Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial

Monica M. Bertagnolli, Craig J. Eagle, Ann G. Zauber, Mark Redston, Aurora Breazna, Kyung Mann Kim, Jie Tang, Rebecca B. Rosenstein, Asad Umar, Donya Bagheri, Neal T. Collins, John Burn, Daniel C. Chung, Thomas Dewar, T. Raymond Foley, Neville Hoffman, Finlay Macrae, Ronald Pruitt, John R. Saltzman, Bruce Salzberg & 2 others Thomas Sylwestrowicz, Ernest T. Hawk

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    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)310-321
    Number of pages12
    JournalCancer Prevention Research
    Volume2
    Issue number4
    DOIs
    StatePublished - Apr 1 2009

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    Celecoxib
    Adenoma
    Safety
    Placebos
    Heart Diseases

    All Science Journal Classification (ASJC) codes

    • Oncology
    • Cancer Research

    Cite this

    Bertagnolli, M. M., Eagle, C. J., Zauber, A. G., Redston, M., Breazna, A., Kim, K. M., ... Hawk, E. T. (2009). Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. Cancer Prevention Research, 2(4), 310-321. https://doi.org/10.1158/1940-6207.CAPR-08-0206

    Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. / Bertagnolli, Monica M.; Eagle, Craig J.; Zauber, Ann G.; Redston, Mark; Breazna, Aurora; Kim, Kyung Mann; Tang, Jie; Rosenstein, Rebecca B.; Umar, Asad; Bagheri, Donya; Collins, Neal T.; Burn, John; Chung, Daniel C.; Dewar, Thomas; Foley, T. Raymond; Hoffman, Neville; Macrae, Finlay; Pruitt, Ronald; Saltzman, John R.; Salzberg, Bruce; Sylwestrowicz, Thomas; Hawk, Ernest T.

    In: Cancer Prevention Research, Vol. 2, No. 4, 01.04.2009, p. 310-321.

    Research output: Contribution to journalArticle

    Bertagnolli, MM, Eagle, CJ, Zauber, AG, Redston, M, Breazna, A, Kim, KM, Tang, J, Rosenstein, RB, Umar, A, Bagheri, D, Collins, NT, Burn, J, Chung, DC, Dewar, T, Foley, TR, Hoffman, N, Macrae, F, Pruitt, R, Saltzman, JR, Salzberg, B, Sylwestrowicz, T & Hawk, ET 2009, 'Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial', Cancer Prevention Research, vol. 2, no. 4, pp. 310-321. https://doi.org/10.1158/1940-6207.CAPR-08-0206
    Bertagnolli, Monica M. ; Eagle, Craig J. ; Zauber, Ann G. ; Redston, Mark ; Breazna, Aurora ; Kim, Kyung Mann ; Tang, Jie ; Rosenstein, Rebecca B. ; Umar, Asad ; Bagheri, Donya ; Collins, Neal T. ; Burn, John ; Chung, Daniel C. ; Dewar, Thomas ; Foley, T. Raymond ; Hoffman, Neville ; Macrae, Finlay ; Pruitt, Ronald ; Saltzman, John R. ; Salzberg, Bruce ; Sylwestrowicz, Thomas ; Hawk, Ernest T. / Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. In: Cancer Prevention Research. 2009 ; Vol. 2, No. 4. pp. 310-321.
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    AU - Bertagnolli, Monica M.

    AU - Eagle, Craig J.

    AU - Zauber, Ann G.

    AU - Redston, Mark

    AU - Breazna, Aurora

    AU - Kim, Kyung Mann

    AU - Tang, Jie

    AU - Rosenstein, Rebecca B.

    AU - Umar, Asad

    AU - Bagheri, Donya

    AU - Collins, Neal T.

    AU - Burn, John

    AU - Chung, Daniel C.

    AU - Dewar, Thomas

    AU - Foley, T. Raymond

    AU - Hoffman, Neville

    AU - Macrae, Finlay

    AU - Pruitt, Ronald

    AU - Saltzman, John R.

    AU - Salzberg, Bruce

    AU - Sylwestrowicz, Thomas

    AU - Hawk, Ernest T.

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    N2 - 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.

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