Still Confusion about the Usefulness of PSA-screening.

13 04 2009

Prostate cancer is the most commonly diagnosed cancer affecting older men and second-biggest cancer killer. pc_epid_fig11a

Prostate Specific Antigen (PSA), a protein mainly produced by the prostate gland, is often elevated in prostate cancer – and often proportional to the prostate cancer volume. Since more men are diagnosed with prostate cancer by using PSA screening, middle-aged men have been advised to undergo a simple blood test to determine their blood PSA levels.

Indeed in the 20 years that the PSA test has been used there has been a significant drop in prostate cancer deaths.

However, this may have also resulted from better treatment modalities.

Furthermore, PSA tests are prone to false negative results (prostate cancer present in the complete absence of an elevated PSA level ), or vice versa, false positive results: elevated PSA occurring in non-cancerous prostate diseases, like prostate infection and benign prostatic hyperplasia (BPH). Some detected prostate cancers may also be indolent, never giving any trouble on the long term. Since the further diagnosis methods (biopsy) and treatment methods (irradiation, surgery, hormonal treatment) often have serious side effects (erectile dysfunction, urinary incontinence and bowel problems), there is a clear need to demonstrate whether PSA screening is worth the high risks of overdiagnosis and overtreatment:

Thus, does PSA screening really saves lives?
And what is the trade off between benefits and harms?

A Cochrane Systematic Review from 2006 [5] (also reviewed in EBM-online) concluded that there was no proof of benefit of PSA-screening. Yet absence of proof is not proof of absence. Moreover, both trials on which the review was based had methodological weaknesses.
Therefore, the main conclusion was to wait for the results from two large scale ongoing randomized controlled trials (RCTs).

The first study results of these two large RCT’s,  that many observers hoped would settle the controversy, have appeared in the March issue of the New England Journal of Medicine (NEJM). [1,2] The results are discussed in an accompanying editorial [3] and in a Perspective Roundtable [4] (with a video).

It should be stressed, however, that these are just interim results.

One of these two studies [1], the prostate component of the U.S. National Cancer Institute’s Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) showed no prostate specific mortality reduction over 11 yrs follow-up in 76,705 men by annual PSA screening and DRE (digital rectal exam). However:

  • The cut off is relatively high (4.0 ng per milliliter), which means that some prostate cancers could have been missed (on the other hand lowering the screening criteria might also have led to a higher false negative response)
  • The control group is “highly contaminated”, meaning that many men in the so called nonscreened arm had a PSA-test anyway ((52% in the nonscreened versus 85% in the screened arm).
  • The 11 yr follow up may be too short to show any significant effect. “Only” 0,1% of the men died of prostate cancer. On the long term the differences might become larger.
  • Since there were only 122 prostate cancer deaths in the screening group versus 135 in the control group, the power of the study to find any differences is mortality seems to be rather low.

The European ERSPC study [2] is larger than the PLCO trial (190,000 men), the cut off rate was lower (3.0 µg/L), and there was less contamination of the nonscreened arm. A shortcoming of the trial is that the diagnosis methods varied widely among centers participating in the trial. The follow-up time is 9 years.

The ESPRC trial noticed a difference in mortality between the screened and non-screened arms. Surprisingly the same outcome led to widely different conclusions, especially in the media (see Ben Goldacre on his blog Bad Science [6])

English newspapers concluded that the ERPSC study showed a clear advantage: Prostate cancer screening could cut deaths by 20% said the Guardian. Better cancer screening is every man’s right was the editorial in the Scotsman (see 6). These newspapers didn’t mention the lack of effect in the US study.

But most US newspapers, and scientists, concluded that the benefits didn’t outweigh the risks.

Why this different interpretation?

It is because 20% is the relative risk reduction. This means that the risk of getting prostate cancer is reduced by 20%. This sounds more impressive than it is, because it depends on your baseline risk. It is the absolute reduction that counts.
Suppose you would have a baseline chance of 10% of getting prostate cancer. Reducing this risk by 20% means that the risk is reduced from 10% to 8%. This sounds a lot less impressive.
But in reality your chance of getting prostate cancer comes closer to 0,1%. Then, a risk reduction of 20% becomes even less significant: it means your risk has decreased to 0,08%.

Absolute numbers are more meaningful. In the ESPRC trial[2], the estimated absolute reduction in prostate-cancer mortality was about 7 deaths per 10,000 men after 9 years of follow-up. This is not a tremendous effect. However the costs are high: to prevent one death from prostate cancer 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated.

Overdiagnosis and overtreatment are probably the most important adverse effects of prostate-cancer screening and are vastly more common than in screening for breast, colorectal, or cervical cancer.

It is difficult to realize the impact of a false negative diagnosis. People tend to think that saving any live is worth any cost. But that isn’t the case.

