White paper: Oncofertility in pediatric patients with Wilms tumor.

The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.

alkylating agent dose

anti‐Müllerian hormone

adolescent and young adult

childhood cancer survivors

Childhood Cancer Survivor Study

cyclophosphamide equivalent dose

confidence interval

Children's Oncology Group

complete remission

cytochrome

diffuse anaplastic

diminished ovarian reserve

event free survival

favorable histology Wilms tumor

fertility preservation

genome wide association study

HARMONIzation and CollAboration

high risk

International Guideline Harmonization Group

intermediate risk

loss of heterozygosity

National Wilms Tumor Study Group

oocyte cryopreservation

oophoropexy

odds ratio

overall survival

ovarian tissue cryopreservation

percutaneous epididymal sperm aspiration

premature ovarian insufficiency

relative risk

radiotherapy

SIOP‐Renal Tumor Study Group

Societe Internationale D'oncologie Pediatrique

single nucleotide polymorphisms

testicular sperm extraction

Volumetric‐Modulated Arc Therapy

whole abdominal radiation therapy

Wilms tumor

INTRODUCTION

The survival rate of childhood cancer has increased tremendously over the past decades. Since the overall survival of patients with Wilms tumor (WT) is currently around 90%, nearly all patients treated for WT reach reproductive age and thus the impact of therapy on future fertility must be considered. , , , , Chemotherapy and radiotherapy are established risk factors for gonadal damage , and both may be part of WT treatment. , Globally, most patients have been treated according to protocols from either the National Wilms Tumor Study Group (NWTSG)/Children's Oncology Group (COG) or Societe Internationale D'oncologie Pediatrique (SIOP). , , , Although most patients diagnosed with WT are prepubertal, fertility preservation (FP) options have recently become available for young patients. However, since some of these FP methods are still experimental, they have been largely reserved for patients at high risk of gonadal damage. , , , , , This manuscript aims to provide an overview of the available evidence on the risk of gonadal damage after WT treatment, including the patient perspective, the options for fertility preservation, ethical and genetic considerations and recommendations concerning FP in patients with WT.

OVERVIEW OF THE ISSUE OF FERTILITY IMPORTANCE TO CANCER PATIENTS

When considering FP for pediatric cancer patients, it is vital to understand the patient and family vantage point (Table S1). While future fertility is generally important to most patients and caregivers, FP is not universally discussed nor undertaken prior to initiation of oncologic therapy, as the immediate focus is on achieving cure. Unfortunately, if FP is not discussed prior to treatment, this may negatively impact the utilization and success rate of FP techniques.

Several surveys have identified attitudes of parents of children with cancer as well as the adolescent and young adult (AYA) patient population toward FP in the setting of a cancer diagnosis. , , These surveys uncovered that nearly all AYA patients and parents are aware of a significant risk of infertility related to cancer therapy, and that FP is important to most of this population. However, only about 20% were willing to take actions toward preserving fertility. This finding is known as the intention‐behavior gap. Nearly half of AYA patients reported limited access, such as being unaware of the options and/or cost concerns, as the reason for not making FP arrangements despite financial support by philanthropic organizations, or public or private health plans being regionally variably available. Insurance coverage of FP costs is usually limited to the procedure and not the storage of gametes, and some insurance plans may not cover all of the procedure costs. Health‐related concerns are prevalent and impair access to FP, noted by about one third of male AYA patients, and over half of female AYAs. These concerns include personally not wanting to delay treatment, physician advising against treatment delay, and concerns about the effect of cancer therapy on future offspring. Personal reasons such as not wanting children or feeling too young to consider such a decision were also noted in about a third of patients. Research studying shared decision making in adolescents and parents of young patients with WT is lacking.

In addition, it is well‐established that many patients regret deciding not to pursue FP. , , The level of regret tends to be higher among those who believe that the opportunity for FP was not discussed or was discussed at a time when it was too late to effectively act on it. Over half of surveyed patients reported feeling a moderate to high amount of concern that infertility has negatively affected their emotions, relationships, and feeling of self‐worth. Additionally, patients who identified themselves as having higher concerns about fertility were more likely to suffer from depression and lower‐quality of life. It has been reported that most male cancer patients/survivors do not feel sufficiently informed and postpubertal boys strongly desire information on FP options. , Similarly, female cancer patients feel it is important to discuss fertility, preferably shortly after diagnosis. , , , , A recently published guideline by the International Guideline Harmonization Group (IGHG) states that current standard care should include informing all pediatric cancer patients and their families on their relative risk of gonadal damage, including the low‐risk group. , , As such, counseling is paramount and clear discussion of the experimental nature of any intervention must be emphasized.

