Screening for prostate cancer

Author
Richard M Hoffman, MD, MPH
Section Editors
Joann G Elmore, MD, MPH
Michael P O'Leary, MD, MPH
Deputy Editor
Michael E Ross, MD
Contributor disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2016. | This topic last updated: Jun 14, 2016.
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 2016, there
are expected to be approximately 181,000 new prostate cancer diagnoses and approximately
26,100 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, in 2012 there were estimated to be 1,112,000 new cases of prostate cancer
and 308,000 prostate cancer deaths, making it the second most commonly diagnosed cancer in
men and the fifth 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]
(see "Risk factors for prostate cancer", section on '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 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].
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 [12].
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 [13];

however, 48 additional patients would need to be diagnosed with prostate cancer 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, including erectile dysfunction,
urinary incontinence, and bowel problems [14]. 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 7 to 10 years of
follow-up [15].
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) 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 prostatespecific antigen".)
Studies have estimated that PSA elevations can precede clinical disease by 5 to 10 years
[16,17] or even longer [18]. 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 [19], and levels elevated by different benign conditions will have
variable recovery times [20-22]. 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
[23,24].
Ejaculation can increase PSA levels by up to 0.8 ng/mL, though levels return to normal
within 48 hours [25,26]. 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 [27], but they generally return to baseline six
to eight weeks after symptoms resolve. Asymptomatic prostatic inflammation can also
elevate PSA levels [28], but this diagnosis is made on biopsy and so cannot generally be
used to defer screening tests [27].
Prostate biopsy may elevate PSA levels by a median of 7.9 ng/mL within 4 to 24 hours
following the procedure [20]. 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 [20]. 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 levels by a median 50 percent within six months of use, though the effects can vary
widely, ranging from 81 percent to +20 percent [29]; dutasteride has been reported to reduce
PSA levels by 48 to 57 percent [30]. Some experts recommend doubling the measured PSA
value before interpreting the result for patients on finasteride [31]. 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 [32]. 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 [33,34].
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 [35].
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 [36,37], though the recent trend towards obtaining 12 samples has increased
the detection rate [38,39].
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 cm 3 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 [40].
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 cm 3 to have a greater risk for
progression, there is no certainty that these cancers will lead to early death or reduce quality of
life [41].
Sensitivity and specificity The traditional cutoff for an abnormal PSA level in the major
screening studies has been 4.0 ng/mL [42-45]. The American Cancer Society systematically
reviewed the literature assessing PSA performance [46]. 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 3.0ng/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 benign prostatic hyperplasia [47].

