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Screening for prostate cancer
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Screening for prostate cancer
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Literature review current through: Sep 2017. | This topic last updated: Sep 14, 2017.

INTRODUCTION — Prostate cancer is common and a frequent cause of cancer death. In the United States, prostate cancer is the most commonly diagnosed visceral cancer; in 2017, there are expected to be approximately 161,000 new prostate cancer diagnoses and approximately 26,700 prostate cancer deaths [1]. Prostate cancer is second only to nonmelanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in United States men. Worldwide, there are an estimated 1,600,000 new cases of prostate cancer and 366,000 prostate cancer deaths annually, making it the most commonly diagnosed cancer in men and the seventh leading cause of male cancer death [2].

For an American male, the lifetime risk of developing prostate cancer is 16 percent, but the risk of dying of prostate cancer is only 2.9 percent [3]. Many more cases of prostate cancer do not become clinically evident, as indicated in autopsy series, where prostate cancer is detected in approximately 30 percent of men age 55 and approximately 60 percent of men by age 80 [4]. These data suggest that prostate cancer often grows so slowly that most men die of other causes before the disease becomes clinically advanced.

Prostate cancer survival is related to many factors, especially the extent of tumor at the time of diagnosis. The five-year relative survival among men with cancer confined to the prostate (localized) or with just regional spread is 100 percent, compared with 29.3 percent among those diagnosed with distant metastases [3]. While men with advanced stage disease may benefit from palliative treatment, their tumors are generally not curable.

Thus, a screening program that could accurately identify asymptomatic men with aggressive localized tumors might be expected to substantially reduce prostate cancer morbidity, including urinary obstruction and painful metastases, and mortality.

Prostate-specific antigen (PSA) testing revolutionized prostate cancer screening. Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening by the early 1990s. Subsequently, professional societies issued guidelines supporting routine prostate cancer screening with PSA [5,6]. PSA testing led to a dramatic increase in the incidence of prostate cancer, peaking in 1992 (figure 1) [7]. The majority of these newly diagnosed cancers were clinically localized, which led to an increase in radical prostatectomy and radiation therapy, aggressive treatments intended to cure these early-stage cancers [8-11].

Prostate cancer screening is controversial, with conflicting data as to efficacy. Thus, professional society guidelines (American College of Physicians [ACP], American Cancer Society [ACS], American Urological Association [AUA], US Preventive Services Task Force [USPSTF], American Society of Clinical Oncology [ASCO]) uniformly recommend supporting men to make informed decisions about screening that reflect their personal preferences and values. In 2009, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a small absolute survival benefit with PSA screening after nine years of follow-up [12]; however, 48 additional patients would need to be diagnosed with prostate cancer to prevent one prostate cancer death. Longer-term follow-up of the ERSPC subjects showed increasing benefit of screening in reducing risks for prostate cancer mortality [13] and metastases [14]. At the same time, the large randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the United States reported no prostate cancer mortality benefit, even after 15 years of follow-up [15,16], but these negative results have been largely discounted due to methodological flaws, including a high contamination rate (PSA testing in the control arm of the study). Investigators now describe the PLCO Cancer Screening Trial as a comparison between organized versus opportunistic screening.

This topic reviews the screening tests that are available for prostate cancer, the efficacy of screening, and the recommendations of major medical associations and societies regarding screening for prostate cancer. Risk factors and the clinical manifestations and diagnosis of prostate cancer are discussed separately. (See "Risk factors for prostate cancer" and "Clinical presentation and diagnosis of prostate cancer".)

PROSTATE-SPECIFIC ANTIGEN (PSA) — Prostate-specific antigen (PSA) is a glycoprotein produced by prostate epithelial cells. PSA levels may be elevated in men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum. (See "Measurement of prostate-specific antigen".)

Studies have estimated that PSA elevations can precede clinical disease by 5 to 10 years [17,18] or even longer [19]. However, PSA is also elevated in a number of benign conditions (table 1), particularly benign prostatic hyperplasia (BPH) and prostatitis. (See "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia" and "Acute bacterial prostatitis".)

Measuring PSA — In addition to the PSA elevations seen with BPH, there are transient causes of PSA elevation (table 1), some of which are significant enough to affect the performance of PSA measurement as a screening test.

We describe PSA values in ng/mL throughout this topic, but this is equivalent to the SI units of mcg/L; that is, 4 ng/mL = 4 mcg/L. (See "Measurement of prostate-specific antigen", section on 'Causes of an elevated serum PSA'.)

PSA has a half-life of 2.2 days [20], and levels elevated by different benign conditions will have variable recovery times [21-23]. PSA testing should be deferred accordingly:

Digital rectal examination (DRE) has minimal effect on PSA levels, leading to transient elevations of only 0.26 to 0.4 ng/mL, and PSA can be measured immediately after DRE [24,25].

Ejaculation can increase PSA levels by up to 0.8 ng/mL, though levels return to normal within 48 hours [26,27]. We do not usually ask men to abstain from sexual activity prior to PSA measurement. However, if an initial measurement is high enough to potentially prompt an intervention (ie, biopsy), but close to a threshold value, it is appropriate to repeat the PSA measurement after having the man abstain from ejaculation for at least 48 hours.

Bacterial prostatitis may elevate PSA levels [28], but they generally return to baseline six to eight weeks after symptoms resolve. Asymptomatic prostatic inflammation can also elevate PSA levels [29], but this diagnosis is made on biopsy and so cannot generally be used to defer screening tests [28].

Prostate biopsy may elevate PSA levels by a median of 7.9 ng/mL within 4 to 24 hours following the procedure [21]. Levels will remain elevated for two to four weeks. Similarly, a transurethral resection of the prostate (TURP) can elevate PSA levels by a median of 5.9 ng/mL [21]. Levels will remain elevated for a median time of approximately three weeks. A screening PSA test should not be performed for at least six weeks following either of these procedures.

Acute urinary retention or recent urethral instrumentation may elevate PSA levels, but the levels can be expected to decrease by 50 percent within one to two days following resolution. A screening PSA test should not be performed for at least two weeks following an episode of acute urinary retention.

The five-alpha reductase inhibitors finasteride and dutasteride lower PSA levels. Finasteride lowers PSA levels by a median 50 percent within six months of use, though the effects can vary widely, ranging from -81 percent to +20 percent [30]; dutasteride has been reported to reduce PSA levels by 48 to 57 percent [31]. Some experts recommend doubling the measured PSA value before interpreting the result for patients on finasteride or dutasteride [32-34]. Longitudinal results from the Prostate Cancer Prevention Trial suggest that PSA values be corrected by a factor of 2 for the first two years of finasteride therapy, and by 2.5 for longer-term use [35]. Results from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial suggested that a rise in PSA levels while on dutasteride is associated with a higher risk for prostate cancer [34,36,37].

Test performance — Determining the accuracy of PSA testing has been difficult because most men with normal PSA values will not undergo biopsy unless their DRE is abnormal. This workup bias tends to overestimate sensitivity and underestimate specificity [38]. Performance can also be overestimated because PSA often detects clinically unimportant cancers. (See 'Overdiagnosis' below.)

Another problem in assessing the accuracy of PSA is that the transrectal needle biopsy is not a perfect gold standard. Investigators have suggested that the false-negative rate can range from 10 to 20 percent [39,40], though the trend towards obtaining 12 samples has increased the detection rate [41,42].

Additionally, protocols that use large numbers of biopsies to evaluate patients with an elevated PSA may be detecting incidental cancers that were not the etiology of the PSA elevation. One review that assumed that nonpalpable cancers smaller than 1.0 cm3 would not cause elevated PSA levels estimated that approximately 25 percent of cancers detected by PSA screening were too small to have accounted for the PSA rise that prompted a biopsy [43].

The diagnostic performance of PSA ideally needs to be calibrated against clinically important cancers. However, there is no consensus on defining such cancers. Although many experts consider tumors with Gleason scores ≥7 and volumes >0.5 cm3 to have a greater risk for progression, there is no certainty that these cancers will lead to early death or reduce quality of life [44].

