Download screening with prostate specific antigen and metastatic

0022-5347/05/1742-0495/0
THE JOURNAL OF UROLOGY®
Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 174, 495– 499, August 2005
Printed in U.S.A.
DOI: 10.1097/01.ju.0000165153.83698.42
SCREENING WITH PROSTATE SPECIFIC ANTIGEN AND METASTATIC
PROSTATE CANCER RISK: A POPULATION BASED CASE-CONTROL
STUDY
JACEK A. KOPEC,*, † VIVEK GOEL, PETER S. BUNTING, JAN NEUMAN, ERIC C. SAYRE,
PADRAIG WARDE, PETER LEVERS AND NEIL FLESHNER‡
From the Department of Health Care and Epidemiology, University of British Columbia (JAK), Arthritis Research Centre of Canada
(ECS), Vancouver, Department of Health Policy, Management and Evaluation (VG), and Department of Radiation Oncology (PW),
University of Toronto, Division of Urology, Sunnybrook and Women’s College Health Sciences Centre (NF), Leadership Sinai Centre for
Diabetes, Mt. Sinai Hospital (JN), Toronto, Department of Laboratory Medicine, The Ottawa Hospital and University of Ottawa, Ottawa
(PSB), Department of Surgery, Southlake Regional Health Centre (PL), Newmarket, Ontario
ABSTRACT
Purpose: Screening of asymptomatic men with prostate specific antigen (PSA) remains a
controversial issue. There is limited evidence that screening is effective in reducing mortality
from prostate cancer. In the current study we determined if screening with PSA reduces the risk
of metastatic prostate cancer.
Materials and Methods: We conducted a population based case-control study among the
residents of Metropolitan Toronto and 5 surrounding counties in Ontario, Canada. Data were
obtained from 236 cases of metastatic prostate cancer and 462 controls randomly sampled from
the source population and frequency matched to cases for age and area of residence. History of
PSA testing, digital rectal examination, symptoms and other data were obtained from medical
records and a self-administered questionnaire. The association between PSA screening and
metastatic prostate cancer was measured by the Mantel-Haenszel odds ratio stratified by
exposure observation time and other potential confounding factors.
Results: In asymptomatic men, the frequency of PSA screening as determined from medical
records was significantly lower among the cases compared with the controls (odds ratio 0.65, 95%
confidence interval 0.45 to 0.93). The odds ratio was 0.52 (0.28 to 0.98) in men 45 to 59 years old
and 0.67 (0.41 to 1.09) in those 60 to 84 years old.
Conclusions: In this case-control study screening of asymptomatic men with PSA was associated with a significantly reduced risk of metastatic prostate cancer. The results need to be
confirmed in randomized controlled trials.
KEY WORDS: Prostatic neoplasms, diagnosis, prostate-specific antigen, case-control studies
Prostate cancer is the most frequently diagnosed cancer in
North American men and the second leading cause of death
due to cancer in men.1 The epidemiology of prostate cancer
has been changed by the introduction of the prostate specific
antigen (PSA) in the late 1980s.2 The PSA test is used as a
screening test, a diagnostic tool and a biological marker to
follow the progress of disease in patients with prostate cancer. Because of widespread use of PSA for opportunistic
screening, the incidence of prostate cancer in the United
States and many other countries increased dramatically in
the early 1990s.3 There has also been a shift toward earlier
stages at diagnosis.2, 3
Whether regular PSA measurements should be performed
in asymptomatic men remains a controversial issue. There is
Submitted for publication October 28, 2004.
Study received University of Toronto Ethics Review Board and
participating hospitals ethics review board approval.
Supported by a grant from the National Cancer Institute of Canada.
* Correspondence: Department of Health Care and Epidemiology,
University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Ave., Vancouver, British Columbia, V5Z 1L7
Canada (telephone: 604-871-4588; FAX: 604-879-3791; e-mail:
[email protected]).
† Supported by a National Health Scholar Award from Health
Canada.
