INTRODUCTION — Prostate cancer is the most commonly diagnosed visceral cancer in the United States. In 2008, an estimated 186,320 prostate cancer cases will be diagnosed, and about 28,660 deaths are expected [1,2]. Prostate cancer is second only to nonmelanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in men.

For an American male, the lifetime risk of developing prostate cancer is 1 in 6, but the risk of dying of prostate cancer is only 2.9 percent [1]. Many more cases of prostate cancer do not become clinically evident, as indicated in autopsy series, where prostate cancer is detected in one-third of men under the age of 80 and in two-thirds of older men [3]. (See "Risk factors for prostate cancer", section on 'Prevalence and age'.) 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 5-year relative survival among men with cancer confined to the prostate (localized) or with just regional spread is 100 percent, compared with 31.9 percent among those diagnosed with distant metastases [1]. While men with advanced stage disease may benefit from palliative treatment, their tumors are generally not curable.

Thus, a screening program that could 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 prostate cancer screening with PSA [4,5]. PSA testing led to a dramatic increase in the incidence of prostate cancer, peaking in 1992 (graph 1) [6]. The majority of these newly diagnosed cancers were clinically localized (graph 2), which led to an increase in radical prostatectomy and radiation therapy, aggressive treatments intended to cure these early-stage cancers [7-10].

However, prostate cancer screening has been a controversial issue because decisions were made about adopting PSA testing in the absence of efficacy data from randomized trials. Subsequently, 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 [11]; however, 48 additional patients would need aggressive treatment to prevent one prostate cancer death. Although the report did not address quality of life outcomes, considerable data show the potential harms from aggressive treatments. Further sustaining the uncertainty surrounding screening, a report from the large United States trial, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, published concurrently with the European trial, found no benefit for annual PSA and digital rectal examination (DRE) screening after seven to ten years of follow-up [12]. The crux of this screening dilemma was aptly stated by the urologist Willet Whitmore [13], who asked "is cure possible in those for whom it is necessary, and is cure necessary in those for whom it is possible?"

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 "Overview of the clinical presentation, diagnosis, and staging of prostate cancer".)

PROSTATE SPECIFIC ANTIGEN (PSA) — 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 [14,15], or even longer [16]. However, PSA is also elevated in a number of benign conditions (table 1), particularly benign prostatic hyperplasia (BPH) and prostatitis. (See "Clinical manifestations and diagnosis of benign prostatic hyperplasia" and "Acute and chronic 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. (See "Measurement of prostate specific antigen", section on 'Causes of an elevated serum PSA'.)

PSA has a half-life of 2.2 days [17], and levels elevated by different benign conditions will have variable recovery times [18-20]. 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 [21,22].
• Ejaculation can increase PSA levels by up to 0.8 ng/mL, though levels return to normal within 48 hours [23,24]. 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 borderline 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 [25], but they generally return to baseline six to eight weeks after symptoms resolve. Asymptomatic prostatic inflammation can also elevate PSA levels [26], but this diagnosis is made on biopsy and so cannot generally be used to defer screening tests [25].
• Prostate biopsy may elevate PSA levels by a median of 7.9 ng/mL within 4 to 24 hours following the procedure [18]. 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 [18]. 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 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 by a median 50 percent within six months of use, though the effects can vary widely, ranging from –81 percent to +20 percent [27]; dutasteride has been reported to reduce PSA 48 to 57 percent [28]. Some experts recommend doubling the measured PSA value before interpreting the result for patients on finasteride [29]. 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 [30].

Test performance — Determining the accuracy of PSA testing has been difficult because most men with normal PSA values will not undergo biopsy unless their digital examination is abnormal. This work-up bias tends to overestimate sensitivity and underestimate specificity [31].

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 [32,33], though the recent trend towards obtaining 12 samples has increased the detection rate [34,35].

Additionally, in protocols that use large numbers of biopsies to evaluate patients with an elevated PSA, cancers may be detected serendipitously 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 [36].

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 [37].

Sensitivity and specificity — The traditional cutoff for an abnormal PSA level in the major screening studies has been 4.0 ng/mL [38-41]. At this level, the sensitivity of PSA has been estimated to be about 70 to 80 percent, while the specificity is estimated to be about 60 to 70 percent [42]. PSA has poorer discriminating ability in men with symptomatic benign prostatic hyperplasia [43].

A nested case-control study looked at 366 men in the Physicians' Health Study who developed a clinically-detected prostate cancer in the early 1980s (before the availability of PSA testing) and 1098 age-matched controls; PSA was later measured from stored serum samples [14]. The PSA cutoff of 4.0 ng/mL had a sensitivity of 73 percent for all cancers detected within four years of entering the study, though the cutoff identified 87 percent of aggressive cancers, defined as advanced stage and/or Gleason score of 7 or greater. The overall specificity of PSA measurement was 91 percent. The authors estimated that a serum PSA >4 ng/mL preceded the clinical detection of cancers by an average of five years (lead time).

An analysis of subjects in the control arm of the Prostate Cancer Prevention Trial, which included generally healthy volunteers with a low initial PSA (≤ 3.0 ng/mL) and normal DRE, found much poorer sensitivity [44]. During the subsequent 7 years, subjects underwent prostate biopsy for all levels of PSA, and a PSA cutpoint of 4.1 ng/mL had a sensitivity of only 21 percent with a specificity of 94 percent for detecting any prostate cancer. Sensitivity was higher for detecting poorly differentiated cancers (Gleason grade ≥8) with a somewhat lower specificity (51 and 89 percent, respectively). As with all screening studies, biopsy may detect cancers that would never have become clinically significant (see 'Overdiagnosis' below.

