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Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force FREE

Roger Chou, MD; Jennifer M. Croswell, MD, MPH; Tracy Dana, MLS; Christina Bougatsos, BS; Ian Blazina, MPH; Rongwei Fu, PhD; Ken Gleitsmann, MD, MPH; Helen C. Koenig, MD, MPH; Clarence Lam, MD, MPH; Ashley Maltz, MD, MPH; J. Bruin Rugge, MD, MPH; and Kenneth Lin, MD
[+] Article and Author Information

From Oregon Health & Science University, Portland, Oregon; Agency for Healthcare Research and Quality, Rockville, Maryland; Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; Stamford Hospital Center for Integrative Medicine and Wellness, Stamford, Connecticut; and Georgetown University School of Medicine, Washington, DC.


Acknowledgment: The authors thank Mary Barton, MD, MPP, and U.S. Preventive Services Task Force Leads Ned Calonge, MD, MPH, Michael LeFevre, MD, MSPH, Rosanne Leipzig, MD, PhD, and Timothy Wilt, MD, MPH for their contributions to this report.

Grant Support: By the Agency for Healthcare Research and Quality (contract number HHSA-290-2007-10057-I-EPC3, Task Order 3).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1085.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, Mailcode BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current Author Addresses: Dr. Chou, Ms. Dana, Ms. Bougatsos, and Mr. Blazina: Oregon Health & Science University, Mailcode BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239.

Dr. Croswell: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850.

Dr. Fu: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mailcode CSB669, Portland, OR 97239.

Dr. Gleitsmann: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mailcode CSB, Portland, OR 97239.

Dr. Koenig: Jonathan Lax Center, 1233 Locust Street, 5th Floor, Philadelphia, PA 19107.

Dr. Lam: Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room WB602, Baltimore, MD 21205-1996.

Dr. Maltz: Center for Integrative Medicine and Wellness, Tully Health Center, 32 Strawberry Hill, Stamford, CT 06902.

Dr. Rugge: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mailcode FM, Portland, OR 97239.

Dr. Lin: Georgetown University School of Medicine, 4422 South Dakota Avenue NE, Washington, DC 20017.

Author Contributions: Conception and design: R. Chou, J.M. Croswell, J.B. Rugge, K. Lin.

Analysis and interpretation of the data: R. Chou, J.M. Croswell, T. Dana, R. Fu, K. Gleitsmann, H.C. Koenig, A. Maltz, J.B. Rugge, K. Lin.

Drafting of the article: R. Chou, T. Dana, K. Gleitsmann, K. Lin.

Critical revision of the article for important intellectual content: R. Chou, J.M. Croswell, K. Gleitsmann, A. Maltz, K. Lin.

Final approval of the article: R. Chou, J.M. Croswell, R. Fu, H.C. Koenig, J.B. Rugge, A. Maltz, K. Lin.

Statistical expertise: R. Chou, R. Fu.

Obtaining of funding: R. Chou.

Administrative, technical, or logistic support: R. Chou, T. Dana, C. Bougatsos, I. Blazina, K. Lin.

Collection and assembly of data: R. Chou, J.M. Croswell, T. Dana, C. Bougatsos, I. Blazina, H.C. Koenig, C. Lam, J.B. Rugge, K. Lin.


Ann Intern Med. 2011;155(11):762-771. doi:10.7326/0003-4819-155-11-201112060-00375
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Background: Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective.

Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer.

Data Sources: MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011).

Study Selection: Randomized trials of prostate-specific antigen–based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms.

Data Extraction: Investigators abstracted and checked study details and quality using predefined criteria.

Data Synthesis: Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found that screening was associated with reduced prostate cancer–specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer–specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits seemed to be limited to men younger than 65 years. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.

Limitations: Only English-language articles were included. Few studies evaluated newer therapies.

Conclusion: 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 treatments, some of which may be unnecessary.

Primary Funding Source: Agency for Healthcare Research and Quality.

Editors' Notes
Context

  • Examining the tradeoffs between potential benefits and harms of prostate cancer screening is a hot topic.

Contribution

  • This updated systematic review for the U.S. Preventive Services Task Force found the following: screening based on prostate-specific antigen led to detection of more cases of prostate cancer, small to no reduction in prostate cancer–specific mortality after about 10 years, and several potential harms related to false-positive test results and subsequent evaluations and therapies.

Caution

  • Evidence regarding the mortality-associated benefits of screening conflicted.

Implication

  • The clinical benefits of screening for prostate cancer remain uncertain. Consequences include evaluations and treatments that have associated complications and that may be unnecessary.

—The Editors

Editor's Note: The related draft recommendation statement was available for public comment at www.uspreventiveservicestaskforce.org. The USPSTF will consider all submitted comments when it finalizes its recommendation. To sign up for notification about the posting of draft recommendation statements, please visit the USPSTF Web site.

Prostate cancer is the most commonly diagnosed cancer in U.S. men (13). Prostate-specific antigen (PSA)–based screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective.

The U.S. Preventive Services Task Force (USPSTF) last reviewed the evidence on prostate cancer screening (4) and issued recommendations in 2008 (5). Since then, large trials of prostate cancer screening have been published (67). Benefits and harms of treatments for prostate cancer were last reviewed by the USPSTF in 2002 (8). This article summarizes 2 recent reviews commissioned by the USPSTF to synthesize the current evidence on screening (9) and treatments (10) for localized prostate cancer.

