Vitamin E & Prostate Cancer Risk - Another Controversial Study

This week the media “pounced” with apparent glee on another Vitamin Study, published in the Journal of the American Medical Association, that claimed “Vitamin E may raise prostate cancer risk”.

Between the unwarranted conclusions offered by the 21 authors of this study and the confusion created by the media,  I naturally have to make some comments based on a critical review of the study and its conclusions. I find the study to be another massive gathering of data from 427 participating institutions, covering a 7 year period followed by some creative statistical analysis (or as some would say – manipulation).

To summarize, the study involved approximately 35,000 (actually 30,000 after dropouts and deaths) men over the age of 50 years and a PSA score of 4 or less, meaning they didn’t appear to have cancer.  They were randomly assigned to one of 4 groups:

1. Placebo (not really a placebo but a Multi-vitamin without Vitamin E nor Selenium) * 
2. Vitamin E (400 IU / day)
3. Selenium (200 μg/d)
4. Vitamin e + Selenium
   *I am not sure where they obtained this kind of multi-vitamin.

They reported a statistically significant increase in the incidence of prostate cancer among the Vitamin E group compared to the “Placebo” group. The differences between the Placebo group and the Selenium group were not significant and that was the same result with the Vitamin E + Selenium groups.

They concluded that “The observed 17% increase in prostate cancer incidence demonstrates the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm.”

Critique:

1. A quick search of PubMed (National Medical Library) shows numerous published papers in the past year that show various benefits of Vitamin E  and anti-oxidant supplementation.
2. The placebo in this study was not really a placebo and likely contained other anti-oxidants like Beta carotene and Vitamin C. So really the comparison should say that the Vitamin E only group had slightly more prostate cancer cases than the multi-vitamin group.
3. They concluded a 17% increase in prostate cancer cases in the Vitamin E group. However when you look at the real numbers:
   Placebo Group – 7,594 participants and 529 cancer cases = 7%
   Vitamin E Group – 7,650 participants and 620 cancer cases = 8%
   It all depends on how you manipulate your statistics and the Lifetime risk of prostate cancer in the United States is currently estimated to be 16% (double the rate of any of the 4 groups in this study.)
   So there were 91 more cancer cases reported in the Vitamin E group over a 7 year period which means there were 13 more cases / year out of approximately 7600 participants and yet that is “statistically significant”.
4. This is another “guilt by association” conclusion, because a biological explanation for the observed increased risk of prostate cancer in the vitamin E arm is not apparent from these data. The researchers even said in the paper, “it is unclear how vitamin E would harm the prostate”.
5. The Council for Responsible Nutrition (http://www.crnusa.org) states “Men shouldn’t rush to judgment about vitamin E based on this study, but instead should consider the body of evidence, the amount being taken, and their individual medical history.
6. The study appears to be well-designed, if you like the traditional drug model. However, nutrients in isolation, are difficult to study because many nutrients act in concert with each other (unlike drugs). e.g. Interestingly, when vitamin E was combined with selenium, the risk was reduced to a non-significant statistic.
7. They also did not study a natural vitamin E product with all 8 versions of Vitamin E know as the tocopherols and the tocotrienols. Consumers need to be aware that there are significant differences among Vitamin E products. Some are synthetic, like “dl α-tocopherol” and “all-rac-alpha-tocopheryl acetate" - used in this study, may have no more than half the biological potency of natural “RRR d-alpha-tocopheryl acetate” when used as a supplement for vitamin E-depleted adult subjects. (American Journal of Clinical Nutrition – July 2000). 1 mg synthetic vitamin E has only 12.5% as much effective bio-availability as true RRR-α-tocopherol.
8. No indication of monitoring of compliance with supplement use nor placebo use. Not surprising with 427 different centres involved. With 427 centres, there is a wide possibility of variations in data collection that would be difficult to control.
9. There was no attempt to assess the Vitamin E status nor the oxidative stress levels of the participants prior to the study interventions. There is likely a differential in Vitamin E response by those who are vitamin E deficient vs those who are Vitamin E adequate.
10. The study also reports that “Cancers not centrally confirmed (17% of the total) were included in the analysis”. Interesting, when an 8% difference of cancer contracted was reported between Placebo and Vitamin E groups and considered statistically significant.
11. The authors acknowledge other research has demonstrated the benefits of vitamin E for Alzheimer’s disease, and age-related macular degeneration. Even with respect to prostate cancer, two other studies (cited within the article) had different results: one demonstrated a 35 percent risk reduction for prostate cancer in men taking 50 mg (75 IU) vitamin E daily for six years and another resulted in no effect on risk.
12. One wonders if an absolute increase in the risk of prostate cancer of 1.6 cases per 1,000 person-years (terms used in the study) is really a ‘significantly increased risk of prostate cancer’ as noted in the article.
13. Vitamin E is an essential nutrient required for all functions of the body. It is fairly common for people not to meet the Recommended Dietary Allowance (22.4 IU or 15 mg) RDA based on very old research and has never been up-dated. Most health practitioners that use nutrient supplementation in their practices would not consider 400 iu as an unusually high dose.
14. It has been well established that antioxidants play a role in improving immune responses and in preventing “Oxidative stress” responsible for inflammatory conditions which are at the root of many major illnesses including heart disease. Example would include: LDL cholesterol is not dangerous until it is oxidized, hence the role if antioxidants: free radicals are not damaging until they become oxidized, hence the role of antioxidants.
15. Finally, at the end of the study, there is a gratuitous dig about dietary supplements being ‘unregulated’, which, aside from being false, it concerns me that underlying bias from the publication about the dietary supplement industry and the fact that these products are not regulated like drugs may provide an ulterior motive for which studies are published and how study results are presented.” Particularly when 7 of the 21 authors have received grant money or are affiliated with one or more drug companies.

Wow! I’ll bet they are glad I wasn’t on the peer review committee that evaluated this publication. I find this large and I am sure rather expensive study has contributed nothing to the greater knowledge of cancer prevention and plants many unjustified seeds of confusion for the consumer and the Media have been complicit in this confusion.

Further Reading:

Vitamin E + Selenium
Need Supplements