Daily use of the COX-2 inhibitor celecoxib (Celebrex) significantly reduces the risk of precancerous polyps reoccurring in the colon or rectum, two research groups reported yesterday at the American Association for Cancer Research (AACR) annual meeting in Washington, D.C.

The results come from the Adenoma Prevention with Celecoxib (APC) Trial, which was jointly sponsored by NCI and Pfizer, and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) with Celecoxib Trial, solely sponsored by Pfizer. The trials had more than 2,000 and 1,500 participants, respectively; all participants previously had colorectal polyps, called adenomas, removed.

In the APC trial, patients taking either of two doses of celecoxib twice a day for approximately 3 years had fewer new adenomas and fewer new advanced adenomas - those most likely to become malignant - than those on placebo. Participants on the 400 mg/day dose had greater reductions (45 percent fewer new adenomas and 66 percent fewer advanced adenomas) than those on the 200 mg/day dose (33 percent and 57 percent, respectively).

In addition, explained the study's principal investigator, Dr. Monica Bertagnolli, an associate professor of surgery at Harvard University, when those who took celecoxib developed new adenomas, they were, on average, fewer in number and smaller in size compared with participants on placebo.

Taken together with the results from earlier animal model and epidemiological studies, the two trials' results prove that COX-2 "is a valid target for trying to prevent the occurrence of colorectal tumors," said Dr. Bertagnolli.

PreSAP participants were randomized to placebo or a single 400 mg dose of celecoxib daily for 3 years. The results were very similar to those of APC, including a 36-percent reduction in the development of new adenomas and a 51-percent reduction in the formation of advanced adenomas.

Dr. Nadir Arber, of the Tel Aviv Sourasky Medical Center in Israel and co-lead investigator for PreSAP, said the trials provided proof of concept that chemoprevention in people at high risk of colorectal cancer is possible.

The case for prevention with celecoxib, however, has been questioned because of data from two clinical trials that showed an increased risk of cardiac events in patients taking COX-2 inhibitors, including celecoxib.

In fact, use of celecoxib among APC participants was halted in December 2004 after an analysis by the trial's Data Safety and Monitoring Board showed a 2.5-fold increased risk of major fatal or nonfatal cardiac events in those taking the drug compared with those on placebo.

Initially, when preliminary results from the PreSAP trial were presented in December 2004, no increased risk of cardiac events was seen. The data presented yesterday, however, did reveal an increased risk.

Overall in the APC trial, 3.4 percent of patients on the 400 mg celecoxib dose had a serious cardiac event (defined as heart attack, stroke, heart failure, or cardiac-related death) versus 2.5 percent on the low dose and 1 percent on placebo. It appears, though, that a past history of cardiac events may increase the risk of a future event once on the drug. A closer look at the APC data revealed that nearly 9 percent of patients taking celecoxib who had a history of cardiac events prior to enrolling in the trial experienced a serious cardiac event during the trial, compared with only 2 percent of those on celecoxib without a history of cardiac events. The rates for those on placebo were 3 percent and 0.7 percent, respectively.

Celecoxib is being tested in a number of cancer prevention trials, based on both animal model and epidemiological studies that showed regular use of nonselective COX inhibitors, such as aspirin or ibuprofen, significantly reduced the incidence of certain precancerous lesions, as well as cancer and cancer-related mortality. It's also being tested in cancer treatment trials, including those for pancreatic, breast, and ovarian cancers, among other solid tumors.

The primary indication for COX-2 inhibitors is for pain relief in patients with osteoarthritis and rheumatoid arthritis. Celecoxib, which has also been approved to help reduce the number of adenomas in those with a familial disorder called FAP that predisposes patients to colorectal cancer, is the only COX-2 inhibitor still available on the U.S. market. Both rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn because of their association with increased cardiac events.

Even with the strong results from these two trials, whether celecoxib should be considered for colorectal cancer chemoprevention is still unclear, said Dr. Ernie Hawk, director of the NCI Office of Centers, Training, and Resources, and a senior investigator on the APC trial. That uncertainty is due in large part to the fact that neither trial was designed or powered to definitely assess cardiac event risk.

"I don't think we can recommend it today for any subset of patients," he said. Future studies need to be done that "tilt the risk-benefit ratio more in the favor of benefit."

By Carmen Phillips