Benefits and Harms of Prostate-Specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force

Prostate cancer is the most common nonskin cancer in U.S. men. An estimated 218890 men received a new diagnosis of prostate cancer in 2007, and 1 in 6 men will receive a diagnosis in their lifetime (1). The American Cancer Society estimates that 27350 men died of prostate cancer in 2006 (2). After peaking in 1991 (29.4 deaths per 100000 men), the prostate cancer mortality rate has gradually decreased. Although this positive trend may be related to increased screening for prostate cancer, other factors, including new treatment approaches, could also account for some or all of the observed decline in mortality (3). The serum prostate-specific antigen (PSA) test was approved by the U.S. Food and Drug Administration in 1986, and its use for prostate cancer screening has increased substantially since the mid-1990s (4). However, PSA testing is not specific to prostate cancer; common conditions, such as benign prostatic hyperplasia and prostatitis, also increase PSA levels. Approximately 1.5 million U.S. men age 40 to 69 years have a PSA level greater than 4.0 g/L, a widely used cutoff value for a positive screening result (5). Refinements designed to improve the PSA test's sensitivity and specificity for prostate cancer include determination of PSA density, PSA velocity, PSA doubling time, and percentage of free PSA (69). Potential harms from PSA screening include additional medical visits, adverse effects of prostate biopsies, anxiety, and overdiagnosis (the identification of prostate cancer that would never have caused symptoms in the patient's lifetime, leading to unnecessary treatment and associated adverse effects). Much uncertainty surrounds which cases of prostate cancer require treatment and whether earlier detection leads to improvements in duration or quality of life. Two recent systematic reviews of the comparative effectiveness and harms of therapies for localized prostate cancer concluded that no single therapy is superior to all others in all situations (10, 11). In 2002, the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against routine screening for prostate cancer. The USPSTF found good evidence that PSA screening can detect early-stage prostate cancer but found mixed and inconclusive evidence that screening and early detection improve health outcomes. Consequently, the USPSTF was unable to determine the balance between benefits and harms of periodic screening for prostate cancer. The analytic framework that guided the previous USPSTF evidence review (Figure) (12) included 8 key questions about benefits and harms of prostate cancer screening and treatment. This evidence update focuses on critical gaps in the evidence that the Task Force identified in the previous review: the lack of good-quality studies linking screening to improved health outcomes; limited information about harms of screening; and a paucity of knowledge about the natural history of PSA-detected, nonpalpable, localized prostate cancer (the most common type of prostate cancer detected today). These evidence gaps produced 3 new key questions for this update: Figure. Analytic framework for screening for prostate cancer. 1. Does screening for prostate cancer with PSA, as a single-threshold test or as a function of multiple tests over time, decrease morbidity or mortality? 2. What are the magnitude and nature of harms associated with prostate cancer screening, other than overtreatment? 3. What is the natural history of PSA-detected, nonpalpable, localized prostate cancer? Methods After consultation with USPSTF liaisons and content experts, we chose a broad definition of PSA screening that included evolving prognostic measures, such as PSA velocity and doubling time. However, a comparison of the performance characteristics of such measures with traditional single-threshold PSA testing is outside the scope of this review. Data Sources For evidence on health outcomes associated with PSA screening, we searched PubMed for English-language articles indexed between 1 January 2002 and 12 July 2007 by using combinations of the Medical Subject Heading (MeSH) terms and keywords prostate neoplasms, screening, prostate-specific antigen, early diagnosis, PSA velocity, PSA doubling time, and prostate specific antigen doubling. For evidence on the harms of screening for prostate cancer, we searched PubMed for English-language articles indexed between 1 January 2002 and 12 July 2007 by using combinations of the MeSH terms and keywords prostate neoplasms; screening; false positive reactions; adverse effects; mass screening/adverse effects; mass screening/psychology; anxiety; quality of life; and health knowledge, attitudes, practice. For evidence on the natural history of PSA-detected, nonpalpable, localized prostate cancer, we searched PubMed for English-language articles indexed between 1 January 2002 and 23 August 2007 by using combinations of the MeSH terms and keywords prostatic