Predicting the Development of BCG-unresponsive Disease among Patients with High-grade Non–muscle-invasive Bladder Cancer: an International Multicenter Analysis

BACKGROUND:Dedicated tools estimating the risk of Bacillus Calmette-Guérin (BCG) failure among patients with high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) are lacking. OBJECTIVE:To develop a risk model predicting the development of BCG-unresponsive disease (defined according to the International Bladder Cancer Group and European Association of Urology [EAU] guidelines) or progression in patients with HG NMIBC receiving adequate BCG therapy. DESIGN, SETTING, AND PARTICIPANTS:This retrospective multicenter study included 2211 patients who were BCG naïve with HG Ta/T1 NMIBC (±carcinoma in situ [CIS]) treated with adequate BCG therapy between January 2003 and December 2024 at 13 academic centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary end point was time to BCG-unresponsive disease or progression to muscle-invasive/metastatic cancer. Multivariable Cox regression identified independent predictors, and a weighted clinical risk score stratified patients into four risk groups. RESULTS AND LIMITATIONS:Independent risk factors included T1 stage (adjusted hazard ratio [aHR] 1.52, 95% confidence interval [CI] 1.10-2.11), persistent HG or T1 tumor at restaging transurethral resection (aHR 2.51, 95% CI 2.06-3.06), multifocality (aHR 1.46, 95% CI 1.22-1.74), concomitant CIS (aHR 1.46, 95% CI 1.21-1.77), and World Health Organization 1973/2004/2016 HG/grade 3 (aHR 1.56, 95% CI 1.24-1.94). Internal validation via 1000 bootstrap samples revealed minimal optimism (0.01) and good calibration. The model demonstrated superior discrimination compared with the European Organization for Research and Treatment of Cancer progression score and EAU 2021 stratification (Harrell concordance index 0.68 vs 0.61 vs 0.56); 5-yr BCG-unresponsive-free survival was 88%, 79%, 60%, and 49%, respectively, across increasing risk groups. CONCLUSIONS:We developed a risk stratification model for patients with HG Ta/T1 treated with adequate BCG therapy. This tool enables individualized assessment of BCG failure risk and may support clinical decision-making.