Scope of the Review

We followed a standardized protocol and developed an analytic framework that focused on the following key questions:

1. Does PSA-based screening decrease prostate cancer–specific or all-cause mortality?

2. What are the harms of PSA-based screening for prostate cancer?

3. What are the benefits of treatment of early-stage or screening-detected prostate cancer?

4. What are the harms of treatment of early-stage or screening-detected prostate cancer?

Detailed methods and data for the review, including search strategies, multiple evidence tables with quality ratings of individual studies, and pooled analyses of some harms data, are available in the full report (10). Also of note, androgen deprivation therapy, cryotherapy, and high-intensity focused ultrasonography are reviewed in the full report (10) but are not presented in this article.

Data Sources and Searches

We searched Ovid MEDLINE from 2002 to July 2011, PubMed from 2007 to July 2011, and the Cochrane Library Database through the second quarter of 2011 and reviewed reference lists to identify relevant articles published in English.

Study Selection

At least 2 reviewers independently evaluated each study to determine inclusion eligibility. We restricted inclusion to published studies. We included randomized trials of screening for prostate cancer in asymptomatic men (including those with chronic, mild lower urinary tract symptoms) that incorporated 1 or more PSA measurements, with or without additional methods, such as digital rectal examination, and reported all-cause or prostate cancer–specific mortality or harms associated with screening. We also included randomized trials and cohort studies of men with screening-detected prostate cancer that compared radical prostatectomy or radiation therapy (the most common primary treatments for localized prostate cancer [1112]) with watchful waiting and reported all-cause mortality, prostate cancer–specific mortality, or prespecified harms (quality of life or functional status, urinary incontinence, bowel dysfunction, erectile dysfunction, psychological effects, and surgical complications). We included studies of clinically localized (T1 or T2) prostate cancer because more than 90% of screening-detected prostate cancers are localized (67, 13). We included only studies that reported risk estimates for mortality adjusted at a minimum for age at diagnosis and tumor grade (no study reported adjusted risk estimates for treatment harms). We also included large (>1000 participants) uncontrolled observational studies of perioperative mortality and surgical complications.

We classified “no treatment,” “observation,” or “deferred treatment” as watchful waiting because patients probably received at least watchful waiting. We also grouped watchful waiting with active surveillance because studies of active surveillance provided insufficient information to determine whether more active follow-up actually occurred (14), and older studies used these terms interchangeably.

Data Extraction and Quality Assessment

One investigator abstracted details on the patient population, study design, analysis, duration of follow-up, and results. A second investigator reviewed data abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF (15) to rate the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process.

Data Synthesis and Analysis

We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, and poor) by using methods developed by the USPSTF on the basis of the number, quality, and size of studies; consistency of results between studies; and directness of evidence (15). We synthesized results of treatment studies descriptively, using medians and ranges, because few randomized, controlled trials (RCTs) were available and studies varied in the populations and interventions evaluated, methodologic quality, duration of follow-up, and other factors. We stratified results according to study type and qualitatively assessed the effects of study quality, duration of follow-up, year of publication, and mean age on results.

Role of the Funding Source

This study was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Staff at AHRQ and USPSTF members helped develop the scope of this work and reviewed draft manuscripts. The draft systematic reviews were reviewed by external peer reviewers not affiliated with the USPSTF, then revised for the final version. Approval from AHRQ was required before this manuscript could be submitted for publication, but the authors are solely responsible for the content and the decision to submit.

Appendix Figures 1 and 2 show the results of the search and study selection process.

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Appendix Figure 1.
Summary of literature search and selection: effectiveness and harms of screening.

BMJ = British Medical Journal; ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

* Not a randomized, controlled trial; systematic review; or meta-analysis; or was a nonrandomized analysis of a randomized, controlled trial.

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Appendix Figure 2.
Summary of literature search and selection: effectiveness and harms of treatment.

KQ = key question; RCT = randomized, controlled trial.

* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.

† Identified from reference lists, suggested by experts, or other methods.

‡ Excluding studies of androgen deprivation therapy, cryotherapy, and high-intensity focused ultrasonography (see the full technical report [10]).

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We identified 2 fair-quality (67) and 3 poor-quality (1620) randomized trials of PSA-based screening (Appendix Table 1). We also included a report describing results from a single center (21) participating in a fair-quality trial (7). Sample sizes ranged from 9026 to 182 160 and maximum follow-up from 11 to 20 years (median, 6 to 14 years).

Table Jump PlaceholderAppendix Table 1.  Randomized, Controlled Trials of Prostate-Specific Antigen–Based Screening

We identified 11 studies (2 RCTs [2229] and 9 cohort studies [3038]) on benefits of prostate cancer treatments and 16 studies (2 RCTs [3942] and 14 cohort studies [4358]) on harms (Appendix Table 2). Sample sizes ranged from 72 to 44 630 and duration of follow-up from 1 to 23 years. Four studies were rated good quality (23, 42, 52, 56, 58), 1 poor quality (29), and the remainder fair quality. Frequent methodologic shortcomings were failure to describe loss to follow-up (6 cohort studies and all 3 RCTs met this criterion) and inadequate blinding of outcome assessors (no cohort studies and 1 RCT met this criterion). Only 2 studies (33, 40) clearly described the control group intervention (Appendix Table 2). We also included 6 observational studies (5964) of surgical complications after prostatectomy.

Table Jump PlaceholderAppendix Table 2.  Studies of Treatments for Localized Prostate Cancer
Key Question 1: Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality?

