Selenium and Vitamin E Supplements for Prostate Cancer: Evidence or Embellishment?

Mark A. Moyad, MPH

Selenium and vitamin E are probably the two most widely utilized supplements for the prevention and treatment of prostate cancer.
Selenium and vitamin E, despite having a wealth of laboratory data, have only demonstrated a benefit as a secondary endpoint in intervention trials for cancer prevention.
Selenium, and especially vitamin E supplements have some prospective data to recommend their use in current or past smokers.
The SELECT trial should give clinicians the best evidence as to whether or not these supplements have a role in prostate cancer.
Selenium and vitamin E supplements have evidence of potential side effects in higher dosages that clinicians need to discuss with patients.

Introduction
Selenium and vitamin E supplements have received more attention than probably any other in the area of prostate cancer. The interest in these supplements are so great that the NIH is sponsoring one the largest chemoprevention trials in prostate cancer history utilizing only these two agents.1 This trial is called "SELECT" which stands for the selenium and vitamin E chemoprevention trial. It will consist of 4 arms:

1) Selenium at 200 mcg/day
2) Vitamin E at 400 mg/day
3) Selenium (200 mcg/day) and vitamin E (400 mg/day)
4) Placebo

A total of 32,000 patients are expected to be recruited from about 300 different sites and the trial itself will last 7-12 years. Patients without a history of prostate cancer or high-grade PIN who are age 55 or older will be eligible for the study. African-americans who are 50 years of age or older will be eligible. This should be the best determnation of where these two supplements stand in the area of prostate cancer prevention or possibly even progression. However, several questions need to be considered before the trial begins. For example, are researchers acting too quickly or do these supplements have enough data right now to be part of this costly clinical trial? How did researchers become so interested in these two supplements exclusively over the hundreds of others available on the market today? Should either or both of these supplements be recommended currently by physicians who deal with patients who are asking about it? Is it possible to find so many men who are not truly taking any or both of these supplements currently? It is difficult right now to answer most of these questions, but in this article I will attempt to answer a few of these and many others.

Selenium Supplements and Dietary Sources

Lower serum levels of the mineral selenium have been linked to numerous cancers over the past few decades.2 In fact, it was this and other findings that encouraged the Nutritional Prevention of Cancer Trial to be initiated.3,4 This was a double-blind trial of dietary selenium supplementation whose primary goal was to establish whether or not selenium supplements have a role in reducing the recurrence of skin cancer. The primary endpoints for this trial were the incidence of basal and squamous cell carcinoma. The first patients in this trial were randomized in 1983. In 1990, after the start of this trial, several secondary endpoints were added such as: mortality from all causes and cancer, and the incidence of lung, colon and prostate cancers. Patients either received 200 mcg of selenium daily or a placebo. When the trial was completed patients randomized to the selenium group had a statistically significant lower incidence (63%) of prostate cancer compared to the placebo group. In fact, the selenium group had a lower incidence of localized disease (RR=0.42) and advanced disease (RR=0.27). However, this particular study did reveal some other important findings. For example:

-selenium.htm');">Selenium had no effect on the primary endpoint (basal and squamous cell cancers)
-selenium.htm');">Selenium only had an effect on secondary endpoints (prostate, lung, and colon)
-Individuals in this study were recruited from selenium deficient areas, so we are not sure if patients
without lower serum levels of selenium could benefit from getting more of this mineral.
-Patients in the lowest and middle tertile of baseline plasma selenium had a significant
effect, while those in the highest tertile did not.
-The 200 mcg of selenium utilized in this trial came from a 0.5 gram high-selenium yeast
tablet. Therefore, is it possible that a non yeast based selenium supplement would have had a similar effect?
-Only 25% of the participants in this trial were women, so we are not exactly sure what role if any, this mineral plays in women's health.

However, one large prospective trial of selenium levels in women did not reveal any benefit of this mineral for the prevention of cancer, including breast carcinoma.5 Therefore, selenium does not have adequate clinical data right now to espouse it's use in women. This is important because it is not uncommon for the spouse of a prostate cancer patient to ask me "Should I be taking this supplement?"

