Can Vitamins Decrease
The Risk Of Women's Cancers?This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to: Frankp@chiro.org
From The June 2003 Issue of Functional Foods & Nutraceuticals
By Ruth PattersonWomen seek the best vitamin supplements to reduce their risk of cancer. Ruth E Patterson, PhD, explores what really works.
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.
Findings regarding multivitamin use are a particular challenge because one cannot isolate the potential effect of the micronutrient of interest, for instance folate, from all the other vitamins and minerals in the supplement. Thus, micronutrients that are seldom taken as single supplements, such as vitamin A, folate, selenium or zinc, almost entirely reflect the use of multivitamins. To investigate micronutrients from supplements, study samples must have sufficient numbers of participants using single supplements to separate out the effects of these micronutrients from multivitamin use. Therefore, studies are presented only on multivitamins and the following micronutrients: vitamins C and E, and calcium. These micronutrients represent the most commonly used single supplements and it is at least plausible that studies of these micronutrients had enough users to isolate their effect from that of multivitamins. [5]
Micronutrients commonly found in vitamin and mineral supplements could prevent—or promote—cancer
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.
Potential Mechanisms
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. [9,10,11]There 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. [20]However, 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. [35]However, 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. [36]There 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. [37]There 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]
Trending Data
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.
State Of The Science
The Women's Health Initiative Dietary Intervention Trial
The Women's Health Initiative (WHI) is studying the health of 161,809 postmenopausal women ages 50 to 79, enrolled from 1993-1998, by 40 clinical centres across the US. The WHI includes two Hormone Therapy Trials, a Dietary Modification Trial, a Calcium/Vitamin D Trial and an Observational Study. [1]
The Dietary Modification (DM) trial is a randomised controlled evaluation of a low-fat diet high in fruits, vegetables and grains. This low-fat dietary pattern is hypothesised to reduce the risk of breast and colorectal cancer (and secondarily, cardiovascular disease) in postmenopausal women. [2]
To test these hypotheses, researchers in the low-fat trial randomly assigned eligible women to the intervention arm (40%, n=19,542) or the usual diet, control arm (60%, n=29,294). Women were eligible if they had an estimated baseline fat intake >=32% of energy consumption, based on the WHI food frequency questionnaire. This screening was meant to exclude women already consuming low-fat diets and thereby increase the difference in dietary fat intake between the control and the low-fat intervention group post-intervention.
The primary goal of the WHI dietary intervention is to reduce total dietary fat to 20 per cent of energy. [3] Additional goals include reducing saturated fat to seven per cent of energy and increasing fruit and vegetable servings to five or more daily and grain servings to six or more daily. To support these goals, women were assigned to groups of eight to 15 participants. Within one year of its start date, each group was given 18 sessions designed to promote dietary and behaviour change. In subsequent years, group maintenance sessions are conducted quarterly. Intervention group participants are asked to self-monitor dietary intake throughout the trial.
The planned termination of the trial is 2005. No previous study has attempted to achieve such a significant dietary change, in as large a sample, for as long a period of time (8.5 years on average).
The Women's Health Initiative Dietary Modification trial has the potential to answer questions of considerable public health importance concerning the effect of a low-fat dietary pattern on breast and colorectal cancers and other chronic diseases.
References
1. The Women's Health Initiative Study Group. Design of the Women's Health Initiative Clinical Trial and Observational Study. Controlled Clinical Trials. 1998;19:61-109.
2. Ritenbaugh C, et al. The WHI Dietary Modification Trial: Overview and Baseline Characteristics of Participants. Annals of Epidemiology (In Press, 2003).
3. Tinker LF, et al. The effects of physical and emotional status factors on adherence to a low-fat dietary pattern in the Women's Health Initiative. J Am Dietetic Assoc 2002;102:799-800.
State Of The Science
The Women's Health Initiative Calcium/Vitamin D Trial
The Women's Health Initiative (WHI) is an ambitious population research investigation addressing the major chronic diseases of postmenopausal women. [1] One component of WHI, the Calcium/Vitamin D (CaD) trial, was designed to test the primary hypothesis that women who are randomised to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and, secondarily, a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo. [2]
Enrollment into the CaD component was delayed by one year to avoid undue participant burden at entry into WHI. Participants in the Dietary Modification and/or Post-menopausal Hormone Therapy trial(s) were invited to join the CaD trial at the first or second annual follow-up visit. Only women who were already randomised into another component of the WHI clinical trial were eligible to join CaD. Women were allowed to continue their own personal use of calcium and vitamin D as long as their personal vitamin D intake did not exceed 600IU. The upper limit of personal vitamin D intake was raised to 1,000IU after the Institute of Medicine released the report on safe upper limits of calcium and vitamin D intake in 1997.
Willing and eligible women were randomly assigned in a double-blind fashion to supplement or placebo. Each active tablet consisted of 500mg elemental calcium (as calcium carbonate) and 200IU vitamin D3. Participants were instructed to take two tablets per day, preferably in divided doses, with meals. This regimen was chosen to maximise absorption of the calcium. Initially, only a chewable formulation was available but in October 1997, in an effort to enhance tolerability, a swallowable form of the CaD supplement and placebo was developed and made available. A visual inspection of the CaD study pills was provided and a taste and/or swallow test was offered before randomisation. At each annual visit, women already enrolled in CaD are given the option of switching to the other formulation if desired.
