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.
Non-muscle-invasive bladder cancer has a high recurrence risk and is typically managed with transurethral resection of bladder tumors followed by intravesical therapy (IVT) induction. Thereafter, guidelines support maintenance IVT, but real-world adherence is reported as low as 2%. Management is complicated by ambiguity regarding which patients derive the greatest benefit, highlighting the need for biomarkers to inform management decisions. Postinduction urine tumor DNA (utDNA) was evaluated as a predictor of maintenance benefit in INSITE, a prospectively designed multicenter observational study. utDNA status was determined using a previously validated algorithm. The primary outcome was recurrence-free survival (RFS). Among 140 evaluable patients, 47% received maintenance IVT. For patients with utDNA-negative status, maintenance therapy provided no significant RFS benefit (hazard ratio [HR] 1.35, 95% confidence interval [CI] = 0.50-3.64, p = 0.6), and RFS was 88% at 24 mo regardless of whether patients received maintenance. Conversely, patients with utDNA-positive status who received maintenance experienced a survival advantage over those who did not (HR 0.22, 95% CI = 0.09-0.52, p < 0.001). RFS was 68% in patients with utDNA-positive status who received maintenance but was just 16% in those who remained untreated at 24 mo. Traditional clinicopathologic risk factors were not significantly associated with recurrence. Postinduction utDNA identifies patients who benefit from maintenance therapy versus those who may consider de-escalation, enabling personalized care within guideline ranges.
