Advisors to the Food and Drug Administration (FDA) last week recommended that "black box" warnings be added to the label of the two COX-2 inhibitors currently for sale in the United States, and to a third that might be reintroduced (rofecoxib, or Vioxx). The warnings would alert physicians and patients to an increased risk of cardiovascular events associated with the drugs' use. The risk, the committee agreed, represents a so-called class effect of COX-2 agents like celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib that were developed to alleviate pain while limiting gastrointestinal effects by blocking the action of the COX-2 enzyme.

Dr. Robert Temple, of the FDA Center for Drug Evaluation and Research, told committee members that the agency was "committed to working as quickly as possible" in considering and implementing the recommendations.

Although COX-2 inhibitors' primary indication is to treat pain associated with osteoarthritis and rheumatoid arthritis, the committee's recommendation to leave the drugs on the market means that at least celecoxib, which the committee almost unanimously agreed is the least likely to be associated with adverse cardiac events, can continue to be studied for use in the prevention and treatment of cancer. Both aspirin and COX-2 inhibitors have shown promise in preventing polyps that can lead to colon cancer.

The 3-day meeting was just one part of a flurry of activity surrounding the "coxib" drugs last week, including a decision by European drug regulators to limit the use of COX-2 drugs only to patients without cardiac problems and the publication of four studies in major medical journals indicating an increased risk of cardiac events and increased blood pressure among patients taking them.

Included among these studies were data on cardiovascular events seen in the APC trial, a randomized, placebo-controlled study jointly funded by NCI and Pfizer Inc., testing whether daily use of a high dose of celecoxib could prevent colon polyp recurrence. No data on polyp reduction from the trial, which was halted in December because of increased cardiac events among patients on celecoxib, are yet available. The data published in the February 16 New England Journal of Medicine (NEJM) revealed that patients taking celecoxib had significantly increased risk of cardiac-related death, nonfatal heart attack, stroke, and congestive heart failure (see NCI Cancer Bulletin, February 15). Also published in the same issue of NEJM were data from the APPROVe trial, which tested whether daily use of high doses of rofecoxib could prevent polyp formation in those at high risk. In that study, rofecoxib use increased cardiovascular event risk, but also reduced the incidence of colon polyps by 24 percent.

Dr. Ernie Hawk, director of the NCI Office of Centers, Training, and Resources, who presented the cardiovascular event data from the APC trial during the meeting, explained that NCI is investigating the use of celecoxib in prevention and treatment trials because both animal model and epidemiological studies have shown profound benefits of COX-2s in preventing colon cancer. More than 30 epidemiological studies, for example, have shown that COX-2s reduced adenoma incidence, cancer incidence, and cancer-associated mortality. Moreover, celecoxib has been shown to reduce the number of adenomas in individuals with familial adenomatous polyposis, a genetic condition strongly associated with colorectal cancer development.

"These agents may very well have a unique set of contributions for patients living with cancer or at risk for cancer," Dr. Hawk said. "The data strongly support this and justify further investigation."

By Carmen Phillips