COX-2 Inhibitor Used to Reduce Number of Polyps in Patients With Familial Adenomatous Polyposis

HOUSTON—Hereditary cancer syndromes sometimes provide researchers with an accelerated look at cancer pathogenesis and can suggest novel approaches to cancer prevention, Patrick M. Lynch, JD, MD, told an investigators’ workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology. As an example, Dr. Lynch cited the use of celecoxib (Celebrex), recently approved by the Food and Drug Administration (FDA) as adjunctive therapy to reduce the number of polyps developed by patients with familial adenomatous polyposis (FAP).

Reducing the massive polyposis of patients with FAP may help postpone colectomy and reduce the risk of developing colorectal cancer, noted Dr. Lynch, who is associate professor of medicine in the Department of Medical Oncology and Digestive Diseases at M. D. Anderson in Houston.

Dr. Lynch reported that studies with celecoxib built on a previous randomized, placebo-controlled trial that had shown “a dramatic reduction in adenoma burden” after 4 months of treatment with sulindac (Clinoril). Previous epidemiologic studies of nonsteroidal anti-inflammatory drugs (NSAIDs) and cancer had also shown a decrease in the risk of colorectal cancer in patients on chronic NSAID therapy.

Attractive Candidates

Cyclooxygenase-2 (COX-2) inhibitors are attractive candidates for chemoprevention because they selectively block the inducible COX-2-mediated arachidonic acid pathway that contributes to pain and inflammation and also to oncogenesis, while leaving the COX-1 pathway relatively intact for maintenance of gastroprotection and platelet function. “COX-2 is expressed in all stages of human colon carcinogenesis,” Dr. Lynch said.

The double-blind, placebo-controlled trial that led to approval of celecoxib for use in FAP included 81 patients randomized to placebo or to celecoxib 100 mg BID or 400 mg BID for 6 months. (The FDA-approved dose of celecoxib for anti-inflammatory use is 200 mg BID.) The researchers used photos and videotapes of GI tract segments marked by anatomic landmarks or by India ink tattoos to assess the effects of therapy.

Adenoma burden (defined as the sum of polyp diameters) was reduced 14.6% by treatment with 100 mg of celecoxib BID (P = NS) and 30.7% by treatment with 400 mg BID (P = .001) (see Figure 1). In one patient the reduction in disease burden was nearly 50% (see Figure 2). Dr. Lynch said that intermediate endpoints such as the number of aberrant crypts are also being evaluated.

Long-Term Benefits Unknown

“Celecoxib is now FDA-approved as adjunctive therapy in FAP to reduce the number of adenomatous colorectal polyps. Long-term clinical benefit in reduction of the number of polyps is unknown, and it is important to remember that celecoxib treatment is not a substitute for indicated surgery in these patients,” Dr. Lynch said. “Usual care and regular monitoring of FAP patients should not be altered. We also do not yet know if the benefits will persist after celecoxib is discontinued.”

Celecoxib could also prevent disease recurrence in the rectum after colectomy, and Dr. Lynch said that there is “a strong suggestion” that some patients also had suppression of adenomas in the duodenum following celecoxib treatment. Use of celecoxib chemoprevention in carriers of the FAP gene prior to the onset of disease will also be studied, as will long-term efficacy. A large multicenter trial of celecoxib chemoprevention in individuals who have had resected sporadic adenomas is expected.