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Coxibs and Colon Polyps: Efficacy with Prohibitive Risk!

We still do not have an effective and safe chemopreventive agent for patients with polyps or for those at high risk for colorectal neoplasia.

Epidemiologic data and prospective controlled trials have demonstrated that use of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased incidence of colorectal neoplasia. However, use of nonselective NSAIDs also is associated with increased risk for adverse gastrointestinal events (related to their ulcer-forming tendency). Because cyclooxygenase (COX)-2 specific inhibitors are less likely to cause ulcers than nonselective NSAIDS, they had been touted as ideal "chemopreventive" agents for decreasing risk for colorectal neoplasia. Unfortunately, these agents also are associated with increased risk for adverse cardiovascular events.

In two well-designed multinational randomized controlled trials of celecoxib for recurrent adenoma prevention, one sponsored by a pharmaceutical company and one jointly sponsored by industry and the National Cancer Institute, researchers began recruiting participants before the cardiovascular issues related to COX-2–specific inhibitors were reported. The patients who were enrolled into these nearly identical trials were at high risk for incident colorectal neoplasms (all had undergone prior endoscopic adenomatous polyp removal). In one trial (PreSAP), patients received once-daily celecoxib (400 mg) or placebo; in the other trial (APC), patients received one of two doses of celecoxib (200 or 400 mg twice daily) or twice-daily placebo. Results of both trials (assessed by colonoscopies at 3 years) showed similar significant reductions in the incidence of colorectal adenomas among patients in all active-treatment arms compared with patients in placebo arms (relative risk, 0.64; P<0.001 for once-daily 400-mg celecoxib; RR, 0.67; P<0.001 for twice-daily 200-mg celecoxib; RR, 0.55; P<0.001 for twice-daily 400-mg celecoxib). However, the incidence of adverse cardiovascular events increased as well and correlated with the dose and frequency of celecoxib administration.

Comment: The epidemiologic and clinical trial evidence for colorectal neoplasia risk reduction with the use of any agent that inhibits cyclooxygenase production is remarkably consistent (approximately 50% relative risk reduction), but unfortunately, this benefit is countered by either increased risk for ulceration and ulcer complications (with nonselective NSAIDs) or adverse cardiovascular events (with COX-2 inhibitors). The editorial accompanying these papers appropriately notes that when the data are taken as a whole, low-dose aspirin probably outperforms other COX-inhibiting compounds if the main goal is decreasing the incidence of subsequent adenomas. We must remember that these data cannot be used to justify routine recommendation of aspirin to patients with colorectal neoplasia, nor should they alter current surveillance intervals in patients who already receive any COX-inhibiting drug. All in all, we still do not have an effective and safe chemopreventive agent to employ in patients with polyps or in those at high risk for colorectal neoplasia.

— M. Brian Fennerty, MD

Published in Journal Watch Gastroenterology August 30, 2006

Citation(s):

Arber N et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006 Aug 31; 355:885-95.

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• Medline abstract (Free)

Bertagnolli MM et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006 Aug 31; 355:873-84.

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• Medline abstract (Free)

Psaty BM and Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas. N Engl J Med 2006 Aug 31; 355:950-2.

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• Medline abstract (Free)