Too Much of a Good Thing?

National Cancer Institute study links multivitamin overuse with aggressive prostate cancer.

By
Joanna Cosgrove
Online Editor

Last month, the National Cancer Institute (NCI) published a study, “Multivitamin Use and Risk of Prostate Cancer in the National Institutes of Health–AARP Diet and Health Study,” which concluded that although regular multivitamin use is not associated with the risk of early or localized prostate cancer, the overuse of multivitamins (taking more than seven per week) can increase the risk of “advanced and fatal prostate cancers,” especially among men with a family history of prostate cancer and men who took individual micronutrient supplements, including selenium, beta carotene or zinc.

The NCI study researchers investigated the association between multivitamin use and risk of prostate cancer (localized, advanced and fatal) in 295,344 men who were cancer free at enrollment in 1995 and 1996. During five years of follow-up, 10,241 participants were diagnosed with incident prostate cancer, including 8765 localized and 1476 advanced cancers. In a separate mortality analysis with six years of follow-up, there were179 cases of fatal prostate cancer.

Representatives from the NCI did not respond to Nutraceuticals World’s request for comments on their study methodology and results.

Daniel Fabricant, PhD, vice president of scientific and regulatory affairs, the Natural Products Association (NPA), Washington, D.C., challenged the NCI’s findings, which were published in the May 16, 2007 issue of the Journal of the National Cancer Institute, citing a number or reasons why the conclusion of the study should be questioned. “To begin with, this is a cohort study, which is not as reliable as the ‘gold standard,’ a randomized controlled trial. So let’s first have some good data in this area before jumping to conclusions,” he said. “The very nature of statistics is that any researcher with many outcome measures, as was the case in this study, will stumble upon a figure that suggests some kind of an effect where there is none, provided that numerous ways of checking the data are used, as again was the case in this study.

“As with many cohort studies, there are a large number of variables involved,” he continued. “These missing observations are filled in by the authors’ evaluation of the numbers and then the resulting bias, of which there is a great deal in this study. This is why the best studies ask one research question at a time with one clear cut outcome being measured. This is a large study that was originally intended to improve our general understanding of the relationship between diet and health. It wasn’t designed to speculate on the potential for risk.”

The study had several important limitations that the authors – to their credit – acknowledge and discuss in the Comment section of the article. These do not render the results ‘invalid,’ but instead suggest that they should be interpreted in the proper context, according to Andrew Shao, Ph.D., vice president of scientific and regulatory affairs, Council for Responsible Nutrition (CRN), Washington, D.C. “For example, the definition of ‘excessive use’ must be questioned, since the survey the researchers used asked if subjects used multivitamins from ‘never’ up to ‘every day.’ Thus, it is unclear how the researchers derived a value for ‘greater than 7x per week.’”

Also suspect was the notion of screening practices. “Differences in screening practices may have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable,” noted Dr. Fabricant. “Although there is no discussion of this as a variable in the study, on the National Cancer Institute's own Web site it acknowledges the impact screening practices have in detecting prostate cancer: ‘The evidence is insufficient to determine whether screening for prostate cancer with prostate-specific antigen (PSA) or digital rectal exam (DRE) reduces mortality from prostate cancer. Screening tests are able to detect prostate cancer at an early stage, but it is not clear whether this earlier detection and consequent earlier treatment leads to any change in the natural history and outcome of the disease.’”

CRN’s Dr. Shao raised the point that the observed associations for some individual nutrients must also be questioned. “These findings were based on subjects’ recall of supplement use over the past 12 months, and no information was collected or analyzed vis-à-vis nutrient dose or duration of use; the absence of time-course or dose-ranging data weakens any notion of causality,” he said. “Most importantly, those at high risk for advanced prostate cancer (i.e. early diagnosis, family history, etc.) are more likely to exhibit certain self-selected behaviors in an attempt to intervene in their situation, including increasing their use of alternative therapies (such as taking more supplements), and proactively seeking care (such as more frequent screening). Likewise, supplement users tend to exhibit aspects of a healthy lifestyle, such as more frequent visits to their physician, which can lead to more screening and early detection.

“The bottom line,” he said, “is that those with advanced prostate cancer are more likely to use supplements, and that is the likely source for the observed relationship. Indeed, the authors acknowledge these as a major confounder, and when they controlled for this in their analysis, the association disappeared.”

While the long-term implications of this study have yet to be seen, Dr. Shao said the study “adds little to the evidence base for the use of multivitamins by the general population to maintain health,” although it did underscore that individuals with a high risk of prostate cancer should be in close contact with their healthcare professional to determine their best course of action.