The prostate-specific antigen (PSA) test is the most important issue in men's health. That's because prostate cancer is the most common internal malignancy in American men, and the great majority of the 240,000 new cases expected this year will be diagnosed because of the PSA test.
The PSA is also the most controversial issue in men's health. The debate began as soon as the test was used to screen for prostate cancer in the early 1990s. Advocates of testing pointed out that the test is the best available way to detect prostate cancer in its earliest, most curable form; that makes testing seem like a no-brainer. But critics pointed out that the test has many false-positive results, which raise the alarm about cancer when none is present, as well as many false-negative results, which provide misleading reassurance to men who actually have prostate cancer. In addition, since the test cannot distinguish between the large number of slow-growing prostate cancers that are harmless and the smaller number of aggressive, dangerous tumors, PSA screening may subject many men to difficult treatments that they do not need.
Both arguments are logical, and experts have continued to advance each position right up to the present.
The United States Preventive Services Task Force (USPSTF) was established in 1984, just a few years before the PSA controversy heated up. Over the years, the Task Force has tried to serve as an objective referee between the competing points of view. And over the years, the USPSTF position has evolved as new studies have become available. Let's review those studies and see how they have affected the Task Force's recommendations.
The USPSTF weighs in
With compelling arguments and passionate advocates on both sides, the USPSTF has spent years evaluating the pros and cons of PSA screening for prostate cancer. In its 2002 report, the Task Force gave the test a grade of I; it concluded that there was insufficient evidence to recommend for or against screening.
Needless to say, that did little to guide physicians and their patients, and it did nothing to stem the tide of PSA testing. But as new studies appeared, the Task Force revisited the question in 2008. Again, screening earned a grade of I, at least for healthy men younger than 75. But things had changed. For healthy men 75 or older and for younger men with a life expectancy of 10 years or less, the USPSTF concluded that "there is moderate certainty that the harms of screening for prostate cancer outweigh the benefits"; for these men, testing earned a grade of D (recommended against).
The recommendation was based on two indisputable facts: most prostate cancers grow very slowly, and all men will die. Older men and those with serious illnesses are much, much more likely to die from something other than prostate cancer that's diagnosed by PSA screening, even if the disease is never treated. Years earlier, Dr. Patrick Walsh, the noted Johns Hopkins urologist and forceful advocate for prostate cancer screening, famously (and humorously) said that he would not do a PSA test on a man older than 75 unless he was brought to the office by both his parents. However, even with this background, the 2008 USPSTF recommendation generated tremendous controversy.
Some doctors hoped that the 2008 recommendation statement would make PSA screening more selective; others worried about the same thing. But it didn't happen. The USPSTF recommendation was well-researched and clearly presented, but it was just a recommendation, and it did little to change clinical practice. A 2011 report noted that 25% of Medicare recipients ages 85 and over received a PSA test, and a 2010 study found that 15% of men with colorectal cancer were screened, despite very short life expectancies. So much for the USPSTF taking away the PSA test.
Science marches on
The debate about PSA testing did not stop after the USPSTF issued its 2008 recommendation statement; if anything, the rhetoric intensified — but so did the research.
Modern medicine has made great strides by basing diagnostic tests and therapeutic decisions on the best scientific evidence available. Scientists know that anecdotes and testimonials cannot provide reliable data. Although we may be moved by the narratives of men who believe PSA screening saved their lives and by the laments of men who believe testing led to treatments that degraded the quality of their lives, these individual stories don't provide reliable information on one side or the other.
Indirect evidence based on comparisons of men who choose PSA screening with those who chose not to be tested are a step up on the scientific ladder, but they're far from conclusive. Indeed, PSAdvocates and PSAgnostics have offered many dueling observational studies to support each position.
The only way to resolve the question is with randomized clinical trials. In these studies, volunteers are randomly assigned to receive PSA testing or to continue their normal medical care without getting PSA tests at preselected intervals. Trials of screening for prostate cancer may or may not include a doctor's digital rectal exam (DRE). In any case, the trials specify a PSA cutoff value that leads to a prostate biopsy. If the biopsy reveals cancer, the patient is treated by his own physicians according to their best-practice standards. Finally, the researchers track all the men to see whether or not PSA screening reduces the risk of dying from prostate cancer and to find out if screening affects the overall death rate.
Over the years, the PSA believers and doubters have awaited the results of randomized clinical trials to resolve the debate. In fact, the USPSTF has based its 2011 recommendation statement on such trials. Let's have a look at the four major trials released between 2009 and 2011.
1. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial began studying PSA screening in 1993. Over the next eight years, 76,693 men between the ages of 55 and 74 volunteered for the study, which was conducted at 10 medical centers around the U.S. Scientists randomly assigned half the men to receive annual PSA testing for six years along with annual digital rectal exams for four years; men who had PSA levels above 4.0 nanograms per milliliter (ng/ml) or abnormal DREs were advised to seek diagnostic evaluation, which usually involved a prostate biopsy.
