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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)286-295
Number of pages10
JournalGut
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2016

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Celecoxib
Eflornithine
Adenomatous Polyposis Coli
Adenoma
Polyps

ASJC Scopus subject areas

  • Gastroenterology

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

In: Gut, Vol. 65, No. 2, 01.02.2016, p. 286-295.

Research output: Contribution to journalArticle

Lynch, PM, Burke, CA, Phillips, R, Morris, JS, Slack, R, Wang, X, Liu, J, Patterson, S, Sinicrope, FA, Rodriguez-Bigas, MA, Half, E, Bulow, S, Latchford, A, Clark, S, Ross, WA, Malone, B, Hasson, H, Richmond, E & Hawk, E 2016, 'An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis', Gut, vol. 65, no. 2, pp. 286-295. https://doi.org/10.1136/gutjnl-2014-307235
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. / An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. In: Gut. 2016 ; Vol. 65, No. 2. pp. 286-295.
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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.",
author = "Lynch, {Patrick M.} and Burke, {Carol A.} and Robin Phillips and Morris, {Jeffrey S.} and Rebecca Slack and Xuemei Wang and Jun Liu and Sherri Patterson and Sinicrope, {Frank A} and Rodriguez-Bigas, {Miguel A.} and Elizabeth Half and Steffen Bulow and Andrew Latchford and Sue Clark and Ross, {William A.} and Bonnie Malone and Hennie Hasson and Ellen Richmond and Ernest Hawk",
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T1 - An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis

AU - Lynch, Patrick M.

AU - Burke, Carol A.

AU - Phillips, Robin

AU - Morris, Jeffrey S.

AU - Slack, Rebecca

AU - Wang, Xuemei

AU - Liu, Jun

AU - Patterson, Sherri

AU - Sinicrope, Frank A

AU - Rodriguez-Bigas, Miguel A.

AU - Half, Elizabeth

AU - Bulow, Steffen

AU - Latchford, Andrew

AU - Clark, Sue

AU - Ross, William A.

AU - Malone, Bonnie

AU - Hasson, Hennie

AU - Richmond, Ellen

AU - Hawk, Ernest

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

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