Prostate-Specific Antigen Screening and Mortality
from Prostate Cancer
Stephen W. Marcella, MD, MPH1,2, George G. Rhoads, MD, MPH1,2, Jeffrey L. Carson, MD4,
Frances Merlino, RN1, and Homer Wilcox, MS3
1Department of Epidemiology, UMDNJ-School of Public Health, Piscataway, NJ, USA;2Robert Wood Johnson Medical School, New Brunswick,
NJ, USA;3New Jersey Department of Health and Senior Services, Trenton, NJ, USA;4Department of Medicine, Robert Wood Johnson Medical
School, New Brunswick, NJ, USA.
BACKGROUND: There is no available evidence from
randomized trials that early detection of prostate cancer
improves health outcomes, but the prostate-specific
antigen (PSA) test is commonly used to screen men for
OBJECTIVE: The objective of the study is to see if
screening with PSA decreases mortality from prostate
DESIGN, SETTING, AND PARTICIPANTS: This is a
case-control study using one-to-one matching on race,
age, and time of availability of exposure to PSA screen-
ing. Decedents, 380, from New Jersey Vital Statistics
1997 to 2000 inclusive, 55–79 years of age at diagnosis
were matched to living controls without metastatic
prostate cancer. Medical records were obtained from
all providers, and we abstracted information about PSA
tests from 1989 to the time of diagnosis in each index
MEASUREMENTS: Measurements consist of a compar-
ison of screening (yes, no) between cases and controls.
Measure of association was the odds ratio.
RESULTS: Eligible cases were diagnosed each year
from 1989 to 1999 with the median year being 1993.
PSA screening was evident in 23.2–29.2% of cases and
21.8–26.1% of controls depending on the screening
criteria. The unadjusted, matched odds ratio for dying
of prostate cancer if ever screened was 1.09 (95% CI
0.76 to 1.60) for the most restrictive criteria and 1.19
(95% CI, 0.85 to 1.66) for the least restrictive. Adjust-
ment for comorbidity and education level made no
significant differences in these values. There were no
significant interactions by age or race.
CONCLUSIONS: PSA screening using an ever/never
tabulation for tests from 1989 until 2000 did not
protect New Jersey men from prostate cancer mortality.
KEY WORDS: prostate cancer; screening; prostate specific antigen.
J Gen Intern Med 23(3):248–53
© Society of General Internal Medicine 2007
Prostate cancer is the second leading cause of cancer death
among U.S. men and is particularly common among the
elderly. Although there is no evidence from randomized trials
that early detection of prostate cancer improves health out-
comes, the determination of prostate-specific antigen (PSA) to
screen men for prostate cancer is now routine. Approximately
77% of the U.S. male population ages 55–79 has been tested at
least once with the PSA test1.
Screening for prostate cancer with the PSA test is a
contentious issue. Various organizations differ on whether there
is enough justification for population screening2–4. Findings
support the test’s ability to detect early-stage prostate cancer,
but high-grade disease is missed with traditional PSA cut-points
[5–8]. For a screening test to benefit a population, it must detect
cancer at a stage when it is more curable. There is some
evidence that radical prostatectomy can decrease cancer-spe-
cific mortality in clinically detected, early cases9,10, but this has
not been demonstrated for cases detected by screening. Two
case-control studies have reported conflicting results: one,
based on 501 all-cause deaths, including 136 prostate cancer
deaths, found no benefit11and the other, based on 236 cases of
metastatic cases, reported a modest benefit but only after an
unusual statistical adjustment12. A third study showed a
possible benefit from the digital rectal examination but was
unable to estimate the separate influence of PSA testing13.
Our investigation used a statewide cancer registry to
identify cases and recruited community-based controls. We
hypothesized that men dying of prostate cancer were less likely
than matched controls to have had a screening PSA test before
diagnosis of prostate cancer.
DESIGN AND METHODS
Our study paired men who died from prostate cancer in New
Jersey with age- and race-matched controls from the commu-
nity. Information on PSA testing was obtained from medical
This study was presented at a poster session at the Annual Meeting on
Cancer Prevention of the American Association for Cancer Research,
November 14th, 2006 in Boston, USA.
