PSA and prostate cancer

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Draft Recommendation Statement

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The U.S. Preventive Services Task Force will be accepting comments on this draft recommendation statement beginning on Tuesday, October 11, 2011.

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific clinical preventive services for patients without related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

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Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement
DRAFT

Summary of Recommendation and Evidence

The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for prostate cancer.This is a grade D recommendation.

This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history. The Task Force did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer. This recommendation also does not consider the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.

Rationale

Importance

Prostate cancer is the most commonly diagnosed nonskin cancer in men in the United States, with a lifetime risk of diagnosis currently estimated at 15.9%. Most cases of prostate cancer have a good prognosis, but some are aggressive; the lifetime risk of dying from prostate cancer is 2.8%. Prostate cancer is rare before age 50 years and very few men die of prostate cancer before age 60 years. The majority of deaths due to prostate cancer occur after age 75 years (1).

Detection

Contemporary recommendations for prostate cancer screening all incorporate the measurement of serum PSA levels; other methods of detection such as digital rectal examination or ultrasonography may be included. The evidence is convincing that PSA-based screening programs result in the detection of many cases of asymptomatic prostate cancer. The evidence is also convincing that the majority of men who have asymptomatic cancer detected by PSA screening have a tumor that meets histological criteria for prostate cancer, but the tumor either will not progress or is so indolent and slow-growing that it will not affect the man’s lifespan or cause adverse health effects, as he will die of another cause first. The terms “overdiagnosis” or “pseudodisease” are used to describe both of these situations. It is difficult to determine the precise magnitude of overdiagnosis associated with any screening and treatment program. The rate of overdiagnosis of prostate cancer increases as the number of men subjected to biopsy increases. The number of cancer cases that could be detected in a screened population is large; a single study in which men eligible for PSA screening underwent biopsy irrespective of PSA level detected cancer in nearly 25% of men (2). The rate of overdiagnosis will also depend upon the age at which diagnosis is made. Cancer diagnosis in older men with shorter life expectancies is much more likely to be overdiagnosis.

Benefits of Detection and Early Intervention

The primary goal of prostate cancer screening is to reduce deaths due to prostate cancer, and a reduction in either prostate cancer death or overall mortality was the primary outcome addressed in all prostate cancer screening studies assessed by the Task Force. The evidence is convincing that for men aged 70 years and older, screening has no mortality benefit. For men aged 50 to 69 years, the evidence is convincing that the reduction in prostate cancer mortality 10 years after screening is small to none. Screen-detected cancer can fall into one of three categories: cancer that results in death in spite of early diagnosis and treatment, cancer for which early diagnosis and treatment improves survival, and cancer for which the outcome would be good in the absence of screening due to indolent tumors. Ninety-five percent of men with PSA-detected cancer who are followed for 12 years do not die from that cancer, even in the absence of definitive treatment (3). The possibility is very small that death from prostate cancer is less likely in men whose prostate cancer is detected by PSA screening rather than waiting for clinical detection, and the time to any potential benefit is long. No prostate cancer screening study, individually or combined with other screening studies, or study of treatment of screen-detected cancer, has demonstrated a reduction in all-cause mortality.

Harms of Detection and Early Intervention

Harms related to screening. Convincing evidence demonstrates that the PSA test often produces false-positive results (approximately 80% of positive PSA tests are false positives when a cut-off point of 2.5–4.0 ng/mL is used) (4). The evidence is adequate that false-positive PSA tests are associated with negative psychological effects, including a persistent worry about prostate cancer. Men that have a false-positive test are more likely to have additional testing, including biopsies, in the following year than those who have a negative test (5). Over a 10-year period, approximately 15%–20% of men will have an abnormal result that triggers a biopsy, depending upon the PSA threshold and testing interval used (4). The evidence is convincing that prostate biopsy causes fever, infection, bleeding, and transient urinary difficulty in some men (about 68 events per 10,000 biopsies), as well as pain (6, 7).

The evidence is also convincing that PSA-based screening leads to substantial overdiagnosis of prostate tumors. As noted above, overdiagnosis occurs when, despite a tumor’s pathological characteristics, it does not progress to cause illness or death in a man’s lifetime. Overdiagnosis is of particular concern in prostate cancer because a high percentage of men are treated at the time of diagnosis, and a man with an indolent lesion may experience any of the associated harms of a therapy but cannot benefit, by the very nature of the condition, from that intervention.

The USPSTF considered the magnitude of these screening-associated harms to be at least small.

Harms related to treatment of screen-detected cancer. Adequate evidence shows that nearly 90% of men with PSA-detected prostate cancer undergo early treatment with surgery, radiation, or androgen deprivation therapy. Adequate evidence also shows that up to 5 in 1,000 men will die within 1 month of prostate cancer surgery and between 10 and 70 men will have serious complications but survive. Radiotherapy and surgery result in adverse effects, including urinary incontinence and erectile dysfunction in at least 200 to 300 of 1,000 men treated with these therapies. Radiotherapy is also associated with bowel dysfunction (6, 8).

Some clinicians have utilized androgen deprivation therapy for early-stage prostate cancer, particularly in older men, despite the fact that this is not an U.S. Food and Drug Administration (FDA)-approved indication and it has not been shown to improve clinical outcomes in localized prostate cancer. Adequate evidence shows that androgen deprivation therapy for localized prostate cancer is associated with erectile dysfunction (in about 400 out of 1,000 men treated), as well as gynecomastia and hot flashes. In addition, in patients given androgen deprivation therapy for advanced prostate cancer, some evidence suggests an increased risk of other serious harms, such as myocardial infarction and coronary heart disease, diabetes, and fractures, although these harms have not been well studied in men treated for localized prostate cancer (6, 8).

PSA-based screening for prostate cancer results in the diagnosis and treatment of many more cancer cases than would occur without screening; thus, screening results in many more men who are subject to treatment-related adverse events. A sizable proportion of the additional cancer cases that are detected with screening represent overdiagnosis. Overdiagnosed men cannot reap benefit from the intervention, but are subject to all of the related risks of surgery, radiation, or hormone therapy. As such, overtreatment represents a critical consequence of PSA-based screening as currently utilized, most notably in the context of a high propensity for physicians and patients to elect to treat most cases of screen-detected cancer. Even for those men whose screen-detected cancer would otherwise have been later identified symptomatically, a high proportion experience the same outcome, and are thus subjected to the harms of treatment for a much longer period of time (3, 9). The evidence is convincing that PSA-based screening for prostate cancer results in considerable overtreatment.

The USPSTF considered the magnitude of these treatment-associated harms to be at least moderate.

USPSTF Assessment

The common perception that PSA-based early detection of prostate cancer prolongs lives is not supported by the scientific evidence. The findings of the two largest trials highlight the uncertainty that remains about the precise effect that screening may have, and demonstrate that if any benefit does exist, it is very small after 10 years. The European trial found a statistically insignificant 0.06% absolute reduction in prostate cancer deaths for men aged 50 to 74 years, while the U.S. trial found a statistically insignificant 0.03% absolute increase in prostate cancer deaths (6, 7). A meta-analysis of all published trials found no statistically significant reduction in prostate cancer deaths (10). At the same time, overdiagnosis and overtreatment of prostatic tumors that will not progress to cause illness or death are frequent consequences of PSA-based screening. Although about 90% of men are currently treated for PSA-detected prostate cancer in the United States—usually with surgery or radiotherapy—the vast majority of men who are treated do not have prostate cancer death prevented or lives extended from that treatment, but are subjected to significant harms.

The USPSTF concludes that there is moderate certainty that the harms of PSA-based screening for prostate cancer outweigh the benefits.

