COX-2 Inhibitor Reduces Polyp Number in FAP Patients

PHOENIX, Arizona—Drugs that inhibit cyclooxygenase-2 (COX-2) are the hottest thing in arthritis care this year and may have a role to play in combating colorectal cancer, according to a study presented at the American College of Gastroenterology 64th Annual Scientific Meeting.

Gideon Steinbach, MD, PhD, principal investigator of the study, reported that the COX-2 inhibitor celecoxib (Celebrex) significantly reduced the number of precancerous colon polyps in patients with familial adenomatous polyposis (FAP) and caused regression of already formed polyps. Dr. Steinbach is associate internist in the Division of Cancer Prevention, The University of Texas M.D. Anderson Cancer Center.

People who have FAP develop hundreds of polyps, and many of these inevitably pro-gress to colorectal cancer unless surgically removed. Drugs that prevent the development of these polyps in FAP patients are thought to be strong candidates for preventing colorectal cancer in people at risk for less aggressive, more commonplace forms of the disease, Dr. Steinbach said. A successful protective agent could have major public health effects, since colorectal cancer is the third most common cancer in both men and women in most Western countries.

Background on COX-2

Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of the cyclooxy-genase enzyme, the key enzyme in the metabolism of arachidonic acid to prostaglandins and thromboxanes. Recently it was discovered that the cyclooxygenase enzyme includes two isoforms: COX-1 and COX-2.

COX-1 is constitutively expressed in most tissues where it contributes to physiologic functions, Dr. Steinbach said. Its inhibition by NSAIDs has been associated with the common toxicities of these agents, including gastric ulceration and bleeding. COX-2 is an inducible enzyme that is induced in response to cytokines and growth factors at sites of inflammation and in some tumors, including colon adenomas and colon cancer.

Epidemiologic studies have shown that people who have taken NSAIDs for prolonged periods of time have a lower than expected rate of colorectal adenomas and carcinomas.

“Extensive laboratory studies indicate that the tumor preventive effects of NSAIDs are mediated, at least in part, by the inhibition of COX-2,” Dr. Steinbach said in an interview. “Oshima et al have shown that COX-2 gene knockout significantly inhibits polyp formation in a mouse model of FAP. COX-2 inhibition by celecoxib also inhibits tumor formation in a mouse model of FAP.”

Dr. Steinbach noted that the NSAID sulindac has been widely used in patients with FAP, along with surgical removal. Giardello et al (N Engl J Med 328:1313, 1993) reported that sulindac reduced polyp number by 44% and polyp size by 35% of pretreatment values in patients with FAP.

In a recent study, COX-2 expression in tumor epithelial cells was reported to be related to lymph node metastasis, more advanced Dukes staging, and poorer outcome for patients with colorectal cancer (Sheehan et al: JAMA 282:1254, 1999).

Study Design

“The discovery of COX-2 and its expression in tumors raised the possibility that COX-2 could be effectively targeted for the purpose of tumor prevention without the toxicities associated with traditional NSAIDs,” Dr. Steinbach said. “The Celecoxib in FAP Study was based on the research described above. It is the first study of the effect of COX-2 inhibition on a human tumor.”

This randomized, double-blind, placebo-controlled trial enrolled 77 patients with FAP. The colon was intact in 25 patients, while 52 had had a subtotal colectomy. Patients were randomized 1:2:2 to placebo (15 patients), celecoxib 100 mg twice daily (32 patients), or celecoxib 400 mg twice daily (30 patients) for 6 months; 72 patients completed the study.

Outcome measures were the number and size (greater than 2 mm) of colorectal polyps in predefined areas of the colon and rectum at baseline examination and at 6- month follow-up.

This was monitored by videoendoscopy oriented by a small tattoo placed in the rectum of each patient. Videoendoscopy records were scored by blinded reviewers as worse, same, or better than at baseline.

Significant Reduction

Dr. Steinbach reported that use of celecoxib 400 mg twice daily significantly reduced the number of polyps by 28% and that 53% of patients on this celecoxib dose had a reduction of better than 25% in number of polyps.

In contrast, only one patient on placebo had a reduction in number of polyps, and the reduction was only 7%. Blinded physician review of endoscopies confirmed the benefit across the entire colorectum (P = .003).

Mean polyp size decreased by 4.9% in the higher-dose celecoxib group and by 0.7% in the placebo group (P = .055). Celecoxib also reduced the overall colorectal polyp burden, defined as the sum of polyp diameters in the monitored regions. Total polyp burden was reduced by 30.7% in the celecoxib 400 mg twice daily group (P = .001).

“There was a consistent improvement in the celecoxib 400 mg twice daily group, as well as in the celecoxib 100 mg twice daily group, suggesting a dose-response relationship,” Dr. Steinbach said.

The findings support the role of COX-2 in colon tumor growth and the prospect that COX-2 inhibition may serve as a mechanism for colon tumor prevention, Dr. Steinbach concluded. He said that a next step could be to study whether COX-2 inhibition prevents polyp recurrence in patients with sporadic colon tumors.