After seven years of observation, 22% more cases of prostate cancer were detected in the men who had regular PSA screening. But although PSA screening increased the diagnosis of prostate cancer, it did not improve survival. There were 50 deaths in the PSA-screened group and 44 in the comparison group; the 13% higher death rate in the PSA group was not statistically significant. A 2012 report extended these findings to 13 years of follow-up; the results at 13 years mirror the findings at seven years.
2. Like the American study, the European Randomized Study of Screening for Prostate Cancer (ERSPC) began in the early 1990s. A total of 182,000 men between the ages of 50 and 74 volunteered for the study. Scientists randomly assigned half the men to receive PSA screening and the other half to receive their usual medical care. Because the study was conducted in multiple medical centers spread across seven countries, the investigators followed a number of slightly different research protocols. In most cases, PSA screening was performed an average of once every four years and readings of 3.0 ng/ml triggered prostate biopsies. Men who were diagnosed with prostate cancer were treated by their own physicians according to local guidelines.
After about nine years, screening reduced the risk of dying from prostate cancer by 20%, a result that was just at the margin of statistical significance. The benefit was restricted to men between ages 55 and 69 when they entered the study, and there was no change in the overall death rate. And the reduced prostate cancer mortality came at a price: an additional 48 men who were not destined to die from prostate cancer had to be treated to prevent one death from the disease.
3. The Göteborg randomized prostate cancer screening trial's results were first published independently in 2010, but more than half its participants were also included in the results from the much larger ERSPC, which were published in 2009. This dual status raises technical questions of its own: should the Göteborg study be judged as a stand-alone trial, which carries more weight, or as a subgroup analysis of ERSPC, which carries less? That's fodder for statisticians and epidemiologists; most men are more interested in the results.
In December 1994, researchers randomly identified 19,904 men living in Göteborg, Sweden, who were born between 1930 and 1944; their median age was 56. A computer randomly assigned half the men to have a PSA test every two years during the study period, or until they reached age 71. The threshold for prostate biopsy was reduced twice during the study, first from 3.4 ng/ml to 2.9 ng/ml, and then to 2.5 ng/ml.
As expected, men in the PSA group were more likely to be diagnosed with prostate cancer than men in the comparison group (12.7% vs. 8.2%). The malignancies detected in the PSA group also tended to be smaller and less advanced than the cancers in the comparison group. This too was expected, and not surprisingly, it led to more aggressive treatment for the men in the PSA group.
The most interesting and important result of the Göteborg trial is that PSA screening reduced the risk of death from prostate cancer; men in the PSA group enjoyed a 44% lower risk of dying from the disease than men in the comparison group. In all, 12 men needed to be treated to prevent one death from prostate cancer. But although PSA screening lowered the risk of death from prostate cancer, it did not reduce the overall death rate.
4. In 1987, researchers used a population registry to identify all the male residents of Norrköping, Sweden, who were then ages 50 to 69. From this group of 9,026 men, 1,494 men were randomly selected and invited to be screened for prostate cancer every third year; the final screening was restricted to men 69 or younger. The remaining 7,532 men were not invited for testing and served as the comparison group. Because the study began before PSA testing was widely available in Europe, digital rectal exams were used for screening until 1993, when PSA tests were added. Researchers continued to track the men following the final round of screening in 1996. The results of 20 years of follow-up were reported in 2011: screening had not reduced the rate of death from prostate cancer.
Dr. Simon says... a personal note
Since the dawn of the PSA era in the early 1990s, I have written thousands of words about PSA testing in Harvard Men's Health Watch, in The Harvard Medical School Guide to Men's Health, and in various newspapers, magazines, and Internet articles. I have also counseled thousands of patients and their wives about PSA screening. Although my advice has evolved as scientific evidence has accumulated over the years, my bottom line has remained the same: once a man fully understands the pros and cons of PSA testing, it's up to him to decide if the test is right for him. Still, faced with a complex decision, many patients and their wives (as well as my students, friends, and relatives) have asked a perceptive question: what do you decide for yourself, Dr. Simon?
It's a good question, not only because I've considered the issue in detail and discussed it with many experts, but because I'm a man as well as a doctor — and I have a prostate, a happy marriage, fine health, and a zest for life. And I have another reason to take the decision personally, since my father was diagnosed with locally extensive, inoperable prostate cancer at age 52.
I've discussed PSA screening with my personal physician each year since the test became available. My choice has not changed over the years, but it has become easier as the data have come in (and I have grown older): I have chosen not to be screened for prostate cancer.