Clinical Considerations

Patient Population Under Consideration

This recommendation applies to men in the general U.S. population. Older age is the strongest risk factor for development of prostate cancer. However, a more favorable balance of benefits and harms for PSA-based screening does not accompany this increase in risk. Across age ranges, African American men and men with a family history of prostate cancer have an increased risk for developing and dying from prostate cancer compared with other men. However, the observed risk differences for race/ethnicity or family history are each relatively small when compared with the risk differences seen with increasing age (1), and there are no data that suggest that the net benefit of PSA-based screening is altered by race or family history.

The USPSTF did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer. This recommendation also does not include the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.

Screening Tests

PSA-based screening in men aged 50 to 74 years has been evaluated in five unique randomized, controlled trials of single or interval PSA testing with various PSA cut-off points and screening intervals, along with other screening modalities such as digital rectal examination or transrectal ultrasonography (4, 11-14). None of these trials has shown a statistically significant prostate cancer mortality benefit in all enrolled men; most demonstrated a trend toward harm in the screened arm. Two meta-analyses also have not demonstrated a benefit of PSA screening on prostate cancer-specific or overall mortality (10, 15).

The U.S. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) found a nonstatistically significant increase in prostate cancer mortality in the screened group after a median followup of 11.5 years, with results consistently favoring the nonscreened population, even after 11 years of followup (11).

Considering the findings of the two largest trials, the effect of PSA-based screening on death from prostate cancer after 10 years may range from a 0.03% absolute risk increase to a 0.06% absolute risk reduction (6, 7). Screening tests or programs that do not incorporate PSA testing, including digital rectal examination alone, have not been evaluated adequately in controlled studies.

Treatment

Primary management strategies for PSA-detected prostate cancer include watchful waiting (observation and physical examination with palliative treatment of symptoms), active surveillance (periodic monitoring with PSA tests, physical examinations, and repeated prostate biopsy) with conversion to potentially curative treatment at the sign of disease progression or worsening prognosis, and surgery or radiation therapy (17). There is no consensus regarding the optimal treatment of localized disease. From 1986 through 2005, PSA-based screening likely resulted in approximately 1 million additional U.S. men being treated with surgery, radiation therapy, or both compared with before the test was introduced (18).

In the Scandinavian Prostate Cancer Group (SPCG)-4 trial, surgical management of localized, clinically-detected prostate cancer was associated with about a 6% absolute reduction in prostate cancer and all-cause mortality at 12–15 years’ followup; benefit appeared to be limited to men younger than age 65 years (9). Preliminary findings from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) show that after 12 years, intention to treat with radical prostatectomy resulted in nonstatistically significant differences in disease-specific and all-cause mortality compared with observation that were less than 3% in absolute terms, in men with localized prostate cancer detected in the early PSA era (3).

Up to 0.5% of men will die within 30 days of undergoing radical prostatectomy, and 3%–7% will have serious surgical complications. Compared with men who choose watchful waiting, an additional 20% to 30% or more of men treated with radical prostatectomy will experience impotence, urinary incontinence, or both after 1 to 10 years. Radiation therapy is also associated with increases in erectile, bowel, and bladder dysfunction (6, 8).

Other Considerations

Implementation

While the USPSTF discourages the use of screening tests for which the benefits do not outweigh the harms in the target population, it recognizes the common use of PSA screening in practice today and understands that some men will continue to request and some physicians will continue to offer screening. An individual man may choose to be screened because he places a higher value on the possibility of benefit, however small, than the known harms that accompany screening and treatment of screen-detected cancer, particularly the harms of overdiagnosis and overtreatment. This decision should be an informed decision, preferably made in consultation with a regular care provider. No man should be screened without his understanding and consent; community-based and employer-based screening that does not allow an informed choice should be discontinued.

Research Needs and Gaps

Because the balance of benefits and harms of prostate cancer screening is heavily influenced by overdiagnosis and overtreatment, research is necessary to identify ways to reduce the occurrence of these events, including evaluating the effect of altering PSA thresholds for an abnormal test or biopsy on false-positive rates and the detection of indolent disease. Similarly, new screening modalities must improve discriminatory accuracy between indolent disease and disease that is likely to clinically progress, thus reducing the number of men who require biopsy and subsequent treatment for disease that has a favorable prognosis without intervention. Research is also needed to compare the long-term benefits and harms of immediate treatment versus observation with delayed intervention in men with screen-detected prostate cancer. Two randomized, controlled trials—the PIVOT trial (19) and the U.K. Prostate Testing for Cancer and Treatment study (20)—are studying this issue. Preliminary results from the PIVOT trial potentially support raising the PSA threshold for recommending a biopsy and making treatment decisions in men subsequently diagnosed with prostate cancer.

Accurately ascertaining cause of death in older individuals can be problematic; as such, basing clinical recommendations on disease-specific mortality in the absence of an effect on all-cause mortality may not completely capture the health impact and goals of a screening and treatment program. Additional research is required to better assess and improve the reliability of prostate cancer mortality as a valid outcome measure in clinical trials, as well as the best application of the concomitant use of all-cause mortality.

Two large randomized, controlled trials of 5-alpha-reductase inhibitors (finasteride, dutasteride) have shown that these drugs reduce the risk of being diagnosed with prostate cancer in men receiving regular PSA tests. However, the observed reduction resulted from a decreased incidence of low-grade prostate cancer alone (Gleason score <6).The FDA has not approved finasteride and dutasteride for the prevention of prostate cancer, concluding that the drugs do not possess a favorable risk-benefit profile for this indication. The FDA cited associated adverse effects, including loss of libido and erectile dysfunction, but most importantly, it noted that in both trials there was an absolute increase in the incidence of high-grade prostate cancer in men randomized to finasteride or dutasteride compared with controls (21). Additional research would be useful to better understand the association of these drugs with the development of high-grade prostatic lesions, to determine the impact of 5-alpha-reductase inhibitors (or other potential preventive agents) on prostate cancer mortality and identify the population of men that might benefit most from prostate cancer prevention.

Discussion

Burden of Disease

An estimated 217,730 U.S. men received a prostate cancer diagnosis in 2010, and an estimated 32,050 men died from the disease (22). The average age of diagnosis was 67 years and the median age of death from prostate cancer from 2003 through 2007 was 80 years; 71% of deaths occurred in men older than age 75 years (1). African American men have a substantially higher prostate cancer incidence rate than white men (231.9 vs.146.3 cases per 100,000 men), and more than twice the prostate cancer mortality rate (56.3 vs. 23.6 deaths per 100,000 men, respectively) (22).

Prostate cancer is a clinically heterogeneous disease. Autopsy studies have shown that approximately one third of men aged 40–60 years have histologically evident prostate cancer (23); the proportion increases to as high as three fourths in men older than age 85 years (24). Most of these cases represent microscopic, well-differentiated lesions that are unlikely to be of clinical importance. The detection of lesions that are unlikely to be of clinical significance increases with frequency of PSA testing, lower thresholds to indicate an abnormal result, and the number of core biopsies obtained per diagnostic workup.

Scope of Review

The previous evidence update, performed 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 age 75 years. In men aged 75 years or older, the USPSTF found adequate evidence that the incremental benefits of treatment for screen-detected prostate cancer are small to none, and that the harms of screening and treatment outweigh any potential benefits (25). After the publication of initial mortality results from two 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 performed (7). Additionally, the USPSTF requested a separate systematic review of the benefits and harms of treatment for localized prostate cancer (8).