Sensitivity and specificity — The traditional cutoff for an abnormal PSA level in the major screening studies has been 4.0 ng/mL [45-48]. The American Cancer Society (ACS) systematically reviewed the literature assessing PSA performance [49]. In a pooled analysis, the estimated sensitivity of a PSA cutoff of 4.0 ng/mL was 21 percent for detecting any prostate cancer and 51 percent for detecting high-grade cancers (Gleason ≥8). Using a cutoff of 3.0 ng/mL increased these sensitivities to 32 and 68 percent, respectively. The estimated specificity was 91 percent for a PSA cutoff of 4.0 ng/mL and 85 percent for a 3.0 ng/mL cutoff. PSA has poorer discriminating ability in men with symptomatic BPH [50].

Positive predictive value — The test performance statistic that has been best characterized by screening studies is the positive predictive value: the proportion of men with an elevated PSA who have prostate cancer.

Overall, the positive predictive value for a PSA level >4.0 ng/mL is approximately 30 percent, meaning that slightly less than one in three men with an elevated PSA will have prostate cancer detected on biopsy [45,51,52]. For PSA levels between 4.0 to 10.0 ng/mL, the positive predictive value is approximately 25 percent [51]; this increases to 42 to 64 percent for PSA levels >10 ng/mL [51,53].

However, nearly 75 percent of cancers detected within this "gray zone" of PSA values between 4.0 to 10.0 ng/mL are organ-confined and potentially curable [51]. The proportion of organ-confined cancers is lower, less than 50 percent, for PSA values above 10.0 ng/mL [51].

Negative predictive value — The Prostate Cancer Prevention Trial, which biopsied men with normal PSA levels, estimated a negative predictive value of 85 percent for a PSA value ≤4.0 ng/mL [54]. (See "Chemoprevention strategies in prostate cancer", section on 'Finasteride: Prostate Cancer Prevention Trial'.)

Effect of lowering PSA cutoffs — Some investigators have suggested using a lower PSA cutoff because some men with PSA levels below 4 ng/mL and normal digital rectal examinations are found to have prostate cancer [55-58].

In a subset analysis from the placebo arm of the Prostate Cancer Prevention Trial, 449 of 2950 men (15.2 percent) ages 62 to 91 years who had consistently normal PSA levels and digital rectal examinations during the seven years of annual screening had prostate cancer on an end-of-study biopsy; overall, seven (1.6 percent of cancers) had high-grade prostate cancer with a Gleason score of 8 or higher [54]. Among the 675 men with a PSA concentration between 2.1 and 4.0 ng/mL, 167 (24.7 percent) had prostate cancer, and four (3.5 percent of cancers) had prostate cancer with a Gleason score of 8 or higher.

These observations indicate that there is not a clear cutpoint between "normal" and "abnormal" PSA levels. The Prostate Cancer Prevention Trial found that for biopsies performed during follow-up in the control group even a PSA cutoff of 1.1 ng/mL would miss 17 percent of cancers, including 5 percent of poorly differentiated cancers [59]. Thus, any choice of PSA cutoff involves a tradeoff between sensitivity and specificity. While lowering the PSA cutoff would improve test sensitivity, a lower PSA cutoff would also reduce specificity, leading to far more false-positive tests and unnecessary biopsies. It has been projected that if the PSA threshold were to be lowered to 2.5 ng/mL, the number of men defined as abnormal would double, to up to six million in the United States [60]. Additionally, many of the cancers detected at these lower levels may never have become clinically evident, thereby leading to overdiagnosis and overtreatment [61].

Serial PSA measurements — Both detection rates and positive predictive values decline substantially with serial testing [62-65]:

During four rounds of annual PSA screening in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, the number of cancers detected per 1000 men decreased from 14.2 to 9.3 [64]. Similarly, the positive predictive value of a PSA level >4.0 ng/mL decreased from 44.5 to 34.9 percent.

The cancer detection rate for PSA in the European Randomized Study of Screening for Prostate Cancer (ERSPC), which used a four-year screening interval, decreased from 5.1 percent in the first round of screening to 4.4 percent in the second round [65]. The positive predictive value for a PSA level of 3.0 ng/mL or greater decreased from 29.2 to 19.9 percent.

Studies also found that repeated testing increases the likelihood that detected tumors will be clinically organ-confined and be moderately or well differentiated [46,64-66] (see 'Frequency and method of screening' below):

In the PLCO Cancer Screening Trial, the proportion of screening-detected cancers diagnosed at clinical stage I or II increased from 94.2 percent in round one to 98.5 percent in round 2, while the proportion with Gleason scores ≥7 decreased from 10.0 to 6.8 percent [64].

In the ERSPC, the proportion of clinical stage I and II cancers increased from 81.5 to 96.3 percent, while the proportion of poorly differentiated cancers decreased from 8.1 to 3.3 percent [65].

Improving the performance of PSA — Numerous strategies have been proposed to improve the diagnostic performance of PSA when levels are less than 10.0 ng/mL. These strategies include measuring PSA velocity (change in PSA over time) and using age- and race-specific reference ranges [67].

We suggest not routinely using any of these strategies in deciding which men to refer for further evaluation.

PSA velocity — PSA increases more rapidly in men with prostate cancer than in healthy men. The Baltimore Longitudinal Study of Aging (BLSA) found that men with a PSA rate of change (PSA velocity) greater than 0.75 ng/mL/year were at increased risk of being diagnosed with prostate cancer and that PSA velocity was more specific than a 4.0 ng/mL PSA cutoff (90 versus 60 percent specificity) [68]. The study results, though, were based on analyzing the banked serum of only 18 cancer cases. Furthermore, there are significant short-term physiologic variations in the PSA level [69]. Accurately measuring PSA velocity requires three serial readings, ideally with the same assay, obtained over at least a 12- to 24-month period [67,70,71].

However, analyses of subsequent clinical data from randomized trials suggest that PSA velocity adds little predictive information to the total PSA:

The ERSPC data from Rotterdam found that PSA velocity was significantly higher in men with prostate cancer than in men with a negative biopsy (0.62 versus 0.46 ng/mL/year) [72]. However, PSA velocity did not independently predict cancer after adjusting for PSA level.

Another analysis of pooled ERSPC data from the Netherlands and Sweden similarly found that PSA velocity only slightly improved the predictive accuracy of total PSA (area under the receiver operating characteristic curve [AUC] 0.57 versus 0.53) for detecting prostate cancer, but not for detecting high-grade disease [73].

Among the 774 Rotterdam men with a PSA level below 4.0 ng/mL who underwent their first biopsies in the second round of ERSPC, 149 were found to have cancer [74]. PSA velocity did not discriminate between men with cancer and those with negative biopsies. The sensitivity of a PSA velocity cutoff of 0.3 ng/mL/year was only 39 percent, with a false positive rate of 33 percent.

In two separate analyses, the Prostate Cancer Prevention Trial reported on the 5519 men from the placebo group who underwent prostate biopsy following at least two PSA measurements in the preceding two or three years [75,76]. While PSA level was a significant predictor of prostate cancer diagnosis on multivariate modeling, incorporating PSA velocity did not add clinically important predictive information to PSA level alone, particularly for PSA values ≥4.0 ng/mL. When total PSA was less than 4.0 ng/mL and the digital rectal examination (DRE) was normal, a PSA velocity above 0.35 ng/mL/year predicted cancer. However, using velocity would substantially increase the number of unnecessary biopsies while missing more high-grade cancers than would be identified by just lowering the PSA cutoff.

A systematic review of PSA velocity, including 12 comparisons with total PSA for predicting prostate cancer diagnosis, found numerous methodological limitations and essentially no evidence supporting the use of PSA velocity for clinical decision-making [77].

Some investigators have argued that PSA doubling time or percent change is a more appropriate measure of PSA kinetics [78]. PSA velocity is correlated with the total PSA level, which increases exponentially before clinical diagnosis.

Even though PSA velocity may be independently correlated with cancer diagnosis, it adds little to the diagnostic accuracy of PSA alone [79].