The fair-quality U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned 76 693 men between 55 and 74 years of age to annual PSA screening in combination with digital rectal examination versus usual care (6). After 7 years' (complete) follow-up, screening was associated with increased prostate cancer incidence (relative risk [RR], 1.2 [95% CI, 1.2 to 1.3]) but no effect on prostate cancer–specific (RR 1.1 [CI, 0.75 to 1.7]) or all-cause (RR, 0.98 [CI, 0.92 to 1.0]) mortality. Similar results were observed after 10 years (67% of sample; RR, 1.1 [CI, 0.80 to 1.5]). Up to 52% of men assigned to usual care underwent a PSA test at some point during the trial, and 44% of trial participants had undergone PSA screening before entry.

The fair-quality European Randomized Study of Screening for Prostate Cancer (ERSPC) randomly assigned 182 000 men aged 50 to 74 years from 7 countries to PSA testing every 2 to 7 years (depending on center and year) or to usual care (7). Data from 2 other study centers were excluded for reasons not specified in the study protocol. Levels of PSA for diagnostic evaluation ranged from 2.5 to 4.0 µg/L (1 center used 10 µg/L for several years). Recruitment and randomization procedures and age eligibility also varied. After a median of 9 years, prostate cancer incidence was higher in the screened group (net increase, 34 per 1000 men), but there was no statistically significant difference in prostate cancer–specific mortality (RR, 0.85 [CI, 0.73 to 1.0]). A prespecified subgroup analysis of 162 243 men aged 55 to 69 years found that screening was associated with reduced prostate cancer–specific mortality (RR, 0.80 [CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point), for an estimated 1410 men invited to screening and 48 treated to prevent 1 prostate cancer–specific death.

After publication of the main ERSPC results, 1 participating center (Göteborg, Sweden) reported results separately (21). It found PSA screening (threshold, 2.5 to 3.0 µg/L) every 2 years in 20 000 men age 50 to 64 years to be associated with increased prostate cancer incidence (hazard ratio [HR], 1.6 [CI, 1.5 to 1.8]) and decreased risk for prostate cancer–specific mortality (RR, 0.56 [CI, 0.39 to 0.82]; absolute risk reduction, 0.34 percentage point) after a median of 14 years. Outcomes for 60% of participants were included in the main ERSPC report (7). Although no other center separately reported results, only exclusion of the Swedish center data from the overall ERSPC analysis resulted in loss of the statistically significant effect of screening on prostate cancer–specific mortality (RR, 0.84 [CI, 0.70 to 1.01]), suggesting better results than the other centers (7).

Three poor-quality trials (number of men invited to screening ranged from 1494 to 31 333) found no difference between screening-invited and control groups in prostate cancer–specific mortality risk (1617, 20). Two of the trials (17, 19) were included in the 2008 USPSTF review (4); results after 5 years' additional follow-up are now available from 1 of the trials (20). Methodological shortcomings in these trials included failure to describe adequate randomization or allocation concealment methods, poorly described loss to follow-up, and unclear masking of outcomes assessors. One trial used a high PSA cut point (10 µg/L) (16).

Key Question 2: What Are the Harms of PSA-Based Screening for Prostate Cancer?

Direct harms of PSA-based screening were reported in the ERSPC and PLCO trials (67). The Finnish center of the ERSPC trial found that 12% of men received at least 1 false-positive result after 3 rounds of PSA testing (cutoff, 4.0 µg/L) (65). For the entire ERPSC trial, 76% of prostate biopsies for an elevated PSA level identified no cancer (7). In the PLCO trial, the cumulative risk for at least 1 false-positive result was 13% after 4 PSA tests (cutoff, 4.0 µg/L), with a 5.5% risk for undergoing at least 1 biopsy due to a false-positive test result (66).

Physical harms of screening in the PLCO trial included bleeding or pain from digital rectal examination (0.3 event per 10 000 men screened); bruising or fainting due to venipuncture (26 events per 10 000 men screened); and biopsy complications, such as infection, bleeding, and urinary difficulties (68 events per 10 000 evaluations) (6). The Rotterdam, Netherlands, center of the ERSPC trial reported that among 5802 biopsies performed, 200 men (3.5%) developed fever, 20 (0.4%) experienced urine retention, and 27 (0.5%) required hospitalization for signs of prostatitis or urosepsis (67).

None of the RCTs of PSA-based screening provided information on potential psychological harms, such as anxiety, or adverse effects on health-related quality of life. The 2008 USPSTF review found evidence that false-positive PSA test results are associated with adverse psychological effects but could not estimate their magnitude (4).

Key Question 3: What Are the Benefits of Treatment of Early-Stage or Screening-Detected Prostate Cancer?
Prostatectomy

Prostatectomy was compared with watchful waiting in 1 good-quality RCT (n = 695) of men with localized (stage T1b, T1c, or T2) prostate cancer (Appendix Table 3) (2224, 28). It did not specifically enroll men with screening-detected prostate cancer, and about 75% of cancers were palpable (stage T2). By comparison, 36% of localized cancers in the ERSPC screening trial were stage T2 (7). The 2002 USPSTF review included results through 6 years of follow-up (28). Data now available through 15 years showed a sustained decrease in risk for prostate cancer–specific mortality (15% vs. 21%; RR, 0.62 [CI, 0.44 to 0.87]; absolute difference, 6.1 percentage points [CI, 0.2 to 12 percentage points]) and all-cause mortality (RR, 0.75 [CI, 0.61 to 0.92]; absolute difference, 6.6 percentage points [CI, −1.3 to 14 percentage points]) (23). In subgroup analyses, benefits were restricted to men younger than 65 years of age (RR, 0.49 [CI, 0.31 to 0.79] for prostate cancer–specific mortality; RR, 0.52 [CI, 0.37 to 0.73] for all-cause mortality). A small (n = 142), poor-quality RCT found no difference between prostatectomy and no prostatectomy for localized prostate cancer on overall survival through 23 years (29). It did not report prostate cancer–specific mortality.

