Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.

16 11 2008

select

October 27th the news was released that ([see here for entire announcement from nih.gov]

“an initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by the National Cancer Institute (NCI) and other institutes that comprise the National Institutes of Health shows that selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer. The data also showed two concerning trends: a small but not statistically significant increase in the number of prostate cancer cases among the over 35,000 men age 50 and older in the trial taking only vitamin E and a small, but not statistically significant increase in the number of cases of adult onset diabetes in men taking only selenium. Because this is an early analysis of the data from the study, neither of these findings proves an increased risk from the supplements and both may be due to chance.”

SELECT is the second large-scale study of chemoprevention for prostate cancer. Chemoprevention or chemoprophylaxis refers to the administration of a medication to prevent disease. The SELECT trial aimed to determine whether dietary supplementation with selenium and/or vitamin E could reduce the risk of prostate cancer among healthy men. It is a randomized, prospective, double-blind study with a 2×2 factorial design, which means that the volunteering men received either one of the supplements, b2x2-select-vierkantoth supplements or no supplements (but placebo instead), without knowing which treatment they would receive.
The trial volunteers were randomly assigned to one the following treatments:

  1. 200 µg of selenium and 400 IU of vitamin E per day. (both supplements)
  2. 200 µg of selenium per day and placebo
  3. 400 IU of vitamin E per day and placebo
  4. two different placebo’s (neither supplement)
    (µg = micrograms, IU = International Units)

Enrollment for the trial began in 2001 and ended in 2004. Supplements were to be taken for a minimum of 7 years and a maximum of 12 years. Therefore the final results were anticipated in 2013. However, but due to the negative preliminary results, SELECT participants still in the trial are now being told to stop taking the pills. The participants will continue to have their health monitored by study staff for about three more years, continue to respond to the study questionnaires, and will provide a blood sample at their five-year anniversary of joining the trial, to ensure their health and to allow a complete analysis of the study. (see SELECT Q & A).

In an interview with CBS, one of the investigators Dr Katz, said he was highly disappointed and concerned, because he had high hopes for the trial. “I”m disappointed with the study. I’m very concerned about the results of the trial.

more about “Vitamin E A Flop In Prostate Cancer T…“, (with 15 sec advertisement first) posted with vodpod. This video is derived from CBS news.

Dr. Klein, one of the principal investigators, has published as many as 14 publications on the SELECT trial (see PubMed). He has always been a strong advocate of this huge trial.

The question now is:
Was there enough evidence to support such a large trial? Could this result have been foreseen? Would the trial have had different outcomes if other conditions had been chosen?

The SELECT trial seems to add to the ever growing list of disappointing “preventive” vitamin trials. See for instance this blogpost of sandnsurf on “a systematic review of all the published randomized controlled trials (RCTs) on multivitamins and antioxidant supplements in various diseases, and their effect on overall mortality” concluding:

“Taking the antioxidant vitamins A (and its precursor beta-carotene) and E singly or in multivitamins is dangerous and should be avoided by people eating a healthy diet. On a diet like that recommended here, the intake of these and other important vitamins should be high, with no need for supplementation.”

Quite coincidentally I commented to Sandsnurf blogpost referring to the SELECT trial, 1 week before the bad outcome was announced):

Indeed, in many RCT’s vitamin supplements didn’t have the beneficial effects that they were supposed to have. Already in the early nineties, adverse effects of beta-carotene (higher mortality in smokers) have been shown in several RCT’s. Still, because vitamin E had an expected positive effect on prostate cancer in one such trial, vitamin E is now being tested together with selenium (2X2) in a very large prostate cancer trial. Quite disturbingly, 8 times higher doses vitamin E are being used (400IE) compared to the original study. If the Lawson study is right, the outcome might be harmful. Worrying.

It might be argued that it is easy to criticize a study once the outcome is known. However, this critique is not new.

Already in 2002 a very good critique was written by MA Moyad in Urology entitled: Selenium and vitamin E supplements for prostate cancer: evidence or embellishment?

Here I will summarize the most important arguments against this particular trial (largely based on the Moyad paper)

  • SELECT was based on numerous laboratory and observational studies supporting the use of these supplements. As discussed previously such study designs don’t provide the best evidence.
  • The incidence, or rate of occurrence, of prostate cancer was not the primary focus or endpoint of the few randomized controlled trials studies on which the SELECT study was based.
  • A 2×2 design is inadequate for dose-response evaluations, in other words: before you start the trial, you have to be pretty sure about the optimal dose of each supplement and of the interactive effect of vitamin E and selenium in the particular doses used. The interaction between two agents might be synergistic or additive, also with respect to any negative (i.e. pro-oxidant) effect.
  • Eight times higher vitamin E doses (400IE) have been used than in the ATCB study showing a benefit for vitamin E in decreasing prostate cancer risk! This is remarkable, given the fact that high doses of anti-oxidants can be harmful. Indeed, a prospective study has shown, that vitamin E supplements in higher doses (> or =100 IU) are associated with a higher risk of aggressive or fatal prostate cancer in nonsmokers.
  • Other forms of vitamin E and selenium have been proposed to be more effective. For instance dietary vitamin E (gamma tocopherol and/or gamma tocotrienols) might be more effective in lowering prostate cancer risk than the chemically-derived vitamin E (dl-alpha tocopherol acetate) used in SELECT. Also the used selenomethionine might be less effective than organically-bound selenium.
  • Selenium and vitamin E supplements seem to provide a benefit only for those individuals who have lower baseline plasma levels of selenium or vitamin E.
  • There may be other compounds that may be more effective, like finasteride, lycopene, statins (or with respect to food: a healthy lifestyle)

Katz said. “I would have hoped this would have been the way to prevent cancer in this country.”

