Do Multivitamins Prevent Cancer in Men?

Abstract & Commentary

By Melissa Quick, DO, and David Kiefer, MD, Dr. Quick is PGY-2 at the Beth Israel Residency in Urban Family Practice at the Beth Israel Medical Center in New York. Dr. Quick reports reports no financial relationships relevant to this field of study.

Synopsis: A 15-year, placebo-controlled, randomized study in middle-aged and elderly male physicians demonstrated a small yet statistically significant reduction in total cancer risk with multivitamin intake.

Source: Gaziano J, et al. Multivitamins in the prevention of cancer in men: The Physicians’ Health Study II randomized controlled trial. JAMA 2012 doi:10.1001/jama.2012.14641.

The efficacy of multivitamins for preventing chronic diseases and cancers has been engulfed in controversial studies for decades. In fact, the highly influential United States Preventive Task Force — an independent panel of non-governmental experts in prevention and evidence-based medicine — gives an “indeterminate” recommendation to the routine use of vitamin supplementation to prevent cancer and cardiovascular disease.1 Nonetheless, the statistics surrounding multivitamin use and cancer rates are striking. Between 2003 and 2006, 40% of U.S. adults used multivitamins.2 Additionally, one out of every two U.S. men will develop cancer in his lifetime.3 Premised on these statistics, the Physicians’ Health Study II (PHS II) provides new, comprehensive data on the relationship between multivitamin intake and cancer prevention.

A total of 14,641 male U.S. physicians age 50 years or older (at time of enrollment) participated in a 15-year, double-blind, placebo-controlled study. The men were randomized into two groups and were sent monthly dose packs of either a multivitamin, (Centrum Silver donated by Pfizer, n = 7317) or a placebo (n = 7342) to be taken daily. The baseline characteristics of the two groups (noted as multivitamin use vs placebo use, respectively) were comparable, including similarities in mean age (64.2 vs 64.3), body mass index (BMI, 25.9 vs 26), self-reported history of cancer (“No”: 91.1% vs 90.9%), self-reported history of prostate cancer (“No”: 95.5% vs 95.5%), self-reported history of colorectal cancer (“No”: 99.2% vs 99.2%), among other parameters measured. Adherence, adverse effects, cancer diagnoses, cardiovascular events, and risk factors for cancer (e.g., parental history) were assessed annually by questionnaire. A National Death Index search was performed for any participants with no response. Physicians blind to treatment group assessed and reviewed all cancer and mortality endpoints. In addition, 96.9% of reported cancers were confirmed by pathology or cytology reports.

The primary endpoints were total cancer and major cardiovascular events; and the secondary endpoints were prostate, colorectal, and other site-specific cancers. Due to the fact that nearly half of all reported cancers were prostate cancers (the study hypothesizes that increased surveillance may have contributed to this higher-than-expected percentage), a new group, titled “Total cancer minus prostate cancer,” was created to allow additional analysis.

After a mean follow-up of 11.2 years, the rates of total cancer (reported as first cancer events only) were 17.0 and 18.3 per 1000 person years in the multivitamin and placebo groups, respectively, representing an approximate 8% reduction in the multivitamin group (hazard ratio [HR], 0.92; 95% confidence interval [CI] 0.86-0.998; P = 0.04). There was no effect of a multivitamin on prostate cancer risk (HR, 0.98; 95% CI, 0.88-1.09; P = 0.76). However, the risk of total cancer excluding prostate cancer was reduced by 12% (HR, 0.88; 95% CI, 0.79-0.98; P = 0.02). Adherence at the end of follow-up after 11.2 years was 67.5% and 67.1% within the multivitamin group and placebo group, respectively. Reported adverse events were minor, but men in the multivitamin group reported more rashes and epistaxis (rashes: HR 1.07; 95% CI, 1.01-1.14; P = 0.03; epistaxis: HR 1.1; 95% CI, 1.02-1.18; P = 0.01).

Commentary

This study is a welcome addition to previous inconclusive research exploring the connection between daily vitamin supplementation and chronic disease or cancer. The results of this study contradict previous research showing an increase in cancer rates with particular vitamins. Consider, for instance, the slightly increased rate of lung cancer with beta-carotene supplements in smokers in one study.4 The rate of lung cancer was not increased in the PHS II, likely secondary to the lower doses of beta-carotene used and a population that was primarily non-smoking and unexposed to asbestos. As an example, the beta-carotene component in the PHS II was only 375 mcg compared to the 20,000 and 30,000 mcg beta-carotene supplements used in the studies that showed the increased lung cancer.5,6,7 In general, the PHS II used lower doses and a broader vitamin formulation than many previous research studies, which may have contributed to more positive results.

The study being reviewed here had several strengths. It was long-term, with a mean follow-up of 11.2 years (a range of 10.7-13.3 within the total 15-year time period), which may capture some of the chronology of cancer development, although a longer follow-up would be ideal for a disease process such as carcinogenesis. In addition, this was a large trial, improving on the power of the statistics and believability of the results.

However, there are several aspects of the study that warrant further examination. First, the population does not accurately represent the majority of the U.S. population. These men were all middle-aged or elderly physicians, presumably of higher socioeconomic status and with a higher level of awareness of “healthy living” than the average U.S. citizen. For example, the mean BMI in the study population was approximately 26, as compared to the U.S. mean of 28.7 for men.8 Furthermore, a mere 3.6% of the men in the study were current smokers, compared to 21.5% of all male adults in the United States.9 Both obesity and tobacco use have clear associations to cancer, and the population in this study grossly underrepresents the prevalence of these risk factors. It is unclear if comparable data would be reproduced in a future study using more “typical” U.S. men as subjects.