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 [42,48,49]. For PSA levels between 4.0 to 10.0 ng/mL, the positive predictive
value is approximately 25 percent [48]; this increases to 42 to 64 percent for PSA levels
>10 ng/mL [48,50].
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 [48]. The proportion of organconfined cancers drops to less than 50 percent for PSA values above 10.0 ng/mL [48]. 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.
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 [51]. (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/mLand normal digital rectal examinations
are found to have prostate cancer [52-55].
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 endof-study biopsy; overall, seven (1.6 percent of cancers) had high-grade prostate cancer with a
Gleason score of 8 or higher [51]. 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 [56]. 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 [57]. Additionally, many of the cancers detected at these lower levels may never have
become clinically evident, thereby leading to overdiagnosis and overtreatment [58].
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 [59]. 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 Both detection rates and positive predictive values decline
substantially with serial testing [60-63]:
During four rounds of annual PSA screening in the PLCO trial, the number of cancers
detected per 1000 men decreased from 14.2 to 9.3 [62]. 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 ERSPC, which used a 4-year screening interval,
decreased from 5.1 percent in the first round of screening to 4.4 percent in the second
round [63]. 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 [43,62-64] (see 'Frequency
and method of screening' below):
In the PLCO, 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 [62].
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 [63].
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) and using age- and race-specific reference
ranges [65]. We suggest not routinely using any of these strategies in deciding which men to
refer for biopsy. (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) [66]. 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 [67]. Accurately measuring PSA velocity requires three serial
readings, ideally with the same assay, obtained over at least a 12- to 24-month period
[65,68,69].
However, analyses of more recent clinical data from randomized trials suggest that PSA velocity
adds little predictive information to the total PSA:
The European Randomized Study of Screening for Prostate Cancer (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) [70]. 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 ROC curve 0.57 versus 0.53) for detecting prostate cancer, but not for detecting highgrade disease [71].
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 [72]. 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 [73,74]. 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
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
[75].
Some investigators have argued that PSA doubling time or percent change is a more
appropriate measure of PSA kinetics [76]. 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 [77].
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 [78]. The cancer detection rate for this
PSA range in screening populations is approximately 25 percent [48]. However, the detection
rate increased to 56 percent for men with a free-to-total PSA ratio less than 10 percent [78]. 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 [79].
A separate meta-analysis of free PSA noted considerable variability in free PSA assays,
specimen handling, cutoffs, and patient populations [80]. 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. Using the %[-2]ProPSA might reduce unnecessary biopsies for men with PSA values
between 2 and 10 ng/mL. The Prostate Health Index (PHI) is a derived measure that
incorporates %[-2]ProPSA, free PSA, and total PSA. 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 [81]. Quality of the literature was
assessed as moderate-high, but there was significant heterogeneity across studies. Areas under
the receiver operating characteristic curve (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 [82]. However,
there is no high-level clinical evidence supporting these recommendations.
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, digital rectal examination 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 [83]. In 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 [82].
Age-specific reference ranges PSA levels increase with age, largely due to a higher
prevalence of benign prostatic hyperplasia [84]. Although we do not recommend their use, agespecific reference ranges have been developed from normal populations to improve the
discriminating power of PSA [85]:
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 [86].
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
[65].
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
[11]. PSA levels in blacks are higher compared with whites even after adjusting for age, clinical
stage, and histology [87]. 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 [88]:
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 [89]. The clinical utility of the race-specific
reference ranges, which have also been developed for Asians [90], remains uncertain.
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 [41,58,65]. Ongoing efforts are targeted at identifying new serum markers that
will have greater diagnostic accuracy for prostate cancer, particularly for aggressive tumors
[65,91]. (See "Measurement of prostate-specific antigen".)
DIGITAL RECTAL EXAMINATION We suggest not performing digital rectal examination
(DRE) for prostate cancer screening whether alone or in combination with PSA screening.
(See 'Combining PSA and DRE' below.) 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 [92]. 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 [93]. The majority of cancers detected by digital examination
alone are clinically or pathologically advanced [94].
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 [95]. 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 [50]. Although screening
DRE increased the odds likelihood of finding early disease, it was also associated with a threeto nine-fold 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 [96].
Positive predictive value The positive predictive value of an abnormal DRE for prostate
cancer varies from 5 to 30 percent [48,94,97-100]. A meta-analysis calculated an overall positive
predictive value of 28 percent [96].
COMBINING PSA AND DRE We suggest not performing digital rectal examination (DRE) for
prostate cancer screening whether alone or in combination with PSA screening. PSA and DRE
are somewhat complementary, and their combined use can increase the overall rate of cancer
detection [41,48,101-103]. 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 [48,98]. PSA detected significantly more of the cancers than digital

examination (82 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 [100].
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 [13]. The PLCO found no survival benefit with combined PSA and DRE screening
[15].
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 [104]. A PCA3 score, based on the ratio of PCA3 mRNA over 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.
A 2010 review identified 11 clinical trials, representing 2737 subjects, evaluating the diagnostic
performance of PCA3 [105]:
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.
However, 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 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 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 [106]. Based on receiver operating characteristic (ROC) curve analysis of 721 subjects
undergoing biopsy, PCA3 performed only marginally better than total PSA (area under the curve
0.64 versus 0.58, p = 0.14); 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.
While PCA3 may eventually have a role in reducing unnecessary biopsies, there are insufficient
data on clinical outcomes to currently support routine use [107].

