NATAP: Vitamin E Prostate Cancer Linked

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Subject: NATAP: Vitamin E Prostate Cancer LinkedVitamin E tied to higher risk of prostate cancer "Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men"By Genevra Pittman

NEW YORK | Tue Oct 11, 2011 5:21pm EDT

CONCLUSION--Extended follow-up of SELECT participants

shows that healthy men with average risk of prostate cancer subjected to contemporary

community standards of screening and biopsy who took a common dose and formulation of vitamin E (400 IU/d) have a significantly

increased risk of prostate cancer. The observed 17%

increase in prostate cancer incidence demonstrates the potential for seemingly

innocuous yet biologically active substances such as vitamins to cause harm. The lack of benefit from dietary supplementation

with vitamin E or other agents with respect to preventing common health conditions and cancers or improving overall survival,

and their potential harm, underscore the need for consumers to be skeptical of health claims for unregulated over-the-counter

products in the absence of strong evidence of benefit demonstrated in clinical trials. (Reuters Health) -

Men taking daily vitamin E were more likely to get prostate cancer than

those not taking the dietary supplement in a new study of close to 35,000 North Americans.

Over a decade, an additional one or two men out of 100 taking vitamin E would be expected to get prostate cancer, researchers found."If

you have enough of these vitamins in your system... extra doesn't help you any, and too much of something like this can be harmful," Dr. Klein from the Cleveland Clinic, one of the study's authors, told Reuters Health.The findings, released today in the Journal of the American Medical Association, come on the heels of a study suggesting older women who take multivitamins have slightly increased death rates than those who don't (see Reuters Health story of October 10, 2011).Vitamin

and Mineral Supplement Use in Relation to All-Cause Mortality in the Iowa Women's Health Study - Comment on "Dietary Supplements and Mortality Rate in Older Women" - (10/11/11)"There's

a theme here that taking vitamins is not only not helpful but could be harmful" in people who aren't deficient, Klein said.Still, one researcher who wasn't part of the new study said he doubts it means vitamin E causes prostate cancer.According

to the National Cancer Institute, about 241,000 men in the U.S. will be

diagnosed with prostate cancer in 2011, and close to 34,000 will die from the disease.Although men are typically screened regularly for prostate cancer with prostate-specific antigen (PSA) tests, a government-funded task force recently put out draft recommendations saying that the screening doesn't prevent men from

dying of cancer, but may cause undue harm through unnecessary procedures.For the current study, men in the U.S., Canada and Puerto Rico were randomly assigned to one of

four groups. Starting between 2001 and 2004, about 9,000 men each took daily supplements of 400 international units (IU) of vitamin E, 200 micrograms of selenium, vitamin E and selenium together or a vitamin-free placebo pill.The study was halted in late 2008 when the researchers saw a hint of an increased risk of prostate cancer in men taking vitamin E, but they kept

monitoring men for cancer after they stopped taking the supplements. And it turned out that extra risk became clearer over time.By

mid-2011, about seven percent of men who had taken vitamin E only had gotten prostate cancer, compared to six percent of those assigned to the

placebo pills.The researchers didn't find an extra risk of prostate cancer in men who took only selenium or vitamin E together with selenium.Klein

and his colleagues say it's not clear how vitamin E would increase the risk of prostate cancer, and that not all past studies have shown it does any harm to the prostate. Some have even found a lower prostate-cancer risk with vitamin E.He

said the new findings aren't definite proof that vitamin E causes extra

prostate cancers, but that there wasn't anything else that could explain why men taking the vitamin were more likely to be diagnosed with

cancer -- for example, they weren't screened more frequently.The

supplement doses, he added, are much higher than what's in most over-the-counter multivitamins, which typically contain 15 to 25 IU of vitamin E.Prostate cancer researcher Dr. Neil Fleshner, from the University of Toronto, was doubtful that vitamin E does in fact increase the risk of prostate cancer, and said the result may have been a chance finding, or a "false positive.""It's an interesting finding. I'm not sure I believe it," he told Reuters Health. Either way,

he said, vitamin E doesn't seem to be beneficial for prostate health."There's certainly no major evidence that vitamin E helps," he said. "So, why bother?"Vitamin

supplements are known to prevent disease in people who have vitamin deficiencies, Klein said, but so far studies generally haven't found much extra benefit in people who already get enough vitamins through their diet. Specifically, vitamin E has not been shown to protect against heart disease, colon cancer or lung cancer.On the other hand, there is a growing body of evidence suggesting supplements may be harmful in high doses."Vitamins are not innocuous substances," Klein concluded.---------------------------------------

Vitamin E and the Risk of Prostate Cancer - pdf attached

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)AbstractContext The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate

cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with

vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E

and

prostate cancer.

