Intravesical Bacillus Calmette-Guerin (BCG) is the current first-line treatment for high-grade non-muscle-invasive bladder cancer (NMIBC); however, a substantial proportion of patients are unresponsive to BCG treatment. While cystectomy is often recommended in bladder cancer following BCG failure, there are numerous established therapeutic agents and pre-commercialized trials describing treatments for NMIBC following failed BCG treatment. Our objective in this systematic review is to characterize the efficacy these therapeutic agents by reporting their corresponding complete response rates (CRR) and toxicity profiles.
We conducted a systematic review of all available clinical trials evaluating therapies to treat recurring NMIBC after previous intravesical BCG. BCG failure patients who had previously failed one or more courses of prior BCG therapy were included. Studies not in the English language, included muscle-invasive bladder cancer patient populations, or lacked a post-treatment evaluation of response were excluded. We used PubMed®/Medline, Cochrane library, and EMBASE to search for relevant studies. No formal risk of bias assessment was conducted. Complete response rates for 3, 6, 12, 24-month post treatment evaluation, progression rates, cystectomy rates and 12 complications are reported.
A total of 70 studies with 73 reports evaluating 27 treatment options were retained for final analysis. These treatments were reported in 5 categories including intravesical chemotherapy, combination therapy, hyperthermia paired with intravesical chemotherapy, immunotherapy, and novel agents with published years ranging from 1998 to 2021. Single intravesical chemotherapy and the combination of multiple intravesical chemotherapy agents demonstrate varied complete response rates of 10%-83% at 12 months. Limited clinical data evaluating hyperthermia paired with chemotherapy demonstrates 12-month complete response rates of 50%-85%. Despite these reported response rates, progression rates ranged from 0%-18%. Moreover, Immunotherapeutic agents demonstrate progression rates of 7% to 22% at a median of 12 months follow up. Novel agents displayed a wide range of complete response rates (6% to 91%) at 12 months based on the treatment used. Total grade 3 toxicity rates range from 0%-55% for intravesical chemotherapy and combination intravesical chemotherapy agents, 0%-15% for hyperthermia paired with chemotherapy agents, 12%-13% for immunotherapy agents, and 0%-17% for novel agents.
Bladder-preserving treatments accomplish moderate success in NMIBC following BCG failure. As the majority of available clinical trials are single-armed uncontrolled cohorts and contain limited number of patients, strength and comparability of the data is limited. In general, intravesical chemotherapy and hyperthermia paired with Mitomycin C demonstrate some of the highest complete response rates at 12 and 24 months. Similarly, among the pre-commercialized novel agents, N-803 and gene therapy display promising results and may serve as potential future treatment for NMIBC following failed BCG treatment. In terms of toxicity/complication rates, both commercially available and unavailable treatments showcase low toxicity profiles for bladder cancer following BCG failure. The comprehensive analysis provided by this systematic review can serve as a reference for treatment decisions and clinical trial design in the BCG-unresponsive domain.
The Journal of urology. 2022 Sep 06 [Epub ahead of print]
Michael Nazmifar, Cheyenne Williams, Aurash Naser-Tavakolian, John Heard, Charles Rosser, Dan Theodorescu, Michael Ahdoot
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California., Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.