EFFECTIVENESS OF PROSTATE CANCER SCREENING Apart from issues of cost and

acceptability, in order for prostate cancer screening to be valuable, it must reduce diseasespecific 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 [13].
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 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 [108].
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) [109]. 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 4901929) 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 [13]. 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) [110]. 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, the absolute rate difference has dropped only from
0.06 fewer prostate cancer deaths per 1,000 person-years after nine years of follow-up to
the 13-year rate of 0.11 fewer deaths per 1,000 person-years [109]. Furthermore, while the
prostate cancer survival benefit from screening was not initially realized until nine years of
follow-up [13], 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 [111]. A higher proportion of
high-risk 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 [112]. 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 [113]. 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 [114]. The
ERSPC investigators did not report the association of receipt of treatment and cancer
death.
The Gteborg, 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 [115]. In 2014, investigators reported 18-year follow-up data
for what they called a study of "organized" PSA screening compared to "opportunistic
testing" [116]. Cumulative prostate cancer mortality rates were still lower in the screening
group than in the control group (0.98 percent versus 1.5 percent, reflecting 43 fewer
deaths). The Gteborg 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 Gteborg 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 and older, consistent with the finding that
radical prostatectomy did not confer a survival benefit compared with watchful waiting for
men in this age range [117]. However, experts have questioned these explanations
because mortality rates among younger ERSCP subjects were very low, as was the rate of
interval cancers [118]. 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 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 [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 a high proportion
of men in the control group underwent PSA testing (52 percent in the sixth year of the
study). A subsequent subgroup analysis of men in the control arm suggested even higher
rates of contamination; an estimated 80 percent of control subjects underwent at least one
PSA test during the study [119].
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). A subsequent publication looking at longer-term follow-up within

the PLCO (92 percent follow-up through 10 years; 57 percent through 13 years) found
similar prostate cancer mortality results (RR 1.12, CI 1.07-1.17) with no suggestion of
reduced mortality in the patients followed for 13 years (RR 1.09, CI 0.87-1.36) [120]. This
suggests that the differences in results between the ERSPC and the PLCO 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 could be attributable to the very high rate of PSA testing in the control
arm, the high proportion of subjects with recent PSA testing at baseline (because serial
testing is associated with finding fewer and less aggressive cancers), the higher PSA
cutoff for biopsy compared with that used in the ERSPC, or the small number of prostate
cancer deaths. 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 [62]. All of 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.
A 2010 meta-analysis summarized results from six randomized trials (including unique
data from two ERSPC sites), with a total of 387,286 participants [121]. Screening with PSA
with or without DRE compared to 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)
[122].
The concerns that ERSPC mortality findings favoring screening could have been due to
differential treatment for high-risk cancers between the screening and control arms
[111,112,123] have been partially validated by results from the Prostate Cancer Intervention
versus Observation Trial (PIVOT) [124]. PIVOT randomly assigned men with localized prostate
cancer, the majority of whom had been detected by PSA screening, to either radical
prostatectomy or watchful waiting. After a median follow-up of 10 years, men who were
assigned to radical prostatectomy had a reduction in prostate cancer mortality that was not
statistically significant (5.8 versus 8.4 percent; HR 0.63, 95% CI 0.36-1.09). Subgroup analyses
suggested a potentially greater survival benefit for radical prostatectomy among men with PSA
values above 10 ng/mL or high-risk tumor characteristics (based on tumor stage, Gleason, PSA)
compared with the group as a whole. (See "Radical prostatectomy for localized prostate
cancer", section on 'Survival impact of radical prostatectomy'.)
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 [125]. Prostate cancer mortality rates, which initially
increased following the advent of PSA testing, have now declined to slightly below pre-PSA
levels (figure 1) [125].
These mortality trends, however, are difficult to interpret. Some ecologic data suggest an
association between PSA testing and declining mortality rates [126-128]. However, other