Taken together, these findings underscore that FP is important to pediatric cancer patients and survivors, and should be discussed early‐on, when options for FP are greatest. The intention‐behavior gap highlights the importance of providing adequate counseling, to support the desire for FP, and help develop that into a behavior that accomplishes that goal when feasible. While not all children and their parents will elect to proceed with FP, there is strong evidence that future regret is greatly reduced when families feel that they have made an informed decision. ,

OVERVIEW OF WT THERAPY AND ONCOLOGIC OUTCOMES

Although most patients with WT are cured with surgery and two‐drug chemotherapy with very low gonadotoxic potential, almost all patients with relapse will be exposed to intensive therapy, typically including alkylating agents. Notably these patients require counseling again at the time of relapse, providing an opportune time to discuss FP options. Four‐year event free survival (EFS) for Stages II to IV anaplastic WT with current COG/SIOP treatment regimens is 68%, and long‐term survival for higher risk (HR) relapsed favorable histology Wilms tumor (FHWT) who were previously treated with the combination of vincristine, dactinomycin and doxorubicin is around 50%. The evolution of risk stratification has outlined subgroups of WT patients for whom reduction of therapy decreases long‐term treatment‐related morbidity exemplified by patients with very low risk favorable histology Wilms tumor (FHWT, age <2 years and tumor weight <550 g) who achieved excellent outcomes with surgery alone. On the other hand, both COG and SIOP treatment regimens for patients identified as having HR disease can increase the possibility of infertility, with exposure to alkylators, carboplatin and radiation therapy. COG protocols showed that augmentation of therapy leads to improved outcomes among patients with Stage III and IV FHWT whose tumors harbor combined loss of heterozygosity (LOH) for 1p and 16q, with the use of regimen M (five‐drug chemotherapy with vincristine, dactinomycin, doxorubicin, etoposide and cyclophosphamide). SIOP protocols use high‐dose doxorubicin, cyclophosphamide, carboplatin and etoposide for HR patients with identified risk factors of postchemotherapy HR histology, incomplete lung metastasis response, and blastemal‐predominant histology with high blastemal volume. These therapy regimens have reduced the risk of relapse for these patient groups, avoiding the use of marked intensification of therapy at relapse, but increasing the exposure to gonadotoxic agents during initial therapy. , Tables 1 and 2 summarize the most recent published outcomes and current treatment protocols from cooperative trials (COG and SIOP) for WT patients.

TABLE 1

Current treatment protocols and published outcomes according to COG

Stage	Histology	Risk stratification	Chemotherapy	Radiation	Outcomes 4‐year EFS/OS (%)	Gonadotoxicity potential/risk to fertility
I	Favorable	Very low risk	None	None	89.7/100 37	None
		Standard	EE4A (VA) 19 weeks	None	94/98 40	Very low
	Focal/diffuse anaplastic		DD4A (VAD) 25 weeks	10.8 Gy (flank)	100/100 41	Very low
II	Favorable	Standard	EE4A (VA) 19 weeks	None	86/98 40	Very low
	Focal anaplasia		DD4A (VAD) 25 weeks	None	N/a	Very low
	Diffuse anaplasia		Revised UH‐1 (VCDBE) 30 weeks	10.8 Gy (flank)	86.7/86.2 42	Yes
I/II	Favorable	High risk (LOH 1p and 16q)	DD4A (VAD) 25 weeks	None	87.3/100 38	Very low
III	Favorable	Standard	DD4A (VAD) 25 weeks	10.8 Gy (flank/abdomen) + 10.8 Gy boost for gross disease	87.1/94.4 43	Possible depending on radiation field
	Focal anaplasia		DD4A (VAD) 25 weeks	10.8 Gy (flank/abdomen) + 10.8 Gy boost for gross disease	N/a	Possible depending on radiation field
	Diffuse anaplasia		Revised UH‐1 (VCDBE) 30 weeks	10.8 Gy (flank/abdomen) + 10.8 Gy boost for gross disease	80.9/88.6 42	Yes
III/IV	Favorable	High risk‐LOH 1p and 16q 38 OR no CR lung nodule(s) at week 6 for Stage IV 39	Regimen M (VADCE) 31 weeks	10.8 Gy (flank/abdomen) + 10.8 Gy boost for gross disease 12 Gy lungs if lung metastasis	90.2/96.1 38 88.5/99.8 39	Yes
IV	Favorable	Standard AND CR lung nodule(s) at week 6	DD4A (VAD) 25 weeks	No lung rads	79.5/96.1 39	Very low
	Focal anaplasia		Revised UH‐1 (VCDBE) 30 weeks	12 Gy lungs if lung metastasis	N/a	Yes
	Diffuse anaplasia		Revised UH‐2 (VCDBEI) 36 weeks	12 Gy lungs if lung metastasis	41.7/49.2 42	Yes

Abbreviations: CR, complete response; EFS, event‐free‐survival; Gy, Gray; LOH, loss of heterozygosity; OS, overall survival; VA, vincristine, dactinomycin; VAD, vincristine, dactinomycin, doxorubicin; VADCE, vincristine, dactinomycin, doxorubicin, cyclophosphamide and etoposide; VCDBE, vincristine, carboplatin, doxorubicin, cyclophosphamide and etoposide; VCDBEI, vincristine, carboplatin, doxorubicin, cyclophosphamide, etoposide and irinotecan.

