PSA redux: The USPSTF finally recommends NOT getting it!

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The US Preventive Services Task Force (USPSTF), the independent group of physicians and scientists who make recommendations to the government, medical community, and American people on the value of screening tests, recently came out with a new recommendation on the use of laboratory tests for Prostate Specific Antigen (PSA) in screening for prostate cancer.  It recommended AGAINST it --in their terms, a “D” recommendation. Previously, USPSTF had recommended against PSA screening for men over the age of 75, but had not taken a position for or against screening in younger men (an “I” recommendation, insufficient evidence to recommend for or against screening).

My belief is that this is a good, appropriate, and very overdue recommendation which will come as no surprise to those who have read this blog for some time. I, and guest authors, have addressed this issue several times (PSA Screening: What is the value?, Mar 21, 2009; PSA Screening: “One of Medicine's Great Success Stories"?, Oct 27, 2009 (by Robert Ferrer);, Men’s Health? Women’s Health? Valid screening opportunities or “Hallmark Holidays”?, Mar 15, 2011). In addition I have often linked to and cited the work of Kenny Lin, MD, who writes the Common Sense Family Doctor blog, and resigned from the Agency for Healthcare Quality and Research (AHRQ) as a member of the USPSTF support team in November, 2010, over his perception that these recommendations were being delayed by political considerations. Dr. Lin has also written about PSA testing often  (including  "It is time to stop this [PSA] June 21, 2011, PSA testing: will science finally trump politics? Feb 28, 2011) and has recently addressed the new recommendations on Oct 7, 2011, Shannon Brownlee on the pros and cons of early cancer screening.

Of course, a lot of people do not think that this recommendation is a good thing. Two large groups, in particular, oppose the new recommendations: urologists and others who earn their livings treating prostate cancer and “advocacy” groups, supported by many high-profile (as well as just regular folks) men who have survived prostate cancer. Many of these men are quoted in Gardner Harris’ NY Times article “US panel says no to prostate screening for healthy men”, October 7, 2011. One of those who is quoted (actually not in the published NY Times piece, but in another version of Harris’ article published in the Seattle Times, is my colleague Brantley Thrasher, MD, Chair of the Department of Urology at the University of Kansas Medical Center, who said, "It appears to me that screening is accomplishing just what we would like to see: diagnose and treat the disease while it is still confined to the prostate and, as such, still curable."

I like Brant Thrasher, I think he is a good and knowledgeable doctor and great surgeon, but I strongly disagree with him on this one.  As much as we would like, and believe me as a family doctor I would like, and Kenny Lin would like, a test that could find disease early while it was still curable and make a difference in people’s live, PSA is not that test and, at this point prostate cancer is not that disease. These are two separate issues, so let’s take them separately.

PSA is not a good test. Yes, it is often, maybe usually, elevated in men with prostate cancer. Of course, in some men with prostate cancer it is not above the “normal” cutoff. This has led some advocates of PSA screening to suggest use of “PSA velocity”: check it yearly and watch the rate of rise rather than the absolute value. But the bigger problem for PSA as a screening test is that it is often elevated in men who do not have prostate cancer but just have a big prostate (“hypertrophy”, almost universal in men above a certain age), or even DO have cancer, but the very-slow-growing-that-is-not-going-to-kill-you-before-you-die-of-something-else kind, which is by far the most common variety. These men are subjected to ultrasounds, biopsies, and treatments that cause significant morbidity (impotence, incontinence of urine, and “radiation proctitis” of the rectum and anus, developing congestive heart failure from hormone treatment, to name a few) with no benefit.  Baylor physician and panel chair Virginia Moyer notes in the Times article that “This test cannot tell the difference between cancers that will and will not affect a man during his natural lifetime. We need to find one that does.” In 2010, Richard Ablin, PhD, who discovered the a prostate specific antigen (but not the PSA test) in 1970, called use of the test “a public health disaster” and “not much better than a coin toss.” (“The Great Prostate Mistake”, NY Times, March 9, 2010.

