Thursday, August 31, 2006

Celebrex Has 'No Role' Against Colon Cancer

(HealthDay News) -- The final word on whether the cox-2 painkiller Celebrex might be used to prevent colon cancer is a definite "no," according to the long-awaited results of two major studies.

Both of the three-year trials found that the drug reduced the occurrence of precancerous polyps called adenomas in people at risk for colon cancer, but it more than doubled patients' risk for heart attack and other serious cardiovascular events.

"The message is that celecoxib [Celebrex] has no role as a chemotherapeutic agent -- in people with adenomas or in people among the general population. The risks far exceed the potential benefits," said Dr. Bruce Psaty, a professor of medicine, epidemiology and health services at the University of Washington, Seattle.

Psaty co-authored an editorial on the two studies, both of which were expected to be published in the Aug. 31 issue of the New England Journal of Medicine. Both studies received funding from Pfizer Inc., the maker of Celebrex.

Cox-2 inhibitors are part of a class of analgesics called non-steroidal anti-inflammatory drugs (NSAIDs), which also include widely used medications such as aspirin, ibuprofen and naproxen (Aleve). Prescription medications such as Celebrex were originally developed because they are safer on the stomach than other NSAIDs.

However, Celebrex is the only cox-2 inhibitor left on the market. Two other related drugs -- Vioxx and Bextra -- were withdrawn in 2004 and 2005, respectively, following reports of heightened cardiovascular risks.

As mandated by the U.S. Food and Drug Administration, Celebrex now carries a special "black box" warning that advises consumers of the potential heart dangers.

Cox-2 inhibitors work by blocking cyclooxygenase enzymes, which are produced by the body in response to inflammation and are also produced in precancerous tissues.

The latter fact left cancer researchers pondering whether or not long-term use of Celebrex might cut risks for colon cancer.

These two latest trials try to answer that question. The biggest study, called the Adenoma Prevention with Celecoxib (APC) trial, was led by Dr. Monica Bertagnolli, of Brigham and Women's Hospital in Boston. It tracked the incidence of polyps called adenomas in more than 2,000 patients with a prior history of these precancerous growths.

"Adenomas are a precursor of colon cancer -- you could consider them a proxy for colon cancer in the context of this trial," explained co-researcher Dr. John Saltzman, director of endoscopy at Brigham and an associate professor of medicine at Harvard Medical School.

Patients in the trial were divided into three groups: a third received a dummy placebo, a third got 200 milligrams of Celebrex twice daily, and the remaining third received 400 milligrams of the drug twice a day.

The team then had patients come in for regular colonoscopies over the next 3 years.
Celebrex did help bring down the rate of adenoma recurrence, the researchers reported.

While more than 60 percent of those on placebo developed these potentially malignant polyps, that number fell to about 43 percent for those on lower-dose (400 mg/day) Celebrex, and 37.5 percent for those taking the higher dose of Celebrex (800 mg/day).

There was a definite downside to the long-term use of Celebrex, however.

"Compared with placebo, celecoxib was associated with approximately a doubling of the cardiovascular event rates," Psaty noted. Specifically, patients taking lower-dose Celebrex for three years had 2.6 times the rate of serious cardiovascular events -- such as fatal or nonfatal heart attack and/or heart failure -- compared to those taking placebo. That risk more than tripled for those on the higher-dose regimen, the researchers added.

A second three-year study involving nearly 1,600 patients -- this time led by Dr. Bernard Levin of the University of Texas M.D. Anderson Cancer Center in Houston -- found similar results.

The Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial compared patients who took a placebo to those who received 400 milligrams/day of Celebrex.

It found that the drug cut the rate of adenomas by 36 percent after three years. However, long-term use also significantly boosted patients' risk for cardiovascular trouble.

According to Psaty, the take-home message from both trials is that the cardiovascular risks "far outweighed even the most optimistic projections about the drug's cancer-prevention properties."

Saltzman agreed, adding that heart risks associated with Celebrex probably apply to Vioxx and Bextra as well. "My presumption is that it's a class effect," he said.

However, other NSAIDs might still help lower the odds of colon cancer for patients at high risk, the experts said.

"Low-dose aspirin has been looked at already and does show some chemopreventive effects, with about a 20 percent reduction of recurrent adenomas," Saltzman noted. "And certainly low-dose aspirin is used by doctors everywhere to help the heart."

Even though aspirin's anti-cancer benefits aren't as great as those attributed to Celebrex, "I think it is not an unreasonable thing for people to pursue," he said.

The new findings probably won't change the status quo when it comes to the marketing of cox-2 inhibitors, the experts said, since much of the side-effect data had been published before.

"I don't think this gives new or additional information that will help with the determination of whether these drugs should stay on the market," Saltzman said.

More information
There's more on cox-2 inhibitors at the U.S. Food and Drug Administration.

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