March 2, 2012, (Paris, France) — Full-dose Bacillus Calmette-Guérin (BCG) for 3 years is the best possible treatment for patients with intermediate to high-risk nonmuscle-invasive bladder cancer (NMIBC), researchers reported here at European Association of Urology (EAU) 27th Annual Congress.
Maurizio Brausi, MD, a bladder cancer specialist at the Department of Urology, AUSL Modena, B. Ramazzini Hospital in Italy, presented the results of a study that was conducted with the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Cancer study group. It came in third in the EAU Best Abstracts in Oncology 2012.
Dr. Brausi explained that the study was conceived in 1996, when the EORTC had a mound of conflicting data concerning the duration of treatment with BCG. "Also, there was no consensus on toxicity," he explained.
The organization needed to resolve the controversy and determine the optimal treatment dose and duration for NMIBC.
The aim of our study was to reduce adverse effects by reducing the dosage of BCG. Secondarily, we wanted to compare 1-year and 3-year maintenance treatment.
BCG continues to be the most effective treatment for intermediate and high-risk bladder cancer. "Our previous study clearly showed that BCG is better than chemotherapy in intermediate and high-risk patients," he explained (Eur Urol. 2010:57;766-773).
In the current study, Dr. Brausi and colleagues randomized 1316 patients with NMIBC, from 13 countries from 1997 to 2005, to 1 of 4 groups: full-dose (81 mg) BCG for 1 year; one-third dose (27 mg) BCG for 1 year; one-third dose BCG for 3 years; and full-dose BCG for 3 years. Median follow-up was 7.1 years.
The primary end point was the duration of the disease-free interval. Diseases rated as potential events for this end point included recurrence, disease progression to stage T2 disease or higher, the development of carcinoma in situ, recurrence outside the bladder, distant metastases, and death from bladder cancer. Secondary end points included local and systemic adverse effects, progression-free survival, and overall survival.
About 60% of patients had intermediate-risk NMIBC; the remainder had high-risk NMIBC.
There was a difference in disease-free duration in the 4 treatment groups. "We only saw a 10% difference in disease-free time between the patients on one-third dose for 1 year and those on full-dose for 3 years."
"One-third dose for 1 year is insufficient for patients with intermediate to high-risk NMIBC. Full-dose BCG for 3 years is the best possible treatment," Dr. Brausi concluded.
In the European Union, current guidelines state that BCG should be given for at least 1 year, " but our results show that 3 years is better than 1 year," he said.
Treatment discontinuation ranged from 7.2% in patients treated with one-third dose for 1 year to 9.1% for those treated with the full dose for 3 years.
"This isn't too concerning," Dr. Brausi said. "In fact, in our previous study, the rate of patients stopping treatment was 19%. These results could be due to the improvement in administering BCG by centers that followed educational programs for preventing side effects of BCG therapy. If you administer BCG properly, in a hospital outpatient setting, you can reduce your toxicity," he noted.
The most common local adverse effects were bacterial and/or chemical cystitis (56.2%), hematuria (46.0%), and frequency (45.1%). The most common systemic adverse effects were general malaise (15.5%) and fever (8.1%).
There were no significant differences in disease progression, overall survival, or discontinuation because of toxicity in the 4 groups.
Dr. Brausi hopes that clinicians will change their treatment of NMIBC with BCG. "We would like to popularize these findings to encourage change because this is good information with effective results."
Wim Witjes, MD, from and the Department of Urology at the University of Nijmegen, the Netherlands, noted that "normally, when you set up a study, you make a calculation of the required number of patients to show a certain difference. In this case, they required 1288 patients and 828 events to show a 10% difference between the 4 groups. However, they managed to show a difference with fewer patients than anticipated."
Because there were fewer patients and only 50% of events were actually reached, it is my personal opinion that this is an inconclusive study. [There needs to be a] comparison of all the groups, apart from the one-third dose at 1 year, which is clearly significantly inferior."
Dr. Witjes, who is also part of the EAU Central Research Office, is setting up a BCG study comparing reduced-frequency BCG rather than reduced-dosage BCG.
The trial was conducted by the EORTC GU cancer group. This publication was supported by grants 5U10 CA11488-26 through 2U10 CA011488-40 from the National Cancer Institute in Bethesda, Maryland. Dr. Brausi and Dr. Witjes have disclosed no relevant financial relationships.
European Association of Urology (EAU) 27th Annual Congress: Abstract 1050. Presented February 27, 2012.
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