Accuracy of Screening

The conventional PSA cut-off point of 4.0 ng/mL detects many cases of prostate cancer; however, some cases will be missed. Using a lower cut-off point detects more cases of cancer, but at the cost of labeling more men as potentially having cancer. For example, lowering the PSA cut-off point to 2.5 ng/mL would more than double the number of U.S. men aged 40 to 69 years with abnormal results (26), and the majority of these would be false-positive results. It also increases the likelihood of detection of indolent tumors with no clinical importance. Conversely, raising the PSA cut-off point to >10.0 ng/mL would reduce the number of men aged 50 to 69 years with abnormal results from approximately 1.2 million to around 352,000 individuals (26). There is no PSA cut-off point at which a man can be guaranteed to be free from prostate cancer (27).

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 performed during a single procedure; the more biopsies performed, 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 cut-off points, 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 utilizing PSA velocity in the absence of other indications could lead to 1 in 7 men undergoing a biopsy with no increase in predictive accuracy (28).

Effectiveness of Early Detection and Treatment

Two poor-quality 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 (13, 14). A third poor-quality trial from Canada showed similar results when an intention-to-screen analysis was used (12). The screening protocols for these trials varied; all included one or more PSA tests with cut-off points ranging from 3.0 to 10.0 ng/mL, in addition to digital rectal examination and/or transrectal ultrasonography.

The prostate component of the PLCO trial randomized 76,693 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 utilized a PSA cut-off point of 4.0 ng/mL. Diagnostic followup for positive screening tests and treatment choices were made by the participant and his personal physician; 90% of men with a prostate cancer diagnosis received active treatment (surgery, radiation, and/or hormonal therapy). After 7 years (complete followup), a nonstatistically significant trend toward increased prostate cancer mortality was seen in the screened arm (rate ratio [RR], 1.14 [95% CI, 0.75–1.70]) compared with men in the control arm. Similar findings were observed after 10 years. The primary criticism of this study relates to the high contamination rate; approximately 50% of men in the control arm received at least one PSA test during the study, although the investigators specifically increased both the number of screening intervals and the duration of followup to attempt to compensate for the contamination effects. About 40% of participants had received a PSA test in the 3 years prior to enrollment, though subgroup analyses stratified by history of PSA testing prior to study entry did not reveal differential effects on prostate cancer mortality rates (11).

The ERSPC trial randomized 182,000 men aged 50 to 74 years from seven European countries to PSA testing every 2 to 7 years or to usual care. PSA cut-off points ranged from 2.5 to 4.0 ng/mL, depending on study center (one center utilized a cut-off point of 10.0 ng/mL for several years). Sixty-six percent of men who received a prostate cancer diagnosis chose immediate treatment—surgery, radiation therapy, hormonal therapy, or some combination. After a median followup of 9 years, there was no statistically significant difference in prostate cancer mortality for all enrolled men (RR, 0.85 [95% CI, 0.73 to 1.00]). In a prespecified subgroup analysis limited to men aged 55 to 69 years, a statistically significant reduction in prostate cancer deaths was seen (RR, 0.80 [95% CI, 0.65–0.98]). Subgroup analyses demonstrated a nonsignificant trend toward increased prostate cancer mortality in screened men aged 50 to 54 and 70 to 74 years. The observed difference in prostate cancer mortality for the subgroup of men aged 55 to 69 years first emerged at approximately 9 years (the median length of followup for the trial); thus, the effect size may change (increase or disappear) with further followup. The authors estimated that 1,410 men would need to be screened and 48 additional men would need to be treated to prevent one prostate cancer death (4). Primary criticisms of this study relate to inconsistencies in age requirements, screening intervals, PSA thresholds, and enrollment procedures utilized among the study centers, as well as the exclusion of data from two study centers in the analysis. There is also concern that differential treatments between the study and control groups may have had an impact on outcomes. Of note, men in the screened group were more likely to have been treated in a university setting than men in the control group, and a control subject with high-risk prostate cancer was more likely than a screened subject to receive radiotherapy, expectant management, or hormonal therapy instead of radical prostatectomy (29).

After the publication of the ERSPC results, a single center from within that trial (Göteborg, Sweden) reported data separately. At this center, 20,000 men aged 50 to 64 years were randomized to an invitation to screening with PSA every 2 years or to usual care; median followup was 14 years. A PSA cut-off point of 3.0 ng/mL was initially used but was lowered to 2.5 ng/mL. Fifty-eight percent of participants diagnosed with prostate cancer in the screened arm chose immediate treatment. The rate ratio for prostate cancer mortality in the screened arm was 0.56 (95% CI, 0.39–0.82); the absolute risk reduction was 0.34% (16). Outcomes for 60% of this center’s participants had previously been reported as part of the full ERSPC publication, and comparative mortality rates are not available for any other individual study center, making it somewhat challenging to interpret these findings in context. An analysis in the overall ERSPC publication demonstrated that, of all participating countries, Sweden demonstrated the most favorable effect on the combined prostate cancer mortality reduction estimate, and that the overall study results for the “core” population were no longer statistically significant when findings from Sweden were excluded (4). None of the other centers published individual results.

Two meta-analyses found no statistically significant differences in prostate cancer mortality (RR, 0.88 [95% CI, 0.71–1.09] and 0.95 [95% CI, 0.85–1.07]) or overall mortality (RR, 0.99 [95% CI, 0.98–1.01] and 1.00 [95% CI, 0.98–1.02]) in men undergoing PSA-based screening compared with controls (10, 15).

There have been few randomized, controlled trials comparing prostate cancer treatments with watchful waiting. A randomized, controlled trial of 695 men with localized prostate cancer (SPCG-4) reported an 11.7% (95% CI, 4.8–18.6) absolute reduction in the risk of distant metastases in patients assigned to radical prostatectomy versus watchful waiting after 15 years’ followup. An absolute reduction in prostate cancer mortality (6.1% [95% CI, 0.2–12]) and a trend toward a reduction in all-cause mortality (6.6% [95% CI, −1.3 to 14.5]) were also observed over this time period. Subgroup analysis suggests that the benefits of prostatectomy may have been restricted to younger (<65 years) men, but were seen in men with PSA values less than 10 and Gleason histological scores of 6 or less. Additionally, radical prostatectomy reduced the use of hormonal therapy by 23.8%. The applicability of these findings to cancer detected via PSA-based screening is limited, as only 5% of participants were diagnosed with prostate cancer via some form of screening, 88% had palpable tumors, and more than 40% of participants presented with symptoms (9, 30).

Preliminary results from the PIVOT trial have become available. The PIVOT trial was composed of men with prostate cancer detected after the initiation of widespread PSA testing and took place within the United States. The trial randomized 731 men aged 75 years or younger (mean age, 67 years) with a PSA value less than 50 ng/mL (mean PSA value, 10 ng/mL) and clinically localized prostate cancer to radical prostatectomy versus watchful waiting. One third of participants were African American. Based upon PSA value, 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 followup of 10 years, there were no statistically significant differences in prostate cancer-specific or all-cause mortality between men treated with surgery versus observation (absolute risk reduction, 2.7% [95% CI, −1.3 to 6.2] and 2.9% [95% 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 mortality did not vary by patient characteristics (including age, race, health status and comorbidities, or Gleason histologic score), but there was variation by PSA level and possibly tumor risk category. In men in the radical prostatectomy group with a PSA value greater than 10 ng/mL at diagnosis, there was an absolute risk reduction of 7.2% (95% CI, 0.0–14.8) and 13.2% (95% CI, 0.9–24.9) for prostate cancer-specific and all-cause mortality, respectively, compared with men in the watchful waiting group. However, men in the radical prostatectomy group with PSA values of 10 ng/mL or less, or those with low-risk tumors, did not experience a reduction in prostate cancer-specific or all-cause mortality, and there was a potential suggestion (nonstatistically significant) of increased harm when compared with the watchful waiting arm (3).