This quote says a lot (from Ray Sahelian)

A few years ago my dad was found to have a high PSA test. He was 74 at the time. He underwent multiple visits to the doctor over the next few months with repeated PSA tests and exams, and eventually a biopsy indicated he had a small prostate cancer. I remember my dad calling me several times a month during that period constantly asking my thoughts on how he should proceed with radiation or other treatments for his cancer. My dad had a preexisting heart condition known as atrial fibrillation. I suggested he not undergo any treatment for the small cancer but just to follow the PSA levels. His doctor had agreed with my opinion. His PSA test stayed relatively the same over the next few years and the prostate cancer did not grow larger. My dad died at 78 from a heart rhythm problem. Ever since the discovery of the high PSA level, he was constantly worried about this prostate gland. What good did it do to have this PSA test at his age? It only led to more doctor visits, a painful prostate gland biopsy, and constant worry. Maybe the constant worry even made his heart weaker.

Indeed more men die with prostate cancer than of it.It’s estimated that appr 30% of American men over age 60 have small, harmless prostate cancers.

Although still hypothetical, non-invasive tests that would discriminate between low- and high risk prostate cancer could be a real solution to the problem. One such candidate might be the recently discovered urine test for sarcosine [7]

In conclusion
PSA-screening is associated with an earlier diagnosis of prostate cancer, but the present evidence shows at the most a slight reduction in prostate related mortality. Since screening and subsequent testing do have serious side effects, there seems a trade off between uncertain benefits and known harms. However, definite conclusions can only be drawn after complete follow-up and analyses of these and other studies [1,2,3]

REFERENCES

  1. ResearchBlogging.orgAndriole, G., Grubb, R., Buys, S., Chia, D., Church, T., Fouad, M., Gelmann, E., Kvale, P., Reding, D., Weissfeld, J., Yokochi, L., Crawford, E., O’Brien, B., Clapp, J., Rathmell, J., Riley, T., Hayes, R., Kramer, B., Izmirlian, G., Miller, A., Pinsky, P., Prorok, P., Gohagan, J., Berg, C., & , . (2009). Mortality Results from a Randomized Prostate-Cancer Screening Trial New England Journal of Medicine DOI: 10.1056/NEJMoa0810696
  2. Schroder, F., Hugosson, J., Roobol, M., Tammela, T., Ciatto, S., Nelen, V., Kwiatkowski, M., Lujan, M., Lilja, H., Zappa, M., Denis, L., Recker, F., Berenguer, A., Maattanen, L., Bangma, C., Aus, G., Villers, A., Rebillard, X., van der Kwast, T., Blijenberg, B., Moss, S., de Koning, H., Auvinen, A., & , . (2009). Screening and Prostate-Cancer Mortality in a Randomized European Study New England Journal of Medicine DOI: 10.1056/NEJMoa0810084
  3. Barry, M. (2009). Screening for Prostate Cancer — The Controversy That Refuses to Die New England Journal of Medicine, 360 (13), 1351-1354 DOI: 10.1056/NEJMe0901166
  4. Lee, T., Kantoff, P., & McNaughton-Collins, M. (2009). Screening for Prostate Cancer New England Journal of Medicine, 360 (13) DOI: 10.1056/NEJMp0901825
  5. Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer. Cochrane Database Syst Rev. 2006;3:CD004720.[Medline]
  6. Goldacre, Ben (2009) Bad Science: Venal-misleading-pathetic-dangerous-stupid-and-now-busted.net. (2009/03/), also Published in The Guardian, 21 March 2009
  7. Sreekumar A et al. (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression Nature 457 (7231): 910-914 DOI: 10.1038/nature07762
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An Antibiotic Past May Save Lives at the ICU.

16 03 2009

3241003338_60b07d7aba

Respiratory tract infections acquired in the intensive care unit (ICU) are important causes of morbidity and mortality, the most significant risk factor being mechanical ventilation. It is thought that hospital pneumonia commonly originates from flora colonized in the patient’s oropharynx (the area of the throat at the back of the mouth). Therefore, reduction of respiratory tract infections has been obtained by putting patients in semirecumbent instead of supine position. Another approach is selective decontamination. There are two methods of selective decontamination, SDD and SOD.

  1. SDD, Selective Decontamination of the Digestive tract consists of the administration of topical nonabsorbable antibiotics in the oropharynx and gastrointestinal tract, often concomitant with systemic antibiotics. It aims to reduce the incidence of pneumonia in critically ill patients by diminishing colonization of the upper respiratory tract with aerobic gram-negative bacilli and yeasts, without disrupting the anaerobic flora.
  2. SOD, Selective Oropharyngeal Decontamination is application of local antibiotics in the oopharynx only.

