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Background: Bacillus Calmette-Guérin (BCG) maintenance therapy for 3 yr following BCG induction can reduce the progression of urothelial bladder carcinoma versus BCG induction alone, but is associated with high toxicity., Objective: To investigate whether a modified 3-yr BCG maintenance regimen following induction therapy is more effective than standard BCG induction therapy alone and exhibits a low toxicity profile., Design, Setting, and Participants: Patients from the outpatient clinics of the participating centres with high-risk non-muscle-invasive bladder carcinoma (NMIBC) were randomised between October 1999 and April 2007., Intervention: Participants received BCG induction once-weekly for 6 wk (no maintenance arm) or BCG induction followed by one BCG instillation every 3 mo for 3 yr (maintenance arm)., Outcome Measurements and Statistical Analysis: Primary endpoints were disease-free interval (DFI) and time to progression (TTP). Secondary endpoints included survival duration and toxicity. Differences between treatment arms were tested using Student's t test and χ(2) and log-rank tests., Results and Limitations: A total of 397 patients were randomised, 195 to the no-maintenance and 202 to the maintenance arm. A median time to recurrence was not reached in either treatment arm. DFI was similar between the arms (hazard ration [HR] 0.83; 95% CI 0.61-1.13; p=0.2) with disease relapse at 5 yr of 33.5% and 38.5%, respectively. TTP was also similar between the treatment arms (HR 0.79; 95% CI 0.50-1.26; p=0.3), with a progression rate at 5 yr of 16% and 19.5%, respectively. There were no significant differences between the treatment groups for overall survival and cancer-specific survival at 5 yr. Twenty and five patients in the maintenance and no-maintenance arms, respectively, stopped treatment because of toxicity. The most common local side effects were frequency (65% of patients), dysuria (63%), and haematuria (43%); the most frequent systemic side effects were general malaise (7.2%) and fever (34%)., Conclusions: In NMIBC patients treated with maintenance therapy comprising a single BCG instillation every 3 mo for 3 yr following standard induction BCG, we did not observe a decrease in recurrence and progression rates versus induction therapy alone., Patient Summary: Patients who undergo surgery to remove bladder cancer are usually treated with bacillus Calmette-Guérin (BCG) for 6 wk if there is a high risk of disease recurrence. Extending BCG therapy by 3 yr can further minimise disease recurrence and progression, but is associated with more side effects. We report that a modified 3-yr BCG treatment regimen showed low toxicity, but seemed to be no more effective than 6-wk treatment., Trial Registration: CUETO 98013., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Intravesical bacillus Calmette-Guérin (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<0.001). In recurrent T1 tumors, the potential benefit of the sequential scheme was more evident than in the remaining subgroup (18.8% vs 12.8%), with a number needed to treat of five versus eight to avoid an event and with similar toxicity., 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-Guérin (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., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)