Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non–muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis

Abstract

Context

Currently, there is no standard of care for patients with non–muscle-invasive bladder cancer (NMIBC) who recur despite bacillus Calmette-Guerin (BCG) therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.

Objective

To systematically synthesize and describe the efficacy and safety of current and emerging treatments for NMIBC patients after treatment with BCG.

Evidence acquisition

A systematic literature search of MEDLINE, Embase, and the Cochrane Controlled Register of Trials (period limited to January 2007–June 2019) was performed. Abstracts and presentations from major conference proceedings were also reviewed. Randomized controlled trials were assessed using the Cochrane risk of bias tool. Data for single-arm trials were pooled using a random-effect meta-analysis with the proportions approach. Trials were grouped based on the minimum number of prior BCG courses required before enrollment and further stratified based on the proportion of patients with carcinoma in situ (CIS).

Evidence synthesis

Thirty publications were identified with data from 23 trials for meta-analysis, of which 17 were single arm. Efficacy and safety outcomes varied widely across studies. Heterogeneity across trials was reduced in subgroup analyses. The pooled 12-mo response rates were 24% (95% confidence interval [CI]: 16–32%) for trials with two or more prior BCG courses and 36% (95% CI: 25–47%) for those with one or more prior BCG courses. In a subgroup analysis, inclusion of ≥50% of patients with CIS was associated with a lower response.

Conclusions

The variability in efficacy and safety outcomes highlights the need for consistent endpoint reporting and patient population definitions. With promising emerging treatments currently in development, efficacious and safe therapeutic options are urgently needed for this difficult-to-treat patient population.

Patient summary

We examined the efficacy and safety outcomes of treatments for non–muscle-invasive bladder cancer after bacillus Calmette-Guerin therapy. Outcomes varied across studies and patient populations, but emerging treatments currently in development show promising efficacy.

Introduction

Non–muscle-invasive bladder cancer (NMIBC) represents the majority (75%) of newly diagnosed cases [1]. Among NMIBCs, carcinoma in situ (CIS), high-grade (HG) T1, and HG Ta tumors are considered to be at high risk for tumor recurrence and disease progression [2], [3]. The standard treatment for high-risk NMIBC is transurethral resection of the bladder tumor, followed by adjuvant therapy with intravesical bacillus Calmette-Guerin (BCG) [2], [3], [4]. However, while 84% of CIS patients initially achieve a complete response (CR) with BCG [5], up to 50% fail to maintain a durable response [6], [7], [8]. In patients with HG NMIBC recurring after BCG, available bladder-sparing treatment options are limited. Valrubicin is approved by the US Food and Drug Administration (FDA) for patients with disease after BCG (BCG-refractory CIS) [82], [32], but response rates are suboptimal and not durable [6], [11]. Other bladder-sparing agents include a second course of BCG (for those who have not received adequate BCG) or intravesical chemotherapy with gemcitabine, mitomycin C (MMC), docetaxel, or sequential gemcitabine/docetaxel combination [12], [13].

In 2018, the FDA issued guidance on how to define BCG-unresponsive disease for the design of future clinical trials [9]. For BCG-unresponsive patients, radical cystectomy is currently recommended [2], [3], [13], but this procedure is associated with substantial morbidity and a non-negligible mortality risk [14], [15]. Participation in clinical trials is another option, particularly for patients who refuse to undergo or are ineligible for cystectomy [16]. Combined with a shortage in global BCG supplies [17], this unmet medical need warrants development of agents to improve the outcomes of bladder-sparing therapies.

This study sought to assess the efficacy and safety evidence of current and emerging treatments for patients with NMIBC, who recurred following treatment with BCG, through a systematic literature review (SLR) and meta-analysis. It also aimed to summarize real-world efficacy and safety from select observational studies and characterize emerging therapies from ongoing trials.