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Efficacy of bacillus Calmette-Guerin Strains for Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Network Meta-Analysis.

ABSTRACT: PURPOSE:We sought to determine the efficacy of genetically distinct bacillus Calmette-Guérin strains in preventing disease recurrence in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS:We conducted a systematic review and network meta-analysis of trials evaluating bacillus Calmette-Guérin strains against all possible comparators (different bacillus Calmette-Guérin strains, chemotherapy and nonbacillus Calmette-Guérin biological therapies) with intravesical chemotherapy as the common comparator. MEDLINE® (http://www.ncbi.nlm.nih.gov/pubmed) served as the primary data source, with the search from inception to October 2016 for clinical trials involving patients with nonmuscle invasive bladder cancer receiving bacillus Calmette-Guérin. Primary outcome measure was bladder cancer recurrence, defined as recurrent bladder tumor of any grade or stage. Random effect network meta-analysis provided estimates for outcomes and is presented as odds ratios. RESULTS:Across all possible comparators (65 trials, 12,246 patients, 9 strains) there were 2,177 recurrences in 5,642 treated patients (38.6%) and 2,316 recurrences in 5,441 comparators (42.6%). With chemotherapy as the common comparator (28 trials, 5,757 patients, 5 strains) Tokyo-172 (OR 0.39, 95% CI 0.16-0.93), Pasteur (OR 0.49, 95% CI 0.28-0.86) and TICE® (OR 0.61, 95% CI 0.40-0.93) strains were significantly better than chemotherapy at preventing recurrence. No bacillus Calmette-Guérin strain demonstrated significant superiority when compared to any other strain at preventing recurrence in the network meta-analysis. CONCLUSIONS:Bacillus Calmette-Guérin strains exhibited significant differences in efficacy compared to chemotherapy. However, no definitive conclusions could be reached regarding strain superiority, and head-to-head trials are greatly needed to further understand the importance of strain selection in determining bacillus Calmette-Guérin efficacy.

SUBMITTER: Boehm BE

PROVIDER: S-EPMC6464123 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Efficacy of bacillus Calmette-Guérin Strains for Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Network Meta-Analysis.

Boehm Brock E BE Cornell John E JE Wang Hanzhang H Mukherjee Neelam N Oppenheimer Jacob S JS Svatek Robert S RS

The Journal of urology 20170310 3

<h4>Purpose</h4>We sought to determine the efficacy of genetically distinct bacillus Calmette-Guérin strains in preventing disease recurrence in patients with nonmuscle invasive bladder cancer.<h4>Materials and methods</h4>We conducted a systematic review and network meta-analysis of trials evaluating bacillus Calmette-Guérin strains against all possible comparators (different bacillus Calmette-Guérin strains, chemotherapy and nonbacillus Calmette-Guérin biological therapies) with intravesical c ...[more]

PMID: 28286068

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Project description:BackgroundIntravesical 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 nonmuscle 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.MethodsWe 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 guidelines. The relative risks of clinical outcomes, including recurrence, progression, cancer-specific mortality, and all-cause mortality according to dose (standard vs low), duration (induction vs maintenance), and strain of BCG were presented as the pooled risk ratio (RR) and 95% confidence interval (CI).ResultsNineteen 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 without heterogeneity among the included studies. Although there were no significant differences between dose or duration and other clinical outcomes. On direct comparison in each study comparing BCG strains, the Tice stain 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.ConclusionThe 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.

Project description: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 (http://www.crd.york.ac.uk/prospero/).

Project description:ContextThere is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR.ObjectiveTo elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results.Evidence acquisitionWe performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis.Evidence synthesisMedian CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities.ConclusionsWe demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space.Patient summaryIn this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

Dataset Information

Efficacy of bacillus Calmette-Guerin Strains for Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Network Meta-Analysis.

Publications

Efficacy of bacillus Calmette-Guérin Strains for Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Network Meta-Analysis.

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