‡ Financial interest and/or other relationship with BioAdvantex
Pharma, Chiron, Aventis, AstraZeneca and Novartis.
See Editorial on page 413.
little evidence to date that screening with PSA is effective in
reducing mortality from prostate cancer. A recent casecontrol study in the US showed a benefit from combined
digital rectal examination (DRE) and PSA screening but the
data were insufficient to assess the effect of PSA alone.4
Several ecological analyses of population data from the
United States and other countries failed to demonstrate a
correlation between screening and death rates from prostate
cancer5⫺8, while a study in Austria found a significant association.9 A randomized trial of PSA screening was conducted
in Quebec but the results are difficult to interpret because of
a low screening rate in the intervention arm.10 Two major
randomized trials of screening effectiveness are in progress,
1 in the United States and 1 in Europe, but their results will
not be available for several years.11
Given the current controversy regarding the effectiveness
of PSA, we conducted a population based case-control study
to determine if screening asymptomatic men with PSA reduces the risk of metastatic prostate cancer. Metastatic prostate cancer has a poor prognosis and death from prostate
cancer is almost always caused by distant metastases. If
screening is effective, we would expect a reduction in metastatic prostate cancer risk before a reduction in mortality.
Also, the effect on metastatic prostate cancer should not be
confounded by recent improvements in the management of
advanced disease.
495
496
CASE-CONTROL STUDY OF SCREENING WITH PROSTATE SPECIFIC ANTIGEN
METHODS
Data collection. The study population included residents of
Metropolitan Toronto and 5 surrounding counties in Ontario,
Canada. Cases were men who developed metastatic prostate
cancer between August 1, 1999 and May 31, 2002. They had
to be between 40 and 84 years old when diagnosed with
metastatic prostate cancer, diagnosed with prostate cancer
on or after January 1, 1990, living in the study area at the
time of prostate cancer diagnosis and able to answer a questionnaire in English. We identified new cases of metastatic
prostate cancer by monthly searching of computerized lists of
prostate cancer patients treated at 2 Regional Cancer Centers serving the study population and by regular monthly
contacts by telephone, mail, or email with the urologists and
oncologists in the study area who would normally treat men
with metastatic prostate cancer. Controls were men without
metastatic prostate cancer selected randomly from the municipal tax records database for the study area. Men diagnosed with nonmetastatic prostate cancer were eligible. The
controls were sampled throughout the period of case accrual
and frequency matched to the cases for age (5-year intervals)
and area of residence (8 areas). In addition, they had to live
in the same area as the cases at the time of prostate cancer
diagnosis and be able to answer a questionnaire in English.
We selected approximately 2 controls for each case. For the
purpose of data collection and analysis, each control was
assigned a reference date corresponding to the date of prostate cancer diagnosis in a case from the same area and age
group.
Self-reported data were obtained on age, ethnicity, marital
status, education, income, height, weight, employment history, exposure to certain occupational carcinogens, smoking,
alcohol use, history of physical activity, diet, vitamin supplementation, vasectomy, sexual activity, family history of cancer, comorbid conditions, use of health services, urinary
symptoms, prostate related tests and procedures and history
of PSA testing. We reviewed each participant’s medical
records obtained from his family physician and, if appropriate, 1 or more specialists. Information was collected on PSA
history, genitourinary symptoms, history of benign prostatic
hyperplasia (BPH) and treatment, digital rectal and transrectal ultrasound examinations, previous prostate biopsies,
major surgical procedures, second cancers, and other comorbidity. The charts were reviewed by experienced and trained
data abstractors. In most cases the abstractors were blinded
to the case-control status of the subject. We performed an
inter-abstractor reliability sub-study on a sample of 88
charts. The reason for each PSA test and the results of digital
rectal examinations were determined independently by 2 of
the investigators (PSB and JN).
