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© 1999 American Society for Clinical Oncology
Alternative and Complementary Therapies in Oncology CareFrom the Hollings Cancer Center, Medical University of South Carolina, Charleston, SC. Address reprint requests to Daniel W. Nixon, MD, Hollings Cancer Center, Medical University of South Carolina, 141 MUSC Complex, Ste 302, Charleston, SC 29425; email nixond{at}musc.edu THE NATIONAL CANCER INSTITUTE1 has estimated that 80% or more of all cancer risk is somehow related to lifestyle, environment, tobacco smoke, and diet. The best estimate is that diet is related to slightly more cancers than tobacco is. If diet is this important, how can we sort out the factors in diet that promote cancer, the factors that prevent cancer, the factors that inhibit cancer, and the factors that are probably not of any importance? A large body of epidemiologic evidence links obesity and an affluent "Western" lifestyle to several types of cancer. The Western lifestyle is associated with a far greater risk of cancer of the breast, colon, and prostate. People in undernourished areas, in contrast, tend to have more squamous cancers of the head and neck, cervix, and esophagus. This observation alone teaches us that there is something in nutrition that must be studied because it is very important in malignant disease. The most frequent cause of cancer death is cachexia. Shields Warren2 showed this in the 1930s, and it has repeatedly been shown to be true. In cases of cancer cachexia, a patient's tumor grows and continues to grow while the host shrinks. This is tumor-associated starvation. Around 1980, on the basis of conventional wisdom, our research group decided to attempt to overcome cancer cachexia by increasing patients' intake of calories and other nutrients, either by tube feeding or oral feeding.3 We succeeded in having them reach the caloric goals that we set for them. However, we learned that we could not replenish lean body mass; we could not put "good" weight back on our patients. The patients could put on water weight and a small amount of fat weight but couldn't create more lean body mass. When we reviewed the patients' oncologic outcomes, we actually found that some cancer patients, and colon cancer patients in particular, had worse outcomes when they were nonvolitionally fed. The survival for the fed patients with advanced colon cancer was approximately 80 days, and, for those patients who were left alone, it was approximately 360 days. This was a great difference in a randomized National Cancer Institue–supported study. It suggests that there are nutritional factors that may promote cancer in certain instances. When we reviewed these patients in retrospect, we began to notice that we had probably been giving them too much fat and fat calories. Over the last 10 years, we have focused on clinical trials using fat-intake reduction in patients with adenocarcinoma of the breast, colon, or prostate. What can physicians tell their patients about fat as a promoting influence in cancer? People who eat a high-fat diet and do not exercise enough will become obese. In the United States, the incidence of obesity is increasing. A series of animal experiments4 at the National Cancer Institute was performed, in which overfed animals were found to have a greater total number of cells and a greater number of cell divisions. Our hypothesis was that metabolic overload, which caused increased cell division because of the increased number of calories—and, specifically, fat calories—created an environment for the development of aberrant cell growth and malignant disease. This topic has been the focus of a great deal of research by Rose et al5,6 at the American Health Foundation and by others.7 Fat and certain fatty acids, such as linoleic acid, promote breast cancer cell growth in the laboratory. Fat therefore makes people fat, obesity is associated with metabolic overload, and fatty acids can have a direct stimulatory effect in cancer cells in the laboratory, all of which can set the stage for cancer. The fat cell itself, via a process within the cell, can increase circulating estrogen levels, which are known stimulators of tumor growth; this again suggests that obesity is a risk factor for cancer. There is a great deal of data available now about animal fat containing concentrations of pesticides and carcinogens, and dichlorodiphenyltrichloroethane (DDT) residues can remain in breast fat for many years after