A phase-specific benefit-toxicity framework for perioperative trials in muscle-invasive bladder cancer: A focused review andtrial-level mapping analysis.

The perioperative treatment landscape for muscle-invasive bladder cancer is changing rapidly with the emergence of immune checkpoint inhibitor- and antibody-drug conjugate-based strategies. Trials such as NIAGARA, EV-304/KEYNOTE-B15, and EV-303/KEYNOTE-905 have shown substantial improvements in event-free survival, overall survival, and pathological response. However, efficacy endpoints alone may be insufficient to evaluate perioperative regimens, because treatment is delivered across neoadjuvant, surgical, and adjuvant phases. Each phase introduces distinct sources of burden, including treatment-related toxicity, discontinuation of neoadjuvant therapy, delay or failure to undergo radical cystectomy, postoperative complications, and failure to initiate or complete adjuvant therapy. To address this gap, we propose a phase-specific benefit-toxicity framework for interpreting modern perioperative trials in muscle-invasive bladder cancer. We define deliverability as the feasibility of completing the intended neoadjuvant-surgical-adjuvant treatment pathway. Recent studies such as EV-304, NIAGARA, EV-303, and VESPER provide a timely opportunity to map perioperative benefit, toxicity, and deliverability at the trial level, although endpoints, safety reporting, and comparator arms differ across trials. Because perioperative therapy spans neoadjuvant, surgical, and adjuvant phases, the framework uses the neoadjuvant benefit-harm balance as the primary interpretive axis while contextualizing surgical feasibility and postoperative treatment continuity. The aim is not to rank regimens, but to visualize how therapeutic benefit and treatment burden are balanced across heterogeneous trial designs. Phase-specific mapping may provide a more clinically interpretable approach for assessing modern perioperative combination regimens and for designing future trials that better capture treatment feasibility, surgical safety, and completion of the intended treatment pathway.