Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement (continued)
Burden of Disease
An estimated 240,890 U.S. men received a prostate cancer diagnosis in 2011, and an estimated 33,720 men died of the disease (35). The average age of diagnosis was 67 years and the median age of those who died of prostate cancer from 2003 through 2007 was 80 years; 71% of deaths occurred in men older than 75 years (1). Black men have a substantially higher prostate cancer incidence rate than white men (232 vs. 146 cases per 100,000 men) and more than twice the prostate cancer mortality rate (56 vs. 24 deaths per 100,000 men, respectively) (35).
Prostate cancer is a clinically heterogeneous disease. Autopsy studies have shown that approximately one third of men aged 40 to 60 years have histologically evident prostate cancer (36); the proportion increases to as high as three fourths in men older than 85 years (37). Most cases represent microscopic, well-differentiated lesions that are unlikely to be of clinical importance. Increased frequency of PSA testing, a lower threshold for biopsy, and an increase in the number of core biopsies obtained all increase the detection of lesions that are unlikely to be of clinical significance.
Scope of Review
The previous evidence update, done for the USPSTF in 2008, found insufficient evidence that screening for prostate cancer improved health outcomes, including prostate cancer–specific and all-cause mortality, for men younger than 75 years. In men aged 75 years or older, the USPSTF found adequate evidence that the incremental benefits of treatment of screen-detected prostate cancer are small to none and that the harms of screening and treatment outweigh any potential benefits (38). After the publication of initial mortality results from 2 large randomized, controlled trials of prostate cancer screening, the USPSTF determined that a targeted update of the direct evidence on the benefits of PSA-based screening for prostate cancer should be done (39). In addition, the USPSTF requested a separate systematic review of the benefits and harms of treatment of localized prostate cancer (10). Since the release of the USPSTF's draft recommendation statement on prostate cancer screening and its supporting systematic evidence reviews, updated results from the ERSPC and PLCO trials and data on harms related to prostate biopsy from the ProtecT trial have become available; these publications were used to inform this final recommendation statement.
Accuracy of Screening
The conventional PSA cutoff of 4.0 μg/L detects many cases of prostate cancer; however, some cases will be missed. Using a lower cutoff detects more cases of cancer, but at the cost of labeling more men as potentially having cancer. For example, decreasing the PSA cutoff to 2.5 μg/L would more than double the number of U.S. men aged 40 to 69 years with abnormal results (16), and most of these would be false-positive results. It also increases the likelihood of detection of indolent tumors with no clinical importance. Conversely, increasing the PSA cutoff to greater than 10.0 μg/L would reduce the number of men aged 50 to 69 years with abnormal results from approximately 1.2 million to roughly 352,000 (16). There is no PSA cutoff at which a man can be guaranteed to be free from prostate cancer (40).
There are inherent problems with the use of needle biopsy results as a reference standard to assess the accuracy of prostate cancer screening tests. Biopsy detection rates vary according to the number of biopsies done during a single procedure; the more biopsies done, the more cancer cases detected. More cancer cases detected with a “saturation” biopsy procedure (≥20 core biopsies) tend to increase the apparent specificity of an elevated PSA level; however, many of the additional cancer cases detected this way are unlikely to be clinically important. Thus, the accuracy of the PSA test for detecting clinically important prostate cancer cases cannot be determined with precision.
Variations of PSA screening, including the use of age-adjusted PSA cutoffs, free PSA, and PSA density, velocity, slope, and doubling time, have been proposed to improve detection of clinically important prostate cancer cases. However, no evidence has demonstrated that any of these testing strategies improve health outcomes, and some may even generate harms. One study found that using PSA velocity in the absence of other indications could lead to 1 in 7 men having a biopsy with no increase in predictive accuracy (41).
Effectiveness of Early Detection and Treatment
Two poor-quality (high risk of bias) randomized, controlled trials initiated in the 1980s in Sweden each demonstrated a nonstatistically significant trend toward increased prostate cancer mortality in groups invited to screening (21, 22). A third poor-quality (high risk of bias) trial from Canada showed similar results when an intention-to-screen analysis was used (20). The screening protocols for these trials varied; all included 1 or more PSA tests with cutoffs ranging from 3.0 to 10.0 μg/L; in addition, digital rectal examination and transrectal ultrasonography were variably used.
