhood cancer others such as impaired fertility will be a heavy load on parents' expectations and patient's quality of life.
Ovarian sparing surgery Gonadal damage and severe loss of function is not a rare condition among children cured for cancer.
Chemotherapy Despite the young age of those patients, methods exist to try to reduce gonadal insult or to preserve
Radiotherapy gonadal function. Some of them are well studied and controlled; others are more experimental with
Gonad cryopreservation
encouraging results so far. This article aims to summarize all the procedures that can be offered to young
patients treated for cancer in order to protect, as possible, their fertility potential.
& 2016 Elsevier Inc. All rights reserved.

Introduction chlorambucil, cyclophosphamide, ifosfamide, melphalan, busulfan,

and procarbazine.9 Myeloablative chemotherapy regimens
Childhood cancers are rare diseases as they represent 130–160 (e.g., high-dose cyclophosphamide combined with busulfan or
cases per million children with considerable variations between Thio-tepa), increasingly used as preparation for stem cell
countries.1,2 Most of them are embryonic tumors, the genesis of transplantation, induce a high incidence of ovarian function
which is quite different from tumors encountered in adulthood. impairment.10
Improvements in therapy and intensive care have increased the Ionizing radiation acts on dividing and nondividing cells. As
overall 5-year survival rate from 45% for patients diagnosed in the with chemotherapy, the effects of radiotherapy on ovarian
mid-1970s to 80%.3 Estimates place the number of childhood function depend on the patient's age, field of treatment, daily
cancer survivors in the United States at 420,000 at the end of treatment doses, and total amount of radiation received. Doses of
2013.4 Long-term survivors of childhood cancer are, however, at 10–20 Gy in children and 4–6 Gy in adults are associated with
risk for serious, disabling, life threatening, or fatal treatment- permanent ovarian failure.11 In addition, irradiation of the uterus
related late effects including second malignancies, cardiac and in the childhood is known to predispose to premature delivery or
vascular abnormalities, and pulmonary complications.5,6 to get offsprings with low birth weight.12
Testicular or ovarian damage may be caused by radiation As the follicle pool is fixed at birth (nearly one million
therapy directly to the gonads or brain (hypothalamic–pituitary primordial follicles) and decreases with time, the risk of partial
axis damage) or by cytotoxic chemotherapy. The risk of infertility or total acute ovarian failure (AOF)—that is, loss of ovarian function
depends not only on the type of malignancy and its specific within 5 years following completion of cancer treatment—induced
treatment, but also on the sex of the patient, as the effects of by chemotherapy or radiotherapy increases as the patient ages.
chemotherapy and radiation therapy manifest differently in the The global incidence of AOF in childhood cancer survivors ranges
male and female reproductive systems.7,8 from 6.3% to 12%, and the relative risk of AOF after chemotherapy
Gonadotoxic chemotherapeutic agents include mainly alkylat- ranges from 2 to 9 compared with control subjects. Even when
ing agents that act as inhibitors of DNA synthesis by creating childhood cancer survivors retain ovarian function after complet-
covalent lesions between DNA strands and ultimately block ing cancer treatment, the risk of developing premature ovarian
cellular division. The most injurious of the alkylating agents are failure, defined as cessation of menses before age 40 years, is
increased.9,13
n
In males, alkylating agents may affect spermatogenesis, but
Corresponding author at: Department of Pediatric Surgery, Hôpital Necker
testosterone secretion is usually well preserved. In contrast,
Enfants-Malades, 149 rue de Sèvres, 75015 Paris.
E-mail address: [email protected] (S. Sarnacki). radiation therapy affects both spermatogenesis and testosterone
1 These two authors contributed equally to this work. secretion. Sperm production is susceptible to damage at doses of

http://dx.doi.org/10.1053/j.sempedsurg.2016.09.006
1055-8586/& 2016 Elsevier Inc. All rights reserved.
 L. Raffoul et al. / Seminars in Pediatric Surgery 25 (2016) 318–322 319

