Randomized Prospective Phase III Trial of Difluoromethylornithine vs Placebo in Preventing Recurrence of Completely Resected Low Risk Superficial Bladder Cancer

Purpose: Ornithine decarboxylase catalyzes the rate limiting step in polyamine synthesis and its activity can be inhibited by difluoromethylornithine, which has been shown in preclinical studies, to prevent bladder cancer. Materials and Methods: To assess the ability of difluoromethylornithine to prevent recurrence of low risk superficial bladder cancer, 454 patients with newly diagnosed (283) or occasionally recurrent (171), stage Ta (425) or T1 (29), grade 1 (263) or grade 2 (191), completely resected urothelial cancer were randomized to receive 1 gm difluoromethylornithine daily or placebo for 1 year. Patients were followed with cystoscopy every 3 months for 2 years and then semiannually for 2 years or until first recurrence. Index and recurrent tumors underwent central pathology review. Results: No serious drug related toxicities were seen in either arm. Two patients died of bladder cancer at 2 and 4 years after randomization, both in the difluoromethylornithine arm. At 42 months followup, 103 patients in the difluoromethylornithine arm (46%) and 97 in the placebo arm (43%) (p = 0.30) experienced at least 1 tumor recurrence. Over 73% of recurrences occurred within 1 year in each arm. Each arm had similar responses for each stratification factor. During the 42 months of followup, 10 (4.4%) difluoromethylornithine and 9 (3.9%) placebo treated patients had progression to TIS or grade 3 disease, and 2 (0.9%) in the difluoromethylornithine arm and none in the placebo arm developed stage T2+ cancers. Conclusions: A year of difluoromethylornithine did not prevent recurrence of completely resected low risk superficial bladder cancer, when started shortly after surgery.