Received July 20, 2007
Revised November 13, 2007
Accepted November 29, 2007
Published online January 3, 2008
records of cases from 1989 to the time of first suspicion of
prostate cancer and from the records of the matched control
for the identical time period. We obtained access to medical
records through the wife of the deceased, if a case, and
through the subject himself if a control. We made an exhaus-
tive attempt to obtain every record from every provider of care.
Retrieval of records was assisted by a New Jersey statute that
requires health care providers to release medical information
about their patients to entities performing state-assisted
studies with public health significance14. We obtained signed
authorizations by the spouse of the case or the control subject.
This study was approved by Institutional Review Boards from
the UMDNJ-Robert Wood Johnson Medical School and the
New Jersey Department of Health and Senior Services.
We identified potential cases from New Jersey Vital Records.
Married men who died from prostate cancer between 1997 and
2000 at age 55–79 years were eligible. There were 1,767 men in
this age range who had prostate cancer listed as the cause of
death. We required cases to be married at the time of death to
increase the probability that there would be a knowledgeable,
surviving informant to assist in identifying medical care
providers. Eliminating those who were not married, or after
review of the death certificate, did not have prostate cancer as
the underlying cause of death, left 1,023 men in the sample. Of
these, we were able to contact 718 spouses for a contact rate of
70%. A total of 553 responded affirmatively, and we excluded
166 for ineligibility after reviewing medical records or if a
spouse could not provide sufficient information leaving us with
387 cases. Specifically, we excluded men whose medical
records did not document symptomatic, metastatic prostate
cancer at or near the time of death.
For each case, we matched one control subject by age (same
5-year age group) and race (white or black). Potential controls
living in New Jersey and 55–64 years of age were identified by
Northeast Research and The Watsroom, Inc. by previously
described random digit dialing methods15. Potential controls
aged 65–79 were identified by Westat, Inc. from New Jersey
Medicare tapes. In the event of multiple controls, we selected
the one that was closest in age. If a potential control did not
respond, or proved ineligible, we selected the next closest in
age. All controls were married. As the basis of protection from
screening is in early detection, any control with early prostate
cancer was included as they may have benefited from screen-
ing, and it would be a bias against screening to exclude them.
Controls with metastatic prostate cancer were excluded as
they were unlikely to have benefited from any screening.
We invited widows of cases and also invited control men, to
participate. Controls were offered a $20 incentive at first
contact. Because it was deemed insensitive to offer money to
the widows of cases at the time of recruitment, we sent $20
after completion of the study with a “thank you” letter. We
obtained basic demographic information and secured written
permission for release of medical records.
Review of Medical Records
We linked each case to a New Jersey Cancer Registry record and
requested copies of all pertinent medical records from providers
identified on the death certificate, in the registry, or from the
interview. For controls, we followed up all sources of care
identified in the interview. When other providers were identified
in medical records not previously described, we sought records
from these sources as well. In addition to PSA testing, we
abstracted cancer grade and stage, comorbidities, and long-
term medications from medical records and the cancer registry.
Comorbidity was tabulated as a simple count of the number of
chronic diseases. Controls with non-metastatic prostate cancer
were not excluded if diagnosed after the case.
Period of Observation for PSA Tests
For each case-control pair, we tabulated PSA tests during the
identical time period. This period started January 1, 1989, the
first year that PSA testing came into significant clinical use in
New Jersey and ended with the date of clinical suspicion of
prostate cancer in the case. We defined this “date of suspicion”
as the time of the first clinical finding leading to a biopsy (even
if negative) or to frequent (more than once per year) follow-up
examinations and PSA tests. A PSA test cannot be classified as
screening during this period of suspicion.