TABLE 2

Current treatment protocols and published outcomes according to SIOP

Stage	Preoperative chemotherapy	Risk stratification	Postoperative chemotherapy	Radiotherapy	Outcomes 5‐year EFS/OS % SIOP‐2001	Gonadotoxicity potential/risk to fertility
I	AV 4 weeks	Low		None	N/a	Very low
		Intermediate a	AV1 4 weeks	None	N/a	Very low
		High	AVD 27 weeks	None	96/100 44	Very low
II	AV 4 weeks	Low	AV2 27 weeks	None	N/a	Very low
		Intermediate a , b	AV2 27 weeks or AVD a 27 weeks	None	84.8/95.5 91.6/97.6 45	Very low
III	AV 4 weeks	Low	AV2 27 weeks	None	N/a	Very low
		Intermediate a , b	AV2 27 weeks or AVD a 27 weeks	14.4 Gy to flank + 10.8 Gy boost (only in case of) gross disease or positive nodes	85.1/96.0 90.5/93.8 45	Possible depending on radiation fields.
II and III	AV 4 weeks	High	HR‐1 (DCBE) 34 weeks	25.2 Gy to flank + 10.8 Gy boost (only in case of) gross disease or positive nodes	77/82 44	Yes
IV	AVD 6 weeks	Low: Lung CR No lung CR	AVD150/250 27 weeks HR‐2 (DCBE) 34 weeks	No lung RT 15 Gy lung	N/a N/a	Very low Yes
	AVD 6 weeks	Intermediate: Lung CR No lung CR	AVD150/250 27 weeks HR‐2 34 weeks	No lung RT 15 Gy lung + abdominal RT (see local Stage I‐III)	N/a N/a	Very low Yes
	AVD 6 weeks	High: Lung CR No lung CR	HR‐2 34 weeks	No lung RT 15 Gy lung + abdominal RT(see Stage I‐III)	N/a	Yes Yes

Abbreviations: AV1/AV2, vincristine, dactinomycin; AVD, vincristine, dactinomycin, doxorubicin; AVD150/250, vincristine, dactinomycin, doxorubicin (dose 150/250 mg/m2); CR, complete response; EFS, event‐free‐survival; Gy, Gray; HR‐1/HR‐2 (DCBE), doxorubicin, cyclophosphamide, carboplatin, etoposide; OS, overall survival; RT, radiotherapy.

With tumor volume >500 mL at diagnosis.

Nonepithelial and nonstromal postchemotherapy nephrectomy histology.

90.2/96.1

88.5/99.8

91.6/97.6

90.5/93.8

GENERAL IMPACT OF WT CHEMOTHERAPY ON FERTILITY

The COG treatment approach to WT comprises upfront tumor resection whenever feasible, usually followed by risk‐adapted chemotherapy and, in certain circumstances, radiation treatment. In comparison, apart from specific clinical‐radiological features, the SIOP‐Renal Tumor Study Group (RTSG) advocates preoperative chemotherapy followed by risk‐adapted treatment after surgery. The differences in the COG and SIOP treatment approaches may present different logistic (timing) opportunities for FP. SIOP usually starts preoperative chemotherapy immediately after radiological or histological confirmation. This regimen does not contain gonadotoxic agents so FP is not likely to be needed at that time. Postoperative RT and chemotherapy can usually be well anticipated, allowing a window in time to achieve FP, possibly combined with the tumor nephrectomy. Notably, COG protocols currently mandate initiating chemotherapy within 14 days after surgery/biopsy, and the stage and histology results may only be available after 10 to 12 days. This may leave only a short window for decision‐making and FP prior to the start of chemotherapy, even in willing patients and parents. However, prior chemotherapy is not an absolute contra‐indication for ovarian tissue cryopreservation and testicular biopsy. The impact of chemotherapy on future fertility is determined by the cumulative doses of chemotherapy agents utilized. Table 3 summarizes the chemotherapy regimens and cumulative doses used by the most recently completed and published COG studies and the current SIOP‐RTSG UMBRELLA protocols. The potential effects of chemotherapy on future fertility differ based on gender; hence, fertility risks are discussed separately for female and male survivors. Overall, fertility impact of chemotherapy for WT patients is largely related to the cumulative doses of cyclophosphamide received (Tables 3 and 4). Of note, patients with relapsed WT usually receive doses of cyclophosphamide, ifosfamide, doxorubicin, and radiation therapy, sometimes including a high dose chemotherapy regimen or a stem cell transplant, that places them at high risk of infertility regardless of the specific chemotherapy regimen utilized. Tables 4 and 5 combine the fertility risk associated with both chemotherapy and radiation modalities.

TABLE 3

Cumulative chemotherapy doses per treatment regimen used by COG and the SIOP Renal Tumor Study Group (SIOP‐RTSG)

COG	Cumulative dose (mg/m2 unless otherwise specified)
Chemotherapy agent	EE4A	DD4A	VAD a	Regimen M	Regimen I	Revised UH‐1	Revised UH‐2
Vincristine	21	25	18	25	23	22.5	34.5 b
Dactinomycin	0.315 mg/kg	0.225 mg/kg	0.18 mg/kg	0.145 mg/kg	0	0	0
Doxorubicin	0	150	140	195	225	225	225
Cyclophosphamide	0	0	0	8800	15 400	14 800	14 800
Carboplatin	0	0	0	0	0	2800	2800
Etoposide	0	0	0	2000	2000	2000	2000
Irinotecan	0	0	0	0	0	0	800 b

Note: In Table 2 it is specified to which risk groups the regimens AV, AVD, AV‐1, AV‐2 and HR are given.

VAD is a preoperative regimen for bilateral Wilms tumor.

Including 2 cycles of vincristine and irinotecan given during the upfront window on the COG AREN0321 clinical trial.

Cumulative doxorubicin dose for both pre‐ and postoperative chemotherapy.