Table Jump PlaceholderAppendix Table 3.  Prostate Cancer–Specific and All-Cause Mortality

Eight cohort studies (median n = 2264 [range, 316 to 25 900]) with a duration of follow-up ranging from 4 to 13 years consistently found prostatectomy for localized prostate cancer to be associated with decreased risk for all-cause mortality (6 studies; median adjusted HR, 0.46 [range, 0.32 to 0.67] [31, 3337]) and prostate cancer–specific mortality (5 studies; median adjusted HR, 0.32 [range, 0.25 to 0.50] [30, 33, 3536, 38]) compared with watchful waiting (Appendix Table 3). The largest was a fair-quality, propensity-adjusted analysis of data from the U.S. Surveillance, Epidemiology and End Results (SEER) program (n = 25 900) of men 65 to 80 years of age that found decreased risk for all-cause mortality after 12 years (adjusted HR, 0.50 [CI, 0.66 to 0.72]) (37). A large (n = 22 385), fair-quality Swedish cohort study also found prostatectomy to be associated with decreased risk for all-cause mortality after 4 years of follow-up, after adjustment for age, Gleason score, and PSA level (adjusted HR, 0.41 [CI, 0.36 to 0.48]) (31).

Radiation Therapy

No RCTs compared radiation therapy versus watchful waiting. Five cohort studies (median n = 3441 [range, 334 to 30 857]) with follow-up ranging from 4 to 13 years consistently found that radiation therapy (external-beam radiation therapy [EBRT] or unspecified modality) for localized prostate cancer was associated with decreased risk for all-cause mortality (5 studies; median adjusted HR, 0.68 [range, 0.62 to 0.81] [31, 3538]) and prostate cancer–specific mortality (5 studies; median adjusted HR, 0.66 [range, 0.63 to 0.70]) compared with watchful waiting (Appendix Table 3) (30, 3538). The largest study, a previously described analysis of SEER data, found radiation therapy to be associated with decreased propensity-adjusted risk for all-cause mortality (adjusted HR, 0.81 [CI, 0.78 to 0.85]) (37). A large Swedish cohort study (also described earlier) found radiation therapy to be associated with decreased risk for all-cause mortality (adjusted HR, 0.62 [CI, 0.54 to 0.71]) (31).

Key Question 4: What Are the Harms of Treatment of Early-Stage or Screening-Detected Prostate Cancer?
Prostatectomy
Urinary Incontinence and Erectile Dysfunction.

Prostatectomy was associated with increased risk for urinary incontinence compared with watchful waiting in 1 RCT (RR, 2.3 [CI, 1.6 to 3.2]) (41) and 4 cohort studies (median RR, 4.0 [range, 2.0 to 11]) (Appendix Table 4) (47, 49, 53, 56). In the RCT, the absolute increase in risk for urinary incontinence with surgery was 28 percentage points (49% vs. 21%) (41). In the cohort studies, the median rate of urinary incontinence with watchful waiting was 6% (range, 3% to 10%), with prostatectomy associated with a median increase in absolute risk of 18 percentage points (range, 8 to 40 percentage points) (47, 49, 53, 56).

Table Jump PlaceholderAppendix Table 4.  Erectile Dysfunction and Urinary Incontinence

Prostatectomy was also associated with an increased risk for erectile dysfunction compared with watchful waiting in 1 RCT (RR, 1.8 [CI, 1.5 to 2.2]) (41) and 5 cohort studies (median RR, 1.5 [range, 1.3 to 2.1]) (Appendix Table 4) (47, 49, 5354, 56). In the RCT, the absolute increase in risk for erectile dysfunction with surgery was 36 percentage points (81% vs. 45%) (41). In the cohort studies, the median rate of erectile dysfunction with watchful waiting was 52% (range, 26% to 68%), with prostatectomy associated with a median increase in absolute risk of 26 percentage points (range, 21 to 29 percentage points) (47, 49, 5354, 56).

Differences in study quality, duration of follow-up, or year of publication did not seem to explain differences in estimates across studies. The studies provided few details about the specific surgical procedures evaluated, although open retropubic radical prostatectomy was the dominant procedure when most of the studies were conducted (68). One observational study stratified estimates for erectile dysfunction and urinary incontinence by use of a nerve-sparing (n = 494; 68% and 9.4%, respectively) versus a non–nerve-sparing (n = 476; 87% and 15%, respectively) technique (56).

Consistent with the studies reporting dichotomous outcomes, 8 cohort studies that evaluated urinary and sexual function outcomes by using continuous scales found that prostatectomy was associated with worse outcomes compared with watchful waiting (Appendix Table 4) (43, 46, 48, 51, 53, 5557).

Quality of Life.

Eight studies reported generic quality of life (43, 46, 48, 5051, 53, 5556). Two studies reported very similar Short-Form 36 (SF-36) physical and mental component summary scores after prostatectomy and watchful waiting (Appendix Table 5) (43, 56). On specific SF-36 subscales, prostatectomy was associated with better physical function (6 studies; median difference, 8 points [range, 2 to 16 points]) (43, 46, 48, 51, 53, 55) and emotional role function subscale scores (7 studies; median difference, 8 points [range, −5 to 13 points]) (43, 46, 48, 5051, 53, 55), with small or no clear differences on other SF-36 subscales.

Table Jump PlaceholderAppendix Table 5.  Summary Scores for Disease-Specific and Generic Health-Related Quality of Life
Surgical Complications.

