Aleksander Ślusarczyk, Pietro Scilipoti, Roberto Contieri, Wojciech Krajewski, Francesco Claps, José Daniel Subiela, Laura S. Mertens, Keiichiro Mori, Elisabeth Grobet‐Jeandin, J. Caño Velasco, Karl H. Tully, Francesco Soria, P. Del Olmo Duran, A. Lafuente Puentedura, Renee A. G. Lijnen, Mattia Longoni, Gautier Marcq, Andrea Mari, Ekaterina Laukhtina, Luca Afferi, Simone Albisinni, Andrea Gallioli, Francesco Del Giudice, Stephen A. Boorjian, Alberto Briganti, Shahrokh F. Shariat, Paolo Gontero, P. Radziszewski, Marco Moschini, Benjamin Pradere, Urothelial carcinoma working group
OBJECTIVE: To validate International Bladder Cancer Group (IBCG) definitions of Bacillus Calmette-Guérin (BCG)-unresponsive and BCG-exposed non-muscle-invasive bladder cancer (NMIBC) and assess prognostic heterogeneity across various BCG-failure types. PATIENTS AND METHODS: From a multicentre international cohort of 3806 BCG-treated patients, 591 who developed high-grade NMIBC recurrence following BCG between 2003 and 2024 were included. Progression-free survival (PFS) was the primary endpoint; cancer-specific (CSM) and overall mortality (OM) were secondary endpoints. Cumulative incidence functions, competing-risk models and multivariable Cox regression were used. RESULTS: Patients with BCG-unresponsive and BCG-exposed disease showed similar PFS, CSM, and OM (all P > 0.05). When stratified into five subgroups, prognosis varied: 5-year progression rates were 29% for BCG-unresponsive, 32.5% for late relapse (between 6 and 24 months) after adequate BCG, 30% for BCG-exposed with inadequate BCG (<24 months from induction), 6.2% for BCG-resistant, and 14% for very late relapse (>24 months since last BCG) (P < 0.01). In multivariable analysis, BCG-exposed after inadequate BCG (subdistribution hazard ratio [sHR] 3.42, 95% confidence interval [CI] 1.33-8.84), late relapse (sHR 3.74, 95% CI 1.59-8.78), and BCG-unresponsive (sHR 2.34, 95% CI 1.00-5.44) were associated with higher progression risks compared to very late relapse. Limitations include retrospective design and treatment heterogeneity. CONCLUSIONS: Under IBCG definitions, BCG-unresponsive and BCG-exposed NMIBC have similarly poor outcomes. A refined classification reveals prognostic heterogeneity, with late relapses after adequate BCG demonstrating outcomes comparable to BCG-unresponsive, and very late relapses conferring better prognosis.