I'll continue to revisit the question, both personally and professionally, and I urge you to do the same. In my view, there is no wrong answer for healthy men in midlife; as long as a man is fully informed about the pros and cons of testing, the decision is up to him. And I'll do my best to keep you fully informed about new developments in prostate cancer diagnosis and treatment in the future.
Testing the trials
The four randomized clinical trials used different study protocols and reported different results. All were responsible trials accepted for publication in top medical journals — PLCO and ERSPC in The New England Journal of Medicine, Göteborg in Lancet Oncology, and Norrköping in BMJ. But none of the trials is perfect, and each has strengths and weaknesses.
As an American trial that recruited men up to age 74 and used the typical U.S. schedule of yearly PSA testing and (for the first four years of participation) digital rectal exams as well as a PSA cutoff of 4.0 ng/ml, the PLCO comes closest to reflecting the experience of typical readers. A weakness of the trial is that 52% of men in the comparison group chose to have PSA tests on their own. Still, the difference in screening rates is large enough that if testing produced a benefit, it should have shown up in a study this large.
ERSPC has the advantage of being the largest study of the four, but the disadvantage of involving slightly different research protocols in many centers across seven European countries.
The Göteborg study is hard to evaluate because 11,852 of its 19,904 participants were also included in the ERSPC report. These men should not be counted twice; if they are subtracted from the ERSPC trial, the larger European results no longer demonstrate a significant survival benefit from PSA testing.
Although the Norrköping study includes the longest follow-up period, it is the weakest of the four studies, with the smallest study population and the fewest PSA tests.
The Göteborg study provides the strongest evidence in favor of PSA screening, but it must be interpreted in concert with the ERSPC trial, which found a much more modest benefit — or no significant benefit if the Göteborg men are excluded — and the PLCO and Norrköping studies, which found no benefit.
For the sake of argument, consider the implications of the full ERSPC trial, which is often cited as proof that PSA testing saves lives. The study's 20% reduction in the relative risk of death from prostate cancer is certainly encouraging, but since the average American's risk of dying from prostate cancer is just 3%, a 20% reduction would reduce his personal risk to 2.4%, an absolute benefit of just 0.6%. At the same time, a man diagnosed with prostate cancer as a result of PSA screening would have a 48-to-1 chance of receiving treatment that was unnecessary.
It's understandably hard for ordinary gents to wrap their heads around all these trials and results. That's why the impartial review from the USPSTF is so helpful. But even before the Task Force released its 2011 recommendation, experts from Florida performed an independent meta-analysis of six randomized controlled trials of prostate cancer screening in 387,286 men. The conclusion: screening does not produce a significant reduction in the risk of dying from prostate cancer or in the overall death rate.
Why not test anyway?
Even if screening does not reduce the overall risk of dying from prostate cancer, some men do benefit. Why shouldn't a man be tested in the hope that he'll be a member of this select minority?
It's a fair question, and some men might reasonably answer it by opting for a PSA test. But before rolling up their sleeves to have blood drawn, men should know that even though testing may help some men, it will lead to side effects for many.
None of the randomized clinical trials of PSA screening has yet reported on how testing affects quality of life, but other clinical observations fill in that gap.
A worrisome PSA result typically leads to a repeat blood test and then, if the result is similar, to an ultrasound-guided transrectal prostate biopsy. The biopsy is considered to be a minor procedure, but many men find it frightening. Local anesthesia can control pain, but some men develop bleeding, urinary obstruction, or infection. And as the number of tissue samples obtained with each biopsy has increased, the rate of complications has risen. In 2005, 4.1% of men who underwent biopsies at the Toronto Medical Center developed complications serious enough to require hospitalization within 30 days; infection was the leading culprit. A 2011 American study reported similar results. New antibiotic programs may help prevent these infections, but these reports remind us that a prostate biopsy is an invasive procedure.
Although deferred treatment (watchful waiting, active surveillance) is slowly gaining acceptance among older men with low-grade prostate cancer, most American men with newly diagnosed prostate cancer choose to have active treatment with surgery or radiation therapy. Even in the best of hands, the risk of complications is substantial. The USPSTF estimates that for every three men who undergo prostatectomy and every seven who undergo radiation therapy, one will develop erectile dysfunction; an independent 2011 study found that only 37% to 48% of men enjoyed good erectile function two years after treatment for prostate cancer. And the USPSTF estimated that for every five men who undergo prostatectomy, one will develop urinary incontinence.
Many men would freely trade erectile dysfunction or urinary incontinence for life, but it's not that simple, since both the Florida meta-analysis and the USPSTF evaluation conclude that PSA screening did not reduce the risk of dying from prostate cancer. And even the ERSPC trial, which is often cited by PSA supporters, tells us that 48 men will undergo unnecessary treatment for every life saved by PSA screening.