TABLE 4

Infertility risk per treatment regimen

Treatment regimen	Female	Male	CED score (mg/m2)
COG treatment regimens
Surgery only/observation	Low risk	Low risk	0
EE4A	Low risk	Low risk	0
DD4A	Low risk	Low risk	0
Regimen M	High risk	High risk	8800
Regimen I a	High risk	High risk	15 400
Regimen revised UH‐1	High risk	High risk	14 800
Regimen revised UH‐2	High risk	High risk	14 800
SIOP‐RTSG treatment regimens
AV, AV‐1, AV‐2	low risk	Low risk	0
AVD	Low risk	Low risk	0
HR	high risk	High risk	8100

Abbreviations: AV, AV‐1, AV2, regimen containing vincristine, dactinomycin; AVD: regimen containing vincristine, dactinomycin, doxorubicin; CED, cyclophosphamide equivalent dose; DD4A: regimen containing vincristine, dactinomycin, doxorubicin; EE4A, regimen containing vincristine, dactinomycin; HR, high risk regimen; Regimen I, regimen containing vincristine, doxorubicin, cyclophosphamide, etoposide; Regimen M: regimen containing vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide; Regimen revised UH‐1: regimen containing vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide; Regimen revised UH‐2: regimen containing vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, Irinotecan.

Currently only used for bilateral patients and for CCSK patients.

TABLE 5

Risk of compromised fertility associated with treatment modality for Wilms tumor, according to gender (adapted from Klipstein)

	Risk	Treatment predisposing to compromised fertility	Effect on reproduction
Female	High	Alkylating‐agent chemotherapy (Cyclophosphamide equivalent dose 6 g/m2 in women and girls <20 year, Ifosfamide, Melphalan) 11 Radiation affecting the female reproductive system (whole abdomen, pelvis, lumbosacral spine, total body) >10 Gy in postpubertal girls 15 Gy in prepubertal girls Oophorectomy	Acute ovarian failure (ovarian failure within 5 years of diagnosis), premature menopause (cessation of menses before age 40 years)
	Intermediate	Radiation affecting the uterus (whole abdomen, pelvis, lumbosacral spine, total body)	Uterine vascular insufficiency, uterine growth impairment. Spontaneous abortion, neonatal death, premature labor, neonate with low birth weight, fetal malposition
Male	High	Alkylating‐agent chemotherapy (Cyclophosphamide equivalent dose 4 g/m2, Ifosfamide, Melphalan) 10 Pelvic radiation affecting the male reproductive system (1–6 Gy scatter to testes)	Azoospermia, oligospermia
	Intermediate	Pelvic surgery (retroperitoneal node or tumor dissection, cystectomy) Radiation to pelvis, bladder, or spine (1‐6 Gy scatter to testes) Chemotherapy with heavy metals: carboplatin >2 g/m2	Retrograde ejaculation, anejaculation Erectile dysfunction Azoospermia, oligospermia

Alkylating‐agent chemotherapy (Cyclophosphamide equivalent dose 6 g/m2 in women and girls <20 year, Ifosfamide, Melphalan)

Alkylating‐agent chemotherapy (Cyclophosphamide equivalent dose 4 g/m2, Ifosfamide, Melphalan)

FERTILITY RISKS FOR FEMALE WT SURVIVORS

In relation to the age of exposure to gonadotoxic agents, ovarian damage from chemotherapeutic agents can result in delayed/absent/arrested puberty in pre‐ or peripubertal patients and diminished ovarian reserve (DOR) or premature ovarian insufficiency (POI), and infertility in postpubertal individuals. The evidence describing effects on reproductive outcomes is mostly based on retrospective data, which makes it difficult to determine the exact effects of individual chemotherapy agents. However, alkylating agents, such as cyclophosphamide and ifosfamide, have a clear impact on female reproductive health in a dose‐related manner when given either alone or in combination. The most important predictors of risk are the cumulative dose of radiotherapy and alkylating agents, and the patient's age at the time of therapeutic exposure. If doxorubicin was included in the treatment, survivors are additionally at risk of developing cardiomyopathy during pregnancy.

DOR is characterized by sustained menses and normal gonadotropins, but reduced indexes of ovarian reserve for age and is important in the counseling of childhood cancer survivors (CCS), as it may represent a window for performing posttreatment fertility preservation. POI is defined by persistent amenorrhea combined with a follicle‐stimulating level >30 IU/L before the age of 40 years. In the St. Jude Lifetime Cohort study of 921 female cancer survivors, POI is associated with administration of high‐dose cyclophosphamide. The cyclophosphamide equivalent dose (CED) and alkylating agent dose score (AAD) are two methods used to calculate the cumulative dose of alkylating agents (Text S1). , Multivariable analysis showed independent associations between POI and CED ≥8000 mg/m2 (8000‐11 999 mg/m2 [HR = 2.77; 95% CI, 1.18‐6.51] and 12 000‐19 999 mg/m2 [HR = 3.90; 95% CI, 1.80‐8.43]).

