The Great Prostate Mistake

Abstract

Published: March 9, 2010 Tucson EACH year some 30 million American men undergo testing for prostate-specific antigen, an enzyme made by the prostate. Approved by the Food and Drug Administration in 1994, the P.S.A. test is the most commonly used tool for detecting prostate cancer. André da Loba The test's popularity has led to a hugely expensive public health disaster. It's an issue I am painfully familiar with — I discovered P.S.A. in 1970. As Congress searches for ways to cut costs in our health care system, a significant savings could come from changing the way the antigen is used to screen for prostate cancer. Americans spend an enormous amount testing for prostate cancer. The annual bill for P.S.A. screening is at least $3 billion, with much of it paid for by Medicare and the Veterans Administration. Prostate cancer may get a lot of press, but consider the numbers: American men have a 16 percent lifetime chance of receiving a diagnosis of prostate cancer, but only a 3 percent chance of dying from it. That's because the majority of prostate cancers grow slowly. In other words, men lucky enough to reach old age are much more likely to die with prostate cancer than to die of it. Even then, the test is hardly more effective than a coin toss. As I've been trying to make clear for many years now, P.S.A. testing can't detect prostate cancer and, more important, it can't distinguish between the two types of prostate cancer — the one that will kill you and the one that won't.

Full text

The Great Prostate Mistake
By RICHARD J. ABLIN
Published: March 9, 2010
Tucson
EACH year some 30 million American men undergo testing for prostate-specific antigen, an
enzyme made by the prostate. Approved by the Food and Drug Administration in 1994, the P.S.A.
test is the most commonly used tool for detecting prostate cancer.
André da Loba
The test’s popularity has led to a hugely expensive public health disaster. It’s an issue I am painfully
familiar with — I discovered P.S.A. in 1970. As Congress searches for ways to cut costs in our
health care system, a significant savings could come from changing the way the antigen is used to
screen for prostate cancer.
Americans spend an enormous amount testing for prostate cancer. The annual bill for P.S.A.
screening is at least $3 billion, with much of it paid for by Medicare and the Veterans
Administration.
Prostate cancer may get a lot of press, but consider the numbers: American men have a 16 percent
lifetime chance of receiving a diagnosis of prostate cancer, but only a 3 percent chance of dying
from it. That’s because the majority of prostate cancers grow slowly. In other words, men lucky
enough to reach old age are much more likely to die with prostate cancer than to die of it.
Even then, the test is hardly more effective than a coin toss. As I’ve been trying to make clear for
many years now, P.S.A. testing can’t detect prostate cancer and, more important, it can’t distinguish
between the two types of prostate cancer — the one that will kill you and the one that won’t.
Instead, the test simply reveals how much of the prostate antigen a man has in his blood. Infections,
over-the-counter drugs like ibuprofen, and benign swelling of the prostate can all elevate a man’s
P.S.A. levels, but none of these factors signals cancer. Men with low readings might still harbor
dangerous cancers, while those with high readings might be completely healthy.
In approving the procedure, the Food and Drug Administration relied heavily on a study that
showed testing could detect 3.8 percent of prostate cancers, which was a better rate than the
standard method, a digital rectal exam.
Still, 3.8 percent is a small number. Nevertheless, especially in the early days of screening, men
with a reading over four nanograms per milliliter were sent for painful prostate biopsies. If the
biopsy showed any signs of cancer, the patient was almost always pushed into surgery, intensive
radiation or other damaging treatments.

The medical community is slowly turning against P.S.A. screening. Last year, The New England
Journal of Medicine published results from the two largest studies of the screening procedure, one
in Europe and one in the United States. The results from the American study show that over a
period of 7 to 10 years, screening did not reduce the death rate in men 55 and over.
The European study showed a small decline in death rates, but also found that 48 men would need
to be treated to save one life. That’s 47 men who, in all likelihood, can no longer function sexually
or stay out of the bathroom for long.
Numerous early screening proponents, including Thomas Stamey, a well-known Stanford
University urologist, have come out against routine testing; last month, the American Cancer
Society urged more caution in using the test. The American College of Preventive Medicine also
concluded that there was insufficient evidence to recommend routine screening.
So why is it still used? Because drug companies continue peddling the tests and advocacy groups
push “prostate cancer awareness” by encouraging men to get screened. Shamefully, the American
Urological Association still recommends screening, while the National Cancer Institute is vague on
the issue, stating that the evidence is unclear.
The federal panel empowered to evaluate cancer screening tests, the Preventive Services Task
Force, recently recommended against P.S.A. screening for men aged 75 or older. But the group has
still not made a recommendation either way for younger men.
Prostate-specific antigen testing does have a place. After treatment for prostate cancer, for instance,
a rapidly rising score indicates a return of the disease. And men with a family history of prostate
cancer should probably get tested regularly. If their score starts skyrocketing, it could mean cancer.
But these uses are limited. Testing should absolutely not be deployed to screen the entire population
of men over the age of 50, the outcome pushed by those who stand to profit.
I never dreamed that my discovery four decades ago would lead to such a profit-driven public
health disaster. The medical community must confront reality and stop the inappropriate use of
P.S.A. screening. Doing so would save billions of dollars and rescue millions of men from
unnecessary, debilitating treatments.
Richard J. Ablin is a research professor of immunobiology and pathology at the University of
Arizona College of Medicine and the president of the Robert Benjamin Ablin Foundation for
Cancer Research.

