1. health and fitness
2. disease
3. cancer

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How to Use Prostate-Specific Antigen in the
Early Detection or Screening for Prostatic
Carcinoma
Michael K. Brawer, MD
Introduction
Prostate cancer represents the most common male malignancy and the second
most common cause of cancer-related
mortality in American men. In 1995, it is
estimated that 244,000 men will be diagnosed with prostate cancer and 40,400
will succumb from this malignancy.1 Despite these sobering statistics, incidence
and mortality appear to be increasing.
While the autopsy prevalence of prostate
cancer far exceeds clinically manifest disease, Seidman et al2 and Scardino et al3
have demonstrated that of the 42 percent
of men older than 50 years harboring prostatic carcinoma, 9.5 percent will have a
clinical diagnosis, and 2.9 percent will
succumb.
Of the three possibilities to reduce
cancer-related mortality—increased early detection, improved therapy, and reduced incidence—only increased early
detection appears feasible at present. A
major effort is under way to reduce cancer incidence in many organ systems with
chemopreventive approaches. For prostate cancer, a large-scale, multicenter trial
randomizing men to finasteride (a 5- reductase inhibitor) or placebo, in a
chemopreventive approach, is under
way.4 However, it will be many years be-
Dr. Brawer is a Professor in the Department of
Urology at the University of Washington and Chief
of the Section of Urology at the Seattle Veteran’s
Administration Medical Center.
148
fore the outcome of this investigation is
known. While significant strides have
been made in lessening the morbidity of
therapy directed with curative intent
(primarily radiation therapy and radical
prostatectomy), the fact that mortality in
men presenting with advanced disease
has not changed significantly in the past
several decades suggests that either most
men present with noncurable malignancy
or our therapeutic armamentarium is inadequate. As a result significant efforts
have been made to identify more men
with curable cancer.
Background
The recognition that serum prostate-specific antigen (PSA) levels are elevated in
most men with clinically diagnosed
prostate cancer served as an impetus to
investigate the possible role of this analyte for early detection or screening. Considerable evidence suggested, however,
that this approach would not be effective,
as many reports indicated a significant elevation of PSA levels in men with benign
prostatic hyperplasia (BPH) (Table 1).5-8
As BPH is an almost universal finding in
men of an age group likely to be tested
for prostate cancer, early investigators
believed that there was no role for PSA in
early detection or screening.
One piece of evidence suggesting
a potential fallacy in this argument
stemmed from the observation that the
serum PSA level in the seminal plasma is
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Table 1
Serum PSA in Patients with Histologically Confirmed
Benign Prostatic Hyperplasia
Author
Assay
Patients with
PSA>4.0
(percent)
Patients with
PSA>10.0
(percent)
–
Stamey et al5
Pros-Check
88
Ercole et al6
Tandem-R
21
3
Ferro et al7
Tandem-R
–
33
Hudson et al8
Tandem-R
21
2
PSA = prostate-specific antigen.
about a million-fold higher than the level
in the systemic circulation.9 Therefore,
there must be extraordinary barriers between the lumen of the prostatic acini and
ductule and the systemic circulation. Employing a variety of immunohistochemical and other techniques, these barriers
can be readily identified. Figure 1 demonstrates a schematic of these barriers,
which include the basal cell layer, the prostatic basement membrane, intervening
stroma, the capillary basement membrane, and the capillary endothelial cell.
