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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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





The (un)usefulness of regular breast exam

7 09 2008

Regular breast exam, either by women theirselves (BSE, breast self exam) or a doctor or nurse, has been promoted for many years, because this would help to detect breast cancer earlier, and “when breast cancer is found earlier, it’s easier to treat and cure” . At least that is what most people believe and what has been advocated by organizations and Internet companies (i.e. selling special gloves) (see figure).

The idea that regular breast exam is truly beneficial, however, has recently been challenged by a Cochrane Systematic Review, conducted by Kösters and Gøtzsche.[1] This review has stirred up quite a debate among doctors, guideline-makers, patients and women. Many major organizations and advocacy groups have stopped recommending routine BSE. Reactions of patients vary from ‘reluctant’ to ‘confused that it is no longer needed’ or even a bit angry (‘it is my body and I decide whether I check it or not’). See for instance these reactions: 1, 2, 3. Coverage in the media is sometimes misleading, but reactions of (some) doctors or “experts in the field” also do not always help to convey a clear message to the public either. Some seize the opportunity to rant against EBM (Evidence Based Medicine) in general, which makes things even less transparent, see for instance this post by Dr Rich (although he has some good points as well), this story in the Herald and this one in Medcape.

In a question-answer like way I try to cover the story.

1. What is the conclusion from the study?
The authors conclude that regular breast examination (BE) does more harm than good and is therefore not recommended.

2. Which harm, which good?
Breast examination didn’t lower mortality (not beneficial), whereas it led to more unnecessary biopsies (harm).

3. Why did they look at mortality only?
They didn’t, they also scored the number and stage of cancers identified. However mortality (or really survival) is an outcome that matters most for patients. Suppose the screening finds more breast cancers, but early intervention does not lead to any cure, than the early recognition of the cancer is of no real value to the patient.

4. Why are more unnecessary biopsies considered as harm?
Biopsies are an invasive procedure and lead to unnecessary anxiety, that can have a long-lasting effect on psychological well-being. Extra tests to rule out that it is not cancer also cost a lot of money. Whether it is ‘worth it’ depends on whether -and to which extent- people’s lives are saved (or quality of life improved).

5. What kind of study is it?
It is a systematic review (of controlled clinical trials) made by the Cochrane Collaboration (see glossary). Generally these systematic reviews are of high methodological quality, because of the systematic and explicit methods used to identify, select and critically appraise relevant research. After extensively searching for all trials, only controlled clinical trials (studies of the highest evidence) with predefined characteristics are included. Thus authors are really looking for all the high level evidence there is, instead of grabbing some papers from the drawer or looking at the core English language journals only.

6. Is this new information?
No, not really. In fact this systematic review is an update of a previous version, published in 2003. The studies included and the conclusions remain the same. As shown from the scheme below (taken from a figure in a very interesting opinion paper entitled “Challenges to cancer control by screening” (see abstract here), the attitude towards breast self examination already changed soon after the original trials were published.

Nature Reviews Cancer 3, 297 (2003)

M.N. Pollak and W.D. Foulkes: Nature Reviews Cancer 3, 297 (2003)

7. Omg? ….
All Cochrane Systematic have to be regularly updated to see if there isn’t any new evidence that could alter the conclusions. In this case, after updating the search, no new studies of good quality were found. However, there are still some trials ongoing.

8. Can we rely on these conclusions? Is the Cochrane Review of good enough quality?
The Cochrane Review itself is of high quality, but the two randomized studies included, one from Russia (1999: ~122,500 participants) and one from Shanghai (2002: ~266,000 participants) have some serious flaws. For instance, both studies did not have an adequate allocation concealment (keeping clinicians and participants unaware of the assignments). An inadequate concealment undermines the validity of a trial (see for instance this 2002 Lancet paper). Also, description of statistical methods was lacking. Furthermore, data from the Moscow-branch of the Russian study were incomplete (these are excluded), mammography might have been used additionally and in the Shanghai trial there was a large difference in all-cause mortality in favor of the control group, suggesting that the two groups were imbalanced from the start.