Objective To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.

Design, Setting, and Participants

A total of 35 533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22,

2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal

examination not suspicious for prostate cancer, and

age 50 years or older for black men and 55 years or older for all others.

The primary analysis included 34 887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium;

8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on

their

participants through July 5, 2011.

Interventions Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum

of 7 and maximum of 12 years.

Main Outcome Measures Prostate cancer incidence.

Results This report includes 54 464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary

report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group

developed prostate cancer (hazard ratio

---

, 1.17;

99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin

E, 0.8 for selenium, and 0.4 for the combination.

Conclusion Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. Lifetime risk of prostate cancer in the United States is currently estimated to be 16%.1​ Although most cases are found at an early, curable stage, treatment is costly and urinary, sexual, and bowel-related adverse

effects are common.2 Even men who choose active surveillance as an initial management strategy face anxiety, uncertain prognosis, and a measurable

risk of sepsis with follow-up biopsies,3​ and more than one-third of those who initially defer therapy are ultimately treated.4,5​ With such a high prevalence, risk of morbidity from treatment, and treatment-related costs, primary prevention of prostate

cancer is an attractive option.

With considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate

cancer risk, we

conducted and reported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer

prevention.6

Coordinated by SWOG, a federally funded cancer research cooperative group, the Selenium and Vitamin E Cancer Prevention Trial

(SELECT) began accrual on August 22, 2001, and randomized 35 533 men into 4 groups: selenium with matching placebo, vitamin

E with matching placebo, both agents, or placebo.

Based on a preplanned interim analysis, the independent data and safety monitoring committee met on September 15, 2008, and

recommended the early discontinuation of study supplements because of lack of efficacy for risk reduction and because futility

analysis demonstrated no possibility of benefit to the

planned degree with additional follow-up.6​As reported in the initial article,6

with a median follow-up of 5.5 years, the numbers of prostate cancers detected were 473 (hazard ratio

---

, 1.13; 99% CI,

0.95-1.35) for vitamin E; 432 (HR, 1.04; 99% CI, 0.87-1.24) for selenium; 437 (HR, 1.05; 99% CI, 0.88-1.25) for selenium plus

vitamin E; and 416 (HR, 1.0) for placebo. Although these results were not statistically significant, the data and safety monitoring

committee expressed concern about the increased risk of prostate cancer observed in the vitamin E plus placebo group, which

approached statistical significance (P = .06) and a statistically nonsignificant increased risk of type 2 diabetes mellitus in the selenium plus placebo group (P = .16).

Since that time, participant follow-up has continued, allowing observation of additional events. On May 20, 2011, the data

and safety monitoring committee reviewed trial data and recommended reporting the finding regarding increased risk of prostate

cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the

preplanned final analysis at 7 years after the last participant was randomized.METHODSDetailed descriptions of the rationale, design, conduct, and initial results of SELECT have been previously published.6​,7

The study enrolled healthy men at average risk of prostate cancer based

on a baseline prostate-specific antigen (PSA) of

≤4 ng/mL and normal digital rectal examination (DRE) commencing at age 50 years for black men or at age 55 years for all others.

Men were randomized into 1 of 4 groups: selenium (200 μg/d from L-selenomethionine) with matching vitamin E placebo, vitamin E (400 IU/d of all rac -α-tocopherol acetate) with matching selenium placebo, both agents, or matching placebo (Figure 1).Participants without prostate cancer were monitored every 6

months with an annual limited physical examination including blood

pressure, weight, and smoking status; participants who developed prostate cancer during the study were monitored annually

thereafter. Participants were recommended to undergo PSA and DRE testing and prostate biopsy based on the standard of

care

in their community and in accordance with the participant's preference. To facilitate adherence, a multivitamin containing

no selenium or vitamin E was offered. All participants were required to provide written informed consent and the local institutional

review board of each study site approved the study.