In an effort to understand how PSA
arrived in the systemic circulation, we
studied a series of prostatectomy specimens from men undergoing simple
prostatectomy (transurethral resection or
simple open) for presumed BPH.10 We
observed that among the 35 patients with
an elevated serum PSA level (>4.0 ng/ml,
preoperative, Hybritech Tandem assay),
all but one had incidental carcinoma, prostatic intraepithelial neoplasia (PIN), or
foci of acute inflammation. Of the 26 men
who had only BPH or BPH associated
with chronic inflammatory cell foci, only
one had an elevated PSA level. This suggested to us that changes in some of these
barriers were necessary before PSA
Vol. 45 No. 3 may/june 1995
could leak into the capillary bed. Disruption of these barriers has been identified
in both prostatic carcinoma as well as
PIN.11-14
PSA Screening
To evaluate the role of serum PSA in an
early detection or screening strategy, Catalona et al15,16 from Washington University at St. Louis and our own group at the
University of Washington17 conducted
screening in a media-recruited cohort of
men older than 50 years. After analysis of
PSA levels by the Hybritech Tandem assay, ultrasound-guided biopsies were performed in those with a PSA level greater
than 4.0 ng/ml (Table 2).18-21 With initial
biopsy, positive predictive values (PPV)
of 30.5 to 34.4 percent and detection rates
of 2.6 to 3.1 percent were realized. Compared with mammography, for which
PPVs of 20 percent have been realized,22,23 the application of this simple
serum assay becomes exceedingly attractive for early detection.
A number of additional authors
have reported relatively consistent PPVs
of 33 to 50 percent for Hybritech PSA assay greater than 4.0 ng/ml in disparate
149
H o w
Basement
Membrane
t o
Prostatic
Lumen
u s e
P r o s t a t e - S p e c i f i c
Intervening
Stroma
Prostatic Lumenal Cell
Capillary Basement Membrane,
Endothelial Cell
Fig. 1. Schematic of the histology of prostatic
carcinoma. Note the significant tissue barriers
between the prostatic lumen and the surrounding capillary bed.
screening, referral, and mixed populations (Table 3).15-17,19,24-29
Importance of the Digital Rectal
Exam (DRE)
Despite the impressive yield for PSAbased screening alone, it is widely recognized that a significant number of men
will have prostatic carcinoma and a PSA
level less than 4.0 ng/ml. In our ultrasound-guided biopsy series, in which all
men underwent six systematic sector
biopsies, 54 (21.3 percent) of the men
with cancer had a PSA level less than 4.0
ng/ml.30
Catalona et al18 evaluated 6,630 men
with DRE and serum PSA. Two hundred
sixty-four cancers were identified. Fortyeight of the carcinomas (18.2 percent)
were in men with an abnormal DRE
alone. Thus, it is obvious that the PSA as150
A n t i g e n
say should not be used exclusively for the
detection of prostate cancer, but should
be combined with a carefully performed
DRE.
The American Cancer Society recently revised its recommendation for the
annual cancer prevention check-up to include DRE and serum PSA assay for
men older than 50 years or for younger
men who are at increased risk owing to
being African American or having a significant family history.31 The Food and
Drug Administration has recently approved the Hybritech PSA assay for early
detection in conjunction with DRE.
Several caveats should be mentioned with regard to obtaining serum for
PSA testing. A number of factors have a
significant effect on serum PSA level, as
shown in Table 4. In general PSA should
be obtained in an ambulatory setting before significant prostatic manipulation.
Standard rectal examination has been
shown by several investigators to not significantly elevate the serum PSA level.30,32-34 However, more significant prostatic trauma or alteration of the hormonal
milieu will cause considerable alteration
of PSA level.
Enhancing the Specificity
of PSA Testing
Considerable efforts are being made to
improve the performance of PSA testing.
Figure 2 shows the consistent inverse relationship between sensitivity (the chance
of a test being positive when the patient
has the disease) and specificity (the
chance of a test being negative when the
patient does not have the disease). The
data depicted derive from 1,920 men undergoing systematic sector biopsy of their
prostates from our institutions.
