Evaluating BCG response in primary and metachronous non-muscle invasive bladder cancer following prior upper tract urothelial cancer: A systematic review and meta-analysis

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INTRODUCTION: Emerging evidence suggests that metachronous non-muscle invasive bladder cancer (m-NMIBC) recurrence after prior upper tract urothelial carcinoma (UTUC) treatment is distinct from primary NMIBC (p-NMIBC). Correspondingly, their disease trajectories and treatment responses may differ vastly. This systematic review aims to evaluate the differences in Bacillus Calmette-Guérin (BCG) response between m-NMIBC and p-NMIBC. METHODS: A comprehensive literature search (PubMed, Embase, and Scopus) was performed to identify relevant studies that reported BCG outcomes for p-NMIBC and m-NIMBC. Endpoints analyzed were high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). This study followed the PRISMA guidelines. Both one-stage and two-stage meta-analyses were performed. RESULTS: Six cohort studies with 1,292 patients were identified. Three studies utilized propensity-matched scoring to account for differences in baseline clinical characteristics. BCG prescription was observed in 89% of the whole cohort, with 4 studies treating all included patients with BCG. Patients with m-NMIBC demonstrated worse HG-RFS (one-stage meta-analysis: HR 0.47, 95% CI 0.38-0.59, P < 0.001; two-stage meta-analysis: HR 0.44, 95% CI 0.38-0.50, P < 0.001, I² = 0%). M-NMNIBC also demonstrated worse PFS compared to p-NMIBC (one-stage meta-analysis: HR 0.54, 95% CI 0.35-0.83, P = 0.005; two-stage meta-analysis: HR 0.45, 95% CI 0.22-0.90, P = 0.035, I² = 0%). There were no significant differences for CSS (one-stage meta-analysis: HR 0.53, 95% CI 0.24-1.17, P = 0.116) and OS (one-stage meta-analysis: HR 1.24, 95% CI 0.64-2.42, P = 0.520). Overall risk of bias was moderate across the included studies. CONCLUSIONS: This review observed that m-NMIBC exhibits a poorer response to BCG compared to p-NMIBC, with significantly higher rates of HG-recurrence and disease progression. These observations reflect a potential biological distinction between the 2 entities, and highlight important implications in clinical trial design and risk stratification.

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