Yet Another Negative Trial with Vitamins in Prostate Cancer: Vitamins C and E.

15 12 2008

Within a week after the large 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 benefits were found from either vitamin C or E when it came to preventing prostate ànd other cancers.
Both trials are now prepublished in JAMA. The full text articles and the accompanying editorial are freely available [3, 4, 5].

In The Physicians’ Health Study II Randomized Controlled Trial (PHS II), researchers tested the impact of regular vitamin E and C supplements on cancer rates among 14,641 male physicians over 50: 7641 men from the PHS I study and 7000 new physicians.

The man were randomly assigned to receive vitamin E, vitamin C, or a placebo. Besides vitamin C or E, beta carotene and/or multivitamins were also tested, but beta carotene was terminated on schedule in 2003 and the multivitamin component is continuing at the recommendation of the data and safety monitoring committee.

Similar to the SELECT trial this RCT had a factorial (2×2) design with respect to the vitamins E and C [1]: randomization yielded 4 nearly equal-sized groups receiving:

  • 400-IU synthetic {alpha}-tocopherol (vitamin E), every other day and placebo (similar to the SELECT trial)
  • 500-mg synthetic ascorbic acid (vitamin C), daily and placebo
  • both active agents
  • both placebos.

Over 8 years, taking vitamin E had no impact at all on rates of either prostate cancer (the primary outcome for vitamin E), or cancer in general. Vitamin C had no significant effect on total cancer (primary outcome for vitamin C) and prostate cancer. Neither was there an effect of vitamin E and/or C on other site-specific cancers.

How can the negative results be explained in the light of the positive results of earlier trials?

  • The conditions may differ from the positive trials:
    • The earlier positive trials had less methodological rigor. These were either observational studies or prostate cancer was not their primary outcome (and may therefore be due to chance). (See previous post The best study design for dummies).
    • Clinical data suggest that the positive effect of vitamin E observed in earlier trials was limited to smokers and/or people with low basal levels of vitamin E, whereas animal models suggest that vitamin E is efficacious against high fat-promoted prostate cancer growth (20), but lacks chemopreventive effects (i.e. see [1,4] and references in [5], a preclinical study we published in 2006).
      Indeed, there were very low levels of smoking in the PHS II study and the effect of the vitamins was mainly assessed on induction not on progression of prostate cancer.
    • 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! [1,4]
  • Other forms of vitamin E and selenium have been proposed to be more effective.
  • As Gann noted in the JAMA-editorial, the men in both recent studies were highly motivated and had good access to care. In SELECT, the majority of men were tested for PSA each year. Probably because of this intense surveillance, the mean PSA at diagnosis was low and prostate cancers were detected in an early, curable stage. Strikingly, there was only 1 death from prostate cancer in SELECT, whereas appr. 75-100 deaths were expected. There also were indications of a deficit in advanced prostate cancer in PHS II, although a much smaller one.
    In other words (Gann):
    “how can an agent be shown to prevent serious, clinically significant prostate cancers when PSA testing may be rapidly removing those cancers from the population at risk before they progress?”
  • Similarly, in the SELECT trial there was no constraint on the use of other multivitamins and both studies put no restriction on the diet. Indeed the group of physicians who participated in the PHS II trial were healthier overall and ate a more nutritious diet. Therefore Dr Shao wondered
    “Do we really have a placebo group – people with zero exposure? None of these physicians had zero vitamin C and E” [7]. In the Netherlands we were not even able to perform a small phase II trial with certain nutrients for the simple reason that most people already took them.

What can we learn from these negative trials (the SELECT trial and this PHS II-trial)?

  • Previous positive results were probably due to chance. In the future a better preselection of compounds and doses in Phase 2 trials should determine which few interventions make it through the pipeline (Gann, Schroder).
  • Many other trials disprove the health benefits of high dose vitamins and some single vitamins may even increase risks for specific cancers, heart disease or mortality [9]. In addition vitamin C has recently been shown to interfere with cancer treatment [10].
  • The trials make it highly unlikely that vitamins prevent the development of prostate cancer (or other cancers) when given as a single nutrient intervention. Instead, as Dr Sasso puts it “At the end of the day this serves as a reminder that we should get back to basics: keeping your body weight in check, being physically active, not smoking and following a good diet.”
  • Single vitamins or high dose vitamins/antioxidants should not be advised to prevent prostate cancer (or any other cancer). Still it is very difficult to convince people not taking supplements.
  • Another issue is that all kind of pharmaceutical companies keep on pushing the sales of these “natural products”, selectively referring to positive results only. It is about time to regulate this.

1937004448_dfcf7d149f-vitamines-op-een-bordje1

Sources & other reading (click on grey)

  1. Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial)
  2. Podcasts: Cochrane Library and MedlinePlus: (post on this blog)
  3. Vitamins E and C in the Prevention of Prostate and Total Cancer in Men: The Physicians’ Health Study II Randomized Controlled Trial. J. Michael Gaziano et al JAMA. 2008;0(2008):2008862-11.[free full text]
  4. 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 [free full text].
  5. Randomized Trials of Antioxidant Supplementation for Cancer Prevention: First Bias, Now Chance-Next, Cause. Peter H. Gann JAMA. 2008;0(2008):2008863-2 [free full text].
  6. Combined lycopene and vitamin E treatment suppresses the growth of PC-346C human prostate cancer cells in nude mice. Limpens J, Schröder FH, et al. J Nutr. 2006 May;136(5):1287-93 [free full text].

