Prostate cancer

Prevention
Screening

Family Practice
Internal Medicine
Preventive Medicine
Urology

Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Nurses
Physician Assistants
Physicians

• To summarize the current U.S. Preventive Services Task Force (USPSTF) recommendations and supporting scientific evidence on screening for prostate cancer
• To update the 2002 USPSTF recommendations on screening for prostate cancer

Adult males

Screening for prostate cancer using prostate-specific antigen (PSA)

Key Question 1: Does screening for prostate cancer with prostate-specific antigen (PSA), as a single-threshold test or as a function of multiple tests over time, decrease morbidity or mortality?

Key Question 2: What are the magnitude and nature of harms associated with prostate cancer screening other than overtreatment?

Key Question 3: What is the natural history of PSA-detected, non-palpable, localized prostate cancer?

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Note from the National Guideline Clearinghouse (NGC): A targeted evidence review was prepared by the Agency for Healthcare Research and Quality (AHRQ) staff for use by the U.S. Preventive Services Task Force (USPSTF) (see the "Availability of Companion Documents" field).

In 2002, the USPSTF found insufficient evidence to recommend for or against routine screening for prostate cancer. The USPSTF found good evidence that prostate-specific antigen (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 (see Figure in the Evidence Update [see the "Availability of Companion Documents" field]) 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:

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?

After consultation with USPSTF liaisons and content experts, AHRQ staff 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, PubMed was searched 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, PubMed was searched 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, PubMed was searched 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.

Additional articles were identified 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 considered case–control studies and ecological data related to this key question, these study types were excluded 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. Studies that reported only harms resulting from prostate cancer treatment were excluded.

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 the most applicable information on natural history was retrieved, studies that predominantly involved patients with non–PSA-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 were excluded.

10 articles met inclusion criteria for this evidence update.

Expert Consensus

Not applicable

Systematic Review with Evidence Tables

Balance Sheets
Expert Consensus

The U.S. Preventive Services Task Force (USPSTF) systematically reviews the evidence concerning both the benefits and harms of widespread implementation of a preventive service. It then assesses the certainty of the evidence and the magnitude of the benefits and harms. On the basis of this assessment, the USPSTF assigns a letter grade to each preventive service signifying its recommendation about provision of the service (see Table below). An important, but often challenging, step is determining the balance between benefits and harms to estimate "net benefit" (that is, benefits minus harms).

Table 1. U.S. Preventive Services Task Force Recommendation Grid*

*A, B, C, D, and I (Insufficient) represent the letter grades of recommendation or statement of insufficient evidence assigned by the U.S. Preventive Services Task Force after assessing certainty and magnitude of net benefit of the service (see the "Rating Scheme for the Strength of the Recommendations" field).

The overarching question that the Task Force seeks to answer for every preventive service is whether evidence suggests that provision of the service would improve health outcomes if implemented in a general primary care population. For screening topics, this standard could be met by a large randomized, controlled trial (RCT) in a representative asymptomatic population with follow-up of all members of both the group "invited for screening" and the group "not invited for screening."

Direct RCT evidence about screening is often unavailable, so the Task Force considers indirect evidence. To guide its selection of indirect evidence, the Task Force constructs a "chain of evidence" within an analytic framework. For each key question, the body of pertinent literature is critically appraised, focusing on the following 6 questions:

1. Do the studies have the appropriate research design to answer the key question(s)?
2. To what extent are the existing studies of high quality? (i.e., what is the internal validity?)
3. To what extent are the results of the studies generalizable to the general U.S. primary care population and situation? (i.e., what is the external validity?)
4. How many studies have been conducted that address the key question(s)? How large are the studies? (i.e., what is the precision of the evidence?)
5. How consistent are the results of the studies?
6. Are there additional factors that assist us in drawing conclusions (e.g., presence or absence of dose-response effects, fit within a biologic model)?

The next step in the Task Force process is to use the evidence from the key questions to assess whether there would be net benefit if the service were implemented. In 2001, the USPSTF published an article that documented its systematic processes of evidence evaluation and recommendation development. At that time, the Task Force's overall assessment of evidence was described as good, fair, or poor. The Task Force realized that this rating seemed to apply only to how well studies were conducted and did not fully capture all of the issues that go into an overall assessment of the evidence about net benefit. To avoid confusion, the USPSTF has changed its terminology. Whereas individual study quality will continue to be characterized as good, fair, or poor, the term certainty will now be used to describe the Task Force's assessment of the overall body of evidence about net benefit of a preventive service and the likelihood that the assessment is correct. Certainty will be determined by considering all 6 questions listed above; the judgment about certainty will be described as high, moderate, or low.

