Celecoxib for the Prevention of Sporadic Colorectal Adenomas
Monica M. Bertagnolli, M.D., Craig J. Eagle, M.D., Ann G. Zauber, Ph.D., Mark Redston, M.D., Scott D. Solomon, M.D., KyungMann Kim, Ph.D., Jie Tang, M.S., Rebecca B. Rosenstein, Ph.D., Janet Wittes, Ph.D., Donald Corle, M.S., Timothy M. Hess, M.S., G. Mabel Woloj, Ph.D., Frédéric Boisserie, William F. Anderson, M.D., M.P.H., Jaye L. Viner, M.D., M.P.H., Donya Bagheri, M.S., D.A.B.T., John Burn, M.D., Daniel C. Chung, M.D., Thomas Dewar, M.D., T. Raymond Foley, M.D., Neville Hoffman, M.D., Finlay Macrae, M.D., Ronald E. Pruitt, M.D., John R. Saltzman, M.D., Bruce Salzberg, M.D., Thomas Sylwestrowicz, M.D., Gary B. Gordon, M.D., Ph.D., Ernest T. Hawk, M.D., M.P.H., for the APC Study Investigators
Background Studies showing that drugs that inhibit cyclooxygenase-2(COX-2) reduce the number of colorectal adenomas in animalsand patients with familial adenomatous polyposis suggest thatCOX-2 inhibitors may also prevent sporadic colorectal neoplasia.
Methods We randomly assigned patients who had adenomas removedbefore study entry to receive placebo (679 patients) or 200mg (685 patients) or 400 mg (671 patients) of celecoxib twicedaily. Randomization was stratified for the use of low-doseaspirin. Follow-up colonoscopies were performed at one and threeyears after randomization. The occurrence of newly detectedcolorectal adenomas was compared among the groups with the life-tableextension of the Mantel–Haenszel test.
Results Follow-up colonoscopies were completed at year 1 in89.5 percent of randomized patients, and at year 3 in 75.7 percent.The estimated cumulative incidence of the detection of one ormore adenomas by year 3 was 60.7 percent for patients receivingplacebo, as compared with 43.2 percent for those receiving 200mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidenceinterval, 0.59 to 0.77; P<0.001) and 37.5 percent for thosereceiving 400 mg of celecoxib twice a day (risk ratio, 0.55;95 percent confidence interval, 0.48 to 0.64; P<0.001). Seriousadverse events occurred in 18.8 percent of patients in the placebogroup, as compared with 20.4 percent of those in the low-dosecelecoxib group (risk ratio, 1.1; 95 percent confidence interval,0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dosegroup (risk ratio, 1.2; 95 percent confidence interval, 1.0to 1.5; P=0.06). As compared with placebo, celecoxib was associatedwith an increased risk of cardiovascular events (risk ratiofor the low dose, 2.6; 95 percent confidence interval, 1.1 to6.1; and risk ratio for the high dose, 3.4; 95 percent confidenceinterval, 1.5 to 7.9).
Conclusions These findings indicate that celecoxib is an effectiveagent for the prevention of colorectal adenomas but, becauseof potential cardiovascular events, cannot be routinely recommendedfor this indication. (ClinicalTrials.gov number, NCT00005094
[ClinicalTrials.gov]
.)
Source Information
From Brigham and Women's Hospital, Boston (M.M.B., M.R., S.D.S., J.R.S.); Pfizer, New York (C.J.E., J.T., R.B.R., G.M.W., F.B.); Memorial Sloan-Kettering Cancer Center, New York (A.G.Z.); the University of Wisconsin, Madison (K.K., T.M.H.); the Statistics Collaborative, Washington, D.C. (J.W.), the National Cancer Institute, Bethesda, Md. (D.C., W.F.A., J.L.V., E.T.H.); CCS Associates, Mountain View, Calif. (D.B.), the University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom (J.B.); Massachusetts General Hospital, Boston (D.C.C.); Harris Methodist Hospital Fort Worth, Fort Worth, Tex. (T.D.); Regional Gastroenterology Associates of Lancaster, Lancaster, Pa. (T.R.F.), Sir Charles Gairdner Hospital, Perth, Australia (N.H.); the Royal Melbourne Hospital, Melbourne, Australia (F.M.), Nashville Medical Research Institute, Nashville (R.E.P.); Atlanta Gastroenterology Associates, Atlanta (B.S.); St. Paul's Hospital, University of Saskatchewan, Saskatoon, Canada (T.S.); and G.D. Searle, Skokie, Ill. (G.B.G.).
Address reprint requests to Dr. Bertagnolli at the Division of Surgical Oncology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at mbertagnolli{at}partners.org.
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