Harms of Screening and Treatment

False-positive PSA test results are common and vary depending on the PSA cut-off point and frequency of screening. After four PSA tests, men in the screening arm of PLCO had a 12.9% cumulative risk of receiving at least one false-positive result (defined as PSA >4.0 ng/mL and no prostate cancer diagnosis after 3 years) and a 5.5% risk of having at least one biopsy due to a false-positive result (31). Men with false-positive PSA test results are more likely to worry specifically about prostate cancer, have a higher perceived risk for prostate cancer, and report problems with sexual function compared with control participants for up to 1 year after testing (32). In one 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 undergo repeated PSA testing and additional biopsies during the 12 months following the initial negative biopsy (33).

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%) (34). Pain and discomfort are also associated with prostate biopsy. The documented range varies widely, from around one quarter to more than 90% of men, depending on the definition of “pain/discomfort” utilized, use of analgesia, number of core biopsies taken (as taking more samples appears to be associated with greater pain), and age of the patient (as younger men have reported higher levels and frequencies of pain than older individuals) (35).

The low specificity of the PSA test coupled with its inability to distinguish indolent from aggressive tumors means that a substantial number of men are being overdiagnosed with prostate cancer. Estimates derived from the ERSPC trial suggest overdiagnosis rates of 48% to 67% of prostate cancer cases detected by the PSA test (36, 37). 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 men diagnosed with clinically localized prostate cancer through PSA testing undergo early treatment—primarily radical prostatectomy and radiation therapy.

Radical prostatectomy is associated with a 20% increased absolute risk of urinary incontinence and a 30% increased absolute risk of impotence compared with watchful waiting (i.e., increased 20% over a median rate of 6% and 30% over a median rate of 45%, respectively) after 1 to 10 years. Perioperative deaths or cardiovascular events occur in about 0.5% and 0.6%–3% of patients (6, 8). Comparative data on outcomes using different surgical techniques are limited; one population-based observational cohort study using U.S. Surveillance, Epidemiology, and End Results (SEER) and Medicare linked data found that minimally invasive/robotic radical prostatectomy for prostate cancer was associated with higher risks for genitourinary complications, incontinence, and erectile dysfunction than open radical prostatectomy (38).

Radiation therapy is associated with a 17% absolute increase in risk of impotence (i.e., increased 17% over a median rate of 50%) and an increased risk of bowel dysfunction compared with watchful waiting after 1 to 10 years; the effect is most pronounced in the first few months after treatment (6, 8).

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 (39). Androgen deprivation therapy is associated with an increased risk of impotence compared with watchful waiting (absolute risk difference, 43%), as well as systemic effects such as hot flashes and gynecomastia (6, 8). 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.

Estimate of Magnitude of Net Benefit

No trial has shown a decrease in overall mortality with the use of PSA-based screening through 11 years of followup. Most randomized trials have 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 morbidities associated with overdiagnosis and overtreatment. In a prespecified subgroup of men aged 55 to 69 years in the ERSPC trial, a small (0.07%) absolute reduction in prostate cancer deaths was observed after a median followup of 9 years. No statistically significant effect was seen when all enrolled men (ages 50 to 74 years) were included in the analysis. The time until any potential cancer-specific mortality benefit 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 (40); as such, even among men diagnosed with prostate cancer via PSA screening, very few will have prostate cancer death prevented or their lives extended as a result of screening.

The harms of PSA-based screening for prostate cancer include a high rate of false-positive results and accompanying negative psychological effects, complications associated with diagnostic biopsy, and, most importantly, a risk for overdiagnosis coupled with overtreatment. Depending on the modality employed, treatments for prostate cancer carry the risk of death, cardiovascular events, urinary incontinence, impotence, and bowel dysfunction.

The mortality benefits of PSA-based prostate cancer screening through 10 years are small to none, while the harms are moderate to substantial. Therefore, the USPSTF concludes with moderate certainty that PSA-based screening for prostate cancer, as currently utilized and studied in randomized, controlled trials, has no net benefit.

How Does Evidence Fit With Biological Understanding?

PSA-based screening and subsequent treatment, as currently practiced in the United States, presupposes that the majority of asymptomatic prostate cancer cases will ultimately become clinically important and lead to poor health outcomes. However, long-term, population-based cohort studies of conservatively managed men with localized prostate cancer do not support this hypothesis. A review of the Connecticut Tumor Registry—initiated before the PSA 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 followup, the overall risk of dying from prostate cancer was 18 deaths per 1,000 person-years. For men with well-differentiated prostate cancer, it was 6 deaths per 1,000 person-years; far more of these men had died from causes other than prostate cancer (75% vs. 7%) (41). An analysis of the SEER database after the widespread introduction of PSA-based screening examined the risk of death in men with localized prostate cancer who did not undergo initial attempted curative therapy. The 10-year prostate cancer mortality rate for well- or moderately-differentiated tumors among men aged 66–69 years at diagnosis was 0%–7%, depending on tumor stage, versus 0%–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 (42).

Update of Previous USPSTF Recommendation

This recommendation replaces the 2008 recommendation (25). 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 should be offered to men aged 40 years or older (43). The American Cancer Society emphasizes informed decisionmaking for prostate cancer: men at average risk should receive information beginning at age 50 years, while African American men or men with a family history of prostate cancer should receive information at age 45 years (44). The American College of Physicians (45) and the American College of Preventive Medicine (46) recommend that clinicians discuss the potential benefits and harms of PSA screening with men aged 50 years and older, consider their patients’ preferences, and individualize screening decisions.

Appendix: U.S. Preventive Services Task Force

Members of the U.S. Preventive Services Task Force* at the time this recommendation was drafted 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); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); 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); George J. Isham, MD, MS (HealthPartners, Minneapolis, Minnesota); Rosanne M. Leipzig, MD, PhD (Mount Sinai School of Medicine, New York, New York); Joy Melnikow, MD, MPH (University of California Davis, Sacramento, California); Bernadette Melnyk, PhD, RN (Ohio State University College of Nursing, Columbus, Ohio); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); Carolina Reyes, MD, MPH (Virginia Hospital Center, Arlington, Virginia); J. Sanford Schwartz, MD, MBA (University of Pennsylvania Medical School and the Wharton School, Philadelphia, Pennsylvania); and Timothy J. Wilt, MD, MPH (University of Minnesota Department of Medicine and Minneapolis Veteran Affairs Medical Center, Minneapolis, Minnesota). Ned Calonge, MD, MPH, a previous Task Force member, also made significant contributions to this recommendation.

* For a list of current Task Force members, go to http://www.uspreventiveservicestaskforce.org/about.htm.

Table 1: What the Grades Mean and Suggestions for Practice

Grade	Definition	Suggestions for Practice
A	The USPSTF recommends the service. There is high certainty that the net benefit is substantial.	Offer/provide this service.
B	The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.	Offer/provide this service.
C	The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.	Offer/provide this service only if other considerations support offering or providing the service in an individual patient.
D	The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.	Discourage the use of this service.
I Statement	The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.	Read “Clinical Considerations” section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.

Table 2: Levels of Certainty Regarding Net Benefit

Level of Certainty	Description
High	The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.
Moderate	The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as: the number, size, or quality of individual studies; inconsistency of findings across individual studies; limited generalizability of findings to routine primary care practice; or lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.
Low	The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: the limited number or size of studies; important flaws in study design or methods; inconsistency of findings across individual studies; gaps in the chain of evidence; findings not generalizable to routine primary care practice; or a lack of information on important health outcomes. More information may allow an estimation of effects on health outcomes.