The largest (n = 101 604) study of short-term (≤30-day) complications after prostatectomy reported a 30-day perioperative mortality rate of 0.5% in Medicare claimants (60); 3 other large observational studies reported similar findings (59, 6162). Advanced age and increased number of serious comorbid conditions were associated with higher perioperative mortality, although absolute rates were less than 1% even in men at higher risk. In the Medicare database study, perioperative rates of serious cardiovascular events were 3% and rates of vascular events (including pulmonary embolism and deep venous thrombosis) were 2% (60). In 2 other studies (n = 1243 [63] and 11 010 [59]), rates of cardiovascular events were 0.6% and 3% and rates of vascular events 1% and 2%, respectively. Serious rectal or ureteral injury due to surgery ranged from 0.3% to 0.6% (60, 63).

Other Harms.

Five studies (reported in 6 publications) found no clear differences between prostatectomy and watchful waiting in risk for bowel dysfunction (4142, 4647, 49, 56). One RCT found no difference between prostatectomy and watchful waiting in risk for high levels of anxiety, depression, or worry after 4 years (42).

Radiation Therapy
Urinary Incontinence and Erectile Dysfunction.

Radiation therapy was associated with increased risk for urinary incontinence compared with watchful waiting in 1 small RCT, but the estimate was very imprecise (RR, 8.3 [CI, 1.1 to 63]) because of small numbers of events (1 in the watchful waiting group) (Appendix Table 4) (39). There was no clear increase in risk in 4 (total n = 1910) cohort studies (median RR, 1.1 [range, 0.71 to 2.0]) (47, 49, 53, 56).

Radiation therapy was associated with increased risk for erectile dysfunction compared with watchful waiting in 6 cohort studies, with similar estimates across studies (median RR, 1.3 [range, 1.1 to 1.5]) (Appendix Table 4) (47, 49, 5354, 56, 58). Rates of erectile dysfunction ranged from 26% to 68% (median, 50%) with watchful waiting; radiation therapy was associated with a median increase in pooled absolute risk of 14 percentage points (range, 7 to 22 percentage points).

Five of the six studies did not provide details about the type of radiation therapy (for example, EBRT versus brachytherapy) or dosing regimen. One good-quality cohort study reported a 7.0% rate of urinary incontinence after high-dose brachytherapy (n = 47), 5.4% after low-dose brachytherapy (n = 58), and 2.7% after EBRT (n = 123) (56). Rates of erectile dysfunction were 72%, 36%, and 68%, respectively.

Consistent with the studies reporting dichotomous outcomes, 10 studies found radiation therapy to be associated with worse sexual function compared with watchful waiting on the basis of continuous scales, although no clear differences were seen in sexual bother scores and measures of urinary function (Appendix Table 4) (40, 43, 46, 48, 51, 53, 5558).

Quality of Life.

Ten studies reported generic quality of life (40, 43, 46, 48, 5051, 53, 5556, 58). Three studies found no differences between radiation therapy and watchful waiting in SF-36 physical (median difference, 0 points [range, −3 to 0 points]) or mental (median difference, 0 points [range, −2 to 1 point]) component summary scores (Appendix Table 4) (43, 56, 58). Results favored watchful waiting on the physical role function subscale (7 studies; median difference, −9 points [range, −22 to 1 point]) (43, 46, 48, 51, 53, 55, 58), with no clear differences on other SF-36 subscales.

Other Harms.

Six cohort studies consistently found radiation therapy to be associated with worse Prostate Cancer Index bowel bother (median difference, −6 points [range, −10 to −2 points]) and function (median difference, −8 points [range, −15 to −3 points) than watchful waiting (43, 48, 51, 53, 56, 58). In studies that evaluated bowel function serially, effects seemed to be most pronounced in the first few months after radiation therapy and gradually improved (40, 46, 51, 57). This might help explain the inconsistent results among studies that reported dichotomous outcomes. Although 1 study found radiation therapy associated with substantially increased risk for bowel urgency after 2 years (3.2% vs. 0.4%; RR, 7.5 [CI 1.0 to 56]) (47), 2 studies with longer duration of follow-up (5.6 [49] and 3 years [56]) found no increased risk.

One cohort study reported similar effects of EBRT and brachytherapy on Prostate Cancer Index bowel function and bother (43). Another study found low-dose brachytherapy to be associated with smaller effects on bowel bother (about 3-point change from baseline) compared with high-dose brachytherapy (9-point change) or EBRT (8-point change) (56).

No study reported effects of radiation therapy versus watchful waiting on anxiety or depression.

The Table shows our summary of the evidence. Screening based on PSA identifies additional cases of prostate cancer, but most trials found no statistically significant effect on prostate cancer–specific mortality. Recent meta-analyses of randomized trials included in this review found no pooled effect of screening on prostate cancer–specific mortality (6970). However, the 2 largest and highest-quality trials reported conflicting results (67). The ERSPC trial found PSA screening every 2 to 7 years to be associated with a 20% relative reduction in risk for death from prostate cancer in a prespecified subgroup of men aged 55 to 69 years (7), whereas the PLCO trial found no effect (6). High rates of previous PSA screening and contamination in the control group of the PLCO trial may have reduced its ability to detect benefits, although these factors do not explain the trend toward increased risk for prostate cancer–specific mortality in the screened group. The proportion of men in the PLCO trial who initially chose active surveillance or expectant management instead of curative treatment was lower than in the ERSPC trial (10% vs. 19%), and the PLCO trial evaluated a shorter screening interval (annual vs. every 2 to 7 years), suggesting that more conservative screening and treatment strategies might be more effective than more aggressive ones. Chance could also explain the apparent discrepancy between the 2 trials because the risk estimate CIs overlapped. Additional follow-up might help resolve the discrepancy, given the long lead time (10 to 15 years) that may be necessary to fully understand the effect of PSA-based screening.

