Neoadjuvant Chemotherapy Prior to Trimodality Therapy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis

Background and objective: Neoadjuvant chemotherapy (NACT) before radical cystectomy improves outcomes in muscle-invasive bladder cancer (MIBC), but its value before trimodality therapy (TMT; maximal transurethral resection of the bladder tumor plus concurrent chemoradiation) is uncertain. This review aims to evaluate whether the addition of NACT to TMT is associated with improved survival in patients with MIBC. Methods: We systematically searched the MEDLINE, Embase, and Web of Science databases (February 2025). Eligible studies reported adjusted estimates for overall (OS), cancer-specific (CSS), or disease-free (DFS)/recurrence-free survival in patients undergoing TMT, comparing those who received versus those who did not receive NACT. Random-effect meta-analyses pooled multivariable hazard ratios (HRs). The risk of bias was assessed with ROBINS-I (PROSPERO registration: CRD420251120157). Key findings and limitations: = 116). Overall certainty is limited by nonrandomized design, heterogeneity in patient selection, TMT protocols and response definitions, and the modest number of adjusted studies. Conclusions and clinical implications: Across adjusted observational data, addition of NACT before TMT was not associated with a survival benefit. However, patients who respond to NACT experience a substantially better prognosis. Prospective trials testing modern neoadjuvant strategies-particularly immunotherapy- and targeted therapy-based regimens-within the standardized TMT protocols are warranted. Patient summary: We reviewed studies in which chemotherapy was given before a bladder-sparing approach, called trimodality therapy (tumor removal plus chemoradiation). Overall, this treatment approach did not improve survival, although patients who responded to the pretreatment did better. Newer drugs, including immunotherapy, should be tested in this setting.