Hundreds of studies have reported on the relationships between diet and cancer, but far fewer have examined the effects of supplements specifically. Ruth Patterson, PhD, examines whether vitamins and minerals can combat cancers of the breast, cervix, endometrium and ovaries
Recent randomised controlled trials of supplements have yielded some unexpected findings. In trials of high-risk individuals (smokers or asbestos workers), beta-carotene, which had been believed to prevent cancer, was found to actually increase the incidence of lung cancer, while vitamin E had no effect on lung cancer risk.1,2 Selenium, which was hypothesised to reduce risk of non-melenomatous skin cancers, had no effect on skin cancer, but instead reduced the risk of a broad range of other cancers.3 A New York Times front page story stated: "Consumers are, in effect, volunteering for a vast, largely unregulated experiment with substances that may be helpful, harmful or simply ineffective."4
The purpose of this review is to present data from studies on humans that investigated the use of vitamin supplements and risk of female cancers of the breast, cervix, endometrium and ovaries. To examine the role of supplement use, only studies that presented findings on multivitamins or nutrients from supplements, separate from food, will be included. Studies on total intake of nutrients (diet plus supplements) are not presented because it is not possible in such studies to separate effects of other bioactive compounds present in foods, such as phytochemicals, from those of the specific micronutrients of interest.
As an introduction, this paper will briefly review potential mechanisms whereby dietary supplements could prevent cancer. The majority of the review is devoted to synthesising results from studies that have provided data on supplement use and female cancer risk. Finally, issues relevant to this research are presented, with emphasis on problems in supplement studies. Hereafter, the term 'vitamin supplement' will include both vitamin and mineral supplements, and the term 'multivitamin' refers to a one-a-day type multivitamin with minerals.
Based on hundreds of epidemiologic studies on diet and cancer, there is extensive evidence that plant foods lower the risk of human cancers.6,7,8 The World Cancer Research Fund book, "Food, Nutrition and the Prevention of Cancer: A Global Perspective," concluded that a strong and consistent pattern shows that diets high in vegetables and fruit intake decrease the risk of many cancers.
The mechanisms underlying these associations are likely complex. A large number of compounds in plant foods may influence the risk of cancer, including both micronutrients for normal metabolism and other bioactive compounds with unknown metabolic significance. Human, animal and in vitro studies have identified many bioactive compounds that may influence the risk of cancer. Included among potential agents are a variety of vitamins (such as retinol, vitamins C and E, and folic acid), their precursors (such as beta-carotene), minerals (calcium and selenium) and other bioactive compounds.
Laboratory studies have suggested many mechanisms whereby micronutrients commonly found in vitamin and mineral supplements could prevent— or promote— cancer.
Most attention has focused on the antioxidant micronutrients, such as carotenoids, vitamins C and E, selenium and zinc.9,10,11There are many potentially relevant functions for antioxidants, including protection of cell membranes and DNA from oxidative damage, scavenging and reduction of nitrites, and serving as co-factors for enzymes that protect against oxidative damage.7 However, these compounds may also, in high doses or under certain conditions, have pro-oxidant effects.12
Improved understanding of cancer biology will be needed for identifying the metabolic processes that can be affected by vitamin and mineral supplementation. Currently, the mechanisms of action for some nutrients include:
- Vitamin A plays a role in the differentiation of normal epithelial cells and the maintenance of intercellular communication through gap junctions, thus repressing the processes leading to abnormal cell replication.13
- Vitamin C enhances immune response and connective tissue integrity.7
- Vitamin D may reduce risk of colon cancer because it controls the availability and intracellular functions of calcium.10
- Folic acid deficiencies may increase hypomethylation of DNA, with subsequent loss of the normal controls on gene expression.14
- Iron may increase risk of cancer because it enhances the growth of transformed cells and acts as a pro-oxidant, thereby increasing carcinogenic DNA changes and general oxidative stress.15
- Calcium could reduce colon cancer risk by binding bile acids and normalizing colorectal epithelial cell proliferation.16,17
- Selenium may block the clonal expansion of early malignant cells, perhaps by modulating cell cycle proteins and apoptotic proteins.18
Studies Of Supplements
Table 1 summarises the epidemiologic evidence for associations between multi-vitamins and supplemental vitamins C and E, and calcium, and the cancers of the breast, cervix, endometrium and ovaries. Findings related to other specific nutrients in multivitamins, such as folate or selenium, and these cancers, could inform associations of cancer with multivitamin use.