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Volume 360:1310-1319 March 26, 2009 Number 13
Next
Mortality Results from a Randomized Prostate-Cancer
Screening Trial
Gerald L. Andriole, M.D., E. David Crawford, M.D., Robert L. Grubb, III, M.D.,
Saundra S. Buys, M.D., David Chia, Ph.D., Timothy R. Church, Ph.D., Mona N.
Fouad, M.D., Edward P. Gelmann, M.D., Paul A. Kvale, M.D., Douglas J. Reding,
M.D., Joel L. Weissfeld, M.D., Lance A. Yokochi, M.D.,
Barbara O'Brien, M.P.H., Jonathan D. Clapp, B.S.,
Joshua M. Rathmell, M.S., Thomas L. Riley, B.S., Richard
B. Hayes, Ph.D., Barnett S. Kramer, M.D., Grant
Izmirlian, Ph.D., Anthony B. Miller, M.B., Paul F. Pinsky,
Ph.D., Philip C. Prorok, Ph.D., John K. Gohagan, Ph.D.,
Christine D. Berg, M.D., for the PLCO Project Team
Editor's note: Do the benefits of PSA
screening outweigh the risks? Watch
video of a roundtable discussion,
participate in a poll, and contribute your
comments in our Clinical Directions
feature — Screening for Prostate Cancer.
Commenting closes April 1, 2009.
ABSTRACT
Background The effect of screening with prostate-specific–
antigen (PSA) testing and digital rectal examination on the
rate of death from prostate cancer is unknown. This is the first
report from the Prostate, Lung, Colorectal, and Ovarian
(PLCO) Cancer Screening Trial on prostate-cancer mortality.
Methods From 1993 through 2001, we randomly assigned
76,693 men at 10 U.S. study centers to receive either annual
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screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the
screening group were offered annual PSA testing for 6 years and digital rectal examination
for 4 years. The subjects and health care providers received the results and decided on the
type of follow-up evaluation. Usual care sometimes included screening, as some
organizations have recommended. The numbers of all cancers and deaths and causes of
death were ascertained.
Results In the screening group, rates of compliance were 85% for PSA testing and 86% for
digital rectal examination. Rates of screening in the control group increased from 40% in
the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital
rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000
person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the
control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of
death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44
deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years
were 67% complete and consistent with these overall findings.
Conclusions After 7 to 10 years of follow-up, the rate of death from prostate cancer was
very low and did not differ significantly between the two study groups. (ClinicalTrials.gov
number, NCT00002540 [ClinicalTrials.gov] .)
The benefit of screening for prostate cancer with serum prostate-specific–antigen (PSA) testing,
digital rectal examination, or any other screening test is unknown. There has been no
comprehensive assessment of the trade-offs between benefits and risks. Despite these uncertainties,
PSA screening has been adopted by many patients and physicians in the United States and other
countries. The use of PSA testing as a screening tool has increased dramatically in the United States
since 1988.1 Numerous observational studies have reported conflicting findings regarding the
benefit of screening.2 As a result, the screening recommendations of various organizations differ.
The American Urological Association and the American Cancer Society recommend offering annual
PSA testing and digital rectal examination beginning at the age of 50 years to men with a normal
risk of prostate cancer and beginning at an earlier age to men at high risk.3,4 The National
Comprehensive Cancer Network recommends a risk-based screening algorithm, including family
history, race, and age.5 In contrast, the U.S. Preventive Services Task Force recently concluded that
there was insufficient evidence in men under the age of 75 years to assess the balance between
benefits and side effects associated with screening, and the panel recommended against screening
men over the age of 75 years.6
Evidence from randomized trials would be of great assistance in making decisions about whether to
pursue prostate-cancer screening. One randomized trial of PSA-based screening reported a benefit,
but the results have been generally discounted because of serious methodologic concerns, including
a lack of intention-to-screen analysis.7 Two ongoing randomized, controlled trials of prostate-cancer
screening are being conducted to determine the effect of screening on prostate-cancer mortality: the
Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the United States and the
European Randomized Study of Screening for Prostate Cancer (ERSPC).8,9 In the United Kingdom,
another ongoing trial, the Comparison Arm for the PROTECT (Prostate Testing for Cancer and
Treatment) study (CAP), combines the assessment of screening and treatment.10

The prostate component of the PLCO trial was designed to determine the effect of annual PSA
testing and digital rectal examination on mortality from prostate cancer.11 Previous reports have
described the results of the baseline round and three later rounds of screening12,13 and the
characteristics of men undergoing biopsy14 in the intervention group. This report provides
information on prostate-cancer incidence, staging, and mortality in both study groups during the
first 7 to 10 years of the study.
Methods
Subjects
The design of the PLCO trial has been described previously.11 From 1993 through 2001, men and
women between the ages of 55 and 74 years were enrolled at 10 study centers across the United
States. Each institution obtained annual approval from its institutional review board to carry out the
study, and all subjects provided written informed consent. Individual randomization was performed
within blocks stratified according to center, age, and sex. The primary exclusion criteria at study
entry were a history of a PLCO cancer, current cancer treatment, and, starting in 1995, having had
more than one PSA blood test in the previous 3 years.
Screening Methods
Subjects who were assigned to the screening group were offered annual PSA testing for 6 years and
annual digital rectal examination for 4 years. PSA tests were analyzed with the Tandem-R PSA
assay until January 1, 2004, and with the Access Hybritech PSA after that date (both assays were
manufactured by Beckman Coulter). All tests were performed at a single laboratory. As was
standard in the United States at the time of the trial's initiation, a serum PSA level of more than 4.0
ng per milliliter was considered to be positive for prostate cancer. Digital rectal examinations were
performed by physicians, qualified nurses, or physician assistants. The results of the examinations
were deemed to be suspicious for cancer if there was nodularity or induration of the prostate or if
the examiner judged the prostate to be suspicious for cancer on the basis of other criteria, including
asymmetry. At study entry, subjects completed a baseline questionnaire that inquired about
demographic characteristics and medical and screening histories. In addition, a biorepository for the
collection and storage of blood and tissue samples was an integral component of the trial.15
All men who underwent screening and their health care providers were notified of the PSA value
and the results of the digital rectal examination. Men with positive results for the PSA test or
suspicious findings on the digital rectal examination were advised to seek diagnostic evaluation. In
accordance with standard U.S. practice, diagnostic evaluation was decided by the patients and their
primary physicians. Staff members at the PLCO study centers obtained medical records related to
diagnostic follow-up of positive screening results, and medical-record abstractors recorded
information on relevant diagnostic procedures.
The rate of compliance with screening was calculated as the number of subjects who were screened
divided by the number of those who were expected to be screened. Screening outside the trial
protocol in the control group was assessed through random surveys. The reasons for and frequency
of use of various procedures, including the screening tests under evaluation in the trial, were queried
every 1 to 2 years. In each survey, a new random sample of 1% of subjects was chosen. Two groups
were identified from responses on the baseline questionnaire: those who had undergone repeated
prostate screening in the 3 years before trial entry and those who had not. For the latter, the