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.

References

1. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, et al. SEER Cancer Statistics Review, 1975–2008. Bethesda, MD: National Cancer Institute; 2011. Accessed athttp://seer.cancer.gov/csr/1975_2008/index.html on 6 October 2011.
2. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-24.
3. Wilt TJ. The VA/NCI/AHRQ Cooperative Studies Program #407: Prostate cancer Intervention Versus Observation Trial (PIVOT): main results from a randomized trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. Paper presented at: 107th Annual Meeting of the American Urological Association; May 2011; Washington, DC. 
4. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-8.
5. Lin K, Lipsitz R, Miller T, Janakiraman S; U.S. Preventive Services Task Force. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:192-9.
6. Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, et al. Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2011 Oct 7. [Epub ahead of print]
7. Lin K, Croswell JM, Koenig H, Lam C, Maltz A. Prostate-Specific Antigen-Based Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Evidence Synthesis No. 90. AHRQ Publication No. 12-05160-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
8. Chou R, Dana T, Bougatsos C, Fu R, Blazina I, et al. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 91. AHRQ Publication No. 12-05161-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
9. Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364:1708-17.
10. Ilic D, O’Connor D, Green S, Wilt TJ. Screening for prostate cancer: an updated Cochrane systematic review. BJU Int. 2011;107:882-91.
11. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-9.
12. Labrie F, Candas B, Cusan L, Gomez JL, Bélanger A, et al. Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial. Prostate. 2004;59:311-8.
13. Sandblom G, Varenhorst E, Rosell J, Löfman O, Carlsson P. Randomised prostate cancer screening trial: 20 year follow-up. BMJ. 2011;342:d1539.
14. Kjellman A, Akre O, Norming U, Törnblom M, Gustafsson O. 15-year followup of a population based prostate cancer screening study. J Urol. 2009;181:1615-21.
15. Djulbegovic M, Beyth RJ, Neuberger MM, Stoffs TL, Vieweg J, et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ. 2010;341:c4543.
16. Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725-32.
17. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer.Ann Intern Med. 2008;148:435-48.
18. Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986–2005. J Natl Cancer Inst. 2009;101:1325-9.
19. Wilt TJ, Brawer MK, Barry MJ, Jones KM, Kwon Y, et al. The Prostate cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials. 2009;30:81-7.
20. Moore AL, Dimitropoulou P, Lane A, Powell PH, Greenberg DC, et al. Population-based prostate-specific antigen testing in the UK leads to a stage migration of prostate cancer.BJU Int. 2009;104:1592-8.
21. Theoret MR, Ning YM, Zhang JJ, Justice R, Keegan P, Pazdur R. The risks and benefits of 5a-reductase inhibitors for prostate-cancer prevention. N Engl J Med. 2011;365:97-9.
22. American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010. Accessed athttp://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010 on 6 October 2011.
23. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol. 1993;150:379-85.
24. Grönberg H. Prostate cancer epidemiology. Lancet. 2003;361:859-64.
25. U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-91.
26. Welch HG, Schwartz LM, Woloshin S. Prostate-specific antigen levels in the United States: implications of various definitions for abnormal. J Natl Cancer Inst. 2005;97:1132-7.
27. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005;294:66-70.
28. Vickers AJ, Till C, Tangen CM, Lilja H, Thompson IM. An empirical evaluation of guidelines on prostate-specific antigen velocity in prostate cancer detection. J Natl Cancer Inst. 2011;103:462-9.
29. Wolters T, Roobol MJ, Steyerberg EW, van den Bergh RC, Bangma CH, et al. The effect of study arm on prostate cancer treatment in the large screening trial ERSPC. Int J Cancer. 2010;126:2387-93.
30. Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group-4 randomized trial. J Natl Cancer Inst. 2008;100:1144-54.
31. Croswell JM, Kramer BS, Kreimer AR, Prorok PC, Xu JL, et al. Cumulative incidence of false-positive results in repeated, multimodal cancer screening. Ann Fam Med. 2009;7:212-22.
32. McNaughton-Collins M, Fowler FJ Jr, Caubet JF, Bates DW, Lee JM, et al. Psychological effects of a suspicious prostate cancer screening test followed by a benign biopsy result. Am J Med. 2004;117:719-25.
33. Fowler FJ Jr, Barry MJ, Walker-Corkery B, Caubet JF, Bates DW, et al. The impact of a suspicious prostate biopsy on patients’ psychological, socio-behavioral, and medical care outcomes. J Gen Intern Med. 2006;21:715-21.
34. Raaijmakers R, Kirkels WJ, Roobol MJ, Wildhagen MF, Schröder FH. Complication rates and risk factors of 5802 transrectal ultrasound-guided sextant biopsies of the prostate within a population-based screening program. Urology. 2002;60:826-30.
35. De Sio M, D’Armiento M, Di Lorenzo G, Damiano R, Perdonà S, et al. The need to reduce patient discomfort during transrectal ultrasonography-guided prostate biopsy: what do we know? BJU Int. 2005;96:977-83.
36. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102:605-13.
37. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868-78.
38. Hu JC, Gu X, Lipsitz SR, Barry MJ, D’Amico AV, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302:1557-64.
39. Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA. 2008;300:173-81.
40. Lu-Yao G, Stukel TA, Yao SL. Changing patterns in competing causes of death in men with prostate cancer: a population based study. J Urol. 2004;171:2285-90.
41. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005;293:            2095-101      .
42. Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009;302:1202-9.
43. Carroll P, Albertsen PC, Greene K, Babaian RJ, Carter HB, et al. Prostate-Specific Antigen Best Practice Statement: 2009 Update. Linthicum, MD: American Urological Assocation; 2009. Accessed at http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf on 6 October 2011.
44. Wolf AM, Wender RC, Etzioni RB, Thompson IM, D’Amico AV, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010;60:70-98.
45. American College of Physicians. Screening for prostate cancer. Ann Intern Med. 1997;126:480-4.
46. Lim LS, Sherin K; ACPM Prevention Practice Committee. Screening for prostate cancer in U.S. men: ACPM Position Statement on Preventive Practice. Am J Prev Med. 2008;34:164-70.

Current as of October 2011

---

Internet Citation:

U.S. Preventive Services Task Force. Screening for Prostate Cancer: Draft Recommendation Statement. http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/draftrecprostate.htm

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PSA & New York Times

Healthy men should no longer receive a P.S.A. blood test to screen forprostate cancer because the test does not save lives over all and often leads to more tests and treatments that needlessly cause pain,impotence and incontinence in many, a key government health panel has decided.

Well

Tara Parker-Pope answers some of the most common questions about P.S.A. testing and what the task force recommendations mean for men.

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The draft recommendation, by the United States Preventive Services Task Force and due for official release next week, is based on the results of five well-controlled clinical trials and could substantially change the care given to men 50 and older. There are 44 million such men in the United States, and 33 million of them have already had a P.S.A. test — sometimes without their knowledge — during routine physicals.

The task force’s recommendations are followed by most medical groups. Two years ago the task force recommended that women in their 40s should no longer get routine mammograms, setting off a firestorm of controversy. The recommendation to avoid the P.S.A. test is even more forceful and applies to healthy men of all ages.

“Unfortunately, the evidence now shows that this test does not save men’s lives,” said Dr. Virginia Moyer, a professor of pediatrics at Baylor College of Medicine and chairwoman of the task force. “This test cannot tell the difference between cancers that will and will not affect a man during his natural lifetime. We need to find one that does.”