But the bigger issue is that there is no good evidence that treatment of any kind – surgical, radiation, hormonal – makes any difference in the outcome of prostate cancer. Surgeons like Brant Thrasher think it does, and he may be some day proven correct , at least in some circumstances, currently there is much more evidence supporting that it doesn’t than that it does. If you have the common, less-aggressive kind of prostate cancer, you won’t die from it, with or without treatment. If you have the rarer, highly-aggressive kind, you will probably die from it, with or without treatment.  The Times article notes that  “…advocates for those with prostate cancer promised to fight the recommendation. Baseball’s Joe Torre, the financier Michael Milken and Rudolph W. Giuliani, the former New York City mayor, are among tens of thousands of men who believe a P.S.A. test saved their lives.” They may believe it, but they are probably (I obviously don’t have access to their medical records) wrong. The test diagnosed prostate cancer, they were treated for prostate cancer, and they are alive. QED. But it’s false logic, an association that doesn’t demonstrate cause. If they are alive now, they would be alive (at least as far as the prostate cancer is concerned) without the treatment. And they wouldn’t have those “little” problems like incontinence and impotence that seem like a small price to pay for not dying of cancer, but are a big price if the treatment didn’t make any difference. The famous folks who have died of prostate cancer, like Frank Zappa, died despite treatment.

The Times quotes Thomas Kirk, of Us TOO, the nation’s largest advocacy group for prostate cancer survivors, saying “The bottom line is that this is the best test we have, and the answer can’t be, ‘Don’t get tested.’” He’s wrong. That is the answer. We not only need a test that can distinguish the “bad” kind of prostate cancer that will kill you from the kind that probably won’t, we need treatments that evidence shows makes a difference in survival and quality of life if you do have the bad kind. In the meantime, getting tested is likely to create more harm than benefit.

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PSA Screening: “One of Medicine's Great Success Stories"?

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Guest blog by Robert Ferrer, MD MPH

I spent 2 days at home recently with the H1N1 flu and caught up on some of my newspaper reading. In the Oct 11, 2009 New York Times Magazine, (p.38) was an advertising supplement, "Health and Wellness Outlook Special Report: Cancer Treatment Options," paid for by some of our finest cancer centers. [1] In the prostate cancer section, I found this interesting assertion, in big capital letters: "The PSA test for prostate cancer detection and management is one of medicine's great success stories." It goes on to say that 90% of prostate ca is now diagnosed when curable and that the death rate has declined by 40% since the PSA test began to be widely used in the 1980's. The source is the chair of urology and senior vice president for translational research at Roswell Park Cancer Institute in Buffalo, where the the PSA test was developed.

I found the assertion curious because this past March the New England Journal of Medicine published 2 long-awaited studies[2],[3] on whether PSA testing was effective: one found a modest benefit and the other virtually none. Both noted that a very large number of men had to be screened and treated for every one who benefited. These articles received extensive press coverage. And just as I was going to my laptop today to assemble this and other maybe-not-such-a-great-success-story evidence for PSA screening, this week's JAMA showed up with a terrific paper by Esserman, Shieh, and Thompson.[4] They have this to say about PSA screening:

"After 2 1/2 decades of screening for [breast and] prostate cancer, conclusions are troubling: Overall cancer rates are higher, many more patients are being treated, and the absolute incidence of aggressive or later-stage disease has not been significantly decreased. Screening has some effect, but it comes at significant cost, including over-diagnosis, overtreatment, and complications of therapy."

So how do we get from "great success story" to "troubling"? How can diagnosing cancer early not be a good thing? The answer lies in the kind of cancers we can detect with screening. Slow growing cancers, the kind unlikely to kill you, grow... slowly and so are around for a long time to be detected by screening. On the other hand, fast growing cancers can go from undetectable to lethal even in the year between cancer screenings. So the cancers we detect through screening are more likely to be the non-lethal kind. Well, isn't that still a good thing? Can't cancer harm without killing?

Yes, but the issue here is what we call "cancer." Our screening tests can detect collections of cells that are, by pathologists' standards, "cancer" when viewed under the microscope, yet not every collection of such cells is destined act like cancer; that is, to grow or spread (metastasize) to other parts of the body. Some are destined to remain dormant until the person eventually dies of something else. And therein lies the problem with PSA screening. It detects many of the ones destined to be dormant or slow growing for every one destined to be lethal. The exact number is uncertain, but the large European study in the NEJM this March estimated 1410 men needed to be screened and 48 cases of prostate cancer treated to prevent 1 death. [2] The American study released in parallel found the benefits to be even smaller. [3]

What this means, is that the consequence of PSA testing for many men is adding 6-12 years of life diagnosed -- and often treated -- as a cancer patient, without actually living any longer.

