Impacts of platinum-based chemotherapy on subsequent testicular function and fertility in boys with cancer

BACKGROUND: Children with cancer often face infertility as a long-term complication of their treatment. For boys, compromised testicular function is common after chemotherapy and currently there are no well-established options to prevent this damage. Platinum-based agents are used to treat a wide variety of childhood cancers. However, platinum agents are not currently included in the cyclophosphamide equivalent dose (CED), which is used clinically to assess the risks to fertility posed by combination chemotherapy in children with cancer. OBJECTIVE AND RATIONALE: This was a systematic search of the literature designed to determine the evidence for effects of platinum-based cancer treatment on the prepubertal human testis in relation to subsequent testicular function and fertility. SEARCH METHODS: PubMed and EMBASE were searched for articles published in English between 01 January 1966 and 05 April 2020 using search terms including ‘cancer treatment’, ‘chemotherapy’, ‘human’, ‘prepubertal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related terms. Abstracts were screened and full-text articles were obtained for those that met the three major inclusion criteria (age ≤12 years at treatment, exposure to platinum-based chemotherapeutic and measure of reproductive function). Screening of bibliographies for full-text articles was used to identify additional studies. OUTCOMES: Our initial search identified 1449 articles of which 20 (1.3%) studies (n = 13 759 males) met all inclusion criteria. A control group (healthy individuals or siblings) was included for 5/20 (25%) studies. A total of 10/20 (50%) studies provided sub-analysis of the relative gonadotoxicity of platinum-based agents. The primary outcome measures were: pregnancies and fatherhood; semen analysis; and hormonal function. For pregnancies and fatherhood, three studies (n = 10 453 males) reported negative associations with platinum-agents, including the largest (n = 5640) controlled study (hazard ratio = 0.56, P = 0.0023), whilst two other studies (n = 1781) with platinum sub-analysis reported no association. For semen analysis (based on World Health Organization criteria), platinum-based chemotherapy was associated with azoospermia in one study (n = 129), whilst another (n = 44) found no association and the remainder did not perform platinum-based sub-analysis. For hormone analysis, conflicting results were obtained regarding potential associations between platinum-based agents and elevated FSH (a proxy for impaired spermatogenesis); however, the majority of these studies were based on low numbers of patients receiving platinum-based chemotherapy. WIDER IMPLICATIONS: Overall, these results indicate that platinum-based chemotherapy should be included in clinical calculators, for example CED, used to determine gonadotoxicity for childhood cancer treatment. These findings have important implications for clinicians regarding counselling patients and their carer(s) on fertility risk, guiding requirements for fertility preservation strategies (e.g. testicular tissue cryopreservation) and modification of treatments to reduce or eliminate the risk of infertility in childhood cancer survivors.