The Childhood Cancer Survivor Study (CCSS) evaluated fertility outcomes in 20 720 previously untreated patients age <21 years at diagnosis, who survived for at least 5 years, and who were diagnosed with an eligible cancer at 27 participating institutions between 1970 and 1986. Four‐hundred and ninety‐eight patients with WT were included in the analysis. For all patients, when controlled for education level, marital status, age at diagnosis, ethnicity, and smoking status, multivariate models demonstrated lower chance of pregnancy for those treated with cyclophosphamide (RR = 0.8; 95% CI, 0.68‐0.93; P = .005). The impact was dose related, with fertility decreasing with increased dose. When CED was categorized by quartile, female survivors diagnosed between 1970 and 1999 who were exposed to the upper quartile (≥11 295 mg/m2) had a lower likelihood of pregnancy than those not exposed (HR = 0.85; 95% CI, 0.74‐0.98; P = .023). Notably, the evidence regarding the threshold for ovarian damage is scarce, and ranges from 6000 to 12 000 mg/m2. Currently a CED score of >6000 mg/m2 is classified as high risk. , ,

FERTILITY RISKS FOR MALE WT SURVIVORS

In general, Leydig cell function is preserved, but germ cell failure is very common in men treated with high cumulative doses of cyclophosphamide (≥7500 mg/m2). To date in the SIOP‐RTSG, no retrospective analyses have been done to correlate childhood WT treatment with gonadal function in adulthood. However, within the CCSS, 1622 survivors completed the Male Health Questionnaire, with a self‐reported prevalence of infertility of 46% (defined as taking >1 year to get a female pregnant). Forty‐nine male patients with kidney tumors were included in this analysis. In addition, a report from the St. Jude Lifetime Cohort Study found laboratory‐evaluated impaired gonadal function in 55.6% of 304 male survivors of childhood cancer. In the CCSS multivariable analysis, an AAD of ≥3 (RR = 2.13; 95% CI, 1.69‐2.68) was associated with a high risk for infertility vs an AAD <3. Male survivors who received cumulative cyclophosphamide doses of ≥7412 mg/m2 reported a significantly decreased likelihood of fathering a child compared with those not exposed. Notably, although irreversible gonadal impairment may occur, in some patients with azoospermia before or after treatment, recovery is seen over time in sperm production. ,

IMPACT ON FERTILITY AFTER RADIOTHERAPY FOR WT

Radiotherapy (RT) is an established, efficacious modality for treating select WT patients. NWTS‐3 demonstrated that EFS of patients with Stage III FHWT treated with 1000 cGy of abdominal radiation was not significantly different from that of patients who received 2000 cGy. Standard of care RT in the COG and SIOP protocols is described in Table 6. AREN0321 established 1980 cGy flank RT is beneficial in cases of diffuse anaplastic (DA) WT Stage III tumors. , Whole lung RT is standard of care for treating pulmonary metastases in the COG protocol, excepting cases of favorable histology with lung‐only metastases who have complete response to chemotherapy by week 6 (Table 6). While the impact of whole lung RT on gonadal damage is expected to be minimal since ovaries and testes are not located in the radiation field, increased risk of complications during pregnancy and labor may occur due to radiation and anthracycline induced cardiotoxicity. In SIOP‐RTSG, approximately 25% of patients receive abdominal RT. In most patients the pelvic area is not included in the radiation field but 20% of irradiated patients (5% of the total number of patients with WT) are also treated on a HR protocol which includes cyclophosphamide. A radiation boost is delivered to any micro‐ or macroscopic residual abdominal disease. In SIOP, no radiation is needed in local Stage I with anaplasia. , Whole lung RT is given for intermediate risk (IR) tumors with no complete remission (CR) after preoperative chemotherapy and/or metastasectomy and to all HR tumors. (Table 6).

TABLE 6

Cumulative radiotherapy doses used by COG and SIOP RTSG

	Local Stage II	Local Stage III	Intraabdominal dissemination	Macroscopic residual tumor	Lung metastasis
COG
	DA: 1080 cGy flank RT (6 fractions)	1080 cGy flank RT (6 fractions) DA: 1980 cGy flank RT	1050 cGy WART		>12 months: 1200 cGy (8 fractions) a <12 months: 1050 cGy (7 fractions) a
SIOP
IR		14.4 Gy flank RT (8 fractions)	WART: 15 Gy (10 fractions)	Boost 10.8 Gy	12 Gy b
HR	DA: 25.2 Gy flank RT (14 fractions)	25.2 Gy flank RT (14 fractions)	WART: 19.5 Gy (13 fractions)	Boost 10.8 Gy	15 Gy

Abbreviations: CR, complete response; DA, diffuse anaplastic type; Gy, Gray; HR, high risk; IR, intermediate risk; RT, radiotherapy; WART, whole abdomen RT.

Exception: favorable histology + lung‐only metastases (CR at week 6).

IR (no CR after preoperative chemotherapy and/or metastasectomy).

These established regimens result in variable gonadal exposure in male and female patients. Patients with early‐stage local disease and lung metastases may require lung‐only RT and have very low dose gonadal exposure from indirect internal and external scatter. Those requiring flank RT may have little to no direct exposure in males and variable exposure in females depending upon lesion size at diagnosis and age of the patient, which influences the location of the ovaries. In cases with a large primary tumor or those requiring whole abdominal radiation therapy (WART), gonadal tissue may receive full prescription dose (see Figures S1‐S4 for illustrations of flank and WART dose distributions for female and male pediatric WT patients). New approaches to reducing target volumes for flank radiation by combining highly conformal target volumes with Volumetric‐Modulated Arc Therapy (VMAT) will likely have a clinical benefit by dose reduction to organs of risk. In the first single center study of VMAT, excellent locoregional control could be achieved by this technique. Unfortunately, gonadal toxicity was not formally assessed in these two papers, but this risk is predicted to be reduced.

