© The Author 2007. Published by Oxford University Press.
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Secondary Chemoprevention of Barrett's Esophagus With Celecoxib: Results of a Randomized Trial
On behalf of the Chemoprevention for Barrett's Esophagus Trial Research Group
Affiliations of authors: Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI (EIH); Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (MIC, EM); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD (SP, JGH, AAF); Department of Gastroenterology, UCLA Center for the Health Sciences, Los Angeles, CA (WMM); Department of Gastroenterology, Weill Medical College of Cornell University, New York, NY (AJD); Emory University School of Medicine, Atlanta, GA (VWY); The Robert Wood Johnson Foundation, Princeton, NJ (AOS); Division of Cancer Prevention, National Cancer Institute, Rockville, MD (EH)
Correspondence to: Elisabeth I. Heath, MD, CBET Coordinating Center, The Johns Hopkins Center for Clinical Trials, 615 North Wolfe St, Rm 5010, Baltimore, MD 21205 (e-mail: heathe{at}karmanos.org).
Background: Barrett's esophagus is a premalignant condition that is a risk factor for the development of esophageal adenocarcinoma, a disease whose incidence is rapidly increasing. Because aspirin and other nonsteroidal anti-inflammatory drugs, such as celecoxib, may decrease the risk of developing esophageal cancer, we investigated the effect of long-term administration of celecoxib in patients with Barrett's esophagus with dysplasia.
Methods: Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb multicenter randomized placebo-controlled trial of celecoxib in patients with Barrett's esophagus and low- or high-grade dysplasia. Patients were randomly assigned to treatment with 200 mg of celecoxib or placebo, both administered orally twice daily, and then stratified by grade of dysplasia. The primary outcome was the change from baseline to 48 weeks of treatment in the proportion of biopsy samples with dysplasia between the celecoxib and placebo arms. Secondary and tertiary outcomes included evaluation of changes in histology and expression levels of relevant biomarkers. All statistical tests were two-sided.
Results: From April 1, 2000, through June 30, 2003, 222 patients were registered into CBET, and 100 of them with low- or high-grade Barrett's dysplasia were randomly assigned to treatment (49 to celecoxib and 51 to placebo). After 48 weeks of treatment, no difference was observed in the median change in the proportion of biopsy samples with dysplasia or cancer between treatment groups in either the low-grade (median change with celecoxib = –0.09, interquartile range [IQR] = –0.32 to 0.14 and with placebo = –0.07, IQR = –0.26 to 0.12; P = .64) or high-grade (median change with celecoxib = 0.12, IQR = –0.31 to 0.55, and with placebo = 0.02, IQR = –0.24 to 0.28; P = .88) stratum. No statistically significant differences in total surface area of the Barrett's esophagus; in prostaglandin levels; in cyclooxygenase-1/2 mRNA levels; or in methylation of tumor suppressor genes p16, adenomatous polyposis coli, and E-cadherin were found with celecoxib compared with placebo.
Conclusions: Administration of 200 mg of celecoxib twice daily for 48 weeks of treatment does not appear to prevent progression of Barrett's dysplasia to cancer.
| CONTEXT AND CAVEATS Prior knowledge Aspirin and nonsteroidal anti-inflammatory drugs, such as celecoxib, may decrease the risk of developing esophageal cancer. Study design Phase IIb multicenter randomized placebo-controlled trial of celecoxib in patients with Barrett's esophagus and low- or high-grade dysplasia. Contribution Celecoxib (200 mg) taken twice daily for 48 weeks does not appear to prevent progression of Barrett's dysplasia to cancer. Implications At low doses, celecoxib is not a good chemopreventive agent for esophageal cancer. Limitations The 200-mg dose of celecoxib twice daily may have been too low to have an effect. Intra- and interobserver agreement on grading of dyplasia was low, and the natural reversion of dysplasia without intervention was more likely to occur among patients with low- than with high-grade dysplasia.
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Manuscript received December 24, 2005; revised February 20, 2007; accepted March 2, 2007.
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J Natl Cancer Inst 2007 99: 493.
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