BCG+MMC trial: adding mitomycin C to BCG as adjuvant intravesical therapy for high-risk, non-muscle-invasive bladder cancer: a randomised phase III trial (ANZUP 1301)

Abstract

BackgroundDespite adequate trans-urethral resection of the bladder tumour (TURBT), non-muscle-invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression. Instillation of Bacillus Calmette-Guérin (BCG) into the urinary bladder after TURBT (adjuvant intravesical administration) reduces the risk of both recurrence and progression, and this is therefore the standard of care for high-risk tumours. However, over 30 % of people still recur or progress despite optimal delivery of BCG. Our meta-analysis suggests that outcomes might be improved further by using an adjuvant intravesical regimen that includes both mitomycin and BCG. These promising findings require corroboration in a definitive, large scale, randomised phase III trial using standard techniques for intravesical administration.Methods and designThe BCG + MMC trial (ANZUP 1301) is an open-label, randomised, stratified, two-arm multi-centre phase III trial comparing the efficacy and safety of standard intravesical therapy (BCG alone) against experimental intravesical therapy (BCG and mitomycin) in the treatment of adults with resected, high-risk NMIBC. Participants in the control group receive standard treatment with induction (weekly BCG for six weeks) followed by maintenance (four-weekly BCG for ten months). Participants in the experimental group receive induction (BCG weeks 1, 2, 4, 5, 7, and 8; mitomycin weeks 3, 6, and 9) followed by four-weekly maintenance (mitomycin weeks 13, 17, 25, 29, 37, and 41; BCG weeks 21, 33, and 45). The trial aims to include 500 participants who will be centrally randomised to one of the two treatment groups in a 1:1 ratio stratified by T-stage, presence of CIS, and study site. The primary endpoint is disease-free survival; secondary endpoints are disease activity, time to recurrence, time to progression, safety, health-related quality of life, overall survival, feasibility, and resource use.Trial registrationThis trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613000513718).

Current clinical trials in non–muscle invasive bladder cancer

“…[12] While intravesical BCG therapy is superior to MMC therapy in reducing rate of recurrence and tumor progression, a phase II trial has found the combination of MMC with BCG to be better than BCG therapy alone in improving recurrence-rates (42% vs. 58%). [13] The on-going phase III trial is evaluating the efficacy of the MMC and BCG combination intravesical therapy in high-risk NMIBC patients by assessing the disease free survival over 5 years.…”

BCG immunotherapy for non-muscle invasive bladder cancer: is efficacy related to toxicity?

“…Fluoroquinolones may reduce the occurrence of moderate or severe toxicity [29]. Newer techniques under investigation to evaluate efficacy and toxicity include the addition of mitomycin C to BCG as adjuvant intravesical therapy [30]. Currently however, there is no effective preventative method for BCG toxicity.…”

BCG + Mitomycin trial for high‐risk non‐muscle‐invasive bladder cancer: progress report and lessons learned

“…The BCG + Mitomycin trial (ACTRN12613000513718; http://ClinicalTrials.gov NCT02948543; ANZUP 1301) is an ongoing randomized phase III trial, aiming to compare the efficacy and safety of the addition of intravesical mitomycin chemotherapy to standard intravesical BCG in patients with resected, high‐risk non‐muscle‐invasive bladder cancer (NMIBC) . Our meta‐analysis suggested reduced rates of recurrence (relative risk 0.75; 95% CI 0.61–0.92; P < 0.01) and progression (relative risk 0.45; 95% CI 0.25–0.81; P < 0.01) with combination treatment as compared to treatment with BCG alone in patients with Ta or T1 disease, but not in those with pure carcinoma in situ (CIS) ; however, this remains unproven for all subgroups of high‐risk NMIBC, or when treatment is delivered without electromotive delivery (as is usual), and requires corroboration in a definitive, large‐scale, randomized phase III trial.…”