There are limited published reports detailing the impact of RT on fertility in WT survivors, and most of these include small patient numbers. In a study of 23 prepubertal children aged 6 months to >4 years following therapy for WT, 1500 to 3000 cGy hemiabdominal RT or WART resulted in serum hormone levels which indicate gonadal damage in both males and females compared with normal controls and those receiving chemotherapy only.

An analysis of testicular function of 10 young adult WT survivors who received 268 to 983 cGy to the testes from WART without chemotherapy revealed all of these men to have decreased testicular volume compared to “normal males of the same age” and eight of the nine with evaluable sperm counts had oligo‐ or azoospermia.

The impact of RT prior to puberty on ovarian size, based on ultrasound analysis, was conducted on 18 female WT survivors, 14 of whom were evaluated postpuberty. Of 10 postpubescent females treated with 400 to 4096 cGy flank RT, five had a small or not visible ipsilateral ovary; the ovaries of all three treated with 2100 to 3000 cGy WART were small or not seen. Of note, the uterine length was also decreased in the postpubertal females treated with WART. In general, cases with major tumor rupture that require WART are most at risk. , ,

In a more recent questionnaire‐based analysis of male fertility in a large retrospective cohort of 6224 childhood cancer survivors participating in the CCSS, 429 of whom had WT, testicular RT dose >750 cGy was significantly associated with decreased likelihood of being able to establish paternity compared with those not receiving RT. This study identified the subgroup with younger age at diagnosis (0‐4 years), in which most WT subjects fall, to be associated with higher likelihood of being able to sire a child. This analysis, however, did not separate survivors by cancer type and is confounded by variable chemotherapy exposure.

In addition to potential impact on gonadal function, late effects of RT to the abdominopelvic region in young children may impair normal growth and development of the irradiated pelvic bones, vasculature and organs including the uterus, which are critical to successful gestation (Table 5). There have been several studies of pregnancy outcomes of WT survivors, including those receiving RT either to flank only or to upper abdomen/WART on NWTS 1‐4. Review of 309 medical records of at least 20‐week gestation pregnancies showed female WT survivors receiving >2500 cGy flank RT to have increased risk for preterm labor (OR = 2.36), fetal malposition (OR = 6.26), and birth before 36 weeks gestation (OR = 4.07) compared with nonirradiated female survivors, whereas there was no difference noted in those receiving chemotherapy only or in pregnancies conceived with male survivors treated in NWTS 1‐4. While radiation may result in decreased distensibility of the uterus during pregnancy, leading to preterm delivery, no correlation between birth weight in offspring and radiation dose has been found. , , RT dose to ipsilateral and contralateral ovary as well as to the uterus from flank RT was estimated to range from 2% to 7% of the prescription dose.

>12 months: 1200 cGy (8 fractions)

<12 months: 1050 cGy (7 fractions)

Regarding radiation‐dose correlations, as little as 5 Gy cumulative exposure to reproductive organs augments the risk of infertility by a factor of 1.6. Of female WT survivors from NWTS 1‐4 cohort who received RT beyond the flank, only seven (5.5%) of 126 with known RT fields had at least one pregnancy. Nine of 10 babies were live born from five female survivors receiving upper abdominal RT only, whereas only one of four pregnancies resulted in a viable child from two female survivors who received WART. Notably, the WART dose was 1050 cGy for the live birth and 2100 cGy for the three nonviable pregnancies. These findings support earlier retrospective analyses of pregnancy outcomes of WT survivors, including one study by Li et al of 114 pregnancies in 99 WT survivors (65 female, 34 male), which showed a 30% incidence of adverse outcomes including perinatal death and low birthweight in females receiving 2000 to 3500 cGy flank RT compared with 3% in nonirradiated female survivors or wives of irradiated male survivors. The relative risk (RR) of perinatal mortality (RR 7.9; P < .0001) and low birthweight (RR 4.0; P < .0001) was significantly higher in the mothers irradiated for WT than expected for pregnancy outcomes for white women in the United States at that time. In another study of 47 WT survivors, 43 of whom received abdominal RT, female WT survivors had a more than 4‐fold increased risk of adverse birth outcomes, including preterm birth and birth defects, compared with sibling controls and wives of male WT survivors. The addition of chemotherapy did not modify this risk. Adverse pregnancy outcomes following RT for WT in the above studies have been attributed to uterine fibrosis, impaired placentation, vascular insufficiency, altered bone growth, scarring/adhesions, and/or genitourinary malfunction. , , , The most important factor for a successful pregnancy after pelvic radiotherapy is the cumulative dose to the ovaries and uterus and the age of the patient at the time of radiation. Prepubertal age at time of antineoplastic therapy exposure has been associated with a lower risk of ovarian failure, with mathematical models suggesting this finding may be due to increased follicular reserve in these very young patients. , While younger age is considered protective for gonadal damage, the growth and function of the uterus may be impaired due to the radiation. Radiation to a prepubertal uterus may lead to incomplete pubertal growth and development. This may pose difficulties regarding embryo implantation or fetal growth (to term).

