Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Abstract

Summary Background Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. Methods We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01–20·3] at diagnosis, 29·0 years [18·4–56·1] at assessment, and a median of 21·0 years [10·5–41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Findings Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 CED for azoospermia (OR 1·22, 95% CI 1·11–1·34), and for oligospermia (1·14, 1·04–1·25), but age at diagnosis and age at assessment were not. Interpretation Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m2. Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.

Fertility issues in patients with hematologic malignancies

“…The risk of impaired spermatogenesis is low when the cyclophosphamide equivalent dose is Ͻ4000 mg/m 2 , but is still dose-dependent, with odds of azoospermia increasing by 22% and oligospermia by 14% for every 1000 mg/m 2 increase in cyclophosphamide equivalent dose. 24 Nevertheless, sperm recovery may occur in 20%-25% of patients after even the most intensive therapies including myeloablative HCT, 20 although it may be delayed by years after therapy. [25][26][27] Despite this, male cancer survivors are ϳ50% less likely than their siblings to father children, and this risk was greatest in men receiving radiation to the testes Ͼ7.5 Gy or alkylating agents at the highest dose ranges.…”

“…32 Reimplantation of ovarian tissue in a heterotopic location is less invasive, but also requires artificial reproductive techniques (IVF) for uterine implantation. Since 2004, 33 24 live births have been reported using this technique; all of these were reimplanted orthotopically and ϳ50% of them required assisted reproductive techniques for successful implantation. 34 Advantages of ovarian tissue cryopreservation include: (1) gonadal tissue harvest may occur immediately; there is no hormonal therapy, preparation, or waiting period required as there is for oocyte harvesting; (2) like oocyte cryopreservation, a male partner/ sperm donor is not required; (3) endocrine function (not just fertility) may be restored in recipients of reimplanted tissue; and (4) this is an (experimental) option for pre-pubertal children.…”

Childhood to adult transition and long-term follow-up after blood and marrow transplantation

“…11 High-dose cyclophosphamide can contribute to ovarian failure in females and azoospermia in males. 12,13 Andrew experienced another type of endocrine dysfunctionarrest of the bones. BMT recipients are at increased risk for developing decreased bone mineral density and growth disorders after transplantation.…”

Fertility preservation options for children and adolescents with cancer

“…3 Although toxicity follows a dose-dependent pattern, no safe cutoff below which recovery is guaranteed has been identified. 4 These agents are regularly used in the treatment of brain tumours, leukemia, neuroblastoma, sarcomas, and others.…”