Dose, Duration and Strain of Bacillus Calmette-Guerin in the Treatment of Non-Muscle Invasive Bladder Cancer: Systematic Review and Meta-Analysis of Randomized Clinical Trials

Abstract

Introduction: Intravesical bacillus Calmette-Guerin (BCG) instillation is widely used as an adjuvant therapy after transurethral resection of bladder tumor (TURBT) in patients with intermediate-and high-risk non-muscle invasive bladder cancer (NMIBC). However, the effective dose, duration and strain of BCG have not yet been clearly determined. We aimed to elucidate the relationship between dose, duration, and strain of BCG and clinical outcomes in NMIBC patients treated with TURBT. Methods: We conducted a literature search in Embase, Scopus, and PubMed databases for all relevant articles published up to October 2016 in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The relative risks of clinical outcomes, including recurrence, progression, cancer-specific mortality, and all-cause mortality according to dose (standard versus low), duration (induction versus maintenance), and strain of BCG were presented as the pooled risk ratio (RR) and 95% confidence interval (CI). Results: Nineteen studies meeting the inclusion criteria were finally selected in this meta-analysis. The risk of recurrence was significantly highly observed in case of low dose BCG (RR, 1.17

95% CI 1.06-1.30) and induction BCG (RR, 1.33

95% CI 1.17-1.50) only group. While there were no significant differences between dose or duration and other clinical outcomes. Chi-square-based Q statistic and Higgins I-squared statistic test revealed that there was no significant inter-study heterogeneity in all analyses. On direct comparison in each study comparing BCG strains, the Tice strain showed a relatively high probability of recurrence compared with the Connaught (RR, 1.29

95% CI 1.01-1.64) and RIVM (RR, 2.04, 95% CI 1.28-3.25) strains. Funnel plot testing revealed no significant publication bias. Conclusions: The use of standard dose and maintenance BCG instillation may be effective to reduce recurrence rate after TURBT for NMIBC. Further large scale, well-designed and prospective studies, with stratification of the patients into risk group at randomization, will be required to determine the optimal guideline of BCG use to improve clinical outcomes in NMIBC.