9. Can the results of these rather old trials from countries as China and Russia be directly translated to the situation in Western Countries with a high standard of care?
Intuitively I would say ‘probably not’. However, we still don’t know whether the current western quality of care would actually lead to a better outcome after early detection, because it has never be tested in a well performed controlled trial.

10. Is this outcome applicable to anyone?
No, the studies are applicable to healthy, middle-aged woman without any particular risk. Screening methods might be more useful or even required for woman at high risk (i.e. familiar predisposition, previous ovarian or breast cancer).

11. Still, in recent interviews experts in the field say they do know that BSE is beneficial. One doctor for instance referred (in this Medscape paper) to a recent trial, that concluded that breast self-examination should be promoted for early detection of breast cancer (see here).
Either these doctors/experts give their personal opinion, refer to unpublished data or to studies with a lower evidence level. For instance the study referred to by Dr. Goldstein above was a retrospective study looking at how accurately woman could detect a breast tumor. Retrospective studies are more biased (see previous post on levels of evidence for dummies). Furthermore this study didn’t evaluate a hard outcome (survival, better prognosis) and there are just as many retrospective studies that claim the opposite, i.e. this article of Newcomb et al in J Natl Cancer Inst. 1991(abstract).

12. Should woman refrain from breast self examination then?
I found a short article (half A4) in the Dutch woman’s magazine (!) Viva very clear and concise.
Four woman gave their opinion.

A patient who had had a previous breast tumor kept on checking it (high risk group).

The director of a patient association said: “there is no evidence that BSE is beneficial: don’t feel quilty if you don’t check your breasts. But it might have a reassuring effect if you do”.
The spokeswoman of the Dutch association “struggle against cancer” (KWF) said that they didn’t promote structural breast exam any longer, but they advised to “know your body” and know the alarm signals (retracting nipple etc), much the same way as you check for alterations in nevi. Most woman find small alterations anyway, said another, for instance when taking a shower.
Indeed, exemplified by my own experience: 18 years ago my mother detected breast cancer when feeling a lump in her breast under the shower (malignant, but curable).

The Cochrane authors are also very clear in their review about the necessity of women noticing changes to their breast.

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Listen to this Podcast featuring the Cochrane authors to learn more about their findings

[audio: http://cochrane.org/podcasts/review_summaries/mp3/issue3_2008_breast.mp3%5D

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Periodieke borstcontrole, uitgevoerd door vrouwen zelf of door artsen/verplegers, is jarenlang gepromoot, omdat je hierdoor eerder borstkanker zou ontdekken, waardoor het beter te genezen is. Deze gedachte wordt actief uitgedragen door verschillende organisaties en Internetbedrijven (die bijvoorbeeld speciale handschoenen verkopen, zie figuur).

Dat regelmatige borstcontrole zinvol zou zijn, wordt echter tegengesproken door een recent Cochrane Systematisch Review, uitgevoerd door Kösters and Gøtzsche.[1] Dit review heeft heel wat losgemaakt bij dokters, makers van richtlijnen, patienten en vrouwen in het algemeen. Veel belangrijke organisaties bevelen niet langer het maandelijks controleren van de borsten aan. De reacties van (engelstalige) patienten varieert van ‘opgelucht’ tot ‘in verwarring gebracht’ of lichtelijk boos (‘ik maak verdorie zelf nog wel even uit wat ik doe’). Zie bijv. enige reacties hier: 1, 2, 3. De berichtgeving door sommige media is soms misleidend. Dat is vaker zo, maar vervelender is het dat reacties van sommige artsen of ‘experts’ heel gekleurd zijn, waardoor de boodschap niet goed overkomt bij het publiek. Sommigen grijpen de gelegenheid aan om even goed op EBM (Evidence Based Medicine) af te geven, zie bijv. deze post van Dr Rich (die overigens ook zinnige dingen opmerkt), dit bericht in de Herald and dit in Medcape (zie onder).

Ik zal proberen om dit onderwerp in een vraag-en antwoord-vorm te bespreken.