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 [38,45,46]. For PSA levels between 4.0 to 10.0 ng/mL, the positive predictive value is about 25 percent [45]; this increases to 42 to 64 percent for PSA levels >10 ng/mL [45,47].

However, nearly 75 percent of cancers detected within the "gray zone" of PSA values between 4.0 to 10.0 ng/mL are organ confined and potentially curable [45]. The proportion of organ-confined cancers drops to less than 50 percent for PSA values above 10.0 ng/mL [45]. Thus, detecting the curable cancers in men with PSA levels less than 10.0 ng/mL presents a diagnostic challenge because the high false-positive rate leads to many unnecessary biopsies.

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 [48-51].

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 biopsy; 67 (2.3 percent) had high-grade prostate cancer with a Gleason score of 7 or higher (table 2) [52]. Among men with a PSA concentration between 2.1 and 4.0 ng/mL, 24.7 percent had prostate cancer, and 5.2 percent had prostate cancer with a Gleason score of 7 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 [44]. 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 US [53]. Additionally, many of the cancers detected at these lower levels may never have become clinically evident, thereby leading to overdiagnosis and overtreatment [54].

There is also evidence that diagnosing prostate cancer at low PSA levels does not affect outcome. A study of 875 men undergoing radical prostatectomy found only a limited association between preoperative PSA levels of 2 to 9 ng/mL and cure rates [55]. The disease-free survival curves did not significantly diverge until the preoperative PSA levels reached 7 ng/mL, suggesting that diagnosing cancers at a lower PSA level may be unnecessary. Most of the PSA elevation below 7 ng/mL was attributed to benign hyperplastic tissue. The investigators emphasized the need for a better serum marker to identify early-stage aggressive cancers.

Serial PSA measurements — Less information is available for serial PSA measurements. Both detection rates and positive predictive values decline substantially by the second year of consecutive testing [56,57].

However, two studies suggest that repeated testing increases the likelihood that detected tumors will be pathologically organ confined [39,58]. The sensitivity of PSA screening every four years was evaluated in a population-based cohort participating in a randomized European study of screening [59]. Sensitivity was estimated by comparing the rate of interval cancers (ie, cancers detected between screenings) in the screened group with the number diagnosed in controls over the same four-year period [60]. The sensitivity of PSA screening was 79.8 percent when all 25 interval cancers in the screened group were compared with the 135 cancers detected in the controls and 85.5 percent when the seven cancers that were diagnosed in men who refused an initially recommended biopsy at the first screen were excluded. Since the more typical screening interval in the United States is every one or two years, sensitivity would be expected to be similar or even higher. (See 'Frequency and method of screening' below.)

Secular trends in the utility of PSA — A United States study that looked at the correlation between PSA level and prostate cancer during five-year intervals at a university hospital found that while serum PSA was correlated with prostate cancer stage, grade, and size in the interval from 1983 to 1988, in the interval from 1998 to 2003 it was correlated only with prostate weight (related to benign prostatic hypertrophy) [61].

The authors concluded that in this era of intense screening for prostate cancer, PSA has ceased to be a useful marker, and biopsies in men with an elevated PSA level are only picking up the background prevalence of prostate cancer [61,62]. That is, the same rates of prostate cancer could be found in men of the same age without regard to PSA level, and in many cases the detected tumors would never become clinically significant (see 'Overdiagnosis' below. The authors point out that a study that performed saturation prostate biopsies in men with negative sextant biopsies also found no significant association between PSA level and prostate cancer [63].

The results of these studies raise further concerns about the utility of PSA as a marker for clinically significant prostate cancer; however, additional studies are needed before a change in practice is warranted.

Improving the accuracy 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), PSA density (PSA per unit volume of prostate), free PSA, complexed PSA, and using age- and race-specific reference ranges [64]. (See "Measurement of prostate specific antigen".)

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) [65]. 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 [66]. Accurately measuring PSA velocity requires three serial readings, ideally with the same assay, obtained over at least a 12- to 24-month period [64,67,68].

A more recent study based on European Randomized Study of Screening for Prostate Cancer (ERSPC) data from the Netherlands 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) [69]. However, PSA velocity did not independently predict cancer after adjusting for PSA level. Among the 774 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 [70]. 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.

Some investigators have argued that PSA doubling time or percent change is a more appropriate measure of PSA kinetics [71]. 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 [72].

PSA velocity also appears to be associated with prognosis in men with localized prostate cancer. A study of 1095 men with localized prostate cancer found that over a median follow-up of 5.1 years after radical prostatectomy, compared with men with a lower PSA velocity, men with a rise in PSA concentration above 2.0 ng/mL during the year before cancer diagnosis had a significantly shorter time to death [73]. A greater than 2.0 ng/mL rise in PSA concentration during the year before cancer diagnosis was also associated with a significantly shorter time to death among 358 men with clinically localized disease who were treated with external beam radiation therapy [74].

Similarly, PSA velocity years before prostate cancer diagnosis may predict survival. One study examined outcomes related to PSA velocity in 980 men: 856 without prostate cancer, 104 with prostate cancer who were alive or died of another cause, and 20 who died of prostate cancer [75]. The study found that a higher PSA velocity (>0.35 ng/mL/year) 10 to 15 years before prostate cancer diagnosis, when most PSA levels were below 4.0 ng/mL, was associated with an increased risk of death from prostate cancer 25 years later.