Like the USPSTF, the American Cancer Society (ACS) has changed its position over time, with revisions in 2001, 2005, and 2010; new guidelines are being developed. At present, the ACS says that "prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher-risk groups should receive this information before age 50 years." The American College of Preventive Medicine concludes that there is not enough evidence to recommend routine prostate cancer screening with either the PSA or the digital rectal exam.
The European Association of Urology's 2011 guidelines state that "current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen for prostate cancer." The Canadian Urological Association suggests that screening should be offered to men starting at age 50, providing the men have at least a 10-year life expectancy and have been fully informed about the harms and benefits of testing. In 2009, the American Urological Association recommended PSA screening for well-informed men with an estimated 10-year life expectancy who wish to pursue early diagnosis starting at age 40; new recommendations are being prepared.
The Task Force and you
The 2011 USPSTF recommendation statement stirred up a hornet's nest of strong reactions, but its actual conclusions are measured and cautious: "Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatment, some of which may be unnecessary."
In essence, the USPSTF position has changed from its 2002 judgment that there was no evidence that PSA screening saves lives, to the 2008 view that testing does not help men 75 and older, and then to the position that there is now evidence that screening does not prolong life and that it may do more harm than good. As a result, the Task Force now recommends against routine PSA screening for prostate cancer; in its terminology, the test gets a grade of D.
The USPSTF recommendation is couched in dry, technical language because it is not directed to the media or the public at large, but to primary care physicians. It is not a commandment carved in stone but a recommendation written on paper (and on the Web). It does not say your doctor cannot order a PSA test or that your insurance will not pay for it. But it does suggest a change in the dialogue between doctor and patient.
For years, most expert medical panels have recommended that doctors offer PSA testing to appropriately selected men, then let each man decide for himself. That position still stands, but there's a new wrinkle. In light of the 2011 Task Force evaluation of evidence, doctors should let their patients know that PSA testing may do more harm than good before asking for a decision. It's a new wrinkle for shared decision-making about the PSA, but it's merely a new application of a basic rule of good medical practice: informed consent. And for men who simply cannot decide for themselves, the default decision has now shifted from ordering a PSA to not performing the test.
Should I have a PSA test?
Medical researchers and policymakers need to know whether mass screening programs prevent illness and premature death. In the case of PSA screening, the best available evidence is that testing produces little or no reduction in the risk of dying from prostate cancer. And although the major randomized clinical trials have not yet released data on the side effects of treatment, it is likely that since screening does not substantially reduce the risk of death, the side effects of overdiagnosis and overtreatment will mean that screening does more harm than good.
Public policy is one thing, personal preference quite another. We have long maintained in these pages that while there is no right answer about PSA screening, there are two wrong answers; you must be tested, and you should never be tested. As before, each man should consult with his physician (and often his spouse), then decide for himself. And the decision can change from year to year as new information comes in.
The USPSTF recommendation against routine screening applies to healthy men with no symptoms of prostate cancer and no particular prostate cancer risk factors. Doctors and patients should take the recommendation seriously, but they should also understand that one size does not fit all. If the test has any benefit, it is most likely to occur in healthy, younger men, perhaps ages 45 to 70 for men at high risk, ages 50 to 65 for others; unfortunately, these same men are the ones most likely to be distressed by side effects of treatment, such as sexual dysfunction and urinary incontinence.
Similarly, men at a higher than average risk of prostate cancer, such as African Americans and those with a family history of the disease, might be more likely to benefit from screening. Unfortunately, there is not enough evidence to support or refute that possibility, since higher-risk men are underrepresented in the trials; in the American PLCO study, for example, less than 4.5% of participants were African American, and less than 7% had a family history of prostate cancer. At the other end of the spectrum, older men and those with serious medical conditions are the least likely to benefit from PSA screening and are the most likely to be harmed by testing.
Enormous amounts of brainpower, work, and money have been devoted to research on PSA screening, and even more study is needed. The major clinical trials, including the PLCO and ERSPC, are still ongoing, so we can expect updated reports. The American PIVOT (Prostate Cancer Intervention Versus Observation Trial) and British PROTECT (Prostate Testing for Cancer and Treatment) studies are also under way.
Without devaluing these efforts, it may be time to redirect some energy and funding to other crucial issues, starting with ways to prevent the disease. We also have a desperate need for good markers to tell if a man is at risk for aggressive prostate cancer, for better ways to distinguish harmless cancers from potential killers, and for research to find treatments that can cure aggressive tumors.
The new USPSTF recommendation statement is an important evolutionary development, but it is not the last word on PSA testing, and it has not done much to quiet the controversy. Still, one thing the most passionate PSA advocates and skeptics can agree on is that America's prostate cancer death toll is far, far too high.
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