Treatment studies can help inform screening decisions by providing information about potential benefits of interventions once prostate cancer is detected. However, only 1 good-quality randomized trial compared an active treatment for localized prostate cancer with watchful waiting (23). It found that prostatectomy was associated with decreased risk for all-cause and prostate cancer–specific mortality after 15 years of follow-up, although benefits seemed to be limited to younger men on the basis of subgroup analyses. Because the RCT did not enroll men specifically with screening-detected prostate cancer, its applicability to screening is uncertain. Although cohort studies consistently found prostatectomy and radiation therapy to be associated with decreased risk for all-cause and prostate cancer–specific mortality compared with watchful waiting, estimates are susceptible to residual confounding, even after statistical adjustment.

Screening is associated with potential harms, including serious infections or urine retention in about 1 of 200 men who undergo prostate biopsy as a result of an abnormal screening result. False-positive screening results occurred in 12% to 13% of men randomly assigned to PSA-based screening (6566), with 1 trial reporting no prostate cancers in three quarters of screening-triggered biopsies (7). Screening also is likely to result in overdiagnosis because of the detection of low-risk cancers that would not have caused morbidity or death during a man's lifetime, and overtreatment of such cancers, which exposes men to unnecessary harms (71). Over three quarters of men with localized prostate cancer (about 90% of screening-detected cancers are localized) undergo prostatectomy or radiation therapy (1112). On the basis of data from the ERSPC trial, the rate of overdiagnosis with screening was estimated to be as high as 50% (72), and 48 men received treatment for every prostate cancer–specific death prevented (7). Treating approximately 3 men with prostatectomy or 7 with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction, and treating approximately 5 men with prostatectomy instead of watchful waiting would result in 1 additional case of urinary incontinence. Prostatectomy and radiation therapy were not associated with worse outcomes on most measures related to general health-related quality of life compared with watchful waiting, suggesting that negative effects related to specific harms may be offset by positive effects (perhaps related to less worry about untreated prostate cancer). Prostatectomy was also associated with perioperative (30-day) mortality (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.

The evidence on treatment-related harms reviewed for this report seemed to be most applicable to open retropubic radical prostatectomy and EBRT, although details of specific surgical techniques or radiation therapy techniques and dosing regimens were frequently lacking. We found little evidence with which to evaluate newer techniques for prostatectomy (including nerve-sparing approaches that use laparoscopy, either robotic-assisted or freehand) compared with watchful waiting, but found no pattern suggesting that more recent studies reported different risk estimates than older studies. Limited data suggest that low-dose brachytherapy may be associated with fewer harms than high-dose brachytherapy or EBRT (56). A potential harm of radiation therapy not addressed in this review is secondary posttreatment carcinogenic effects (7374).

Other treatments used for localized prostate cancer are reviewed in the full report, available on the USPSTF Web site (10). Although androgen deprivation is the next most commonly used therapy for localized prostate cancer after prostatectomy and radiation therapy (11), it is comparatively uncommon and is not recommended as primary therapy (7576) because of evidence suggesting ineffectiveness (32), as well as an association with important adverse events, such as coronary heart disease, myocardial infarction, diabetes, and fractures, when given for more advanced prostate cancer (7779).

Our study has limitations. We excluded non–English-language articles, which could result in language bias, although we identified no non–English-language studies that would have met inclusion criteria. We included cohort studies of treatments, which are more susceptible to bias and confounding than well-conducted randomized trials. However, confounding by indication may be less of an issue in studies that evaluate harms (80), and analyses stratified by study design did not suggest differential estimates. If patients are selected for a specific prostate cancer treatment in part because of a lower perceived risk for harms, the likely effect on observational studies would be to underestimate risks. For mortality outcomes, which may be more susceptible to confounding by indication, we included only studies that performed statistical adjustment. Finally, studies did not distinguish well between active surveillance and watchful waiting. Active surveillance might be associated with more harms (due to repeated biopsies or subsequent interventions) than watchful waiting, and studies with well-described active surveillance interventions that are consistent with current definitions for this therapy are needed (14).

In summary, PSA-based screening is associated with detection of more prostate cancers; small to no reduction in prostate cancer–specific mortality after about 10 years; and harms related to false-positive test results, subsequent evaluation, and therapy, including overdiagnosis and overtreatment. If screening is effective, optimal screening intervals and PSA thresholds remain uncertain. The ERSPC trial evaluated longer screening intervals (2 to 7 years) and in some centers lower PSA thresholds (2.5 to 4.0 µg/L) as compared with typical U.S. practice (6). When available, results from the Prostate Cancer Intervention Versus Observation Trial, which compared prostatectomy with watchful waiting for screening-detected cancer, may help clarify which patients would benefit from prostatectomy or other active treatments, potentially reducing harms from unnecessary treatment (81).

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Figures

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Appendix Figure 1.
Summary of literature search and selection: effectiveness and harms of screening.

BMJ = British Medical Journal; ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

* Not a randomized, controlled trial; systematic review; or meta-analysis; or was a nonrandomized analysis of a randomized, controlled trial.

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Appendix Figure 2.
Summary of literature search and selection: effectiveness and harms of treatment.

KQ = key question; RCT = randomized, controlled trial.

* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.

† Identified from reference lists, suggested by experts, or other methods.