The more recently published PLCO and ERSPC trials were the principal trials considered by the USPSTF. The fair-quality prostate component of the PLCO trial randomly assigned 76,685 men aged 55 to 74 years to annual PSA screening for 6 years (and concomitant digital rectal examination for 4 years) or to usual care. It used a PSA cutoff of 4.0 μg/L. Diagnostic follow-up for positive screening test results and treatment choices were made by the participant and his personal physician; 90% of men with prostate cancer diagnoses received active treatment (surgery, radiation, hormonal therapy, or some combination). After 7 years (complete follow-up), a nonstatistically significant trend toward increased prostate cancer mortality was seen in the screened group (RR, 1.14 [CI, 0.75 to 1.70]) compared with men in the control group (19). Similar findings were seen after 13 years (RR, 1.09 [CI, 0.87 to 1.36]) (23). The primary criticism of this study relates to the high contamination rate; approximately 50% of men in the control group received at least 1 PSA test during the study, although the investigators increased both the number of screening intervals and the duration of follow-up to attempt to compensate for the contamination effects. In addition, approximately 40% of participants had received a PSA test in the 3 years before enrollment, although subgroup analyses stratified by history of PSA testing before study entry did not reveal differential effects on prostate cancer mortality rates (19). Contamination may attenuate differences in the 2 groups but would not explain both an increased prostate cancer incidence and mortality rate in men assigned to screening.
The fair-quality ERSPC trial randomly assigned 182,160 men aged 50 to 74 years from 7 European countries to PSA testing every 2 to 7 years or to usual care. Prostate-specific antigen cutoffs ranged from 2.5 to 4.0 μg/L, depending on study center (1 center used a cutoff of 10.0 μg/L for several years). Subsequent diagnostic procedures and treatment also varied by center. Sixty six percent of men who received a prostate cancer diagnosis chose immediate treatment (surgery, radiation therapy, hormonal therapy, or some combination). Among all men who were randomly assigned, there was a borderline reduction in prostate cancer mortality in the screened group after a median follow-up of 9 years (RR, 0.85 [CI, 0.73 to 1.00]) (4). Similar results were reported after 11 years of follow-up and were statistically significant (RR, 0.83 [CI, 0.72 to 0.94]) (15). After a median follow-up of 9 years in a prespecified subgroup analysis limited to men aged 55 to 69 years, a statistically significant reduction in prostate cancer deaths was seen in the screened group (RR, 0.80 [CI, 0.65 to 0.98]) (4). After 11 years of follow-up, a similar reduction was seen (RR, 0.79 [CI, 0.45 to 0.85]); the authors estimated that 1055 men needed to be invited to screening and 37 cases of prostate cancer needed to be detected to avoid 1 death from prostate cancer (15). Of the 7 individual centers included in the mortality analysis, 2 (Sweden and the Netherlands) demonstrated statistically significant reductions in prostate cancer deaths with PSA screening. The magnitude of effect was considerably greater in these 2 centers than in other countries (Figure). Primary criticisms of this study relate to inconsistencies in age requirements, screening intervals, PSA thresholds, and enrollment procedures used among the study centers, as well as the exclusion of data from 2 study centers in the analysis. There is also concern that differential treatments between the study and control groups may have had an effect on outcomes. Of note, men in the screened group were more likely than men in the control group to have been treated in a university setting, and a control participant with high-risk prostate cancer was more likely than a screened participant to receive radiotherapy, expectant management, or hormonal therapy instead of radical prostatectomy (42). Furthermore, ascertainment of cause of death in men with a diagnosis of prostate cancer included men whose prostate cancer was detected at autopsy. How this cause-of-death adjudication process may affect estimates is unknown, but previous research has demonstrated difficulties in accurately ascertaining cause of death and that small errors could have an important effect on results (43, 44).
After publication of the initial ERSPC mortality results, a single center from within that trial (Göteburg, Sweden) reported data separately. Outcomes for 60% of this center's participants were reported as part of the full ERSPC publication, and the subsequent country-specific results within the ERSPC trial reflect the separately reported results from Sweden (which included some men not included in the overall ERSPC trial) (45).