Exposure was defined as having a screening (nondiagnostic) PSA test. We excluded all tests performed after the
diagnosis of prostate cancer or the corresponding reference
date for the controls. We also excluded PSA tests where there
was evidence in the chart that the physician ordering the test
suspected prostate cancer. Furthermore, we excluded tests
performed after a positive or suspicious digital rectal examination for prostate cancer or a transrectal ultrasound, a
repeat of a previous PSA test and all tests following a positive
or suspicious imaging study (bone scan, computerized tomography or x-ray) for metastatic cancer. We also excluded PSA
tests performed after the subject reported frequent daytime
urination, post-void dribbling, hesitancy, incomplete emptying of bladder, intermittent stream, urgency, weak stream,
dysuria, nocturia, hematuria, hemospermia, other genital or
urinary symptoms, or bone pain. Although such symptoms do
not necessarily indicate prostate cancer, the exclusion of
tests performed in symptomatic men reduced the possibility
of erroneously counting diagnostic tests as screening. All
subjects signed a consent form for participation in the study.
The study was approved by the University of Toronto Ethics
Review Board and by the ethics review boards of the participating hospitals.
Data analysis. Cases and controls were initially compared
in univariate analyses with respect to sociodemographic variables, prostate cancer risk factors, frequency of urinary
symptoms, frequency of DRE and health usage variables. In
the analysis of PSA screening it was necessary to control for
exposure observation time. We analyzed the frequency of
PSA screening among cases and controls in a life table constructed with 2-year intervals starting in 1990. Subjects
whose observation time ended in a given interval without a
PSA test (for example, because they developed urinary symptoms or had a positive DRE) were treated as censored observations. We used the propensity score method to control for
other confounding variables.12 The propensity score was obtained from a multiple logistic regression model. Several
variables were associated with case-control status at ␣ ⫽ 0.10
and were retained in the model, namely age, region, family
history of prostate cancer, weight, consumption of butter and
doctor visits for health problems. The score was divided into
tertiles and used as a stratification variable. As a measure of
effect, we calculated the stratified Mantel-Haenszel odds ratio with test based confidence limits.13 Results were obtained
for the full sample and for 2 age groups, 45 to 59 and 60 to 84
years old. We conducted a sensitivity analysis to assess the
effect of excluding PSA tests in men who had a positive or
suspicious DRE. All analyses were done with SAS®.
RESULTS
Data were obtained for 236 cases and 462 controls. The
average age at prostate cancer diagnosis among the cases
was 68.2 years and the average age at metastatic prostate
cancer diagnosis was 71.5 years. Distant metastases were
detected by bone scan in 72.1% of the cases. Other methods
included computerized tomography (12.7%), x-ray (4.6%),
magnetic resonance imaging (4.1%), bone biopsy (4.1%) and
other techniques (2.4%).
In univariate analysis, no significant differences between
the cases and controls were seen with respect to socioeconomic status, immigrant status, most dietary factors, recreational and work related activities, frequency of BPH, or
frequency of DREs (table 1). Cases were heavier by an average of 5.8 lbs and were more likely to have had a family
member with prostate cancer. As shown in the figure cases
were less likely to report urinary symptoms, except for the
final year before the diagnosis/reference date.
In crude data 58 cases (24.6%) and 126 controls (27.3%)
had a screening PSA test (table 2). The overall MantelHaenszel odds ratio, adjusted for exposure observation time
as well as matching and confounding variables, was 0.65
(95% confidence interval 0.45 to 0.93) in favor of screening.
When the data were analyzed according to age, the odds ratio
was 0.52 (0.28 to 0.98) for men 45 to 59 years old and 0.67
(0.41 to 1.09) for those 60 to 84 years old.
DISCUSSION
In this population based case-control study, we found that
screening of asymptomatic men with PSA reduced their risk
of metastatic prostate cancer by 35%. The effect is clinically
important, especially considering that the majority of the
exposed controls were screened only once. We observed a
benefit of screening in men less than 60 years old as well as
those 60 years old or older. The association was stronger in
younger men, however the study did not have enough power
to demonstrate a significant difference in effect according to
age.
