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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

European Urology 2015 Mar;67(3):508-516



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.


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.


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.

Take Home Message

Mitomycin C (MMC) plus bacillus Calmette-Guérin (BCG) is more effective than BCG alone in improving the disease-free interval. The combination schedule is more toxic than BCG alone even when decreasing the MMC dose to 10 mg. The sequential scheme could be offered to bladder cancer patients with a high likelihood of recurrence, such as those with recurrent T1 tumors, keeping in mind its potential additional marginal benefit and high toxicity.

Keywords: BCG, MMC plus BCG, Intermediate- to high-risk groups, Randomized trial, Subgroup analysis.


a Department of Urology, Instituto Valenciano de Oncología, Valencia, Spain

b Department of Statistics, Hospital La Paz, Madrid, Spain

c Department of Urology, Complejo Hospitalario Universitario a Coruña, La Coruña, Spain

d Department of Urology, Hospital Central de Asturias, Oviedo, Spain

e Department of Urology, Hospital Cruces, Bilbao, Spain

f Department of Urology, Hospital Universitario Marques de Valdecilla, Santander, Spain

g Department of Urology, Hospital Universitario La Paz, Madrid, Spain

h Department of Urology, Hospital de Galdakao, Bilbao, Spain

i Department of Urology, Hospital de Basurto, Bilbao, Spain

j Department of Urology, Hospital Princesa Sofia, Madrid, Spain

k Department of Urology, Hospital de la Princesa, Madrid, Spain

l Department of Urology, Hospital Xeral, Vigo, Spain

m Department of Urology, Hospital Universitario de San Carlos, Madrid, Spain

n Department of Urology, Hospital General, Jerez de la Frontera, Spain

o Department of Urology, Hospital Alvarez Buylla, Mieres, Spain

p Department of Urology, Hospital Negrin, Las Palmas de Gran Canaria, Spain

q Department of Urology, Hospital Virgen del Camino, Pamplona, Spain

r Department of Urology, Clínica La Luz, Madrid, Spain

lowast Corresponding author. Department of Urology, Instituto Valenciano de Oncología, C/Prof. Beltran Baguena 8, 46009 Valencia, Spain. Tel. +34 961114030; Fax: +34 961114346.