ecologic studies have shown declining mortality rates even in the absence of intensive
screening [129].
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 prostate cancer".)
Evidence is also becoming available from changing patterns of screening in response to
changes in recommendations. Based on an evidence review of PSA-based randomized
screening trials [130], the US Preventive Services Task Force issued draft guidelines against all
PSA screening in October 2011 that were affirmed in the final 2012 recommendation [131,132].
(See 'Recommendations of others' below.) A study found an 18 percent relative decline in
screening of men ages 50 and older in the United States between 2010 and 2013 [133]. Overall
prostate cancer incidence rates, particularly forlocal/regional-stage disease, declined
significantly among men ages 50 and older from 2011 to 2012, representing an estimated
33,519 fewer annual cases. However, incidence rates of distant-stage disease increased
significantly among those 75 years and older. Whether any of these trends will be associated
with changes in prostate cancer mortality is uncertain.
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 [134]. However, treatment advancements may
have also contributed to the declining mortality rates.
The European Randomized Study of Screening for Prostate Cancer (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 qualityadjusted life years gained after PSA screening [135]. 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 [136].
A study used microsimulation modeling of observational and clinical trial data to try to determine
the comparative effectiveness of alternative PSA screening strategies [137]. Outcome measures
included the lifetime number of PSA tests, false-positive results, cancer detection,
overdiagnosis, prostate cancer deaths, and lives saved. Compared to 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 ageadjusted PSA biopsy criteria appeared to reduce the number of tests and the risks for falsepositive 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 [138].
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
[139], more recent studies suggest both higher rates of infectious complications and that the
rate of infectious complications may be increasing over time [140-143]. Hospitalization rates for
infectious complications in these studies have ranged from 0.6 to 4.1 percent [142].
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 [144], 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 [145]. However, other
studies have suggested much lower mortality rates following biopsy [142]. Population-based
studies include an analysis of US 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 [140]. An analysis of registry data from Canada
found a 30-day mortality rate of 0.09 percent [141]. Randomized trials with follow-up on 1147
biopsies [146], and 10,474 biopsies [147], reported no biopsy-related deaths.
Prostate biopsy can also lead to anxiety and physical discomfort [148]. 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 [149,150]. 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 [151].
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 PSA testing [3].
Although approximately 80 percent of detected cancers are considered clinically
important based on tumor size and grade [152], 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 [153-155].
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 [156]. 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 [157].

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 [17]. 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)
[158], 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 [159]. 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 [160].
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 [161,162],
though the rate approaches 1 percent in men over 75 years [163].
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
[14,164,165].
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 [14,164,166].
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 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 [118,123,167-169].

The United States Preventive Services Task Force Guidelines [170], American College of
Physicians [171], American Urologic Association [172], American Cancer Society [46], and the
Canadian Task Force on the Periodic Health Examination [173] all stress the importance of
informed decision making.
The American College of Physicians and the American Cancer Society have provided useful
summaries of discussion points to consider when counseling patients about prostate cancer
screening [46,171,174]:
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. For most men, the
chances of harm from PSA screening outweigh the benefits.
Most men who choose not to have PSA testing will not be diagnosed with prostate cancer
and will die from some other cause.
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 exam (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 current 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 that only men with high PSA or Gleason score are
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
complications 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
[175].
Clinicians find it challenging to provide comprehensive, consistent, and balanced information
about prostate cancer screening decisions during clinic visits [12,176]. Consequently, efforts
have focused on using decision support tools to help patients understand screening issues and
make informed decisions for screening [177,178].
Investigators have evaluated a number of interventions to facilitate such informed prostate
cancer screening decisions including videotapes [179-181], patient group discussions [179],
brief scripts read to patients during clinic visits [182], verbal and written material provided before

