Boston, MA — The much-anticipated primary results of the Adenoma Prevention with Celecoxib (APC) and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials are in [1,2]. Reporting in the August 31, 2006 issue of the New England Journal of Medicine, researchers have found that celecoxib (Celebrex, Pfizer) shows promise in reducing colorectal adenomas. But they also warn that the cardiovascular risks of selective COX-2 inhibition remain high and the danger should be closely monitored.

"These two trials provide strong evidence that among patients with colonic adenomas, the use of celecoxib for up to three years reduces the risk of metachronous adenoma," Drs Bruce Psaty and John Potter (University of Washington, Seattle) note in an editorial in the same issue of the journal [3]. "These placebo-controlled trials were too small to evaluate the role of celecoxib in preventing colorectal cancer. Nevertheless, in these same studies, significant cardiovascular risks were demonstrated. In patients with adenomas who undergo repeated colonoscopies, the increase in cardiovascular events caused by celecoxib outweighs what may be an optimistic projection of its potential benefit in decreasing colorectal-cancer events."

The editorialists say that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population.

The APC trial included 2035 patients in a study of 200- or 400-mg twice-daily doses of celecoxib. The PreSAP trial included more than 1560 patients evaluating a single 400-mg daily dose. Psaty and Potter say the placebo-controlled trials were well designed and well conducted and had many features in common, including sample size, age of the patients, exclusion criteria, and duration of the run-in phase to assess adherence.

Efficacy outcomes for the two trials were similar. Treatment with celecoxib as compared with placebo in both studies was associated with a reduction in the risk of metachronous adenomas and advanced adenomas. The relative risk of an advanced adenoma among patients who took 200 mg of celecoxib twice daily in the APC trial (0.43; 95% CI 0.31-0.61) was similar to that among patients who took 400 mg of celecoxib once daily in the PreSAP trial (0.49; 95% CI 0.33-0.73).

Although the number of colorectal cancers was small in both studies, the authors write, the incidence was slightly higher among those receiving celecoxib than among those receiving placebo. Psaty and Potter point out that a meta-analysis across the two trials showed a relative risk of 1.5 (95% CI 0.5-4.7).

They say that the trials provide convincing evidence that celecoxib prevents metachronous adenomas in patients with a history of adenomas. "These findings are consistent with the results of placebo-controlled trials of aspirin for the prevention of adenomas as well as with a large body of observational evidence suggesting that the use of one of a variety of nonsteroidal anti-inflammatory drugs may reduce the incidence of colorectal cancer by about 50%," the editorialists write.

In both trials, celecoxib compared with placebo was associated with an increased risk of cardiovascular events. The risk associated with high-dose celecoxib in the APC trial was pronounced (relative risk 3.4, 95% CI 1.5-7.9). For the dose of 200 mg twice daily in this trial, the relative risk of 2.6 (95% CI 1.1-6.1) was higher than the relative risk of 1.3 (95% CI 0.6-2.6) for 400 mg of celecoxib once daily in the PreSAP trial (p for the difference between relative risks=0.2).

"Combined data from the APC and PreSAP trials, which have been included in a recent meta-analysis, suggest an increase by a factor of about two in cardiovascular risk associated with celecoxib as compared with placebo," write Psaty and Potter.

Reporting for the APC study investigators, lead author Dr Monica Bertagnolli (Brigham and Women's Hospital, Boston, MA) concurs that because of the cardiovascular risk associated with COX-2 inhibitors, celecoxib cannot be routinely recommended for the prevention of colorectal adenomas.

However, writing on behalf of the PreSAP trial investigators, lead author Dr Nadir Arber (Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Israel) suggests that with monitoring, celecoxib may still have a role to play in reducing the risk of colorectal adenomas.

He writes, "Celecoxib may be effective against existing adenomas perhaps missed on an index colonoscopy and against the formation of new adenomas, as evidenced by reductions in the newly diagnosed adenomas at year 1 and year 3. This effect is consistent with experimental evidence in animals and humans and with epidemiologic data."