However, as in the case of using the PSA velocity to diagnose cancer, it is unclear whether the association between PSA velocity and prognosis is due to tumors being more aggressive or just being detected at a later time from onset [71]. Although the National Comprehensive Cancer Network is now recommending that biopsy be considered when the PSA velocity is above 0.35 ng/mL/year [76], no studies have prospectively evaluated the efficacy of using PSA velocity as a criterion for biopsy, particularly for low PSA levels.

PSA density — The PSA density measurement is based upon the observation that prostate cancers can produce approximately 10 times more PSA per volume of prostate tissue than benign conditions [17,77]. PSA density measurements, which adjust PSA values for prostate volume, have been reported to better discriminate between cancer and noncancer groups than PSA levels alone [78].

However, PSA density measurements require transrectal ultrasound or magnetic resonance imaging to assess prostate volume, which limits applicability in primary care settings. Additionally, precisely estimating prostate volume is difficult [67].

Data from a large multicenter screening trial suggested that using a cutoff PSA density of 0.15 ng/mL/cm3 (a commonly recommended cutoff value) would miss nearly 50 percent of cancers detected in men with a normal digital rectal examination and PSA levels between 4.0 to 10.0 ng/mL [79]. Adjusting the PSA density cutoff value for total PSA level might improve the test sensitivity [80].

Measuring the PSA density of the prostatic transition zone has also been proposed to improve the specificity of PSA since the hyperplastic tissue that can elevate PSA is almost completely localized to this area of the prostate [64]. Using a PSA transition zone density greater than 0.22 ng/mL/cm3 as a biopsy criterion was estimated to reduce the number of negative biopsies by 24.4 percent based upon data from an Austrian screening study [81]. However, given the logistic difficulties of performing density measurements as well as their lack of reproducibility, the transition zone density is not currently accepted for routine clinical practice [64].

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 [82]. The cancer detection rate for this PSA range in screening populations is about 25 percent [45]. However, the detection rate increased to 56 percent for men with a free-to-total PSA ratio less than 10 percent [82]. 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 [83].

A separate meta-analysis of free PSA noted considerable variability in free PSA assays, specimen handling, cutoffs, and patient populations [84]. 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.

Complexed PSA — Another strategy to improve PSA specificity has been to measure complexed PSA (cPSA). Most circulating PSA is bound to alpha-1-antichymotripsin. A study using archival serum found that, at 95 percent sensitivity, cPSA had a specificity of 26.7 percent compared with 15.6 percent for the free-to-total PSA ratio and 21.8 percent for total PSA [85].

A prospective study in 831 men undergoing prostate biopsy found that cPSA was more specific than total PSA [86]. For men with a total PSA concentration between 4 to 10 ng/mL, when a cPSA cutpoint was chosen to achieve a sensitivity of 90 percent, cPSA had a higher specificity than total PSA (13.3 versus 8.6 percent), but it was less specific than percent free PSA and percent complexed PSA (21.5 and 21.9 percent, respectively). For men with a total PSA concentration between 2 to 6 ng/mL, cPSA was more specific than other methods.

The marginal benefit of measuring complexed PSA over total PSA remains uncertain.

Age-specific reference ranges — PSA levels increase with age, largely due to a higher prevalence of benign prostatic hyperplasia [87]. Although we do not recommend their use, age-specific reference ranges have been developed from normal populations to improve the discriminating power of PSA [88]:

• 40 to 49 years — 0 to 2.5 ng/mL
• 50 to 59 years — 0 to 3.5 ng/mL
• 60 to 69 years — 0 to 4.5 ng/mL
• 70 to 79 years — 0 to 6.5 ng/mL

Raising the PSA biopsy threshold in older men improves specificity, reducing the number of unnecessary biopsies. Conversely, lowering the threshold in younger men improves sensitivity and increases detection of early-stage tumors.

A retrospective analysis of a large screening cohort reported that applying age-specific reference standards would miss 47 percent of clinically localized cancers in men 70 and older and lead to a 45 percent increase in unnecessary biopsies for men in their 50s [89].

The clinical utility of age-specific reference ranges remains uncertain, and they are not recommended by the US Food and Drug Administration (FDA) or PSA assay manufacturers [64].

Race-specific reference ranges — Black men in the United States have the world's highest incidence of prostate cancer and are the most likely to present with advanced stage disease [10]. PSA levels in blacks are higher compared with whites even after adjusting for age, clinical stage, and histology [90]. This difference has been attributed to blacks having larger tumor volumes across all clinical stages.

Although we do not recommend their use, race-specific PSA reference ranges have been established in the hope of achieving earlier diagnosis [91]:

• 40 to 49 years — 0 to 2.5 ng/mL (whites); 0 to 2.0 ng/mL (blacks)
• 50 to 59 years — 0 to 3.5 ng/mL (whites); 0 to 4.0 ng/mL (blacks)
• 60 to 69 years — 0 to 3.5 ng/mL (whites); 0 to 4.5 ng/mL (blacks)
• 70 to 79 years — 0 to 3.5 ng/mL (whites); 0 to 5.5 ng/mL (blacks)

However, a study of 651 men undergoing radical prostatectomy found that the race-specific reference ranges, which raise the cutoff for blacks 50 years and older compared with whites, would be associated with similar or worse outcomes [92]. The clinical utility of the race-specific reference ranges, which have also been developed for Asians [93], remains uncertain.

