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-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.