Refining BCG ‐failure classifications in non‐muscle‐invasive bladder cancer

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 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.