Journal of the National Cancer Institute Advance Access published online on May 27, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn184
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© Oxford University Press 2008.
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An Apple a Day May Be Safer Than Vitamins
Many cancer patients and healthy individuals regularly take vitamin and mineral supplements, often with their physician's blessing. Although many doctors may not believe that supplements prevent disease, most think that they can't hurt. But a growing body of research indicates that, at least in some cases, vitamin and mineral supplements may not be entirely benign.
Several new reports, including a commentary in this issue of the Journal (p. 773–778), are raising concerns about the safety and efficacy of vitamin and mineral supplements in healthy individuals and cancer patients and survivors. Some experts see a need for further studies, whereas others say that there are sufficient negative data to stop vitamin trials altogether.
"A good place for research to start would be food and lifestyle intervention trials," instead of vitamin studies, said Tim Byers, M.D., professor of epidemiology and community health at the University of Colorado School of Medicine in Denver.
Recently, an expert panel, which included Byers, issued strong recommendations to cancer patients and survivors against taking any nutritional supplements. Entitled Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, the extensive report, released in November 2007 by the American Institute for Cancer Research (AICR) and its international affiliate, the World Cancer Research Fund, analyzed more than 440 studies on cancer risk, foods, and vitamin and mineral supplements conducted during the past 20 years. The expert panel warned that certain nutritional supplements appear to be harmful for cancer patients and survivors, countering the conventional wisdom that although vitamins may not help, they cannot hurt.
Another new study, published in February by Cornelia Ulrich, Ph.D., and colleagues at the University of Washington in Seattle, found that more cancer patients and survivors take vitamin and mineral supplements than do healthy individuals: 64%–81% of cancer survivors use any vitamin or mineral supplements, and 26%–77% use multivitamins, compared with about half of U.S. adults who use dietary supplements and a third who use multivitamin supplements. Breast cancer survivors reported the highest use of supplements, and prostate cancer survivors reported the lowest. The study also found that although supplement use is widespread among cancer patients, most do not tell their physicians that they are using them.
"Until future studies clarify the association between vitamin use among cancer survivors and prognosis, physicians should encourage open communication with their patients regarding supplement use. We should ask what our patients are taking or considering taking, and why, and we can offer suggestions on other ways of achieving goals," Ulrich said. "Sharing information on supplements with patients can help them make better decisions."
A third study, published in March by Christopher Slatore, M.D., and colleagues at the University of Washington examined long-term use of supplemental multivitamins, vitamins C and E, and folate. They found no risk reduction in lung cancer, and long-term, high-dose vitamin E supplementation even slightly increased the risk.
Taken together, these studies raise important questions about the safety of vitamin and mineral supplements, and experts in the field are discussing whether a moratorium should be called on supplement use to prevent and treat disease until more studies are performed.
Widespread interest in studying supplements and cancer continues and is reflected in ongoing research sponsored by the National Institutes of Health's National Center for Complementary and Alternative Medicine and elsewhere. Current trials include testing selenium and vitamin E for the prevention of prostate cancer, the effect of soy isoflavones on prostate cancer, and a pill containing a vegetable and herb mix in advanced non–small-cell lung cancer patients.
The news is not all bad for supplements. The AICR panel did discuss some possible positive effects of supplements in cancer patients and survivors: It noted that calcium probably protects against colorectal cancer at certain doses, and selenium probably protects against prostate cancer.
However, these exceptions are overshadowed by the mass of evidence presented by the AICR indicating that certain supplements may be harmful. For example, there is convincing evidence that high-dose beta-carotene supplements appear to cause lung cancer in tobacco smokers, the report finds.
The message of the new report is unmistakable. "The evidence does not support the use of high-dose supplements of microconstituents as a means of improving outcome in patients with a diagnosis of cancer," Byers said. "And although some studies in specific high-risk groups have shown evidence of cancer prevention from some supplements, this finding may not apply to the general population. It is unwise to recommend widespread nutrient supplementation as a means of cancer prevention."
The report advises against self-administration of supplements as protection against specific cancers, Byers said, notwithstanding the findings on calcium and selenium, which apply in specific settings and at specific doses. The report's recommendations apply to cancer survivors as well, except when treatment has compromised gastrointestinal function.
Wholesome Foods
The panel distinguished between supplements and whole foods. Unlike supplements, whole foods may protect against certain cancers, the panel concluded. The data are consistent that foods containing certain nutrients, including folate, carotenoids, vitamin C, and selenium, probably prevent several different types of cancer.
"Nutrients found in food need to work with other nutrients found in food," said panel member Laurence Kolonel, M.D., Ph.D., deputy director of the University of Hawaii's cancer research center in Honolulu. Fruits and vegetables contain not only vitamins and minerals but also many hundreds of phytochemicals—biologically active chemicals found in fruits and vegetables—some of which are known to have medicinal effects but whose functions are not well understood. Indeed, other unknown substances in foods might be responsible for their cancer protection, Byers said.
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The panel hypothesized that the nutrients in whole foods interact in an unknown but synergistic manner to reduce risk. "Picking one nutrient out and giving it at a pharmacologic dose, which assumes that the maximum tolerated dose is the optimal dose, may disturb biological systems in ways we do not understand," Byers said. "So far, we have not been able to improve on nature's way of combining many nutrients."
Another possible reason that food offers protection against cancer is that diets high in fruits and vegetables are simply lower in foods known to be associated with a higher risk of certain cancers, such as processed foods and red meat, the report noted.