At study visits, men were asked about new

medical events in the previous 6 months. The primary end point of the study was

prostate cancer incidence as determined by routine clinical management and confirmed by central pathology review. Blinded

follow-up continued until October 23, 2008, at which time participants discontinued use of study supplements. Prostate cancer

status was determined by self-report at each 6-month study visit. Medical records were obtained thereafter and clinical stage

and diagnostic method were abstracted. The pathology report and tissue were forwarded to the SELECT central pathology laboratory

for confirmation of diagnosis and for assignment of

Gleason score. Median baseline and follow-up plasma vitamin E and selenium

levels are included in the original report.6​Follow-up continued in an unblinded fashion at study sites from October 2008 until July 2011. The final study site visits

included follow-up for study end points and a blood

sample from participants diagnosed with prostate cancer. An independent

data and safety monitoring committee met yearly commencing with study inception, reviewing data on safety, adherence, and

prostate and other cancer diagnoses. On September 15, 2008, the committee recommended reporting initial results related to

the lack of efficacy of the agents on prevention of

prostate cancer. Since that time the committee has continued to meet yearly

via teleconference.

Statistical AnalysisThe primary end point was prostate cancer incidence resulting from routine community care. Cancers not centrally confirmed

(17% of the total) are included in the analysis.

Five prespecified comparisons of the 4 study groups were conducted: selenium

vs placebo, vitamin E vs placebo, selenium plus vitamin E vs placebo, selenium vs selenium plus vitamin E, and vitamin E

vs

selenium plus vitamin E. Although a 1-sided significance level of .005 was specified to test for the preventive effect for

each supplement comparison and thus 99% confidence intervals are reported, we have reported 2-sided P values throughout because the comparison of prevention vs increased risk of cancer is a 2-sided question.6A proportional hazards model was used to compare prostate cancer and other cancer incidence between placebo and each of the

3 study groups with active agents. Men without the end point of interest were censored at their last contact date. An additional

analysis was performed on all the data using a variable for selenium supplementation, a variable for vitamin E supplementation,

and an interaction term. In all cases, the proportional hazards assumption was evaluated by assessing each study group × time

interaction. The cumulative incidence curves for

prostate cancer were generated accounting for the competing risk of death.8​ A χ2 test was used to test the difference in the relative risk of diabetes. Data were analyzed using SAS version 9.2 (SAS Institute

Inc, Cary, North Carolina).RESULTSThe current report includes data as of July 5, 2011. There are 54 464 additional person-years of follow-up since the primary

report, an increase of 23%. A summary of baseline characteristics is displayed in Table 1 and an updated flow diagram in Figure 1. The frequency of use of DRE and PSA is displayed in Table 2; there were no differences between groups in the intensity of PSA testing, absolute PSA levels, PSA change from study entry

to year 1, nor rates of testing following study unblinding.A total of 521 additional prostate cancers have been diagnosed since the initial report: 113 in the placebo group, 147 in

the vitamin E group, 143 in the selenium group, and 118 in the combination group (Table 3). The rate of prostate cancer detection was greater in all treatment groups when compared with placebo but was statistically

significant only in the vitamin E alone group (HR, 1.17; 99% CI, 1.004-1.36; P = .008; Table 3). After adjustment for the marginal effects of vitamin E and selenium, the interaction between vitamin E and selenium was

statistically significant (P = .02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together. The risk of Gleason

7 or greater disease was higher for all 3 interventions (vitamin E: HR, 1.16 [99% CI, 0.86-1.58]; selenium: HR, 1.21 [99%

CI, 0.90-1.63]; combination: HR, 1.23 [99% CI, 0.91-1.66]) but did not reach statistical significance for any group (Table 3). The elevated risk estimate for vitamin E was consistent across both low- and high-grade disease.The cumulative incidence curves of prostate cancer by supplement group compared with placebo are presented in Figure 2.

