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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.
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.
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
© 2014 European Association of Urology, Published by Elsevier B.V.