    News
  7. The New York Times (2008/11/19) Study: Vitamins E and C Fail to Prevent Cancer in Men.
  8. BBC news: (2008/12/10) Vitamins ‘do not cut cancer risk’.
  9. The New York Times (2008/11/20) News keeps getting worse for vitamins.
  10. The New York Times (2008/10/01) Vitamin C may interfere with cancer treatment.




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Podcasts: Cochrane Library and MedlinePlus

13 12 2008

podcastI added two podcasts to the Google-speadsheet wiki: Best Medical podcasts, made by Ves Dimov (see my previous post here): Cochrane reviews and Medline Plus.

Ves Dimov has described his top 5 podcasts in another post [1]. For other medical podcasts see [2,3,4].

A podcast is nothing more than a digital audio or video file, just like any other song or MP3 file on your computer. They can be listened to, saved and shared on the internet. Although podcasts were initially meant for i-pods (hence podcast), you can also subscribe to podcasts by other Podcast-readers, Web browsers or RSS-Readers.

I would like to shortly review the two podcasts.

1. Cochrane Reviews (Click here for Feed)

The Cochrane Library, published by John Wiley for The Cochrane Collaboration, is updated and expanded every three months.
The Cochrane podcasts are freely available audio summaries of:

  • highlights of each quarterly issue. This is just a summary of main topics. Example below (with bad handling of the microphone):
  • a selection of systematic reviews from The Cochrane Library. I found the ones below very interesting and may blog about them later.
    It is often said that Cochrane Reviews are difficult to understand and that even physicians find them hard to read. The podcasts I’ve heard are very informative and understandable for doctors, journalists, librarians and patients. The essentials of the conclusions are very clear. I think it would be a good thing if all Cochrane Reviews were podcasted this way.

Adverse events of formoterol (and salmeterol) in asthma

St John’s wort for major depression

podcasts-cochrane-library

Cochrane Podcasts of issue 4 2008: you can listen or subscibe to and/or download/embed the podcasts

2. MedlinePlus (click here for feed)

The MedlinePlus podcasts is a weekly series of highlights of health news and accompanying information from MedlinePlus.The update is generally given by Donald A.B. Lindberg, M.D., Director of the National Library of Medicine.
It is very clearly indicated how you can listen or subscribe to these podcasts. There is also a transcript.

The last audio is about the negative results of the huge Vitamine E-Selenium (SELECT) Prostate Cancer, I described almost a month ago in this post.
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.

podcasts-medlineplus

More Reading, viewing or listening (click on grey):

  1. MD Ves Dimov has described his top 5 podcasts, including JAMA Audio Commentary and NEJM This Week podcast at his blog. He also gives a short description how you can subscribe to the podcasts/videocasts.
  2. Very good and complete medical podcasts-directory at learnoutloud.com. Not only podcast-series, but also individual podcasts, such as class lessons of statistics (which are difficult to follow without seeing figures) or psychology.
  3. Dean Giustini: [pdf] “Podcasting” howto + select list of medical podcasts http://weblogs.elearning.ubc.ca/googlescholar/CHLA_ABSC_podcasting.pdf
  4. new2.gif See also:Dean Giustini, UBC Health and Library Wiki: Podcasts and Videocasts (very comprehensive!)
  5. And if you want to know more why podcasts are useful than view this short commoncraft you-tube video.

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nl vlag NL flagEen podcast is gewoon en digitaal audio of video bestand, net als elk ander MP3 bestand op je computer. Je kunt ze beluisteren, downloaden en delen. Hoewel podcasts oorspronkelijk voor i-pods bedoeld waren (vandaar podcast), kun je je ook op podcasts abonneren via andere Podcast-readers, Web browsers of RSS-Readers.

Hier bespreek ik twee podcasts die ik aan de Google-speadsheet wiki Best Medical podcasts heb toegevoegd (zie eerder bericht): Cochrane reviews en Medline Plus.

Ves Dimov heeft zijn top 5 podcasts op zijn blog beschreven [1]. Voor andere medische podcasts, zie [2,3].

1. Cochrane Reviews (Klik hier voor feed)

The Cochrane podcasts zijn gratis audio samenvattingen van:

  • De belangrijkste onderwerpen van elke 3-maandelijkse update van de Cochrane Library.

2. MedlinePlus (klik hier voor feed)

Medline Plus podcasts zijn een wekelijkse serie van hoogtepunten uit het gezondheidsnieuws van de MedlinePlus. De update wordt meestal verzorgd door Donald A.B. Lindberg, M.D., baas van de National Library of Medicine.
Het wordt duidelijk aangegeven hoe je de podcasts kunt beluisteren en hoe je een abonnement (feed) kunt nemen. Er is ook een transcript. Dit heb je er wel een beetje bij nodig. De tekst is verder duidelijk, maar erg droog en lang (incl disclaimers en links. “go to double u double u double u …dot com etcetera”).

Hier is een audio van de laatste week over de negatieve resultaten van de grootschalige Vitamine E-Selenium (SELECT) prostaat kanker trial, Idie ik een maand geleden reeds op dit blog beschreef.

Meer lezen: zie links in engelstalig gedeelte.