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The Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary panel of bladder cancer experts to put forth consensus recommendations regarding the conduct of bladder cancer clinical trials. The goals of the consensus statements were to provide guidance for researchers on selecting appropriate study endpoints, patient eligibility criteria, evaluations, statistical analyses, and correlative studies. The panel developed individualized stage-specific clinical trial design recommendations to encompass trials on low-to-intermediate risk non-muscle invasive bladder cancer (NMIBC), high-risk NMIBC, trials involving neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), MIBC trials in the adjuvant setting, and trials in metastatic urothelial carcinoma.

Highlights from the consensus recommendations are as follows.

• In low-to-intermediate risk NMIBC, trials evaluating ablative therapies should utilize marker lesions (0.5-1 cm in size) after all other lesions are resected. The primary endpoint of these trials should be complete response, defined as absence of disease at the treated tumor sites at 3 month follow-up. In trials evaluating adjuvant therapies, time to first recurrence should be the primary endpoint. The panel underlines that while single-arm phase II studies are permitted, randomized controlled trial designs provide more meaningful assessment of activity endpoints.

• In high-risk NMIBC, studies evaluating carcinoma in situ with or without papillary disease or papillary disease alone should consider complete response at 6 months or recurrence-free survival as appropriate endpoints. The panel provides granular recommendations for Bacillus Calmette-Guérin (BCG)-naïve, BCG-exposed, and BCG-unresponsive populations, with considerations for acceptable BCG dose adjustments within the context of ongoing BCG shortages.

• In trials evaluating neoadjuvant therapies for MIBC, the panel highlights that pathologic complete response has not been well established as a correlative surrogate to overall survival (OS). Thus, trials should include a co-primary endpoint such as event-free survival (EFS). Specifically, for trials of concurrent chemoradiation, bladder-intact EFS should be considered as the primary endpoint. Further recommendations focus on study design, cisplatin-eligibility, and cystectomy candidacy status of trial participants.

• In MIBC trials evaluating adjuvant therapies, the panel considers disease-free survival and overall survival (OS) as the most meaningful endpoints. The design of such trials should be prospective, randomized, and controlled. The panel highlights the potential role for plasma circulating tumor DNA to stratify patients' risk of micrometastatic disease and recommends its integration in future trial designs.

• In metastatic urothelial carcinoma trials, OS, defined as time from study randomization to date of death from any cause, is considered the appropriate primary endpoint. During trial design, studies should categorize participants into chemotherapy-naïve (cisplatin-eligible vs -ineligible) and chemotherapy-treated patients to determine the comparative study arm. The panel acknowledges the rapidly evolving standard-of-care therapies and their impact on deciding the comparative arm of future trials in this arena.

The recommendations provided by the SITC-IBCG expert panel establish the foundation of conformity in bladder cancer research and will serve as a blueprint for bladder cancer investigators during future clinical trial design.

Muhannad Alsyouf, MD, is a urologic oncologist and assistant professor of urology at Loma Linda University in California and Riverside University Health System in Moreno Valley, California.

Read the consensus recommendations here and an interview about them here.