Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial

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.

Figure 1. APC trial CONSORT-E flowchart

Reasons for withdrawal from the study prior to efficacy endpoint determination were classified as follows: 1) Violation of study entry criteria, e.g., unable to confirm the presence of an adenoma on baseline colonoscopy; 2) Withdrew following development of an adverse event or other medical reason; 3) Withdrew consent for study participation, including all study withdrawal for non-medical reasons, failed to complete a post-randomization colonoscopy for non-medical reasons, or other protocol non-compliance; 4) Lost to follow-up, i.e., investigators were unable to contact patient following randomization despite repeated attempts. Study sites reported the first and last days of medication use for each participant. Compliance with study medication use was calculated as the duration of study medication use in days, divided by 1095 days.

Figure 2. Adenomas detected during study observation period

The top six figures represent colonoscopy results for individual timepoints. The year 1 and year 3 results include only patients who did not have an adenoma detected on previous colonoscopies. The year 5 result depicts the results for all individuals receiving a year 5 colonoscopy, irrespective of whether or not one or more adenomas had been detected at previous colonoscopies. The bottom six figures report the cumulative results over 5 year observation period. The year 1 and year 3 colonoscopy results correspond to the time of planned study drug use. By the year 5 colonoscopy, approximately 94% of subjects had been off study drug for at least one year.