Few randomized, controlled trials have compared treatments for localized prostate cancer with watchful waiting. A randomized, controlled trial of 695 men with localized prostate cancer (Scandinavian Prostate Cancer Group Study 4) reported an absolute reduction in the risk for distant metastases (11.7% [CI, 4.8% to 18.6%]) in patients assigned to radical prostatectomy versus watchful waiting after 15 years of follow-up. An absolute reduction in prostate cancer mortality (6.1% [CI, 0.2% to 12.0%]) and a trend toward a reduction in all-cause mortality (6.6% [CI, -1.3% to 14.5%]) were also seen over this period. Subgroup analysis suggests that the benefits of prostatectomy were limited to men aged 65 years or younger. The applicability of these findings to cancer detected by PSA-based screening is limited, because only 5% of participants were diagnosed with prostate cancer through some form of screening, 88% had palpable tumors, and more than 40% presented with symptoms (13, 17). An earlier, poor-quality study found no mortality reduction from radical prostatectomy versus watchful waiting after 23 years of follow-up (46). Another randomized trial of 214 men with localized prostate cancer detected before initiation of PSA screening that compared EBRT versus watchful waiting presented preliminary mortality results after completion of the evidence review. At 20 years, the observed survival did not differ between men randomly assigned to watchful waiting and EBRT (31% vs. 35%; P = 0.26). Prostate cancer mortality at 15 years was high in each group but did not differ between groups (23% vs. 19%; P = 0.51). External beam radiotherapy did reduce distant progression and recurrence-free survival (25).
Preliminary results from PIVOT have also become available since the evidence review was completed. PIVOT, conducted in the United States, included men with prostate cancer detected after the initiation of widespread PSA testing and, thus, included a much higher percentage of men with screen-detected prostate cancer. The trial randomly assigned 731 men aged 75 years or younger (mean age, 67 years) with a PSA level less than 50 μg/L (mean, 10 μg/L) and clinically localized prostate cancer to radical prostatectomy versus watchful waiting. One third of participants were black. On the basis of PSA level, Gleason score, and tumor stage, approximately 43% had low-risk tumors, 36% had intermediate-risk tumors, and 21% had high-risk tumors. After a median follow-up of 10 years, prostate cancer–specific or all-cause mortality did not statistically significantly differ between men treated with surgery versus observation (absolute risk reduction, 2.7% [CI, -1.3% to 6.2%] and 2.9% [CI, -4.1% to 10.3%], respectively). Subgroup analysis found that the effect of radical prostatectomy compared with observation for both overall and prostate cancer–specific mortality did not vary by patient characteristics (including age, race, health status, Charlson comorbidity index score, or Gleason score), but there was variation by PSA level and possibly tumor risk category. In men in the radical prostatectomy group with a PSA level greater than 10 μg/L at diagnosis, there was an absolute risk reduction of 7.2% (CI, 0.0% to 14.8%) and 13.2% (CI, 0.9% to 24.9%) for prostate cancer–specific and all-cause mortality, respectively, compared with men in the watchful waiting group. However, prostate cancer–specific or all-cause mortality was not reduced among men in the radical prostatectomy group with PSA levels of 10 μg/L or less or those with low-risk tumors, and potential (nonstatistically significant) increased mortality was suggested when compared with the watchful waiting group (12).
Harms of Screening and Treatment
False-positive PSA test results are common and vary depending on the PSA cutoff used and frequency of screening. After 4 PSA tests, men in the screening group of the PLCO trial had a 12.9% cumulative risk of receiving at least 1 false-positive result (defined as a PSA level greater than 4.0 μg/L and no prostate cancer diagnosis after 3 years) and a 5.5% risk of having at least 1 biopsy due to a false-positive result (47). Men with false-positive PSA test results are more likely than control participants to worry specifically about prostate cancer, have a higher perceived risk for prostate cancer, and report problems with sexual function for up to 1 year after testing (48). In 1 study of men with false-positive PSA test results, 26% reported that they had experienced moderate to severe pain during the biopsy; men with false-positive results were also more likely to have repeated PSA testing and additional biopsies during the 12 months after the initial negative biopsy (49). False-negative results also occur, and there is no PSA level that effectively rules out prostate cancer. This has, in part, led to recommendations for doing prostate biopsy at lower PSA thresholds than previously used in randomized screening trials (for example, <2.5 μg/L).
Harms of prostate biopsy reported by the Rotterdam center of the ERSPC trial include persistent hematospermia (50.4%), hematuria (22.6%), fever (3.5%), urinary retention (0.4%), and hospitalization for signs of prostatitis or urosepsis (0.5%) (50). The ProtecT study, an ongoing randomized, controlled trial evaluating the effectiveness and acceptability of treatments for men with PSA-detected, localized prostate cancer, found that 32% of men experienced pain; fever; blood in the urine, semen, or stool; infection; transient urinary difficulties; or other issues requiring clinician follow-up after prostate biopsy that they considered a “moderate or major problem.” At 7 days after biopsy, 20% of men reported that they would consider a future biopsy a “moderate or major problem” and 1.4% of men were hospitalized for complications (6). Similar findings were reported at 30 days after biopsy in a U.S. study of older, predominately white male Medicare beneficiaries (51).
