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A phase-specific benefit-toxicity framework for perioperative trials in muscle-invasive bladder cancer: A focused
Masanao Shinohara1, Takuma Narita2, Tomoko Hamaya2
1Department of Urology, Hirosaki University School of Medicine, Hirosaki, Japan; Department of Urology, Ageo Central General Hospital, Ageo, Japan.
Abstract:
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.
Insights
New frameworks are needed to evaluate perioperative treatments for muscle-invasive bladder cancer, considering toxicity and treatment completion across all phases. This approach assesses benefit-toxicity and deliverability for better clinical interpretation and future trial design.
Area of Science:
- Oncology
- Clinical Trials
- Urologic Oncology
Background:
- The perioperative treatment of muscle-invasive bladder cancer is evolving with new immune-based therapies.
- Current trials show improved survival and pathological response but lack comprehensive evaluation of treatment burden across phases.
Purpose of the Study:
- To propose a phase-specific benefit-toxicity framework for interpreting perioperative regimens in muscle-invasive bladder cancer.
- To define and assess 'deliverability'—the feasibility of completing neoadjuvant, surgical, and adjuvant treatment pathways.
Main Methods:
- Developing a framework that maps perioperative benefit, toxicity, and deliverability across different treatment phases.
- Utilizing data from trials like NIAGARA, EV-304, EV-303, and VESPER for analysis.
- Prioritizing the neoadjuvant benefit-harm balance while considering surgical feasibility and adjuvant therapy completion.
Main Results:
- Efficacy endpoints alone are insufficient for evaluating complex perioperative regimens.
- Each phase (neoadjuvant, surgical, adjuvant) presents unique challenges impacting treatment completion.
- A phase-specific approach can visualize the balance between therapeutic benefit and treatment burden.
Conclusions:
- A phase-specific benefit-toxicity framework offers a more clinically interpretable method for assessing modern perioperative combination regimens.
- This framework aids in designing future trials that better capture treatment feasibility, surgical safety, and pathway completion.
- The proposed approach aims to visualize, not rank, regimens, providing insights into benefit-toxicity trade-offs across heterogeneous trial designs.