Isn’t it a little bit naive to expect such huge effects (25% less prostate cancers) just by taking 2 supplements, given the thoughts summarized above?

In the interview, shown in the CBS-interview LaPook concludes “This is a major disappointment, but it is also progress. Because it’s also important to know what does not prevent cancer.”

Well I wonder whether it is ethical ànd scientifically valid, to do such a costly experiment with 35.000 healthy volunteers, based on such little evidence. Do we have to test each single possibly effective food ingredient as a single intervention?

SOURCES:
Official publications and information

- EA Klein: http://www.ncbi.nlm.nih.gov/pubmed/12756490
- Lippman SM, J Natl Cancer Inst. 2005 Jan 19;97(2):94-102. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). (PubMed record)
- new2.gif The results of the SELECT trial are published in JAMA: Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial. Scott M. Lippman, Eric A. Klein et al SELECT)JAMA. 2008;0(2008):2008864-13, published online December 9th 2008.

- SELECT Q&A: www.cancer.gov/newscenter/pressreleases/SELECTQandA
- General information on SELECT http://www.crab.org/select/
- Information on Study design (from Cancer Gov.clinical trialsSWOG s0000) and from clinicaltrials.gov

- More information on study designs and the ATCB trial (on which this study was based) in a previous post: the best study design for dummies

NEWS
- CBS Evening News Exclusive: Vitamin E And Selenium Fail To Prevent The Disease In Large Clinical Trial, NEW YORK, Oct. 27, 2008
- Los Angelos Times; Vitamin E, selenium fail to prevent prostate
- Emaxhealth: NCI stops prostate cancer prevention trial. With many good links to further information

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12 responses

16 11 2008
Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer. · Prostate Cancer

[...] News wrote an interesting post today onHere’s a quick excerpt [...]

17 11 2008
MK

Not exactly a comment:
For you to explore: VADLO – Biomedical Search Engine.

18 11 2008
Valstar, DCA en de IGZ. « Cryptocheilus Weblog

[...] van Niet Toxische Tumor Therapie hebt volgestopt met middelen als calcium en vitamine D…. of selenium en vitamine E….of foliumzuur en vitamine B6 en B12 is het in dit licht wel zo gemakkelijk dat je kunt [...]

19 11 2008
Dutch Grand Round is up: Grote Visite | Dr Shock MD PhD

[...] De Gezondheidszorg leuker en effectiever the new Dutch Grand Round with contributions by Laika’s MedlibLog and Medblog.nl, go have a [...]

10 12 2008
Het orthomoleculaire konijn kijkt vol in de koplampen… « Cryptocheilus Weblog

[...] van Niet Toxische Tumor Therapie hebt volgestopt met middelen als calcium en vitamine D…. of selenium en vitamine E….of foliumzuur en vitamine B6 en B12 is het in dit licht wel zo gemakkelijk dat je kunt [...]

14 12 2008
Podcasts: Cochrane Library and MedlinePlus « Laika’s MedLibLog

[...] The last audio is about the negative results of the huge Vitamine E-Selenium (SELECT) Prostate Cance… It is rather long (with disclaimers and links like “go to double u double u double u …dot com etcetera”), but understandable and about interesting topics. [...]

15 12 2008
Yet Another Negative Trial with Vitamins in Prostate Cancer: Vitamins C and E. « Laika’s MedLibLog

[...] SELECT (Selenium and Vitamin E Cancer Prevention) Trial was halted due to disappointing results (see previous posts: [1] and [2]), the negative results of yet another large vitamin trial were announced [7]. Again, no [...]

6 02 2009
jan

In Belgium people still take these meds widely

23 02 2009
MnSOD, Carotenoids & Prostate Cancer - “You are what you eat” depends on who you are. « Laika’s MedLibLog

[...] recent randomized trials did not confirm positive effects of vitamin E and C and Selenium (see previous post on the negative SELECT and the PHS II-trial) and data from the PLCO (Prostate, Lung, Colorectal, Ovarian) Trial [2] [...]

3 07 2009
david walpole

The select trial has demonstrated that as long as selenium plasma levels are up
to 1.7 umol/lt, there is no advantage in higher levels. Since the trialists were stated as being “replete at baseline”,this has been fully confirmed. It is people with levels below this , 1.7, that are able to be made less vulnerable with seleniun suplementation. This was shown in the N.P.C. trial reported in J.A.M.A. 25 Dec 1996.j

1 02 2010
#NotSoFunny – Ridiculing RCTs and EBM « Laika’s MedLibLog

[...] effects of vitamin E on cardiovascular disease (opposite) or certain cancers [...]

9 04 2010
Science-Based Medicine » Yes, Jacqueline: EBM ought to be Synonymous with SBM

[...] effects of vitamin E on cardiovascular disease (opposite) or certain cancers [...]

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