Classification of PSA Tests
Based on medical records review, we classified reasons for PSA
testing as follows: (1) screening, (2) lower urinary tract
symptoms, (3) physical exam consistent with benign prostatic
hypertrophy (BPH), (4) physical signs consistent with possible
tumor such as a nodule, (5) previous history of an abnormality
in either the digital rectal examination or PSA, and (6) other
symptom or sign(s) possibly related to metastatic disease such
as undefined back or bone pain. These categories were coded
independently of one another as they may not be mutually
In addition to the above classification that was applied to all
PSA tests, we periodically convened a panel of three investiga-
tors (SWM, GGR, JLC) to review each PSA done within
6 months of the date of clinical suspicion of diagnosis without
knowledge of the case-control status of the subject. This was
done as an added precaution to ensure that those tests done
close to a suspicion of diagnosis were in fact, true screens. We
classified each PSA as “screening” or done for possible
symptoms or a physical abnormality consistent with prostate
cancer. PSA screening was defined in the context of a yearly
examination, routine laboratory tests, “annual”, or specifically
designated as a “screen”. When there was a difference in
classification between these blinded judgments and the earlier
categorization, the blinded judgments were used. In the initial
chart review, it was not possible to blind the abstracter to
case/control status. Changes from the initial classification
were uncommon (less than 5% of the PSA tests within this 6-
month interval). In addition, we randomly repeated the blinded
review for the same PSA test for about 10%.of the tests; the
panel returned the same classification >98% of the time.
Marcella et al.: Prostate Cancer Screening and Mortality
We compared cases and controls using chi-square analysis for
categorical variables and Student’s t test for continuous
variables. Conditional logistic regression was employed to
model the outcome (case/control) status as a function of the
independent variables16. We considered a priori that the key
predictor, screening with one or more PSAs (yes or no), socioeco-
nomic status as measured by education level, and a categorical
number of comorbidities to be the independent variables.
We performed three analyses using different criteria for PSA
screening: (1) least restrictive: either lower urinary tract
symptoms or BPH could be present, (2) moderately restrictive:
BPH on physical exam or by history but no evidence of lower
urinary tract symptoms, and (3), most restrictive: no evidence
of lower urinary tract symptoms or BPH. We used SAS software
9.1 (SAS Institute, Inc., Cary, NC) for all analyses.
We confirmed that controls were representative of the source
population with respect to the frequency of PSA testing by
comparing their PSA frequencies to those obtained from the
New Jersey Behavioral Risk Factor Surveillance System
(BRFSS) sponsored by the Centers for Disease Control and
Prevention1. For this comparison, we re-tabulated our control
rates to include all PSA tests done from 1989 through 2000,
not just the PSAs done during the time interval ending at the
date of clinical suspicion of the matching case.
Response Rates and Control Screening Rates
The overall response rate for cases was 77% (N=553) with 387
eligible after the interview and medical record review. The
control response rate was 57% (N=610) with 442 eligible after
review. We were able to match 380 cases with controls. The
extent of PSA testing for our controls was very similar to that of
the age-comparable population of New Jersey male residents
surveyed in the BRFSS1. Table 1 shows the percentages of men
ever tested with the PSA test by age range.
Comparison of Cases and Controls
A comparison of demographic variables and comorbidity
between cases and controls is shown in Table 2. Ten percent
of cases and 11% of controls were black due to one case-
control pair mismatch for race leaving 379 cases and 379
controls available for analysis. The mean age of the two groups
was within 1 year. Cases were less likely to have graduated
from high school, and controls were more likely to have
attended graduate or professional school. Cases and controls
were similar to one another with respect to the number of
comorbidities in years before the case diagnosis of prostate
Tumor Characteristics and Survival Times
The year 1993 was the median year of diagnosis for cases.
Stage at diagnosis and Gleason scores for the cases are shown
in Table 3. We could not obtain Gleason scores for 7%. About
25% of cases had Gleason scores of 6 or less, 46% had scores
of 7 or 8, and 23% had scores of 9 or greater. The time from
suspicion to diagnostic confirmation was ≤1 month for 66.7
and 70% for those with distant and non-distant disease,
respectively. The median length of survival from suspicion of
cancer was 2.9 years for those with distant disease compared
to 6.2 years for those with non-distant disease. Forty (10.5%)
controls had a history of prostate cancer that was identified
subsequent to the date of suspicion of the matched case. The
Gleason score was 7 or 8 in 22.5% of these controls and 6 or
less in the remainder.