Summary — There is no consensus on using any of the PSA modifications, and none of them has been shown 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 [37,54,64]. However, recommendations may change given that most ERSPC sites used a cutoff of 3.0 ng/mL [11].

Ongoing efforts are targeted at identifying new serum markers that will have greater specificity for prostate cancer as well as a better prognostic value [64,94]. (See "Measurement of prostate specific antigen".)

DIGITAL RECTAL EXAMINATION — Digital rectal examination (DRE) has long been used to diagnose prostate cancer. Abnormal prostate findings include nodules, asymmetry, or induration. DRE can detect tumors in the posterior and lateral aspects of the prostate gland; an inherent limitation to the digital examination is that only 85 percent of cancers arise peripherally where they can be detected with a finger examination [95]. Stage T1 cancers are nonpalpable by definition.

No controlled studies have shown a reduction in the morbidity or mortality of prostate cancer when detected by DRE at any age [96]. The majority of cancers detected by digital examination alone are clinically or pathologically advanced [97]. Thus, the greatest value of DRE may be its use in combination with PSA testing (see 'Combining PSA and DRE' below.

Test performance — Urologists have been found to have relatively low interrater agreement for detecting prostate abnormalities [98]. 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 [47]. Although screening DRE increased the likelihood of finding early disease, it also increased the odds three- to ninefold 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 [99].

Positive predictive value — The positive predictive value of an abnormal DRE for prostate cancer varies from 5 to 30 percent [45,97,100-103]. A meta-analysis calculated an overall positive predictive value of 28 percent [99].

COMBINING PSA AND DRE — Prostate specific antigen (PSA) and digital rectal examination (DRE) are somewhat complementary, and their combined use can increase the overall rate of cancer detection [37,45,104-106]. 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 [45,101]. PSA detected significantly more of the cancers than digital examination (82 percent versus 55 percent). Overall, 45 percent of the cancers were detected only by PSA, while just 18 percent were detected solely by digital examination.

Investigators reported a positive predictive value of 10 percent for a suspicious digital examination when the PSA level was normal. However, the positive predictive value was 24 percent for an elevated PSA level with a normal digital examination. 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 [103].

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 ERSPC, which found a small survival benefit with PSA screening, did not consistently require DRE [11]. The PLCO found no survival benefit with combined PSA and DRE screening [12].

OTHER TESTS

Transrectal ultrasonography — Transrectal ultrasonography (TRUS) is an outpatient procedure that requires no sedation or analgesia and is relatively well tolerated by most men.

TRUS is not recommended as a primary screening test for prostate cancer because of its low sensitivity and positive predictive value. As an example, in one study almost 40 percent of cancers would have been missed if prostate biopsies had been performed only in men with suspicious findings on TRUS [45]. Furthermore, TRUS is not a feasible screening test in primary care clinics. TRUS is typically used to guide prostate biopsy rather than as a screening test.

Prostate biopsy — Screening for prostate cancer could be accomplished by routine prostate biopsy. Transrectal biopsy is a relatively simple outpatient technique.

The standard procedure was to obtain a specimen with a biopsy gun in any suspicious areas, followed by tissue cores from the base, middle, and apical areas on each side of the prostate (sextant biopsies). More recently, sextant biopsies have begun to be replaced by extended biopsy schemes that add lateral biopsies of the peripheral zones [107]. (See "Overview of the clinical presentation, diagnosis, and staging of prostate cancer", section on 'Prostate biopsy'.) Complications include mild rectal spotting, hematospermia, or hematuria; rarely, patients experience more significant rectal bleeding or sepsis.

Use of this procedure for screening purposes is limited by cost, unacceptability to large numbers of men, and the need for a urologic referral. For these reasons, it is not recommended as a screening test.

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 PSA screening (an average of once every four years) or a control group that was not offered screening [11]. 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 DRE, transrectal ultrasonography, and/or measurements of free PSA levels. The rate of prostate cancer screening in the control group was not reported.

After a median follow-up of nine years, for the 162,243 men between the ages of 55 and 69 the primary outcome of prostate cancer mortality was 20 percent lower in the group offered screening (rate ratio 0.80, 95% CI 0.65-0.98). The absolute risk difference in prostate cancer mortality was 0.71 deaths per 1000 men, which suggests that 1410 men needed to be screened to prevent one prostate cancer death over nine years. Prostate cancer was diagnosed more frequently in the screening group (8.2 versus 4.8 percent), such that 48 additional cases of prostate cancer would need to be detected by screening to prevent one death from prostate cancer over nine years. Several centers collected quality-of-life data, however these results have not yet been published.

Although the absolute mortality benefit for screening was low, several factors could have biased the results toward no effect. While not addressed in the study report, a substantial proportion of the control group likely received PSA testing, as evidenced by the 31 percent of cancers that were diagnosed with stage T1c (tumor identified by needle biopsy). 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 five to ten year lead time associated with PSA testing, follow-up duration may have been insufficient to accurately estimate the survival benefit. However, any survival benefit from screening would not be realized for many years, while the burdens of screening and treatment, including harms from overdiagnosis and overtreatment, would occur immediately and potentially have lifelong consequences.

Several biases could also have favored the screening group [108]. A higher proportion of cancers diagnosed in the screening group were aggressively treated (surgery or radiation) compared to the control group, so some of the outcome differences could be related more to improved treatment than screening. 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 [109]. The ERSPC investigators did not report the association of cancer death and receipt of treatment.

