An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis
Patrick M Lynch, Carol A Burke, Robin Phillips, Jeffrey S Morris, Rebecca Slack, Xuemei Wang, Jun Liu, Sherri Patterson, Frank A Sinicrope, Miguel A Rodriguez-Bigas, Elizabeth Half, Steffen Bulow, Andrew Latchford, Sue Clark, William A Ross, Bonnie Malone, Hennie Hasson, Ellen Richmond, Ernest Hawk, Patrick M Lynch, Carol A Burke, Robin Phillips, Jeffrey S Morris, Rebecca Slack, Xuemei Wang, Jun Liu, Sherri Patterson, Frank A Sinicrope, Miguel A Rodriguez-Bigas, Elizabeth Half, Steffen Bulow, Andrew Latchford, Sue Clark, William A Ross, Bonnie Malone, Hennie Hasson, Ellen Richmond, Ernest Hawk
Abstract
Background and aim: Although 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.
Methods: The 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.
Results: 112 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).
Conclusions: CXB 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 number: ClinicalTrials.gov number N01-CN95040.
Trial registration: ClinicalTrials.gov NCT00033371.
Keywords: ADENOMA; CANCER; CHEMOPREVENTION; FAMILIAL ADENOMATOUS POLYPOSIS; POLYP.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Source: PubMed