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Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Authors' Affiliations: ¹ Brigham and Women's Hospital, and ² Massachusetts General Hospital, Boston, Massachusetts, ³ Pfizer, Inc., ⁴ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁵ University of Wisconsin, Madison, Wisconsin; ⁶ CCS Associates, Inc., Mountain View, California; ⁷ University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; ⁸ Harris Methodist Hospital, Ft. Worth, Fort Worth, Texas; ⁹ Regional Gastroenterology Associates of Lancaster, Lancaster, Pennsylvania; ¹⁰ Sir Charles Gairdner Hospital, Perth, Western Australia, Australia; ¹¹ The Royal Melbourne Hospital, Melbourne, Victoria, Australia; ¹² Nashville Medical Research Institute, Nashville, Tennessee; ¹³ Atlanta Gastroenterology Associates, Atlanta, Georgia; ¹⁴ St. Paul's Hospital, University of Saskatchewon, Saskatoon, Saskatchewon; Canada, ¹⁵ National Cancer Institute, Bethesda, Maryland; and ¹⁶ M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Monica M. Bertagnolli, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8910; Fax: 617-582-6177; E-mail: mbertagnolli{at}partners.org.

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

Commentary

New, Long-term Insights from the Adenoma Prevention with Celecoxib Trial on a Promising but Troubled Class of Drugs

Raymond N. DuBois
Cancer Prevention Research 2009 2: 285-287. [Full Text] [PDF]

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