The high likelihood of false-positive results from the PSA test, coupled with its inability to distinguish indolent from aggressive tumors, means that a substantial number of men undergo biopsy and are overdiagnosed with and overtreated for prostate cancer. The number of men who have biopsies is directly related to the number of men having PSA testing, the threshold PSA level used to trigger a biopsy, and the interval between PSA tests. Estimates derived from the ERSPC and PLCO trials suggest overdiagnosis rates of 17% to 50% of prostate cancer cases detected by the PSA test (3, 52, 53). Overdiagnosis is of particular concern because, although these men cannot benefit from any associated treatment, they are still subject to the harms of a given therapy. Evidence indicates that nearly 90% of U.S. men diagnosed with clinically localized prostate cancer through PSA testing have early treatment (primarily radical prostatectomy and radiation therapy) (7, 8).
Radical prostatectomy is associated with a 20% increased absolute risk for urinary incontinence and a 30% increased absolute risk for erectile dysfunction compared with watchful waiting (that is, increased 20% above a median rate of 6% and 30% above a median rate of 45%, respectively) after 1 to 10 years (9, 10). Perioperative deaths or cardiovascular events occur in approximately 0.5% or 0.6% to 3% of patients, respectively (9, 10). Comparative data on outcomes using different surgical techniques are limited; 1 population-based observational cohort study using the SEER database and Medicare-linked data found that minimally invasive or robotic radical prostatectomy for prostate cancer was associated with higher risks for genitourinary complications, incontinence, and erectile dysfunction than open radical prostatectomy (54).
Radiation therapy is associated with a 17% absolute increase in risk for erectile dysfunction (that is, increased 17% above a median rate of 50%) and an increased risk for bowel dysfunction (for example, fecal urgency or incontinence) compared with watchful waiting after 1 to 10 years; the effect on bowel function is most pronounced in the first few months after treatment (9, 10).
Localized prostate cancer is not an FDA-approved indication for androgen deprivation therapy, and clinical outcomes for older men receiving this treatment for localized disease are worse than for those who are conservatively managed (55). Androgen deprivation therapy is associated with an increased risk for impotence compared with watchful waiting (absolute risk difference, 43%), as well as systemic effects, such as hot flashes and gynecomastia (9, 10). In advanced prostate cancer, androgen deprivation therapy may generate other serious harms, including diabetes, myocardial infarction, or coronary heart disease; however, these effects have not been well-studied in men treated for localized prostate cancer. A recent meta-analysis of 8 randomized, controlled trials in men with nonmetastatic high-risk prostate cancer found that androgen deprivation therapy was not associated with increased cardiac mortality (56).
Estimate of Magnitude of Net Benefit
All but 1 randomized trial has failed to demonstrate a reduction in prostate cancer deaths with the use of the PSA test, and several—including the PLCO trial—have suggested an increased risk in screened men, potentially due to harms associated with overdiagnosis and overtreatment. In a prespecified subgroup of men aged 55 to 69 years in the ERSPC trial, a small (0.09%) absolute reduction in prostate cancer deaths was seen after a median follow-up of 11 years. The time until any potential cancer-specific mortality benefit (should it exist) for PSA-based screening emerges is long (at least 9 to 10 years), and most men with prostate cancer die of causes other than prostate cancer (57). No prostate cancer screening study or randomized trial of treatment of screen-detected cancer has demonstrated a reduction in all-cause mortality through 14 years of follow-up.
The harms of PSA-based screening for prostate cancer include a high rate of false-positive results and accompanying negative psychological effects, high rate of complications associated with diagnostic biopsy, and—most important—a risk for overdiagnosis coupled with overtreatment. Depending on the method used, treatments for prostate cancer carry the risk for death, cardiovascular events, urinary incontinence, erectile dysfunction, and bowel dysfunction. Many of these harms are common and persistent. Given the high propensity for physicians and patients to elect to treat screen-detected cancer, limiting estimates of the harms of PSA testing to the harms of the blood test alone, without considering other diagnostic and treatment harms, does not reflect current clinical practice in the United States.
