The Dose-Response Relationship Between Cumulative Alkylating Agent Exposure and Sperm Concentration in Adult Survivors of Childhood Cancer: A Report from the St. Jude Lifetime (SJLIFE) Cohort Study.

10066 Background: Male survivors of childhood cancer treated with alkylating agents (AA) are at risk for azoospermia; however, the long-term dose-response relationship is unknown. Methods: Of the 685 male SJLIFE participants treated with AA but no radiation therapy, 387 (56.5%) provided an evaluable semen sample (mean age at diagnosis: 8.3 years, mean age at evaluation: 28.6 years, and mean years from diagnosis to evaluation: 20.3 years). 73 had one or more subsequent semen analyses (median interval between semen analyses 5.4 years; interquartile range 4.2 – 6.6 years). Survivors were categorized as azoospermia, oligospermia (sperm concentration > 0 and < 15 million/ml), or normospermia (sperm concentration ≥ 15 million/ml). AA exposure was estimated using the cyclophosphamide equivalent dose (CED). Risks were estimated using the odds ratio (OR) and 95% confidence intervals (CI) from multinomial logistic regression analyses. Results: Among survivors 22.5% had azoospermia, 26.6% oligospermia, and 50.9% normospermia (Table). Motility and progressive motility were not associated with increasing CED categories among normospermic or oligospermic participants. Multinomial logistic regression including CED, age at diagnosis and at follow-up demonstrated that, for each 1,000 mg/m2 increase in CED, the odds of azoospermia increased by 1.14 (95% CI 1.09, 1.20), and the odds of azoospermia and oligospermia increased by 1.22 (95% CI, 1.14, 1.30). Azoospermia and oligospermia were best distinguished from normospermia using a CED cutoff of 7,000 mg/m2 based on the Youden Index. Nearly all participants initially identified with azoospermia (24 out of 25) maintained this diagnosis upon later evaluation. Conclusions: Nearly half of adult childhood cancer survivors who received alkylating agents without radiation therapy experience impaired sperm production, either low sperm count (oligospermia) or no sperm at all (azoospermia). The association increases with increasing CED. Recovery of spermatogenesis is unlikely among those who present azoospermic. CED = 7,000 mg/m2 is the optimal cutoff for differentiating risk for oligo- or azoospermia from normospermia. [Table: see text]