The impact of oxaliplatin on the gonads: From bench to bedside.

Abstract

584 Background: Recent studies have indicated a significant increase of young colorectal cancer patients, who may then face unique survivorship issues as fertility concerns. The impact of oxaliplatin on gonadal function remains unclear. We prospectively evaluated oxaliplatin-induced gonadotoxicity in a cohort of young patients. In a preclinical setting, the impact of oxaliplatin on the gonads was prospectively studied in mice. Methods: Newly diagnosed female (< 43 years) and male (<45 years) patients who were candidates for oxaliplatin-based protocol were enrolled into the study. Hormonal profile (including AMH and menstrual pattern) was measured in female patients and in male patients at baseline and within 6 months post-treatment. In the pre-clinical setting, pubertal mice (female and male cohorts) were injected with oxaliplatin or saline (control) and sacrificed at various time-points (1 week, 1 or 3 months) post-treatment. Ovarian reserve was estimated by serial serum AMH. Testicular function was evaluated by serial serum inhibin and sperm count. Gonads had been retrieved at each time point for immunohistochemical study of apoptosis (TUNEL, Ki67) and repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL). Results: Eighteen patients (10 women; 8 men) were enrolled. Median age for women was 34y (range 27-43) and for men 39y (33-44). AMH decreased in all women post-treatment, but was measurable in 8/10 patients (p<0.05). FSH was elevated yet in the premenopausal range in these patients. Three patients remain menstruating during treatment. Additional five patients resumed menstruation within 6 months post-treatment. In female mice oxaliplatin induced moderate apoptosis at 1-month post treatment with a recovery of the histology compared with control mice at later time points. Inhibin was slightly decreased in men post-treatment. In male mice oxaliplatin exerted moderate apoptosis and transient decrease in spermatocyte staining in histological sections and a non-significant decrease in sperm count. Conclusions: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. Future prospective large-scale studies are warranted in order to affirm these outcomes.