Both approaches were first introduced in the Netherlands. Most trials suggested that SDD lowered infection rates, but lacked statistical power to demonstrate an effect on mortality. However, meta-analyses and three single-center, randomized studies, did show a survival benefit of SDD in critically ill patients. Several studies had suggested that the local variant, SOD, was also effective, but SOD was never directly compared with SDD in the same study. Because of methodological issues and concern about increasing antibiotic resistance the use of both SDD and SOD has remained controversial. Even in the Netherlands where guidelines recommended the use of SDD after a Dutch publication in the Lancet (de Jonge et al, 2003) had shown the mortality to drop with 30% in the Academic Medical Center in Amsterdam, only 25% of the emergency doctors followed the guidelines.

The present Dutch study, published in the NEJM (2009), was undertaken to determine the effects on mortality in a head to head comparison of SDD and SOD. The effectiveness of SDD and SOD was determined in a crossover study using cluster randomization in 13 Dutch ICU’s, differing in size and teaching status. Cluster randomization means that ICU’s rather than the individual patients were randomized to avoid that one treatment regimen would influence the outcome of another regimen. Crossover implies that all three treatments (SDD, SOD, standard care) were administered in a random order in all ICU’s.

A total of 5939 patients were enrolled in this large study. Patients were eligible if they were expected to be intubated for more than 48 hours or to stay in the ICU for more than 72 hours. The SDD regimen involved four days of intravenous cefotaxime along with topical application of tobramycin, colistin and amphotericin B; the SOD regimen used only the topical antibiotics. Both regimens were compared with standard care. The duration of the study was six months, and the primary end point was 28-day mortality.

Of the 5,939 patients, 1,990 received standard care, 1,904 received SOD and 2,405 received SDD. Crude mortality rates in the three groups were 27.5%, 26.6% and 26.9%, respectively. These differences are not very huge and benefit was only discernable after adjustment for covariates (age, sex, APACHE II score, intubation status, medical specialty, study site, and study period): adjusted* odds ratios for 28-day mortality were 0.86 (95% CI, 0.74 to 0.99) in the SOD group and 0.83 (95% CI, 0.72 to 0.97) in the SDD group compared with standard care. This corresponded with the needed-to-treat numbers (NNT’s) of 29 and 34 to prevent one casualty at day 28 for SDD and SOD, respectively.

The limitations of the study (acknowledged by the authors) were the absence of concealment of allocation (due to the study design it was impossible to conceal the allocation for doctors at the wards), differences at baseline between the standard care and treatment groups and a mismatch between the original analysis plan and the study design (originally specified in-hospital death was the primary end point, but this did not take into account analysis of cluster effects.)

Selective Decontamination also improved microbiological outcomes, such as carriage of gram-negative bacteria in the respiratory and intestinal tracts and ICU-acquired bacteriemia. During the study periods the prevalence rates for antibiotic-resistant gram-negative bacteria were lower in the SOD and SDD periods than during the standard-care periods.

The authors concluded that both SDD and SOD were effective compared with standard care. Given the similarity in effects on survival between the treatment groups, the SOD regimen seems preferable to the SDD regimen, becauses it minimizes the risk of antibiotic resistance which poses a major threat to patients admitted to ICU’s. It should be noted that MRSA-infections are very rare in the Netherlands and in Scandinavia. The outcome of the study might therefore be different after long term treatment and/or in regions with a high prevalence of MRSA.

References

ResearchBlogging.orgde Smet, A., Kluytmans, J., Cooper, B., Mascini, E., Benus, R., van der Werf, T., van der Hoeven, J., Pickkers, P., Bogaers-Hofman, D., van der Meer, N., Bernards, A., Kuijper, E., Joore, J., Leverstein-van Hall, M., Bindels, A., Jansz, A., Wesselink, R., de Jongh, B., Dennesen, P., van Asselt, G., te Velde, L., Frenay, I., Kaasjager, K., Bosch, F., van Iterson, M., Thijsen, S., Kluge, G., Pauw, W., de Vries, J., Kaan, J., Arends, J., Aarts, L., Sturm, P., Harinck, H., Voss, A., Uijtendaal, E., Blok, H., Thieme Groen, E., Pouw, M., Kalkman, C., & Bonten, M. (2009). Decontamination of the Digestive Tract and Oropharynx in ICU Patients New England Journal of Medicine, 360 (1), 20-31 DOI: 10.1056/NEJMoa0800394

de Jonge E, Schultz M, Spanjaard L, et al. Effects of selective decontamination of the digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 2003;362:1011-1016 (PubMed citation)

Wim Köhler (2009) Smeren tegen infectie, NRC Handelsblad, Wetenschapsbijlage 3,4 januari (Dutch, online)

Barclay, L & Vega, C (2009) Selective Digestive, Oropharyngeal Decontamination May Reduce Intensive Care Mortality, Medscape

File, T.M., Bartlett J.G.,& Thorner, A.R. Risk factors and prevention of hospital-acquired (nosocomial); ventilator-associated; and healthcare-associated pneumonia in adults.www.uptodate)

Photo Credit (CC): http://www.flickr.com/photos/30688696@N00/3241003338/ (JomCleay)





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.








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.

Vodpod videos no longer available.

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