An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis

• Published in: Gut Vol. 65; no. 2; pp. 286 - 295
• Main Authors: Lynch, Patrick M, Burke, Carol A, Phillips, Robin, Morris, Jeffrey S, Slack, Rebecca, Wang, Xuemei, Liu, Jun, Patterson, Sherri, Sinicrope, Frank A, Rodriguez-Bigas, Miguel A, Half, Elizabeth, Bulow, Steffen, Latchford, Andrew, Clark, Sue, Ross, William A, Malone, Bonnie, Hasson, Hennie, Richmond, Ellen, Hawk, Ernest
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.02.2016
• Subjects: Adenomatous Polyps - drug therapy; Adenomatous Polyps - genetics; Adenomatous Polyps - pathology; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinogens; Celecoxib - administration & dosage; Celecoxib - adverse effects; Celecoxib - therapeutic use; Colorectal cancer; Cyclooxygenase 2 Inhibitors - administration & dosage; Cyclooxygenase 2 Inhibitors - adverse effects; Drug dosages; Eflornithine - administration & dosage; Endoscopy; Enzymes; Female; Hearing loss; Humans; Laboratory animals; Male; Middle Aged; Mutation; Patients; Polyamines; Rodents; Sigmoidoscopy; Studies; Tumor Burden; Tumors; Young Adult; ADENOMA; POLYP; CHEMOPREVENTION; FAMILIAL ADENOMATOUS POLYPOSIS; CANCER
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2014-307235

Background and aimAlthough Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any.MethodsThe primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria.Results112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02).ConclusionsCXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves.Trial registration numberClinicalTrials.gov number N01-CN95040.