Emerging evidence suggests that metachronous bladder recurrence after prior UTUC treatment (m-NMIBC) is distinct from primary NMIBC (p-NMIBC). They are likely to be more aggressive and show poorer response to Bacillus Calmette-Guérin (BCG). This systematic review aims to evaluate differences in BCG outcomes between m-NMIBC and p-NMIBC.

A comprehensive literature search of PubMed, Embase, and Scopus was performed to identify relevant studies that reported outcomes for p-NMIBC and m-NIMBC. The primary endpoints analyzed were recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). Both one and two-stage meta-analyses were performed.

Seven cohort studies were identified. Patients with p-NMIBC consistently showed longer RFS (one-stage meta-analysis: HR 0.57, 95% CI 0.46–0.71, p<0.001; two-stage meta-analysis: HR 0.44, 95% CI 0.38–0.50, p<0.001, I²=0%). Recurrence rates were notably higher in m-NMIBC (45.2–55.9%) compared to p-NMIBC (22.8–40.0%). P-NMIBC also demonstrated better outcomes for PFS (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%). For OS, initial one-stage meta-analysis findings indicated longer OS for p-NMIBC (HR 0.64, 95% CI 0.56–0.73, p<0.001), but was no longer significant on two-stage meta-analysis, with moderate heterogeneity (HR 0.88, 95% CI 0.18–4.23, p=0.751, I²=64%). CSS showed no significant difference between p-NMIBC and m-NMIBC (one-stage meta-analysis: HR 0.53, 95% CI 0.24–1.17, p=0.116; two-stage meta-analysis: HR 0.58, 95% CI 0.00–1.20, p=0.420, I²=0%).

Patients with m-NMIBC following prior treatment for UTUC exhibit a significantly poorer response to BCG compared to those with p-NMIBC, with nearly double the rates of recurrence and disease progression. Incorporating UTUC history into future risk prediction models is essential for more accurate prognostication and clinical trials design.