The mortality benefits of PSA-based prostate cancer screening through 11 years are, at best, small and potentially none, and the harms are moderate to substantial. Therefore, the USPSTF concludes with moderate certainty that the benefits of PSA-based screening for prostate cancer, as currently used and studied in randomized, controlled trials, do not outweigh the harms.
How Does Evidence Fit With Biological Understanding?
Prostate-specific antigen–based screening and subsequent treatment, as currently practiced in the United States, presupposes that most asymptomatic prostate cancer cases will ultimately become clinically important and lead to poor health outcomes and that early treatment effectively reduces prostate cancer–specific and overall mortality. However, long-term, population-based cohort studies and randomized treatment trials of conservatively managed men with localized prostate cancer do not support this hypothesis. A review of the Connecticut Tumor Registry, which was initiated before the PSA screening era, examined the long-term probability of prostate cancer death among men (median age at diagnosis, 69 years) whose tumors were mostly incidentally identified at the time of transurethral resection or open surgery for benign prostatic hyperplasia. Men received observation alone or early or delayed androgen withdrawal therapy. After 15 years of follow-up, the prostate cancer mortality rate was 18 deaths per 1000 person-years. For men with well-differentiated prostate cancer, it was 6 deaths per 1000 person-years; far more of these men had died of causes other than prostate cancer (75% vs. 7%) (58). An analysis of the SEER database after the widespread introduction of PSA-based screening examined the risk for death in men with localized prostate cancer who did not have initial attempted curative therapy. The 10-year prostate cancer mortality rate for well- or moderately-differentiated tumors among men aged 66 to 69 years at diagnosis was 0% to 7%, depending on tumor stage, versus 0% to 22% for other causes. The relative proportion of deaths attributable to other causes compared with prostate cancer increased substantially with age at prostate cancer diagnosis (59). In the only randomized, controlled trial comparing early intervention versus watchful waiting that included men primarily detected by PSA testing, prostate cancer mortality at 12 years or more was infrequent (7%) and did not differ between men randomly assigned to surgery versus observation (12).
Update of Previous USPSTF Recommendation
This recommendation replaces the 2008 recommendation (38). Whereas the USPSTF previously recommended against PSA-based screening for prostate cancer in men aged 75 years and older and concluded that the evidence was insufficient to make a recommendation in younger men, the USPSTF now recommends against PSA-based screening for prostate cancer in all age groups.
Recommendations of Others
The American Urological Association recommends that PSA screening, in conjunction with a digital rectal examination, should be offered to asymptomatic men aged 40 years or older who wish to be screened, if estimated life expectancy is greater than 10 years (60). It is currently updating this guideline (61). The American Cancer Society emphasizes informed decision making for prostate cancer screening: men at average risk should receive information beginning at age 50 years, and black men or men with a family history of prostate cancer should receive information at age 45 years (62). The American College of Preventive Medicine recommends that clinicians discuss the potential benefits and harms of PSA screening with men aged 50 years or older, consider their patients' preferences, and individualize screening decisions (63). The American Academy of Family Physicians is in the process of updating its guideline, and the American College of Physicians is currently developing a guidance statement on this topic.
Appendix: U.S. Preventive Services Task Force
Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized* are Virginia A. Moyer, MD, MPH, Chair (Baylor College of Medicine, Houston, Texas); Michael L. LeFevre, MD, MSPH, Co-Vice Chair (University of Missouri School of Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Sinai School of Medicine, New York, New York; James J. Peters Veterans Affairs Medical Center, Bronx, New York); Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens, Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Adelita Gonzales Cantu, RN, PhD (University of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania); Joy Melnikow, MD, MPH (University of California, Davis, Sacramento, California); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); Douglas K. Owens, MD, MS (Stanford University, Stanford, California); Carolina Reyes, MD, MPH (Virginia Hospital Center, Arlington, Virginia); and Timothy J. Wilt, MD, MPH (University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota). Former USPSTF members who contributed to the development of this recommendation include Ned Calonge, MD, MPH, and Rosanne Leipzig, MD, PhD.
* For a list of current Task Force members, go to http://www.uspreventiveservicestaskforce.org/about.htm.
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Source: This article was first published in Annals of Internal Medicine (Ann Intern Med 2012;22 May).
AHRQ Publication No. 12-05160-EF-2
Current as of May 2012
U.S. Preventive Services Task Force. Screening for Prostate Cancer: Final Recommendation Statement. AHRQ Publication No. 12-05160-EF-2. http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatefinalrs.htm