A number of methodological issues should be considered
when interpreting the findings. Cases in this study came
from a geographically defined population and controls were
CASE-CONTROL STUDY OF SCREENING WITH PROSTATE SPECIFIC ANTIGEN
497
TABLE 1. Distributions of selected self-reported variables among
cases and controls
Variable
Cases (%)
Controls (%)
Age at diagnosis of prostate Ca:
45–54
11 (4.7)
29 (6.3)
55–64
66 (28.0)
124 (26.8)
65–74
110 (46.6)
226 (48.9)
75–84
49 (20.8)
83 (18.0)
Country of birth:
Canada
126 (53.4)
254 (55.0)
Other
108 (45.8)
207 (44.8)
Not stated
2 (0.8)
1 (0.2)
Ethnicity:
White
185 (78.4)
372 (80.5)
Black
6 (2.5)
3 (0.6)
Other
43 (18.2)
86 (18.6)
Not stated
2 (0.8)
1 (0.2)
Marital status:
Married or common-law
193 (81.8)
396 (85.7)
Single, divorced or widowed
42 (17.8)
65 (14.1)
Not stated
1 (0.4)
1 (0.2)
Education:
Less than high school
76 (32.2)
144 (31.2)
High school with or without
76 (32.2)
147 (31.8)
trade/technical training
College or university
80 (33.9)
169 (36.6)
Not stated
4 (1.7)
2 (0.4)
Gross household income:
Less than $30,000
26 (11.0)
58 (12.6)
$30,000–49,999
48 (20.3)
92 (19.9)
$50,000–100,000
42 (17.8)
114 (24.7)
More than $100,000
16 (6.8)
49 (10.6)
Not stated
104 (44.1)
149 (32.3)
Usual type of activity in daily
work:
Sitting
74 (31.4)
161 (34.8)
Light
64 (27.1)
128 (27.7)
Moderate
50 (21.2)
93 (20.1)
Strenuous
47 (19.9)
69 (14.9)
Not stated
1 (0.4)
11 (2.4)
Relative diagnosed with prostate Ca:*
Yes
51 (21.6)
56 (12.1)
No
178 (75.4)
401 (86.8)
Not stated
7 (3.0)
5 (1.1)
Urinary symptoms:*,†
Yes
68 (28.8)
181 (39.2)
No
161 (68.2)
274 (59.3)
Not stated
7 (3.0)
7 (1.5)
Diagnosis of BPH:
Yes
50 (21.2)
116 (25.1)
No
185 (78.4)
345 (74.7)
Not stated
1 (0.4)
1 (0.2)
Visits to doctors for routine examination:
Never
28 (11.9)
40 (8.7)
Once in 2–5 yrs
65 (27.5)
108 (23.4)
Once/yr or more
139 (58.9)
309 (66.9)
Not stated
4 (1.7)
5 (1.1)
Ever had DRE:
Yes
188 (79.7)
395 (85.5)
No
40 (16.9)
60 (13.0)
Not stated
8 (3.4)
7 (1.5)
* p ⱕ0.05.
† Urinary symptoms were defined as being bothered 10 years ago, at least
“half the time,” by 1 or more of symptoms of a sensation of not emptying
bladder after urination, having to urinate again less than 2 hours after
finishing, stopping and starting several times during urination, difficulty
postponing urination, weak urinary stream, pushing or straining to begin
urination or getting up to urinate during the night.
randomly selected from the same source population. Although we may have missed some cases treated outside of the
Regional Cancer Centers, such cases would have been rare.
Response rates to the mailed questionnaire were 69% among
the cases and 51% among the controls, ie in the range typically found in mail population surveys in North America. In
a study population composed mostly of older men, almost half
of them born outside Canada, such response rates seem reasonable. Medical records were obtained for 90% of the respondents (93% of the cases and 88% of the controls). Because the
Cumulative proportion of cases and controls with prostate related
symptoms before prostate cancer diagnosis/reference date.
subjects were not informed about the study hypothesis, it
seems unlikely that their participation would have been
linked to PSA screening. Nevertheless, a potential for selection bias is a limitation of the study.
