Gonadal Failure Is Common in Long-Term Survivors of Childhood High-Risk Neuroblastoma Treated With High-Dose Chemotherapy and Autologous Stem Cell Rescue

Abstract

Background: Neuroblastoma is the most common extra-cranial solid tumor in children. Intensive therapy including autologous stem-cell transplantation (HSCT) has improved the poor prognosis of high-risk neuroblastoma (HR-NBL) but may impair gonadal function. Objectives: To investigate the gonadal function and fertility in long-term survivors of childhood HR-NBL. Design: A cohort including all Finnish ( n = 20; 11 females) long-term (>10 years) survivors of HR-NBL and an age- and sex-matched control group ( n = 20) was examined at a median age of 22 (16–30) years. Oncologic treatments, pubertal timing, hormonal therapies and the number of off-spring were recorded, and pituitary and gonadal hormones were measured. Results: Altogether 16/20 of the long-term survivors of HR-NBL entered puberty spontaneously; puberty was hormonally induced in four survivors (three females). Among the 8/11 female survivors with spontaneous puberty, seven had spontaneous menarche, but 5/8 developed ovarian failure soon after puberty. Nine females currently needed estrogen substitution. AMH, a marker of ovarian reserve, was lower in the female survivors than controls (median 0.02 vs. 1.7 μg/l, p < 0.001). As a group, male survivors had smaller testicular size (8.5 vs. 39 ml, p < 0.001) and lower inhibin B (<10 vs. 170 ng/l, p < 0.001) compared with control males, with altogether 6/9 survivor males fulfilling the criteria of gonadal failure (absent puberty, small testicle size or increased FSH with need of testosterone substitution). Gonadal failure was more common in female and male survivors treated with total-body irradiation. Three survivors (one male) had offspring, all treated without total-body irradiation and moderate dose of alkylating chemotherapy. Growth velocity was compromised in all survivors after HR-NBL diagnosis, with absent pubertal growth spurt in 7/17 survivors with complete growth data. Conclusion: Gonadal failure is common in long-term survivors of HR-NBL treated with HSCT. Fertility may be preserved in some survivors treated without total-body irradiation.

Impacts of platinum-based chemotherapy on subsequent testicular function and fertility in boys with cancer

“…However, this increased risk was not statistically significant under both univariate and multivariate analysis, even at high doses (≥500 mg/m 2 for cisplatin, ≥2000 mg/m 2 for carboplatin). In a small study involving nine males with neuroblastoma ranging from 0.2 to 3.6 years of age at diagnosis, only one male patient was observed to have fathered a child ( Utriainen et al , 2019 ). This patient had received cisplatin and etoposide as induction chemotherapy, followed by high-dose melphalan.…”

“…A study involving 129 males diagnosed between the ages of 0–17 years reported azoospermia in 4/5 (80%) of those who had received what the authors considered a ‘sterilizing’ dose (>500 mg/m 2 ) of cisplatin (without radiotherapy), compared with 0/8 (0%) of those who had received <500 mg/m 2 of cisplatin ( Romerius et al , 2011 ). Two studies included a control group of age-matched healthy participants ( Muller et al , 1996 ; Utriainen et al , 2019 ). A study involving 33 males aged 0–19 years with various cancers showed azoospermia in 2/14 (14%) and oligozoospermia in 3/14 (21%) of long-term survivors compared with normospermia in 8/8 (100%) of healthy age-matched controls ( Muller et al , 1996 ).…”

“…However, the contribution of cisplatin to the semen parameters was not reported ( Muller et al , 1996 ). The second study involving a control group investigated nine male childhood cancer survivors who commenced treatment with alkylating-based chemotherapy, with or without cisplatin, between the ages of 0–3 years ( Utriainen et al , 2019 ). Only one patient had a sperm count performed in adulthood.…”

“…Only one patient had a sperm count performed in adulthood. He had received cisplatin and had fathered a child, although interestingly he had a low total sperm count (0.8 × 10 6 /ml) with oligo-asthenozoo-spermia ( Utriainen et al , 2019 ). Specific correlation of semen analysis with platinum exposure was only reported in one study ( Green et al , 2014a ): this study involved 214 subjects treated for various cancers from the age of 0–19 years.…”

“…Cumulative exposure to cisplatin has been reported in relation to gonadotrophin data in a cohort of 20 patients (nine males) diagnosed with high-risk neuroblastoma at between 0 and 3 years of age ( Utriainen et al , 2019 ). Cisplatin was part of their initial treatment and carboplatin was used for conditioning for HSCT, which included TBI in 10 (50%) cases.…”