The planned termination date of the CaD trial is 2005. This trial will provide rigorous tests of the hypotheses that CaD supplementation reduces risk of fracture and colorectal cancer in post-menopausal women. This trial has the largest sample size, longest duration of follow-up and widest distribution of calcium intake of any clinical trial to date. These strengths will also permit evaluation of treatment effect in important sub-groups of women, including those of different ages, race and ethnic backgrounds and at different levels of baseline risk.
References
1. The Women's Health Initiative Study Group. Design of the Women's Health Initiative Clinical Trial and Observational Study. Controlled Clinical Trials. 1998;19:61-109.
2. Jackson RD, et al. The Women's Health Initiative Calcium-Vitamin D Trial: Overview and Baseline Characteristics of Participants. Annals Epidemiol (In Press, 2003).
3. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes FaNBIOM. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride. Washington, DC. National Academy Press, 1997.
Table 1: Studies Of Multi- And Supplemental Vitamins C, E, Calcium
And Risk Of CancersAuthor/Year Location (cases) (cases/controls) Supplement
(high dose)Relative Risk of >/=
High Dose vs NoneBreast Cancer Shibata
1992Leisure World
11,580 retirees in California (219 cases)Vitamin C (500mg)
Vitamin E (200 mg)0.9 (0.7-1.2)
0.9 (0.7-1.2)Roban
1993Canadian Breast Screen
56,837 women (519 cases)Vitamin C (250mg)
Vitamin E (4mg)1.5 (1.1-2.0)
1.0 (0.7-1.5)Kushi
1996Iowa Women’s Health Study
34,387 women (879 cases)Vitamin C (1,000mg)
Vitamin E (250mg)0.8 (0.5-1.2)
1.0 (0.8-1.2)Shin
2002Nurses’ Health Study
88,691 women in US (2,345 cases)Calcium (900mg) 0.93 (0.81-1.08) Zhang
1999Nurses’ Health Study
77,925 women in US (2,523 cases)Vitamin C (1300mg)
Vitamin E (600mg)
Multivitamin (10yrs)1.0 (0.8-1.4)
0.9 (0.7-1.2)
1.0 (0.9-1.1)Ewertz
1990Denmark
(1,486/1,336)Vitamins ABCD (current)
Vitamins ABCD + minerals (current)
Vitamins ABCDE (current)1.3 (1.0-1.7)
1.3 (0.8-1.9)
1.2 (0.9-1.7)Ewertz
1990Denmark
(1,486/1,336)Vitamins ABCD (current)
Vitamins ABCD + minerals (current)
Vitamins ABCDE (current)1.3 (1.0-1.7)
1.3 (0.8-1.9)
1.2 (0.9-1.7)Freudenheim
1996Premenopausal women in
New York (297/311)Vitamin C (264mg)
Vitamin E (31mg)1.0 (.06-1.5)
1.0 (0.6-1.5)Moorman
2001North Carolina
(861/790)Multivitamins (3 yrs)
Vitamin C (3 yrs)
Vitamin E (3 yrs)0.83 (0.59-1.17)
1.0 (0.62-1.62)
0.78 (0.46-1.35)Invasive Cervical Cancer La Vecchia
1984Italy (191/191) Vitamin A 0.3 (Ptrend=0.17) [b] Ziegler
1990Alabama, Illinois, Colorado, Florida,
Pennsylvania (271/502)Multivitamin
Vitamin A
Vitamin C
Vitamin E
Folic Acid0.6 (Ptrend=0.15) [b]
0.8 (Ptrend=0.51) [b]
0.7 (Ptrend=0.24) [b]
0.7 (Ptrend=0.40) [b]
0.7 (Ptrend=0.52) [b]Endometrial Cancer Barbone
1993Alabama (US)
(103/236)Vitamins A and D
Vitamin C
Vitamin E
Calcium1.7 (1.0-3.0)
1.4 (0.9-2.4)
1.4 (0.8-2.3)
0.8 (0.4-1.3)Shu
1993China
(268/269)Any Supplement 0.9 (0.5-1.6) Terry
2002Sweden
(709/2,887)Calcium (daily vs none)
Iron (daily vs none)0.5 (0.3-0.9)
1.7 (0.9-3.3)Ovarian Cancer Fleischauer
2001New York
(168/251)Vitamin C (highest vs none)
Vitamin E (highest vs none)
Vitamin A (highest vs none)
Beta-carotene (highest vs none)
Selenium (highest vs none)0.53 (0.29-0.95) [d]
0.43 (0.26-0.72) [d]
1.16 (0.69-1.96) [d]
1.15 (0.67-1.97) [d]
0.90 (0.56-1.45) [d]Goodman
2002Hawaii or Los Angeles
(558/607)Calcium (highest vs none) 0.81 (0.56-1.17) [d]
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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.
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6. World Cancer Research Fund. Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, D.C.: American Institute for Cancer Research, 1997.
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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.
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42. Patterson RE, et al. Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev 1998; 7:79-81
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