UROLOGICAL ONCOLOGY

doi: 10.1590/S1677-55382010000400024

Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder
Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, Prescott S, Kirkali Z, van de Beek C, Gorlia T, de Reijke TM; EORTC Genito-Urinary Tract Cancer Group
EORTC Headquarters, Brussels, Belgium
Eur. Urol. 2010; 57: 766-773

• Background: Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients.
  Objective: The aim of the study was to compare the long-term efficacy of BCG and epirubicin.
  Design, Setting, and Participants: From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911.
  Intervention: Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36.
  Measurements: End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival.
  Results and Limitations: With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence (p<0.001), distant metastases (p=0.046), overall survival (p=0.023), and disease-specific survival (p=0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients.
  Conclusions: In patients with intermediate- and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG.

• Editorial Comment
  The efficacy of BCG against recurrences in high-risk patients has long been recognized. Previous papers and meta-analyses have also shown that BCG favorably acts against progression of disease. Even further data supported the notion that this was also true for intermediate-risk patients. However, many authors were not satisfied with the database for these conclusions and in recent times, others have contributed with opposite results.
  This EORTC paper now, with its high number of patients (975 randomized and 837 eligible) and its inherent quality of statistical analysis puts an end to many of these questions (and poses several new ones). In this randomized study of BCG against epirubicin (EPI) the results clearly show an advantage of BCG in terms of time to first recurrence, and even more important, in terms of distant metastases and survival (!). Moreover, the favorable results were even more pronounced in the intermediate-risk group. The question still remaining is why time to progression was not different between the treatment groups. According to the authors, BCG appeared to reduce the risk of progression (hazard ratio 0.56) but there were too few progressions (n=25) to make meaningful comparisons.
  Certainly, this paper will have a significant impact on the guidelines on non-muscle invasive bladder cancer and on the routine clinical treatment of this disease.

Dr. Andreas Bohle
Professor of Urology
HELIOS Agnes Karll Hospital
Bad Schwartau, Germany
E-mail: boehle@urologie-bad-schwartau.de