Prostate-specific antigen screening in prostate cancer: perspectives on the evidence.

Ethan BaschDespite multiple prospective clinical trials, observational stud-ies, retrospective analyses, and simulation models, intense con-troversy persists regarding the value of screening for prostate cancer with the prostate-specific antigen (PSA) test. Similar data have been used to draw conflicting conclusions, and clinical practice guidelines appear discordant on the merits of screening (1–4). Where are the areas of guideline agreement? There is general consensus that there is limited or no benefit of PSA screening among older men (ie, those aged ≥70 or 75 years) or those with limited life expectancy (ie, <10–15 years). There is agreement that there are real harms associated with downstream clinical actions taken in response to PSA screening. And there is agreement that there is overtreatment of low-grade tumors once discovered, with growing encouragement to pursue programs of active surveillance in such men, with nascent but expanding evidence in this area (5). For men considering PSA screening, an informed discussion with their provider is universally advised.Although guidelines have recently come into greater agree-ment with each other, differences do remain. In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA screening in all men (1). The American Society of Clinical Oncology followed by agreeing with this approach only for older men but advising informed decision-making in younger men (2). Subsequently, the American Urological Association substantially revised its prior recommendations by advising against screening in men aged 70 years or older as well as in those aged less than 55 years unless at high risk of disease, with informed decision-mak-ing suggested for those between the ages of 55 and 69 years (3). These recommendations are similar to those from the American College of Physicians (4,6). Why has the scientific evidence been so challenging to inter-pret? The main culprit is the history of how PSA screening evolved, without rigorous prospective evaluation of its impact on outcomes that matter to people—such as survival and quality of life. The test became widely practiced starting in the 1980s in the absence of such evidence. It has been challenging to evaluate benefits and harms on a widely practiced test. For example, the rates of PSA screening “contamination” in the no-screening control arm of the Prostate, Lung, Colorectal and Ovarian trial was estimated at approximately 70% (7 ) and in the European Randomized Study of Screening for Prostate Cancer (ERSPC) was estimated at greater than 20% (8) (although in both cases it was likely higher). Unfortunately, the current regulatory context in which molecu-lar diagnostic tests are developed still does not require the gen-eration of clinically meaningful outcomes data (also referred to as clinical utility data). As a result, there is a substantial risk that future screening tests will emerge with similar evidence challenges. Most commercially available screening tests today are developed and marketed as laboratory diagnostic tests, which have low barriers to market entry and are not required to demonstrate evidence of clinical benefit (9). Many physicians likely assume incorrectly that these tests have proven effectiveness and safety.Recent efforts have been made to strengthen methodologi-cal standards for evaluation of diagnostic tests. For example, the Patient-Centered Outcomes Research Institute (PCORI), estab-lished in 2010 by the US Patient Protection and Affordable Care Act, has established a standard that recommends to “focus studies of diagnostic tests on patient-centered outcomes, using rigorous study designs with preference for randomized controlled trials” (10). In 2013, the Center for Medical Technology Policy (CMTP) issued an Effectiveness Guidance Document similarly recommend-ing that clinical utility be assessed prospectively for new diagnostic tests (11). However, the current US regulatory framework does not have any mechanism for requiring this level of evidence for diagnostic or screen-ing tests. This is an area of urgently needed attention as countless new tests are developed and marketed to our colleagues and patients.Two perspectives on the evidence for PSA screening are pro-vided in this issue of the Journal from opposing camps on this issue, first from Dr Timothy Wilt on the hazards of PSA screen-ing and then from Dr Peter Scardino on the merits of tailored PSA screening and treatment strategies. These perspectives, and the above comments, build on an educational session at the 2013 American Society of Clinical Oncology annual meeting on this topic (12).