These overall results and the patient population in selenium supplement study encourage the question " Are patients with a deficiency of selenium the only ones who could potentially benefit from a supplement?" This is difficult to say at this time. Selenium is not necessarily easy to obtain from food sources.6 In fact, table 1 lists some healthy food sources of selenium; however, the actual content of selenium in food varies greatly depending on which region of the country you live in.7

• All of the participants were heavy smokers (about 20 cigarettes/day) so do these results have any bearing on nonsmokers?
• The vitamin E supplement used in this study only contained 50 milligrams of synthetic vitamin E, not higher levels (400 mg/day) that will be taken during the SELECT trial. In fact, it is difficult if not impossible to find a commercially available individual vitamin E supplement that contains only 50 mg of synthetic vitamin E.
• Vitamin E had no impact on the time interval between prostate cancer diagnosis and death. In my opinion, many clinicians and patients believe that vitamin E has demonstrated some impact on prostate cancer progression because in the ATBC trial their was a lower number of prostate cancer deaths in the vitamin E group. However, this data was misconstrued because a lower number of cases being diagnosed will automatically be tantamount to a lower rate of death from prostate cancer. This does not necessarily mean that vitamin E will impact the progression of already diagnosed prostate cancer.
• The men with the highest serum levels of vitamin E had the lowest testosterone levels.24

So, it could be possible that if vitamin E is preventing prostate cancer in smokers it is doing so by lowering androgen levels. -Men in the highest weight category had a 39% increase in the risk of prostate cancer.25

This was a fascinating result because it was so dramatic and because it received so little media attention, while the supplement results seemed to dominate headlines across the country.

-Men receiving beta-carotene supplements had 23% increase in prostate cancer incidence and a 15% increase in mortality.23 Does this mean that the secondary endpoints are not a quality finding because with one supplement it demonstrated a benefit and with the other it demonstrated a negative finding. This could also mean that beta-carotene supplements are indeed a potential hazard in smokers, as is the case from findings from other trials. -Men who combined vitamin E with aspirin had a greater risk of oral bleeding compared to those who only took aspirin.26

-Men taking vitamin E had a slight (nonsignificant) increase in hemorragic stroke. Is it possible that only small quantities of vitamin E supplements in smokers could have a hazardous side effect?26

-Men in this trial had lower mean selenium levels compared to men in the selenium supplement trial.

So, is it possible that the only smokers who could potentially benefit from taking vitamin E are those with overall low levels of other key antioxidants.  

A small prospective study from Switzerland with a 17-year follow-up found a significantly increased risk of prostate cancer deaths among smokers with low serum levels of vitamin E (RR=8.3).27 However, there were only 30 deaths from prostate cancer among the almost 3000 men followed. Another similar correlation was found in the prospective Physicians' Health Study, which had a 13-year follow-up period and 259 cases of aggressive prostate cancer diagnosed.28 This study found that smokers with the highest levels of serum alpha-tocopherol experienced an almost 50% decrease in the risk of aggressive prostate cancer, while nonsmokers did not demonstrate any association. More recently, the US Health Professional Follow-up Study examined prospectively the intake of vitamin E supplements and prostate cancer risk.29 There were 1896 total cases of prostate cancer in this study, and 522 of these cases were extraprostatic, while 232 were metastatic or fatal. There was no association between vitamin E supplements and prostate cancer for nonsmokers. However, among current and recent smokers, those men who consumed more than 100 I.U. of supplemental vitamin E daily had a 56% decrease risk of advanced or fatal prostate cancer compared with nonusers. Therefore, 4 separate trials (ATBC, Swiss study, Physicians' Health Study, and US Health Professionals Follow-up Study) have all found a link between vitamin E and a reduction of prostate cancer, and possibly prostate cancer progression in smokers. Dietary vitamin E is generally found in various nuts, seeds, and oils.7 See Table 2 for some dietary sources of vitamin E.

