BCG Intolerance in Nonmuscle Invasive Bladder Cancer—A Systematic Review

Background: Most patients with localized bladder cancer are initially managed with endoscopic resection. For high-grade nonmuscle invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guerin (BCG) therapy is the gold standard adjuvant treatment. However, 30%–40% of patients fail BCG treatment with lack of response or disease relapse. An understudied area of treatment failure is BCG intolerance, where patients drop out of treatment due to adverse effects. 

Objectives: To examine the incidence and underlying reasons for BCG intolerance among adult patients with NMIBC. 

Methods: We conducted a search on Embase, MEDLINE, and Cochrane Central Register of Controlled Trials for studies from January 1, 1974 to January 10, 2023, retrieving 3340 articles. Two authors independently conducted screening and data extraction with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inclusion criteria include English-language studies reporting dropout rates and reasons for discontinuation of BCG therapy in NMIBC patients. 

Results: BCG dropout rates reported among the 28 included studies varied widely from 0% to 52% (estimated summary proportion 12.8%, 95% CI 9%–17%). There was significant heterogeneity in study design. Subgroup analyses show a dose-dependent effect on dropout rates (3.3% vs. 20%, X² = 83.6, p = < 2.2 × 10⁻¹⁶). Dropout rates vary with BCG strains: the Connaught strain had the highest at 21.1%, while the Pasteur strain had 2%. Clinical outcomes for BCG intolerance are not widely reported. 

Conclusions: Dropout rates due to BCG intolerance average 12.8%. As cessation of treatment could lead to an increased risk in progression or recurrence of disease, strategies to mitigate BCG intolerance would be valuable.