The SELECT trial (Selenium and Vitamin E Cancer Prevention Trial) [1] opened July 25, 2001. It was the most expensive PCa prevention trial to date. 35,533 men. It is touted by some as the last word on the subject of selenium supplementation (& vitamin E, which I might write about one day). However, there are some serious flaws in the design IMO.
The dose for the selenium arms was 200 microg/day from L-selenomethionine.
One problem with L-selenomethionine is that the body will happily use it in place of methionine when building protein. Some will end up in miscellaneous tissues Who can say how much is available to the prostate?
Some will recall that I am wary of anything that might be a methyl donor, due to hypermethylation in aggressive PCa. Methionine itself converts to SAM, the universal methyl donor in the body.
An attraction to some, I think, is the bioavailability of selenomethionine. The inorganic sodium selenite that I favor [2] is usually shunned. Other forms (from a very quick look at products offered by Swanson):
- selenium glycinate
- selenium yeast
- SelenoExcell® organically bound high- selenium yeast
- L-Se-methylselenocysteine
- Sodium Selenate (not selenite)
& probably others.
Some will eat a couple of Brazil nuts daily - very high in selenium. SelenoExcell® claims to have the same form, but do not say what that is. L-selenomethionine?
It is likely that most users of selenium supplements will be taking the L-selenomethionine, which is not a good reason to look no further when designing a large study. I suppose that for reasearchers, one form is as good as another, so use the popular one?
Whatever. The big problem with SELECT is that selenium deficiency is rare in the U.S. population. "Mean dietary intake of selenium of U.S. participants was 153 mcg for men {which} exceed the recommended selenium intake for adults and are further evidence of adequate selenium intakes in the U.S" [3]. The reason is that American (& Canadian) wheat is grown in selenium-rich soil, & most people get enough selenium from bread.
When Britain joined the Common Market 45 years ago, North American wheat was replaced by European wheat, which is grown in selenium-poor soil. Average dietary intake in 1995 was 39 mcg [4]. Huge drop.
A 2003 study revealed that UK farming soil was deficient in selenium. i.e. the levels of selenium were insufficient to prevent deficiency in grazing animals - or in people eating on local produce.
A parallel SELECT study in Britain might have shown quite different results.
I'm not a huge fan of Mark Moyad, but here he is in 2002 [5]:
"Results from numerous laboratory and observational studies support the use of these supplements {Selenium and vitamin E}, and data from recent prospective trials also add partial support. However, a closer analysis of the data reveals some interesting and unique associations. Selenium supplements provided a benefit only for those individuals who had lower levels of baseline plasma selenium. Other subjects, with normal or higher levels, did not benefit and may have an increased risk for prostate cancer."
What I recall from the old selenium studies is that you didn't want to be in the lowest grouping (usually quintile or quartile, but even decile). But that is for a U.S. population. In the UK one would not expect risk to be limited to the very lowest grouping.
Selenium is one of those minerals where one reads warnings of the dangers of high levels. I don't know where Moyad got the idea that higher levels might increase PCa risk, but I think he showed prescience back in 2002.
Moyad begins his article with "Selenium and vitamin E are probably 2 of the most popular dietary supplements considered for use in the reduction of prostate cancer risk. This enthusiasm is reflected in the initiation of the Selenium and Vitamin E Chemoprevention Trial (SELECT)."
So in 2002 (we are led to believe), a significant number of U.S. men were using selenium to prevent PCa.
But the SELECT designers ignored the above & gave everyone "200 microg/day", regardless of selenium status. 200 mcg is a fairly common supplemental dose, but is that why it was chosen? What was the basis for assuming it was optimal? They could have used two or more doses.
Why did they think it useful to give 200 mcg to all of the men who were selenium-sufficient?
But worse, men who were already supplementing at high levels were not told to stop.
What Moyad might have predicted was (1) a small number of men were lifted out of deficiency & (2) a larger number of men pushed into unusually high levels - possibly dangerous levels.
"Study supplements were discontinued at the recommendation of the Data and Safety Monitoring Committee at a planned 7-year interim analysis because the evidence convincingly demonstrated no benefit from either study agent" [6].
A recent paper perhaps helps us understand the SELECT result [7]:
"Our discovery of a U-shaped dose-response between toenail selenium concentration and prostatic DNA damage in dogs remarkably parallels data on the relationship between selenium status and prostate cancer risk in men. Notably, the dog U-curve provides a plausible explanation for the unanticipated increase in prostate cancer incidence among men with highest baseline selenium who received selenium supplementation in the largest-ever prostate cancer prevention trial (SELECT)."
***
In the new vitamin D study [8], cholecalciferol was used "at a dose of 2000 IU per day". Not clear why 2,000 IU was used. The idea that a dose, rather than a blood level, was the most significant measure might seem odd to men who have had trouble attaining their target level.
LEF had to reformulate their cholecalciferol with oil because of poor uptake. No mention whether oil was in use here.
Plasma vitamin D (25-D aka calcidiol) varies by lattitude. A single dose makes no sense.
"Among the 15,787 participants who had blood samples that could be analyzed, the mean ... serum total 25-hydroxyvitamin D level at baseline was 30.8" ng/mL.
Vitamin D sufficiency - old style - is 30 ng/mL (sometimes 32). So a significant number of people (actually 55%) were sufficient according to older experts - why treat them?
Unless one buys into a higher level for sufficiency, such as 50 mg/mL (new style), but there is no mention of that.
Was the team unaware of the Nordic papers showing a U-shaped risk curve, with lowest risk below 30 ng/mL? Perhaps they disregarded them. Some would consider it risky (unethical) to treat those already D-sufficient.
"12.7% had levels below 20 ng per milliliter" (deficiency)
"32.2% had levels from 20 to less than 30 ng per milliliter" (insufficiency.
I think that most with agree that the deficient subjects should be treated, but what was the effect of 2,000 IU on those folk? Was it adequate to lift them above 30 ng/mL? Maybe not.
"In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 ..; for breast cancer, 1.02 ..; for prostate cancer, 0.88 ..; for colorectal cancer, 1.09 ...".
i.e. a 12% reduction for PCa. 192 cases in the D arm & 219 cases in the controls.
But what I would like to see is some analysis of 25-D levels in the cases. We have no idea. Isn't that more significant than being told that the cases were given 2,000 IU & developed cancer anyway, so D is ineffective?
***
I suppose that it is foolish of me to expect study designers to select participants that they expect to be helped & exclude those who might be harmed (as in SELECT), and to have target plasma levels (as in the case of D - toenail levels for selenium).
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/190...
[2] swansonvitamins.com/nutrico...
[3] americannutritionassociatio...
[4] nutrition.org.uk/attachment...
[5] ncbi.nlm.nih.gov/pubmed/119...
[6] ncbi.nlm.nih.gov/pmc/articl...
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