But advocates for those with prostate cancer promised to fight the recommendation. Baseball’s Joe Torre, the financier Michael Milken and Rudolph W. Giuliani, the former New York City mayor, are among tens of thousands of men who believe a P.S.A. test saved their lives.

The task force can also expect resistance from some drug makers and doctors. Treating men with high P.S.A. levels has become a lucrative business. Some in Congress have criticized previous decisions by the task force as akin to rationing, although the task force does not consider cost in its recommendations.

“We’re disappointed,” said Thomas Kirk, of Us TOO, the nation’s largest advocacy group for prostate cancer survivors. “The bottom line is that this is the best test we have, and the answer can’t be, ‘Don’t get tested.’ ”

But that is exactly what the task force is recommending. There is no evidence that a digital rectal exam or ultrasound are effective, either. “There are no reliable signs or symptoms of prostate cancer,” said Dr. Timothy J. Wilt, a member of the task force and a professor of medicine at the University of Minnesota. Frequency and urgency of urinating are poor indicators of disease, since the cause is often benign.

The P.S.A. test, routinely given to men 50 and older, measures a protein — prostate-specific antigen — that is released by prostate cells, and there is little doubt that it helps identify the presence of cancerous cells in the prostate. But a vast majority of men with such cells never suffer ill effects because their cancer is usually slow-growing. Even for men who do have fast-growing cancer, the P.S.A. test may not save them since there is no proven benefit to earlier treatment of such invasive disease.

As the P.S.A. test has grown in popularity, the devastating consequences of the biopsies and treatments that often flow from the test have become increasingly apparent. From 1986 through 2005, one million men received surgery, radiation therapy or both who would not have been treated without a P.S.A. test, according to the task force. Among them, at least 5,000 died soon after surgery and 10,000 to 70,000 suffered serious complications. Half had persistent blood in their semen, and 200,000 to 300,000 suffered impotence, incontinence or both. As a result of these complications, the man who developed the test, Dr. Richard J. Ablin, has called its widespread use a “public health disaster.”

One in six men in the United States will eventually be found to have prostate cancer, making it the second most common form of cancer in men after skin cancer. An estimated 32,050 men died of prostate cancer last year and 217,730 men received the diagnosis. The disease is rare before age 50, and most deaths occur after age 75.

Not knowing what is going on with one’s prostate may be the best course, since few men live happily with the knowledge that one of their organs is cancerous. Autopsy studies show that a third of men ages 40 to 60 have prostate cancer, a share that grows to three-fourths after age 85.

P.S.A. testing is most common in men over 70, and it is in that group that it is the most dangerous since such men usually have cancerous prostate cells but benefit the least from surgery and radiation. Some doctors treat patients who have high P.S.A. levels with drugs that block male hormones, although there is no convincing evidence that these drugs are helpful in localized prostate cancer and they often result in impotence, breast enlargement and hot flashes.

Of the trials conducted to assess the value of P.S.A. testing, the two largest were conducted in Europe and the United States. Both “demonstrate that if any benefit does exist, it is very small after 10 years,” according to the task force’s draft recommendation statement.

The European trial had 182,000 men from seven countries who either got P.S.A. testing or did not. When measured across all of the men in the study, P.S.A. testing did not cut death rates in nine years of follow-up. But in men ages 55 to 69, there was a very slight improvement in mortality. The American trial, with 76,693 men, found that P.S.A. testing did not cut death rates after 10 years.

Dr. Eric Klein of the Cleveland Clinic, an expert in prostate cancer, said he disagreed with the task force’s recommendations. Citing the European trial, he said “I think there’s a substantial amount of evidence from randomized clinical trials that show that among younger men, under 65, screening saves lives.”

The task force’s recommendations apply only to healthy men without symptoms. The group did not consider whether the test is appropriate in men who already have suspicious symptoms or those who have already been treated for the disease. The recommendations will be open to public comment next week before they are finalized.

Recommendations of the task force often determine whether federal health programs likeMedicare and private health plans envisioned under the health reform law pay fully for a test. But legislation already requires Medicare to pay for P.S.A. testing no matter what the task force recommends.

Still, the recommendations will most likely be greeted with trepidation by the Obama administration, which has faced charges from Republicans that it supports rationing of health care services, which have been politically effective, regardless of the facts.

After the task force’s recommendation against routine mammograms for women under 50, Health and Human Services Secretary Kathleen Sibelius announced that the government would continue to pay for the test for women in their 40s. On Thursday, the administration announced with great fanfare that as a result of the health reform law, more people with Medicare were getting free preventive services like mammograms.

Dr. Michael Rawlins, chairman of the National Institute for Health and Clinical Excellence in Britain, said he was given a P.S.A. test several years ago without his knowledge. He then had a biopsy, which turned out to be negative. But if cancer had been detected, he would have faced an awful choice, he said: “Would I want to have it removed, or would I have gone for watchful waiting with all the anxieties of that?” He said he no longer gets the test.

But Dan Zenka, a spokesman for the Prostate Cancer Foundation, said a high P.S.A. test result eventually led him to have his prostate removed, a procedure that led to the discovery that cancer had spread to his lymph nodes. His organization supports widespread P.S.A. testing. “I can tell you it saved my life,” he said.

A version of this article appeared in print on October 7, 2011, on page A1 of the New York edition with the headline: U.S. Panel Says No To Prostate Test For Healthy Men.

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Cribado de cancer de prostata – Screening of prostaste cancer

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Editorial del NEJM 26 de Marzo 2009


