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EW NEWS & OPINION September 2014 vitamin E or selenium at doses that exceed recommended dietary intakes." Dr. Luchs noted that both AREDS formulations used 400 IU/ day of vitamin E, but the risk found in the SELECT studies "may be less- ened with other supplementation found in the AREDS formulations." "The results of the AREDS study, the Alpha-Tocopherol, Beta Car- otene (ATBC) and the Physicians Health Study II (PHS II) studies have not demonstrated a harmful effect of supplementation of vitamin E on prostate cancer," Dr. Chew said. EW References 1. Kristal AR, Darke AK, Morris JS, et al. Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk. J Natl Cancer Inst. 2014 Mar;106(3):djt456. 2. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549–56. 3. Chew E and Clemons T. Vitamin E and prostate cancer. Ophthalmology. 2012;119(9):1938–1939. Editors' note: Dr. Chew has no financial interests related to her comments. Dr. Luchs has financial interests with OJO. Contact information Chew: echew@nei.nih.gov Luchs: drojo@ojonectar.com E itself is not a risk factor" in increasing the risk of prostate cancer. Dr. Luchs' products all in- clude vitamin E (albeit at 200 IUs), and he uses them himself daily. "The AREDS formulation has been around since 2001, and we haven't seen any epidemics of pros- tate cancer; if there was a clinical concern, we should have expected to see a spike related to the increased intake of vitamin E by now," Dr. Luchs said. "Given that we have not seen a spike, I suspect that any effect is minimal at best." In AREDS, of the 975 men ran- domized to the no-antioxidants arm, 73 developed prostate cancer; 68 of the 987 men randomized to the antioxidants arm (which included 400 IU/day of vitamin E) developed prostate cancer; the differences were not statistically significant. Kristal et al. noted other studies found selenium status at presentation may be a risk factor for prostate cancer, but could not replicate results when using the same baseline data. However, the data from SELECT "suggest complex interactions be- tween selenium and vitamin E," the authors wrote, but said the increased risk with vitamin E alone was "unex- pected and remains unexplained." The group called it "unlikely" another trial of high-dose selenium or vitamin E supplementation would be undertaken. Based on their study results, however, the authors highly recommended men over age 55 "avoid supplementation with either the formulation in the pre-speci- fied analyses suggests additional beneficial effects, especially when evaluated in a direct comparison with beta-carotene and in those in the lowest dietary level of intake of lutein and zeaxanthin. At the time, Emily Chew, MD, deputy director of the Division of Epidemiology and Clinical Applica- tions of the NEI, said "participants with low dietary intake of lutein and zeaxanthin at the start of the study but who took an AREDS formulation with lutein and zeaxanthin during the study were about 25% less likely to develop advanced AMD com- pared with participants with similar dietary intake who did not take lutein and zeaxanthin." Removing the beta-carotene aspect did not alter the formula's protective effect and may improve the safety of the formulation as former smokers taking beta-carotene were more likely to develop lung cancer. Clinical relevance The NEI's stance is that this latest study on prostate cancer and elevated vitamin E intake is not something that should cause a revision of the AREDS formulation. "We have examined this issue with our AREDS data," Dr. Chew said. "Our thoughts are the following: "The SELECT study found the risk of prostate cancer at 7 years of median follow-up was increased by 17% in the men randomized to supplementation with vitamin E alone compared to placebo. This is the relative risk. What is the abso- lute risk and what does this mean clinically? There will be between 1 and 2 more prostate cancers per 1,000 patients who would be given vitamin E for one full year. Interest- ingly, in men who received both vi- tamin E and selenium, there were no increased rates of prostate cancer." Other study results differed in their findings, with some either showing a protective effect or no effect on the incidence of prostate cancer. "There is evidence to show vitamin E may be protective to some extent," said Jodi Luchs, MD, founder of OJO fortified eyecare nectar (Long Island, N.Y.). "If you look at the wealth of evidence out there, it mostly shows that vitamin The SELECT study linked the two, but some clinicians question the clinical relevance N ewer research indicates that 400 international units (IU) of vitamin E daily increased the risk of prostate cancer among men with lower selenium status. The U.S. National Cancer In- stitute initiated the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to determine if selenium, vitamin E, or both could reduce the risk of developing prostate cancer in otherwise healthy men. Initiated in 2001, the study supplementation stopped earlier than anticipated after initial results found a low benefit level from the supplementation. Af- ter additional follow-up, the vitamin E/prostate cancer risk became statis- tically significant. An earlier study on the same cohort found the risk of prostate cancer at 7 years of median follow-up was increased by 17% in the men randomized to supplementation with vitamin E alone compared with placebo. The Age-Related Eye Disease Study (AREDS) established that daily high doses of various supple- ments can reduce the progression to advanced age-related macular degeneration (AMD). In the original AREDS formulation, antioxidants studied included vitamin C, vitamin E, beta-carotene, zinc, and copper. In 2006, the National Eye Institute (NEI, Bethesda, Md.) initiated a second study (AREDS2) to reevaluate the AREDS formulation, as other studies had found beta-carotene was associated with an increased risk of lung cancer in people who smoked. AREDS2, therefore, recommended the addition of lutein and zeaxan- thin as an alternative to beta-caro- tene. In the first AREDS trial, par- ticipants with AMD who took the AREDS formulation were 25% less likely to progress to advanced AMD over the 5-year study period, com- pared with participants who took a placebo. In AREDS2, there was no overall additional benefit from add- ing omega-3 fatty acids. A mixture of lutein and zeaxanthin added to 25 by Michelle Dalton EyeWorld Contributing Writer Vitamin E linked to prostate cancer

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