Sequential Combination of Mitomycin C Plus Bacillus Calmette-Guérin (BCG) Is More Effective but More Toxic Than BCG Alone in Patients with Non–Muscle-invasive Bladder Cancer in Intermediate- and High-risk Patients: Final Outcome of CUETO 93009, a Randomized Prospective Trial

Abstract Background Intravesical bacillus Calmette-Guerin (BCG) is an effective therapy in non–muscle-invasive bladder cancer (NMIBC), but it has limitations in terms of recurrence and toxicity. Objective To determine whether the sequential combination of mitomycin C (MMC) and BCG is superior to BCG alone in increasing a disease-free interval (DFI). Design, setting, and participants We conducted a prospective randomized trial including 407 patients with intermediate- to high-risk NMIBC and allocated 211 to the MMC and BCG arm and 196 to the BCG-alone arm. Outcome measurements and statistical analysis The trial was designed to provide concurrently a power of 80% for the detection of a relative risk reduction of 35% (hazard ratio [HR]: 0.65) of disease relapse with a type I error of 0.05. Times to events were estimated using cumulative incidence functions and compared using the Cox regression model. We used the Kaplan-Meier technique to estimate survival curves. Results and limitations In the intention-to-treat analysis at 5 yr, DFI was significantly improved by the sequential scheme (HR: 0.57; 95% confidence interval [CI], 0.39–0.83; p =0.003), reducing the disease relapse rate from 33.9% to 20.6%. Higher toxicity was observed with the combination, even reducing the MMC dose, especially in G3 local toxicity compared with BCG with a difference of 17.4% (95% CI, 7.6–27.2; p Conclusions Although the sequential scheme is more effective than BCG alone in reducing disease relapse, due to higher toxicity it could be offered only to patients with a high likelihood of recurrence, such as those with recurrent T1 tumors. Patient summary We analyzed the outcomes of a randomized trial demonstrating that in intermediate- to high-risk non–muscle-invasive bladder cancer, mitomycin C and bacillus Calmette-Guerin (BCG) reduced disease relapse compared with BCG alone but was more toxic. Consequently, it could be offered only to patients with recurrent T1 tumors. Trial registration CUETO 93009.