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     • The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies, including pregnant and lactating women, children, the elderly, and people with chronic illnesses. Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins. Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate.

• With the exception of vitamins for which there is compelling evidence of net harm (e.g., beta-carotene supplementation in smokers), there is little reason to discourage people from taking vitamin supplements. Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet. All patients should receive information about the benefits of a diet high in fruits and vegetables, as well as information on other foods and nutrients that should be emphasized or avoided in their diet (see 2002 USPSTF recommendations on counseling to promote a healthy diet).4

• Patients who choose to take vitamins should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes (DRI) of the Institute of Medicine. Some vitamins, such as A and D, may be harmful in higher doses; therefore, doses greatly exceeding the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) should be taken with care while considering whether potential harms outweigh potential benefits. Vitamins and minerals sold in the United States are classified as “dietary supplements,” and there is a degree of quality control over content if they have a U.S. Pharmacopeia (USP) seal.5 Nevertheless, imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds.

• The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses. There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods.

• The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects. In 1996, the USPSTF recommended folic acid for all women who are planning, or capable of, pregnancy (see 1996 USPSTF chapter on screening for neural tube defects).6

• Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications (e.g., folic acid supplementation for those patients taking methotrexate).

Scientific Evidence

The USPSTF reviews1-3 focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on the primary prevention of cancer and cardiovascular disease. These reviews were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases.7-9 The reviews focused on prospective trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease.

The value of vitamins naturally occurring in food, the use of vitamin supplements for the prevention of other conditions (e.g., neural tube defects), and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these reviews.

Vitamin A

No prospective trials have examined the effect of vitamin A supplements alone on the risk for cancer. Observational studies provide no evidence that such supplements prevent cancer in men. In women, observational studies have reported a statistically significant inverse association between use of vitamin A supplements and the risk for colon and breast cancer.10,11 Despite efforts to adjust for confounding variables, the observational, non-random design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements. No evidence from prospective trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease. One good-quality cohort study found no effect of vitamin A supplementation on reducing cardiovascular disease mortality.12

Vitamin C

No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported. Observational studies have generally shown no significant associations between use of vitamin C supplements and the risk for cancers of the breast, prostate, colon, or lung.12-14 The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results.12,15,16

Vitamin E

Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease. A randomized controlled trial (RCT) involving Finnish male smokers found that vitamin E supplementation was not protective against lung cancer but may have a beneficial impact on prostate cancer.14 Because prostate cancer was not a primary endpoint of the trial, and the trial suffered from other limitations, further evidence is needed to confirm this finding. Observational studies have shown no significant association between vitamin E supplement use and the risk for prostate, lung, or breast cancer.2 One study suggested that vitamin E protects against colon cancer, but the influence of confounding variables cannot be fully excluded.

17 Among primary prevention trials, 2 good-quality14,18 and 1 fair-quality trial19 found no significant benefit of vitamin E supplementation on preventing cardiovascular disease.20 Only 1 of 7 trials of vitamin E supplementation for secondary prevention demonstrated a significant reduction in cardiac events.1 Some prospective cohort studies have suggested a significant benefit, but the results are mixed and the influence of confounding variables cannot be excluded.1

Beta-carotene

A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung, prostate, colon, breast, or non-melanoma skin cancer.14,21-25 Beta-carotene supplements were associated with an increased risk for lung cancer among smokers, especially heavy smokers, in 2 RCTs.14,25 Results from 4 RCTs demonstrate no reduced risk for cardiovascular events or mortality after beta-carotene supplementation.14,21,22,26-28

Antioxidant Vitamin Combinations

Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results. A recent RCT reported no significant effect of daily supplementation of a combination of antioxidants: vitamin E, vitamin C, and beta-carotene.29 Some studies have suggested an adverse effect of antioxidant combinations on cancer, but the results may have been confounded by the inclusion of beta-carotene.2 Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease13,30,31, but other studies, including well-designed RCTs, have shown no benefit.29,32,33 One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements.34

Multiple Vitamin Combinations

The incremental benefit of taking supplemental doses of folic acid and the B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements.35 In these analyses, folic acid supplementation was associated with significantly decreased risk for colon cancer, but the protective effect requires confirmation in prospective trials. There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease.

Among cohort studies, 1 good-quality study reported a significant reduction in coronary events,36 2 good-quality studies reported no significant effect on mortality,16,37 and 1 fair-quality study reported an increase in all-cause mortality in men.31 No trial has examined the effect of either folate or multivitamins on the primary prevention of cardiovascular disease, but such studies are currently underway.

Potential Harms of Vitamin Supplementation

There are several known adverse effects caused by excessive doses of vitamins; for example, moderate doses of vitamin A supplements may reduce bone mineral density, and high doses may be hepatotoxic or teratogenic. A small but significant increase in lung cancer mortality observed in trials of smokers has been ascribed to beta-carotene supplementation; adverse effects of beta-carotene supplementation on non-smokers have not been observed on other trials. The adverse effects of vitamin supplementation were not reported in most studies reviewed by the USPSTF. More studies are needed to better understand the harms of vitamin supplementation.