Our analysis included 36 cases that were asymptomatic at
the time of prostate cancer diagnosis and had a positive PSA
test within the preceding 6 months. While some of these
cases may not have been captured by our study in the absence of screening, excluding any such cases would have
increased the effect in favor of screening.
We controlled for the effect of matching by age and area of
residence, as well as confounding by suspected risk or protective factors for prostate cancer and screening with digital
rectal examination. We considered the possibility that men
who undergo screening may be more health conscious and
more likely to engage in other preventive strategies or seek
medical care for any problems, and that such behaviors may
protect against metastatic prostate cancer. To control for the
effect of health care usage behavior, we included visits to
doctors as a potential confounding variable. Confounding by
unknown factors can never be ruled out in a nonrandomized
study. However, such factors would have to be strongly associated with metastatic prostate cancer and PSA screening.
Differences between the crude and adjusted odds ratios were
primarily due to longer observation times in the cases. The
main reason was a later onset of symptoms in the cases,
especially in the older age group (see figure, table 2).
Differential misclassification of PSA information in medical records seems unlikely since most of the reviews were
done blindly and the abstractors followed detailed instructions. Our reliability study demonstrated excellent agreement between the abstractors. We found 96.8% agreement
for having a PSA, 93.9% for a digital rectal examination and
91.1% for symptoms of prostatism. The level of agreement
was also high for the coding of digital rectal examination
results (96.6%) and reasons for PSA testing (90.7%).
We defined a screening (nondiagnostic) PSA test as one
performed before the onset of symptoms, as recommended in
the literature.14 Although prostate related symptoms are
usually associated with BPH, similar symptoms may be
present in patients with prostate cancer. The dramatic increase in the frequency of symptoms just before the diagnosis
of prostate cancer suggests that the inclusion of symptomatic
men would have resulted in a substantial misclassification of
diagnostic tests as screening. We classified PSA tests performed after a positive or suspicious DRE as diagnostic
rather than screening. It is possible that some of these tests
would have been done anyway for screening purposes. In 16
subjects, 15 cases and 1 control, reclassifying such tests as
screening would have changed their status from unexposed
to exposed. All these tests were done within 3 months of the
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CASE-CONTROL STUDY OF SCREENING WITH PROSTATE SPECIFIC ANTIGEN
TABLE 2. Adjusted odds ratios for association between screening with PSA and risk of metastatic prostate cancer in asymptomatic men
Cases
Controls
Time Adjusted
Odds Ratio*
95% Confidence
Interval
Fully Adjusted
Odds Ratio†
95% Confidence
Interval
Total
236
462
Not PSA screened
178
336
1.00
—
1.00
—
PSA screened
58
126
0.66
0.47, 0.93
0.65
0.45, 0.93
Age 45–59
101
195
Not PSA screened
83
138
1.00
—
1.00
—
PSA screened
18
57
0.51
0.28, 0.93
0.52
0.28, 0.98
Age 60–84
135
267
Not PSA screened
95
198
1.00
—
1.00
—
PSA screened
40
69
0.73
0.46, 1.15
0.67
0.41, 1.09
* Mantel-Haenszel odds ratio stratified by exposure observation time.
† Mantel-Haenszel odds ratio stratified by exposure observation time and tertiles of the propensity score. Several variables were included in the propensity
score, namely age, region, family history of prostate cancer, weight, consumption of butter and doctor visits for health problems.
DRE. Additional analyses showed that in about 20% of negative DREs, a screening PSA test followed within 3 months.
Applying this proportion, we performed a sensitivity analysis
assuming that 3 of the 15 cases with a PSA test following a
suspicious/positive DRE may have been done for screening.
With this assumption the result would remain virtually unchanged (odds ratio 0.68, 0.48 to 0.97).