exposure. There is some contradictory data available now that suggests that DDT may be an antiestrogen and may therefore not be as serious a problem in breast cancer as we originally thought8; however, it is unlikely that anybody wants DDT in their fat. An early American Cancer Society–funded clinical trial,9 called the Breast Cancer Dietary Intervention Project, involved breast cancer patients between the ages of 48 and 75, who were screened, assessed, and randomized to a 30% fat (reasonably low-fat) or a 15% fat, very-low-fat diet. The patients were then observed to determine whether they would comply with the low-fat diet and what the end results would be. The pilot phase showed that patients would comply with the 15% fat diet. This study has been superseded by the Women's Intervention Nutrition Study (WINS),10 which is funded by the National Cancer Institute and coordinated by the American Health Foundation. In these studies, there are currently almost 2,000 women whose compliance with either the 30% or 15% fat diet is being evaluated, and soon there should be an answer based on this kind of evidence-based trial regarding whether fat-intake manipulation can serve as an adjuvant treatment in breast cancer. If so, the oncologist will have another tool in the armamentarium to use. Our clinical group does try to make certain that our breast cancer patients being administered adjuvant chemotherapy who are not on a nutritional protocol do not gain weight. There are studies in the literature11 that show that chemotherapy- and hormonal therapy–associated weight gain may be an adverse prognostic event, and cancer patients frequently do gain weight while undergoing adjuvant chemotherapy. Again, when the WINS study is complete, we should also have data regarding this factor. If the results from this study do not show a link between fat and weight gain, cancer researchers will have to look for other factors. If the results do show a link, researchers will have something else to offer their patients in the way of beneficial nutrition advice. This is the whole point of "evidence-based medicine." In our clinic, we advise our patients to look for hidden fat in foods. Some fats can be plainly seen, but fat can be "hidden" in other foods, such as bologna and hot dogs. There may be an equal amount of fat in these foods as in bacon, for example, and maybe even more because of the fats sometimes added to these prepared foods. If physicians want their patients to comply with a low-fat, high-fiber, high-phytochemical diet, a good dietician is needed to counsel them. We try to educate our patients about the effects of different fats in their diets and about the clear relationship between saturated fats, certain polyunsaturated fats, and cancer progression. A patient once brought Leviticus 3:17 to my attention: "A lasting ordinance for the generations to come throughout the world: you must not eat any fat." The verse does not say 30% or less fat: it says none. There is no need even for clinical trials with this advice: Moses knew this 3,500 years ago. There has been a great deal of recent controversy about fiber, as reported in the New England Journal of Medicine12 and elsewhere.13 Fiber is the indigestible part of plants that is composed of lignin and indigestible carbohydrates, with soluble and insoluble varieties. People who consume approximately 2,000 to 2,500 calories a day should consume approximately 25 to 30 grams of fiber a day. In a pilot phase of an American Cancer Society—sponsored trial14 using a high-fiber cereal versus a low-fiber cereal, patients have complied with use of the high-fiber cereal. On the basis of some recent negative data from other trials, researchers will now have to decide what to do next; perhaps a nonsteroidal anti-inflammatory drug could be added to the fiber to see whether a low-fiber diet and a high-fiber diet with or without the nonsteroidal anti-inflammatory drug has different effects in cases of colon cancer. Currently, the most interesting results from laboratory and clinical studies involve phytochemicals from fruits and vegetables and berries. Our group15 is currently researching the effects of ellagic acid, a simple polyphenol compound—probably a natural insecticide—that is found in raspberries, figs, and red grapes. Pomegranates, for some reason, have the highest level of ellagic acid we have determined in the laboratory. We are currently using raspberries as our test substance. Our group studied healthy