LONG TERM RESULTS OF A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL OF INTERFERON ALPHA-2B AND LOW DOSE BCG IN PATIENTS WITH HIGH RISK NON-MUSCLE-INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVES: When administered at full-dose in a maintenance schedule of 36 months, Bacillus Calmette- Guerin (BCG) immunotherapy reduces recurrence and progression of high risk non-muscle-invasive bladder cancer (NMIBC). However, many patients do not complete a full course of therapy due to its toxicity or non-compliance. We report long-term results of a trial to evaluate the efficacy and toxicity of reduced dose Connaught-strain BCG with lowdose interferon alpha-2b (IFNa-2b) compared to full-dose BCG in a short schedule of weekly instillations. METHODS: This was a prospective, randomized, double blinded, controlled, multi-institution clinical trial in which 140 patients with Stage Ta or T1 bladder cancer and/or CIS were assigned to one of three treatment groups following transurethral resection. Patients received 6-weekly intravesical instillations of full-dose BCG (81mg) or low-dose BCG (27mg) or low-dose BCG plus IFNa-2b (10MU) followed by 3-weekly booster instillations six weeks after the 6th instillation. They underwent close surveillance with regular cystoscopy, urine cytology and other tests such as intravenous urography. End points were time to local recurrence, recurrence-free probability and mortality. RESULTS: Overall, the treatment was well tolerated. Both local and systemic symptoms were significantly decreased in the low-dose BCG plus IFNa-2b arm compared to full-dose BCG during the first 6 instillations but not for the booster instillations. The evaluable study cohort (n=108) was followed for up to 207 months, with a total of 35 recurrences and 56 deaths. Five years after randomization, the probability of being recurrence-free were 56.4% and 78.2% in the full-dose BCG and low-dose combination therapy arms respectively (p=0.037). The mean time to recurrence was 118 months for full-dose BCG compared to 145 months for the combination therapy. CONCLUSIONS: Reducing the dose of BCG decreased its toxicity during the induction course while efficacy was increased by combining low-dose BCG with IFNa-2b. A short course of “6+3” combined therapy using reduced dose BCG may be sufficient to achieve similar results to longer term, full-dose BCG maintenance therapy. This finding is of significance as it provides an alternative therapy for high risk NMIBC patients at the current time when BCG stocks are limited globally.