The difference in rates of prostate cancer between vitamin E and placebo became apparent during the participants' third

year in the trial, at which point the HR was 1.10, and increased slightly each year thereafter. The proportional hazards assumption

was reasonable for each study group (all P ≥ .17). The unadjusted absolute increase in risk of cases of prostate cancer per 1000 person-years compared with placebo

was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.Virtually all men with prostate cancer were without metastases at diagnosis (Table 4). Gleason 6 was the most common grade over all. For those with more aggressive disease, Gleason 7 was the most common score.

Stage and grade distributions were similar among groups.In the initial SELECT report a statistically nonsignificant increased risk of type 2 diabetes mellitus (as defined by self-report

or new use of glitazone medications) was observed in the selenium supplementation group (HR, 1.07). In the updated results

the HR is 1.04 and is not statistically significant

(P = .34; Table 5). Table 5

also displays updated data on the prespecified secondary end points of lung, colorectal, and total other cancers, deaths,

and grade 4 cardiovascular events. There are no statistically significant differences in the HRs between groups, suggesting

neither benefit nor harm from dietary supplementation with selenium or vitamin E for these end points.COMMENTPrevention of prostate cancer remains an important public health goal because of the relatively high incidence and the high

likelihood of curative-intent treatment of this cancer even when indolent disease is present,9 and treatment related costs and morbidity. Although 2 large randomized trials have demonstrated that 5α-reductase inhibitors

reduce prostate cancer risk by 20% to 25%,10​,11 the use of these agents is controversial because of concerns related to an observed increased risk of high-grade disease.12​

SELECT was designed to assess the effect of selenium and vitamin E alone and in combination as supplements to a normal diet

on their ability to prevent prostate cancer in men at average risk. Other randomized studies have shown no benefit to dietary

supplementation with selenium, lycopene, or soy in reducing the risk of invasive cancer in men with high-grade prostatic intraepithelial

neoplasia on biopsy.13,14​In this article, we report an observation

of important public health concern that has emerged with continued follow-up of

SELECT participants. With primary end point ascertainment based on contemporary community practice across the United

States,

Canada, and Puerto Rico using PSA and DRE as indications for biopsy, the risk of prostate cancer at 7 years of median

follow-up

was increased by 17% in men randomized to supplementation with vitamin E alone, a difference that started to appear about

3 years after randomization. Although there is debate about how to best handle accumulating results after the publication

of primary findings and the appropriate threshold for statistical significance, the increased rate of prostate cancer in the

vitamin E group was seen as early as 2006 and continued until the present analysis (HRs ranged from 1.12 to 1.17) suggesting

that the current results are not an outlier observation due to multiple looks at the data. Extended follow-up with additional

events has resulted in narrowed confidence intervals.

A biological explanation for the observed

increased risk of prostate cancer in the vitamin E arm is not apparent from these

data. The risk does not appear to be due to an increased biopsy rate prompted by changes in DRE, PSA, or unblinding. There

was not a statistically significant increased risk of prostate cancer in the vitamin E and selenium combination group (HR,

1.05; P = .46), suggesting that selenium may have a protective effect by dampening the increased risk associated with vitamin E alone,

a hypothesis reinforced by the P value (.02) of the interaction term in the marginal analysis. Tests of this hypothesis and other potential explanations for

the results will be addressed by analysis of the effects of baseline plasma vitamin E levels and their interaction with baseline

plasma and toenail selenium levels from samples collected from participants at study entry. Despite the lack of a mechanistic

explanation, the findings show that vitamin E supplementation in the general population of healthy men significantly increases

the risk of being diagnosed with prostate cancer.