more than 1.2 Gy, whereas residual Leydig cell function seems to these tumors relies on the local tumor control obtained nowadays
be present even at radiation doses up to 20 Gy. Prepubertal boys with less radical surgical management than in past decades. For
seem to be more susceptible to the effects of irradiation on urogenital RMS, treatment could be achieved without surgery
spermatogenesis and Leydig cell function than adolescent and when remission is obtained after chemotherapy, or be completed
adult males. by local brachytherapy avoiding mutilating surgery, which is
Thus, while most of the children will now successfully be currently exceptional.17–19 For vaginal GCT, surgical resection of
treated for cancer, the question of fertility preservation has the primary location is always mandatory but efficiency of neo-
become a major question and a real challenge. Assisted medical adjuvant chemotherapy usually allows to avoid mutilating surgery
procreation technologies are indeed restrained by the prepubertal and to perform a partial colpectomy.
state of the gonads at the initiation of treatment, which excludes
embryo cryopreservation, mature oocytes cryopreservation, or
semen cryopreservation. Fertility preservation in female patients submitted to
gonadotoxic treatments

Fertility preservation in ovarian and female genital tract Ovarian transposition

Benign ovarian tumors represent 85–90% of ovarian lesions in Ovarian transposition has been the first procedure proposed for
children, and consist of teratomas (benign germ-cell tumors) and children with cancer in order to preserve ovarian function from
more rarely, serous or mucinous cystadenomas (benign epithelial damage due to abdominal and pelvic radiation.20 It should be
tumors). When clinical, imaging, and biological features plead considered in all cancer children with tumors requiring radio-
for these benign lesions, ovarian sparing surgery is mandatory therapy that extends to the pelvis. Rhabdomyosarcoma of the
for the following 2 main reasons: (1) up to 13% of ovarian bladder, vagina, or uterus, and Ewing and non-Ewing bone and
teratomas are bilateral (either synchronous or metachronous)14; soft tissue pelvic sarcomas, are the main tumors requiring ovarian
(2) unilateral ovariectomy leads to depletion of the total number of transposition. Such tumors are managed with 42–58 Gy, doses that
primordial follicles and therefore might increase the risk of are much greater than those causing ovarian failure. The aim of
premature or early menopause, although not clearly demonstrated ovarian transposition is to mobilize the ovaries outside of the
in children.15 radiation field after ruling out a possible tumor extension to the
In everyday practice, deciding whether to spare the ovary ovaries. The place where the ovaries have to be positioned is
because the lesion seems benign or to perform a total ovariectomy guided by the radiotherapy plan, in agreement with the surgeon
because signs of malignancy are present is not always straightfor- and the radiotherapist. Metallic clips are usually used as a land-
ward. Two different situations should be considered. In the first mark for the radiotherapy planning. When the tumor is not
case, the young girl is painless and the surgeon has enough time to located in the pelvis or when no initial surgery is planned, ovarian
perform and analyze reliable imaging ensuring that it does not transposition is performed through laparoscopy.20–23 So far, very
show any sign of malignancy and to dose tumor markers (AFP, few studies have reported long-term results of ovarian trans-
BHCG, Inhibine B, AMH, and Calcemia). In contrast, when the position in children.22,24 Preservation of endocrine function has
patient is complaining of an acute abdomen due to adnexal torsion been estimated to range between 60% and 83%.25–27 Concerning
(that could be secondary to an ovarian lesion) or ovarian rupture, side effects, the major complication reported is painful ovarian
the best approach is to perform a laparoscopic exploration in cysts,28 which raises the question of a detransposition upon
emergency. If an ovarian rupture is diagnosed, peritoneal inspec- completion of treatment. This side effect is not systematic and
tion, sampling of ascites, and complete ovariectomy or adnexec- depends on the procedure performed.22 Thus, it seems reasonable
tomy should be done. If an adnexal torsion is seen, simple to adopt a wait and see policy before planning a detransposition. In
detorsion is recommended as it allows them to perform imaging order to avoid reoperation, De Lambert et al.23 proposed a
and markers dosage in the post-operative period. Decision could temporary transposition of the ovary via a stitch passed through
be then taken according to the first situation. Operative technique the abdominal wall and the skin in cases of short pelvic radiation
always starts with the exploration of abdominal cavity through treatment. Other side effects include abdominal pain and bowel
laparoscopy, along with sampling of ascites or any peritoneal obstruction.
suspect lesion (particularly on the diaphragm). Ovarian sparing
surgery is then performed through a Pfannenstiel incision.
Although this approach is debatable, as some surgeons still prefer Ovarian suppression
laparoscopy, this technique allows to spare as much as possible of
ovarian parenchyma and avoid any spillage of the peritoneum in The use of oral contraceptives or gonadotropin-releasing hor-
case of the presence of a non secreting malignant component in mone (GnRH) analogs for ovarian suppression during chemo-
the lesion. Finally, follow-up with repetitive ultrasounds of pelvis therapy is one of the suggested strategies to preserve fertility. It
during childhood should be performed in order to rule out creates a pseudoprepubertal state with an overall decrease in
metachronous ipsilateral or contralateral lesions at an early stage. ovarian function.29,30
This follow-up gives the opportunity to inform the young girl However, the protective effect of such a treatment during
about the symptoms that should alert for a potential adnexal chemotherapy is quite debatable. A recent meta-analysis and
torsion and in case of an important amputation of the ovarian systematic review conducted by Elgindy et al.31 showed that GnRH
parenchyma of the different assisted medical procreation techni- analogs during chemotherapy do not significantly increase
ques available after puberty. resumption of ovarian function after the end of chemotherapy
Preservation of fertility should also be considered when surgery (RR ¼ 1.12, 95% CI: 0.99–1.27), with no convincing evidence that
is planned for genital tract tumors. Different entities encountered the analog offers protection of ovarian reserve. On the contrary,
with, by frequency are as follows: rhabdomyosarcoma (RMS) of other studies conducted by Oktay et al.,32 and Lambertini et al.33
the vagina or uterus cervix, malignant germ-cell tumors (GCT) of proved that ovarian suppression during chemotherapy do reduce
the vagina, and other rare entities such as clear cell adenocarci- premature ovarian failure. The previously cited studies concern the
noma, this last subtype being diagnosed later in life.16 Prognosis of adult population and this approach may be discussed in our
320 L. Raffoul et al. / Seminars in Pediatric Surgery 25 (2016) 318–322