Association of PSA Screening and Mortality from
We analyzed the association between PSA screening and death
from prostate cancer using three definitions of PSA “screen-
ing”. Using the most restrictive definition, we documented
Table 1. Frequency of “Ever Been Tested” with a PSA test:
Comparison of Study Controls with Those from the NJ Behavior Risk
Factor Surveillance System*
N Number in each strata, n number in each strata who were screened at
*Survey of PSA tests as of 2001
†BRFSS percentages calculated with weights to correct for the sampling
design to more accurately represent the general population of the state
Table 2. Comparison of Cases and Controls
Characteristic Cases Controls
High school grad
Grad or pro school
Age at time of diagnosis
*P for trend
Marcella et al.: Prostate Cancer Screening and Mortality
screens for 23.2% and 21.8% of cases and controls, respec-
tively. The matched odds ratio estimate was 1.09 (95% CI,
0.76–1.58; Table 4). Using the moderately or least restrictive
definitions for PSA screening modestly increased the number
of tests in both groups, but yielded nearly identical matched
Controls were more educated than the cases as shown in
Table 2, but educational level was not much related to the
frequency of PSA screening (data not shown). We used
conditional logistic regression to adjust for differences between
cases and controls for the number of comorbidities and
education level. These adjustments did not affect the results
(Table 4). No statistically significant interactions were seen for
age or race with PSA, but the point estimates for black men
were 0.43 (p=0.16) and 0.56 (p=0.24) using the most restric-
tive and least restrictive definitions, respectively.
In this population-based study of 380 prostate cancer deaths
and 380 matched controls, we found no evidence that PSA
screening, as used clinically in the 1990s, reduced prostate
cancer mortality. In view of the widespread use of PSA
screening and the morbidity, expense, and worry experienced
by patients needing biopsies and surgery related to screening,
this result is disturbing. Case-control studies have success-
fully identified the benefits of fecal occult blood screening and
colonoscopy for colon cancer17–19, cytological screening for
cervical cancer20,21, and mammography for breast cancer22.
Our results are nearly identical to those found by Concato et
al. using a similar population-based, case-control design11.
Both their study and this one use “ever screened” as the metric
of exposure, rather than tabulating screening in specific short
intervals before diagnosis. This is important because screening
can affect the date of diagnosis. In a patient with preclinical
prostate cancer, the occurrence of screening has a high
probability of leading to the diagnosis. Such patients will
usually not have been screened in the years immediately
before diagnosis because had they been tested earlier, the
diagnosis would likely have been made then. Tabulating
screening as ever/never largely avoids this problem.
Interpretation of a third case-control study of PSA screening
is complicated by this issue. Kopec et al.12found no difference
in the proportion of cases and controls that had ever been
screened, in agreement with the negative findings cited above.
However, these authors apparently counted PSA tests in
controls during the period of clinical suspicion in the cases
and also stratified their analysis of PSA tests by time period
before diagnosis in a manner that likely overweighted the
experience in prior years when a deficit of screening in the
cases was to be expected. These procedures produced an
adjusted result showing a benefit of screening that we believe
may have been spurious.
The most significant potential limitation of all the observa-
tional studies is in determining what constitutes a “screen”.
