Semen parameters in unirradiated, alkylating agent-exposed childhood cancer survivors in the St. Jude Lifetime Cohort Study.
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OBJECTIVE: To study the long-term dose-response relationship of alkylating agents (AA) on azoospermia and oligospermia among adult childhood cancer survivors treated with or without platinating agents or epipodophyllotoxins. DESIGN: Retrospective cohort with longitudinal follow-up. SUBJECTS: Male survivors of childhood cancer ≥18 years of age and 5 or more years after diagnosis at the time of semen analysis. EXPOSURE: Alkylating agents, platinating agents, epipodophyllotoxins, anthracyclines. No radiation therapy. The AA exposure was estimated using the cyclophosphamide equivalent dose (CED). Platinating agent exposure was categorized using the cisplatin equivalent dose (CiED). Etoposide exposure was categorized using the cumulative dose median. MAIN OUTCOME MEASURES: Participants were categorized as azoospermic, oligospermic (sperm concentration >0 and <15 million/mL), or normospermic (sperm concentration ≥15 million/mL). RESULTS: Approximately 22.1% of childhood cancer survivors had azoospermia, 26.7% oligospermia, and 51.1% normospermia. The odds of azoospermia or oligospermia increased by 1.111 (95% confidence interval [CI], 1.053-1.173) for each 1,000 mg/m2 increase in CED, by 9.683 (95% CI 2.048-45.792) for CiED >500 mg/m2, and by 4.738 (95% CI, 2.274-9.871) for treatment with etoposide >10,000 mg/m2. Risk for azoospermia and oligospermia among those not treated with a platinating agent was best distinguished from risk for normospermia using a CED cutoff of 7,200 mg/m2 on the basis of the Youden index. CONCLUSION: Nearly half of those who received AA without radiation therapy experience oligospermia or azoospermia. CED, CiED, and treatment with etoposide are significantly associated with azoospermia and oligospermia. These results will inform pretreatment counseling of patients and therapeutic study design.