In the United States, most men over the age of 50 years have had a prostate-specific–antigen (PSA) test,¹ despite the absence of evidence from large, randomized trials of a net benefit. Moreover, about 95% of male urologists and 78% of primary care physicians who are 50 years of age or older report that they have had a PSA test themselves,² a finding that suggests they are practicing what they preach. And indeed, U.S. death rates from prostate cancer have fallen about 4% per year since 1992, five years after the introduction of PSA testing.³ Perhaps the answer to the PSA controversy is already staring us in the face. At the same time, practice guidelines cite the unproven benefit of PSA screening, as well as the known side effects,^4,5 which largely reflect the high risks of overdiagnosis and overtreatment that PSA-based screening engenders.⁶
The first reports from two large, randomized trials that many observers hoped would settle the controversy appear in this issue of the Journal. In the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Andriole et al.⁷ report no mortality benefit from combined screening with PSA testing and digital rectal examination during a median follow-up of 11 years.⁸ In the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, Schröder et al.⁸ report that PSA screening without digital rectal examination was associated with a 20% relative reduction in the death rate from prostate cancer at a median follow-up of 9 years, with an absolute reduction of about 7 prostate cancer deaths per 10,000 men screened.⁸ The designs of the two trials are different and provide complementary insights.
First, one must ask, “Why were these results published now?” Neither set of findings seems definitive; that is, there was neither a clear declaration of futility in the PLCO trial nor an unambiguous net benefit in the ERSPC trial. Both studies are ongoing, with future updates promised. The report on the ERSPC trial follows a third planned interim analysis, which found a marginally significant decrease in prostate-cancer mortality after adjustment of the P value for the two previous looks in an attempt to avoid a false positive conclusion (yet apparently preserving no alpha for the planned final analysis). On the other hand, the investigators in the PLCO trial made the decision to publish their results now because of concern about the emerging evidence of net harm compared with potential benefits associated with PSA screening. Both decisions to publish now can be criticized as premature, leaving clinicians and patients to deal with the ambiguity.
The ERSPC trial is actually a collection of trials in different countries with different eligibility criteria, randomization schemes, and strategies for screening and follow-up. The report by Schröder et al. is based on a predefined core group of men between 55 and 69 years of age at study entry. Subjects were generally screened every 4 years, and 82% were screened at least once. Contamination of the control group with screening as part of usual care is not described. Biopsies were generally recommended for subjects with PSA levels of more than 3.0 ng per milliliter. It is unclear whether the clinicians and hospitals treating patients with prostate cancer differed between the two study groups.
Adjudications of causes of death were made by committees whose members were unaware of study-group assignments, though not of treatments. This point is important, since previous research has suggested that the cause of death is less likely to be attributed to prostate cancer among men receiving attempted curative treatment.⁹ Misattribution might then create a bias toward screening, since the diagnosis of more early-stage cancers in the ERSPC trial led to substantially more attempted curative treatments.
The ERSPC interim analysis revealed a 20% reduction in prostate-cancer mortality; the adjusted P value was 0.04. The estimated absolute reduction in prostate-cancer mortality of about 7 deaths per 10,000 men after 9 years of follow-up, if real and not the result of chance or bias, must be weighed against the additional interventions and burdens. The 73,000 men in the screening group underwent more than 17,000 biopsies, undoubtedly many more than did men in the control group, though the latter is not reported. Men had a substantially higher cumulative risk of receiving the diagnosis of prostate cancer in the screening group than in the control group (820 vs. 480 per 10,000 men). Diagnosis led to more treatment, with 277 versus 100 per 10,000 men undergoing radical prostatectomy and 220 versus 123 per 10,000 undergoing radiation therapy with or without hormones, respectively (tentative estimates given the unknown treatments in both groups).
Although estimates of the benefit of screening were somewhat greater for men who actually underwent testing (taking into account noncompliance) than for those who were not tested, the side effects would be proportionately higher as well. Given these trade-offs, the promise of future ERSPC analyses addressing quality of life and cost-effectiveness is welcome indeed. The ERSPC results also reemphasize the need for caution in screening men over the age of 69 years, given an early trend toward higher prostate-cancer mortality with screening in this age subgroup, although this finding may well be due to chance alone.
A final point to make about the ERSPC trial is that to the extent that the diagnosis and treatment of prostate cancer in the screening group differed from those in the control group, it becomes difficult to dissect out the benefit attributable to screening versus improved treatment once prostate cancer was suspected or diagnosed. A similar distribution of treatments among seemingly similar patients with cancer is only partially reassuring in this regard.
Despite a longer median follow-up, the PLCO trial was smaller and therefore less mature than the ERSPC trial, with 174 prostate-cancer deaths driving the power of the study, as compared with 540 such deaths in the ERSPC trial. The screening protocol was homogeneous across sites with an enrollment age of 55 to 74 years and annual PSA tests for 6 years and digital rectal examinations for 4 years, with about 85% compliance. Subjects in the screening group who had a suspicious digital rectal examination or a PSA level of more than 4.0 ng per milliliter received a recommendation for further evaluation. This strategy helped to ensure that any difference in outcome was attributable to screening, rather than downstream management. The effectiveness of screening, of course, will be determined by the effectiveness of subsequent “usual care,” but this is the same usual care that many practitioners assume has been responsible for the falling U.S. death rate from prostate cancer. Adjudication of causes of death was similar to that in the ERSPC trial.
Though the PLCO trial has shown no significant effect on prostate-cancer mortality to date, the relatively low number of end points begets a wide confidence interval, which includes at its lower margin the point estimate of effect from the ERSPC trial. Other likely explanations for the negative findings are high levels of prescreening in the PLCO population and contamination of the control group. Contamination was assessed by periodic cross-sectional surveys, with about half the subjects in the control group undergoing PSA testing by year 5. It is unclear whether these estimates reflect testing that year or since trial inception; if the former, the cumulative incidence may be even higher. The smaller difference in screening intensity between the two study groups in the PLCO trial, as compared with the ERSPC trial, is reflected in a smaller risk of overdiagnosis (23% vs. more than 70%) and a less impressive shift in cancer stage and grade distributions. Given that study-group contamination from the use of digital rectal examination was less problematic (only about 25%), ongoing results from both of these trials may necessitate rethinking the role of digital rectal examination in cancer screening.
After digesting these reports, where do we stand regarding the PSA controversy? Serial PSA screening has at best a modest effect on prostate-cancer mortality during the first decade of follow-up. This benefit comes at the cost of substantial overdiagnosis and overtreatment. It is important to remember that the key question is not whether PSA screening is effective but whether it does more good than harm. For this reason, comparisons of the ERSPC estimates of the effectiveness of PSA screening with, for example, the similarly modest effectiveness of breast-cancer screening cannot be made without simultaneously appreciating the much higher risks of overdiagnosis and overtreatment associated with PSA screening.
The report on the ERSPC trial appropriately notes that 1410 men would need to be offered screening and an additional 48 would need to be treated to prevent one prostate-cancer death during a 10-year period, assuming the point estimate is correct. And although the PLCO trial may not have the power as yet to detect a similarly modest benefit of screening, its power is already more than adequate to detect important harm through overdiagnosis. However, the implications of the trade-offs reflected in these data, like beauty, will be in the eye of the beholder. Some well-informed clinicians and patients will still see these trade-offs as favorable; others will see them as unfavorable. As a result, a shared decision-making approach to PSA screening, as recommended by most guidelines, seems more appropriate than ever.
Finally, despite these critiques, both groups of investigators deserve high praise for their persistence and perseverance: to manage such monstrous trials is a herculean task, made no easier when so many observers think the results are self-evident. Further analyses will be needed from these trials, as well as from others — such as the Prostate Cancer Intervention Versus Observation Trial (PIVOT) in the United States (ClinicalTrials.gov number, NCT00007644 [ClinicalTrials.gov] )¹⁰ and the Prostate Testing for Cancer and Treatment (PROTECT) trial in the United Kingdom (Current Controlled Trials number, ISRCTN20141297 [controlled-trials.com] )¹¹ — if the PSA controversy is finally to sleep the big sleep.
No potential conflict of interest relevant to this article was reported.

Source Information
From Massachusetts General Hospital and Harvard Medical School, Boston.

This article (10.1056/NEJMe0901166) was published at NEJM.org on March 18, 2009.
References

1. Ross LE, Berkowitz Z, Ekwueme DU. Use of the prostate-specific antigen test among U.S. men: findings from the 2005 National Health Interview Survey. Cancer Epidemiol Biomarkers Prev 2008;17:636-644. [Free Full Text]
2. Chan EC, Barry MJ, Vernon SW, Ahn C. Brief report: physicians and their personal prostate cancer-screening practices with prostate-specific antigen: a national survey. J Gen Intern Med 2006;21:257-259. [CrossRef][ISI][Medline]
3. Ries LAG, Melbert D, Krapcho M, et al. SEER cancer statistics review, 1975–2005. Bethesda, MD: National Cancer Institute, 2008. (Accessed March 6, 2009 at http://seer.cancer.gov/csr/1975_2005/.)
4. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. CA Cancer J Clin 2008;58:161-179. [Free Full Text]
5. U. S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185-191. [Free Full Text]
6. Barry MJ. Why are a high overdiagnosis probability and a long lead time for prostate cancer screening so important? J Natl Cancer Inst (in press).
7. Andriole GL, Grubb RL III, Buys SS, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-1319. [Free Full Text]
8. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-1328. [Free Full Text]
9. Newschaffer CJ, Otani K, McDonald MK, Penberthy LT. Causes of death in elderly prostate cancer patients and in a comparison nonprostate cancer cohort. J Natl Cancer Inst 2000;92:613-621. [Free Full Text]
10. Wilt TJ, Brawer MK, Barry MJ, et al. The Prostate cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials 2009;30:81-87. [CrossRef][ISI][Medline]
11. Donovan J, Hamdy F, Neal D, et al. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study. Health Technol Assess 2003;7:1-88. [Medline]

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INCREASING SAW PALMETTO EXTRACT NOT EFFECTIVE IMPROVING LOWER URINARY

ORIGINAL CONTRIBUTION

Effect of Increasing Doses of Saw Palmetto Extract on Lower Urinary Tract Symptoms: A Randomized Trial

Saw palmetto extract often is used to relieve lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH). Barry and colleagues randomly assigned 357 men with BPH-related lower urinary tract symptoms to receive saw palmetto extract or placebo for 72 weeks. 