Some PSAs identified in medical records with little documen-
tation may be interpreted as a screen when, in fact, they may
have been ordered for suspicion of cancer or for urinary
symptoms related to early cancer. However, three investigators
blinded to case/control status reviewed all PSAs done within
6 months of the index case’s date of clinical suspicion (or the
comparable time for the control). We obtained very similar
results using different thresholds for classifying a PSA as a
screen, and the PSA frequencies of our controls were similar to
those reported in the New Jersey BRFSS. However, it is still
possible we missed some PSAs. If more PSAs were missed in
controls than in cases, the study results would be biased
against the efficacy of screening. This seems unlikely as we
directly interviewed controls about providers who might have
ordered a PSA, whereas for cases, we relied on other medical
records and the spouse to identify providers. We only counted
Table 4. Results of Conditional Logistic Regression: Odds Ratios for
Prostate Cancer Mortality and PSA Screening in 379 Cases and 379
OR (95% CI) OR (95% CI)OR (95% CI)
Most restrictive No evidence of lower urinary tract symptoms or BPH,
moderate restrictive BPH but no evidence of lower urinary tract
symptoms, least restrictive either lower urinary tract symptoms or BPH
could be present
*One case-control pair was mismatched for race and was not included in
†Adjusted for education and number of comorbid conditions in the year
before prostate cancer diagnosis
Table 3. Gleason Scores and Clinical Stage of Cases
5 or less
Localized (T1/2, node −)
Regional (T3/4 or node +)
Year of diagnosis
Marcella et al.: Prostate Cancer Screening and Mortality
documented PSAs. The impact of excluding non-married
subjects on ascertainment of PSA screens is unknown.
The confidence intervals are wide, and although a lower
95% bound of 0.76 includes a possible protective effect of 24%,
we believe that the consistency of the point estimates around
unity makes a protective effect less likely. We chose prostate
cancer-specific mortality as our outcome. Overall mortality is
also a relevant outcome in a population of men with prevalent
comorbidity and the possibility of misclassification of the
cause of death and the increased potential for treatment side-
effects. However, using all-cause mortality as an outcome may
make it difficult to show an effect of screening because the
majority of these men will die of comorbidity rather than
Evidence supporting the efficacy of PSA screening has been
limited to date. Although the benefit of prostatectomy has been
demonstrated for early prostate cancer, the studies thus far have
depended on traditional, clinical detection of prostate cancer9,10.
One would expect that most of the cases in the randomized trial
of surgery vs watchful waiting9would have been detected by a
PSA screen (had it been commonly used in the source popula-
tion), but such screening would also have detected many slowly
progressive cases. Many cases would not be expected to benefit
from surgery thus diluting the overall benefit. Indeed, a compet-
ing risk analysis of watchful waiting for men diagnosed with
prostate cancer in the pre-PSA era has demonstrated that for low
and moderate grade tumors (Gleason≤6), the risk of dying from
the disease within 15 years is small23.
Two randomized studies on PSA screening are still a few years
away from completion24,25. However, the results of the case-
control studies suggest that any benefit of PSA screening
identified in these trials is likely to be modest. Pending results
from the trials, a conservative stance on PSA screening seems
justified26,27. Even if PSA testing is shown to have a modest,
protective effect on mortality from prostate cancer, it will still be
incumbent on the clinician to help the patient understand the
trade-offs of this imperfect test. The high rates of prostate cancer
incidence and mortality in black men and the protective odds
ratio found for these men in the current study (albeit not
statistically significant), may argue for more liberal use of testing
in that group, but this needs further study with a larger sample
size. We, along with others, await better methods for detecting
prognostically ominous forms of this ubiquitous cancer.
Acknowledgements: The authors thank Betsy A. Kohler, MPH,
CTR, Director of Cancer Epidemiology Services, NJDHSS for help
with obtaining registry records; Eddy A. Bresnitz, MD, MS, Deputy
Commissioner/State Epidemiologist, NJDHSS for facilitating the
cooperation of physicians; Janet B. Schoenberg, MPH, MPhil, for
help with the initial planning of the study; Antonio M. Savillo, MD for
communicating with the hospital tumor registrars; and Orlando
Mills, MD, MPH for his writing of the grant in support of the study
and for initial pilot work. Stephen Marcella, George Rhoads, and
Jeffrey Carson received financial support from the National Cancer
Institute Grant: NCI-RO1 CA71734-01A1.
Conflict of Interest: None of the authors have any conflict of
interest to declare. The funding agency did not have a role in any
aspect of the study including data collection, analysis, preparation
of the manuscript, or the decision to publish.
Corresponding Author: Stephen W. Marcella, MD, MPH; Depart-
ment of Epidemiology, UMDNJ-School of Public Health, Room 205,
Hoes Lane West Piscataway, NJ, 08854, USA (e-mail: marcelsw@
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