proportion who reported having had a PSA test as part of a routine physical examination in the
previous year was computed; those who had had repeated PSA screenings, who comprised 9.8% of
the control group, did not receive the annual surveys during the PLCO study years of screening, and
screening was assumed to persist at 100% each year. A weighted average of these two percentages
was calculated to provide an estimated overall "contamination" rate for subjects in the control group
who underwent screening.
Primary and Secondary End Points
Cause-specific mortality for each of the PLCO cancers was the primary end point. In addition, data
on PLCO cancer incidence, staging, and survival were collected and monitored as secondary end
points. All diagnosed cancers, both PLCO and non-PLCO, and all deaths occurring during the trial
were ascertained, primarily by means of a mailed annual questionnaire, which asked about the type
of cancer and the date of diagnosis in the previous year. Subjects who did not return the
questionnaire were contacted by repeat mailing or telephone.
This active follow-up was supplemented by periodic linkage to the National Death Index to enhance
completeness of end-point ascertainment. Clinical stage was determined with the use of the tumor–
node–metastasis staging system and categorized according to the fifth edition of the AJCC
[American Joint Committee on Cancer] Cancer Staging Manual.16 Death certificates were obtained
to confirm the death and to provisionally determine the underlying cause. Since the true underlying
cause may not always be evident or accurately recorded on the death certificate, the trial used a
special end-point adjudication process to assign the cause of death in a uniform and unbiased
manner.17 All deaths from causes that were potentially related to one of the PLCO cancers were
reviewed, including any cause of death in which the subject had a PLCO cancer or a possible
metastasis from a PLCO cancer and all deaths of unknown or uncertain cause. Reviewers of these
deaths were unaware of study-group assignments for deceased subjects.
Statistical Analysis
The primary analysis was an intention-to-screen comparison of prostate-cancer mortality between
the two study groups. Event rates were defined as the ratio of the number of events (cancer
diagnoses or deaths) in a given time period to the person-years at risk for the event. Person-years
were measured from randomization to the date of diagnosis, death, or data censoring (whichever
came first) for incidence rates and to the date of death or censoring (whichever came first) for death
rates. Confidence intervals for rate ratios for incidence and mortality were calculated with the use of
asymptotic methods, assuming a normal distribution for the logarithm of the ratio and a Poisson
distribution for the number of events.18
From the initiation of the trial, an independent data and safety monitoring board considered reports
every 6 months and reviewed the accumulating data. In November 2008, the board unanimously
recommended that the current results on prostate-cancer mortality be reported, after notification of
study investigators and subjects, on the basis of data showing a continuing lack of a significant
difference in the death rate between the two study groups at 10 years (with complete follow-up at 7
years) and information suggesting harm from screening. This recommendation was not the result of
crossing a statistical futility boundary but, rather, was triggered by concern that men and their
physicians were making decisions on screening on the basis of inadequate information, that the data
available from the trial were complete up to 7 years and consistent up to at least 10 years, and that
public health considerations dictated that the available results should be made known. However, the

monitoring board also supported follow-up of the subjects until all of them had reached at least 13
years of follow-up.
Results
Subjects
The baseline characteristics of the subjects were virtually identical in the two study groups (Table
1). At 7 years, vital status was known for 98% of the men in the two groups (see the Supplementary
Appendix, available with the full text of this article at NEJM.org). At 10 years, vital status was
known for 67% of the subjects, although 23% had not been enrolled for 10 years. The median
duration of follow-up was 11.5 years (range, 7.2 to 14.8) in the two groups.
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Table 1. Characteristics of the Subjects at Baseline.
Compliance with the screening protocol overall was 85% for PSA testing and 86% for digital rectal
examination. These findings are similar to the design estimates of 90% for each test. Screening
results for the first four rounds were reported previously.13 In the control group, the rate of PSA
testing was 40% in the first year and increased to 52% in the sixth year; for subjects who reported
having undergone no more than one PSA test at baseline (89% of subjects), the rate of PSA testing
was 33% in the first year and 46% in the sixth year. The rate of screening by digital rectal
examination in the control group ranged from 41 to 46%.
Figure 1A shows the accumulation of cases of prostate cancer in the two study groups. At 7 years, 2
years after the cessation of screening, prostate cancer had been diagnosed in more subjects in the
screening group (2820) than in the control group (2322) (rate ratio, 1.22; 95% confidence interval
[CI], 1.16 to 1.29). At 10 years, with follow-up complete for 67% of subjects, the excess in the
screening group persisted, with 3452 subjects versus 2974 subjects (rate ratio, 1.17; 95% CI, 1.11 to
1.22).
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Figure 1. Number of Diagnoses of All Prostate Cancers (Panel A) and
Number of Prostate-Cancer Deaths (Panel B).

Table 2 shows the characteristics of subjects with prostate cancer in each group, according to the
circumstances of detection, through 10 years of follow-up. The large majority of prostate cancers
were stage II at diagnosis, regardless of the mode of detection in the screening group; nearly all
were adenocarcinomas, and more than 50% had a Gleason score of 5 to 6 (on a scale from 2 to 10,
with higher scores indicating more aggressive disease). Overall, the numbers of subjects with
advanced (stage III or IV) tumors were similar in the two groups, with 122 in the screening group
and 135 in the control group, though the number of subjects with a Gleason score of 8 to 10 was
higher in the control group (341 subjects) than in the screening group (289 subjects).
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Table 2. Tumor Stage, Histopathological Type, and Gleason Score for All Prostate
Cancers at 10 Years, According to Method of Detection and Time of Diagnosis.
The treatment distributions were similar in the two groups within each tumor stage. For example,
among subjects with stage II tumors, as their primary treatment, 44% of the screening group and
40% of the control group underwent prostatectomy, 22% of the screening group and 21% of the
control group underwent irradiation alone, and 18% and 21%, respectively, underwent irradiation
and hormonal therapy. Among subjects with stage III tumors, 24% of the screening group and 16%
of the control group underwent irradiation alone, and 47% and 52%, respectively, underwent
irradiation plus hormone therapy. Among subjects with stage IV tumors, 75% of the screening group
and 72% of the control group received hormone therapy only. Overall, nearly 11% of the subjects in
the screening group and 10% of those in the control group did not undergo any known treatment.
Mortality
At 7 years, there were 50 deaths attributed to prostate cancer in the screening group and 44 in the
control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70) (Figure 1B and Table 3). Through year 10,
with follow-up complete for 67% of the subjects, the numbers of prostate-cancer deaths were 92 in
the screening group and 82 in the control group (rate ratio, 1.11; 95% CI, 0.83 to 1.50). At 10 years,
the median follow-up time for subjects with prostate cancer was 6.3 years in the screening group
and 5.2 years in the control group.
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Table 3. Death Rates from Prostate Cancer per 10,000 Person-Years at 10
Years.
There was little difference between the two groups in terms of the proportion of deaths according to
tumor stage. In the screening group, 60% of the subjects had stage I or II tumors, 2% had stage III