This is a review of epidemiologic research and therefore includes only studies of humans. These studies include two types: cohort and case-control studies.
Cohort studies measure the supplement use of a group of disease-free participants. This group is then followed to assess the occurrence of disease outcomes. Cohorts are attractive for studies of supplement use because they can assess the effects of many types, doses and combinations of supplements with multiple cancers. Their primary limitation is that supplement use is self-selected, so that factors such as diet or exercise may interfere with an investigator's ability to isolate the effect of supplement use from other healthy lifestyle behaviours.
In case-control studies, participants are selected based on whether they do (case) or do not (control) have cancer. The groups are then compared to see whether supplement use varies by disease status. Selection bias can occur if supplement users are more likely than non-users to agree to be controls in a study. This bias is probable because supplement users are more interested in health issues than non-users, and therefore more likely to participate in a research study. Selection bias may therefore lead to finding a protective effect of a supplement, which may be erroneous.
Breast cancer: There is little evidence that multivitamins or supplemental vitamins C or E influence the risk of breast cancer. In reports from four cohort studies 19,20,21,22 and three case-control studies,23,24,25 the only statistically significant finding, from the Canadian National Screening Study, was an increased risk of breast cancer associated with vitamin C supplement use.20However, there was a significantly reduced risk of death from breast cancer amongst women who consumed supplemental vitamin A, C or E in the American Cancer Society (ACS) cohort study.26
Furthermore, in a pooled diet-breast cancer analysis of nine case-control studies involving 7,000 cases, researchers found that vitamin C was the dietary factor most strongly associated with reduced risk of breast cancer.27(OR=0.73; p=0.03)
There is some evidence that multivitamins reduce the risk of breast cancer amongst regular alcohol drinkers, probably due to the folic acid content.28 This is supported by two other cohort studies reporting that higher folate consumption (from diet and/or supplements) was associated with decreased risk of breast cancer amongst alcohol drinkers.29,30 Although the mechanism for this interaction is not entirely clear, it is hypothesised that alcohol intake results in DNA damage that may be modulated by folate, given its role in DNA synthesis and methylation.
There has been only one study of calcium supplements and female breast cancer. Amongst post-menopausal women, there was no overall association of calcium supplements with breast cancer, although there appeared to be a benefit among those in the lowest tertile of dietary calcium intake (¾ 200mg per day).31
Cervical cancer: Two case-control studies of supplement and invasive cervical cancer suggest a protective effect of multivitamins, vitamins A and folate (which were likely obtained mostly from multivitamins) and vitamins C and E.32,33 Although none of these findings were statistically significant, it is important to note that these studies were rather small and had limited power to detect associations of supplements and cancer. In addition, nutritional studies of cervical cancer to date have been limited by the fact that human papillomavirus (HPV), which is a powerful risk factor for this cancer, was not measured. Therefore, these studies do not account for HPV infection.
Endometrial cancer: The published data are conflicting for this association. In a small case-control study, researchers found evidence for increased risk of endometrial cancer among women taking supplemental A and D (probably an effect of taking multivitamins) and supplemental vitamins C and E.34 However, none of these associations were statistically significant. Calcium, conversely, seemed protective, although again the association was not significant.