patients in a clinical research unit and fed them raspberries to determine how much ellagic acid they absorbed; the peak absorption is approximately 5 hours. We therefore examined ellagic acid and DNA synthesis in our laboratory. For example, DNA synthesis in untreated cervical cancer cells increases rapidly. When we exposed these cancerous cells to ellagic acid in the amount that one gets from eating a cup of raspberries, DNA synthesis basically stops for a period of time, and in our study, a very profound apoptotic cell death occurred among human cervical cancer cells approximately 36 hours after being exposed to ellagic acid. Our group is currently studying a number of patients, each of whom has been eating 1 cup of raspberries once a day; they are allowing us to perform biopsies of their colons every 3 months. We are using KR67 assays in this study to determine whether the dose of ellagic acid in 1 cup of raspberries returns the rate of cell proliferation back toward normal in patients with hyperactive colon mucosa, colon polyps, and patients who have had colon cancer. In trying to prove why fruits, vegetables, and grains are good for us, researchers need this kind of data. This particular project will be complete in approximately 6 more months, and our group will be able to publish that data. In summary, the information that we need to inform our patients about nutrition comes from studies such as the WINS trial previously mentioned, the fiber trial on colon polyps previously mentioned, and others. Work continues toward an answer regarding the importance of nutrition in cancer. The American Health Foundation, the only National Cancer Institute–funded cancer center devoted to prevention, is driving hard toward completing these clinical trials, starting new clinical trials, and completing them so that physicians can have an answer to the questions of nutrition in cancer soon. REFERENCES 1. National Cancer Institute: Cancer Control Objectives for the Nation: 1985-2000. Bethesda, MD, NIH publication 86-2880, 1986 2. Warren S: The immediate causes of death in cancer. JAMA184:610-615, 1932 3. Nixon DW, Moffit S, Lawson DH, et al: Total parenteral nutrition as an adjunct to chemotherapy of metastatic colorectal cancer. Cancer Treat Rep65:121-128, 1981 (suppl 5) 4. Albanes D, Salbe AD, Levander OA, et al: The effect of early caloric restriction on colonic cellular growth in rats. Nutr Cancer13:73-80, 1990[Medline] 5. Rose DP, Connolly JM, Liu XH, et al: Dietary fatty acids and human breast cancer cell growth, invasion, and metastasis. Adv Exp Med Biol364:83-91, 1994[Medline] 6. Rose DP, Connolly JM, Meschter CL:
Effect of dietary fat on human breast cancer growth and lung metastasis in
nude mice. J Natl Cancer Inst83:1491-1495, 1991 7. Carroll KK, Khor HT: Effect of level and type of dietary fat on incidence of mammary tumors induced in female Sprague-Dawley rats by 7,12-dimethylbenz( ) anthracene. Lipids6:415-420, 1971[Medline] 8. De Voto E, Millikan R, et al: Risk of breast cancer associated with dichlorodiphenyltrichloro-ethene (DDE) measured in plasma of women in North Carolina. Am J Epidemiol 147: SER Abstracts, 1998 (abstr 91) 9. Kristal AR, Shattuck AL, Bowen DJ, et al: Feasibility of using volunteer research staff to deliver and evaluate a low-fat dietaryintervention: The American Cancer Society Breast Cancer Dietary Intervention Project. Cancer Epidemiol Biomarkers Prev6:459-467, 1997[Abstract] 10. Buzzard IM, Faucett CL, Jeffery RW, et al: Monitoring dietary change in a low-fat dietary intervention study: Advantages of using 24-hour dietary recall vs food records. J Am Diet Assoc96:574-579, 1996[Medline] 11. Camoriano JK, Loprinzi CL, Ingle JN, et al: Weight change in women treated with adjuvant therapy or observed following mastectomy for node-positive breast cancer. J Clin Oncol8:1327-1334, 1990[Abstract] 12. Fuchs CS, Giovannucci EL, Colditz
GA, et al: Dietary fiber and the risk of colorectal cancer and adenoma in
women. N Engl J Med340:169-176, 1999 13. Singh PN, Fraser GE: Dietary risk
factors for colon cancer in a low-risk population. Am J
Epidemiol148:761-774, 1998 14. Edinboro PC, Lawrence W Jr, Nixon DW, et al: Volunteers as adjunct researchers in a cancer prevention trial. Cancer83:2384-2390, 1998[Medline] 15. Narayanan BA, Geoffroy O, Willingham MC, et al: p53/p21 (WAF1/CIP1) Expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett136:215-221, 1999[Medline]
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