tumors, and 36% had stage IV tumors; in the control group, 52% of the subjects had stage I or II
tumors, 4% had stage III tumors, and 39% had stage IV tumors.
Analyses within strata according to the screening status at baseline showed no indication of any
reduction in prostate-cancer mortality in the screening group, as compared with the control group, in
any of the subgroups. Thus, at 7 years, among the 34,755 men in the screening group and 34,590 in
the control group who reported having undergone no more than one PSA test at baseline, there were
48 prostate-cancer deaths in the screening group and 41 deaths in the control group (rate ratio, 1.16;
95% CI, 0.76 to 1.76); at 10 years, there were 83 deaths in the screening group and 75 in the control
group (rate ratio, 1.09; 95% CI, 0.80 to 1.50). Similarly, among 3588 men in the screening group
and 3760 men in the control group who reported having had two or more PSA tests in the previous 3
years at baseline, there were two deaths in the screening group and three deaths in the control group
at 7 years (rate ratio, 0.70; 95% CI, 0.12 to 4.17) and nine deaths in the screening group and seven
in the control group at 10 years (rate ratio, 1.34; 95% CI, 0.50 to 3.59).
At 7 years, the total numbers of deaths (excluding those from prostate, lung, or colorectal cancers)
were 2544 in the screening group and 2596 in the control group (rate ratio, 0.98; 95% CI, 0.92 to
1.03); at 10 years, the numbers of such deaths were 3953 and 4058, respectively (rate ratio, 0.97;
95% CI, 0.93 to 1.01). The distribution of the causes of death was similar in the two groups (Table
4).
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Table 4. Causes of Death at 10-Year Follow-up.
Screening-Related Risks
Risks incurred from a screening process can result from the screening itself or from downstream
diagnostic or treatment interventions. In the screening group, the complications associated with
screening were mild and infrequent. Digital rectal examination led to very few episodes of bleeding
or pain, at a rate of 0.3 per 10,000 screenings. The PSA test led to complications at a rate of 26.2 per
10,000 screenings (primarily dizziness, bruising, and hematoma) and included three episodes of
fainting per 10,000 screenings. Medical complications from the diagnostic process occurred in 68 of
10,000 diagnostic evaluations after positive results on screening. These complications were
primarily infection, bleeding, clot formation, and urinary difficulties. Treatment-related
complications, which are generally more serious, include infection, incontinence, impotence, and
other disorders. Such complications are now being catalogued in a quality-of-life study and are
particularly pertinent in cases of overdiagnosis.
Discussion
We are reporting here for the first time on the PLCO trial with respect to prostate-cancer mortality.
At 7 years, screening was associated with a relative increase of 22% in the rate of prostate-cancer
diagnosis, as compared with the control group. This increase occurred even though the rate of
compliance in screening (85%) was slightly below the level we anticipated in the study design
(90%) and there was more-than-expected screening in the control group.

Screening was associated with no reduction in prostate-cancer mortality during the first 7 years of
the trial (rate ratio, 1.13), with similar results through 10 years, at which time 67% of the data were
complete. However, the confidence intervals around these estimates are wide. The results at 7 years
were consistent with a reduction in mortality of up to 25% or an increase in mortality of up to 70%;
at 10 years, those rates were 17% and 50%, respectively. There was little difference between the two
study groups in the number of deaths from other causes. However, among men with prostate cancer
at 10 years, 312 in the screening group and 225 in the control group died from causes other than
prostate cancer, and the excess in the screening group was possibly associated with overdiagnosis of
prostate cancer.
There are several possible explanations for the lack of a reduction in mortality so far in this trial.
First, annual screening with the PSA test using the standard U.S. threshold of 4 ng per milliliter and
digital rectal examination to trigger diagnostic evaluation may not be effective. In the ERSPC trial,
a PSA cutoff level of 3 ng per milliliter was used, with potentially increased sensitivity but reduced
specificity. In our trial, a lower cutoff level might have resulted in the diagnosis of more prostate
cancers earlier by screening. It has been shown that cancers that are detected by PSA screening at a
level of less than 4 ng per milliliter have a favorable prognosis.9 Since increased detection of more
of such good-prognosis tumors might have increased the rate of overdiagnosis, such a change
probably would have had little or no effect on the rate of death from prostate cancer.
Second, the level of screening in the control group could have been substantial enough to dilute any
modest effect of annual screening in the screening group. Although the estimated rate of screening
in the control group was higher than the original design estimate of 20%, it was similar to the 38%
level anticipated in the protocol revision in 1998.11 To be included in our definition of "PSA
contamination," a subject in the control group needed to have had a PSA test within the past year as
part of a routine physical examination. It was thought that such a situation would most closely
represent the experience of PSA screening among compliant men in the screening group. However,
this definition could be overly restrictive, since PSA testing that occurred outside these measures
could still have had an effect on prostate-cancer incidence and mortality in the control group.
Nonetheless, in the early years of the study, the level of testing in the screening group was
substantially higher than that in the control group, and although the difference lessened later, testing
levels remained distinctly higher in the screening group. The screening that occurred in the control
group was not enough to eliminate the expected effects of annual screening — such as earlier
diagnosis and a persistent excess of cases, largely due to overdiagnosis — in the screening group.
Third, approximately 44% of the men in each study group had undergone one or more PSA tests at
baseline, which would have eliminated some cancers detectable on screening from the randomized
population, especially in health-conscious men (who tend to be screened more often, a form of
selection bias); thus, the cumulative death rate from prostate cancer at 10 years in the two groups
combined was 25% lower in those who had undergone two or more PSA tests at baseline than in
those who had not been tested.
Fourth, and potentially most important, improvement in therapy for prostate cancer during the
course of the trial probably resulted in fewer prostate-cancer deaths in the two study groups, which
blunted any potential benefits of screening.19,20 It is important to note that our policy of not
mandating specific therapies after cancer detection on screening resulted in substantial similarities
in treatment according to tumor stage between the two study groups.