‡ Excluding studies of androgen deprivation therapy, cryotherapy, and high-intensity focused ultrasonography (see the full technical report [10]).

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Tables

Table Jump PlaceholderAppendix Table 1.  Randomized, Controlled Trials of Prostate-Specific Antigen–Based Screening
Table Jump PlaceholderAppendix Table 2.  Studies of Treatments for Localized Prostate Cancer
Table Jump PlaceholderAppendix Table 3.  Prostate Cancer–Specific and All-Cause Mortality
Table Jump PlaceholderAppendix Table 4.  Erectile Dysfunction and Urinary Incontinence
Table Jump PlaceholderAppendix Table 5.  Summary Scores for Disease-Specific and Generic Health-Related Quality of Life

References

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Letters

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Comments

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USPSTF needs to consider another endpoint besides mortality
Posted on October 11, 2011
Murray S.Feldstein, Urologist
Mayo Clinic Arizona
Conflict of Interest: None Declared

While there is much to applaud in the task force's report, I think their conclusions may do more harm than good. They have studied mortality as a primary endpoint. As an elderly urologist who spent almost half of his career in the pre-PSA era, I can personally attest to another and perhaps even more important factor that is being overlooked: that of suffering from advanced prostate cancer.

No longer do I see patients with bulky cancers who bleed and obstruct their urinary tracts. Many of these patients required emergency procedures and were left with permanent indewelling catheters. The patient presenting with diffuse painful osseous metastasis is now rare. Performing emergency orchiectomies plus radiation or surgical decompression for impending paraplegia seems less common.

Patients like these could live for years and still die of other diseases. They will not register as a success of PSA screening if only mortality is considered. In one study that studied the presence of metastasis as the primary endpoint, screened patients experienced a 48% reduction in the number of patients developing metastatic disease.1

The task force has made some excellent points. The AUA has modified its guidelines to take into account the evidence as it has emerged. More judicious use of PSA and recommendations for treatment of early cancer are necessary. Better methods for distinguishing those cancers destined to spread or kill need to be developed. However, if the task force's conclusions are interpreted by the public at large as a condemnation of early diagnosis of prostate cancer using PSA, we will be thrown back to the era when digital rectal exams diagnosed dangerous cancers too late.

Respectfully, Murray S. Feldstein M.D. Phoenix Arizona

Reference

1. Aus G, Bergdahl S, Lodding P., Lilja H, Hugosson J; Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer--results from a prospective, population-based randomized controlled trial. Eur J Urol 51: 659-64, 2007

Conflict of Interest:

Urologist

Need to Consider Racial Diversity of American Population
Posted on October 19, 2011
M'Liss A.Hudson, MD
Washington University in St. Louis School of Medicine, Division of Urology
Conflict of Interest: None Declared

To the Editor:

I am disheartened by the publication of "Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force" which suggests PSA screening is ineffective and harmful to American men. I do not believe the "exhaustive review of the latest eveidence" dscribed by the authors is applicable to American men.

American Cancer Society Cancer Fact and Figures for African Americans 2011-12 continue to report that 35,110 cases of prostate cancer are expected to occur in AA men, accounting for 40% of all cancer diagnosed in AA men. One in five men will be diagnosed with prostate cancer in their lifetime. The average annual prostate cancer incidence rate among AA men (2003-2007) was 229.4/100,000 men, 60% higher than white men. AA men have the highest incidence rate in the world and are twice as likely to die of prostate cancer than whites.

2010 Census shows the U.S. population racial distribution is whites 79%, African Americans 13.8%, Asicans 4% and Hispanic ethnicity is reported at 12.5%.

The seven articles chosen from the 379 articles retrieved as meeting inclusion criteria for determination of the effectiveness of PSA screening (Table 1) are derived from predominantly Caucasian men of northern or western European heritage (predominantly Scandinavia). Several of these studies re-analyze the same cohorts or portions of previously reported cohorts. Thus, the data is mainly derived from the ERSPC and PLCO studies. The PLCO study was the only one to include American men and to report race/ethnicity. It included African Americans (4.5%), Asians (4.0%), Hispanics (2.1%) and Pacific Islanders/Native Americans (0.8%) and thus is not fully representative of the U.S. population. This same study has been oft criticized due to the contamination of the control group (those not undergoing PSA testing within the study) of whom 44% had undergone a PSA blood test prior to enrolling, and 52% who had PSA testing done outside the study during follow-up.

I remain unconvinced that these recommendations are applicable to anyone other than Scandinavian men over the age of 50 years. Adopting them without considering the increasing racial diversity of the American population seems unwise.

Conflict of Interest:

None declared

Errors of fact, statistics and interpretation in the USPSTF review on prostate cancer screening
Posted on October 26, 2011
Sigrid V.Carlsson, MD PhD, Andrew Vickers, Hans Lilja, and Jonas Hugosson
Department of surgery (Urology), Memorial Sloan-Kettering Cancer Center, New York, U.S.A
Conflict of Interest: None Declared

By giving a grade of "D" for prostate cancer screening, the U.S. Preventive Services Task Force (USPSTF) concluded that "there is moderate or high certainty that [prostate cancer screening] has no net benefit or that the harms outweigh the benefits". We have sympathy with the recommendations against current screening practices in the U.S. However, the report from the USPSTF contained important errors of fact, interpretation or statistics.

Firstly, the largest trial of PSA screening, the European Randomized study of Screening for Prostate Cancer (ERSPC) has not yet reported at its pre-specified main follow-up time. To draw conclusions that screening results "in small or no reduction in prostate cancer-specific mortality", suggests that definitive conclusions of no benefit can be drawn from an ongoing trial with ambiguous results at interim follow-up. Further, data on overall mortality from early follow-up of a screening trial cannot be used to conclude that "screening does not save lives" as screening trials lack necessary statistical power to address this issue.

