Celecoxib demonstrates benefit in preventing premalignant colorectal adenomas, but cardiovascular risk raises concerns

Although use of the cyclooxygenase (COX)-2 inhibitor celecoxib has demonstrated benefit in preventing premalignant colorectal adenomas, generally the agent should not be recommended for this purpose due to the risk of cardiovascular events, according to 1 recent trial. In a second study of celecoxib use and adenomas, treatment with celecoxib 400 mg/d markedly lowered the incidence of colorectal adenomas within 2 years after the removal of polyps.

The first trial, the Adenoma Prevention with Celecoxib (APC) randomized, placebo-controlled trial, focused on the potential for celecoxib to lower the incidence of colorectal adenomas found via endoscopy. Efficacy of the drug in prevention of colorectal cancer was not measured. From 1999 to 2002, participants were recruited (age range, 31 to 88 years) from 91 clinical sites across the United States, Canada, and the United Kingdom. All patients had adenomas removed prior to the study's start and had a high likelihood of recurrent adenomas based on number or size of previous adenomas.

To test celecoxib's safety and anti-tumor effectiveness, 2,035 patients were randomly assigned to placebo (679 patients) or celecoxib 200 mg BID (685 patients) or 400 mg BID (671 patients). The stratification was determined according to whether patients used low-dose aspirin (≤325 mg every other day or ≤162.5 mg every day). After randomization, colonoscopies were conducted at Years 1 and 3 of follow-up. At 2-month intervals, patients were asked to report use of concomitant medication and adverse effects.

A total of 89.5% (n=1,822) of the randomized patients received follow-up colonoscopies at Year 1; 75.7% (n=1,541) had the procedure at Year 3. Due to a higher occurrence of cardiovascular events in groups taking celecoxib, drug use was discontinued in 2004.

For those taking placebo, 354 patients developed ≥1 adenoma; of those taking celecoxib 200 mg BID, 252 went on to develop ≥1 adenoma; 213 patients taking celecoxib 400 mg BID also developed ≥1 adenoma. By Year 3, estimated cumulative incidence of locating ≥1 adenoma was 60.7% for those receiving placebo; 43.2% for those receiving 200 mg BID (RR=0.67; 95% CI, 0.59– 0.77; P<.001); and 37.5% of patients taking 400 mg BID (RR=0.55; 95% CI, 0.48–0.64; P<.001). Significant adverse events affected 23% of participants in the 400-mg BID group (RR=1.2; 95% CI, 1.0–1.5; P=.06); 20.4% of those in the 200-mg BID group (RR=1.1; 95% CI, 0.9–1.3; P=.5); and 18.8% of the placebo group. An increased risk of cardiovascular occurrences was linked to celecoxib compared with placebo (RR for celecoxib 200 mg BID=2.6; 95% CI, 1.1– 6.1; RR for celecoxib 400 mg BID=3.4; 95% CI, 1.5–7.9).

The authors noted that they did not directly evaluate the effect of celecoxib on colorectal cancer. They stated that further research may have benefit to those at highest risk for colorectal cancer, as celecoxib was proven efficacious in the prevention of more advanced lesions.

The trial was sponsored by Pfizer and the National Cancer Institute.

The second trial, Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP), was a randomized, placebo-controlled, double-blind study of celecoxib 400 mg/d. A total of 1,561 patients across 107 sites in 32 countries who had had adenomas removed before enrollment were randomly assigned to celecoxib (n=933) or placebo (n=628). Participants were stratified based on use/nonuse of aspirin.

Detection of adenomas at Years 1 or 3 via endoscopy was the primary end point.