Finally, the follow-up may not yet be long enough for benefit from the earlier detection of an
increased number of prostate cancers in the screening group to emerge. Data are accruing on the
natural history of screen-detected prostate cancer. Thus, a report from the Rotterdam component of
the ERSPC trial suggests a lead time of 12.3 years at the age of 55 years and 6 years at the age of 75
years, with estimated overdiagnosis rates of 27% and 56%, respectively.21 Wider application of
improvements in prostate-cancer treatment is probably at least in part responsible for declining
death rates from prostate cancer in most countries.22 For example, if a patient's life is prolonged by
the use of hormone therapy, the opportunities for competing causes of death increase, especially
among older men. Computations of lead time provide little information on prognosis, except to the
extent that patients with long lead times are likely to have a better prognosis than those with short
lead times. In our study, the average lead time achieved by increased early diagnosis through
screening was approximately 2 years (Figure 1A). At 7 years, 73% of prostate cancers had been
screen-detected in the screening group. In addition, the possibly emerging reduction in the incidence
of tumors with a Gleason score of 8 to 10 in the screening group might portend a future reduction in
mortality.
However, we now know that prostate-cancer screening provided no reduction in death rates at 7
years and that no indication of a benefit appeared with 67% of the subjects having completed 10
years of follow-up. Thus, our results support the validity of the recent recommendations of the U.S.
Preventive Services Task Force, especially against screening all men over the age of 75 years.6
Risks incurred by screening, diagnosis,23,24 and resulting treatment25,26,27,28,29,30,31 of prostate
cancer are both substantial and well documented in the literature. To the extent that overdiagnosis
occurs with prostate-cancer screening, many of these risks occur in men in whom prostate cancer
would not have been detected in their lifetime had it not been for screening. The effect of screening
on quality of life is a subject of an ongoing substudy and should be completed within the next
several years. Follow-up in the PLCO trial is planned to continue until all subjects reach at least 13
years. A final report will be presented once the planned duration of follow-up is completed.
Supported by contracts from the National Cancer Institute.
Dr. Andriole reports receiving consulting and lecture fees from GlaxoSmithKline and grant support from Aeterna
Zentaris, Antigenics, Ferring Pharmaceuticals, and Veridex; Dr. Crawford, being chair of the Prostate Conditions
Education Council and receiving lecture fees from GlaxoSmithKline and AstraZeneca; Dr. Grubb, receiving research
support from GlaxoSmithKline; Dr. Gelmann, receiving lecture fees from Momenta Pharmaceuticals and Daiichi
Sankyo and having an equity interest in Genentech and GlaxoSmithKline; and Dr. Kvale, receiving grant support from
Roche. No other potential conflict of interest relevant to this article was reported.
We thank the study subjects for their contributions in making this study possible.
* Members of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial project team are listed in the
Supplementary Appendix, available with the full text of this article at NEJM.org.
Source Information
The authors' affiliations are listed in the Appendix.
This article (10.1056/NEJMoa0810696) was published at NEJM.org on March 18, 2009.
Address reprint requests to Dr. Berg at the Division of Cancer Prevention, National Cancer Institute, National Institutes
of Health, 6130 Executive Blvd., Rm. 3112, Bethesda, MD 20892-7346, or at bergc@mail.nih.gov.
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Appendix
The authors' affiliations are as follows: the Washington University School of Medicine, St. Louis
(G.L.A., R.L.G.); Huntsman Cancer Institute, Salt Lake City (S.S.B.); UCLA Immunogenetics
Center, Los Angeles (D.C.); University of Minnesota, Minneapolis (T.R.C.); University of Alabama
at Birmingham School of Medicine, Birmingham (M.N.F.); Lombardi Cancer Center, Georgetown
University, Washington, DC (E.P.G.); Henry Ford Health System, Detroit (P.A.K.); Marshfield
Clinic Research Foundation, Marshfield, WI (D.J.R.); University of Pittsburgh Medical Center
Cancer Pavilion, Pittsburgh (J.L.W.); Pacific Health Research Institute, Honolulu (L.A.Y.);
Anschutz Cancer Pavilion, University of Colorado, Denver (E.D.C.); Westat, Rockville, MD (B.O.);
Information Management Services, Rockville, MD (J.D.C., J.M.R., T.L.R.); National Cancer
Institute (R.B.H., G.I., P.F.P., P.C.P., J.K.G., C.D.B.) and the Office of Disease Prevention (B.S.K.),
National Institutes of Health, Bethesda, MD; and the Dalla Lana School of Public Health,

University of Toronto, Toronto (A.B.M.).
The following persons are either current or former members of the data and safety monitoring
board: Current Members: J.E. Buring (chair), Brigham and Women's Hospital; D. Alberts, Arizona
Cancer Center; H.B. Carter, Johns Hopkins School of Medicine; G. Chodak, Midwest Prostate and
Urology Health Center; E. Hawk, M.D. Anderson Cancer Center; H. Malm, Loyola University; R.J.
Mayer, Dana–Farber Cancer Institute; S. Piantadosi, Cedars–Sinai Medical Center; G.A. Silvestri,
Medical University of South Carolina; I.M. Thompson, University of Texas Health Sciences Center
at San Antonio; C.L. Westhoff, Columbia University. Former Members: J.P. Kahn, Medical
College of Wisconsin; B. Levin, M.D. Anderson Cancer Center; D. DeMets, University of
Wisconsin; J.R. O'Fallon, Mayo Clinic; A.T. Porter, Harper Hospital; M.M. Ashton, Edina, MN;
W.C. Black, Dartmouth–Hitchcock Medical Center.
The following persons are either current or former members of the end-point verification team:
Current Members: P.C. Albertsen (chair), University of Connecticut Health Center; J.H.
Edmonson, Rochester, MN; W. Lawrence, Medical College of Virginia; R. Fontana, Rochester, MN;
A. Rajput, Roswell Park Cancer Institute. Former Members: A.B. Miller, University of Toronto;
M. Eisenberger, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; I. Jatoi, National
Naval Medical Center; E. Glatstein, University of Pennsylvania Medical Center; H.G. Welch,
Dartmouth Medical School.
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Volume 360:1320-1328 March 26, 2009 Number 13
Next
Screening and Prostate-Cancer Mortality in a
Randomized European Study
Fritz H. Schröder, M.D., Jonas Hugosson, M.D., Monique J. Roobol, Ph.D., Teuvo
L.J. Tammela, M.D., Stefano Ciatto, M.D., Vera Nelen, M.D., Maciej Kwiatkowski,
M.D., Marcos Lujan, M.D., Hans Lilja, M.D., Marco Zappa, Ph.D., Louis J. Denis,
M.D., Franz Recker, M.D., Antonio Berenguer, M.D., Liisa
Määttänen, Ph.D., Chris H. Bangma, M.D., Gunnar Aus,
M.D., Arnauld Villers, M.D., Xavier Rebillard, M.D.,
Theodorus van der Kwast, M.D., Bert G. Blijenberg,
Ph.D., Sue M. Moss, Ph.D., Harry J. de Koning, M.D.,
Anssi Auvinen, M.D., for the ERSPC Investigators
Editor's note: Do the benefits of PSA
screening outweigh the risks? Watch
video of a roundtable discussion,
participate in a poll, and contribute your
comments in our Clinical Directions
feature — Screening for Prostate Cancer.
Commenting closes April 1, 2009.
ABSTRACT
Background The European Randomized Study of Screening
for Prostate Cancer was initiated in the early 1990s to
evaluate the effect of screening with prostate-specific–antigen
(PSA) testing on death rates from prostate cancer.
Methods We identified 182,000 men between the ages of 50
and 74 years through registries in seven European countries
for inclusion in our study. The men were randomly assigned to
a group that was offered PSA screening at an average of once
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every 4 years or to a control group that did not receive such screening. The predefined
core age group for this study included 162,243 men between the ages of 55 and 69 years.
The primary outcome was the rate of death from prostate cancer. Mortality follow-up was
identical for the two study groups and ended on December 31, 2006.
Results In the screening group, 82% of men accepted at least one offer of screening.
During a median follow-up of 9 years, the cumulative incidence of prostate cancer was
8.2% in the screening group and 4.8% in the control group. The rate ratio for death from
prostate cancer in the screening group, as compared with the control group, was 0.80
(95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference
was 0.71 death per 1000 men. This means that 1410 men would need to be screened and
48 additional cases of prostate cancer would need to be treated to prevent one death from
prostate cancer. The analysis of men who were actually screened during the first round
(excluding subjects with noncompliance) provided a rate ratio for death from prostate
cancer of 0.73 (95% CI, 0.56 to 0.90).
Conclusions PSA-based screening reduced the rate of death from prostate cancer by 20%
but was associated with a high risk of overdiagnosis. (Current Controlled Trials number,
ISRCTN49127736 [controlled-trials.com] .)
Measurement of serum prostate-specific antigen (PSA), a biomarker for prostate cancer,1 is useful
for the detection of early prostate cancer.2 Nevertheless, the effect of PSA-based screening on
prostate-cancer mortality remains unclear.3 The European Randomized Study of Screening for
Prostate Cancer (ERSPC) was initiated in the early 1990s to determine whether a reduction of 25%
in prostate-cancer mortality could be achieved by PSA-based screening.4 Preliminary data from this
study have been published and can be accessed at www.erspc.org. Another randomized screening
trial in the United States, the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial,
was initiated around the same time, and interim results are also reported in this issue of the
Journal.5
Methods
Study Design
We designed the ERSPC as a randomized, multicenter trial of screening for prostate cancer, with the
rate of death from prostate cancer as the primary outcome. An independent data and safety
monitoring committee reviewed the trial, and interim analyses were carried out according to a
monitoring and evaluation plan in which the outcome of the trial was to be presented to the research
group once a statistically significant result corrected for interim analyses was reached.6,7 The
study's protocol was reviewed by local and governmental ethics committees (for details, see
Supplementary Appendix 4, available with the full text of this article at NEJM.org).
Recruitment and randomization procedures differed among countries and were developed in
accordance with national regulations. In Finland, Sweden, and Italy, the trial subjects were
identified from population registries and underwent randomization before written informed consent
was provided (population-based effectiveness trial). In the Netherlands, Belgium, Switzerland, and
Spain, the target population was also identified from population lists, but when the men were invited
to participate in the trial, only those who provided consent underwent randomization (efficacy trial).