Antioxidants’ Value Unproven
The AICR panel's conclusions echo those of several other studies conducted over the past two decades examining supplements and cancer incidence. Their results have questioned the safety and efficacy of using individual vitamins and minerals and multivitamin supplements to prevent cancer (see sidebar).
The notion that antioxidant supplements, such as beta carotene, selenium, and vitamins C and E, are important in maintaining health and fighting the aging process is still unproven and was challenged recently by Goran Bjelakovic, M.D., of the University of Nis in Serbia, who has conducted several analyses of epidemiological studies. In a recent JNCI editorial, (J Natl Cancer Inst 2007;99:742–743) Bjelakovic suggested a few possible explanations for why studies of antioxidants and cancer produce negative results, and he questioned whether oxidative stress—the production of highly reactive molecules, which are produced in the body as it reacts with oxygen and can damage cells and tissues—is the primary cause of chronic disease and aging or a result. He advised that supplements be studied in different populations before they are marketed. That recommendation may not be realistic in the U.S., however, where vitamin and minerals are considered food supplements and not subject to FDA testing.
Rethink, Cancel, or Do More New Trials?
"Moving forward, we need to rethink studies and conduct more prevention trials with foods rather than supplements," Byers said. He recommends conducting food trials with cancer survivors, "a motivated group," which can be smaller than epidemiological studies. Kolonel agrees and goes even further to say that he does not support any more supplement research for cancer. "The first research on diet, supplements, and food, conducted back in 1982, and every one since, came to the same conclusions: get your necessary nutrients from food."
But Ulrich disagreed. "Much more interdisciplinary research is needed," she said. Supplements can improve the nutritional status of cancer patients who cannot eat a healthful diet, and some epidemiological evidence exists that certain supplements may benefit patients with small-cell lung cancer, she said. "At this point, though, we cannot make science-based recommendations to patients" about taking supplements to prevent cancer.
"We need more research to understand the role of vitamin supplement use in the prognosis of various cancers; standardized definitions of vitamin use; and observational studies examining outcomes of supplement use in relation to treatment efficacy, recurrence, survival, and quality of life," she said. "Then we can do randomized trials."
Folate and Cancer: A Double-edged Sword?
Ulrich has been studying the effects of folate intake on the development and progression of colorectal cancer. "Antifolate drugs have been used to treat cancer for over 50 years, so it seemed logical to examine its effects on cancer," she said. Epidemiological and animal studies indicate that higher intake of folate, fruits, and vegetables is associated with decreased risk of primary colorectal polyps. "We know that folate deficiency leads to mutations and chromosomal damage, effects that are also central to the efficacy of antifolate therapies such as methotrexate," she said.
Taking folate supplements before cancerous lesions appear may prevent tumor development and may have a role in cancer prevention, but adding folate to the diets of patients who already have polyps appears to fuel their growth. In a 2007 chemoprevention study, researchers found an increased risk in advanced adenomas but not in the development of new ones in individuals taking folate supplements. "Timing is everything in folate and cancer," Ulrich wrote in an accompanying editorial. "This vitamin appears to have a bimodal role in carcinogenesis."
In soon-to-be published research in Cancer Epidemiology, Biomarkers, and Prevention, Ulrich notes that folate supplementation in both food and pill form may be harmful for older adults, who are both more likely to take supplements than younger adults. About 30% of adults aged 60 or more years have colorectal polyps. Ulrich has developed a mathematical model of polyp development that finds that, to have benefit, folate supplementation must begin during early childhood, or it will be of little benefit and can be dangerous if begun late in life.
Because many cancer patients gain weight during treatment and lose strength at the same time, studies designed to address these issues with vitamin-dense food, not supplements, makes sense, Byers said. "The problem with oncology is that patients are set back functionally by treatments; we treat them and turn them loose without rehabilitating them."
Studies Indicate Potential Harms Associated With Supplements
- An April 2008 study from the University of Toronto presented at the annual meeting of the American Association for Cancer Research showed that folic acid supplementation given in utero, but not postnatally, protected rats from developing colorectal cancer.
- A March 2008 analysis of more than 77,000 vitamin users showed that supplements do not protect against lung cancer and sometimes increase the risk. In those who developed lung cancer over 4 years, there was a small but statistically significant association between vitamin E supplements and lung cancer; risk rose in a dose-dependent manner and was highest in smokers.
- A 2007 prevention study published in the Journal of the American Medical Association found that patients taking beta carotene, alone or in combination with other antioxidants, showed an increase in mortality from all causes. Other studies point to beta carotene as a possible cocarcinogen.
- A 2007 polyp prevention study in patients with polyps published in JAMA showed that folate supplementation did not reduce risk of colorectal adenomas but rather increased risk of advanced and multiple adenomas at 6–8 years of follow-up, suggesting that undetected precursor lesions are more likely to progress with supplements.
- A 2007 study of beta carotene and vitamins A and E published in JNCI found that they did not decrease mortality but actually sometimes increased it.
- A 2007 study of antioxidants and prostate cancer also published in JNCI showed that multivitamin use not was associated with a risk of early or localized cancer, but high levels of use were associated with an increased risk of advanced and fatal prostate cancer in men with a family history of the disease.
- A 2006 randomized trial in the International Journal of Cancer showed all-cause mortality to be significantly higher in head and neck cancer patients taking vitamin E and beta carotene supplements during radiation therapy and 3 years afterward.
- A 2005 trial with vitamin E supplements published in JNCI found that patients had higher rates of second primary cancers during supplementation and lower rates after supplementation was discontinued.
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J Natl Cancer Inst 2008 100: 773-783.
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