Continued efforts to limit RT dose to the adjacent organs‐at‐risk, including but not limited to the gonads, is essential to improve reproductive success in this patient population. Advances in molecular biology and imaging as well as increased international collaboration between COG and SIOP will be very beneficial in this respect. An example of this partnership is the monthly HARMONIzation and CollAboration (HARMONICA) meetings in which SIOP and COG collaborate on numerous projects including plans for a unified approach to FP in children with renal tumors. Refining flank field and dose exposures in a manner that optimizes cancer control while concurrently limiting gonadal toxicity is also a topic amenable to international discussion. In addition, education and counseling of the parents of these young patients about the risk‐benefit ratio of tumor control and late fertility risks, as well as early involvement of endocrinology/fertility experts, is critical to optimize outcomes and expectations.

OPTIONS FOR FERTILITY PRESERVATION

As early as 2005, multiple international organizations, including the National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society for Medical Oncology, American Academy of Pediatrics, Children's Oncology Group, and the American Society of Reproductive Medicine created strong guidelines around FP. For postpubertal patients, there are clear data to guide counseling and intervention. Challenges to FP efforts include patient and provider knowledge of options, as well as logistical considerations. For example, FP measures should generally precede administration of any chemotherapy or radiation treatment. If possible, the FP surgery will be combined with another surgical procedure (line placement, nephrectomy) to limit the number of times a child has to undergo anesthesia and surgery. This poses an additional logistic challenge. This time pressure often factors into decisions made by patients and families. Furthermore, not all pediatric oncology treatment centers offer all FP options, which may further delay FP and initiation of definitive oncologic therapy. , , , , ,

Females with preoperative tumor rupture and most relapsed WT patients are at especially high risk of gonadal damage due to radiation and chemotherapy intensification. In these cases, fertility counseling is mandatory and FP procedures may be considered. Fertility risk is generally triaged early after initial diagnosis, however, sometimes the definitive treatment plan and subsequent gonadal damage risk is determined after the assessment of the initial treatment period. The response determines the treatment intensity and potential impact on fertility. Furthermore, treatment intensification may need to occur at any time depending on disease response or other factors. Thus, FP discussion and plan for FP intervention is needed when intensification is suggested.

Currently, FP for patients with WT is largely experimental. Most patients are prepubertal, there are no established methods considered clinically standard for FP for prepubertal males, and just a single option for prepubertal females. As previously noted, patients report a desire to learn more about FP and regret that they were not more comprehensively counseled; as such, clinicians should proactively initiate conversations around standard and experimental options for FP. Figures 1 and 2 summarize FP options for patients, and Table S2 provides more details about each option. , , , Other options that exist for both genders include adoption, surrogacy, and the use of donor sperm/eggs or embryos.

FIGURE 1

Male fertility preservation options

FIGURE 2

Female fertility preservation options. †Only in selected cases receiving abdominal radiotherapy (RT) with an ovary in the RT field. *In rare cases, older patients with a partner may want to opt for embryo cryopreservation. However, for most Wilms tumor patients this will not be an option. ^Currently, no strong evidence exists that hormonal suppression has a protective effect on gonadal damage in children. However, it can be used in addition to other fertility preservation methods

Boys

Postpubertal boys are defined as Tanner stage ≥3, corresponding to a testicular volume of ≥6 cc. Therapy‐related impaired spermatogenesis, testosterone deficiency, hypogonadotropic and hypergonadotropic hypogonadism may all lead to infertility. In prepubertal boys, options for FP are testicular biopsy, testicular sperm extraction (TESE) and percutaneous epididymal sperm aspiration (PESA). , , , , However, these procedures are not standard of care in all countries for young children. In postpubertal boys, freezing of ejaculated sperm is offered also in case of a low risk of gonadal damage. For boys who are Tanner ≥3 with unsuccessful attempts at masturbation, electroejaculation can be considered. However, due to the invasive nature of the procedure, this should be considered primarily as an option for patients with high estimated risk of gonadal damage.

Girls

Cryopreservation of ovarian tissue (OTC) is now offered around Europe and at selected centers in the United States to prepubertal and postpubertal girls with cancer who are at high risk of infertility. , An ovary can be completely or partially removed and harvested tissue frozen. Oocyte cryopreservation (OC) is another FP option available in some jurisdictions for postpubertal girls in which postponement of cancer treatment for at least 2 weeks is feasible. Due to the intensive hormone therapy required and the psychological impact, this is offered to physically and emotionally mature postmenarcheal girls, usually aged 16 years and older. As most WT patients are prepubertal, this is a very rare occurrence. Nevertheless (young) adult WT patients are registered. Oophoropexy (OP), in which the ovary is surgically secured in a location outside of the planned radiation field, is rarely used in WT patients, when flank radiation reaches into the pelvis. For WART only heterotopic OP would be applicable and this has multiple limitations.

Currently, future success of pregnancy after auto‐transplantation of prepubertally harvested ovarian tissue is under extensive investigation. , , As the effect of OTC on the future ovarian function is still unknown, OTC is limited to patients with a high risk of infertility. Additionally, dormant malignant cells may be present in the harvested ovarian tissue sample, which complicates auto‐transplantation. However, promising preclinical research is being conducted to ensure ovarian tissue can be used safely. , GnRH antagonists use to preserve ovarian function is highly debated and currently is not considered a reliable/effective option for children and AYAs for fertility preservation according to international consensus.

In the United States and many other countries, FP services (including both procedural costs and storage of the procured tissue) are not universally covered by insurance programs, although some need‐based financial assistance programs are available. , There is a general shift toward covering these services and procedures in some states, but it is far from a universally available service. In most European countries, FP for oncologic reasons is covered by insurance programs. Notably, while FP options are available in high income nations, access to these options in middle‐ and low‐income countries is more limited. Therefore, finding strategies for less gonadotoxic therapy remains important.

