Cyclooxygenase-2 inhibitors significantly reduce the risk for sporadic colorectal adenomas in high-risk patients, according to presentations at the annual meeting of the American Association of Cancer Research.

Investigators from the Adenoma Prevention with Celecoxib Study (APC) enrolled 2,035 patients to a randomized, double-blind trial of celecoxib to prevent colorectal adenomas. Results of the study revealed that celecoxib significantly reduced formation of large intestinal adenomas during a three-year period after removal of polyps in patients at high risk of developing colorectal cancer.

Of the participants, 679 patients received a placebo, 685 patients received 200 mg of celecoxib and 671 patients received 400 mg of celecoxib, administered twice daily. Randomization took into consideration the use of low-dose aspirin in 31 percent of participants. A follow-up colonoscopy was conducted in 89 percent of participants after one year and in 76 percent at three years.

The incidence of one or more benign tumors during colonoscopy was 61 percent in placebo patients; in patients taking celecoxib this percentage was reduced by 45 percent. The relative risk of advanced neoplasms with adenomas more than one centimeter in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer were also drastically reduced in patients using celecoxib, with 66 percent fewer tumors in these patients.

“The results of this study show that patients at risk for developing colorectal cancer have dramatically fewer pre-malignant tumors when they take celecoxib,” said Monica Bertagnolli, MD, associate professor of surgery, Harvard University, Boston, Mass.

“This work shows that drugs that inhibit COX-2 activity are important tools in developing effective preventive therapies for colorectal cancer.”

A prior study has shown that administration of the COX-2 inhibitor, celecoxib, is associated with a reduction in colorectal adenoma size and number in familial adenomatous polyposis. Therefore, researchers in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) with Celecoxib Trial tested the effectiveness of celecoxib in reducing the incidence of sporadic colorectal adenomas.

The PreSAP study enrolled 1,561 patients in 32 countries. PreSAP researchers examined effectiveness of 400 mg celecoxib daily to reduce new adenomas and the grade, size and number of new adenomas.

The trial started in March 2001 with patients who had undergone removal of all colorectal polyps. Patients were excluded if they had familial polyposis, hereditary nonpolyposis colorectal cancer, or a history of inflammatory bowel disease. During the trial, patients did not take nonsteroidal anti-inflammatory drugs except cardioprotective doses of aspirin.

“Results of our study showed that celecoxib holds great promise for the prevention of cancer,” said Nadir Arber, MD, MSc, Head, Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Israel. “For patients at high-risk of developing colorectal cancer, celecoxib may be considered while weighing the risk of potential cardiovascular events.”

Patients were split into a 3:2 ratio of celecoxib and placebo and divided by baseline aspirin use (17 percent, placebo; 16.6 percent celecoxib) or non-use (83 percent placebo; 83.4 percent celecoxib); 933 patients received celecoxib and 628 received placebo. Of the total patients, 88.7 percent underwent a colonoscopy with or without removal of polyps at one year and 79.2 percent at year three.

The administration of celecoxib was stopped after the Adenoma Prevention with Celecoxib (APC) study found at 33 months a two-to-three-fold increase in serious adverse cardiovascular events. PreSAP data at the time of the APC announcement indicated a hazard ratio of 1.2 for those taking celecoxib compared with placebo for death from cardiovascular events and nonfatal myocardial infarction or stroke.

The incidence of adenomas at year three was 49.3 percent in the placebo group but significantly lower in the group taking celecoxib. In high-risk patients, recurrence was also greatly reduced. The prevalence of adverse events was similar in both the placebo (74 percent) and celecoxib groups (76.8 percent), although patients taking celecoxib had a higher risk of cardiovascular events than those taking placebo (7.5 percent versus 4.6 percent).

Arber said, “Research has shown that in order to reduce incidence of cancer, we need to develop better prevention methods for those at highest risk of developing the disease.

“We are encouraged by these results and hope the data from both the APC and PreSAP trials lead to the continuation and implementation of additional clinical trials with COX-2 inhibitors for the prevention of colorectal and other cancers, such as breast. Understanding the molecular mechanisms by which these compounds work is another important scientific goal.”