• » Abstract 
• » Full Text 
• » Author Video/Audio Interview 

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New drugs for prostate cancer

Image via CrunchBase

By ANDREW POLLACK

Published: June 27, 2011

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A group of new drugs is promising to prolong the lives and relieve the symptoms of men with advanced prostate cancer, but could also add billions of dollars to the nation’s medical bills.

Bone-scan images before and after treatment with Cabozantinib. The dark spots are where cancer had spread to bones.

Multimedia

Interactive Feature

Promising Treatments for Prostate Cancer Patients

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Jenny Mass

Mark Moldanado, a retired postal worker in Omaha, said that Jevtana had helped keep his cancer in check.

In the last 15 months, three new drugs that extended the lives of prostate cancer patients in clinical trials have been approved by the Food and Drug Administration and several other promising medicines are in clinical trials. Before last year, only one drug had been shown to improve survival — docetaxel, which was approved in 2004.

“What a great time it is in prostate cancer,” Dr. Daniel J. George of the Duke Cancer Institute proclaimed earlier this month at the annual meeting of the American Society of Clinical Oncology.

And it’s a great time for the drug makers, with several drugs competing to fill a niche for longer-term survival. Analysts estimate that some of the new drugs, particularly Dendreon’s Provenge and Johnson & Johnson’s Zytiga, could reach annual sales of $1 billion or even much more.

The recently approved drugs and most of those in development are for cases in which the disease has spread beyond the prostate gland and is no longer held in check by hormone therapy.

Men with that late-stage cancer had a median survival of about a year and a half using docetaxel. The new drugs each added two to five months to median survival when tested in clinical trials. Doctors say that men taking more than one of the drugs in succession would be expected to live more than two years.

But the price of these drugs has already stirred concerns about the costs of care among patients, providers and insurers. For example, Provenge costs $93,000 for a course of treatment, while Zytiga costs about $5,000 a month. Another of the new drugs, Sanofi’s Jevtana, costs about $8,000 every three weeks.

With other pricey drugs on the way, said Joel Sendek, an analyst at Lazard, “We could be talking easily $500,000 per patient or more over the course of therapy, which I don’t think the system can afford, especially since 80 percent of the patients are on Medicare.”

Medicare has already fired what some analysts interpret as a warning shot over prices, conducting a yearlong inquiry into whether to pay for Provenge. In its final decision, due Thursday, Medicare is expected to pay for the drug when used according to the label.

Medicare officials denied that price was the reason for the review. But some patient advocates and politicians portrayed the review as a step toward rationing.

Private insurers are also paying only if drugs are used according to the label, according to doctors and patient advocates.

“The reality is, there’s pushback,” said Dr. Oliver Sartor of Tulane University.

Still, for now, one company’s price is prompting the next one to follow suit.

“The pricing environment is encouraging and getting better for us,” Andrew Kay, the chief executive of Algeta, told securities analysts earlier this month, after announcing that his company’s experimental drug had extended median survival nearly three months in a clinical trial.

Mr. Kay said he had initially thought that his company, which is based in Norway, would charge about $25,000 for a typical course of treatment with the drug, Alpharadin. But with the rival drug Jevtana costing about $50,000, Algeta and its partner, Bayer, are considering a higher price.

About 218,000 men in the United States get prostate cancer each year and about 32,000 die, according to the American Cancer Society.

In many cases, the cancer is caught before it has spread beyond the prostate gland and can be cured with surgery or radiation therapy.

If the cancer has spread, men usually are given drugs, particularly Abbott Laboratories’ Lupron, that suppress the body’s production of the hormone testosterone, which can fueltumor growth.

The new drugs, for now at least, are for use when this hormone-deprivation therapy has stopped working.

“This is a small subset of people with prostate cancer,” said Dr. Charles Myers, a prostate cancer specialist in private practice in Charlottesville, Va., who is a survivor of the disease himself. However, he noted, “It’s the group of people who are dying.”

Provenge was approved in April 2010 for patients whose cancer was late-stage but not yet causing many symptoms.

Once symptoms, mainly bone pain, have appeared, men are likely to receive docetaxel, a generic drug also sold by Sanofi as Taxotere .

Two other new drugs are approved for use only after docetaxel has been tried. One, Sanofi’s Jevtana, is a chemotherapy drug in the same class as docetaxel; it was approved in June 2010. The other is Johnson & Johnson’s Zytiga, approved this April.

Many patients and doctors are most enthusiastic about Zytiga and Provenge because they are alternatives to chemotherapy, which many men want to avoid because of side effects. Provenge works by training the body’s immune system to fight the tumor.

Zytiga is a new form of hormone therapy. While Lupron mainly blocks production of testosterone by the testes, there is still some hormone produced by the adrenal gland or even by the tumor itself. Zytiga, by inhibiting an enzyme called CYP17, clamps down on testosterone production.

Doctors and patients say the new drugs can offer some men a decent quality of life, although they are not free of side effects. For instance, Zytiga, also known as abiraterone, can cause hypertension and liver damage and must be taken with the steroid prednisone.

Many men are likely to try several of the drugs. Mark Maldonado, a retired postal worker in Omaha, said that Jevtana had helped keep his cancer in check without debilitating side effects. But knowing that the drug would eventually stop working, he and his doctor “talked about abiraterone being the next step in our progress through the drugs.”

More competition is coming. Takeda Pharmaceutical and Medivation, a San Francisco company, are separately developing other drugs that block testosterone’s production or its effects.

Some of the most exciting advances, doctors say, are in the area of fighting the spread of prostate cancer to the bone. Such bone metastases are very common in men with advanced prostate cancer and account for most of the death and disability from the disease.

Cabozantinib, an experimental drug being developed by Exelixis, seems to be able to virtually eradicate bone metastases in some patients, at least as measured by bone scans, something no other drug has done.

Amgen won F.D.A. approval in November for Xgeva, a drug that reduces the risk of fractures and other problems caused by cancer in the bones. The drug can also delay the spread of cancer to the bones, according to the results of a more recent trial.

Dr. Christopher J. Logothetis, of the M. D. Anderson Cancer Center, predicted further progress.

“It’s beyond the individual drugs,” he said. “One sees a manual now on how to go forward.”

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5-alpha reductase inhibitors (5-ARIs): Label Change – Increased Risk of Prostate Cancer

5-alpha reductase inhibitors (5-ARIs): Label Change – Increased Risk of Prostate Cancer

Drugs in the 5-ARI class include finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn

AUDIENCE: Urology, Family Medicine, Internal Medicine

ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).

BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Proscar, Avodart, and Jalyn are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Propecia is approved to treat male pattern hair loss.

RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information.

Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online:www.fda.gov/MedWatch/report.htm1
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm

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