Free PSA — The observation that PSA exists in a free form as well as bound to macromolecules has been used to develop additional assays to improve test specificity. The ratio of free-to-total PSA is reduced in men with prostate cancer. Investigators have proposed that biopsies be performed only in men with lower ratios. A large multicenter, prospective trial evaluated men 50 to 75 years with PSA levels between 4.0 and 10.0 ng/mL, including 379 with prostate cancer and 394 with benign prostate disease [80]. The cancer detection rate for this PSA range in screening populations is approximately 25 percent [51]. However, the detection rate increased to 56 percent for men with a free-to-total PSA ratio less than 10 percent [80]. The investigators selected an optimal cutoff of 25 percent as a criterion for biopsy, which would have reduced the number of unnecessary biopsies by 20 percent in their study cohort. However, men with a normal free-to-total PSA ratio still had an 8 percent probability of having cancer, which may not be low enough to convince patients and clinicians to forego biopsy. A meta-analysis came to similar conclusions that free-to-total PSA ratio is generally only clinically helpful at extreme values of the ratio [81].

A separate meta-analysis of free PSA noted considerable variability in free PSA assays, specimen handling, cutoffs, and patient populations [82]. The authors concluded that more research was necessary to determine the optimal cutoff and to accurately assess the diagnostic performance and utility of the test in screening populations.

[-2]ProPSA — [-2]ProPSA (also known as p2PSA) is a specific isoform of the PSA proenzyme proPSA. The Prostate Health Index (PHI) is a derived measure that incorporates %[-2]ProPSA, free PSA, and total PSA. While the use of the %[-2]ProPSA and PHI might reduce unnecessary biopsies for men with PSA values between 2 and 10 ng/mL, this approach requires further study.

A meta-analysis estimated a pooled specificity (reflecting the potential reduction in unnecessary biopsies) of 0.33 (95% CI 0.31-0.35) for %[-2]ProPSA and 0.32 (95% CI 0.29-0.34) for the PHI [83]. Quality of the literature was assessed as moderate-high, but there was significant heterogeneity across studies. AUC ranged from 0.70 to 0.77 for PHI and 0.64 to 0.78 for %[-2]ProPSA. A few studies found associations between higher values for %[-2]ProPSA and PHI, and higher Gleason scores. The National Comprehensive Cancer Network (NCCN) recommends considering PHI in making biopsy decisions for men with PSA levels between 3 and 10 ng/mL, particularly for those who have had a previous negative biopsy [84]. However, the clinical evidence supporting these recommendations is limited.

Four kallikrein assays — Total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2 are incorporated into a testing panel to increase detection of aggressive cancers. The 4Kscore Test combines the blood test results with age, DRE findings, and previous biopsy results. A large prospective study showed that the 4Kscore Test had an AUC of 0.82 for detecting cancers with Gleason score ≥7 [85]. By comparison, a model based on just total PSA and free PSA had an AUC of 0.75. The NCCN recommends the 4Kscore Test for the same indications as PHI, though the clinical impact of using the 4Kscore Test for biopsy decisions is also uncertain [84].

Summary — There is no consensus on using any of the PSA modifications, and none of them has been shown in clinical trials to reduce the number of unnecessary biopsies or improve clinical outcomes. The total PSA cutoff of 4.0 ng/mL has been the most accepted standard because it balances the tradeoff between missing important cancers at a curable stage and avoiding both detection of clinically insignificant disease and subjecting men to unnecessary prostate biopsies [44,61,67]. Ongoing efforts are targeted at identifying new serum markers that will have greater diagnostic accuracy for prostate cancer, particularly for aggressive tumors [67,86]. (See "Measurement of prostate-specific antigen".)

DIGITAL RECTAL EXAMINATION (DRE) — We suggest not performing digital rectal examination (DRE) for prostate cancer screening either alone or in combination with prostate-specific antigen (PSA) screening. Although DRE has long been used to diagnose prostate cancer, no controlled studies have shown a reduction in the morbidity or mortality of prostate cancer when detected by DRE at any age [87]. (See 'Combining PSA and DRE' below.)

There are inherent limitations to the DRE. It can detect palpable abnormalities (eg, nodules, asymmetry, or induration) in the posterior and lateral aspects of the prostate gland where the majority of cancers arise; however, other areas of the prostate where cancer occurs are not reachable by a finger examination [86]. Furthermore, the majority of cancers detected by DRE alone are clinically or pathologically advanced [88], and stage T1 prostate cancers are nonpalpable by definition.

DRE is also not recommended for colorectal cancer screening. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'Tests used for screening'.)

Test performance — Urologists have been found to have relatively low interrater agreement for detecting prostate abnormalities [89]. No data are available for the test performance characteristics of DRE in primary care.

Approximately 2 to 3 percent of men 50 or more years old who undergo a single DRE have induration, marked asymmetry, or nodularity of the prostate. In one analysis, an abnormal screening DRE doubled the odds of detecting a clinically important cancer (defined as a having a tumor volume greater than 0.5 mL) that was confined to the prostate [53]. Although screening DRE increased the odds likelihood of finding early disease, it was also associated with a three- to ninefold increase in the odds of finding extraprostatic extension of tumor (presumably not amenable to curative therapy).

Sensitivity and specificity — A meta-analysis of DRE estimated a sensitivity for detecting prostate cancer of 59 percent and a specificity of 94 percent [90].

Positive predictive value — The positive predictive value of an abnormal DRE for prostate cancer varies from 5 to 30 percent [51,91-95]. A meta-analysis calculated an overall positive predictive value of 28 percent [90].

COMBINING PSA AND DRE — We suggest not performing digital rectal examination (DRE) for prostate cancer screening whether alone or in combination with prostate-specific antigen (PSA) screening. PSA and DRE are somewhat complementary, and their combined use can increase the overall rate of cancer detection [44,51,96-98]. However, there is no high-level evidence that DRE screening improves survival outcomes.

As an example, a multicenter screening study of 6630 men reported a detection rate of 3.2 percent for DRE, 4.6 percent for PSA, and 5.8 percent for the two methods combined [51,93]. PSA detected significantly more of the cancers than DRE (82 versus 55 percent). Overall, 45 percent of the cancers were detected only by PSA, while just 18 percent were detected solely by DRE.

Investigators reported a positive predictive value of 10 percent for a suspicious DRE when the PSA level was normal. However, the positive predictive value was 24 percent for an elevated PSA level with a normal DRE. Among men with a normal PSA level, abnormalities on DRE appear less likely to be from a cancer if the PSA concentration is below 1.0 ng/mL than if the PSA concentration is between 3.0 to 4.0 ng/mL [95].

Although these data suggest a potential benefit for combining PSA and DRE in detecting prostate cancer, randomized trials have not confirmed a benefit on prostate cancer outcomes. The European Randomized Study of Screening for Prostate Cancer (ERSPC), which found a small survival benefit with PSA screening, did not consistently require DRE [12]. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial found no survival benefit with combined PSA and DRE screening [15,16].

OTHER TESTS

PCA3 — The prostate cancer antigen 3 gene (PCA3), which was identified in 1999, is highly overexpressed in almost all prostate cancer tissue specimens but not in normal or hypertrophied tissue [99]. A PCA3 score, based on the ratio of PCA3 mRNA over prostate-specific antigen (PSA) mRNA (which is not related to serum PSA levels or cancer), can be determined from a urine specimen collected after a vigorous digital rectal examination. PCA3 has been evaluated for guiding biopsy decisions when PSA levels are in an indeterminate range (2.5 to 10.0 ng/mL) and for men with previously negative biopsies but persistently elevated PSA levels.

While PCA3 may eventually have a role in reducing unnecessary biopsies, more data on clinical outcomes are needed to support routine use [100]. PCA3 is approved by the US Food and Drug Administration (FDA), however, for helping to inform decisions on whether to repeat a prostate biopsy in men ≥50 years with one or more previous negative biopsies.

A 2010 review identified 11 clinical trials, representing 2737 subjects, evaluating the diagnostic performance of PCA3 [101]:

In four studies evaluating patients with indeterminate PSA, sensitivity ranged from 53 to 84 percent and specificity ranged from 71 to 80 percent.

In three studies with at least 200 patients that provided data on PCA3 performance following a previous negative biopsy, sensitivity ranged from 47 to 58 percent, and specificity ranged from 71 to 72 percent. PCA3 outperformed PSA and percent free PSA in independently predicting a positive biopsy.

