Combination of Intravesical Bacille Calmette-Guérin and Chemotherapy vs. Bacille Calmette-Guérin Alone in Non-muscle Invasive Bladder Cancer: A Meta-Analysis

Abstract

Background: About 75% of newly diagnosed bladder cancer cases suffer from non-muscle invasive bladder cancer (NMIBC), which used to recur and progress despite transurethral resection of bladder tumor (TURBT). This meta-analysis was conducted to examine if combined application of intravesical bacille Calmette-Guérin (BCG) with chemotherapy is associated with better prognosis. Methods: Systematic searches of randomized controlled trials (RCTs) concerning NMIBC were performed in PubMed, EMbase, CENTRAL, CNKI, WanFang, VIP, CBM databases, and some specialized websites. Two researchers independently implemented study selection, quality assessment and data extraction. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for treatment effects on recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS) were directly extracted, if available, or estimated using relevant data from included studies. Side effects, such as fever, gastrointestinal reaction, cystitis, irritative bladder symptoms and hematuria, were also extracted as outcome measurements, and associated relative risks (RRs) were calculated to assess treatment safety. RevMan 5.3 software was used to perform statistical analyses. Results: Thirteen RCTs containing 1,754 patients with NMIBC were included in this meta-analysis. Compared with BCG alone, the combination therapy significantly improved RFS (HR = 0.53, 95% CI: 0.43–0.66, P < 0.01), OS (HR = 0.66, 95%CI: 0.50–0.86, P = 0.002), and DSS (HR = 0.48, 95%CI: 0.29–0.80, P = 0.005). While PFS showed no obvious difference between combination therapy and BCG alone (HR = 0.65, 95%CI: 0.25–1.68, P = 0.38). The rate of fever (RR = 0.50, 95%CI: 0.27–0.91, P = 0.02), irritative bladder symptoms (RR = 0.69, 95%CI: 0.52–0.90, P = 0.007) and hematuria (RR = 0.50, 95%CI: 0.28–0.89, P = 0.02) were significantly decreased in patients treated with combination therapy compared to those with BCG alone. There were no statistically significant differences between combination therapy and BCG alone in toxicity (RR = 0.69, 95%CI: 0.34–1.40, P = 0.30), gastrointestinal reaction (RR = 2.54, 95%CI: 0.61–10.60, P = 0.20) or cystitis (RR = 0.67, 95%CI: 0.29–1.54, P = 0.34). Conclusions: Combined application of intravesical BCG and chemotherapy appears to be an effective treatment for patients with intermediate- to high-risk NMIBC, but not for those with tumor in situ alone or recurrent bladder cancer.

<p>Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update</p>

“…Moreover, side effects were significantly decreased in patients who received BCG plus chemotherapy. 77 The efficacy of intravesical therapies can also be improved through delivery adaptations such as hyperthermia, electromotive drug administration or new devices.…”

Non-Muscular Invasive Bladder Cancer: Re-envisioning Therapeutic Journey from Traditional to Regenerative Interventions

“…In a murine model, acetylic salicylic acid and pentoxifylline seem to be effective in improving BCG efficacy [92]. In a systemic meta-analysis, it was concluded that compared to BCG alone, the synergistic effect of intravesical BCG and chemotherapy improved recurrence free survival, overall survival and disease specific survival with significantly decreased rate of fever, irritative symptoms and hematuria therapy among NMIBC patients [93]. Nonetheless, the therapeutic efficacy of BCG is undermined owing to its associated local and systemic side effects such as dysuria, haematuria, cystitis, sepsis, malaise and fever [83,90].…”

New Roadmaps for Non-muscle-invasive Bladder Cancer With Unfavorable Prognosis

“…A debated point which requires intense further investigation is to understand if BCG substrains, generated over time, could alter the host response. The main substrains used are Russia, Moreau, Japan, Sweden, and Birkhaug (elimination of region of differentiation 1) and BCG Prague, Glaxo, Danish, Tice, Frappier, and others (deletion region of differentiation 2) (Hayashi et al, 2010;Kasempimolporn et al, 2018). However, findings available so far are not sufficient to support more effectiveness of specific BCG strain over another.…”

“…- Intravesical chemotherapeutic drugs , alone or in combination, are used for high-risk NMIBC such as pirarubicin, gemcitabine, and epirubicin (Kang et al, 2016 ); intravesical application of mitomycin C is a chemotherapeutic agent most used in patients who do not respond to BCG (Fankhauser et al, 2020 ). The latter approach is also useful for patients who have developed significant side effects; the combination of BCG treatment with chemotherapeutic agents has demonstrated the reduction of side effects and an improvement of tolerability to BCG (Huang et al, 2019 ).…”