Low-Dose Versus Standard Dose of Bacillus Calmette-Guerin in the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Whether low-dose Bacillus Calmette-Guerin (BCG) treatment can reduce the side effects while maintaining efficacy for patients with nonmuscle invasive bladder cancer (NMIBC) is controversial. To investigate whether low-dose BCG treatment can reduce the side effects while maintaining efficacy for patients with NMIBC when compared with standard-dose BCG treatment. A comprehensive literature search of PubMed, EMBASE, CINAHL, LILACS, and CENTRAL databases was conducted to identify relevant randomized controlled trials (RCT) or quasi-randomized controlled trials (qRCT) that have assessed the efficacy of low- and standard-dose BCG therapy for patients with NMIBC. Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Criteria. Six RCTs and 2 qRCTs were eligible for meta-analysis. Low-dose BCG instillation was not inferior to reduce the risk of bladder tumor recurrence (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.00–1.31; P = 0.05), meanwhile no difference was found regarding tumor progression (HR = 1.08; 95%CI, 0.83–1.42; P = 0.57). However, low-dose BCG provided a significantly lower incidence of overall side effects (RR = 0.75; 95%CI, 0.60–0.94; P = 0.01), systemic side effects (RR = 0.57; 95%CI, 0.34–0.97; P = 0.04), severe side effects (RR = 0.52; 95%CI, 0.36–0.74; P = 0.0003), and withdrawal due to BCG toxicity (RR = 0.49; 95%CI, 0.26–0.91; P = 0.02). In contrast, local side effects were comparable between low- and standard-dose arms (RR = 0.89; 95%CI, 0.73–1.08; P = 0.24). Low-dose BCG instillation significantly reduces the incidence of overall side effects, especially severe and systemic symptoms in patients with NMIBC, while the oncological control efficacy of low-dose BCG is not inferior to standard-dose BCG. Further studies with stratification using different risk factors at randomization are required to assess whether the efficacy of low-dose BCG is comparable to standard dose BCG for different risk of patients. PROSPERO registration No CRD42014014871 (www.crd.york.ac.uk/prospero/).