Secondary chemoprevention of Barrett's esophagus with celecoxib: results of a randomized trial.
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.
Heath
Elisabeth I
EI
Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA. heathe@karmanos.org
Canto
Marcia Irene
MI
Piantadosi
Steven
S
Montgomery
Elizabeth
E
Weinstein
Wilfred M
WM
Herman
James G
JG
Dannenberg
Andrew J
AJ
Yang
Vincent W
VW
Shar
Albert O
AO
Hawk
Ernest
E
Forastiere
Arlene A
AA
D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015820:Cadherins / Q000235:genetics; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011230:Precancerous Conditions / Q000517:prevention & control*; D011720:Pyrazoles / Q000627:therapeutic use* / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use* / Q000633:toxicity
D015820:Cadherins; D016861:Cyclooxygenase Inhibitors; D010919:Placebos; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib