Maintenance Therapy with 3-monthly Bacillus Calmette-Guérin for 3 Years is Not Superior to Standard Induction Therapy in High-risk Non–muscle-invasive Urothelial Bladder Carcinoma: Final Results of Randomised CUETO Study 98013

• Published in: European urology Vol. 68; no. 2; pp. 256 - 262
• Main Authors: Martínez-Piñeiro, Luis, Portillo, José A, Fernández, Jesús M, Zabala, José A, Cadierno, Iker, Moyano, José L, Solsona, Eduardo, Unda, Miguel, Beardo, Pastora, Rodríguez-Molina, Jesús, Chantada, Venancio, Palou, Joan, Muntañola, Pedro, Alonso Dorrego, José M, Pérez-Garcia, Franciso J, Silva, Juan M, Chesa, Nicolás, Montesinos, Manuel, Ojea, Antonio, Madero, Rosario, Martínez-Piñeiro, José A
• Format: Journal Article
• Language: English
• Published: Switzerland Elsevier B.V 01-08-2015
• Subjects: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Bacillus Calmette-Guérin; BCG Vaccine - administration & dosage; BCG Vaccine - adverse effects; Bladder cancer; Carcinoma - drug therapy; Carcinoma - mortality; Carcinoma - pathology; Chi-Square Distribution; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Maintenance Chemotherapy; Maintenance therapy; Male; Middle Aged; Multivariate Analysis; Risk Factors; Spain; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - pathology; Urology; Urothelium - drug effects; Urothelium - pathology; Spain; Bacillus Calmette-Guérin; Maintenance therapy; Bladder cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2015.02.040

Abstract 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 χ2 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