Discussion

The findings of this review must be placed in context because it focused only on vitamin supplements and their role in preventing cancer and cardiovascular disease. The value of taking vitamin supplements for other purposes, such as folic acid supplementation by women capable of pregnancy to prevent the birth of babies with neural tube defects, has stronger scientific support.

Although the health benefits of vitamin supplementation remain uncertain, there is more consistent evidence that a diet high in fruit, vegetables, and legumes has important benefits; other constituents besides vitamins may account for the benefits of such diets. Furthermore, dietary supplementation with folic acid, vitamin B-6 (pyridoxine), and vitamin B-12 (alone or in combination) appears to lower plasma homocysteine levels, and higher levels of homocysteine may be an independent risk factor for cardiovascular disease.38 However, definitive evidence of the role of vitamin supplementation on altering cardiovascular outcomes is lacking. The results of a secondary prevention trial will be available within the next few years.

Recommendations of Others

The American Academy of Family Physicians states that “the decision to provide special dietary intervention or nutrient supplementation must be on an individual basis using the family physician's best judgment based on evidence of benefit as well as lack of harmful effects. Megadoses of certain vitamins and minerals have been proven to be harmful.”39 The Canadian Task Force on Preventive Health Care is reviewing the role of vitamin E supplementation on the prevention of cardiovascular disease and cancer.40 The American Cancer Society recommends a well-balanced diet and does not recommend the use of vitamin and mineral supplements as a preventive or therapeutic intervention.41 The American Heart Association Dietary Guidelines Revision 2000 recommends that vitamin and mineral supplements are not a substitute for a balanced and nutritious diet designed to emphasize the intake of fruits, vegetables, and grains.42

References

1. Morris C, Carson S. Vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Int Med 2003;139:56-70.

2. Ritenbaugh C, Streit K, Helfand M. Routine vitamin supplementation to prevent cancer: a summary of the evidence from randomized controlled trials for the U.S. Preventive Services Task Force. Available at: www.preventiveservices.ahrq.gov.

3. Shetty P, Atkins D. Routine vitamin supplementation to prevent cancer: update of evidence from randomized controlled trials, 1999-2002. Available at: www.preventiveservices.ahrq.gov.

4. Pignone M, Ammerman A, Fernandez L, et al. Counseling to promote a healthy diet in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Am J Prev Med 2003;24(1):75-92.

5. U.S. Pharmacopeia Dietary Supplement Verification Program. Available at: www.usp-dsvp.org. Accessed April 30, 2002.

6. Screening for Neural Tube Defects. U.S. Preventive Services Task Force. Guide To Clinical Preventive Services, 2nd ed. Washington, DC: Office of Disease Prevention and Health Promotion; 1996: 467-83. Available at: http://www.ahrq.gov/clinic/uspstf/uspsneur.htm. Accessed May 8, 2003.

7. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Dietetic Assoc 1996;96:1027-39.

8. Ross RK. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993;362:801-9.

9. Diaz MN, Frei B, Vita JA, Keaney Jr. JF. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997;337:408-16.

10. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Nat Cancer Inst 1999:547-56.

11. Bostick RM, Potter JD, McKenzie DR, et al. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's health Study. Cancer Res 1993;53:4230-7.

12. Kushi LH, Stampfer MJ, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 1996;334:1156-62.

13. Hunter DJ, Manson JE, Colditz GA, et al. A prospective study of the intake of vitamins C, E and A and the risk of breast cancer. N Engl J Med 1993:234-40.

14. The Alpha-Tocopherol B-CCPSG. The Effect of Vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35.

15. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology 1992;3:194-202.

16. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64:190-6.

17. Kushi LH, Fee RM, Sellers TA, Zheng W, Folsom AR. Intake of vitamins A,C, and E and postmenopausal breast cancer. The Iowa Women's Health Study. Am J Epidemiol 1996;144:165-74.

18. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000:154-60.

19. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001;357:89-95.

20. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996:150-5.

21. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145-9.

22. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: The Women's Health Study. J Nat Cancer Inst 1999;91:2102-6.

23. Frieling U, Schaumberg D, Kupper T, Muntwyler J, Hennekens CH. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study. Arch Dermatolo 2000;136:179-84.

24. Cook NR, Stampfer MJ, Ma J, et al. Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate cancer. Cancer 1999;86:1783-92.

25. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. JNCI 1996;88:1550-9.

26. Greenberg ER, Baron JA, Karagas MR, et al. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA 1996;275:699-703.

27. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial [published erratum appears in JAMA 1998 May 20;279(19):1528]. JAMA 1996;275:693-8.

28. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med 1998;158:668-75.

29. Heart Protection Study Collaboration Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:23-33.

30. Klipstein-Grobusch K, Geleijnse JM, J.H. den Breeijen JH, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: The Rotterdam tudy. Am J Clin Nutr 1999;69:261-6.

31. Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath Jr. CW. Multivitamin use and mortality in a large prospective study. Am J Epidemiol 2000;152:149-62.

32. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromma A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180-9.

33. Age-related Eye disease Study Research Group. A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E and beta-carotene for age-related cataract and vision loss: AREDS Report No. 9. Arch Ophthalmol 2001;119:1439-52.

34. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and anioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA 2002;288:2432-40.

35. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:517-24.

36. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-64.

37. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk population of U.S. male physicians and subsequent cardiovascular mortality. Arch Intern Med 2002;162:1472-76.

38. Taylor BV, Oudit GY, Evans M. Homocysteine, vitamins, and coronary artery disease: Comprehensive review of the literature. Can Fam Physician 2000;46:2236-45.

39. American Academy of Family Physicians. AAFP Clinical Recommendations. Available at: http://www.aafp.org/policy/camp/19.html. Accessed Mar 27, 2002.

40. Canadian Task Force on Preventive Health Care. Available at: http://www.ctfrpc.org/Whats%20New/reviews_in_progress.html. Accessed Mar 27, 2002.

41. American Cancer Society. Prevention and early detection: Nutrition for risk reduction. Available at: http://www.cancer.org/eprise/main/docroot/ped/ped_3?sitearea+PED&level=1. Accessed Mar 27, 2002.

42. American Heart Association. Vitamins and mineral supplements: AHA scientific position. Available at: http://216.185.112.5/presenter.jhtml?identifier=4788. Accessed Mar 27, 2002.


Members of the Task Force

Members of the U.S. Preventive Services Task Force are Alfred O. Berg, M.D., M.P.H., Chair, USPSTF (Professor and Chair, Department of Family Medicine, University of Washington, Seattle, WA); Janet D. Allan, Ph.D., R.N., CS, Vice-chair, USPSTF (Dean, School of Nursing, University of Maryland-Baltimore, Baltimore, MD); Paul Frame, M.D. (Tri-County Family Medicine, Cohocton, NY, and Clinical Professor of Family Medicine, University of Rochester, Rochester, NY); Charles J. Homer, M.D., M.P.H.* (Executive Director, National Initiative for Children’s Healthcare Quality, Boston, MA); Mark S. Johnson, M.D., M.P.H. (Chair, Department of Family Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ); Jonathan D. Klein, M.D., M.P.H. (Associate Professor, Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY); Tracy A. Lieu, M.D., M.P.H.* (Associate Professor, Department of Ambulatory Care and Prevention, Harvard Pilgrim Health Care and Harvard Medical School, Boston, MA); Cynthia D. Mulrow, M.D., M.Sc.* (Clinical Professor and Director, Department of Medicine, University of Texas Health Science Center, and Director, National Program Office for Robert Wood Johnson Generalist Physician Faculty Scholars Program, San Antonio, TX); C. Tracy Orleans, Ph.D. (Senior Scientist and Senior Program Officer, The Robert Wood Johnson Foundation, Princeton, NJ); Jeffrey F. Peipert, M.D., M.P.H.* (Director of Research, Women and Infants’ Hospital, Providence, RI); Nola J. Pender, Ph.D., R.N.,* (Professor Emeritus, University of Michigan, Ann Arbor, MI); Albert L. Siu, M.D., M.S.P.H. (Professor of Medicine, Chief of Division of General Internal Medicine, Mount Sinai School of Medicine, New York, NY); Steven M. Teutsch, M.D., M.P.H. (Senior Director, Outcomes Research and Management, Merck & Company, Inc., West Point, PA); Carolyn Westhoff, M.D., M.Sc. (Professor, Department of Obstetrics and Gynecology, Columbia University, New York, NY); and Steven H. Woolf, M.D., M.P.H. (Professor, Department of Family Practice and Department of Preventive and Community Medicine, Virginia Commonwealth University, Fairfax, VA).

*Member of the USPSTF at the time this recommendation was finalized.

Contact the Task Force
Address correspondence to: Chair, U.S. Preventive Services Task Force; c/o Project Director, USPSTF; 540 Gaither Road; Rockville, MD 20850; E-mail: uspstf@ahrq.gov.

Available Products

This recommendation and rationale statement, plus complete information on which this statement is based, including evidence tables and references, are available on the USPSTF Web site at http://www.preventiveservices.ahrq.gov.
Individual copies of this statement are available online through the National Guideline Clearinghouse™ at: http://www.guideline.gov; or may be obtained in print from the AHRQ Publications Clearinghouse: Phone Toll-Free 1-800-358-9295; E-mail ahrqpubs@ahrq.gov.

The summary of the evidence and the recommendation statement are also available in print by subscription to the Guide to Clinical Preventive Services, Third Edition: Periodic Updates. Contact the AHRQ Publications Clearinghouse (call 1-800-358-9295 or E-mail ahrqpubs@ahrq.gov).

Recommendations made by the USPSTF are independent of the U.S. Government. They should not be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Source: This recommendation first appeared in Ann Intern Med 2003;139(1):51-5.

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