• In the United States Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) 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 [12]. A PSA level above 4.0 ng/mL or an abnormal DRE were indications for biopsy. A high proportion of men in the control group underwent PSA testing (52 percent in the sixth year of the study).

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). 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).

The negative results could be attributable to the high rate of PSA testing in the control arm, the higher PSA cutoff for biopsy compared with that used in the ERSPC, or the relatively short follow-up period. Additionally, approximately 16 percent of subjects in the screening group did not receive either prostatectomy or radiotherapy. An earlier PLCO 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 [110]. All these factors could bias the PLCO trial toward a null result, and also suggest that further follow-up is not likely to yield positive results.

One earlier randomized trial of screening for prostate cancer reported positive findings, but the data analysis was flawed. In this population-based study in Quebec, 46,193 men aged 45 to 80 years identified from electoral records were randomly assigned to screening with prostate specific antigen (PSA) and digital rectal examination (DRE) versus no screening [56]. In an analysis that excluded the 77 percent of men in the screening arm who declined screening and excluded the 6.5 percent of men in the control group who were screened, the prostate cancer mortality rate in men undergoing screening was reported to be 67.1 percent lower than in the control group. When the data were evaluated by a more appropriate intention-to-screen analysis, there were no mortality differences between the two groups (4.6 versus 4.8 deaths per 1000 persons, respectively). Additionally, the results suggesting benefit seemed biologically implausible, since the survival benefit became apparent within only three years, a very short time for a screening program to be effective given the long lead time for prostate cancer.

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.

Over the past decade, Surveillance Epidemiology and End Results (SEER) tumor registry data have shown a significant decline in the incidence of advanced stage disease, potentially consistent with effective screening [111]. Prostate cancer mortality rates, which initially increased following the advent of PSA testing, have now declined to pre-PSA levels (graph 1) [111].

These mortality trends, however, are difficult to interpret. Some ecologic data suggest an association between PSA testing and declining mortality rates:

• In Austria, the state of Tyrol introduced mass screening in 1993. Within five years, investigators observed a more than threefold adjusted decrease in prostate cancer mortality rates in Tyrol compared with the rest of the country where screening was less common [112].
• Data from Olmsted County in Minnesota demonstrated that age-adjusted 1993 to 1997 prostate cancer mortality rates declined 22 percent (95% CI –49 to 17) compared with rates measured in years before PSA testing [113].
• A study found that age-adjusted prostate cancer mortality peaked in the early 1990s in both the United States and the United Kingdom, but then declined much faster in the US, where PSA screening became common, than in the UK, where PSA screening was less common (yearly decline -4.2 versus -1.1 percent) [114].

However, other ecologic studies have shown declining mortality rates even in the absence of intensive screening:

• Trends in prostate cancer mortality rates in Wales and England from 1991 to 1997 were comparable to trends in the United States. Mortality rates declined by 1.7 percent in the United Kingdom, even though PSA screening was not routinely performed and even discouraged [115].

Regional practice variation has allowed investigators to evaluate the effect of screening and treatment on prostate cancer mortality within the United States:

• Medicare beneficiaries in Seattle received more intensive PSA screening and aggressive cancer treatment from 1987 to 1990 than beneficiaries in Connecticut. However, there were no differences in prostate cancer-specific mortality over 11 years of follow-up; the adjusted mortality rate ratio was 1.03 (95% CI 0.95-1.11) in Seattle compared with Connecticut [116].

Alternative explanations have been proposed for declining mortality rates:

• Better treatment could also reduce mortality rates, particularly androgen deprivation therapy for men with advanced-stage cancer. These treatments could allow men to survive long enough to die from a comorbid condition.
• Some experts have argued that the curious mortality trends observed in the PSA era (an initial rise and subsequent decline that paralleled the incidence trends) could also be explained by attribution bias [117]. This bias occurs when deaths are incorrectly attributed to prostate cancer in men whose deaths were actually caused by another disease. If a fixed proportion of deaths in people known to have prostate cancer are consistently misattributed to prostate cancer, then the mortality rates would follow the rising and falling incidence of cancer in the population, as was observed in the 1990s.

Case-control studies have also examined the relationship between screening and prostate cancer outcomes. A large nested case-control study found no evidence that PSA screening for prostate cancer reduces all-cause mortality (odds ratio 1.08, 95% CI 0.71-1.64) [118]. Two other case-control studies found no significant reduction in prostate-cancer mortality with PSA screening (odds ratio 1.19 (95% CI 0.76 - 1.60)) [119] or the combination of PSA and DRE screening (odds ratio 0.70, 95% CI 0.46, 1.1) [120]. However, another case-control study found that screening was associated with a decreased risk of metastatic prostate cancer [121]. Methodologic differences may explain these conflicting results [122].

Evidence from modeling studies — Simulation models using data from Surveillance Epidemiology and End Results (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 [123]. However, treatment advancements may have also contributed to the declining mortality rates.

HARM FROM SCREENING

Risks of screening — Although prostate biopsies very rarely (<1 percent) cause complications serious enough to require hospitalization [124], the procedure can lead to anxiety and physical discomfort [125]. 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 [126,127]. 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 [128].

