Can A Vitamin A Day Keep Cancer Away?

Millions of Americans take a multivitamin daily. Millions do not. Should healthcare providers recommend a daily multivitamin to patients who do not already take one? Or discourage those who do? A recent survey of nearly 12,000 adults found that the most commonly used supplements were multivitamin-minerals and the most common reason for using dietary supplements was “to improve overall health.” Other reasons included “to maintain health,” “to supplement the diet,” and “to prevent health problems.”¹  The Physicians’ Health Study (PHS) II, which examined the effects of multivitamins on the prevention of total cancer in men, is the first and only large-scale, placebo-controlled trial testing the long-term effects of a multivitamin for the prevention of chronic disease.² Current US Preventive Task Force (USPSTF) guidelines state that the evidence is insufficient to recommend for or against the use of vitamin supplements for the prevention of cancer or cardiovascular disease.³ Results of previous observational trials have been inconsistent and studies examining high dose single-ingredient vitamins have increased mortality and cancer risk.^4,5

The PHS II is the largest (N=14,641) and arguably the best-designed study (randomized, double blind, placebo controlled) investigating the benefits of a daily multivitamin. Its predecessor study, PHS I, examined the role of low dose aspirin and beta-carotene in the prevention of cardiovascular events. Inclusion criteria of the PHS II were male physicians aged 50 years and older. Physicians with a history of cirrhosis, active liver disease, anticoagulant use, and serious illness that might prevent participation were excluded.  Participants were not allowed to consume multivitamins or individual supplements containing more than 100% of the recommended dietary allowance of vitamins E, C, or A, or beta carotene. Interestingly, a history of cancer, myocardial infarction, or stroke were not exclusion criteria. Participants were randomized in blocks of 16 stratified by age, prior cancer, prior cardiovascular disease, and original beta-carotene assignment (from PHS I if applicable). Participants were mailed multivitamins (Centrum^® Silver^®) or placebo to be taken daily.  After completing a required 12-week placebo run-in period, only participants who took at least 2/3 of their tablets were randomized into treatment and placebo groups. Yearly questionnaires assessed adherence, adverse events, new end points, and risk factors. Primary endpoints for the study were total incident cancers (excluding non-melanoma skin cancer) and major cardiovascular events.

Follow-up was 11.2 years – certainly long enough to detect a meaningful benefit from multivitamin use – and it was excellent at >98%. Intention-to-treat analysis was used until occurrence of cancer, death, loss to follow-up, or the end of the trial. The study was powered to detect a 10% reduction in total cancer. The mean age of the participants was 64.3 years at the start of the study and the baseline characteristics were similar in the multivitamin and placebo groups. Not surprisingly, the patient population was relatively healthy and often engaged in health maintenance behaviors (e.g. high frequency of daily aspirin use, low proportion of smokers, high medication adherence rates). Adherence rates at 4 years were similar (76.8% for the multivitamin group and 77.1% for placebo).

Multivitamin use significantly reduced the incidence of total cancer compared to placebo (17 vs. 18.3 events per 1000 person years; hazard ratio 0.92; 95% CI, 0.86-0.998; P=.04). The number needed to treat with multivitamins for 11 years would be 83 to prevent 1 cancer.  While these results may sound modest, it is important to keep in mind the large population of patients who take multivitamins or who might benefit from starting one. There was no significant difference in the incidence of site-specific cancers. There was also no significant difference in total mortality (HR 0.94; 95% CI, 0.88–1.02; P = 0.13).  The authors of the PHS II concluded that daily multivitamin use modestly but significantly reduced the incidence of cancer. These results suggest that the combination of low-dose vitamins and minerals is more effective than the high-dose supplement strategies examined in previous trials.⁵

The PHS II patient population is arguably healthier than the general patient population due to their knowledge of preventive medicine and access to wellness resources.   The fact that PHS II demonstrated a modest but significant benefit in a “healthy” patient population is noteworthy.  Previous studies which failed to show a benefit of multivitamin use also enrolled well-nourished populations.⁶

PHS II used an easily recognizable and widely available branded multivitamin in order to increase the generalizability of the results; however, the product formulation changed slightly after the conclusion of the study.  Thus it is unknown if the formulation on the market today would produce the same benefits.² The multivitamin arm was a small part of the Physician’s Health Study – a study that involves many analyses, multiple endpoints, and several treatment arms which may lead some to question the significance of the findings.  The use of a combined endpoint (“all cancers”) as the primary outcome may lead some readers to assume that all types of cancer follow similar pathophysiology and origin.⁶ However, the study was not powered to look at site specific cancers; so the potential impact that multivitamin use might have on specific cancers can only be speculated.²

Results from the PHS II suggest that a simple, combined multivitamin which provides nutrients at recommended levels of dietary intake may modestly reduce the incidence of total cancer in men over age 50.²  While the findings are favorable, the study does have some important limitations, most notably the lack of generalizability to women and younger patients. The PHS II does leave us with a number of interesting questions. In light of its impact on total cancer, should a multivitamin be included in the food pyramid for the general, healthy, aging male population?  The typical American may not be getting enough of the recommended amounts of vitamins and minerals. Should the USPSTF recommendations change in light of this study? We believe healthcare providers should start recommending a daily multivitamin for their healthy male patients who do not already take one. While other healthy lifestyle behaviors (e.g. smoking cessation; low-fat, high-fiber diet) have a much greater impact on cancer prevention, a simple multivitamin a day might help keep cancer away.