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© Oxford University Press 2006.
NEWS |
Celecoxib Shown Effective in Preventing Colon Polyps
Celecoxib reduces the occurrence of polyps in the colon and rectum, and it is especially effective in the most difficult patients, two prevention trials have found.
The research is important because it proves that a cyclooxygenase 2 (COX-2) inhibitor like celecoxib can reduce the number of colon and rectal polyps, but the FDA has not approved it to treat those at risk because of fears that the drug will cause heart attacks, strokes, or other cardiac problems.
"We have discovered that COX-2 is a really valid target for trying to prevent the development of tumors, particularly tumors that have a risk of becoming cancerous," said Monica Bertagnolli, M.D., associate professor of surgery at Harvard Medical School in Boston and one of the trials' principal investigators.
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The studies do not prove that fewer and smaller polyps will actually reduce the risk of cancer, something the trials were not designed to examine.
Concerns about cardiovascular problems with other COX-2 inhibitors caused one of the celecoxib trials to be shut down. The cardiovascular troubles caused by the anti-inflammatory and painkiller also called Celebrex are greatest in those already proven to have cardiac problems but also increased for those who were not considered at risk.
The results from the trials—Adenoma Prevention with Celecoxib (APC) trial and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP)—were announced at the April meeting of the American Association of Cancer Research in Washington, D.C.
In the APC trial, cosponsored by the National Cancer Institute (NCI) and drug manufacturer Pfizer Inc. of New York, celecoxib was tested in 2,035 men and women from 100 centers mostly in United States but also in the United Kingdom, Australia, and Canada. Over 3 years, the participants were randomly assigned to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo twice a day.
Patients on the lower dose had 33% fewer new adenomas and 57% fewer advanced adenomas than the control group. Those on the higher dose had 45% fewer new adenomas and 66% fewer advanced adenomas. Also, the new adenomas that celecoxib users did develop were, on average, smaller than those on placebo.
"We saw the effects at 1 year and then again at 3 years. Trials usually last for 3–4 years, which requires a huge expenditure of resources. Finding an effect so early is huge," said Ernest T. Hawk, M.D., a principal investigator of the trial from NCI. "It's not only important for being able to interest industry in pursuing chemoprevention, but it is also important for the whole field because potentially you could do 1-year trials."
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The PreSAP trial involved 1,561 participants from 32 countries; 933 people received 400 mg of celecoxib once daily and 628 received a placebo. Over 3 years, those receiving celecoxib had 36% lower rate of adenomas than those taking placebo (Adenomas were detected in 49% of placebo patients, compared with 33% of celecoxib users). Their risk for advanced adenomas was reduced by 51%.
"Not only is the trial an important proof of concept that celecoxib is an effective drug [for decreasing the rate of polyp occurrence], but we also found that the people who benefit the most are the people at the highest risk," said Nadir Arber, M.D., one of the principal investigators of the PreSAP trial and professor of medicine and gastroenterology at Tel-Aviv Sourasky Medical Center in Israel. "That is a major advance."
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This isn't the first time that celecoxib has been proven effective. A previous prevention trial tested 77 patients with familial adenomatous polyposis, a condition in which hundreds of precancerous polyps develop and result in a nearly a 100% risk of colon cancer. Participants who received 400 mg of celecoxib twice a day for 6 months had a 28% reduction in colorectal and duodenal polyps compared with the placebo group. On the basis of the study, Celecoxib was approved in 2000 for the reduction of polyps in the disease.
COX-2 Inhibitors as Cancer Prevention
Celecoxib belongs to a class of medicines known as nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen, that are used to treat pain and inflammation from chronic inflammatory disorders like arthritis. About 17 million people in the United States use an NSAID daily. Gastritis, peptic ulcers, and gastrointestinal bleeding are common side effects of those drugs.
On a molecular level, NSAIDs block the cyclooxygenase enzymes, COX-1 and COX-2, to various degrees. Research had shown that by inhibiting only the COX-2 enzyme, some of the gastrointestinal side effects would disappear. When this finding was borne out in clinical trials, the first three COX-2 inhibitors, celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) were approved by the Food and Drug Administration to treat the symptoms of osteoarthritis and rheumatoid arthritis in 1998, 1999, and 2001, respectively.
More than a decade of research—including bench work, animal studies, and epidemiologic reports—linked COX inhibitors and reduced cancer risk. In vitro, inhibiting the COX pathway increased programmed cell death and reduced cellular and blood vessel proliferation. Animal studies showed a decrease in cancer incidence when NSAIDs were given. Epidemiologic studies suggested that people who regularly take drugs that block COX enzymes have lower rates of certain precancers, cancers, and cancer-related deaths, especially for colorectal cancer.
Testing Begins
To test the cancer prevention hypothesis, Merck launched the Adenomatous Polyp Prevention on Vioxx trial in 2000 with its drug, rofecoxib. But after monitoring 2,586 patients with a history of precancerous polyps for 18 months, the researchers found an increased risk of confirmed cardiovascular events in those on the drug compared with placebo—3.6% of patients (46 of 1,287) in the rofecoxib group had cardiovascular trouble, compared with 2% (26 of 1,299) in the placebo group. The trial was stopped in 2004, and Merck withdrew rofecoxib from the market that same year. Valdecoxib, Pfizer's COX-2 inhibitor, was also associated with an increased risk of heart attacks and stroke, as well as a severe skin allergy known as Stevens–Johnson syndrome. The drug was withdrawn in 2005.
These observations prompted a safety assessment of the APC trial, which had been launched in 1999. In December 2004, an independent board reported that the risk of major fatal and nonfatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) was 2.5 times higher for participants taking the drug than in those on placebo. The trial was suspended on December 17, 2004.
Even though the trial was suspended, researchers continued to monitor participants to determine the drug's effectiveness and to further analyze the cardiovascular risks. A March 2005 paper showed that 1% in the placebo group (7 of 679 patients) had a serious cardiovascular event, including one death. This outcome compared with 2.3% in the lower dose group (16 of 685) and 3.4% in the higher dose group (23 of 671).
Data from the PreSAP trial showed a similar pattern. Although the overall risk was the same for those on celecoxib and on placebo, cardiovascular risk for those on the drug was slightly higher. Of 933 patients taking celecoxib, 23 (2.5%) had cardiovascular problems, compared with 12 (1.9%) of 628 patients taking the placebo. Arber told the AACR audience that the PreSAP trial was not designed to measure toxic effects, which would require more participants monitored for a longer time.
Causes of Cardiovascular Risk
The reason for these increased risks is not clear. Some people have suggested that it might be related to the protective effects of aspirin. However, participants in these trials who took aspirin did not have a different risk from those not taking aspirin.
But there is good news. The cardiovascular problems were more likely to occur in participants who had previous cardiovascular issues. In the APC trial, 8.8% of patients with a prior cardiovascular history had a heart attack, stroke, or other episode while taking celecoxib, compared with 2.2% without a prior history.
"Although these trials are tremendously important, we don't know yet what to recommend for patients," Hawk said. "We don't understand the mechanism underlying cardiovascular risk." The simplest explanation would be sodium retention, which is related to hypertension, he said. "If [the cardiovascular risk] is due to hypertension, that's a perfectly treatable condition that we can monitor. The good news is that we have a lot of promising leads to follow."
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