Abstract
Abstract Study question Do immunotherapy and targeted therapy for melanoma affect male fertility? Summary answer Immunotherapy and targeted therapy for melanoma affect sperm quality. However, the detrimental effects are only transient. Sperm quality recovers once the treatment is discontinued. What is known already Immune checkpoint inhibitors, such as anti-BRAF and anti-MEK inhibitor, are currently used in melanoma patients to modulate the immune system and promote its anti-cancer action. Since these agents do not have an anti-mitotic action, they should not cause damage to spermatogenesis. However, no specific studies on human fertility have been conducted before drug registration. In fact, based only on pre-clinical studies, fertility-lowering effect of the BRAF/MEK inhibitors cannot be excluded. Potential endocrine autoimmune-related adverse events which could alter the hypothalamic-pituitary-gonadal axis such as hypophysitis, could impair spermatogenesis. These potential harmful effects should not be overlooked when counselling patients. Study design, size, duration Male patients scheduled for immunotherapies for melanoma were prospectively recruited at National Cancer Institute in Milan, Italy, between March 2020 and April 2023. Patients were counselled by a reproductive medicine specialist and offered to cryopreserve semen before immunotherapies. A semen analysis was also proposed 6-8 months after the initiation and 6-8 months after the end of immunotherapies. The primary outcome was to compare semen variables before, during and after immunotherapies. Participants/materials, setting, methods All patients underwent therapy with Nivolumab or Dabrafenib for 12 months.Semen samples were all cryopreserved and analysed by a single biologist at the Infertility Unit of Policlinico in Milan. Data are reported as median [Interquartile range-IQR] or number (percentage). Main results and the role of chance Twenty-three men operated on for melanoma and scheduled for immunotherapy were recruited. The age of patients at cryopreservation was 33 years [29–39]. An average of 12 [10-12] sperm paillettes were cryopreserved per patient. Total sperm count and total progressive motile sperm count were 126 millions [75–246] and 90 millions [38–154], respectively. Three patients were lost to follow-up and two patients died after cryopreservation. Twelve patients (52%) returned for a semen analysis during oncological treatment. After a median time of 9 months [8-12] of immunotherapy, a reduction in all semen variables was noted, particularly in total sperm count (77 million [49-189], p = 0.05 compared to basal condition) and the total count of progressive spermatozoa (34 million [23-77], p = 0.02 compared to basal condition). No differences were observed in morphology. Ten (43%) patients returned after the end of immunotherapies. One patient died before completing the follow-up. A recovery of all sperm variables compared to the cryopreserved sample was observed. Total sperm count and total motile sperm count were 190 millions [107–320] and 79 millions [34–140], respectively (p=ns). Two patients thawed their cryopreserved semen for an IVF cycle during immunotherapy. No pregnancy was achieved. Limitations, reasons for caution Our study evaluates male fertility only in terms of semen quality. Alterations of the hypothalamic-pituitary-gonad axis, such as the increase of autoimmune phenomena, have not been studied. Furthermore, the small sample size of our study is a limit. Wider implications of the findings Our study evaluates male fertility only in terms of semen quality. Alterations of the hypothalamic-pituitary-gonad axis, such as the increase of autoimmune phenomena, have not been studied. Furthermore, the small sample size of our study is a limit. Trial registration number not applicable
Published Version
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