Overall, 16.2 percent of PSA tests in the ERSPC screening group were positive, and 11 percent of men with abnormal tests underwent prostate biopsy [11]. However, the positive predictive value for a positive PSA test was only 24.1 percent. These data suggest that screening can substantially increase the number of men suffering harms from biopsy.

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 is now 1 in 6, the lifetime risk of dying from prostate cancer is only 1 in 34 [1].
• Although about 80 percent of detected cancers are considered clinically important based on tumor size and grade [129], 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 [130-132].
• A study that applied computer-simulation models of PSA testing to SEER cancer incidence data estimated that 29 percent of cancers detected in whites and 44 percent of cancers detected in blacks were overdiagnosed [133]. 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 [134].
• Similarly, a study that applied simulation models to the results of the ERSPC estimated a 50 percent overdetection rate with annual screening for men ages 55 to 67 [15]. Given that the screening group in the ERSPC had a 71 percent higher cumulative incidence of prostate cancer than the control group (8.2 versus 4.8 percent) [11], 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 (US) each year after 1986, the year before PSA screening was introduced, until 2005 [135]. 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 US 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 [136].

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 is about 0.5 percent [137], though the rate approaches 1 percent in men over 75 years [138].
• 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 [139,140].

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 [139,141].

Given the ERSPC study estimate that 48 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 nine 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 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.

The United States Preventive Services Task Force Guidelines [142], American College of Physicians [143], American Urologic Association [144], American Cancer Society [104,143], and the Canadian Task Force on the Periodic Health Examination [145] all stress the importance of informed decision making.

Urologists, other experts, and lay people with and without prostate cancer have somewhat different opinions on what information is most important to communicate to men considering screening. In a study that included various groups, there was consensus on the need for information about the possible occurrence of false-negative and false-positive screening results and the uncertainty about whether PSA testing will reduce prostate cancer mortality [146]. Experts would also disclose the uncertain benefits of treating early, localized prostate cancer. The urologists would disclose that prostate cancer is often incurable when symptoms appear, while the nonurologists would disclose that cancer is often asymptomatic. Lay people expressed interest in being told that PSA testing involves a blood test and that testing could provoke anxiety. Lay people also felt it was important to disclose that PSA testing may detect cancer at an earlier stage than digital rectal examination but that PSA testing is controversial.

The American College of Physicians provided a useful summary of discussion points to consider when counseling patients about prostate cancer screening (adapted to include subsequent trial data) [143]:

• Prostate cancer is an important health problem.
• The mortality benefits of repeated screening and aggressive treatment of prostate cancer are limited.
• Digital rectal examinations and PSA measurements can have both false-positive and false-negative results.
• The probability that further invasive evaluation will be required as a result of testing is relatively high.
• Aggressive therapy is necessary to realize any benefit from the discovery of a tumor.
• A small but finite risk for early death and a significant risk for chronic illness, particularly with regard to sexual and urinary function, are associated with these treatments.
• Early detection can save lives.
• Early detection and treatment may avert future cancer-related illness.

Clinicians find it challenging to provide comprehensive, consistent, and balanced information about prostate cancer screening decisions during clinic visits [147]. Consequently, efforts have focused on using decision aids to help patients understand screening issues and make informed decisions for screening [148].

Investigators have evaluated a number of interventions to facilitate such informed prostate cancer screening decisions including videotapes [149-151], patient group discussions [149], brief scripts read to patients during clinic visits [152], verbal and written material provided before a periodic health examination [153], and informational pamphlets distributed at study visits [154] or through the mail [155].

The various strategies of providing information were shown to be consistently effective in increasing patient knowledge about prostate cancer and screening [149-151,154,155]. One study also found that providing men with screening information increased their involvement in making screening decisions and lowered their levels of decisional conflict [153].

Most studies have also demonstrated that men receiving screening information report less interest in undergoing PSA testing [149-151,155] or receiving aggressive prostate cancer treatment [149,150,152,155]. As an example, one study randomly assigned 176 men to usual care, a face-to-face discussion of PSA testing, a videotape developed by The Foundation for Informed Medical Decision Making (information available at www.fimdm.org/decision_sdms.php) [150], or a combination of videotape and discussion [149]. Among men assigned to usual care, 98 percent selected PSA testing, compared with 82 percent with the discussion, 60 percent with the videotape, and 50 percent with the combined intervention.

Another study showed that an educational pamphlet (available at www.va.gov/visn5/docs/psa_screening.pdf) was comparable to the above videotape in enhancing patient knowledge about prostate cancer, increasing participation in decision making for screening, and altering screening preferences [156].

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.

Age to begin screening — Screening should be discussed with men beginning at age 50, though not with men who have a comorbidity that limits their life expectancy to less than 10 years [37,104].

Black men, men with a family history of prostate cancer, and men who are known or likely to have the BRCA1 or BRCA2 mutations should first discuss screening at age 40 to 45 [157]. (See "Risk factors for prostate cancer", section on 'Genetic factors'.)

Others, including other authors for UpToDate, suggest not initiating screening discussions earlier in higher risk men, given that age is a primary determinant of risk and earlier discussions increase the risk of harms related to screening. (See "Overview of preventive medicine in adults", section on 'Prostate cancer'.)

Frequency and method of screening — When a decision is made to screen for prostate cancer, the recommended strategy has been to perform a digital examination and measure a PSA level [37,104]. However, the randomized ERSPC found that PSA screening alone, measured at an average interval of four years (range two to four years), resulted in a significant, though small, reduction in prostate cancer mortality [11]. The PLCO study, which screened with annual PSA and DRE, found no reduction in mortality [12]. The optimal interval and combination of tests remains uncertain, however based on current data we suggest screening every two to four years with PSA alone.