Second, this study overlooks several crucial facts regarding general nutrition and bioavailability of vitamins. Most notably, the “placebo” subjects were not devoid of vitamin intake (this group still ate fruits and vegetables, fortified foodstuffs, etc.), thus diminishing a clear distinction between placebo and control group. Monitoring the precise amount of vitamins and minerals ingested and absorbed from the diet is nearly impossible. Indeed, the PHS II states that both multivitamin and placebo groups ate approximately four servings of fruits and vegetables daily. It is likely that both groups were receiving a high percentage of their daily value of vitamins and minerals from their diets alone. This calls into question whether the subjects receiving a multivitamin actually benefitted from the additional vitamins for several reasons. First, there is a wide-range of nutrient levels that allow for optimal physiological functioning. Thus, additional supplementation of vitamins or minerals does not correlate to increased functionality after a certain threshold is reached.10 Second, the bioavailability of vitamins and minerals in any form varies among individuals.11

Essentially, it is unclear whether the subjects taking a multivitamin did in fact benefit by having a higher level of vitamins compared to the placebo group, who, for all intents and purposes, may have had similar vitamin levels simply secondary to their well-balanced diet and the fortification of foods. If this study showed a clear deficit in nutrients in the placebo group — a level below the threshold for physiological functionality — and a corresponding elevated nutrient level in the multivitamin group, there would be greater credence to the utility of multivitamins as a supplement and preventive measure.

The question remains: Should we be recommending a multivitamin to our patients? Since the fortification of foods in the United States is a common practice, nutritional deficiencies are scarce in this day and age. The topic of proper nutrition is beyond the scope of this article, yet it is important to touch on the basic premises of why a multivitamin is beneficial in the first place. Ideally, we would all get our daily-recommended dose of vitamins and minerals from the food we eat. Unfortunately, time, economics, and access to resources more often than not prevent the majority of us from achieving this goal. In terms of cancer prevention and multivitamins, the NIH maintains, “[t]here is insufficient evidence to recommend for or against the use of multivitamins by the American public to prevent chronic disease.” The reluctance to recommend multivitamins as dietary supplements extends even further when a less traditional use of multivitamins — for cancer prevention — is broached.

Everyone wants to know how to prevent cancer. Are multivitamins a step in the right direction? Perhaps, but the medical establishment is skeptical; for example, in 2007, the World Cancer Research Fund/American Institute for Cancer Research went so far as to state, “Dietary supplements are not recommended for cancer prevention.” Despite the results of the PHS II, conventional wisdom is that the most reliable and safest approach to prevent chronic diseases and cancers is to avoid obesity (ideal BMI between 21 and 23), be physically active daily, have a primarily plant-based diet, limit intake of red meat and processed meat, and limit salt, alcohol, and sugary drinks.12,13,14 The American Cancer Society echoes this, stating, “[m]ore than half of all cancer deaths could be prevented by making healthy choices like not smoking, staying at a healthy weight, eating right, and keeping active.”

So, should we take a daily multivitamin? Until further research develops, it seems the best way to stay healthy and prevent cancer is to follow the guidelines above. Adding a low-dose multivitamin can’t hurt — it just might not be definitively changing the effective level of nutrients in your body. Ultimately, if the results of the PHS II could effectively be reproduced in the general population, an 8% reduction of total cancer in the United States would save many lives — food (or vitamin) for thought!

References

1. Routine Vitamin Supplementation to Prevent Cancer and Cardiovascular Disease, Topic Page. June 2003. U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/uspstf/uspsvita.htm

2. Gahche J, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988–1994). NCHS Data Brief 2011;61:1-8.

3. Altekruse SF, et al, eds. SEER Cancer Statistics Review, 1975-2007. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2007/. Accessed Nov. 13, 2012.

4. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention. Ann Intern Med 2006;145:364-371.

5. 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. N Engl J Med 1994;330:1029-1035.

6. Omenn GS, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.

7. Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin A. Available at: http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/. Accessed Nov. 8, 2012.

8. Flegal KM, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012;307:491-497.

9. Centers for Disease Control and Prevention. Vital Signs: Current Cigarette Smoking Among Adults Aged >/= 18 Years—United States, 2005–2010. Morb Mortal Weekly Rep 2011;60:1207-1212. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6035a5.htm. Accessed Oct. 30, 2012.

10. Morris M, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011;305:1348-1349.

11. Bloomberg, Jeffery, MD. Interview by Tieraona Low Dog, MD. Supplement Research. Integrative Medicine in Residency. Available at: http://integrativemedicine.arizona.edu/program/IMR_2014/dietary_supplements/dietary_supplements_for_prevention/17.html. Accessed Oct. 30, 2012.

12. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR, 2007. Available at: http://www.dietandcancerreport.org/. Accessed Nov. 13, 2012.

13. National Cancer Institute. Cancer Prevention Overview (PDQ®). Bethesda, MD: National Cancer Institute. Available at: http://cancer.gov/cancertopics/pdq/prevention/overview/HealthProfessional. Accessed Nov. 7, 2012.

14. Boeing H, et al. Critical review: Vegetables and fruit in the prevention of chronic diseases. Eur J Nutr 2012;51:637-663.