1. Wat zijn de conclusies uit de studie?
Dat structureel borstonderzoek door vrouwen zelf of door artsen/verplegers meer kwaad dan goed doet, en dus niet langer aanbevolen kan worden.

2. Welk kwaad, welk goed?
Maandelijkse controle van de borsten leidt niet tot minder sterfte (niet ‘beter’), maar wel tot 2x zoveel biopsies (kwaad, ‘harm’).

3. Waarom kijken ze alleen naar sterfte?
Ze keken ook naar het aantal ontdekte kankers en hun stadia, maar sterfte (of eigenlijk overleving) is veel belangrijker voor de patient. Stel dàt je eerder borstkanker vindt door screening, maar dit leidt niet tot genezing en/of een betere kwaliteit van leven, dan schiet de patient daar niets mee op, integendeel (zij weet het langer).

4. Waarom worden biopsies als ‘schadelijk’ gezien?
Een biopsie is een medische ingreep, die -zeker in het geval van vermoede kanker-, een langdurig negatief kan effect hebben op iemand’s psychische gesteldheid. Biopsies en andere testen, die nodig
zijn om kanker uit te sluiten kosten veel geld. Of dit het ‘waard’ is hangt af van hoe nuttig die testen werkelijk zijn, dus of ze de kans op overleving of een betere kwaliteit van leven verhogen.

5. Wat voor een studie is het?
Het is een systematisch review (van “gecontrolleerde” klinische studies), gemaakt door auteurs van de Cochrane Collaboration (zie Glossary). Over het algemeen zijn deze reviews van uitstekende methodologische kwaliteit, omdat studies volgens een vast stramien gezocht, geselecteerd, beoordeeld en samengevat worden. Van te voren worden alle criteria vastgelegd. Dus de auteurs proberen echt alle evidence (positief of negatief, zonder taalbeperking) boven water te krijgen in plaats van wat artikelen uit de kast te trekken of alleen maar de top-tijdschriften te selecteren.

6. Is deze informatie nieuw?
Nee, niet echt. Dit systematische review is in feite een update van een vorige versie uit 2003. De geincludeerde studies en de conclusies zijn hetzelfde. Zoals te zien in het schema hieronder (Nature Reviews Cancer 2003, samenvatting hier), is de houding ten opzichte van borstzelfcontrole al sinds de publicaties van de oorspronkelijke studies (die in het Cochrane Review opgenomen zijn) veranderd. De Amerikaanse Cancer Society beveelt bijvoorbeeld al sindsdien maandelijks zelfonderzoek niet meer aan.

Nature Reviews Cancer 3, 297 (2003)

M.N. Pollak et al: Nature Reviews Cancer 3, 297 (2003)

7. Huh? ….
Alle Cochrane Systematische Reviews behoren regelmatig ge-update te worden om te kijken of er geen nieuwe evidence is die tot een andere conclusie leidt. In dit geval werden er geen nieuwe studies van goede kwaliteit gevonden. Wel lopen er nog enkele studies.

8. Kunnen we van deze conclusies op aan? Zijn Cochrane Reviews van een voldoende kwaliteit?
Het Cochrane Review zelf is van een goede kwaliteit, maar op de 2 studies die opgenomen zijn in het review (een uit Rusland uit 1999 met ca. 122.500 deelnemers en een uit Shanghai uit 2002 met ca. 266.000 deelnemers) is wel het een en het ander aan te merken. In beide studies was de blindering van de patienten en de behandelaars voor de toewijzing van de behandeling (concealment of allocation) onvoldoende. Daarmee wordt zo’n studie minder valide (zie bijv. dit artikel uit de Lancet van 2002). Verder was de beschrijving van de statistische methoden onvolledig, waren gegevens van de Moskouse tak van de studie Russische studie niet compleet (zijn wel uitgesloten) , en was er in de Shanghai studie een groot verschil in algehele sterfte (dus niet alleen borstkanker), wat een duidelijke aanwijzing is dat de 2 groepen al vanaf het begin niet gelijkwaardig waren.