Screening studies have shown that cancer detection rates and the positive predictive value of PSA substantially decrease after the initial screening [56,57]. As an example, among 10,248 participants in a screening study, the cancer detection rate decreased from 3 percent to less than 1 percent with serial testing. The positive predictive value for PSA levels between 4.0 to 9.9 ng/mL decreased from 22 percent to 2 percent by the fourth screening visit; the positive predictive value for PSA ≥10 ng/mL decreased from 57 percent to 4 percent during the same interval [57].

An analysis from the ERSPC compared outcomes from two centers with different screening intervals, Gothenburg (2 years; n = 4202) and Rotterdam (4 years; n = 13,301) [158]. 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 biannually from ages 50 to 75, while still using the 4.0 ng/mL cutoff as a criterion for biopsy referral [159].

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) [160-162]:

• The Prostate, Lung, Colorectal and Ovarian (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 [160]. 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 digital rectal examination (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 European Randomized Study of Screening for Prostate Cancer (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 [161]. The estimated cancer detection rate was 0.15 percent during a four-year interval.

In the PLCO 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 [160]. A separate report came to a similar estimate [163]. 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 [161].

Referrals for biopsy — Men with abnormal prostate exams (nodules, induration, or asymmetry) should be referred to a urologist for a transrectal ultrasound-guided prostate biopsy.

Men with abnormal PSA values can also be referred for biopsy, though some experts recommend first repeating the PSA several weeks later, particularly for borderline elevations below 7.0 ng/mL [55,67]. PSA measurements have considerable short-term variability [66,164]. 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 [165].

In addition to biological variability, PSA may be transiently elevated due to ejaculation, perineal trauma, or prostatitis. Before repeating a borderline elevated PSA test, patients should be asked to refrain from sexual activity and bike riding for at least 48 hours and, if there is evidence of prostatitis, complete a course of antibiotics. (See "Acute and chronic bacterial prostatitis".)

While a PSA level of 4.0 ng/mL had been considered abnormal, the ERSPC used lower PSA ranges (2.5 to 3.0 ng/mL) in conjunction with ancillary tests (DRE, transrectal ultrasonography) to guide biopsy referrals [11]. The PLCO, which used a PSA level of 4.0 ng/mL, found no survival benefit for screening, which lead investigators to question whether a lower PSA threshold should be used [12]. We suggest that a PSA level of 3.0 ng/mL be considered abnormal in determining who should be referred for biopsy.

Biopsy 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. We suggest that men with a PSA below 3.0 ng/mL who experience a rise in PSA level of more than 0.75 ng/mL/year (based on at least three measurements obtained over 12 to 24 months) be referred for biopsy. (See "Overview of the clinical presentation, diagnosis, and staging of prostate cancer", section on 'Serum PSA elevation'.)

Attempts have been made to create risk models for prostate cancer based on multiple variables (eg, PSA, family history, DRE result, PSA velocity, etc.) [166]. Until such models have undergone additional study, we do not recommend using them to decide who should undergo biopsy.

Repeat biopsies — If a biopsy is positive, the cancer will be staged, and the patient will be presented with treatment options. AUA guidelines recommend that patients should resume routine screening if the biopsy is negative [37]. However, given the potential for false-negative results, some investigators have recommended repeating the biopsies.

A study that repeated 100 negative sextant biopsies found cancer in 20 percent [33]. Among five men with high-grade PIN at initial biopsy, all had carcinoma detected on repeat biopsy, as did 5 of 17 (29.4 percent) of men with atypia; only 10 of 69 (14.5 percent) men without PIN or atypia had cancer detected. PSA levels above 20 ng/mL also predict positive repeat prostate biopsies [167].

In a study of serial biopsies in 1051 Austrian and Belgian participants in the European Prostate Cancer Detection study with PSA levels between 4.0 to 10.0 ng/mL, cancer was detected in 83 of 820 (10 percent) men with BPH who underwent repeat biopsy six weeks after a negative biopsy [168]. A percent free PSA less than 30 percent and a PSA density greater than 0.26 ng/mL/cc were the most accurate predictors of cancer detection with areas under the ROC curves of 74.5 percent and 61.8 percent, respectively. Cancer was detected in 5 percent of men undergoing a third biopsy and 4 percent of men undergoing a fourth biopsy. However, tumors detected with these biopsies were significantly smaller and better differentiated than tumors found with the first two biopsies. The authors concluded that repeating one biopsy was justified [169].

In contrast, 272 men in the screening arm of the ERSPC, Rotterdam had a PSA ≥4.0 ng/mL and a negative biopsy and underwent repeat screening four years later [170]. In 217 of the men with a repeat PSA ≥3.0 ng/mL a biopsy was performed; prostate cancer was found in 18 (positive predictive value 8.3 percent). The majority (88.5 percent) of cancers detected during the second round of screening were organ confined, and the authors concluded that there was no need for immediate repeat biopsies in men with a PSA ≥4.0 ng/mL and a negative initial biopsy.

We suggest that men with negative extended biopsies (biopsies performed using an extended protocol as opposed to just sextant biopsies) resume routine screening. (See "Overview of the clinical presentation, diagnosis, and staging of prostate cancer", section on 'Prostate biopsy'.)