Just how much over-diagnosis can we attribute to PSA? In the August 2009 issue of the Journal of the National Cancer Institute, H. Gilbert Welch and Peter Alberson calculate than in the first 19 years of the PSA era, 1987 to 2005, about 1.3 million additional cases were diagnosed and 1 million more men treated.[5] They estimate that about half of these extra cases represent over-diagnosis, meaning that the diagnosed man was very unlikely to die from prostate cancer. So of the roughly 4 million men diagnosed from 1985 to 2005, half a million were over-diagnosed.

What about the fact that, as the Roswell Park urologists note, mortality rates have fallen since PSA testing began in the mid-80's? Doesn't that suggest that PSA is helping? The authors in this week's JAMA paper address this in their analysis. For that claim to be credible, we should be seeing a sharp fall in number of advanced stage prostate cancers, which is what would happen if screening was finding the "bad" cancers early, before they could reach an advanced stage. Although we have indeed seen a fall in advanced cancers it has been nowhere near as sharp as we would expect, given the many more cancers we are finding in the PSA era. We should thus probably look elsewhere to explain the fall in prostate cancer mortality, likely improvements in treatment.

So, given what we know about how well PSA testing performs as a screening test, how can it be advertised as one of medicine's great success stories? As potential explanations, I offer two themes that I believe also offer some larger lessons for why health care is less effective and more expensive than it should be.

Theme 1: Thinking about organs rather than people: If your focus is the prostate, then finding and removing cancerous prostates is the goal. This works well at the level of prostates, but not so well for whole men. With a test as imperfect as the PSA, a small or nonexistent reduction in the risk of dying from prostate cancer is sometimes traded for diminished quality of life, most commonly the incontinence and impotence that affect about 1/4 of men treated for prostate cancer.

Theme 2: Economic incentives favoring procedures. As the numbers above demonstrate, PSA has expanded the number of prostate cancer patients by about a third. The professional urology association has long recommended PSA screening even when the US Preventive Services Task Force, tasked with providing rigorous assessments for screening procedures, has consistently recommended against routine PSA screening.

Themes 1 and 2 intertwine. Greed is not what drives PSA testing. When a urologist can make a prostate cancer diagnosis and provide a "cure," doctor and patient alike perceive it as a valuable service. A life-saving intervention. That the service is well reimbursed appears justified when the stakes seem so high. It is only from the application of healthy skepticism and careful analysis -- of outcomes for people, not organs -- that we can reach better conclusions about the value of what we do.

The topic of PSA screening was previously addressed (if less well) in PSA Screening: What is the Value? March 21, 2009

[1] Anonymous. Health and Wellness Outlook Special Report: Cancer Treatment Options [advertising supplement]. New York Times Magazine, 11 October 2009. p. 33-46
[2] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine. 2009a;360:1320.
[3] Andriole GL, Crawford ED, Grubb III RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009b;360:1310.
[4] Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA. c;302:1686-1692.
[5] Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst. 2009c;101:1325-1329

This topic was also addressed previously in PSA Screening: What is the Value? March 21, 2009
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PSA Screening: What is the value?

Two studies published in the New England Journal of Medicine on line on March 18, 2009 regarding the use of prostate-specific antigen (PSA) screening for prostate cancer have been getting a lot of coverage in the popular media, including NPR and the New York Times. The reason is that these studies do not, overall, indicate that such screening saves significant numbers of lives. In the US study of 77,000 men, the PLCO trial, there was no significant difference in mortality in the group receiving PSA screening (92 deaths in the study group vs. 82 in the control group),[1] while in the European study of 182,000 men, there was a very small reduction in mortality, barely achieving statistical significance.[2] Dr. Allan Brett, summarizing the article in “Journal Watch: General Medicine” notes that “To prevent one prostate cancer death, 1410 men had to be screened, and 48 additional cases of prostate cancer had to be diagnosed and treated. All-cause mortality did not differ in the two groups”.[3]

In fact, the US Preventive Services Task Force, the committee that evaluates prevention strategies including screening tests, has long indicated that there is insufficient evidence to recommend for or against prostate cancer screening using PSA, and recently amended that statement to recommend against screening in men over 75:

“The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 years..
The USPSTF recommends against screening for prostate cancer in men age 75 years or older.”[4]

So what is the fuss? Why does the Times have a front page article entitled “Studies show prostate test saves few lives”.[5] Well, mainly because, despite the lack of recommendation by the USPSTF, doctors have been ordering PSA tests for men over 50 for years. The American Urological Association has recommended it: Regarding early detection of prostate cancer, the expert panel concluded that routine PSA testing should be offered in men when:

“Age is 50 years and greater, unless the man has increased risk factors, such as genetic predisposition via family history or African-American racial status. In these "at risk" men, PSA testing should be offered between 40 - 50 years of age.”[6]

That is to say, there were conflicting recommendations. Perhaps unsurprisingly, the urologists, who are the people who see the prostate cancer and operate on it, had a different sense of both the prevalence of the disease and its bad outcomes, and their ability to alter those outcomes through intervention. But mainly, it is the issue of looking at intermediate variables rather than the outcomes of significance. In this case, looking at whether the PSA can diagnose prostate cancer, rather than whether diagnosing (by any means) and treating prostate cancer saves lives.