The majority of the vitamin E found in the diet is gamma-tocopherol, not alpha-tocopherol which is the type found in most of the bottles of supplemental vitamin E and is the type used in most past clinical trials.30  Why is this important? Several studies of heart disease have found a lower risk of death from heart disease for individuals getting dietary vitamin E compared with supplemental vitamin E. For example, the Iowa Women's Health Study is a prospective cohort study of almost 35,000 postmenopausal women.31 In this study, dietary vitamin E was inversely associated with the risk of death from heart disease. This correlation was especially evident in a subgroup of almost 22,000 who who did not take any vitamin E supplements. Women in the highest dietary intake of vitamin E had a 58% decrease in the risk of death from heart disease. Additionally, women who consumed higher amounts of dietary vitamin E were less likely to smoke. Other past prospective studies have also found an association between higher intakes of dietary vitamin E and a lower risk of heart disease in men and women.32,33

We have recently reported that gamma-tocopherol (from dietary sources) demonstrated greater inhibitory capacity on prostate cancer cell lines versus supplemental (alpha-tocopherol) vitamin E.30 Interestingly, a recent look at men getting higher levels of dietary vitamin E reported a greater reduction of prostate cancer risk versus that of supplemental vitamin E.34 In these two nested case-control studies in two cohorts of men from Maryland, levels of gamma-tocopherol were associated with a slightly lower risk of prostate cancer (RR=0.77) in one study with an 18-year follow-up. In the other 4-year follow-up study, researchers found a statistically significant trend. Men in the highest fifth of plasma gamma-tocopherol had an 80% decrease in the risk of prostate cancer. No significant decreases were found for men getting supplemental vitamin E. These early reports are fascinating but they need to be confirmed in larger prospective studies.

Selenium and Vitamin E Supplements-Analyzing all of the Data

This review of past selenium and vitamin E dietary studies leads this author to ten conclusions that can currently benefit clinicians discussing these supplements with their patients:

1) Supplements of selenium and vitamin E need more clinical data to espouse their use for the prevention of prostate cancer. The SELECT trial will ultimately decide the potential role of these supplements in prostate cancer.

2) There is some data to suggest that supplemental selenium at 200 mcg/day has a role not only in prevention, but in potentially slowing the progression of prostate cancer.

3) There is also some clinical data to suggest that dietary selenium may also prevent and/or slow the progression of prostate cancer.

4) There is some data to suggest that men with low baseline levels of selenium are the ones who could benefit most from selenium supplements.

5) There is no strong clinical data to suggest whether or not increasing selenium intake from diet or supplements benefits nonsmokers and/or smokers and/or recent smokers.

6) There is no strong clinical data to suggest that supplemental vitamin E has a role in the prevention or progression of prostate cancer in nonsmokers.

7) There is some adequate clinical data to suggest a benefit for taking supplemental vitamin E for prostate cancer prevention and progression if you are a current or recent smoker.

8) There is some evidence to suggest that if supplemental vitamin E is effective, than it may be working through a hormonal mechanism.

9) There is some recent evidence to suggest that dietary vitamin E (gamma-tocopherol) may reduce the risk of prostate cancer.

10) Other significant clinical findings have been discovered from the past selenium and vitamin E trials. For example, that extremely obese men may have a large increase in prostate cancer risk.