A study of women in China found modest, nonsignificant protective effects of any supplement on endometrial cancer.35However, in a large, case-control study conducted in Sweden, researchers found that daily intake of calcium supplements (dose not assessed) was associated with a statistically significant 50 per cent decrease of endometrial cancer risk.36There was also a suggestion of an increased risk associated with iron supplements.
Ovarian cancer: Supplemental vitamins C and E appeared to significantly decrease the risk of ovarian cancer by roughly half.37There was no significant effect of vitamin A, beta-carotene or selenium (which were likely to have been largely obtained from multivitamins). In the large and ongoing Nurses Health Cohort Study, researchers found no evidence of an association between dose or duration of use of supplemental vitamins A, C or E and ovarian cancer.38 However, researchers also indicated that they had limited power to assess these relations. Finally, in a 2002 study researchers found a modest, non-significant decreased risk of ovarian cancer with calcium use.39
It is clear from the above review that there is not sufficient high-quality research on vitamin supplements and female cancer risk from which to draw any firm conclusions. Previous studies have been limited by low prevalence of supplement use, crude methods of assessing supplement use, and analytic approaches that did not separate supplements from nutrients obtained from food.
In addition, the studies reviewed here can be compromised because supplement use is a marker for other healthful behaviours. Specifically, supplement users are more likely than non-users to be female, Caucasian, better educated, non-smokers, light drinkers, regular exercisers, consumers of diets higher in fruit and vegetables and lower in fat, obtain regular mammograms, and take other disease-preventive agents such as baby aspirin.40,41,42 In theory, statistical analyses can control for these confounding factors. However, such statistical control cannot be assured, especially if important confounding factors are not known or measured.
In spite of the limitations of the data, a few tentative conclusions can be drawn about supplement use and female cancers. A daily multivitamin and mineral pill may be beneficial and is unlikely to be harmful. While vitamins C and E appear to be safe even at fairly high doses (eg, 500mg Vitamin C, 400IU vitamin E), these data offer only modest evidence that they reduced risk of female cancers. Finally, calcium supplements appear protective and additionally may be useful for prevention of fractures (See sidebar, "The Women's Health Initiative Calcium/Vitamin D Trial," below).
High-quality research on vitamin supplements and cancer risk is needed. If beneficial effects of some supplements are found, these could be rapidly translated into cancer control programmes. Interventions based on food fortification or supplement use would be inexpensive and behaviourally feasible, especially compared with interventions requiring major dietary changes. In addition, if some supplements were found to have no effect, this would be important information to the approximately 100 million adult Americans who take supplements.
Ruth Patterson, PhD, is co-principal investigator of the Coordinating Center of the Women's Health Initiative, involving 65,500 women and the health effects of a low-fat dietary pattern, hormone replacement therapy, and calcium/vitamin D supplementation. She is also co-principal investigator involving 77,000 adults of vitamin use and cancer risk.
1. ATBC SG. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. New Engl J Med 1994; 330:1029-35.
2. Omenn GS, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New Engl J Med 1996; 334:1150-5.
3. Clark LC, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996; 276:1957-63.
4. Brody JE. In vitamin mania, millions take a gamble on health. The New York Times. New York, 1997:20-21.
5. Patterson RE, et al. Vitamin supplements and cancer risk: a review of the epidemiologic evidence. Cancer Causes Control 1997;8:786-802.
6. World Cancer Research Fund. Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, D.C.: American Institute for Cancer Research, 1997.
7. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996; 96:1027-39.
8. Willett WC, Trichopoulos D. Nutrition and cancer: a summary of the evidence. Cancer Causes Control 1996; 7:178-80.
9. Diplock AT. Antioxidant nutrients and disease prevention: an overview. Am J Clin Nutr 1991;53 (suppl):189-193.
10. Weisburger JH. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. Am J Clin Nutr 1992;53 (Suppl):226S-2237S.
11. Willett WC. Micronutrients and cancer risk. Am J Clin Nutr 1994;59 (Suppl):1162S-1165S.
12. Herbert V. Symposium: Prooxidant effects of antioxidant vitamins. J Nutr 1996;126 (suppl).
13. Hossian MZ, et al. Enhancement of gap junctional communication by retinoids correlates with their ability to inhibit neoplastic transformation. Carcinogenesis 1989;10:1743-8.
