Prevention: Is it just the right drug away?

Times Staff Writer

At 66 years old, Vincent Motyl has the gravelly voice and rumbling laugh of a man who's spent much of his life in a halo of cigarette smoke. He grew up amid the industrial soot of Pittsburgh in a houseful of smokers and started a two-pack-a-day habit at 18.

Motyl's father died of lung cancer 22 years ago, at 86; but the old man's longevity doesn't comfort the Culver City mortgage banker, who says he's tried to quit "30, maybe 40 times." He's down to about half a pack a day now. "But of course I think of lung cancer," he says.

So Motyl didn't hesitate to enroll when UCLA's Jonsson Comprehensive Cancer Center launched a clinical trial to test whether medication -- in this case, the arthritis drug celecoxib (also known as Celebrex) -- might reduce the odds of developing lung cancer in a smoker or ex-smoker. He didn't ask what the medication was, and he didn't worry about side effects.

It just made sense, Motyl thought: If a daily pill could prevent cancer, who would not take it?

It is a simple and compelling idea: If some chemical agent -- a common nutrient or a medication already in wide use, for instance -- could block, disrupt or reverse the processes that lead to runaway cell growth, then cancer might never need to be cured. It could be prevented.

If only, say experts in the field, the quest for cancer-preventing drugs were as simple as it sounds, or as readily embraced by physicians and patient advocates as it is by patients like Vincent Motyl. But the effort is an uphill struggle, for several reasons.

Focus and funding are two. Compared with the effort to find drugs to cure and treat cancer, the search for preventive medicine "has been the stepchild" of cancer research, motivating just a small corner of the cancer research community, says Dr. Victor Vogel, a researcher and breast cancer oncologist at the Magee-Womens Hospital/University of Pittsburgh Cancer Institute. "It's not sexy, it's not fancy, and for the pharmaceutical companies, it may not always be very profitable."

Vast stores of money, brainpower and hope have brought forth drugs capable of extending cancer patients' survival by months and sometimes years, say prevention researchers such as Vogel. Meanwhile, drugs shown to have driven down cancer rates in high-risk populations -- ones that have been shown, in studies, to spare people from the ordeal of becoming cancer patients in the first place -- have been mired in debates over side effects.

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An unwary world

In recent years, the Food and Drug Administration has approved two medications -- the cancer drug tamoxifen and the osteoporosis drug raloxifene -- for certain women at high risk of breast cancer. In 1999, breast cancer activists greeted tamoxifen, the first to be approved, with deep distrust because it was found to increase the risk of blood clots, uterine abnormalities and cataracts in post-menopausal women.

A year ago, the FDA approved the second, raloxifene, for breast cancer prevention in post-menopausal women at high risk for breast cancer. The agency concluded that the drug could cut the rate of breast cancer in such women by 44% to 71%, with side effect risks far lower than tamoxifen.

However, patients may not receive that message. In advertising raloxifene directly to consumers, the maker of the drug -- Eli Lilly and Co. -- scarcely mentions the cancer prevention effects, choosing to market the drug primarily for prevention of osteoporosis.

The result, Vogel says, is that most women at high risk of developing breast cancer who could benefit from drugs such as tamoxifen and raloxifene have never heard of these options.

"We're trying to find better, safer drugs all the time and trying to overcome both public and physician ignorance about this," Vogel says. "But you cannot imagine how many people I have to convince."

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Search far and wide

The federal government's comprehensive record of clinical trials (www.clinicaltrials .gov) lists 9,161 studies for pharmacological treatment of cancer in the United States but just 155 for cancer chemoprevention. And several of those 155 have been suspended.

Still, the number and diversity of agents under investigation for prevention is impressive. Researchers are exploring the use of arthritis, diabetes and asthma drugs for protection against lung cancers; a low dose of the cancer chemotherapy drug finasteride to suppress the development of prostate cancer; and drugs that include celecoxib, aspirin and other arthritis medications as well as common antibiotics to prevent the development of cancers of the colon and digestive tract.

