Content uploaded by Grant Izmirlian
Author content
All content in this area was uploaded by Grant Izmirlian
Content may be subject to copyright.
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., and Christine D. Berg, M.D. for the PLCO Project Team*
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 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.
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
Copyright © 2009 Massachusetts Medical Society.
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.
The authors’ affiliations are listed in the Appendix.
*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.
(ClinicalTrials.gov number, NCT00002540.)
No other potential conflict of interest relevant to this article was reported.
NIH Public Access
Author Manuscript
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
Published in final edited form as:
N Engl J Med. 2009 March 26; 360(13): 1310–1319. doi:10.1056/NEJMoa0810696.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Andriole et al. Page 2
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Andriole et al. Page 3
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
(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.
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).
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).
Andriole et al. Page 4
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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) (Fig. 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.
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).
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
Andriole et al. Page 5
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Andriole et al. Page 6
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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 (Fig. 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 treatment25–31 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.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
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.
Andriole et al. Page 7
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
We thank the study subjects for their contributions in making this study possible.
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.
REFERENCES
1. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising
incidence of prostate cancer. JAMA 1995;273:548–552. [PubMed: 7530782]
2. Lin K, Lipsitz R, Miller T, Janakiraman S. Benefits and harms of prostate-specific antigen screening
for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med
2008;149:192–199. [PubMed: 18678846]
3. American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy.
Oncology (Williston Park) 2000;14:267–272. 277-8, 280 passim. [PubMed: 10736812]
4. American Cancer Society guidelines for the early detection of cancer. [Accessed March 6, 2009]. at
http://www.cancer.org/docroot/ped/content/ped_2_3x_acs_cancer_detection_guidelines_36.asp.
5. Kawachi, MH.; Bahnson, RR.; Barry, M., et al. National Comprehensive Cancer Network clinical
practice guidelines in oncology: prostate cancer early detection (v.2.2007). [Accessed March 6, 2009].
at http://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf.
6. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann
Intern Med 2008;149:185–191. [PubMed: 18678845]
Andriole et al. Page 8
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
7. Labrie F, Candas B, Cusan L, et al. Screening decreases prostate cancer mortality: 11-year follow-up
of the 1988 Quebec prospective randomized controlled trial. Prostate 2004;59:311–318. [PubMed:
15042607]
8. Gohagan JK, Prorok PC, Hayes RB, Kramer BS. The Prostate, Lung, Colorectal and Ovarian (PLCO)
Cancer Screening Trial of the National Cancer Institute: history, organization, and status, Control Clin
Trials. 2000;21 Suppl:251S–272S.
9. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized
European study. N Engl J Med 2009;360:1320–1328. [PubMed: 19297566]
10. Martin, RM.; Donovan, JL.; Hamdy, FC., et al. Evaluating population-based screening for localized
prostate cancer in the United Kingdom: the CAP (Comparison Arm for ProtecT) study. London:
Cancer Research UK/Department of Health (C18281/A 8145; [Accessed March 6, 2009]. at
http://ije.oxfordjournals.org/cgi/content/full/dyl305v1
11. Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian
(PLCO) Cancer Screening Trial. Control Clin Trials 2000;21 Suppl:273S–309S. [PubMed:
11189684]
12. Andriole GL, Levin DL, Crawford ED, et al. Prostate cancer screening in the Prostate, Lung,
Colorectal, and Ovarian (PLCO) Cancer Screening Trial: findings from the initial screening round
of a randomized trial. J Natl Cancer Inst 2005;97:433–438. [PubMed: 15770007]
13. Grubb RL III, Pinsky PF, Greenlee RT, et al. Prostate cancer screening in the Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial: update on findings from the initial four rounds of
screening in a randomized trial. BJU Int 2008;102:1524–1530. [PubMed: 19035857]
14. Pinsky PF, Andriole GL, Kramer BS, Hayes RB, Prorok PC, Gohagan JK. Prostate biopsy following
a positive screen in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. J Urol
2005;173:746–750. [PubMed: 15711261]
15. Hayes RB, Reding D, Kopp W, et al. Etiologic and early marker studies in the Prostate, Lung,
Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21 Suppl:349S–
355S. [PubMed: 11189687]
16. Fleming, ID.; Cooper, JS.; Henson, DE., et al., editors. AJCC cancer staging manual. 5th ed.
Philadelphia: Lippincott-Raven; 1997.
17. Miller AB, Yurgalevitch S, Weissfield JL. Death review process in the Prostate, Lung, Colorectal
and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21 Suppl:400S–406S.
