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Screening for prostate cancer

Author Section Editor Deputy Editor


Richard M Hoffman, MD, Robert H Fletcher, MD, MSc David M Rind, MD
MPH

Last literature review version 17.3: September 2009 | This topic last updated:
September 1, 2009 (More)

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 ( show figure 1 ) [ 6] . The
majority of these newly diagnosed cancers were clinically localized ( show figure 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 see "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 ( show table 1 ), particularly benign prostatic hyperplasia (BPH) and
prostatitis. ( See "Clinical manifestations and diagnosis of benign prostatic hyperplasia"
and see "Acute and chronic bacterial prostatitis" ).

Measuring PSA — In addition to the PSA elevations seen with BPH, there are transient
causes of PSA elevation ( show 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 ( show 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 ( show figure 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 ( show figure 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 ).

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GRAPHICS
Prostate cancer: changes over time average annual age-adjusted
incidence and mortality rates in the United States, 1973 - 2001
(2001 US standard)

Source: SEER Program.


Rate of prostate cancer

Age-adjusted rates of prostate cancer by stage and year of diagnosis


in white men in the National Cancer Institute's Surveillance
Epidemiology and End Results (SEER) data base. Screening in the
1980s led to a progressive risk in the incidence of disease that was
primarily organ-confined. The removal of these incidence cases led
to a decline in new cases of prostate cancer after 1992. Screening
also reduced the number of new cases presenting with distant
metastases. Similar findings were noted in black men, except the
absolute incidence of prostate cancer was higher. Data from Farkas,
A, Schneider, D, Perrotti, M, et al, Urology 1998; 52:444.

Benign causes for an elevated PSA

Benign prostatic hyperplasia

Acute prostatitis

Subclinical inflammation

Prostate biopsy

Cystoscopy

TURP

Urinary retention

Ejaculation
Digital rectal examination

Perineal trauma

Prostatic infarction

Relationship of the prostate-specific antigen (PSA) level to the


prevalence of the prostate cancer and high-grade disease*

Men with Men with high-grade


PSA No. of men prostate cancer prostate cancer
level (N=2950) (N=449) (N=67)
0.5
486 32 (6.6) 4/32 (12.5)
ng/ml

0.6-1.0
791 80 (10.1) 8/80 (10.0)
ng/ml

1.1-2.0
998 170 (17.0) 20/170 (11.8)
ng/ml

2.1-3.0
482 115 (23.9) 22/115 (19.1)
ng/ml

3.1-4.0
193 52 (26.9) 13/52 (25.0)
ng/ml

* High-grade disease was defined by a Gleason score of 7 or greater. The


population was restricted to men with a PSA level of 4.0 ng per milliliter or less
throughout the study.
Reproduced with permission from: Thompson, IM, Pauler, DK, Goodman, PJ, et al.
Prevalence of prostate cancer among men with a prostate-specific antigen level
4.0 ng per milliliter. N Engl J Med 2004; 350:2239. Copyright © 2004
Massachusetts Medical Society.
Radical prostatectomy versus watchful waiting

The graphs show the cumulative incidence of death from prostate cancer in a
randomized trial that compared radical prostatectomy with watchful waiting.
Panel A shows results from the study overall, and Panel B shows results
according to age (above or below age 65). Reproduced with permission from:
Bill-Axelson, A, Holmberg, L, Ruutu, M, et al. Radical Prostatectomy versus
Watchful Waiting in Early Prostate Cancer. N Engl J Med 2005; 352:1977.
Copyright © 2005 Massachusetts Medical Society.

Grade 2B recommendation

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approaches may be better for some patients under some
circumstances.
Explanation:
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choose an alternative approach. For Grade 2 recommendations, benefits and
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Grade B means that the best estimates of the critical benefits and risks come
from randomized, controlled trials with important limitations (eg, inconsistent
results, methodologic flaws, imprecise results, extrapolation from a different
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1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or
vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

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A. High-quality evidence: Consistent evidence from randomized trials, or
overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important
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Grade 2C recommendation

A Grade 2C recommendation is a very weak recommendation; other


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A Grade 2 recommendation is a weak recommendation. It means "this is our


suggestion, but you may want to think about it." It is unlikely that you should
follow the suggested approach in all your patients, and you might reasonably
choose an alternative approach. For Grade 2 recommendations, benefits and
risks may be finely balanced, or the benefits and risks may be uncertain. In
deciding whether to follow a Grade 2 recommendation in an individual patient,
you may want to think about your patient's values and preferences or about your
patient's risk aversion.
Grade C means the evidence comes from observational studies, unsystematic
clinical experience, or from randomized, controlled trials with serious flaws. Any
estimate of effect is uncertain.

Recommendation grades
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or
vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or
overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important
limitations, or very strong evidence of some other form
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