a periodic health examination [183], and informational pamphlets distributed at study visits [184]
or through the mail [185].
Current 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 [186]. 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
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 [187].
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 [41,46].
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 [46,188-190]. 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'.)
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
may increase the risk of harms related to screening. (See "Preventive care in adults:
Recommendations", 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 [41,46]. However, the randomized 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 [13]. The PLCO study, which screened with annual
PSA and DRE, found no reduction in mortality [15]. 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.
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) [191]. The 10year 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
[192].
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) [193-195]:
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 [193]. 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 [194]. 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 [193]. A separate report came
to a similar estimate [196]. 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 [194].
Referrals for biopsy 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 an interventional specialist who can evaluate them for a transrectal ultrasoundguided prostate biopsy.
Men with abnormal PSA values can also be referred, although some experts recommend first
repeating the PSA several weeks later, particularly for borderline elevations below
7.0 ng/mL [59,68]. We suggest that primary care providers refer men with a PSA level above
7 ng/mL without further testing; the interventional specialist can decide whether to proceed
directly to biopsy or perform additional testing.
We suggest that men with a PSA level between 4 ng/mL and 7 ng/mL undergo repeat 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
biopsy.
One reason to repeat PSA testing in men with borderline elevations is that PSA measurements
have considerable short-term variability [67,197]. 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 [198]. 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 [13]. 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
[35,61,65,137]. We suggest that a PSA level of 4.0 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, and we do not recommend them for determining who should be
referred for biopsy. Retrospective analyses of data from the ERSPC suggest that the predictive
value of PSA for detecting cancer is not improved by incorporating PSA velocity data [70-72].
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 curve (AUC) ranging from 0.660.79 [199]. 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 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 [41]. 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 [37]. 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
[200].
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 [201]. 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 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
[202].
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 [203]. 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.
Another analysis of the ERSPC, Rotterdam data evaluated factors associated with having
cancer detected during the second round of screening among men with a previous negative
biopsy [204]. Having a previous negative biopsy was the only factor significantly associated with
biopsy outcome in the second round of screening. Among 459 men with a previous negative
biopsy who underwent a second biopsy because their PSA level was still elevated on the
second round of screening, only 48 cancers were detected (positive predictive value 10.5
percent). In comparison, 149 cancers were diagnosed in men with elevated PSA levels who had
not been previously biopsied (positive predictive value 25.6 percent). After adjusting for the
previous negative biopsy in multivariate models, investigators did not find that either total PSA
level (all were above 3.0 ng/mL) or PSA velocity significantly predicted finding cancer on the
second biopsy.
We suggest that men with negative extended biopsies (biopsies performed using an extended
protocol as opposed to just sextant biopsies) be managed similarly to men who have not
previously undergone screening. That is, when screening is next routinely considered, men
should again make an informed decision about testing; if the decision is made to screen, the
same criteria used for the initial biopsy referral should again be applied. (See "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 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 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 [205]. If screening were discontinued for
men with PSA levels of 1.0ng/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 [206].
A population-based cohort study using 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 10year 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 [207].
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 poorlydifferentiated cancers and two or more comorbidities [208].
A decision analysis using Medicare data found that aggressively treating men age 70 and
older could actually decrease the quality adjusted life expectancy [209].
In contrast, another decision model, using results from the Scandinavian randomized trial
of radical prostatectomy versus watchful waiting and case series utilizing threedimensional 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.
Currently, 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 [46]. For men who decide to be screened, the ACS recommends PSA testing with
or without 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
(http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp), which can include age, race,
family history, digital rectal examination findings, previous biopsy results, and use of five
alpha-reductase inhibitors.
The American Urological Association (AUA) updated its guideline in 2013 [172]. 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 higherrisk 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 United States Preventive Services Task Force (USPSTF) updated its
recommendations in 2012 to recommend that men not be screened for prostate cancer,

concluding that there is moderate certainty that the benefits of such screening do not
outweigh the harms [210]. The USPSTF did advise that men requesting screening be
supported in making an informed decision. The USPSTF clinical practice guideline for
screening for prostate cancer, as well as other USPSTF guidelines, can be accessed
through their website.
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 populationbased 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 American Cancer Society, the American Urological Association,
and the US Preventive Services Task Force [171]. 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.
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 information: Prostate cancer screening (PSA tests) (The
Basics)")
Beyond the Basics topics (see "Patient information: Prostate cancer screening (Beyond
the Basics)")
SUMMARY AND RECOMMENDATIONS Although screening for prostate cancer with PSA
can reduce mortality fr