The USPSTF conclusions appear importantly based on the validity of the pooling in two meta-analyses. The two largest and most high-quality studies are the U.S. Prostate, Lung, Colorectal and Ovarian Cancer trial (PLCO) and the ERSPC. However, PSA-testing was widespread before the PLCO trial and in the control group throughout the study. Therefore, the authors of this trial stated that the trial "would not be able to answer the question of whether that level of opportunistic screening is conveying a mortality benefit over no screening".[1] Contamination in ERSPC was less than 15%[2]. It is very hard to justify combining a trial of opportunistic vs. systematic screening with a trial of systematic vs. no screening and then calculate an "average" effect.

The USPSTF authors state "48 men received treatment for every prostate cancer-specific death prevented". This is false: the number was calculated from the number of men diagnosed, not the number treated. Moreover, this statistic depends on the length of follow-up. Models have estimated this ratio to be around 20 at 12 years of-follow-up in the ERSPC[3]; the empirical estimate from the Goteborg trial with 14 years of follow-up is 12[4].

In conclusion, although fair-quality trials have demonstrated an ability of screening to prevent prostate cancer death by 20-44%[4,5], it is not unreasonable to recommend against the current modality to practice PSA screening based on the harms associated with over-diagnosis and risk of toxicity associated with treatment.

References

[1.] Pinsky PF, Blacka A, Kramer BS, Miller A, Prorok PC, Berg C. Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clinical trials. 2010;7(4):303-311.

[2.] Schroder FH, Roobol MJ. ERSPC and PLCO prostate cancer screening studies: what are the differences? Eur Urol. 2010;58(1):46-52.

[3.] Loeb S, Vonesh EF, Metter EJ, Carter HB, Gann PH, Catalona WJ. What is the true number needed to screen and treat to save a life with prostate -specific antigen testing? J Clin Oncol. 2011;29(4):464-467.

[4.] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11(8):725-732.

[5.] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate- cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328.

Conflict of Interest:

Conflict of Interest: Dr. Hans Lilja holds patents for free PSA, hK2, and intact PSA assays. Authors affiliations: 1. Sigrid Carlsson MD PhD, Department of surgery (Urology), Memorial Sloan-Kettering Cancer Center, New York, U.S.A. and Department of Urology, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden. 2. Andrew Vickers Ph.D. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. 3. Hans Lilja MD PhD Attending, Departments of Laboratory Medicine, Surgery (Urology), and Medicine (GU-Oncology), Memorial Sloan-Kettering Cancer Center, New York, USA and Professor (adjunct) Department of Laboratory Medicine, Lund University, Sweden, and Institute of Biomedical Technlogy, University of Tampere, Finland 4. Jonas Hugosson. MD, PhD, Professor, Department of Urology, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden

In response:
Posted on January 18, 2012
RogerChou, Associate Professor of Medicine, Jennifer M. Croswell
Oregon Health & Science University
Conflict of Interest: None Declared

In response: We appreciate the interest by Carlsson and colleagues, Hudson, and Feldstein in our review.[1] First, we would like to clarify that the purpose of the review was to synthesize the evidence on benefits and harms of prostate cancer screening , not to make recommendations about screening. The article was not authored by the U.S. Preventive Services Task Force (USPSTF), but was commissioned and used by the USPSTF to inform its separate draft recommendation.

Carlsson and colleagues incorrectly state that the review's conclusions are based upon the results of two published meta-analyses. In fact, our review reports and summarizes the results of the two major screening trials (the European Randomized study of Screening for Prostate Cancer [ERSPC][2] and the Prostate, Lung, Colorectal, and Ovarian cancer [PLCO] study[3]) separately, with the range of potential benefits, as well as a discussion of the methodological limitations of the trials and potential reasons for discrepancies in their findings. The number needed to treat of 48 was presented as reported by the ERSPC authors, and based on the number of patients who were diagnosed with prostate cancer and received treatments including surgery, radiation therapy, and watchful waiting/active surveillance (the minimum standard of care). Excluding patients who received watchful waiting, the number needed to treat would be about 40. Finally, our article clearly described the duration of follow-up in the screening trials and noted that longer follow-up may be necessary to fully understand potential benefits of screening.

We agree with Hudson that robust data on benefits of screening in certain populations such as African-American men are lacking. However, the large-scale randomized trials provide the current best evidence on potential benefits of screening. In addition, even through screening of populations with a higher prevalence of prostate cancer may result in additional diagnoses, this would not necessarily result in greater benefits relative to harms, because more men would also be subjected to harms related to diagnosis and treatment.

Feldstein points out that metastatic prostate cancer was not evaluated as an outcome in our review. Stage shift is considered an intermediate outcome to prostate cancer mortality and therefore not heavily weighted in USPSTF reviews. Fully understanding effects of screening on metastatic prostate cancer would require assessment of effects of metastatic disease on quality of life (which might be offset by negative effects related to treatment harms); such data were not provided in the screening trials.

References:

1. Chou, R., et al., Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:762-71.

2. Schroder, F.H., et al., Screening and prostate-cancer mortality in a randomized European study. New Engl J Med 2009;360:1320-8.

3. Andriole, G.L., et al., Mortality results from a randomized prostate- cancer screening trial. New Engl J Med 2009;360:1310-19.

Conflict of Interest:

The authors received funding from the Agency for Healthcare Research and Quality to conduct the review on prostate cancer screening.

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