Sex-disaggregated Outcomes and Safety Reporting in Perioperative Systemic Therapy for Muscle-invasive Bladder Cancer: A Systematic Review

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• Picked for Urology (top studies of the week, 8 November 2026): Sex-specific reporting in perioperative muscle-invasive bladder cancer therapy

Abstract

BACKGROUND AND OBJECTIVE: Sex may influence patients' response to chemotherapy or immunotherapy given before or after radical cystectomy. We reviewed all otherwise eligible prospective perioperative interventional studies, including randomized controlled trials and single-arm studies, to determine how often female enrollment, efficacy outcomes, and safety outcomes were reported separately for women and men. METHODS: PubMed, Embase, and the Cochrane Library were searched for phase 1-3 prospective interventional studies, including randomized controlled trials and single-arm studies, evaluating perioperative systemic therapy for nonmetastatic muscle-invasive bladder cancer (MIBC) between 1990 and 2024. Eligibility was based on disease setting, perioperative intervention, prospective design, and full-text availability; reporting of sex-specific outcomes was not required for inclusion and was instead coded as a review outcome. Two reviewers independently screened records, extracted female enrollment and published sex-stratified efficacy or safety outcomes, and assessed risk of bias using design-appropriate tools. Cochrane Risk of Bias 2 was applied to randomized trials and the Methodological Index for Non-Randomized Studies (MINORS) to noncomparative single-arm studies. Outcomes of interest were the proportion of studies reporting efficacy or adverse events (AEs) by sex, the proportion reporting formal sex-by-treatment interaction tests, and the sex-specific hazard ratios (HRs), response rates, or survival estimates provided. KEY FINDINGS AND LIMITATIONS: Twenty-nine reports of 27 unique prospective perioperative trials were included, comprising 21 neoadjuvant and eight adjuvant reports, covering 6376 patients; 1140 (18%) were women. Female enrollment was 17% in neoadjuvant chemotherapy trials, 17% in neoadjuvant immunotherapy trials, 17% in adjuvant chemotherapy trials, and 22% in adjuvant immunotherapy trials. Five reports (17%) reported any sex-disaggregated efficacy outcome, whereas none reported AEs by sex. The pooled Nordic neoadjuvant series reported a female-versus-male HR >1 for overall survival (HR 1.36, 95% confidence interval [CI] 0.97-1.92), although the estimate was imprecise. PURE-01 reported an imprecise female-versus-male event-free survival estimate (HR 1.15, 95% CI 0.44-3.00). In the adjuvant setting, individual cisplatin-based trials provided limited and mostly descriptive sex-specific information, whereas CheckMate-274 nivolumab reported disease-free survival estimates for women (HR 0.76, 95% CI 0.38-1.06) and men (HR 0.66, 95% CI 0.52-0.83), with the reported interaction test not providing clear evidence of heterogeneity (p = 0.58). Among randomized trials, risk of bias was low in eight reports, raised some concerns in eight, and was high in one; single-arm studies scored 12-15 of 16 on MINORS. Reliance on published summaries, limited female representation, and heterogeneous study designs limited formal inference. CONCLUSIONS AND CLINICAL IMPLICATIONS: Women remain underrepresented in perioperative MIBC trials and are absent from safety reporting. The available evidence is insufficient to determine whether clinically meaningful sex-based differences in benefit exist, and modest sex-based differences cannot be excluded. Future trials should ensure balanced recruitment, stratify randomization by sex when randomization is used, and report disaggregated efficacy and toxicity outcomes to support equitable care.

Abstract as published, via PubMed.