American Association for Clinical Chemistry
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November 2011 Clinical Laboratory News: Federal Panel’s PSA Recommendations Stoke Controversy

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November 2011: Volume 37, Number 11


Federal Panel’s PSA Recommendations Stoke Controversy
Does the Harm Finally Outweigh the Benefit of PSA Testing?

By Genna Rollins

The controversy surrounding use of prostate-specific antigen (PSA) testing to screen for prostate cancer heated up last month when the influential U.S. Preventive Services Task Force (USPSTF) issued draft recommendations advising against PSA-based screening in healthy men. The new guidance, with a grade D recommendation, updates USPSTF’s 2008 recommendation, which advised against screening for prostate cancer in men age 75 or older but concluded that there was insufficient evidence to assess the balance of benefits and harms in younger men. A grade D recommendation means that “there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits,” according to the USPSTF website. The panel will be accepting public comments on the recommendations until November 8.

The USPSTF based its recommendations on an evidence review it commissioned from the Evidence-based Practice Center at Oregon Health and Science University (OSHU). This review was funded by the Agency for Healthcare Research and Quality (AHRQ).

Conflicting Evidence

The OSHU researchers examined five screening trials and three randomized trials and 23 cohort studies of treatments that had been published since the USPSTF’s last review of evidence in 2008. The investigators sought to address four key questions: does PSA-based screening decrease prostate cancer-specific or all-cause mortality; what are the harms of PSA-based screening for prostate cancer; what are the benefits of treatment of early-stage or screening-detected prostate cancer; and what are the harms of treatment of early-stage or screening-detected prostate cancer.

The screening trials included the two largest ever conducted in the field, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the European Randomized Study of Screening for Prostate Cancer (ERSPC), results of both of which were published in the same issue of the New England Journal of Medicine (N Engl J Med 2009;360:1310–9 and 1320–8). As previously reported in CLN, these trials produced conflicting results (CLN 2009;35:1–4).

PLCO found after 7 years’ follow-up that in comparison to usual care, annual PSA screening in combination with digital rectal examination was associated with increased prostate cancer incidence but had no effect on prostate cancer-specific or all-cause mortality. Similar results were observed after 10 years. In contrast, ERSPC found that in comparison to usual care, PSA testing every 2–7 years resulted in a net increase in prostate cancer incidence, but no statistically significant difference in prostate cancer-specific mortality. Based upon these studies and others, the OSHU experts concluded that “PSA-based screening results in small or no reduction in prostate cancer-specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary” (Ann Intern Med October 7, 2011 E-375; published ahead of print).

Balancing Benefits and Harms

In making its recommendation, the USPSTF observed that evidence is “convincing” that PSA-based screening programs result in detection of many cases of asymptomatic prostate cancer, but at a cost of false positive tests that result in treatments such as surgery, radiation, and androgen deprivation therapy that all have adverse effects. The panel also noted that the majority of asymptomatic cancers detected via PSA screening, while meeting histological criteria for prostate cancer, would either not progress or be so indolent and slow-growing that it would not affect the patient’s lifespan or cause adverse health effects. The recommendation concluded that “the common perception that PSA-based early detection of prostate cancer prolongs lives is not supported by the scientific evidence,” and that “there is moderate certainty that the harms of PSA-based screening for prostate cancer outweigh the benefits.” The panel did not address the role of PSA testing as part of a diagnostic strategy in men with symptoms that are highly suspicious of prostate cancer, or the use of PSA results in surveillance after diagnosis and/or treatment of the disease.

In published comments, the panel’s chair, Virginia Moyer, MD, professor of pediatrics at Baylor College of Medicine, observed that “unfortunately, the evidence now shows that this test does not save men’s lives. 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.”

A Wave of Feedback

The recommendations set off a wave of commentary by other professional and patient groups, as well as individual physicians. The American Urological Association (AUA) president Sushil S. Lacy, MD, remarked that the AUA was “concerned” that the guidance “will ultimately do more harm than good to the many men at risk for prostate cancer.” In 2009 the AUA issued a PSA screening best practice statement that called for the test to be offered to well-informed men age 40 or older who have a life-span of at least 10 years. In commenting on the updated USPSTF recommendations, Lacy noted that the AUA is in the process of preparing a new clinical guideline on PSA screening.

The American Cancer Society refused to comment specifically on the recommendations, but chief medical officer, Otis Brawley, MD, told the Washington Post that “I have long been concerned, and it has been very apparent for some years, that some supporters of prostate cancer screening have overstated, exaggerated and, in some cases, misled men about the evidence supporting its effectiveness. We need balanced, truthful information to be made widely available to physicians and patients when making important health decisions. Sadly, that has not happened with this disease.”

Lead author of the PLCO Study, Gerald L. Andriole, MD, told CLN, “I think the headline that most men are seeing is doing more harm than good. While I agree that mass screening for all men over 50 has minimal beneficial effects on mortality and potentially significant harmful effects on men's quality of life, I also believe there are certainly subsets of men who would benefit from PSA screening, such as those who are at high risk for the disease. To not screen them, in my judgment, is a step backwards. I would recommend a risk-adjusted application of screening and of treatment.” Andriole is Robert K. Royce distinguished professor and chief of urologic surgery at Washington University School of Medicine in St. Louis.

Other investigators shared Andriole’s sentiments, including Memorial Sloan-Kettering Cancer Center colleagues, Andrew Vickers, PhD, and Hans Lilja, MD, PhD. “PSA screening in the U.S. has involved testing far too many older men who do not need screening, and treating too many men who do not need treatment. But recommending against PSA screening may be throwing the baby out with the bathwater,” the two said. “We should screen smarter, but not abandon PSA-based prostate cancer screening altogether. High level evidence from randomized trials in Europe show that prostate cancer mortality may be reduced by about half among men invited to screening compared to unscreened men, but there is also evidence of over-detection and over-treatment. Therefore, we need to focus on men at highest risk, and it turns out that PSA is an excellent indicator of risk of prostate cancer metastasis or death.” Vickers is associate attending research methodologist, and Lilja, who chaired the prostate cancer writing group for the National Academy of Clinical Biochemistry Laboratory Management Practice Guideline on the use of tumor markers in cancer, is attending research clinical chemist in the departments of clinical laboratories, surgery, and medicine.

The mission of the 16-member independent panel, which functions under the auspices of AHRQ, is to evaluate the benefits of individual services based on age, gender, and risk factors for disease; make recommendations about which preventive services should be incorporated routinely into primary medical care and for which populations; and identify a research agenda for clinical preventive care. Both private insurers and Medicare consider the group’s findings in making coverage determinations. Its influence was broadened by the recent federal healthcare law, which will base some of its coverage requirements on USPSTF recommendations. The impact of the panel’s recommendations on prostate cancer screening coverage and practices remains to be seen, but the debate about PSA testing will no doubt continue.