14. Giovannucci E, et al. Folate, methionine, and alcohol intake and the risk of colorectal adenoma. J Natl Canc Inst 1993;85:875-84.
15. Bird Cl, et al. Plasma ferritin, iron intake, and the risk of colorectal polyps. American Journal of Epidemiology. 1996;144:34-41.
16. Alberts DS, et al. Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps. J Natl Canc Inst 1996;88:81-92.
17. Bostick RM, et al. Calcium and colorectal epithelial cell proliferation: a preliminary randomized, double-blinded, placebo-controlled clinical trial. J Natl Canc Inst 1993;85:132-141.
18. Ip C. Lessons from basic research in selenium and cancer prevention. J Nutr 1998;128:1845-54.
19. Shibata A, et al. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Canc 1992; 66:673-9.
20. Rohan TE, et al. Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study. Cancer Causes Control 1993; 4:29-37.
21. Kushi LH, et al. Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women's Health Study. Am J Epidemiol 1996; 144:165-74.
22. Zhang S, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Canc Inst 1999a; 91:547-56.
23. Ewertz M, Gill C. Dietary factors and breast-cancer risk in Denmark. Intl J Cancer 1990; 46:779-84.
24. Freudenheim JL, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Canc Inst 1996; 88:340-8.
25. Moorman PG, et al. Vitamin supplement use and breast cancer in a North Carolina population. Public Health Nutr 2001; 4:821-7.
26. Watkins ML, et al. Multivitamin use and mortality in a large prospective study. Am J Epidemiol 2000; 152:149-62.
27. Howe GR, et al. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst 1990; 82:561-9.
28. Zhang S, et al. A prospective study of folate intake and the risk of breast cancer. JAMA. 1999b; 281:1632-7.
29. Rohan TE, et al. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000; 92:266-9.
30. Sellers TA, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001; 12:420-8.
31. Shin MH, et al. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002; 94:1301-11.
32. La Vecchia C, et al. Dietary vitamin A and the risk of invasive cervical cancer. Intl J Cancer 1984;34:319-22.
33. Ziegler RG, et al. Diet and the risk of invasive cervical cancer among white women in the United States. Am J Epidemiol 1990;132:432-45.
34. Barbone F, et al. Diet and endometrial cancer: a case-control study. Am J Epidemiol 1993;137:393-403.
35. Subar AF, Block G. Use of vitamin and mineral supplements: demographics and amounts of nutrients consumed. The 1987 Health Interview Survey. Am J Epidemiol 1990; 132:1091-101.
36. Shu XO, et al. A population-based case-control study of dietary factors and endometrial cancer in Shanghai, People's Republic of China. Am J Epidemiol 1993;137:155-65.
37. Terry P, et al. Dietary factors in relation to endometrial cancer: a nationwide case-control study in Sweden. Nutr Cancer 2002;42:25-32.
38. Fleischauer AT, et al. Dietary Antioxidants, Supplements, and Risk of Epithelial Ovarian Cancer. Nutr Cancer 2001;40:92-8.
39. Fairfield KM, et al. Risk of ovarian carcinoma and consumption of vitamin A, C, and E and specific carotenoids: a perspective analysis. Cancer. 2001;92:2318-26.
40. Goodman MT, et al. Association of dairy products, lactose, and calcium with the risk of ovarian cancer. Am J Epidemiol 2002;156:148-57.
41. Slesinski MJ, et al. Dietary intake of fat, fiber and other nutrients is related to the use of vitamin and mineral supplements in the United States: The 1992 National Health Interview Survey. J Nutr 1996;126:3001-8.
42. Patterson RE, et al. Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev 1998; 7:79-81.