The results of analyses from two participating countries were not included in this analysis:
investigators in Portugal discontinued their participation in October 2000 because they were unable
to provide the necessary data, and investigators in France decided to participate in 2001, so data
from their analyses were not included because of the short duration of follow-up. Men in whom
prostate cancer had been diagnosed (according to data from questionnaires or registries) were
ineligible. Within each country, men were assigned to either the screening group or the control
group, without the use of blocks of numbers or stratification on the basis of random-number
generators (Figure 1).
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Figure 1. Enrollment and Outcomes, According to Age Group at
Randomization.
The predefined core age group for this study included 162,243 men
between the ages of 55 and 69 years.
At all study centers, the core age group included men between the ages of 55 and 69 years at entry.
In addition, in Sweden, study investigators included men between the ages of 50 and 54 years, and
investigators in the Netherlands, Italy, Belgium, and Spain included men up to the age of 74 years at
entry. In Switzerland, men between the ages of 55 and 69 years were included, with screening up to
the age of 75 years. In Finland, men were recruited at the ages of 55, 59, 63, and 67 years and were
screened until the age of 71 years. Screening was discontinued in all other centers when the chosen
upper age limit was reached. The validity of randomization was determined by comparing the age
distributions and the rates of death from any cause in the two study groups.
At centers in all countries except Finland, subjects were randomly assigned in a 1:1 ratio to the
screening group or the control group. In Finland, the size of the screening group was fixed at 32,000
subjects. Because the whole birth cohort underwent randomization, this led to a ratio, for the
screening group to the control group, of approximately 1:1.5.
Each center reported data on recruitment, screening, and mortality twice a year to a central data
center. Several task forces and working groups were responsible for quality assurance, including an
epidemiology committee, a quality-control committee, a pathology committee, and a PSA
committee.7 The data and safety monitoring committee had oversight of the trial, with a mandate to
stop the trial on demonstrating a significant difference between the groups or adverse effects of
screening. The monitoring committee received reports on the progress of the trial, including
prostate-cancer mortality. Causes of death, which were obtained from registries and individual chart
review, were assigned according to definitions and procedures developed for the trial. A committee
that analyzed causes of death was formed at each center, and an international committee coordinated
the work of these national committees.8,9
Screening Tests and Indications for Biopsy

Total PSA was measured with the use of Hybritech assay systems (Beckman Coulter). From 1994
through 2000, the Tandem E assay was used, and thereafter the Access assay, with the original
Hybritech calibration always applied.10
Most centers used a PSA cutoff value of 3.0 ng per milliliter as an indication for biopsy. In Finland,
a PSA value of 4.0 ng per milliliter or more was defined as positive and the men were referred for
biopsy; those with a value of 3.0 to 3.9 ng per milliliter underwent an ancillary test — digital rectal
examination until 1998 and calculation of the ratio of the free PSA value to the total PSA value
(with a value of 0.16) starting in 1999 — and were referred for biopsy if the test was
positive. In Italy, a PSA value of 4.0 ng per milliliter or more was defined as positive, but men with
a PSA value of 2.5 to 3.9 ng per milliliter also underwent ancillary tests (digital rectal examination
and transrectal ultrasonography).
In the Dutch and Belgian centers, up to February 1997, a combination of digital rectal examination,
transrectal ultrasonography, and PSA testing (with a cutoff value of 4.0 ng per milliliter) was used
for screening; in 1997, this combination was replaced by PSA testing only.7,11,12 In Belgium, where
the results of a pilot study (from 1991 to 1994) were included in the final data set up to 1995, a PSA
cutoff value of 10.0 ng per milliliter was used initially. Most centers used sextant biopsies guided by
transrectal ultrasonography. As of June 1996, lateralized sextant biopsies were recommended.13 In
Italy, transperineal sextant biopsies were used. In Finland, a biopsy procedure with 10 to 12 biopsy
cores was adopted in 2002 as a general policy for the two study groups.
The screening interval at six of the seven centers was 4 years (accounting for 87% of the subjects);
Sweden used a 2-year interval. In Belgium, the interval between the first and second rounds of
screening was 7 years because of an interruption in funding.
Pathological Evaluation
The primary evaluation of specimens from biopsies and radical prostatectomies was performed by
local pathologists. Central review of the pathological analyses was not carried out. However,
standardization of procedures was coordinated and achieved by the work of the international
pathology committee. (For details on the committee and its functions, see Supplementary Appendix
3.)
Treatment Policies
The treatment of prostate cancer was performed according to local policies and guidelines. The
equality of distribution of treatments that were applied to the screening group and the control group
has been evaluated, with little indication of differences between the two study groups after
adjustment for disease stage, tumor grade, and age (data not shown).14
Follow-up
Follow-up for mortality analyses began at randomization and ended at death, emigration, or a
uniform censoring date (December 31, 2006), with identical follow-up in the two study groups.
Causes of death were evaluated in a blinded fashion and according to a standard algorithm9 or, after
validation, on the basis of official causes of death. The causes were classified by the independent
committees as definite prostate cancer, causes related to screening, probable or possible prostate
cancer, and other intercurrent causes (with or without prostate cancer as a contributory factor).
Decision points that were used for determining the cause of death have been described previously.9