Determining the clinical utility of PCA3 from these studies is difficult. Aside from the relatively small sample sizes, studies differed in their criteria for biopsy referral (PSA levels 2.5 to 3.0 ng/mL, digital rectal examination [DRE] findings, or risk factors), the generation of the PCA3 test used, and the cutpoint for defining an abnormal test. Additionally, none of the studies used PCA3 scores as an indication for biopsy.

The Rotterdam site of the European Randomized Study of Screening for Prostate Cancer (ERSPC) subsequently reported the results of using PCA3 as an initial screening test, with sextant biopsy performed if either the PSA level was ≥3 or the PCA3 score was ≥10 [102]. Based on receiver operating characteristic (ROC) curve analysis of 721 subjects undergoing biopsy, PCA3 performed only marginally better than total PSA; PCA3 also missed the majority of cancers with Gleason >6 or stage ≥T2a, though only 19 men met these criteria. However, the generalizability of these results is uncertain because all subjects had already undergone three rounds of screening, and 29 percent had previous negative biopsies.

EFFECTIVENESS OF PROSTATE CANCER SCREENING — Apart from issues of cost and acceptability, in order for prostate cancer screening to be valuable, it must reduce disease-specific morbidity and/or mortality.

Evidence from randomized trials — Two well-designed large randomized trials have evaluated the effectiveness of screening for prostate cancer and found somewhat differing results:

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), 182,160 men between the ages of 50 and 74 were randomly assigned to prostate-specific antigen (PSA) screening (an average of once every four years) or a control group that was not offered screening [12]. This study used different recruiting and randomization procedures across seven centers in Europe. The study used PSA cutoffs between 2.5 and 4.0 ng/mL (most centers used a cutoff of 3.0 ng/mL) as indications for referral for biopsy, variably supplemented with digital rectal examination (DRE), transrectal ultrasonography, and/or measurements of free PSA levels. The overall rate of prostate cancer screening in the control group was not reported, though 31 percent of cancers were categorized as stage T1c (diagnosed based on elevated PSA level). Investigators subsequently reported PSA testing among 24 percent of the Rotterdam site controls and estimated that 50 percent of the tests were for screening [103].

With follow-up truncated at 13 years for the 162,243 men in a prespecified core group between the ages of 55 and 69, the primary outcome of prostate cancer mortality was 21 percent lower in the group offered screening (rate ratio 0.79, 95% CI 0.69-0.91) [13]. The absolute rates of prostate cancer mortality were 0.43 versus 0.54 per 1000 person-years (absolute rate difference of 0.11 fewer deaths per 1000 person-years; 781 (95% CI 490-1929) men needed to be invited for screening to prevent one prostate cancer death over 13 years). Prostate cancer was diagnosed more frequently in the screening group (9.6 versus 6.2 cases per 1000 person-years), such that 27 additional cases of prostate cancer would need to be detected by screening to prevent one death from prostate cancer after 13 years. All-cause mortality in the core group was not reduced with screening (18.6 versus 18.9 deaths per 1000 person-years; rate ratio 1.00, CI 0.98-1.02). Prostate cancer mortality was also reduced in the entire cohort of men ages 50 to 74 (rate ratio 0.83, CI 0.73-0.94).

Although the absolute mortality benefit for screening was low, several factors could have biased the results toward no effect. Approximately 24 percent of subjects invited for screening did not undergo PSA testing [12]. While not definitively characterized, a substantial proportion of the control group likely received PSA testing (31 percent of cancers were screening-detected). A subsequent analysis of the Rotterdam site data used patient surveys and linkages with a central national laboratory to estimate contamination. Adjusting for contamination and non-adherence with screening, investigators estimated that prostate cancer screening could reduce prostate cancer mortality by as much as 31 percent (95% CI 8-49 percent) [104]. Additionally, at least 25 percent of cancers detected in the screening group did not receive curative treatment with either surgery or radiation. Finally, given the indolent course of prostate cancer and the 5- to 10-year lead time associated with PSA testing, follow-up duration may have been insufficient to accurately estimate the survival benefit. However, the absolute rate difference has dropped only from 0.06 fewer prostate cancer deaths per 1000 person-years after nine years of follow-up to the 13-year rate of 0.11 fewer deaths per 1000 person-years [13]. Furthermore, while the prostate cancer survival benefit from screening was not initially realized until nine years of follow-up [12], the burdens of screening and treatment, including harms from overdiagnosis and overtreatment, occur immediately and potentially have lifelong consequences.

Several biases could also have favored the screening group [105]. A higher proportion of high-risk cancers diagnosed in the screening group were aggressively treated (surgery or radiation) compared with the control group, so some of the outcome differences could be related more to improved treatment than screening [106]. Among Rotterdam Site men treated with radical prostatectomy, those in the screening group were less likely than those in the control group to experience biochemical recurrence (hazard ratio [HR] 0.43, 95% CI 0.23-0.83), and metastasis (HR 0.18, CI 0.06-0.59); prostate cancer mortality was also reduced, but the finding was not statistically significant with only 12 men dying from prostate cancer [107]. Additionally, the committee adjudicating cause of death was aware of cancer treatments. Previous studies have suggested that cause of death is less likely to be attributed to prostate cancer for patients who received aggressive treatment [108]. The ERSPC investigators did not report the association of receipt of treatment and cancer death.

The Göteborg, Sweden Randomized Population-based Prostate Cancer Screening Trial, many of whose subjects were also ERSPC participants, reported a rate ratio of 0.56, 95% CI 0.39-0.82 for prostate cancer mortality among screened versus control subjects at a median follow-up of 14 years [109]. In 2014, investigators reported 18-year follow-up data for what they called a study of "organized" PSA screening compared with "opportunistic testing" [110]. Cumulative prostate cancer mortality rates were still lower in the screening group than in the control group (0.98 versus 1.5 percent, reflecting 43 fewer deaths). The Göteborg study, which used population registries to randomly allocate men to either the screening or control groups, could plausibly be more likely to demonstrate benefit than the other ERSPC sites because it offered screening every two years (versus every four years). Additionally, the Göteborg results were based on a cohort of men ages 50 to 64 compared with ages 55 to 69 in the combined ERSPC report. This suggests that screening may be less beneficial for men ≥65 years, consistent with the finding that radical prostatectomy did not confer a survival benefit compared with watchful waiting for men in this age range [111]. However, experts have questioned these explanations because mortality rates among younger ERSPC subjects were very low, as was the rate of interval cancers, suggesting that including younger subjects and screening more frequently would not account for the observed mortality differences [112]. The Goteborg finding could also be due to chance; the 95% CI for the rate ratio overlapped the 0.79 rate ratio reported by ERSPC. Finally, men in the screening group were more likely to receive attempted curative therapy than those in the control group, particularly radical prostatectomy.

In the United States Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, 76,693 men between the ages of 55 and 74 were randomly assigned to annual screening with PSA and DRE or to usual care, which often included PSA and DRE [15]. A PSA level above 4.0 ng/mL or an abnormal DRE were indications for biopsy. Over 40 percent of study subjects had undergone PSA testing within three years before enrolling in the trial, and subsequent analyses estimated that more than 80 percent of control subjects underwent PSA testing during the study (contamination) [113,114].

In contrast to the ERSPC, after seven years of follow-up there was no reduction in the primary outcome of prostate cancer mortality (50 versus 44 deaths in the screening and control groups, respectively; rate ratio 1.13, 95% CI 0.75-1.70) [15]. Cancer detection in the screening group was significantly higher than in the control group (2820 versus 2322, rate ratio 1.22, CI 1.16-1.29). A subsequent publication looking at longer-term follow-up within the PLCO Cancer Screening Trial found similar prostate cancer mortality results (RR 1.04, CI 0.87-1.24) with no suggestion of reduced overall mortality in the patients followed for a median of 14.8 years (RR 0.98, CI 0.95-1.00) [16]. This suggests that the differences in results between the ERSPC and the PLCO Cancer Screening Trial were not related to the duration of follow-up. Additionally, the investigators found no evidence that screening could be beneficial in any subgroups defined by comorbidity, age, or pretrial PSA testing.

