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Dietary Prevention of Cancer: A Smorgasbord of Options for Moving Ahead

Damaris Christensen

Diet-related factors are thought to account for up to one-third of cancers in developed countries, although there is a broad range of uncertainty attached to these estimates. Cancer prevention experts generally recommend that people maintain a healthy weight, exercise, and eat diets high in fruit, vegetables, and fiber. Much uncertainty, however, remains: some of the observational evidence is contradictory, and some intervention studies looking at the effects of specific nutrients have not confirmed findings from observational studies.



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Cancer prevention experts generally recommend that people maintain a healthy weight, exercise, and eat diets high in fruit, vegetables, and fiber. Although there is much uncertainty about the strength of some associations between dietary factors and cancer, the fact remains that such factors affect everyone.

 
The strongest findings support alcohol as a carcinogen at several sites and implicate obesity and physical inactivity in several other cancers, said Arthur Schatzkin, M.D., Dr.P.H., of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics. But, he added, the observational, or epidemiologic, evidence in other areas is confusing—for example, a few recent studies suggest that fiber may in fact protect against colon cancer even though a number of previous studies have shown no effect, whereas the evidence that fruit and vegetable consumption protects against cancer has weakened in recent years (see News, Vol. 92, No. 22, p. 1794, "Recent Studies Cloud Link Between Diet and Cancer"). Moreover, several large interventional studies developed to examine the role of vitamin E and beta-carotene in preventing lung cancer—seemingly a promising area from epidemiology studies—showed no effect and may even have increased the risk of cancer for men who smoked and took beta-carotene. Another large study showed that selenium did not affect recurrence of skin cancer, as had been predicted.



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Dr. Arthur Schatzkin

 
Amid such results, the fact remains that dietary factors—even if they play a relatively small role in cancer prevention—affect everyone. "We’re dealing with associations [between diet and cancer] that represent very weak to moderate increases in risk," said Schatzkin. "But everybody eats! A 30% decrease in risk can be very important." Thus, cancer researchers are developing new recipes—from improving epidemiologic assessment tools to including genomic data to laboratory work identifying the molecular targets of dietary components—to further clarify the associations between diet and cancer.

Study Design Factors

One important ingredient is to improve the dietary assessment tools used in epidemiologic studies. People are notoriously inaccurate at recalling their food intake; some researchers believe that the food frequency questionnaire is not sufficiently accurate for population studies of diet and cancer.

Another possible avenue for exploration is to design studies that include a wide range of dietary intake of a particular substance. For example, "if the top group of people eat less fiber than the amount needed to show a protective effect against cancer, then a study will of course show no association," Schatzkin said.

Researchers are trying to design studies to minimize other factors that might mask the effects of diet on cancer incidence. One problem with large epidemiologic studies is that dietary factors, such as high intake of fruits and vegetables, are often correlated with other factors known to be associated with lower risk of cancer, such as lower rates of smoking and higher levels of physical activity. Inconclusive results from some intervention studies have led researchers to speculate that the timing of the intervention may be key: By the time people show risk factors for cancer occurrence, for example, the disease may have progressed to the point where it isn’t possible to stop it with diet alone, said Norman Hord, Ph.D., of the Department of Food Science and Human Nutrition at Michigan State University. Newer studies are beginning to attempt to examine interactions between factors such as obesity and dietary intake or between genetic susceptibility factors and dietary factors.

Prospective Studies

"One of the points there’s increasing consensus in the field about is the importance of prospective studies," Schatzkin said. Some of the biggest such studies are the Women’s Health Initiative, the Nurses’ Health Study, and the Health Professionals Follow-up Study. The NIH is also funding a 5-year study of 125,000 Seventh-Day Adventists nationwide to examine the links between diet and chronic diseases, including cancer. Furthermore, Schatzkin noted, the National Cancer Institute is working to develop a consortium of cohorts so that different studies are more comparable.

Many researchers are eagerly awaiting results from the European Prospective Investigation into Cancer and Nutrition (EPIC), the biggest and, in terms of diet, most diverse study to date. EPIC enrolled about a half a million people in 10 European countries from the general population between 1993 and 1999 and will monitor them for at least another decade. By studying large numbers of people living in different countries and eating very different diets, using carefully designed and tested questionnaires coupled with blood samples, EPIC should produce much more specific information about the effect of diet on long-term health than any previous study.