Previous studies offered limited evidence for the effectiveness of screening for prostate cancer. A recent case-control
study by Weinmann et al produced an odds ratio of 0.70 in
favor of screening with DRE and PSA. However, most of the
tests were DREs and it was not possible to assess the separate effect of PSA screening.4 In other case-control studies of
screening with DRE, Friedman et al15and Richert-Boe et al16
reported nonsignificant results, while Jacobsen et al17 found
a strong inverse association. In a randomized trial of PSA
screening, Labrie et al reported an odds ratio of 0.31 when
comparing screened and unscreened men.10 Unfortunately
only 23.1% of those randomized to screening were actually
tested and an intent to screen analysis did not show a significant effect. Lu-Yao et al compared prostate cancer mortality up to 1997 among Medicare beneficiaries in the Seattle
and Connecticut cancer surveillance areas.5 Mortality rates
were similar in the 2 areas although PSA testing was 5.4
times more common in Seattle. In contrast Bartsch et al
demonstrated a significantly greater rate of prostate cancer
mortality decrease after the introduction of mass screening
with PSA in the province of Tyrol compared with the rest of
Austria.9 A number of authors used prostate cancer incidence
as a surrogate for screening frequency. These studies generally found no association between increased incidence and
decreases in mortality.6⫺8 However, the ecological design is
inherently prone to bias. Other factors, such as improved
treatment of prostate cancer and risk factor changes, may
contribute to mortality trends.3 Furthermore, followup may
not have been long enough in some studies.5
CONCLUSIONS
Although the strongest evidence for or against PSA efficacy
will come from large randomized trials, the results of such
trials are several years away. Moreover, generalizability of
the current trials may be limited by their eligibility criteria,
self-selection of participants and other design related issues.11 Our study provides suggestive evidence for the effectiveness of screening with PSA as actually practiced in the
study area in the 1990s and early 2000s. It is possible that a
greater benefit would result from a screening program with
regular screening intervals. Because screening for prostate
cancer is a complex issue, more studies in different populations and using a variety of approaches are needed. It will be
important to further delineate the effect of PSA in men with
prostate related symptoms and estimate the optimal frequency of screening. While reduction in mortality and meta-
static cancer are important, quality of life issues and men’s
preferences need to be carefully evaluated.
Cyrelle Gold reviewed medical records, and Vartouhi
Jazmaji, Nicole Riley and Deva Thiruchelvam assisted with
database management and data entry.
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EDITORIAL COMMENT
Kopec et al report that history of a screening PSA test was 35%
less frequent among men in whom metastatic prostate cancer developed than among controls randomly sampled from the general population. The apparent reduction in risk is notable in that most of the
27% of controls who had a screening PSA were only screened once.
Results from other, primarily nonrandomized studies have been
inconsistent.
Since PSA screening does not prevent prostate cancer, the most
appropriate case-control design would have compared PSA screening
among prostate cancer cases in whom metastases did and did not
develop. The validity of the current design depends on whether PSA
499
use in controls (98% of whom did not have prostate cancer) is confounded with other health behaviors that would be expected to differ
between men with and without prostate cancer. Controlling for confounding factors with the use of the propensity score may not have
adjusted any imbalance in overall health behavior since variables
that may correlate with health behavior (smoking, alcohol, income,
physical activity) were not in the model. Although none of these
variables was individually associated with metastatic prostate cancer at p ⬍0.10, small differences could jointly signify differences in
health behavior. Bias could also arise if recall of past urinary symptoms was underreported by patients with metastatic prostate cancer
as events since their diagnosis, treatment and side effects of treatment assumed greater prominence. However, it is also possible that
the protective effect of screening is somewhat underestimated since
PSA usage was low during the early part of the study period. The
authors are aware of these potential limitations and recognize the
need for a randomized study of mitigate biases in the controls.
Despite these potential concerns the study provides further evidence
that PSA screening can prevent death from prostate cancer.
Bruce J. Trock
Brady Urological Institute
The Johns Hopkins Hospital
Baltimore, Maryland