For this analysis, we have combined the categories of definite and probable prostate cancer and the
category of causes related to screening.
Other Analyses
Aspects of quality of life were evaluated in several study centers. A complete evaluation of all the
steps of screening was conducted in the Netherlands (data not shown).15,16,17,18,19,20,21
Statistical Analysis
The statistical analysis was based on the core age group (including men between the ages of 55 and
69 years at randomization) and on the intention-to-screen principle. Overall mortality was studied to
evaluate the correctness of randomization. Poisson regression analysis was used to estimate the ratio
of mortality in the intervention group to mortality in the control group, stratified according to study
center and age group at randomization. The Nelsen–Aalen method was used for the calculation of
cumulative hazard.22 All P values are two-sided. Interim analyses were conducted for follow-up in
2002, 2004, and 2006, with an alpha spending curve with a division of uneven weights.23 A
preliminary analysis included men who had actually undergone screening in the first round (with
adjustment for noncompliance). The number that would need to be screened to prevent one death
from prostate cancer was calculated as the inverse of the absolute difference in cumulative mortality
from prostate cancer between the two study groups.
The study had a power of 86% to show a statistically significant difference of 25% or more in
prostate-cancer mortality with a P value of 0.05 among men who underwent screening, on the basis
of follow-up through 2008.4 The sample-size calculation, which was part of the power calculation,
took into account noncompliance in the screening group in each study center and the use of PSA
tests outside the protocol assignment in the control group (termed contamination of the control
group). On the basis of an overall level of compliance of 82% and 20% contamination in the control
group, a 25% reduction in the number of men who underwent screening would be equivalent to a
14% reduction in an intention-to-treat analysis. This assumes that men who were screened and those
who were not screened had the same underlying risk and that screening in the control group was as
effective as that in the screening group.
Results
Subjects
Figure 1 shows trial enrollment, study-group assignments, and follow-up of all subjects and of the
core age group. A total of 162,387 men in the core age group underwent randomization; of these
men, 72,952 were assigned to the screening group and 89,435 to the control group. A total of 62
men in the screening group and 82 men in the control group died between identification and
randomization.
Table 1 summarizes the characteristics of the subjects according to the center and the results of
screening. The mean age at randomization was 60.8 years (range, 59.6 to 63.0), with little variation
among the seven countries. In total, 82.2% of the men in the screening group were screened at least
once. Compliance was higher in study centers that obtained consent before randomization (88 to
100%) than in those in which subjects underwent randomization before providing consent (62 to
68%) (for details concerning all age groups, see Table 1A in Supplementary Appendix 5).
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Center.
During the trial, 126,462 PSA-based tests were performed, an average of 2.1 per subject who
underwent screening. Overall, 16.2% of all tests were positive, with a range of 11.1 to 22.3% among
the centers. The average rate of compliance with biopsy recommendations was 85.8% (range, 65.4
to 90.3). Of the men who underwent biopsy for an elevated PSA value, 13,308 (75.9%) had a false
positive result.
We detected 5990 prostate cancers in the screening group and 4307 in the control group. These
numbers correspond to a cumulative incidence of 8.2% and 4.8%, respectively. The positive
predictive value of a biopsy (the number of cancers detected on screening divided by the number of
biopsies expressed as a percentage) was on average 24.1% (range, 18.6 to 29.6). The cumulative
incidence of local prostate cancer was higher in the screening group than in the control group (for
details about tumor stage, grade distribution, and treatment, see Supplementary Appendixes 6 and
7). For example, the number of men with positive results on a bone scan (or a PSA value of more
than 100 ng per milliliter in those without bone-scan results) was 0.23 per 1000 person-years in the
screening group, as compared with 0.39 per 1000 person-years in the control group, a 41%
reduction in the screening group (P<0.001). The proportions of men who had a Gleason score of 6
or less were 72.2% in the screening group and 54.8% in the control group, and the proportions with
a Gleason score of 7 or more were 27.8% in the screening group and 45.2% in the control group.
Prostate-Cancer Mortality
As of December 31, 2006, with average and median follow-up times of 8.8 and 9.0 years in the
screening and control groups, respectively, there were 214 prostate-cancer deaths in the screening
group and 326 in the control group in the core age group. Deaths that were associated with prostate-
cancer–related interventions were categorized as deaths from prostate cancer. The unadjusted rate
ratio for death from prostate cancer in the screening group was 0.80 (95% confidence interval [CI],
0.67 to 0.95; P=0.01); after adjustment for sequential testing with alpha spending due to two
previous interim analyses (based on Poisson regression analysis), the rate ratio was 0.80 (95% CI,
0.65 to 0.98; P=0.04). The rates of death in the two study groups began to diverge after 7 to 8 years
and continued to diverge further over time (Figure 2). Overall mortality results at 30 days are
summarized in Supplementary Appendix 8.
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Figure 2. Cumulative Risk of Death from Prostate Cancer.
As of December 31, 2006, with an average follow-up time of 8.8 years,
there were 214 prostate-cancer deaths in the screening group and 326 in
the control group. Deaths that were associated with interventions were
categorized as being due to prostate cancer. The adjusted rate ratio for
death from prostate cancer in the screening group was 0.80 (95% CI, 0.65
to 0.98; P=0.04). The Nelsen–Aalen method was used for the calculation
of cumulative hazard.

In the intention-to-screen analysis, the absolute difference between the screening group and the
control group was 0.71 prostate-cancer death per 1000 men. This means that in order to prevent one
prostate-cancer death, the number of men who would need to be screened would be 1410 (95% CI,
1142 to 1721), with an average of 1.7 screening visits per subject during a 9-year period. The
additional prostate cancers diagnosed by screening resulted in an increase in cumulative incidence
of 34 per 1000 men, as compared with the control group. In other words, 48 additional subjects
(1410÷1000x34) would need to be treated to prevent one death from prostate cancer.
In an analysis of men who were actually screened during the first round (which was adjusted for
noncompliance), the rate ratio for prostate-cancer death after 9 years was 0.73 (95% CI, 0.56 to
0.90), which meant that 1068 men would need to be screened and 48 would need to be treated to
prevent one death from prostate cancer. The number of men who would need to be treated (48)
remained unchanged in the per-protocol analysis because the same number of deaths were
prevented and the same number of additional cases were diagnosed in men who actually underwent
screening.
Effect of Age on Mortality
In an exploratory analysis of mortality according to age group, there was no evidence of
heterogeneity among age groups (Table 2). Among men between the ages of 50 and 54 years at
baseline, the number of events was small, with no obvious screening effect.
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Table 2. Death from Prostate Cancer, According to the Age at Randomization.
Heterogeneity of Rate Ratios
In an exploratory analysis of heterogeneity according to study center (which was carried out in
accordance with the monitoring plan6), the decrease in the rate of death from prostate cancer in the
screening group could not be attributed to any single center, as evidenced by rate ratios ranging
between 0.74 and 0.84 after the exclusion of each center, one at a time. There was no significant
difference in overall mortality (Table 3).
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Table 3. Rate Ratios for Death from Any Cause and Death from Prostate Cancer,
with Exclusions According to Location of Study Center.

