Oncofertility outcomes in early-onset patients with non-breast solid malignancies: a systematic review.
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BACKGROUND: The combination of a rising incidence of early-onset cancer and the trend towards delayed parenthood has made the impact of treatments on fertility highly significant. While there is abundant evidence on oncofertility outcomes of anti-cancer treatment protocols used in people with breast cancer and haematological malignancies, data regarding gonadal toxicity and fertility preservation in young people with other cancers are lacking. We aimed to systematically review gonadal toxicity, fertility outcomes, and preservation strategies in people with gastrointestinal, sarcoma, lung, and melanoma cancers. METHODS: We conducted a systematic review following the PRISMA guidelines and searched PubMed, Embase, through June 1, 2025. Eligible studies included observational designs and case reports on gonadal function, fertility outcomes, or preservation strategies in adults with the selected cancers. Pregnancy-associated and pediatric studies were excluded. Two reviewers independently screened, extracted data, and assessed quality using the JBI tool. Formal assessment of publication bias as not undertaken, given the limited number of studies per outcome. Due to clinical and methodological heterogeneity, results were synthesised narratively. Heterogeneity was assessed using the I2 statistic. The primary outcomes were treatment-related fertility impairment, including persistent amenorrhea or ovarian failure, return or maintenance of menses, and azoospermia and recovery of spermatogenesis at follow-up. Secondary outcomes included hormonal changes and reproductive outcomes such as pregnancy and live birth. This review was registered with PROSPERO (CRD42024557875). FINDINGS: Of 3337 records screened, 102 studies were included, comprising 33 case-based publications (30 case reports and 3 case series) and 69 analytical studies, including 64 observational studies (6 prospective and 58 retrospective) and 5 other analytical designs. Evidence across studies was highly heterogeneous in design, treatment exposures, and outcome definitions. In melanoma, most survivors appear to retain fertility, though rare cases of immune checkpoint inhibitor-induced orchitis or azoospermia were observed. Sarcoma regimens with alkylating and platinum agents appear to carry the highest risk of persistent gonadal failure in both sexes, with partial sperm recovery possible in some cohorts. In gastrointestinal cancers, chemotherapy-induced gonadal dysfunction was often transient in younger patients, whereas pelvic radiotherapy resulted in near-universal ovarian failure and long-term male hypogonadism. In lung cancer, platinum-based regimens were associated with to premature menopause and endocrine disruption, yet fertility counselling and preservation were rarely provided. Exploratory meta-analyses suggested that pooled estimates were imprecise and limited by substantial heterogeneity. INTERPRETATION: Gonadal toxicity risk varies by cancer type and treatment, while there is a paucity of robust evidence for the impact on malignancies that are emerging in the young population. Future prospective evaluation of gonadal function in the setting of early-onset cancer, as well as adequate evaluation of strategies to preserve fertility and minimise gonadal toxicity, is warranted. FUNDING: No external funding was received for this work. This study received internal institutional support.