The current findings of SELECT differ from findings from other large randomized intervention trials that examined the effects

of vitamin E supplementation on prostate cancer risk. The Alpha-Tocopherol, Beta Carotene (ATBC) trial reported a 35% risk

reduction for prostate cancer in men taking 50 mg/d

of vitamin E for a median of 6.1 years,15

although there are important differences with SELECT: (1) the participants of ATBC were all long-term smokers (36 years on

average) compared with 43% who had never smoked and

8% current smokers in SELECT; (2) prostate cancer was a secondary end

point in ATBC; and (3) men in ATBC were not screened so that prostate cancer was diagnosed at more advanced stages than in

SELECT. In the Physicians Health Study II (PHS II) conducted contemporaneously with SELECT, intervention with 400 IU of vitamin

E every other day for a median of 8 years had no effect on the incidence of prostate cancer (HR, 0.97; 95% CI, 0.85-1.09;

P = .58), although like SELECT there was no effect on total cancer incidence (HR, 1.04; 95% CI, 0.95-1.13; P = .41) or overall mortality (HR, 1.08; 95% CI, 0.98-1.19).16​Furthermore, both ATBC and PHS II were designed and analyzed as factorial trials, so the reported effect of vitamin E is estimated

across the secondary factor (beta carotene or vitamin C, respectively). In contrast, SELECT was designed as a 4-group trial

because of concerns about the potential interaction

of vitamin E and selenium, for which a statistically significant interaction

between these agents was indeed observed.

Given that more than 50% of individuals 60 years or older are taking supplements containing vitamin E and that 23% of them

are taking at least 400 IU/d17 despite a recommended daily dietary allowance of only 22.4 IU for adult men,18​

the implications of our observations are substantial. Consistent with the original SELECT report, longer follow-up did not

demonstrate a benefit for selenium or vitamin E supplementation on risk of colorectal or lung cancer or cardiovascular events.

Although modest benefits for vitamin E supplementation have been observed in a limited number of randomized clinical trials

for Alzheimer disease19 and (as 1 part of a combination of oral antioxidants) for age-related macular degeneration,20​ no benefits were demonstrated for prevention of cardiac events or mortality,21,22​,23 colorectal adenomas,24​ respiratory infections in elderly individuals,25 pre-eclampsia in women with type 1 diabetes,26​ or prevention or progression of cataracts or macular degeneration.27,28​ Moreover, the increased incidence of prostate cancer seen in SELECT, the previously reported increased incidence of lung

cancer with high-dose beta carotene in both ATBC15 and the Beta-Carotene and Retinol Efficacy Trial (CARET),29​ and the increased risk of colon polyps seen in a trial administering high-dose folate,30

suggest that caution should be used when recommending or studying high doses of micronutrients. As opposed to synthetic pharmaceuticals,

these naturally occurring dietary constituents are part of normal physiology, and a U -shaped-dose response curve may exist where either deficiency or supraphysiological doses are harmful.

The findings of SELECT, ATBC, and CARET emphasize the importance of large-scale, population-based, randomized trials in accurately

assessing the benefits and harms of micronutrients as dietary supplements. Because a statistically significant interaction

was observed between vitamin E and selenium, we believe that caution should be used when designing factorial prevention trials

in the future. Although factorial designs are appealing because of their statistical efficiency, interactions can make

it

difficult to evaluate the underlying effects of each treatment component.31​Furthermore, the fact that the increased risk of prostate cancer in the vitamin E group of participants in SELECT

was only

apparent after extended follow-up (allowing for additional events) suggests that health effects from these agents may continue

even after the intervention is stopped, emphasizing

the need for long-term follow-up even in trials closed before the planned

intervention period is completed. Consenting SELECT

participants have the opportunity to transition to a centralized follow-up

study where annual updates to general health and cancer status are obtained either via a mailed questionnaire or data entered

by the participant on the SELECT participant Web site, which will allow additional follow-up to further address these issues.

Previous SectionNext Section

CONCLUSIONExtended follow-up of SELECT participants

shows that healthy men with average risk of prostate cancer subjected to contemporary

community standards of screening and biopsy who took a common dose and formulation of vitamin E (400 IU/d) have a significantly

increased risk of prostate cancer. The observed 17%

increase in prostate cancer incidence demonstrates the potential for seemingly

innocuous yet biologically active substances such as vitamins to cause harm. The lack of benefit from dietary supplementation

with vitamin E or other agents with respect to preventing common health conditions and cancers or improving overall survival,

and their potential harm, underscore the need for consumers to be skeptical of health claims for unregulated over-the-counter

products in the absence of strong evidence of benefit demonstrated in clinical trials.