The negative results are most likely attributable to the very high rate of PSA testing in the control arm, which has been estimated as high as 80 percent [113,114], and to the high proportion of subjects with recent PSA testing at baseline (because serial testing is associated with finding fewer and less aggressive cancers). An earlier PLCO Cancer Screening Trial publication also indicated that substantial proportions of men with abnormal PSA and/or DRE results had not undergone biopsy within three years following the positive screen [64]. All of these factors bias the PLCO Cancer Screening Trial toward a null result.

A 2010 meta-analysis summarized results from six randomized trials (including unique data from two ERSPC sites), with a total of 387,286 participants [115]. Screening with PSA with or without DRE compared with no screening did not reduce death from prostate cancer (relative risk [RR] 0.88, 95% CI 0.71-1.09). However, screening significantly increased the probability of cancer diagnosis (RR 1.46, CI 1.21-1.77). In a 2011 Cochrane meta-analysis that had similar findings, the estimated prostate cancer-specific mortality difference was not statistically significant (RR 0.95, 95% CI 0.85-1.07), but cancer was diagnosed significantly more often in men randomized to screening (RR 1.35, 95% CI 1.06-1.72) [116].

Evidence from observational studies — Before publication of the randomized trials, other data had been cited to support the effectiveness of screening. Given the conflicting results discussed above, observational studies provide information that can fill in some gaps in evidence from the trials.

Surveillance, Epidemiology, and End Results (SEER) tumor registry data showed a significant decline in the incidence of advanced-stage disease in the decades following the introduction of PSA, potentially consistent with effective screening [117]. Prostate cancer mortality rates, which initially increased to nearly 40 in 100,000 annually in the United States following the advent of PSA testing, have now declined to slightly below pre-PSA levels (figure 1) [117].

These mortality trends, however, are difficult to interpret. Some ecologic data suggest an association between PSA testing and declining mortality rates [118-120]. However, other ecologic studies have shown declining mortality rates even in the absence of intensive screening [121].

Alternative explanations have been proposed for declining mortality rates. Better primary treatments could reduce mortality rates among men diagnosed with localized cancer. Additionally, the use of androgen deprivation therapy and other chemotherapies for men with advanced-stage cancer could allow men to survive long enough to die from a comorbid condition. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer" and "Overview of the treatment of disseminated castration-sensitive prostate cancer".)

Subsequent observational data highlight the potential impact of the US Preventive Services Task Force (USPSTF) recommendation against any prostate cancer screening, first issued as a draft guideline in October 2011 and then affirmed in the final 2012 recommendation [122,123]. (See 'Recommendations of others' below.)

Data from the National Health Interview Surveys showed significant declines in screening of men ages 50 and older in the United States between 2010 and 2013, most notably among those ages 50 to 74 [124,125]. Concomitantly, SEER registry data showed significant declines in overall prostate cancer incidence rates among men ages 50 and older, with an estimated 33,519 fewer cases diagnosed in 2012 compared with 2011 [124]. Rates continued declining through 2013 for localized/regional stage disease [126]. However, incidence rates of distant-stage disease increased significantly among those 75 years and older from 2011 to 2013 [127]. Another SEER analysis showed that the incidence of distant-stage disease significantly increased among men ages 50 to 69 between 2004 and 2012 [128].

Evidence from modeling studies — Simulation models using data from SEER registries suggest that PSA screening could account for 45 to 70 percent of the observed decline in prostate cancer mortality rates, mainly by decreasing the incidence of distant stage disease [129]. However, treatment advancements may have also contributed to the declining mortality rates.

The ERSPC investigators used simulation models based on their data and observational studies reporting quality of life outcomes to project lifetime numbers of cancer diagnoses, treatments, deaths, and quality-adjusted life years gained after PSA screening [130]. Overall, annual screening between ages 55 to 69 would result in nine fewer prostate cancer deaths per 1000 men followed for an entire lifetime, with a total of 73 life-years gained. Investigators projected that 98 men would need to be screened and five cancers detected to prevent one prostate cancer death. However, after adjusting for the adverse effects of screening, PSA screening resulted in a gain of only 56 quality-adjusted life-years, with a 95% confidence interval ranging from 97 life-years gained to 21 life-years lost. An editorialist noted that these results demonstrate that screening decisions are very sensitive to patient preferences for potential future health states [131].

A study used microsimulation modeling of observational and clinical trial data to try to determine the comparative effectiveness of alternative PSA screening strategies [132]. Outcome measures included the lifetime number of PSA tests, false-positive results, cancer detection, overdiagnosis, prostate cancer deaths, and lives saved. Compared with a reference strategy of annual PSA testing between ages 50 to 74 with a PSA threshold of 4.0 ng/mL for biopsy referral, strategies that stopped screening at an earlier age, widened testing intervals, and/or used age-adjusted PSA biopsy criteria appeared to reduce the number of tests and the risks for false-positive results and overdiagnosis, while increasing the absolute risk of prostate cancer death by only a fraction of one percentage point. Conversely, screening strategies that lowered the starting age and/or PSA threshold for biopsy referral appeared to markedly increase the number of tests and the risks for false-positive results and overdiagnosis while only marginally decreasing the risk of prostate cancer death. However, concerns were raised about the analyses, including the failure to model risk factors, the use of simplified measures for stage and grade, and not considering patient preferences [133].

HARM FROM SCREENING

Risks of biopsy — Although early reports indicated that prostate biopsies very rarely (<1 percent) caused complications (eg, bleeding, infection) serious enough to require hospitalization [134], subsequent studies suggest both higher rates of infectious complications and that the rate of infectious complications may be increasing over time [135-138]. Hospitalization rates for infectious complications in these studies have ranged from 0.6 to 4.1 percent [137].

Infectious complications can lead to sepsis, which can very rarely lead to death. A modeling study, assuming a biopsy mortality rate of 0.2 percent [139], concluded that prostate cancer screening could be associated with a net increased overall mortality, particularly under the conditions that biopsy rates are high and screening is relatively ineffective [140]. However, other studies have suggested much lower mortality rates following biopsy [137]. Population-based studies include an analysis of United States Medicare data that found a mortality rate of 0.3 percent in the 30 days following biopsy; this was actually 70 percent lower than the 30-day mortality in a comparison population not undergoing biopsy [135]. An analysis of registry data from Canada found a 30-day mortality rate of 0.09 percent [136]. Randomized trials with follow-up on 1147 biopsies [141], and 10,474 biopsies [142], reported no biopsy-related deaths.

Other potential harms from prostate biopsy (eg, bleeding or urinary obstruction) are discussed elsewhere. (See "Prostate biopsy", section on 'Complications'.)

Prostate biopsy can also lead to anxiety and physical discomfort [143]. Among 116 men undergoing biopsy in the Rotterdam screening study, 55 percent reported discomfort with the procedure, including 2 percent who had pain persisting longer than one week.

Being diagnosed with prostate cancer is psychologically distressing, but even patients with a negative biopsy result may be distressed [144,145]. Chronic anxiety can follow a negative prostate biopsy because this apparently favorable result cannot completely rule out prostate cancer given the relatively high false-negative biopsy rate [146].

Overdiagnosis — Overdiagnosis refers to the detection by screening of conditions that would not have become clinically significant. When screening finds cancer that would never have become clinically significant, patients are subject to the risks of screening, confirmatory diagnosis, and treatment, as well as suffering potential psychosocial harm from anxiety and labeling. Overdiagnosis is of particular concern because most men with screening-detected prostate cancers have early-stage disease and will be offered aggressive treatment.

A number of reports have raised concerns about the risk of overdiagnosis with screening:

While the lifetime risk of being diagnosed with prostate cancer has increased from 1 in 11 to 1 in 6, the lifetime risk of dying from prostate cancer has remained around 1 in 34 following the advent of prostate-specific antigen (PSA) testing [3].

Although approximately 80 percent of detected cancers are considered clinically important based on tumor size and grade [147], these are relatively crude prognostic markers. Autopsy series in men who died from other causes have shown a 30 to 45 percent prevalence of prostate cancer in men in their fifties and an 80 percent prevalence in men in their seventies [148-150].