9. Zijn de resultaten uit deze oudere studies uit landen als China en Rusland zondermeer op Westerse landen van toepassing?
Intuitief zou ik zeggen van niet. De zorg in Westerse landen en de hedendaagse behandelingen zijn mogelijk beter. Alleen weten we niet of screening door zelfonderzoek hier wel tot een betere uitkomst zou leiden, omdat dat nooit in goede gecontroleerde studies is bestudeerd.

10. Gelden de conclusies voor alle vrouwen?
Nee, de studies zijn allen gedaan -en daarom alleen van toepassing op gezonde vrouwen van zo’n 35 tot 65 jaar. Screeningsmethoden, waaronder borstzelfonderzoek, zijn wel aan te bevelen voor vrouwen, die tot de risicogroep behoren (vrouwen die erfelijk belast zijn of die eerder al borst- of eierstokkanker hebben gehad).

11. Toch stellen bepaalde deskundigen dat zelfonderzoek wel gunstig is. Een dokter (Dr. Goldstein) verwees daarbij in een interview in Medscape (zie hier) naar een heel recente studie (zie hier).
Deze artsen/deskundigen geven hun persoonlijke mening, verwijzen naar niet-gepubliceerde studies of naar studies met een lagere bewijskracht. De studie waar Dr. Goldstein naar verwijst is bijvoorbeeld een retrospectieve studie, die alleen onderzoekt hoe goed vrouwen borstkanker kunnen vaststellen. Retrospectieve studies hebben altijd meer vertekening (zie een vorig bericht over het beste studietype… voor dummies). Verder keek deze studie niet naar harde uitkomsten (overleving, betere prognose). Daarnaast zijn er evengoed retrospectieve studies die het tegenovergestelde beweren, zie bijvoorbeeld dit artikel van Newcomb PA et al in J Natl Cancer Inst. 1991(abstract).

http://breastselfexam.ca/section1slide2.html

12. Moeten vrouwen dan helemaal geen borstcontrole meer doen?
Ik kwam toevallig ergens op een terrasje een klein stukje in de Viva (1-7 aug 2008) tegen dat ik heel duidelijk vond.
4 Vrouwen gaven hun mening.

Een vrouw die eerder borstkanker had gehad bleef maandelijks controleren (risicogroep).
De directeur van de Borstkankervereniging zei: “Wetenschappelijk is aangetoond dat borstcontrole niet zorgt voor minder sterfte door borstkanker. Voel je niet schuldig als je het niet doet. Doe je het wel om zo je borsten goed te leren kennen, dan heeft dat vooral een psychologisch effect”. De woordvoerdster van de KWF Kankerbestrijding zei dat ze periodieke zelfcontrole niet langer promoten, maar dat ze ook niet zeggen dat het zinloos is. Het is net als bij moedervlekken, die controleer je ook niet gestructureerd, maar als je een verandering ziet ga je wel naar de huisarts. Daarmee in overeenstemming zei de directeur van Pink Ribbon dat 90% van de vrouwen borstkanker zelf opmerkt: als er iets zit merk je het toch wel, bijvoorbeeld tijdens het douchen. Inderdaad kan ik dat uit eigen ervaring bevestigen. Mijn moeder voelde jaren geleden een knobbeltje terwijl ze zich aan het douchen was (kwaardaardig, maar genezen).

De Cochrane auteurs zeggen in hun review ook heel expliciet dat het absoluut noodzakelijk is om naar de dokter te gaan als vrouwen veranderingen aan hun borst opmerken.

“Some women will continue with breast self-examination or will wish to be taught the technique. We suggest that the lack of supporting evidence from the two major studies should be discussed with these women to enable them to make an informed decision.
It would be wrong, however, to conclude that women need not be aware of any breast changes. It is possible that increased breast awareness may have contributed to the decrease in mortality from breast cancer that has been noted in some countries. Women should, therefore, be encouraged to seek medical advice if they detect any change in their breasts that may be breast cancer.”

Hier is de Podcast waarin de Cochrane auteurs over hun studie vertellen.

[audio: http://cochrane.org/podcasts/review_summaries/mp3/issue3_2008_breast.mp3%5D
zie Engels gedeelte hierboven