In making its assessment of certainty about net benefit, the evaluation of the evidence from each key question plays a primary role. It is important to note that the Task Force makes recommendations for real-world medical practice in the United States and must determine to what extent the evidence for each key question—even evidence from screening RCTs or treatment RCTs—can be applied to the general primary care population. Frequently, studies are conducted in highly selected populations under special conditions. The Task Force must consider differences between the general primary care population and the populations studied in RCTs and make judgments about the likelihood of observing the same effect in actual practice.

It is also important to note that 1 of the key questions in the analytic framework refers to the potential harms of the preventive service. The Task Force considers the evidence about the benefits and harms of preventive services separately and equally. Data about harms are often obtained from observational studies because harms observed in RCTs may not be representative of those found in usual practice and because some harms are not completely measured and reported in RCTs.

Putting the body of evidence for all key questions together as a chain, the Task Force assesses the certainty of net benefit of a preventive service by asking the 6 major questions listed above. The Task Force would rate a body of convincing evidence about the benefits of a service that, for example, derives from several RCTs of screening in which the estimate of benefits can be generalized to the general primary care population as "high" certainty (see the "Rating Scheme for the Strength of Recommendations" field). The Task Force would rate a body of evidence that was not clearly applicable to general practice or has other defects in quality, research design, or consistency of studies as "moderate" certainty. Certainty is "low" when, for example, there are gaps in the evidence linking parts of the analytic framework, when evidence to determine the harms of treatment is unavailable, or when evidence about the benefits of treatment is insufficient. Table 4 in the methodology document listed below (see "Availability of Companion Documents" field) summarizes the current terminology used by the Task Force to describe the critical assessment of evidence at all 3 levels: individual studies, key questions, and overall certainty of net benefit of the preventive service.

Sawaya GF et al., Update on the methods of the U.S. Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med. 2007;147:871-875 [5 references].

What the United States Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice

USPSTF Levels of Certainty Regarding Net Benefit

Definition: The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Comparison with Guidelines from Other Groups
External Peer Review
Internal Peer Review

Peer Review. Before the U.S. Preventive Services Task Force makes its final determinations about recommendations on a given preventive service, the Evidence-based Practice Center and the Agency for Healthcare Research and Quality send a draft systematic evidence review to 4 to 6 external experts and to federal agencies and professional and disease-based health organizations with interests in the topic. They ask the experts to examine the review critically for accuracy and completeness and to respond to a series of specific questions about the document. After assembling these external review comments and documenting the proposed response to key comments, the topic team presents this information to the Task Force in memo form. In this way, the Task Force can consider these external comments and a final version of the systematic review before it votes on its recommendations about the service. Draft recommendations are then circulated for comment from reviewers representing professional societies, voluntary organizations and Federal agencies. These comments are discussed before the whole U.S. Preventive Services Task Force before final recommendations are confirmed.

Recommendations of Others. Recommendations for screening for prostate cancer from the following groups were discussed: the American Academy of Family Physicians, the American College of Physicians, the American College of Preventive Medicine, the American Medical Association, the American Cancer Society, and the American Urological Association.

The US Preventive Services Task Force (USPSTF) grades its recommendations (A, B, C, D, or I) and identifies the Levels of Certainty regarding Net Benefit (High, Moderate, and Low). The definitions of these grades can be found at the end of the "Major Recommendations" field.

Summary of Recommendations and Evidence

• 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. This is an I statement.
• The USPSTF recommends against screening for prostate cancer in men age 75 years or older. This is a grade D recommendation.

Clinical Considerations

Patient Population under Consideration

This recommendation applies to men in the general U.S. population.

Risk Assessment

Older men, African-American men, and men with a family history of prostate cancer are at increased risk for diagnosis and death from prostate cancer. Unfortunately, the previously described gaps in the evidence regarding potential benefits of screening also apply to these men.

Screening Tests

The prostate-specific antigen (PSA) test is more sensitive than the digital rectal examination for detecting prostate cancer. The conventional PSA screening cut-point of 4.0 micrograms/L detects many prostate cancer cases; however, some early cases of prostate cancer will be missed by this cut-point. Using a lower cut-point to define an abnormal PSA detects more cases of cancer.

The proportion of cancer cases detected by lower cutpoints that would ever become clinically apparent is unknown; lower cut-points would label many more men as potentially having cancer. For example, lowering the PSA cut-point to 2.5 micrograms/L would more than double the number of U.S. men between 40 and 69 years of age with abnormal results.