A study that applied computer-simulation models of PSA testing to Surveillance, Epidemiology, and End Results (SEER) cancer incidence data estimated that 29 percent of cancers detected in whites and 44 percent of cancers detected in blacks were overdiagnosed [151]. An updated analysis, that also used ERSPC Rotterdam clinical data, estimated an overdiagnosis fraction ranging from 23 to 42 percent among cancers diagnosed by PSA screening [152].

Similarly, a study that applied simulation models to the results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) estimated a 50 percent overdetection rate with annual screening for men ages 55 to 67 [18]. Given that the screening group in the ERSPC had a 72 percent higher cumulative incidence of prostate cancer than the control group after 11 years of follow-up (9.6 versus 6.0 percent) [153], the potential absolute risk for overdiagnosis is substantial.

A study examined the number of men diagnosed and treated for prostate cancer in the United States each year after 1986, the year before PSA screening was introduced, until 2005 [154]. The study estimated that approximately 1.3 million additional men were diagnosed with prostate cancer as a result of screening, of whom approximately 1 million were treated. Assuming that the entire decline in prostate cancer mortality in the United States from 1986 through 2005 was due to screening, an extremely optimistic assumption for PSA screening, approximately 23 men had to be diagnosed and 18 men treated for prostate cancer to prevent one death. The authors concluded that most of the additional cases of prostate cancer found since 1986 represent overdiagnosis.

The risk of overdiagnosis of prostate cancer appears to increase with increasing age [155].

Risks of therapy — Even in the absence of treatment, many men found to have prostate cancer as a result of screening will have a lengthy period of time without clinical problems. However, undergoing radical prostatectomy and radiation therapies can lead to immediate complications:

The operative mortality rate ranges from approximately 0.1 to 0.5 percent [156,157], though the rate approaches 1 percent in men over 75 years [158].

Less serious but more common complications include urinary incontinence, sexual dysfunction, and bowel problems. Radical prostatectomy can substantially decrease sexual function in 20 to 70 percent of men and lead to urinary problems in 15 to 50 percent [159-161].

External beam radiation therapy has been reported to cause erectile dysfunction in 20 to 45 percent of men with previously normal erectile function, urinary incontinence in 2 to 16 percent of previously continent men, and bowel dysfunction in 6 to 25 percent of men with previously normal bowel function [159,160,162].

Given the ERSPC study estimate that 27 men need to be diagnosed with prostate cancer (of whom at least 60 percent received surgery or radiation) to prevent one prostate cancer death during 13 years of follow-up, the quality of life issues related to treatment selection are very important decision-making factors.

APPROACH TO SCREENING — Although screening for prostate cancer with prostate-specific antigen (PSA) can reduce mortality from prostate cancer, the absolute risk reduction is very small. Given limitations in the design and reporting of the randomized trials, there remain important concerns about whether the benefits of screening outweigh the potential harms to quality of life, including the substantial risks for overdiagnosis and treatment complications. Men who are willing to accept a substantial risk of morbidity associated with treatment in return for a small reduction in mortality might reasonably choose to be screened. Men who are at increased risk of prostate cancer because of race or family history may be more likely to benefit from screening.

Informed decision-making — Given the important tradeoffs between potential benefits and harms involved with either screening or not screening for prostate cancer, and the lack of definitive data on screening outcomes, it is particularly important that patients make informed decisions about undergoing testing [112,163-166].

The US Preventive Services Task Force (USPSTF) Guidelines [167,168], American College of Physicians (ACP) [169], American Urologic Association (AUA) [170], American Cancer Society (ACS) [49], and the Canadian Task Force on the Periodic Health Examination [171] all stress the importance of informed decision making.

The ACP and the ACS have suggested useful discussion points to consider when counseling patients, including [49,169]:

Prostate cancer is an important health problem; it is one of the most frequently diagnosed cancers in the United States and a leading cause of cancer death in men.

Prostate cancer screening is controversial, and men should be involved in making the decision whether or not to be screened.

Prostate cancer screening may reduce the chance of dying from prostate cancer. However, the evidence is mixed and the absolute benefit is small.

Most men who choose not to have PSA testing will not be diagnosed with prostate cancer and will die from some other cause. However, some of these men will die from prostate cancer.

In order to determine whether a cancer is causing an abnormal test, men need to undergo a prostate biopsy. However, the PSA test and digital rectal examination (DRE) can both have false-positive and false-negative results. Prostate biopsies may also miss finding cancers and can rarely cause serious infections.

Patients who choose PSA testing are much more likely than those who decline PSA testing to be diagnosed with prostate cancer. Many cancers detected by screening are considered "overdiagnosed," meaning that they never would have caused problems during a man's lifetime.

No available tests can accurately determine which men with a cancer found by screening are most likely to benefit from aggressive treatment (ie, those whose cancers are destined to cause health problems). Most men with prostate cancer will die from other causes; many will never experience health problems from their cancer.

Aggressive therapy is necessary to realize any benefit from finding an early-stage prostate cancer; however, studies show men with high PSA or Gleason score are most likely to benefit.

Surgery and radiation therapies are the treatments most commonly offered in an attempt to cure prostate cancer; however, they can lead to problems with urinary, bowel, and sexual function.

A strategy of active surveillance may be appropriate for men who are at low risk for progression from prostate cancer (PSA <10 ng/mL and Gleason <7). This means not immediately treating a cancer but following PSA tests, DRE, and repeating biopsies to determine whether aggressive treatment is indicated because the cancer is progressing [172]. Active surveillance is increasingly being offered to men with low-risk prostate cancer [173].

Clinicians find it challenging to provide comprehensive, consistent, and balanced information about prostate cancer screening decisions during clinic visits [174,175]. Consequently, efforts have focused on using decision support tools to help patients understand screening issues and make informed decisions for screening [176,177].

Investigators have evaluated a number of interventions to facilitate such informed prostate cancer screening decisions including videotapes [178-180], patient group discussions [178], brief scripts read to patients during clinic visits [181], verbal and written material provided before a periodic health examination [182], and informational pamphlets distributed at study visits [183] or through the mail [184].

Websites providing decision support tools include:

American Cancer Society (ACS)

American Society of Clinical Oncology (ASCO)

Centers for Disease Control and Prevention (CDC)

Mayo Clinic

The content of a screening discussion or the provision of a decision aid should be documented in the medical record, particularly when the patient decides against screening.

A systematic review of 18 trials of patient decision aids for prostate cancer screening found that decision aids consistently improved patient knowledge about prostate cancer and screening, increased participation in decision- making, and made patients more confident about their decisions [185]. Receiving a decision aid generally decreased intention to be screened and resulted in lower screening rates among patients coming for routine office visits (relative risk [RR] 0.88, 95% CI 0.81-0.97). Similarly, in a subsequent large randomized trial, decision aids increased patient knowledge and decisional satisfaction and decreased decisional conflict; however, they had no effect on actual rates of screening [186].

Age to begin screening — Screening should be discussed with average-risk men beginning at age 50, though not with men who have a comorbidity that limits their life expectancy to less than 10 years [44,49].

We suggest that providers first discuss screening with men at high risk for prostate cancer, including black men, men with a family history of prostate cancer, particularly in relatives younger than age 65, and men who are known or likely to have the BRCA1 or BRCA2 mutations, beginning at age 40 to 45 [49,187-189]. Men who are at increased risk of prostate cancer because of race or family history may be more likely to benefit from screening; however, there is relatively little evidence addressing this and these men should be informed that the potential benefits and risks of early screening are uncertain. (See "Risk factors for prostate cancer", section on 'Genetic factors'.)

A Swedish case-control study found a strong association between an elevated (above the median) PSA result before age 50 and being diagnosed with advanced-stage prostate cancer over the subsequent 20 to 30 years [190]. A case-control study among participants in the United States Physicians Health Study found an association between midlife PSA levels and prostate cancer mortality during 30 years of follow-up [191]. Another study using observational data from various sources estimated that a PSA test result before age 50 better stratified prostate cancer mortality risk than either race or family history [192]. Although some authors of these studies suggested measuring PSA in all men before age 50, we do not support this recommendation. There is no clinical evidence that identifying and treating these men will lead to better outcomes; early testing could also increase anxiety and the number of false-positive tests.