Side Effects

No discussion of selenium and vitamin E supplements would be complete without mentioning potential side effects of these popular supplements. The literature reminds us of the potential harm that could exist if someone is selenium deficient. For example, Keshan's disease is a dilated cardimyopathy which is found in individuals with little to no selenium intake (less than 19 mcg/day) in certain areas of China and other countries.35 However, this disease is a rare finding in most countries, and should not be used as evidence to espouse the use of selenium supplements. In fact, I equate this problem with that of scurvy and vitamin C which is difficult if not impossible to find these days in most countries. What about excess levels of selenium ingestion? Selenium supplements have been associated with gastrointestinal problems, pathologic nail bed changes and the loss of fingernails, temporary hair loss, and even fatique.36 However, at 200 mcg/day these side effects, apart from some gastrointestinal upset were not observed in a past trial,3 but for the patient who believes in the "more is better" theory, this could represent a potential problem. Clinicians need to advise patients on the potential harm that could result from taking too much supplemental selenium. A CDC report from 1983 highlights the dangers of high selenium intake.36 Individuals were taking a selenium supplement which actually contained hundreds of more micrograms and milligrams than was reported on the purchased bottle. This resulted in temporary and permanent nail and hair loss, and fatique that was mentioned earlier. Vitamin E, when combined with blood thinners of all types may synergistically increase the risk of internal bleeding.26 It is notable that smokers in the ATBC trial had an increase risk of hemorrhagic stroke at only 50 mg of vitamin E daily. Other clinical studies have demonstrated that getting over 1000 mg of supplemental vitamin E daily may be harmful.37,38,39 For example, it can reduce the body's absorption of other antioxidants (like vitamin C) and may act as a prooxidant at these levels rather than an antioxidant, especially if you are not a smoker.40 It seems that if any of these supplements have an impact on health, than they do within a certain window period. Too little does not do anything and too much has either a negative or no impact. This will be a real challenge of future supplement trials, deciding on the right supplement, at the right dosage, which can give you maximal efficacy and minimal side effects.

Conclusions

Personally, I am surprised at the number of patients and clinicians who are taking or recommending large amounts of supplemental selenium and/or vitamin E for prostate cancer without knowing the specific results of the various clinical studies on these two supplements. Perhaps this is the fault of researchers like myself who have not brought enough objective information to the medical literature. Perhaps, it is also the fault and responsibility of the patient and clinician who needs to remember that supplements work like prescription drugs. Too much is not good, and too little is not good, but in the end the dosage recommended (if any) should come from past clinical trials. Although, there is little doubt that these supplements have a wealth of laboratory data to espouse their use, but beyond that, the data is very weak at best. In fact, the only men that should probably be taking selenium and especially vitamin E supplements for prostate cancer prevention or to slow the progression of this disease are current or recent smokers. Apart from these type of men, there is no strong data to espouse their use. In fact, there seems to be as much data, if not more, to espouse the use or greater intake of better dietary sources of this mineral and vitamin for overall health until we receive better clinical data. And, it could easily turn out in several years that those individuals who focus more on dietary sources right now, stand to benefit the most in terms of prostate cancer prevention or reducing progression. Other critical findings from these past studies need to be reiterated to the patient, for example, that men who maintain an adequate body weight may benefit more than what any supplement could potentially offer.
Finally, I am not completely naive here and I do believe that many patients will continue to take these supplements regardless, because they do not want to wait 10 or 15 years until this supplement question is hopefully resolved. I sympathize and understand this position from my own personal experience. My family has a strong cancer history and I want to reduce this risk in any way that is practical. Therefore, selenium at 200 mcg/day and vitamin E at 50-100 mg/day may make sense for some patients right now. However, taking more of these supplements without physician approval would translate into a complete disregard for the past studies on these supplements and prostate cancer. Recommending higher dosages of vitamin E for example, may make sense for cardiovascular or hot flash reduction, but this data is also inconclusive.41,42
In conclusion, it is important to remember to go for the dietary sources first and supplement second. The dietary sources of these and other supplements is a far greater protector of overall health rather than a specific disease entity. In other words, from a probability standpoint, it seems that patients who consume a moderately healthy diet and exercise will always be in a win-win situation whereas those who depend only on supplements find themselves in a possible win, a possible lose, and a possible no benefit scenario. Selenium and vitamin E have no doubt acquired some intriquing evidence over the past several years; however, we also must not forget that this data has also been the victim of serious embellishment, especialy from some individuals who stand to gain financially from the sales of these supplements.