Effects of piroxicam on prostaglandin E₂ levels in rectal mucosa of adenomatous polyp patients: A randomized phase IIb trial¹

Prostaglandin E₂ (PGE₂) has served as a surrogate end point biomarker in colorectal tumor progression. Colonic mucosa PGE₂ levels of patients with colorectal adenomas or carcinomas have been shown to be higher than in control subjects. Our dose-finding study on piroxicam, a nonsteroidal anti-inflammatory drug with chemopreventive effects in preclinical colon carcinoma models, suggested that 7.5 mg/day was well tolerated and associated with significant depression of rectal mucosa PGE₂ concentrations in comparison with baseline values. We therefore conducted a randomized Phase IIb cancer prevention clinical trial to investigate the chemopreventive properties of piroxicam in patients with a history of resected colorectal adenomatous polyps. After a 2-month run-in period, 47 participants were randomized to piroxicam at a dose of 7.5 mg/day, and 49 were randomized to a placebo. Rectal biopsy specimens were taken at the initial visit, at 2 months later during the run-in period, and at 6, 12, and 24 months after the start of the interventions. Mean PGE₂ concentrations in the rectal mucosa of the piroxicam-treated patients differed significantly between visits (P < 0.001), and the values at the 6-month visit (P < 0.001) and 12-month visit (P = 0.005) differed significantly from the average baseline value. Unfortunately, we observed an incidence of adverse gastrointestinal side effects in patients treated with 7.5 mg/day of piroxicam similar to that seen for arthritis patients treated with 20 mg/day. Consequently, the gastrointestinal toxicitles appear to override the potential benefit that piroxicam may offer as a long-term colon cancer chemopreventive agent.