"We still have a lot of things to learn from observational epidemiology," said Hord. But because large epidemiologic studies are "horrifically expensive," he said, "we need to get more answers out of our large studies." Stored blood and serum samples are turning out to be very fruitful in allowing researchers to go back and look for associations, he said.

Randomized Studies

Along with prospective observational studies, researchers are pursuing randomized studies to get a better grasp of the kinds of dietary changes that may affect cancer risk.

The Physicians’ Health Study II, led by investigators at Harvard Medical School in Boston, is evaluating vitamin E, vitamin C, beta-carotene, and a multivitamin for the prevention of cardiovascular disease, total cancer, and prostate cancer among 15,000 male physicians age 50 or older. The Women’s Health Study, headed by researchers at Boston’s Brigham and Women’s Hospital, is evaluating the benefits and risks of low-dose aspirin and vitamin E on cardiovascular disease and cancer among 40,000 female health professionals.

Some interventional studies have been started to follow up on later analyses of studies aimed at preventing lung cancer with vitamin and mineral supplements. The idea that vitamin E and selenium will reduce a man’s risk of developing prostate cancer is currently being tested in a North American study (called SELECT) that is still recruiting a total of 32,000 healthy men age 55 or older, who will take vitamin E, selenium, or both.

Laboratory Work

"In the last 6 or 7 years, we’ve made significant progress at understanding why the epidemiology studies show a decreased risk of cancer for some diets," said Shivendra Singh, Ph.D., co-leader of the new biochemoprevention program at the University of Pittsburgh Cancer Institute. Just as in cancer treatment research, he said, the science of prevention research is moving so quickly that researchers are trying to identify and selectively target particular molecular pathways important for cancer development. Singh has focused his research on isothiocyanates, compounds found in cruciferous vegetables like broccoli that seem to selectively kill cancer cells but not normal cells in tissue culture. Work on compounds from red wine, green tea, and allium vegetables such as garlic also appears to demonstrate that there is biological plausibility to the idea that such foods could prevent cancers, he said.

"But there is one area where I am not satisfied," he said. "We are kind of slow at moving from the bench into the clinic. Many of these agents which appear to be promising have been known for a number of years." In fact, one of the motivations behind the 2003 formation of UPCI’s biochemoprevention program was to speed the transition of compounds from the laboratory to the clinic, he said. They are currently developing plans for a phase I trial of isothiocyanates in men with prostate cancer. The beta-carotene and lung cancer trial was a setback because people became very cautious about taking the next step and moving compounds into interventional trials even when compounds look promising in the lab, he said. That hesitation is increased when—as for tea—in vitro and animal studies suggest that compounds in tea are active agents against tumorigenesis, but epidemiologic findings are much less compelling.

"Epidemiology studies are very important for identifying nutrition and lifestyle issues, and, from our perspective, they complement what is going on in the basic science arena," said John Milner, Ph.D., of NCI’s Division of Cancer Prevention.

One growing area of research is to develop intermediate markers to measure cancer progression and the effectiveness and activity of any dietary intervention. Accurate intermediate markers could reduce the need for lengthy trials by helping researchers select the most promising compounds for definitive clinical trials. When the epidemiologic evidence is unclear, or when some studies suggest a big reduction in risk and others find no benefit, genetic differences between people may help provide an explanation, researchers suggest. In short, the field of genomics is pushing for its share of the pie in cancer prevention research.

So-called Mendelian randomization studies may complement traditional nutritional epidemiologic investigations. The idea is that genetic polymorphisms, which would occur randomly in a population, may allow researchers to compare, say, people who have higher and lower exposures to folate because of polymorphisms in folate metabolism, thus sharpening the "relative risks" determined in epidemiologic studies. The hope is that, ideally, new "nutrigenomics" tools will allow nutrition researchers to effectively address the interface of diet and metabolism as well as examine the pathways and mechanisms by which diet and nutrition may prevent cancer.

"We’re definitely moving toward preemptive nutrition," based on a person’s genetic background and current health conditions, said Milner. "But it’s important to realize that we have to look at the totality of evidence. Nutrients are not magic bullets. Some people are likely to benefit more than others [from nutritional interventions]... . People’s diets are very complex, and it’s likely that we’re going to find multiple genes" modulating dietary influence on cancer incidence, he said.


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