An African sleeping-sickness drug called eflornithine, marketed as a drug to block unwanted hair growth, is thought to be promising in the prevention of a wide range of cancers, including those of the skin, esophagus, colon, prostate and cervix.

Statins -- the cholesterol-lowering drugs that have shown benefits far outside their prescribed use -- are also under study in the prevention of a variety of cancers.

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A complex process

To be sure, agents that seem promising may later fall by the wayside. A combination of vitamin A and beta-carotene was one of the cancer chemoprevention community's most spectacular disappointments when, in studies completed in the 1990s, the regimen not only failed to reduce lung cancer rates but in fact boosted them among male smokers.

Still, many common nutrients -- including beta-carotene -- remain under investigation as potential cancer-blockers. Folic acid, vitamin D, selenium, lycopene, the spice ingredient curcumin, green tea and resveratrol, a compound found largely in the skins of red grapes, all are being tested in clinical trials.

The wide variety of chemicals that might help prevent cancer reflects the range of processes that go wrong when cells turn malignant. Dr. Michael Sporn, a professor of medicine and pharmacology at Dartmouth Medical School, says that different agents may disrupt the processes leading to cancer at different stages. It may prove that combinations of agents will be the most powerful, he says.

But if the search for cancer-preventing medicines is to bear fruit, he thinks that cancer researchers, clinicians and the government's drug-safety regulators will have to rethink their attitudes about risk, reward and medicine.

"The notion of preventing cancer is intuitively obvious to everyone but the oncology community," Sporn says.

In some ways, cancer-prevention drugs have the deck stacked against them, experts say. Most cancer chemotherapy drugs are known to come with horrific side effects. But the balance of risk and benefit often looks good anyway: Patients and their physicians usually calculate that likely side effects compare favorably with the far worse prospect of letting cancer run its course.

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Risk vs. benefit

In prevention, the calculation of risk and benefit is much more complex. What doctor would ask a patient whose future risk for cancer is uncertain -- and who by all appearances is currently well -- to take a cancer-prevention drug with recognized side effects such as liver toxicity or increased risk of stroke or heart attack?

Sporn calls this the "long uphill battle" that advocates of cancer chemoprevention face. And it is a battle made harder by the fact that a person's cancer risk -- in most cases a complex interaction between genetic predisposition, environmental exposures and pure bad luck -- is poorly defined. Without blood tests or other clear indicators that a patient will likely develop cancer, physicians have shown they are reluctant to prescribe drugs for prevention, even where their benefits have been shown.

The FDA, too, remains wary of the use of drugs to treat patients without clearer signs of impending disease.

But though cancer experts have not found easy markers of cancer risk, Sporn says, there are plenty of patients whose polyps, moles, family history or chromosomes offer ample warning of trouble ahead.

For such people, he says, the risk profile of a potential cancer-preventing drug really should be compared to the very real prospect that the patient will develop a life-threatening cancer and that oncology in many cases will have little prospect of a cure to offer him.

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Rethinking cancer

Advocates of cancer-prevention research see a model for the way things should be in the treatment of cardiovascular disease. In that field, primary care doctors and heart specialists, armed with medications to lower cholesterol and blood pressure, have jumped wholeheartedly into the prevention of heart attacks and strokes. And even as they debate how to measure a patient's future risk, the field has agreed on blood pressure levels and cholesterol measures that are "markers" for heart disease and stroke and has used those to guide medication decisions.

The search for equally reliable indicators of cancer risk remains in its infancy. But doctors who treat cancer and the organs it invades should follow the cardiovascular model, says Dr. Leslie Ford, associate director for clinical research at the National Cancer Institute's Division of Cancer Prevention.

"I challenge oncologists to think differently -- to find people with risk factors for cancer and think about prevention," Ford says. "They haven't gotten there. It's not where the money is . . . and primary care physicians are overcome with other problems. It's a real challenge, but we're plugging along. I'm cautiously optimistic."

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melissa.healy@latimes.com

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On the Web

The hurdles are high for cancer-prevention drugs, as shown by the story of celecoxib, also known as Celebrex. Read about it at latimes.com/cancerextra.

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