Frequency and method of screening — When a decision is made to screen for prostate cancer, the recommended strategy has been to perform a DRE and measure a PSA level [44,49]. However, the randomized European Randomized Study of Screening for Prostate Cancer (ERSPC) found that PSA screening alone, measured at a median interval of four years (range two to seven years), resulted in a significant, though small, reduction in prostate cancer mortality [12]. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which screened men aged 55 to 74 years with annual PSA and DRE, found no reduction in prostate cancer mortality over 15 years [15,16]. The optimal interval and combination of tests remains uncertain; however, based on available data, we suggest screening every two to four years with PSA alone.

An analysis from the ERSPC compared outcomes from two centers with different screening intervals, Gothenburg (two years; n = 4202) and Rotterdam (four years; n = 13,301) [193]. The 10-year incidence of prostate cancer was significantly higher in the center with the shorter screening interval (13.1 versus 8.4 percent). Aggressive interval cancers were uncommon, and cumulative rates of such cancers were similar in the two centers (0.11 versus 0.12 percent, respectively). Follow-up was not long enough to compare mortality rates. There were potentially important differences between the patients and screening methods at these two centers that limit the strength of this nonrandomized comparison of screening intervals.

One study that applied modeling to identify an optimal PSA testing strategy concluded that the most efficient strategy would be to screen men at age 40 and 45 years and then every two years from ages 50 to 75, while still using the 4.0 ng/mL cutoff as a criterion for biopsy referral [194].

Studies have also raised the possibility of less frequent retesting in men with lower initial PSA levels (eg, ≤1.0, 1.5. or 2.0 ng/mL) while still testing annually in those with higher PSA levels (but still below a cutoff for biopsy) [195-197]:

The PLCO Cancer Screening Trial found that only 1.5 percent (95% CI 1.2-1.7) of men with an initial PSA less than 1 ng/mL converted to a PSA greater than 4.0 ng/mL after five years [195]. The report estimated that only 0.12 percent of men with an initial PSA less than 1 ng/mL would be diagnosed with prostate cancer during a five-year interval. The initial PSA level was not correlated with conversion to an abnormal DRE; conversion within three years of baseline screening was nearly 10 percent, even for men with an initial PSA level below 1 ng/mL.

Similar findings for PSA screening were noted in the ERSPC in which the proportion of men with a baseline PSA below 1.0 ng/mL who converted to a level above 3.0 ng/mL was 0.9 percent after four years [196]. The estimated cancer detection rate was 0.15 percent during a four-year interval.

In the PLCO Cancer Screening Trial, a four-year screening interval in men with a PSA below 1.0 ng/mL was estimated to result in a delay in cancer diagnosis of 15.6 months [195]. A separate report came to a similar estimate [198]. The clinical consequences of delayed diagnosis on prostate cancer mortality and morbidity are unknown, although the majority of cancers detected after a four-year screening interval in the ERSPC were early-stage [196].

Referrals to urology to evaluate abnormal results — If digital rectal exam is performed, either for screening or for symptoms, men with abnormal prostate exams (nodules, induration, or asymmetry) should be referred to a urologist who can evaluate them for a prostate biopsy. (See "Prostate biopsy".)

Men with abnormal PSA values should also be referred, although some experts recommend first repeating the PSA several weeks later, particularly for borderline elevations below 7.0 ng/mL [70,199]. We suggest that primary care clinicians refer men with a PSA level above 7 ng/mL without further testing.

We suggest that men with a PSA level between 4 and 7 ng/mL undergo repeat PSA testing several weeks later. Before repeating PSA testing, men should abstain from ejaculation and bike riding for at least 48 hours. Men with symptomatic prostatitis should be treated with antibiotics before retesting (see "Measurement of prostate-specific antigen", section on 'Prostatic inflammation and infection'). Men with a repeat PSA level above 4 ng/mL should be referred for evaluation.

One reason to repeat PSA testing in men with borderline elevations is that PSA measurements have considerable short-term variability [69,200]. A retrospective analysis of stored serum from 972 men found substantial year-to-year fluctuations with 44 percent of men with a PSA above 4.0 ng/mL having normal PSA findings at subsequent annual visits [201]. In addition to biological variability, PSA may be transiently elevated due to ejaculation, perineal trauma, or prostatitis. (See "Acute bacterial prostatitis".)

Although the ERSPC used lower PSA ranges (2.5 to 3.0 ng/mL), test results were used in conjunction with various ancillary tests (DRE, transrectal ultrasonography) to guide biopsy referrals [12]. The total PSA cutoff of 4.0 ng/mL has been the most accepted standard because it balances the tradeoff between missing important cancers at a curable stage and avoiding both detection of clinically insignificant disease and subjecting men to unnecessary prostate biopsies [38,63,67,132]. We suggest that a PSA level of 4.0 ng/mL be considered abnormal in determining who should be referred for evaluation.

Urology referrals may also be based upon PSA velocity, PSA density, measurements of free or complexed PSA, and age- and race-specific PSA levels, although the clinical utility of these modifications is uncertain and we do not recommend them.

Attempts have been made to create risk models for prostate cancer based on multiple variables (eg, PSA, age, family history, DRE result, prostate volume, previous negative biopsies, PSA velocity, free PSA, etc). A meta-analysis concluded that some models improved the predictive value of PSA for detecting prostate cancer, with areas under the receiver operating characteristic curve (AUC) ranging from 0.66-0.79 [202]. Only one model was used to predict clinically significant (high-grade) cancer, with an overall AUC 0.71 (95% CI 0.67-0.75); however, estimates showed a high degree of heterogeneity. Until such models have undergone additional study for clinical effectiveness, we do not recommend using them to decide who should be referred to urology.

Men who are referred to urologists will not necessarily have a biopsy. Relevant considerations include the patient's health status, clinical likelihood for harboring significant disease, and personal wishes. Urologists are increasingly considering the use of risk calculators, genomic tests, and prostate magnetic resonance imaging (MRI) to inform decisions for performing both initial and repeat biopsies. We do not recommend that primary care clinicians order a prostate MRI to guide their decision about whether to refer to urology. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Elevated PSA' and "Prostate biopsy".)

Discontinuing screening — Screening for prostate cancer is unlikely to benefit men with less than a 10-year life expectancy given the generally indolent course of the disease. While most agree with stopping screening of men who develop substantial comorbidities, applying an upper age limit to screening has less of a consensus.

Actuarial tables suggest that among men in average health, only those ages 75 and younger have a 10-year life expectancy, and guidelines recommend against screening older men.

An analysis of data from the Baltimore Longitudinal Study of Aging (BLSA) found that discontinuing PSA testing at age 65 for men with PSA levels 0.5 ng/mL or less would still identify all cancers that would have been detected by age 75 [203]. If screening were discontinued for men with PSA levels of 1.0 ng/mL or less at age 65, then 94 percent of the cancers would still be detected.

A case-control study from a population-based cohort in Sweden estimated that a PSA level ≤1 ng/mL at age 60 was associated with an extremely low risk of prostate cancer metastasis (0.5 percent) or death from prostate cancer (0.2 percent) by age 85 [204].

A population-based cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data evaluated outcomes of 89,877 older men (median age 78) diagnosed with clinically localized prostate cancer between 1992 and 2002 who were managed without attempted curative therapy. The 10-year prostate cancer specific mortality ranged from 8.3 percent (95% CI 4.2-12.8 percent) for men with well-differentiated cancers to 25.6 percent (CI 23.7-28.3 percent) for men with poorly differentiated cancers. Approximately 60 percent of all subjects died from competing causes [205].

Another SEER-Medicare analysis highlighted the importance of considering comorbidity. Among men with localized prostate cancer aged 75 and older, the 10-year prostate cancer mortality without attempted curative therapy was only 5.0 percent (CI 2.5-8.7 percent) for those with moderately differentiated cancers and two or more comorbidities. The 10-year prostate cancer mortality was 18.8 percent (CI 9.3-36.8 percent) for men with poorly differentiated cancers and two or more comorbidities [206].

A decision analysis using Medicare data found that aggressively treating men age 70 and older could actually decrease the quality-adjusted life expectancy [207].