postpubertal patients; in prepubertal children such treatments are for all these young patients, their families, and the caregivers
not recommended, as the ovarian cycle is not settled. in charge.
However, a major problem raised by autografting of previously
cryopreserved ovary is the risk of reintroduction of the primary
Ovarian cryopreservation disease in the patient's organism, especially when the primary
disease is likely to give metastasis to gonads such as leukemia or
Following 3 other methods are theoretically possible in order to lymphoma. Shaw et al.47 managed to prove, in mice models, that
preserve female fertility before sterilizing treatment: in vitro cryopreserved ovarian tissue samples from donors with lymphoma
fertilization followed by cryopreservation of embryos, cryopreser- can transmit cancer to grafted recipients. Recent studies showed
vation of mature oocytes, and cryopreservation of ovarian tissue. that the risk is highest in leukemia patients, moderate in gastro-
In vitro fertilization followed by cryopreservation can only be intestinal cancers, and low in breast cancer, sarcomas, gynecolog-
applied to adult patients with a partner or after sperm donation. ical cancers, Hodgkin's and Non-Hodgkin's lymphomas.48,49 The
Cryopreservation of mature oocytes can be proposed to postpu- means to better detect malignant cells in cryopreserved ovarian
bertal patients but presents some limitations that decrease the cortex is currently under investigation. An alternative for pre- or
appeal to this technique in young adolescents: the delay required post-pubertal patients in these situations would be to cryopre-
for stimulation, the poor number and survival after the freeze– serve oocytes aspirate from pre- or antral follicles of the ovary
thaw process of oocytes, and finally the fact that this technique retrieved and that would be matured and fertilized in vitro.50
relies on endovaginal access.34,35 This technique is however Although very challenging, one live birth has been reported.51
interesting to explain for the future to patients who present a
reduced ovarian tissue capital after surgery.
Finally, the only method suitable for both postpubertal and Fertility preservation in male patients
prepubertal patients is cryopreservation of ovarian cortex consist-
ing of primordial follicles. Main indications nowadays are repre- Testicular sparing surgery
sented by myeloablation before bone marrow transplantation,
total body irradiation, and high-dose chemotherapy with alkylat- Similarly to ovarian sparing surgery, such a technique sounds
ing agents.15 logical and safe in testicular benign tumors. In fact, the most
It seems essential to collect an entire ovary in younger children common types of prepubertal testicular tumors are germ cells
in order to get enough tissue for the future reimplantation process tumors: benign germ-cell tumors (teratoma) followed by yolk sac
since follicular loss can reach up to 65% via this approach.36 In tumors,52 or the contrary depending on the series.53 The most rare
adolescent patients, however, this point is debatable.37 When an types, encountering for less than 5% of the patients are sex cord-
abdominal surgery is planned, the procedure may be performed stromal tumors (granulosa cells tumors and Sertoli or Leydig cells
simultaneously but otherwise, laparoscopy is the procedure of tumors). In the germ cells tumors group, while yolk sac tumors are
choice. After isolation and fragmentation, ovarian cortex fragments malignant and therefore could only be treated by radical orchi-
are slowly frozen in an automated freezer down to temperature of ectomy, testicular sparing surgery has become the standard of care
liquid nitrogen, in which they are stored. Histological analysis of for teratomas. However, surgical technique is performed through
some fragments is mandatory as it allows searching for malignant inguinal incision, with early control of the spermatic cord at the
cells in both cortex and medulla, particularly in tumors with internal ring as in radical orchiectomy and frozen sections can be