[PubMed: 11189691]
18. Ahlbom, A. Biostatistics for epidemiologists. Boca Raton, FL: CRC Press; 1993.
19. Albertsen PC, Hanley JA, Fine J. 20-Year outcomes following conservative management of clinically
localized prostate cancer. JAMA 2005;293:2095–2101. [PubMed: 15870412]
20. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early
prostate cancer. N Engl J Med 2005;352:1977–1984. [PubMed: 15888698]
21. Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostatespecific antigen
screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl
Cancer Inst 2003;95:868–878. [PubMed: 12813170]
22. Etzioni R, Feuer E. Studies of prostate cancer mortality: caution advised. Lancet Oncol 2008;9:407–
409. [PubMed: 18452850]
23. Aus G, Ahlgren G, Bergdahl S, Hugosson J. Infection after transrectal core biopsies of the prostate
— risk factors and antibiotic prophylaxis. Br J Urol 1996;77:851–855. [PubMed: 8705220]
24. Rietbergen JB, Kruger AE, Kranse R, Schröder F. Complications of transrectal ultrasound-guided
systematic sextant biopsies of the prostate: evaluation of complication rates and risk factors within
a population-based screening program. Urology 1997;49:875–880. [PubMed: 9187694]
25. Yao SL, Lu-Yao G. Population-based study of relationships between hospital volume of
prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst 1999;91:1950–
1956. [PubMed: 10564679]
26. Alibhai SMH, Leach M, Tomlinson G, et al. 30-Day mortality and major complications after radical
prostatectomy: influence of age and comorbidity. J Natl Cancer Inst 2005;97:1525–1532. [Erratum,
J Nat l Cancer Inst 2007;99:1648.]. [PubMed: 16234566]
Andriole et al. Page 9
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
27. Potosky AL, Davis WW, Hoffman RM, et al. Five-year outcomes after prostatectomy or radiotherapy
for prostate cancer: the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2004;96:1358–1367.
[PubMed: 15367568]
28. Lim AJ, Brandon AH, Fiedler J, et al. Quality of life: radical prostatectomy versus radiation therapy
for prostate cancer. J Urol 1995;154:1420–1425. [PubMed: 7658548]
29. Hamilton AS, Stanford JL, Gilliland FD, et al. Health outcomes after external-beam radiation therapy
for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin
Oncol 2001;19:2517–2526. [PubMed: 11331331]
30. Fowler FJ Jr, McNaughton Collins M, Walker Corkery E, Elliott DB, Barry MJ. The impact of
androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer
2002;95:287–295. [PubMed: 12124828]
31. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for
localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516–
1524. [PubMed: 17925537]
Andriole et al. Page 10
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Figure 1.
Number of Diagnoses of All Prostate Cancers (Panel A) and Number of Prostate-Cancer Deaths
(Panel B).
Andriole et al. Page 11
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Andriole et al. Page 12
Table 1
Characteristics of the Subjects at Baseline.*
Screening
Group Control
Group
Variable (N = 38,343) (N = 38,350)
percent
Age
55–59 yr 32.3 32.3
60–64 yr 31.3 31.3
65–69 yr 23.2 23.2
70–74 yr 13.2 13.2
Race or ethnic group†
Non-Hispanic white 86.2 83.8
Non-Hispanic black 4.5 4.3
Hispanic 2.1 2.1
Asian 4.0 3.9
Other 0.8 0.9
Missing data 2.4 5.0
Enlarged prostate or benign prostatic hyperplasia 21.4 20.5
Previous prostate biopsy 4.3 4.3
Family history of prostate cancer 7.1 6.7
PSA test within past 3 yr
Once 34.6 34.3
Two or more times 9.4 9.8
Digital rectal examination within past 3 yr
Once 32.8 31.9
Two or more times 22.2 22.0
*PSA denotes prostate-specific antigen.
†Race or ethnic group was self-reported.