Adverse Events
No deaths were reported as a direct complication (e.g., septicemia or bleeding) associated with a
biopsy procedure. Complications associated with screening procedures (including prostate biopsy)
have been reported previously.24,25
Discussion
In an intention-to-screen analysis of data from seven European centers, PSA screening was
associated with a significant absolute reduction of 0.71 prostate-cancer death per 1000 men after an
average follow-up of 8.8 years (median, 9.0). This finding corresponds to a relative reduction of
20% in the rate of death from prostate cancer among men between the ages of 55 and 69 years at
study entry, given an average screening interval of 4 years and a compliance rate of 82% of those
who accepted the offer of screening (rate ratio, 0.80; adjusted P=0.04). To prevent one prostate-
cancer death, 1410 men (or 1068 men who actually underwent screening) would have to be
screened, and an additional 48 men would have to be treated. The high number of men who would
need to be treated could be improved by avoiding the diagnosis and treatment of indolent cancers
during screening or by improving treatment in the remaining men with cancer. The number needed
to screen in our study is similar to that in studies of mammographic screening for breast cancer and
fecal occult-blood testing for colorectal cancer.26,27
Our analysis shows that the results were generally similar in all participating study centers
considered individually (Table 3). The trial was not powered to evaluate mortality differences
between centers or for age subgroups. The results were based on a combined analysis of data from
centers sharing a common core protocol, which defined the minimal criteria for inclusion and the
scope of the primary analysis but allowed wider age ranges or shorter screening intervals. Because
of various recruitment approaches, the estimate of a 20% reduction in prostate-cancer mortality does
not represent the effect of a screening program at the population level or the effect on individual
subjects but instead represents a mixture of such estimates. Despite some variation in screening
procedures, the results from each center were compatible with the main result: a lowering of the
death rate from prostate cancer associated with screening.
The screening interval of 4 years was chosen on the basis of the mean lead time of 5 to 10 years in
PSA-based screening.28,29 However, the lead time of aggressive cancers, which may be the most
important target of screening, is likely to be much shorter.
The benefit of screening was restricted to the core age group of subjects who were between the ages
of 55 and 69 years at the time of randomization. The results that were seen in other age groups are
preliminary and inconclusive. Our findings are early results of the trial, and continued follow-up
will provide further information. Adjustment for noncompliance resulted in a greater effect among
men who actually underwent screening, and after adjustment for both noncompliance and
contamination, the effect of screening in the intention-to-screen analysis is likely to be further
enhanced.
The rate of overdiagnosis of prostate cancer (defined as the diagnosis in men who would not have
clinical symptoms during their lifetime) has been estimated to be as high as 50% in the screening
group.30 Consistent estimates of overdiagnosis (a third of cancers detected on screening) have also

been obtained by identifying potentially indolent prostate cancers on the basis of clinical and
pathological characteristics.31,32,33 Overdiagnosis and overtreatment are probably the most
important adverse effects of prostate-cancer screening and are vastly more common than in
screening for breast, colorectal, or cervical cancer.34
Although the results of our trial indicate a reduction in prostate-cancer mortality associated with
PSA screening, the introduction of population-based screening must take into account population
coverage, overdiagnosis, overtreatment, quality of life, cost, and cost-effectiveness. The ratio of
benefits to risks that is achievable with more frequent screening or a lower PSA threshold than we
used remains unknown. Further analyses are needed to determine the optimal screening interval in
consideration of the PSA value at the first screening and of previously negative results on
biopsy.35,36,37,38
Supported by grants from Europe Against Cancer and the fifth and sixth framework program of the European Union, by
grants from agencies or health authorities in the participating countries, and by unconditional grants from Beckman
Coulter. The studies in each national center were funded by numerous local grants (see Supplementary Appendix 2).
Dr. Hugosson reports receiving lecture fees from GlaxoSmithKline; Dr. Tammela, receiving consulting or lecture fees
from GlaxoSmithKline, Pfizer, AstraZeneca, Leiras, and Novartis; and Dr. Lilja, holding a patent for an assay for free
PSA. No other potential conflict of interest relevant to this article was reported.
* Members of the European Randomized Study of Screening for Prostate Cancer (ERSPC) are listed in the Appendix.
Source Information
The authors' affiliations are listed in the Appendix.
This article (10.1056/NEJMoa0810084) was published at NEJM.org on March 18, 2009.
Address reprint requests to Dr. Schröder at the Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, the
Netherlands, or at secr.schroder@erasmusmc.nl.
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Appendix
The authors' affiliations are as follows: the Departments of Urology (F.H.S., M.J.R., C.H.B.),
Pathology (T.K.), Clinical Chemistry (B.G.B.), and Public Health (H.J.K.), Erasmus Medical
Center, Rotterdam, the Netherlands; the Department of Urology, Sahlgrenska University Hospital,
Göteborg, Sweden (J.H., G.A.); the Department of Urology, Tampere University Hospital (T.L.J.T.),
and Tampere School of Public Health, University of Tampere (A.A.) — both in Tampere, Finland;
the Department of Diagnostic Medical Imaging (S.C.) and Unit of Epidemiology (M.Z.), Institute
for Cancer Prevention, Florence, Italy; Provinciaal Instituut voor Hygiëne, Antwerp, Belgium
(V.N.); the Department of Urology, Kantonsspital Aarau, Aarau, Switzerland (M.K., F.R.); the
Department of Urology, Hospital Universitario de Getafe, Madrid (M.L., A.B.); the Department of

Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden, and Memorial
Sloan-Kettering Cancer Center, New York (H.L.); Oncology Center Antwerp, Antwerp, Belgium
(L.J.D.); Finnish Cancer Registry, Helsinki (L.M.); the Department of Urology, Centre Hospitalier
Regional Universitaire, Lille, France (A.V.); the Department of Urology, Clinique de Beau Soleil,
Montpellier, France (X.R.); and the Cancer Screening Evaluation Unit, Surrey, United Kingdom
(S.M.M.).
The members of the data and safety monitoring committee were as follows: P. Smith (chair), J.
Adolfsson, and T. Hakulinen, who carried out interim analyses of the data by relating the central
messages on the progress of the study to the voting members; J. Chamberlain and B. Collette,
earlier committee members; F. Alexander, who served as the trial statistician until her retirement;
and I. de Beaufort, who served as an advisor. Additional study members are listed in Supplementary
Appendix 1.
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