What? How can finding a cancer early, and treating it, not save lives? “Why,” you might well say, “I have a friend who had a routine PSA screening, and it was high. He had a biopsy, they found cancer, they operated on him, and now he is alive. Isn’t that a good thing?” Well, it’s certainly good that he’s alive. The question is: Would he not be alive, or would he be suffering the pain of metastatic prostate cancer, if he hadn’t had the cancer found and treated? And that is the question we do not know the answer to. And that is why the recent studies are so important.

Simplistically, there are two kinds of prostate cancer: the bad kind that will kill you after probably creating very painful metastases to bone, and the kind which will be lying indolently and asymptomatically in your prostate when you die of something else. But we have no way of distinguishing between these by any of our diagnostic tests. And, more important, we have no idea whether treatment makes a difference – that is, whether the people who die without treatment would have died even if treated, and if the people who survive with treatment would have survived even if not treated.

This is a really big thing. Why would we want to screen lots of men to find a relatively few cancers that we can treat when we don’t even know if treatment makes a difference in death? In the US study, it didn’t. In the European study, it made a small difference in death from prostate cancer, but it took screening 1410 men and treating 48 to save one life from prostate cancer. And the overall death rate, from all causes, was no different.

Better safe than sorry? Maybe, but what the studies did not look at was the side effects from treatment. What about those other 47 men who were treated and whose lives were not saved? The fact is that, while there are many treatments for prostate cancer, all have a significant “side effects”. Treatments such as radical prostatectomy, external beam radiation, radioactive “seed” implants, and newer procedures such as “green laser” very frequently lead to varying degrees of impotence and incontinence, not minor inconveniences! Hormone therapy, whether by removal of testosterone production by removal of the testicles (orchiectomy) or by administration of anti-androgens, have other effects including “cosmetic” ones such as feminization (weight redistribution, breast enlargement) and serious weight gain that can lead to greater morbidity and mortality. So treatment is scarcely benign. And, because we should not forget cost, the cost of the massive screening by PSA, followed by the further testing and procedures and treatment that follow it, is enormous. These studies demonstrate that even without considering cost-effectiveness or the morbidity of treatment, there is little or no benefit to screening in terms of lives saved.

However attractive the idea of screening and early detection is, both to public-health focused primary care physicians like me and to people in general, screening is only of value if it can not only identify disease in the pre-symptomatic phase, but if there is effective treatment that has a patient-important outcome: lower mortality or greater quality of life. PSA screening, at this point, does not meet this criterion.

The NPR segment covering this issue ended with a primary care physician emphasizing that the answer was not just looking at a single PSA value, but rather looking at the change over time. He noted that the ability to do this, as well as to complement monitoring the trend in PSA with serial rectal examinations, was one of the strengths of the primary care relationship. But, with all due respect, and with the great respect I have for primary care, this misses the point. Such a relationship, with its ability to monitor trends, may increase the likelihood of an accurate diagnosis of prostate cancer (i.e., a PSA of 10 that does not change over time may be less likely to mean cancer than one that goes from 2 to 4 to 6) but this still considers a positive outcome to be an accurate diagnosis rather than a decrease in mortality. Absent our ability to distinguish between “good” and “bad” prostate cancer and to know that treatment makes a difference in patient-important outcomes, greater accuracy in diagnosis may just lead to greater cost and greater morbidity.


[1] Andriole GL et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009 Mar 26; 360:1310. published on line at http://dx.doi.org/10.1056/NEJMoa0810696)
[2] Schröder FH et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009 Mar 26; 360:1320. published on line at http://dx.doi.org/10.1056/NEJMoa0810084
[3] Brett, A, Journal Watch General Medicine March 18, 2009
[4] http://www.ahrq.gov/clinic/uspstf/uspsprca.htm
[5] New York Times, Thursday, March 19, 2009, p.1
[6] http://www.usrf.org/news/2000PSAguidelines.html