Key study points:
1. Long term daily multivitamin use was associated with a significant reduction in total cancer incidence, but not cancer mortality or all-cause mortality among older men.
2. Daily multivitamin use was not associated with a reduction in the risk of individual, site-specific cancers.
3. Daily vitamin use was not associated with any major adverse effects.
Primer: Environmental exposures have long been thought to play an important role in the development of neoplasms. And while much effort has been made to reduce ecological toxins that may contribute to cancer development, research in recent years has also strived to define environmental factors that may have chemoprotective effects. Observational studies examining the consumption of antioxidant vitamins (e.g. Vitamins A, E, C, and selenium) and the fruits and vegetables that contain high levels of these chemicals have shown promising improvements in cancer and cardiovascular outcomes. For instance, intake of beta-carotene and vitamin A from foods was inversely associated with breast cancer risk in a large longitudinal observational study, while low levels of selenium and vitamin A have been associated with increased risk of lung cancer among male smokers in a large-scale study. These observational findings have been supported by results from in vivo studies, which have shown that vitamin C and E can inhibit carcinogenesis by 30-60% in animals exposed to known carcinogens.
Although observational studies consistently show an association between dietary intake of certain vitamins and cancer risk, results from randomized clinical trials have largely failed to find any benefit. Thus, current guidelines do not recommend the use of vitamin supplementation in cancer prevention.
However, many of these randomized controlled trials have focused on high doses of one or a few vitamins in combination. Yet, among the general population, vitamin supplementation is most commonly seen as consumption of a daily multivitamin, with nearly one-third of US adults reporting regular use. Thus, the authors of this study designed a large scale, longitudinal, randomized controlled trial to better address the role of multivitamin supplements in cancer chemoprevention.
This [prospective, randomized, placebo controlled] trial: 14,641 male physicians aged 50 years or older were randomized to multivitamin or placebo, vitamin E or placebo, calcium or placebo, or beta-carotene or placebo in a 2x2x2x2 factorial trial. Subjects were followed up for a median of 11.2 years until occurrence of cancer (primary outcome), death, loss to follow-up, or end of the study, whichever came first. Overall adherence was good (76.8% for multivitamin, 77.1% for placebo at 4 years; 72.3% for multivitamin, 70.7% for placebo at 10 years). Intention-to-treat analysis of the data revealed several important findings:
- Men taking the multivitamin had a modest reduction in risk of total cancer incidence (HR 0.92, CI: 0.86-0.998).
- The majority of men with cancer (1,373 of the 2,669) developed prostate cancer. However, multivitamin use was not associated with incidence of prostate cancer or any other site-specific cancers.
- Multivitamin use was not associated with any significant difference in cancer mortality (HR 0.88, CI: 0.77-1.01) or total mortality (HR 0.94, CI: 0.88-1.02)
- Men with no parental history of cancer showed benefit with daily multivitamin use (HR 0.86, CI: 0.76-0.98), but men with a parental history positive for cancer did not (HR 1.05, CI: 0.94-1.17). No other clinical, lifestyle, or dietary factors showed any significant effect modification.
- Daily multivitamin use was associated with increased risk of rash (HR 1.07, CI: 1.01-1.41) but no other consistent or significant side effects.
In sum: This study is the first large scale, randomized, placebo-controlled trial to study the long-term association between multivitamin supplementation and risk of neoplasm formation. While previous studies have failed to find consistent chemoprotective benefits for select vitamins and minerals in the prevention of organ-specific cancers, this trial found a modest, but significant benefit in the use of a diverse multivitamin in the prevention of general cancer incidence. These findings thus support the use of multivitamin supplements in the cancer chemoprevention among older men.
Several limitations exist. First, while the recommended daily dosages of vitamins have changed over the past several years, the authors maintained the use of one particular multivitamin over the course of the study for consistency, thus these results may not be consistent with the effects of currently available multivitamin formulations. Second, the study was limited to older male physicians, thus these findings may not be generalizable to the U.S. population. Finally, observational studies have suggested that the chemoprotective effects may only be observed with long-term vitamin or mineral intake. It is possible that longer treatment or follow-up may provide the increased statistical power needed to uncover benefit in site-specific cancers.
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