1188 - Age at Irradiation and the Risk of Radiation-Associated Hypogonadism in Male Pediatric Cancer Survivors
Presenter(s)
S. Baliga1, L. Xie2, K. Li3, A. Delaney2, J. T. Lucas Jr4, S. Dixon2, M. M. Hudson5, L. S. Constine6, and D. Green2; 1Department of Radiation Oncology, James Cancer Hospital, The Ohio State University Medical Center, Columbus, OH, 2St Jude Children's Research Hospital, Memphis, TN, 3Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, 4Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, 5St. Jude Children's Research Hospital, Memphis, TN, 6Department of Radiation Oncology and Pediatrics, University of Rochester Medical Center, Rochester, NY
Purpose/Objective(s): Male infertility and gonadal dysfunction are common endocrine complications among male childhood cancer survivors (CCS). Radiotherapy (RT) is known to have a dose dependent effect on testicular hormonal function and spermatogenesis. However, the impact of age at time of RT on Leydig cell function remains undefined. Our objective was to explore the association between age at RT on testosterone levels in pediatric male CCS.
Materials/Methods: We performed a retrospective study of 5-year childhood male CCS enrolled in the St Jude Lifetime Cohort Study (SJLIFE) between 2007 and 2020 (n=1,657). Survivors who had at least one testosterone measurement and had data available for testicular RT dose estimation were analyzed. Patients were excluded if age at most recent assessment was <16 , if they received craniospinal RT (CSI), had a vasectomy or Klinefelter syndrome. Logistic mixed-effects regression models with individual-specific random intercepts evaluated the association between low testosterone status (testosterone <300 ng/dL) at each lab measurement and treatment exposures in male CCS, adjusting for age at testosterone measurement, age at primary cancer diagnosis ( =12 vs. >12 years old), and interaction between testes RT and age at cancer diagnosis.
Results: 1,657 patients had 3,101 testosterone measurements. 952 (30.7%) of 3,101 were deemed low. High cumulative alkylating chemotherapy exposure (cyclophosphamide equivalent dose (CED)=8000 mg/m2) (OR: 2.27, 95% CI: 1.31-3.95, p=0.004) and older age at measurement (OR: 1.05 per year, 95% CI: 1.03-1.07, p<0.001) were significantly associated with higher odds of low testosterone. Among CCS diagnosed at >12 years of age, exposure to both lower dose (<5 Gy) (OR:4.62, 95% CI: 1.74-12.26, p=0.002) and higher dose testicular RT (=5 Gy) (OR:7.96, 95%CI: 1.50-42.19, p=0.015) were associated with a higher risk of low testosterone; these associations were also significant among CCS diagnosed =12 years of age with larger effect sizes (for <5 Gy: OR: 8.93, 95% CI: 4.34-18.37, p=<0.001; for 5 Gy: OR: 97.9, 95% CI: 20.8-462.0, p=<0.001). Among CCS exposed to testes dose =5 Gy, patients =12 were more likely to have low testosterone compared to >12 (OR:7.75, 95% CI: 1.14-52.89), p=0.037).
Conclusion: Testicular RT was associated with a strong dose-dependent increase in the risk of hypogonadism among male CCS. Age at exposure significantly modified this relationship, with markedly greater vulnerability among survivors treated at =12 years of age, particularly at doses =5 Gy. These findings suggest a developmental window of heightened Leydig cell radiosensitivity and indicate that gonadal dose thresholds may not be uniform across childhood. The association between increasing age at assessment and lower testosterone further raises concern for premature Leydig cell senescence following RT. These results have important implications for RT planning, survivorship risk stratification, and long-term endocrine surveillance.