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Andriole et al. Page 13
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.*
Variable Screening Group Control Group
According to Method of Detection All Subjects
(N = 3452) All Subjects
(N = 2974)
Never Screened
(N = 154) After Screening
(N = 875) Outside of
Screening
Protocol
(N = 374)
Screen Detected
at Baseline
(N = 549)
Screen Detected
at Yr 1-Yr 5
(N = 1500)
number (percent)
Clinical stage
1 1 (0.6) 5 (0.6) 8 (2.1) 2 (0.4) 2 (0.1) 18 (0.5) 15 (0.5)
II 138 (89.6) 838 (95.8) 347 (92.8) 516 (94.0) 1458 (97.2) 3297 (95.5) 2790 (93.8)
III 5 (3.2) 7 (0.8) 3 (0.8) 12 (2.2) 22 (1.5) 49 (1.4) 56 (1.9)
IV 10 (6.5) 20 (2.3) 9 (2.4) 19 (3.5) 15 (1.0) 73 (2.1) 79 (2.7)
Unknown 0 5 (0.6) 7 (1.9) 0 3 (0.2) 15 (0.4) 34 (1.1)
Histopathological type
Adenocarcinoma
Any 144 (93.5) 824 (94.2) 346 (92.5) 511 (93.1) 1375 (91.7) 3200 (92.7) 2802 (94.2)
Acinar 9 (5.8) 48 (5.5) 25 (6.7) 36 (6.6) 124 (8.3) 242 (7.0) 158 (5.3)
Other 1 (0.6) 3 (0.3) 3 (0.8) 2 (0.4) 1 (0.1) 10 (0.3) 14 (0.5)
Gleason score on biopsy†
2–4 11 (7.1) 1.7 (1.9) 36 (9.6) 64 (11.7) 94 (6.3) 222 (6.4) 137 (4.6)
5–6 78 (50.6) 500 (57.1) 228 (61.0) 278 (50.6) 963 (64.2) 2047 (59.3) 1656 (55.7)
7 39 (25.3) 252 (28.8) 74 (19.8) 132 (24.0) 318 (21.2) 815 (23.6) 779 (26.2)
8–10 16 (10.4) 95 (10.9) 25 (6.7) 55 (10.0) 98 (6.5) 289 (8.4) 341 (11.5)
Unknown 10 (6.5) 11 (1.3) 11 (2.9) 20 (3.6) 27 (1.8) 79 (2.3) 61 (2.1)
*Subjects with available data for tumor staging but not for nodal status or the presence or absence of metastasis were classified as having stage II disease. Percentages may not total 100 because of rounding.
†The Gleason score ranges from 2 to 10, with higher scores indicating more aggressive disease.
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Andriole et al. Page 14
Table 3
Death Rates from Prostate Cancer per 10,000 Person-Years at 10 Years.*
Variable Years after Randomization
1 2 3 4 5 6 7 8 9 10
Screening group
Cumulative deaths — no. 3 6 12 16 26 35 50 59 76 92
Cumulative person-yr— no. 37,864 75,292 112,234 148,635 184,490 219,752 254,295 287,196 316,244 340,230
Death rate 0.8 0.8 1.1 1.1 1.4 1.6 2.0 2.1 2.4 2.7
Control group
Cumulative deaths — no. 1 4 12 18 23 34 44 56 65 82
Cumulative person-yr— no. 37,838 75,231 112,123 148,444 184,154 219,135 253,317 285,777 314,463 338,083
Death rate 0.3 0.5 1.1 1.2 1.2 1.6 1.7 2.0 2.1 2.4
Rate ratio (95% CI) 3.00
(0.31–28.82) 1.50
(0.42–5.31) 1.00
(0.45–2.22) 0.89
(0.45–1.74) 1.13
(0.64–1.98) 1.03
(0.64–1.65) 1.13
(0.75–1.70) 1.05
(0.73–1.51) 1.16
(0.83–1.62) 1.11
(0.83–1.50)
*Rate ratios are the rates of death in the screening group divided by those in the control group.
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Andriole et al. Page 15
Table 4
Causes of Death at 10-Year Follow-up.*
Cause Screening Group Control Group
no (%)
Any†3953 (100.0) 4058 (100.0)
Cancer†916 (23.2) 918 (22.6)
Ischemic heart disease 857 (21.7) 843 (20.8)
Stroke 107 (2.7) 109 (2.7)
Other circulatory disease 684 (17.3) 723 (17.8)
Respiratory disease 415 (10.5) 416 (10.3)
Digestive disease 141 (3.6) 133 (3.3)
Infectious disease 74 (1.9) 85 (2.1)
Endocrine or metabolic disease or immune disorder 155 (3.9) 188 (4.6)
Nervous system disease 128 (3.2) 113 (2.8)
Accident 238 (6.0) 235 (5.8)
Other 238 (6.0) 295 (7.3)
*Causes of death were determined by death certificate.
†Causes of death from any cause and cancer do not include prostate, lung, and colorectal cancer.
N Engl J Med. Author manuscript; available in PMC 2010 September 23.