Variations of PSA screening, including the use of age-adjusted PSA cut-points, free PSA, PSA density, PSA velocity, PSA slope, and PSA doubling time, have been proposed to improve detection of "clinically important" prostate cancer cases. However, no evidence suggests that any of these testing strategies improves health outcomes.

Suggestions for Practice

Given the uncertainties and controversy surrounding prostate cancer screening in men younger than age 75 years, a clinician should not order the PSA test without first discussing with the patient the potential but uncertain benefits and the known harms of prostate cancer screening and treatment. Men should be informed of the gaps in the evidence and should be assisted in considering their personal preferences before deciding whether to be tested.

Treatment

Because of the uncertainty about the benefits of treating prostate cancer detected by screening men younger than age 75 years, there is no consensus regarding optimal treatment. Current management strategies for localized prostate cancer include watchful waiting (observation with palliative treatment for symptoms only), active surveillance (periodic biochemical monitoring with conversion to curative treatment for signs of disease progression), radical prostatectomy, external-beam radiation therapy, and brachytherapy (or radioactive seed implantation therapy).

If treatment for prostate cancer detected by screening improves health outcomes, the population most likely to benefit from screening will be men age 50 to 74 years. Even if prostate cancer screening is determined to be effective, the length of time required to experience a mortality benefit is greater than 10 years. Because a 75-year-old man has an average life expectancy of about 10 years, very few men age 75 years or older would experience a mortality benefit. Similarly, men younger than age 75 years who have chronic medical problems and a life expectancy of fewer than 10 years are also unlikely to benefit from screening and treatment.

Screening Intervals

The yield of screening in terms of cancer cases detected declines rapidly with repeated annual testing. If screening were to reduce deaths, PSA screening as infrequent as every 4 years could yield as much of a benefit as annual screening.

Definitions:

What the United States Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice

USPSTF Levels of Certainty Regarding Net Benefit

Definition: The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.

None provided

The type of supporting evidence is not specifically stated for each recommendation.

Benefits of Detection and Early Treatment

• In men younger than age 75 years, the U.S. Preventive Services Task Force (USPSTF) found inadequate evidence to determine whether treatment for prostate cancer detected by screening improves health outcomes, compared with treatment after clinical detection.
• In men age 75 years or older, the USPSTF found adequate evidence that the incremental benefits from treatment for prostate cancer detected by screening are small to none.

Harms of Detection and Early Treatment

• The USPSTF found convincing evidence that treatment for prostate cancer detected by screening causes moderate- to-substantial harms, such as erectile dysfunction, urinary incontinence, bowel dysfunction, and death. These harms are especially important because some men with prostate cancer who are treated would never have developed symptoms related to cancer during their lifetime.
• There is also adequate evidence that the screening process produces at least small harms, including pain and discomfort associated with prostate biopsy and psychological effects of false-positive test results.

• The U.S. Preventive Services Task Force (USPSTF) makes recommendations about preventive care services for patients without recognized signs or symptoms of the target condition.
• Recommendations are based on a systematic review of the evidence of the benefits and harms and an assessment of the net benefit of the service.
• The USPSTF recognizes that clinical or policy decisions involve more considerations than this body of evidence alone. Clinicians and policy-makers should understand the evidence but individualize decision-making to the specific patient or situation.

Staying Healthy

Effectiveness
Patient-centeredness

Not applicable: The guideline was not adapted from another source.

1996 (revised 2008 Aug)

United States Preventive Services Task Force - Independent Expert Panel

The U.S. Preventive Services Task Force (USPSTF) is a federally-appointed panel of independent experts. Conclusions of the U.S. Preventive Services Task Force do not necessarily reflect policy of the U.S. Department of Health and Human Services (DHHS) or its agencies.

United States Government

U.S. Preventive Services Task Force (USPSTF)

The U.S. Preventive Services Task Force has an explicit policy concerning conflict of interest. All members disclose at each meeting if they have a significant financial, professional/business, or intellectual conflict for each topic being discussed. Task Force members with conflicts may be recused from discussing or voting on recommendations about the topic in question.

This summary was completed by ECRI on June 30, 1998. The information was verified by the guideline developer on December 1, 1998. This summary was updated on November 10, 2002. The information was verified by the guideline developer on November 15, 2002. This NGC summary was updated by ECRI Institute on July 28, 2008. The updated information was verified by the guideline developer on August 13, 2008.