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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6 responses

13 04 2009
airbeds

Thanks, this was very informative and cleared up a lot of questions i had. I think I fall in the group not so inclined, at this point, to favor the screening.

13 04 2009
Chris O'Neill

Regarding the claim:

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:

this fails to distinguish between the effects of PSA screening and prostate cancer treatments, i.e. the only necessary consequence of PSA screening is extraction of a blood sample which is not a serious consequence. It’s up to the person whose PSA is measured to choose what they want to do about the result. The serious choice comes when someone decides what to do after a biopsy shows they have cancer.

Also, in my experience, a biopsy is not that painful, far less painful than a prostatectomy. In my opinion, you’d be crazy not to try to detect and remove prostate cancer when you’re relatively young (younger than 65-70). Prostate cancer usually takes at least 10 years to kill you but if you’re younger than 60 when you get it then it will very likely kill you.

14 04 2009
Lee Smith

As one of many men who were diagnosed with Prostate Cancer in our 50′s(myself 12 years ago) we are very thankful that we got a PSA test. Current practice is not just the PSA test – wham bam – out with the prostate. Perhaps that was what the men in the studies underwent but certainly not a rational approach to prostate cancer, no more rational then sticking one’s head in the sand by avoiding PSA testing. The studies don’t talk at all about the actual process I underwent. Multiple PSA tests, leading to a biopsy, leading to a pathology report revealing fairly agressive cancer in half of my biopsy samples. I was then faced with trying to sort out the options — watchful waiting –(now replaced with more agressive active surveillance, radical prostatectomy (now including minimally invasive robotic surgery, external beam radiation, seed implantation, cryosurgery. New advances all the time. But the bottom line was looking at the more meaningful statistics — what were the chances with my PSA, my agressiveness, my spatial distribution, that I would still have organ contained cancer, and if so what are the changes it would stay in the organ. These are important questions — questions men who buy the no PSA may unfortunately not get to ask. True, the medical Drs may keep them alive through chronic treatment of an ultimately non stoppable invasive cancer, but don’t you agree we men should know all our options including the opportunity to remove the cancer completely before it get out? If I were a conspiracy buff, I would hypothesize that the MDs are fighting the surgeons for who gets the chance to deal with prostate cancer, the surgeons before it spreads or the MDs afterwards. Go to any major prostate cancer website and you will see how much more nuanced and sophisticated approaches to PSA testing is now compared to studies a decade ago. The studies are obsolete and they aren’t even done yet since the wait isn’t long enough. The MDs feel we are “men enough” to learn of our conditions and make our own decisions — so they conclude it’s better we don’t know. No thank you big brother MD

14 04 2009
Lee Smith

The ladies are facing the same “challenge” of being accused of being overtreated for breast cancer. This was on a breast cancer discussion group, submitted by a woman who chose mastectomy rather than lumpectomy and radiation even though both produced the same survival rate (she had a diagnosis of DCIS which is considered non/pre invasive stage 0 cancer) via a digital mammogram. Recently a clamor has arisen to discourage digital mammograms because they reveal “too many” early stage breast cancers some of which will not become invasive. Sound familiar guys. This woman made her choice based on recurrence rate which was 1.5% for mastectomy versus 15% (half invasive) for lumpectomy. She tried two lumpectomies but couldn’t get a margin better than 1 mm. These are the kinds of considerations and numbers both men and women need to consider when they are unfortunate to have a diagnosis of early stage cancer: A couple of years ago as we prepared to enter retirement we began meeting with a financial advisor. Before we even began discussing our assets, investments, life style goals, we had to fill out a survey on “tolerance of risk” and this struck me as strange. After all we wanted objective advice from a knowledgable professional as to how best have enough money to live comfortably for the rest of lives with some left over for the kids, etc. Well it turns out there is no such objective advice as we see only too well for the past two years of wall street etc. Nevertheless, after a DX of DCIS I realize there is the weird parallel. There is no fully objective way to decide what to do. It’s also a question of what risk one want’s to tolerate. I’m thinking that the medical profession might do well to stress that as well. They did say “it’s a personal decision” but not very convincingly. But it really is isn’t it. And perhaps just as our financial advisor was able to produce a series of charts and graphs with potential pathways and probablities based on the decisions we made now and the permutations and combinations that might be encountered, our MDs should do the same thing as best they can chart out the next 25 years of our lives based on the decisions we make now and the range of possibilities as presently understood. We sort of end up doing that informally, but perhaps it should be part of the normal package rather than the blanket misleading statements we are handed by the MDs and the media. Chance and choice are important and the value systems of MDs may or may not correspond to our own as I sensed over and over again!!!

14 04 2009
Grand Rounds Vol. 5 No. 30 | Pharmamotion

[...] confusion about the usefulness of PSA screening? Laika’s MedLibLog summarizes the (interim) results of two large randomized controlled trials on [...]

5 05 2009
Joseph Ernst

The “Usual care group” was also “screened”, or at least 1/2 of the group received PSA testing. Even these studies are not (I hope) suggesting we turn back the clock and stop all PSA testing. Has the mortality before PSA testing been forgotten? Although it would be a “historical control” which is not usually highly regarded, death is absolute and a good measure of effectiveness. A substantially better comparison would be to measure the quality of life of those that have prostate cancer but did not die of it. I suspect a few had miserable lives, and if you extend the study a few more years, more deaths from (initially treatable) prostate cancer would likely emerge.

Testing versus screening. That is what these studies compare.

If you want to eliminate PSA testing, you need to do a study with the control group receiving no testing whatsoever, and I doubt anyone has the cojones to recommend such a study.

I pity any physician that takes it upon him or herself (on the basis of information like this) to stop “screening” his patients with PSA. I pity his patients even more.

The greatest potential harm from this type of non-comparison comparison study is the misunderstanding on the part of the patients. “I’ve heard that PSA testing doesn’t do any good, and hardly anyone dies of prostate cancer.”

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