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

Brigham and Women's Hospital, Boston, MA 02115, USA.
Cancer Prevention Research (Impact Factor: 5.27). 04/2009; 2(4):310-21. DOI: 10.1158/1940-6207.CAPR-08-0206
Source: PubMed

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.

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Available from: Donya Bagheri, Jul 21, 2015
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    • "The majority of clinical trials examining the anti-proliferative effects of anti-inflammatory agents have been conducted in bowel and lung cancer. Cox2 inhibitors prevent the progression of bowel polyps [74] and they have demonstrated a chemoprotective role in patients at high risk of developing lung cancer [75]. However, large studies have not found improvement in survival or oncological outcomes when celecoxib is added to palliative lung cancer-treatment regimens [76] [77]. "
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    • "inflammatory drugs (for example, aspirin) or selective COX-2 inhibitors (COXIBs, for example, celecoxib) decreases the risk of developing CRC (Wang and Dubois, 2006). Celecoxib (2 Â 400 mg/day) was shown to significantly reduce the number of colorectal and duodenal polyps in familial adenomatous polyposis patients (Steinbach et al., 2000), and is now approved as adjunctive therapy to decrease the risk of CRC development in familial adenomatous polyposis patients (Bertagnolli et al., 2009). Long-term use of high doses of COXIBs as chemopreventive strategy in sporadic CRC, however, is not recommended because of the elevated risk of potentially severe cardiovascular complications (Cuzick et al., 2009). "
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    • "In the trials with celecoxib, a 2.5-to 3-fold increased relative risk for cardiovascular thromboembolic events was observed with a 400 mg twice-daily dosing celecoxib schedule compared with placebo, whereas a once-daily dosing schedule or 200 mg twice-daily dosing demonstrated much less risk rate compared with placebo (Solomon et al., 2006), indicating a trend for a dose-related increase in cardiovascular events. However, the detailed analysis of the APC trial found that a history of atherosclerotic heart disease was the only specific risk factor associated significantly with celecoxib to adverse cardiovascular events (Bertagnolli et al., 2009). Furthermore, a recent pooled analysis of adjudicated data from 6 placebo-controlled trials further demonstrated that the celecoxib-related cardiovascular risk is positively correlated with the drug dose and the baseline cardiovascular risk (pretreatment cardiovascular status) in patients (Solomon et al., 2008). "
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