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The discovery last year that the painkillers Vioxx and Celebrex may increase the risk of heart problems wasn’t just a disappointment to people with chronic pain and the doctors who treat

them. The news has threatened to cut off a promising arm of research in cancer prevention. For the last decade, scientists have been compiling evidence that those and other nonsteroidal

anti-inflammatory drugs seem to interfere with the early processes that can give rise to cancer, particularly cancers of the digestive tract. Now, as many as 50 clinical trials are in limbo,

say researchers who gathered last week in Anaheim for the annual meeting of the American Assn. for Cancer Research. Those trials have been testing not only the newer drugs -- the so-called

Cox-2 inhibitors -- but also over-the-counter cousins such as aspirin and ibuprofen. “NSAIDs have been agents that have been of great interest” to cancer researchers, said Dr. Robert

Bresalier, chairman of the department of gastrointestinal medicine and nutrition at M.D. Anderson Cancer Center in Houston. “But I think we need to consider the question of risk versus

benefit.” Research presented at the convention underscored the balancing act that researchers and doctors face when recommending nonsteroidal medications in chemoprevention -- defined as the

use of natural or synthetic substances to reduce the risk of cancer. Norwegian scientists presented data showing that aspirin, ibuprofen, naproxen and three other traditional NSAIDs help

smokers cut their risk of oral cancer by half. (Oral cancer is fatal within five years in about 50% of people who develop the disease.) But smokers taking the drugs did not have lower death

rates overall -- probably because they were experiencing more cardiovascular problems from the therapy, said Dr. Jon Sudbo, the lead author of the study from the Norwegian Radium Hospital in

Oslo. “This really raises a question of safety in cancer prevention treatment,” Sudbo said. The discovery of a potential cardiovascular risk comes at a time when nonsteroidals have moved

into the forefront of chemoprevention research. Years of animal studies and observational studies showed the drugs seemed to prevent cancer. Dozens of studies funded by the National Cancer

Institute are, or were, underway to study the drugs’ effects on several types of cancer, including colon, breast, bladder, lung and prostate cancer. Approved for people with arthritis and

other chronic pain conditions, the newer nonsteroidal drugs known as Cox-2 inhibitors came under scrutiny last year when studies showed a higher rate of heart attack, stroke and

cardiovascular deaths among people taking the drugs. Cox-2 inhibitors block cyclooxygenase enzymes, which are produced in response to inflammation and by precancerous and cancerous tissues.

Unlike traditional nonsteroidal drugs, they are less likely to cause stomach bleeding when taken for extended periods of time. Vioxx and Bextra have since been taken off the market but

Celebrex remains. Some studies have also suggested that long-term use of the traditional nonsteroidal drugs may increase cardiovascular risk, and Sudbo’s study is an early indication that

all such drugs may raise risk. Much of the early success using Cox-2 inhibitors has been in preventing the polyps that can lead to colon cancer. Scientists from the National Cancer Institute

presented a study at last week’s conference showing that Celebrex alters a specific set of genes in the colons of patients at high risk for a hereditary form of colon cancer, which may

suppress the formation of colon polyps. Researchers from Rutgers University showed that low doses of Celebrex and the cholesterol drug Lipitor taken together were more effective at limiting

colon cancer in lab animals than higher doses of the drugs given separately. But future research is in peril. One large clinical trial of Celebrex to reduce the occurrence of precancerous

colon polyps was halted in December after investigators discovered the risk of heart attack, stroke and cardiovascular death was 2.5 times higher for people taking the drug than for people

taking a placebo. Several chemoprevention studies using Vioxx were also halted last year, and the future of smaller studies involving Celebrex is unclear. Drug companies making nonsteroidal

drugs may back away from cancer prevention studies, said Dr. Raymond DuBois, a professor of molecular oncology at Vanderbilt University Medical Center in Nashville. “One of the issues is

that when you do a large trial like this they cost upwards of hundreds of thousands of dollars,” he said. “They are not going to invest that kind of money when it leads to a negative image.”

Cancer researchers involved in nonsteroidal research will gather next month at the National Cancer Institute to mull over their options, DuBois said. But several researchers say they

believe their chemoprevention trials can continue with some revamping. For example, some studies will shift to lower doses of nonsteroidals or low-dose combinations of chemopreventive

therapies. Future research may also reveal that some of the nonsteroidal drugs are safer than others, said Dr. Jaye Viner of the National Cancer Institute’s division of cancer prevention.

“We may be moving toward a realization of which nonsteroidals can be used safely in which patients,” she said. Moreover, patients at high risk for some types of dangerous cancers, such as

colon or lung cancer, may decide that taking a medication to cut their cancer risk outweighs the risk of suffering a heart attack or stroke from the drug. “We need to remember that

individuals might be willing to accept that there are no easy decisions,” Viner said. MORE TO READ