Testicular Function in Childhood Osteosarcoma Survivors: Uncovering the Effects of Modern Chemotherapy Regimens
Margarett Shnorhavorian, MD, MPH1, John K. Amory, MD, MPH1, Saro Armenian, DO, MPH2, Eric Chow, MD, MPH3, Holcombe Grier, MD4, Smita Bhatia, MD5, Debra Spoljaric, RN, MSN, CPNP, FNP-C6, Amanda Adler, MS3, Jonathan Gill, MD7, Wendy Leisenring, Sc.D8, Michael K. Skinner, Ph.D9, Stephen M Schwartz, Ph.D, MPH8.
1University of Washington, SEATTLE, WA, USA, 2City of Hope, Duarte, CA, USA, 3Seattle Children's Hospital, SEATTLE, WA, USA, 4Dana-Farber Cancer Center, Boston, MA, USA, 5University of Alabama, Brimngham, AL, USA, 6Washington University, St. Louis, MO, USA, 7The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 8Fred Hutchinson Cancer Research Center, SEATTLE, WA, USA, 9Washington State University, Pullman, WA, USA.
BACKGROUND:Male childhood cancer survivors often face substantial challenges from the reproductive toxicity of cancer chemotherapy. This study investigates the testicular effects of cisplatin in male adolescent and young adult (AYA) survivors of osteosarcoma, compared to male controls without a history of cancer.
Methods:We identified male osteosarcoma survivors treated with cisplatin from Children's Oncology Group (COG) protocols (AOST0331, INT0133, APEC14B1) and compared them to age- and current residence-matched controls from the general population. Testicular function was measured using biomarkers of steroidogenesis and spermatogenesis. Blood and seminal fluid samples were collected, with the latter obtained using a mail kit. Age adjusted differences in mean testosterone, LH, FSH, and Inhibin B between survivors and controls were estimated using generalized linear models. Associations between survivor status and seminal fluid parameters were measured as age-adjusted prevalence ratios (PRs) and corresponding 95% confidence intervals (CIs) estimated using Poisson regression with robust error variance estimation.
Results:177 Survivors and 175 Controls were enrolled. Median time since treatment for survivors was was 9.9 years (IQR: 2.9, 26.2). Largest age group of survivors was 20-24 years (n=67, 37.9%). Majority of survivors were White (n=147, 84%) and non-Hispanic (n=144, 83.2%) .Survivors had only slightly higher age-adjusted testosterone (12.6 ng/dL, 95% CI = -60.0, 34.9) and LH concentrations (0.9 mIU/mL, 95% CI = -1.7, -0.2) than controls, whereas age-adjusted FSH concentration was higher (4.4 mIU/mL, 95% CI = 2.7, 6.1), and Inhibin B concentration was lower (132.8 pg/mL, 95% CI = 99.4, 166.3) than controls. Sperm concentration and morphology measurements were available for 139 survivors and 191 controls. Compared to controls, survivors had much lower sperm concentrations but a similar proportion of normal sperm. Among survivors, sperm concentrations were considerably lower for those who had received ifosfamide or etoposide, while the proportion of sperm that was normal were only somewhat lower among those who had received these drugs. After classifying sperm concentrations according WHO standards, survivors had an elevated prevalence of azoospermia (PR=2.3, 95% CI 1.9, 2.9) as well as mild and moderate oligospermia.
Conclusions:This comprehensive study evaluates the impact of modern chemotherapy regimens on testicular function in male AYA survivors of childhood osteosarcoma. By uncovering the adverse effects of treatment and identifying high-risk groups, we can better inform cancer patients about potential testicular function challenges and develop tailored strategies for maintaining testicular health, ultimately enhancing their post-treatment quality of life.
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