potential ovarian spread (hematological cancer and neuroblas- useful to rule out malignancy. Regarding sex cord-stromal tumors,
toma) and also to estimate the follicular wealth of the tissue, although considered malignant, the excellent prognosis after
notably in case of previous gonadotoxic treatment. inguinal orchiectomy in non-metastatic tumors54,55 and increasing
Cryopreserved ovarian fragments might further be used for reports of complete cure after testicular sparing surgery56–58 has
either autografting or in vitro maturation of primordial follicles; prompted to discuss the possibility of sparing surgery in localized
the latter corresponding to very preliminary results so far since, in tumors. Moreover, Fresneau et al.55 proposed to offer sparing
humans, this process takes place within a 6 months period and surgery in all types of childhood testicular tumors provided that
implies complex cellular division (meiosis) and maturation (epi- they are small (less than the third of the testicular parenchyma),
genetic marks).38–40 Thus, since Donnez et al.41 and Meirow et al.42 well delimited on ultrasound, without AFP and/or HCG secretion,
published the first 2 pregnancies obtained after autograft of and after intraoperative testicular frozen section assessment to
ovarian cortex, over 60 pregnancies have been documented in exclude the diagnosis of a malignant germ-cell tumor.
literature after autologous grafting of previously cryopreserved
adult ovarian tissue.43 The ovarian function is restored after
4 months following grafting and around 25% of these women will Fertlity preservation in male patients submitted to gonadotoxic
have pregnancies. In prepubertal patients, results are not assess- treatments
able, as most of these patients have not yet achieved the age of
parental desire. Studies in ewes models showed that autografting While semen cryopreservation is an established way to pre-
of cryopreserved prepubertal ovarian cortex led to restauration serve fertility in male adults, it is very difficult in adolescents. In
of puberty and fertility with no apparent oocytes epigenetic fact, pubertal boys are often unable to yet provide a semen sample
anomalies.40,44 Similarly, Poirot et al.45 in 2012 confirmed that via masturbation. In such cases, a sample can be obtained via
induction of puberty was efficient by heterotopic autografts of penile vibratory stimulation or electroejaculation, which must be
ovarian fragments. In 2015, Demeestere et al.46 reported the first done under general anesthesia.59 What makes this fertility pres-
pregnancy after cryopreservation at a pediatric age. The patient, ervation technique most difficult is the fact that semen samples in
who required myeloablation before bone marrow transplantation adolescence are frequently of poor quality60; this is due, on one
for sickle cell anemia, was 14 years old, puber but premenarchal, at hand, to the disease itself61 and, on the other hand, to the freeze–
the age of cryopreservation. She gave birth 13 years later to a thawing process used for cryopreservation. This process will
normal child after 2 years of bilateral autografting of ovarian impair sperm motility and damage chromatin structure and sperm
fragments (4 in the contralateral ovary and 4 in the broad morphology.62 After cryopreservation, stored spermatozoa are
ligament) and natural conception. This case is an encouraging step further used for in vitro fertilization (mainly ICSI procedure).
 L. Raffoul et al. / Seminars in Pediatric Surgery 25 (2016) 318–322 321

Such a technique does not apply to prepubertal boys because conditioning for haematopoietic stem cell transplantation during infancy and
they lack mature spermatozoa. Thus, following the example of childhood. Bone Marrow Transplant. 2004;33(10):1049–1056.
11. Meirow D1, Nugent D. The effects of radiotherapy and chemotherapy on female
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13. Green DM1, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive
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