neoplasms, natural history, epidemiology, disease progression, survival analysis, watchful waiting, active surveillance, population surveillance, expectant management, and conservative management. We identified additional articles through a search of the Cochrane Library, recommendations of experts, and a hand search of reference lists from major review articles and studies. Study Selection Two reviewers independently reviewed the title lists, abstracts, and full articles by using predetermined inclusion and exclusion criteria. Articles selected by at least 1 reviewer advanced to the next stage of review. For key question 1, eligible studies were randomized, controlled trials (RCTs), meta-analyses, and systematic reviews that compared screening with no screening (or usual care) in general primary care populations and reported morbidity or mortality outcomes. Although the 2002 USPSTF review (12) considered casecontrol studies and ecological data related to this key question, we excluded these study types from this part of the evidence update to avoid potential sources of confounding that are inherent in nonrandomized studies. For key question 2, eligible studies were randomized or nonrandomized comparative studies that reported quantitative health or quality-of-life outcomes related to a false-positive screening result. We excluded studies that reported only harms resulting from prostate cancer treatment. For key question 3, eligible studies were RCTs and cohort studies that reported health outcomes of patients with stage T1c (nonpalpable, localized, PSA-detected) prostate cancer who did not receive active treatment (including patients assigned to watchful waiting or active surveillance protocols). To ensure that we retrieved the most applicable information on natural history, we excluded studies that predominantly involved patients with nonPSA-detected cancer (defined as comprising 80% of the study population), were too small to draw reliable conclusions about health outcomes (defined as <50 patients in the watchful waiting or surveillance group), or did not provide separate data on patients with stage T1c prostate cancer. Data Extraction and Quality Assessment For all citations that met the initial eligibility criteria, 2 reviewers reviewed the full articles and independently rated their quality by using previously published USPSTF criteria (13). Disagreements between reviewers regarding article inclusion and quality rating were resolved through a consensus process. We assessed the quality of RCTs and cohort studies on the following items: initial assembly and maintenance of comparable groups; absence of important differential loss to follow-up or overall high loss to follow-up; use of equal, valid, and reliable outcome measurements; clear definition of interventions; and appropriateness of outcomes. We evaluated systematic reviews and meta-analyses on the following items: comprehensiveness of sources considered, appropriateness of search strategy, standard appraisal of included studies, validity of conclusions, recency, and relevance. The Appendix Table describes more thoroughly the criteria and definitions for USPSTF quality ratings. Appendix Table. U.S. Preventive Services Task Force Hierarchy of Research Design and Quality Rating Criteria Data Synthesis and Analysis We synthesized the data qualitatively by key question in tabular and narrative formats. Data from the 2002 USPSTF review (12) relevant to key questions 1 and 2 are included to facilitate an overall assessment of the body of evidence. We did not perform quantitative synthesis because of the paucity and heterogeneity of included studies. Role of the Funding Source The general work of the USPSTF is supported by the Agency for Healthcare Research and Quality. This review did not receive specific funding. Results We identified 390 potentially relevant articles on health outcomes associated with PSA screening, 421 potentially relevant articles on harms of prostate cancer screening, and 91 potentially relevant articles on the natural history of PSA-detected prostate cancer. Appendix Figures 1, 2, and 3 contain details of the stages of review and reasons for study exclusion. We obtained 68 articles for full-text review; 10 articles met inclusion criteria for this evidence update. Appendix Figure 1. Key question 1: stages of article review. RCT = randomized, controlled trial. Appendix Figure 2. Key question 2: stages of article review. Appendix Figure 3. Key question 3: stages of article review. Key Question 1 Does screening for prostate cancer with PSA, as a single-threshold test or as a function of multiple tests over time, decrease morbidity or mortality? No good- or fair-quality RCTs addressed this question. Two poor-quality RCTs with important flaws in design and analysis (Table 1) do not show a mortality benefit from PSA screening independently or in a meta-analysis. We identified no RCTs that measured health outcomes from PSA screening by means other than single-th