By contrast, another decision model, using results from the Scandinavian randomized trial of radical prostatectomy versus watchful waiting and case series utilizing three-dimensional conformal external beam radiation, concluded that many healthy men in their 70s or 80s with at least moderate-grade disease would benefit from aggressive therapy. However, subsequent results from the Scandinavian trial suggest that mortality benefits from radical prostatectomy may be limited to men younger than age 65.

Clinical trial data are insufficient to resolve this issue, though the ERSPC initially found a screening survival benefit only among the core group of men ages 55 to 69.

RECOMMENDATIONS OF OTHERS

The American Cancer Society (ACS) emphasizes the need for involving men in the decision whether to screen for prostate cancer. Men need to have sufficient information regarding the risks and benefits of screening and treatment to make an informed and shared decision; providing them with a decision aid may facilitate the decision-making process [49]. For men who decide to be screened, the ACS recommends prostate-specific antigen (PSA) testing with or without digital rectal examination (DRE) for average-risk men beginning at 50 years of age. Screening should not be offered to men with a life expectancy less than 10 years. Men whose initial PSA level is greater than or equal to 2.5 ng/mL should undergo annual testing; men with a lower initial level can be tested every two years. The guidelines also recommend beginning screening discussions at age 40 to 45 in patients at high-risk of developing prostate cancer (eg, black men and men with a first-degree relative with prostate cancer diagnosed before age 65). The guideline also recommends keeping the biopsy referral threshold at 4.0 ng/mL. However, for men with PSA levels from 2.5 to 4.0 ng/mL, the guideline encourages individualized decision-making and risk assessment [208], which can include age, race, family history, DRE findings, previous biopsy results, and use of five alpha-reductase inhibitors.

The American Urological Association (AUA) updated its guideline in 2013 [209]. The AUA recommends against screening men younger than 40 and also does not recommend routine screening for average-risk men ages 40 to 54, men older than 70, or men with a life expectancy of less than 10 to 15 years. Decisions should be individualized for higher-risk men ages 40 to 54, and the AUA noted that some men over age 70 in excellent health might benefit from screening. The AUA strongly recommends shared decision-making in deciding on PSA screening in men ages 55 to 69. The guideline panel could find no evidence to support the continued use of DRE as a first-line method of screening. The AUA stated that a screening interval of two years for men who choose screening may be preferred to annual screening and that screening intervals can be individualized based on baseline PSA level. The guideline noted the lack of evidence for using any tests (eg, PSA derivatives, PSA kinetics, PSA molecular markers, urinary markers, imaging, or risk calculators) other than PSA for triggering a biopsy referral. While the AUA did not recommend a specific threshold for biopsy referral, they did suggest using a threshold of 10.0 ng/mL for men 70 years and older.

The US Preventive Services Task Force (USPSTF) issued draft recommendations in 2017 to individualize decision-making about prostate cancer screening for men ages 55 to 69, including informing each man about the potential benefits and harms of screening and eliciting his values and preferences for screening. Previously, USPSTF recommended not screening men of any age for prostate cancer [210]; the 2017 draft guidelines continue to recommend against screening men 70 years and older. The USPSTF concluded that new evidence shows screening offers a small potential benefit for reducing the risks of prostate cancer mortality and the occurrence of metastatic disease [13,14,168]. Additionally, the harms from overtreating PSA-detected cancers are being mitigated by increased uptake of active surveillance [173]. USPSTF also concluded that evidence was insufficient to make specific recommendations regarding earlier screening discussions for higher-risk groups: African-American men and those with a family history of prostate cancer.

The Canadian Task Force on Preventive Health Care makes strong recommendations against screening for prostate cancer with PSA for men younger than 55 or older than 69, and makes a weak recommendation against screening with PSA for men ages 55 to 69 [211].

The United Kingdom National Screening Committee does not recommend screening for prostate cancer [212].

The Australian Cancer Council states that the evidence does not support population-based screening and recommends a patient-centered approach that individualizes the decision [213].

The European Society for Medical Oncology (ESMO) recommends against population-based screening and in favor of an individualized approach using shared decision-making [214]. ESMO further states that there is inconsistent evidence on screening men younger than 50 and between 70 and 75 years of age, and evidence that the harms of screening outweigh the benefits for men over age 75.

The Clinical Guidelines Committee of the American College of Physicians (ACP) produced a "guidance statement" in 2013 based on their rigorous review of guidelines developed by other United States organizations, including the American College of Preventive Medicine, the ACS, the AUA, and the USPSTF [169]. The ACP guidance statement recommends that clinicians inform men ages 50 to 69 about the limited potential benefits and substantial harms of prostate cancer screening and only screen men who express a clear preference for being screened. The guidance statement also recommends against screening for prostate cancer in average-risk men under the age of 50 and against screening in men over the age of 69 or with a life expectancy less than 10 to 15 years.

The National Comprehensive Cancer Network (NCCN) guidelines recommend discussing the benefits and risks of prostate cancer screening beginning at age 45 [84]. PSA testing should be offered to men willing to be screened; a baseline DRE could also be considered, particularly for men with elevated PSA values. Subsequent testing would be based on the PSA results, ranging from one- to two-year intervals to three- to four-year intervals. The NCCN supports screening until age 75.

The American Society of Clinical Oncology (ASCO) recommends that providers discuss screening with men with a life expectancy ≥10 years [215]. These discussions, which can be facilitated with decision support tools, should note that screening may save lives but is associated with potential harms arising from biopsies and unnecessary treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Screening for prostate cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Prostate cancer screening (PSA tests) (The Basics)")

Beyond the Basics topics (see "Patient education: Prostate cancer screening (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — Although screening for prostate cancer with prostate-specific antigen (PSA) can reduce mortality from prostate cancer, the absolute risk reduction is very small. Given limitations in the design and reporting of the randomized trials, there remain important concerns that the benefits of screening are outweighed by the potential harms to quality of life, including the substantial risks for overdiagnosis and treatment complications. (See 'Approach to screening' above.)

Because individual patient preferences for specific health outcomes are a deciding factor in determining whether to screen for prostate cancer, men who are potential candidates for screening should be engaged in discussions or decision-making processes that inform them and evoke these preferences. Using decision aids may help ensure that patients receive consistent, complete, and objective information and may optimize time. Summary points suggested by the American Cancer Society (ACS) are discussed above. (See 'Informed decision-making' above.)

Health care providers should periodically discuss prostate cancer screening with men who are expected to live at least 10 years and are old enough to be at significant risk for prostate cancer. (See 'Age to begin screening' above.)

In average-risk men, we suggest that discussions begin at age 50 years (Grade 2B).

In men at high risk for prostate cancer, we suggest that discussions begin at age 40 to 45 years (Grade 2C). High-risk men include black men; men with a family history of prostate cancer, particularly in relatives younger than age 65; and men who are known or likely to have the BRCA1 or BRCA2 mutations. While these men who are at increased risk may be more likely to benefit from screening, there is relatively little evidence addressing this and these men should be informed that the potential benefits and risks of early screening are uncertain.

When a decision is made to screen, we suggest that screening be performed with PSA tests at intervals ranging from every two to four years (Grade 2B). We suggest not performing digital rectal examination (DRE) as part of screening (Grade 2C). (See 'Frequency and method of screening' above.)

When a decision is made to screen, we suggest that screening stop after age 69 or earlier when comorbidities limit life expectancy to less than 10 years, or the patient decides against further screening (Grade 2B). Stopping screening at age 65 may be appropriate if the PSA level is less than 1.0 ng/mL. (See 'Discontinuing screening' above.)

Men with an abnormal DRE (if performed) or PSA level above 7 ng/mL should be referred, without further testing, to a urologist who can evaluate them for a prostate biopsy. (See 'Referrals to urology to evaluate abnormal results' above.)

We suggest that men with a PSA level between 4 and 7 ng/mL undergo repeat testing several weeks later (Grade 2C). Prior to repeat PSA testing, men should abstain from ejaculation and bike riding for at least 48 hours. Men with symptomatic prostatitis should be treated with antibiotics before retesting. Men with a repeat PSA level above 4 ng/mL should be referred to a urologist who can evaluate them for a prostate biopsy. (See 'Referrals to urology to evaluate abnormal results' above.)

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