Stopping 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 only men 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 Aging Study 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 [171]. 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.
• An observational study of Swedish men who were diagnosed with clinically localized prostate cancer (at a mean age of 72 years) found that the men choosing watchful waiting had an 11 percent chance of dying from prostate cancer during 15 years of follow-up, compared with 10 percent among men who received initial treatment [172]. However, when follow-up of the men choosing watchful waiting was extended to 21 years, the mortality rate from prostate cancer increased approximately threefold for men who survived beyond 15 years [173]. The authors concluded that aggressive treatment might be warranted for men with a life expectancy exceeding 15 years, corresponding to an age at diagnosis of 70 years.
• In contrast to the results of the Swedish study, a population-based cohort study of 767 Connecticut men who were ages 55 to 74 when diagnosed with clinically localized prostate cancer, and who were treated with observation or androgen deprivation therapy, found that annual prostate cancer mortality remained stable for men surviving beyond 15 years [174]. The men were followed for more than 20 years (median follow-up 24 years) and the adjusted mortality rate beyond 15 years was similar to that during the first 15 years (rate ratio 1.1, 95% CI 0.6-1.9).
• A decision analysis using Medicare data found that aggressively treating men age 70 and older could actually decrease the quality adjusted life expectancy [175].
• In contrast, another decision model, using results from the Scandinavian randomized trial of radical prostatectomy versus watchful waiting [176] 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 [177]. However, subsequent results from the Scandinavian trial suggest that mortality benefits from radical prostatectomy may be limited to men younger than age 65 (graph 3) [178].

Currently, clinical trial data are insufficient to resolve this issue.

RECOMMENDATIONS FOR SCREENING BY EXPERT GROUPS — None of the major medical associations and societies have reissued guidelines following the publication of trial data from the ERSPC and PLCO studies. Previously, these expert groups had not come to a clear consensus regarding recommendations for screening for prostate cancer.

• The United States Preventive Services Task Force (USPSTF) concluded that there is insufficient evidence to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 [179]. The USPSTF recommends against screening for prostate cancer in men ages 75 or older because the harms of screening outweigh the benefits. The USPSTF clinical practice guideline for screening for prostate cancer, as well as other USPSTF guidelines, can be accessed through the website for the Agency for Healthcare Research and Quality at www.ahrq.gov/clinic/uspstfix.htm.
• The Canadian Task Force on Preventive Health Care recommends against screening for prostate cancer with PSA or TRUS and states that there is insufficient evidence to recommend for or against screening with DRE [180].
• A number of European groups, including the European Union, recommend against screening for prostate cancer while awaiting the results of randomized trials [181].
• The American Cancer Society (ACS) emphasizes the need for clinicians to provide men with adequate information regarding the risks and benefits of screening [104]. The ACS recommends that serum PSA testing and DRE should be offered annually to men 50 years of age and older who have a life expectancy of 10 years. The guidelines also stress the benefit of screening beginning at age 45 in patients at high-risk of developing prostate cancer (eg, black men and men with a first-degree relative with prostate cancer diagnosed at a younger age). PSA testing is recommended for men who ask their clinicians to make the decision about screening on their behalf. The American Urological Association (AUA) also supports this policy [182].
• Similar to the AUA and ACS, the American College of Physicians (ACP) recommendation states that "Rather than screening all men for prostate cancer as a matter of routine, physicians should describe the potential benefits and known harms of screening, diagnosis, and treatment; listen to the patient's concerns; and then individualize the decision to screen" [143]. The ACP also suggests that men between the ages of 50 to 69 years are most likely to benefit from screening. Black men and men with a positive family history of prostate cancer should be informed of their higher lifetime risk, although the available evidence does not suggest that they need to be treated differently from men at average risk.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Prostate cancer screening".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS — Although screening for prostate cancer with 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. (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:

• - Discussions should present men with information on the risks and benefits of screening, such as those in the summary points suggested by the American College of Physicians that are discussed above (see 'Informed decision making' above. Using existing written or video decision aids may help ensure that patients receive consistent, complete, and objective information and may optimize the time spent discussing screening during a clinic visit.
• - 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. We suggest that discussions begin at age 50 in average risk white men and at age 40 to 45 in black men, men with a positive family history, and men who are known or likely to have the BRCA1 mutation (Grade 2B). Men who are at increased risk of prostate cancer because of race or family history may be more likely to benefit from screening. (See 'Age to begin screening' above.)

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

• When a decision is made to screen, we suggest that screening be performed until comorbidities or age (75 years) 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 'Stopping screening' above.)

• Men with an abnormal DRE or PSA level above 7 ng/mL should be referred for transrectal ultrasound-guided prostate biopsy without further testing. (See 'Referrals for biopsy' above.)

• We suggest that men with a PSA level between 3 ng/mL 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 prostatitis should be treated with antibiotics before retesting. Men with a repeat PSA level above 3 ng/mL should be referred for transrectal ultrasound-guided prostate biopsy. (See 'Referrals for biopsy' above.)

• Men with a PSA below 3.0 ng/mL should not normally undergo biopsy. However, we suggest that men who experience a rise in PSA level of more than 0.75 ng/mL/year (based on at least three measurements obtained over 12 to 24 months) be referred for biopsy (Grade 2C). (See 'Referrals for biopsy' above.)

• We suggest that men with negative extended biopsies (biopsies performed using an extended protocol as opposed to just sextant biopsies) resume routine screening (Grade 2C). (See 'Repeat biopsies' above.)