ETHICS OF FERTILITY PRESERVATION IN PATIENTS WITH WT

An overview of ethical considerations concerning FP has recently been published by the PanCareLIFE consortium in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). It is important to consider ethical, cultural, and religious issues since available FP options for prepubertal boys and girls involve invasive procedures, the harvested tissue contains gametes, and not all FP technologies are standard of care for all patients. Most WT patients are minors, and there is no universal consensus at what age a child is competent to make medical decisions. Issues such as the use of stored gametes after reaching adulthood as well as handling the material after the death of a child with cancer pose ethical dilemmas. Finally, the risk of not being able to guarantee the efficacy of auto‐transplanted tissue in future settings raises additional ethical challenges. , , , , , , ,

Since most patients diagnosed with WT are under the age of 10 years (median: 3.4 years), parents are typically the medical decision‐makers. Yet internationally the importance of respecting the autonomy of children is reflected in the need for assent or consent for research or treatment, though these ages vary by country. , , While the parents are the primary decision‐makers, the patient's perspective should be incorporated, and clinicians should ensure that information is provided to the child in an age‐appropriate manner. It is important to primarily keep the interest of the child in mind, as the decision made by parents may be influenced by their own interests. The possibility may arise that the view of a maturing child may differ from the view of his or her parents. Especially in the case of OTC, the fact that 50% of the ovarian reserve is removed and stored, automatically reducing that child's ovarian reserve by 50%, and that future efficacy of use of the material is uncertain need to be considered and weighed.

THE IMPACT OF GENETIC SUSCEPTIBILITY ON FP

The most important known risk factors for treatment‐related gonadal damage in WT are use of alkylating agents (boys and girls) and full abdominal radiotherapy (girls). However, previously published work shows that female patients with similar oncologic treatment at the same age can have variable gonadal damage. , This interindividual variability suggests that genetic factors modify gonadotoxicity of the treatment. , ,

So far, large‐scale genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), such as rs11668344 (BRSK1), rs365132 (UIMC1) and rs16991615 (MCM8), relevant for age at natural menopause or POI in the general population. , , , , , , In contrast, only two GWAS studies have been performed to explore genetic susceptibility of cancer treatment‐related gonadal damage in girls. , , Brooke et al identified and replicated a common haplotype associated with increased prevalence of premature menopause among childhood cancer survivors exposed to ovarian RT. Results of a European GWAS study are currently pending. BRSK1 (rs11668344) appears to be a relevant SNP in childhood cancer survivors treated with 8000 mg/m2 cyclophosphamide or more. , It is hypothesized that the presence of the BRSK1 SNP leads to a less efficient DNA damage response system and this may result in more damage caused by the alkylating agents in healthy cells, including the gonadal cells. In addition, SNPs in cytochrome (CYP) 450 genes have been shown to be associated with cyclophosphamide metabolism and ovarian function, and recently also with anti‐Müllerian hormone (AMH) levels in CCSS. , , The field of genetic susceptibility as it relates to oncofertility is new and should be further explored.

The role of genetic variation in male infertility in the general population is still unclear and has not been studied extensively in male childhood cancer patients. Although evidence is limited, it should be mentioned during counseling that genetic susceptibility may contribute to the risk of future infertility in childhood cancer when discussing fertility in newly diagnosed and especially relapsed WT patients.

CONCLUSIONS

Fertility concerns in WT survivors may be related to treatment (surgical intervention, chemotherapy, and/or radiotherapy) or underlying patient‐specific risk factors (including syndromes associated with WT development). Fortunately, the reproductive organs are rarely directly affected by surgical intervention for primary WT. Unfortunately, the young age of most children diagnosed with WT makes fertility preservation prior to treatment difficult, although both testicular and ovarian tissue harvest have been described. The absence of effective and widely available methods to preserve fertility in very young patients undergoing cancer treatment may place an emotional burden on families. It should not be assumed that parents will initiate a discussion about fertility preservation and thus, initiation of this discussion by the treating team together with an offer of a consult from an oncofertility team, where available, should be a standard of care for all patients with WT.

In summary, with improved survival for children treated for WT there is an associated risk of late effects including fertility impairment. Refinements in oncologic treatments and an understanding of late effects help to limit morbidity. However, patient, family, and clinician education on fertility preservation in this population is necessary to provide the best and most holistic care possible. Our goal is that this review serves as a statement that we must turn our focus to this area as stated by G.J. D'Angio, “cure is not enough.”

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

AUTHOR CONTRIBUTIONS

All authors contributed to the writing of the manuscript. All coauthors reviewed the final article. In all, this document represents a fully collaborative work. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

ETHICS STATEMENT

Not applicable.

Text S1 Calculations for cyclophosphamide equivalent dose and alkylating agent dose.

Table S1. Patient and family perspectives.

Table S2. Fertility preservation (FP) options presently available.

Figure S1. Female right flank radiation (COG dosage: 1080 cGy).

Figure S2. Female whole abdomen radiation (COG dosage: 1050 cGy).

Figure S3. Male right flank radiation (COG dosage: 1080 cGy).

Figure S4. Male whole abdomen radiation (COG dosage: 1050 cGy).

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