During the past year, the study of the potential use of COX-2 (cyclooxygenase-2) inhibitors to prevent colorectal and breast cancer has come under intense scrutiny. Recent research questioned the safety of these medicines as pain relievers, which was the initial indication, as well as for chemoprevention of cancer. Now, the latest data show that COX-2 inhibitors are highly effective in preventing pre-malignant tumors of the colon, and therefore may be useful in preventing colorectal cancer among high-risk patients.

According to two studies presented today at the 97th Annual Meeting of the American Association for Cancer Research, the over-expression of the COX-2 enzyme is related to the growth and spread of colorectal tumors. COX-2 inhibitors may reduce the occurrence of the precursor, colorectal adenomas (benign tumors) in patients with a family history of the disease, as well as the development of sporadic colorectal tumors.

Celecoxib reduces sporadic colorectal adenomas: Results from the Adenoma Prevention with Celecoxib (APC) trial.: Abstract No. CP-3

Investigators from the Adenoma Prevention with Celecoxib Study (APC) enrolled 2,035 patients to a randomized, double-blind trial of the COX-2 inhibitor, celecoxib (Celebrex®), to prevent colorectal adenomas. Results of the study revealed that celecoxib significantly reduced the formation of large intestinal adenomas during a 3-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. The randomization of this trial 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 76 percent received a follow-up colonoscopy at three years.

The incidence of one or more benign tumors during colonoscopy was 61 percent in those taking placebo; in patients taking celecoxib this percentage was reduced by 45 percent (p<0.0001). The relative risk of advanced neoplasms (tumor) with adenomas more than one centimeter in diameter or with tubulovillous or villous features (premalignant rectal polyps), severe dysplasia (abnormal growth) or invasive cancer were also drastically reduced in patients using celecoxib, with 66 percent fewer tumors in these patients (p<0.0001).

“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, M.D., 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,” she said.

Chemoprevention of Colorectal Adenomas With Celecoxib in an International Randomized, Placebo-Controlled, Double-Blind Trial: Abstract No. CP-3

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 (FAP). 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 was a randomized, double-blind, placebo-controlled study enrolling 1,561 patients at 107 sites in 32 countries. PreSAP researchers hoped to determine the effectiveness of taking 400 mg celecoxib once daily to reduce the number of patients with 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, known as a polypectomy. Patients were excluded if they had FAP, hereditary nonpolyposis colorectal cancer (with an absence of polyps) or a history of inflammatory bowel disease. During the trial, patients did not take nonsteroidal anti-inflammatory drugs (NSAIDs) except cardioprotective doses of aspirin.

“Results of our study showed that celecoxib holds great promise for the prevention of cancer,” said Nadir Arber, M.D., M.Sc., 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 heart attack 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 (p<0.0001). In high-risk patients, the recurrence was also greatly reduced (p=0.0002). 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).

Said Dr. Arber, “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.”