For prostate cancer most efforts are
directed toward increasing specificity. This
stems from the likelihood that men are not
going to be tested only once in their lifetime, but will undergo serial testing, perhaps annually as suggested by the AmeriCa—A cancer Journal for Clinicians
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Table 2
Yield from PSA-Based Screening Studies
Number of
Patients
Positive
Predictive
Value
(percent)
Observed
Detection Rate
(percent)
Estimated
Detection Rate
(percent)
Catalona et al16
9,629
34.4
3.1
–
Catalona et al (Serial)16
9,333
41.9
2.1
–
Author
Catalona et al
18
6,630
31.5
3.3
4.6
Brawer and Lange19
1,249
30.5
2.6
4.6
Brawer et al (Serial)20
701
17.1
2.0
6.7
Brawer et al (Serial)21
738
18.6
1.8
3.8
PSA = prostate-specific antigen.
can Cancer Society.31 Thus, a false-negative test, which might occur with a lesssensitive assay, is likely to be of less significance. The test result may become positive
while the malignancy is still curable.
In contrast, false-positive tests result
in a large burden in terms of increased expenditures for subsequent, unnecessary
medical procedures and increased anxiety for misdiagnosed patients. In prostate
cancer, an abnormality in PSA level or
DRE mandates transrectal ultrasound
and ultrasound-guided biopsy according
to most experts. A strategy to reduce
false positives necessitates tests that have
increased specificity.
Current approaches to improve the
specificity of PSA-based screening include PSA velocity, PSA density, agespecific PSA values, and investigation of
different circulating forms of the PSA
molecule.
PSA VELOCITY
Carter et al35,36 reported in 1992 that an
annual increase of 0.75 ng/ml in serum
PSA level indicated men who would deVol. 45 No. 3 may/june 1995
velop prostatic carcinoma. They based
their observations on sera collected as
part of the Baltimore Longitudinal Aging
Study. Serum specimens were collected
from men over many years in a general
study of the phenomena of aging. The optimum cutoff of sensitivity and specificity
to predict which of the men ultimately developed prostatic carcinoma was a PSA
velocity of 0.75 ng/ml per year. It should
be noted that in this study a minimum of
seven years passed between determinations of PSA levels.
We were unaware of the usefulness
of this rate when we developed our strategy for serial follow-up of men with an
initial normal PSA level in our screening
study.20 We arbitrarily selected an annual
increase of 20 percent over the baseline in
subsequent years—a number not dissimilar to the observation of Schmid et al37 for
PSA doubling time in untreated prostatic
carcinoma. PPVs in the second and third
year of the series were 17.1 percent and
18.6 percent with observed detection
rates of 2.0 percent and 1.8 percent, respectively. If the PPV remained the same,
estimated detection rates for the entire
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Table 3
Positive Predictive Value for PSA Greater Than 4.0 ng/ml
Author
Year
Babaian and Camps24
1991
Bazinet et al25
1994
19
No. of
Biopsies
Positive Predictive
Value (percent)
Mixed
67
31.3
Referral
565
37.0
Population
Brawer and Lange
1989
Referral
188
54.2
Brawer et al17
1992
Screening
105
30.5
Catalona et al15
1991
Screening
112
33.0
Catalona etal16
1993
Screening
1,325
37.1
Catalona et al
18
1994
Screening
686
31.5
Cooner et al26
1988
Referral
96
51.2
Cooner et al27
1990
Referral
436
35.0
Mettlin et al28
1991
Screening
70
41.4
1994
Referral
2,020
41.0
29
Rommel et al
PSA = prostate-specific antigen.
cohort including those men not returning
for evaluation would have been 6.7 percent and 3.8 percent in the second and
third year, respectively.
Catalona et al16 used a crossover to
4.0 ng/ml from an initial lower value and
noted a detection rate of 2.1 percent and
PPV of 41.9 percent. Recently, Porter et
al38 reported on an enlarged series from
our institution with one- and two-year intervals between determination of PSA
levels. With about a one-year interval between PSA-level determinations, no PSA
velocity parameter (including median
PSA velocity, median percent PSA increase per year, 0.75 ng/ml per year, or an
increase of 20 percent) was useful in selecting men with prostatic carcinoma.
Moreover, in a smaller series with at least
a two-year interval between PSA levels,
we were still unable to use PSA velocity
to separate men with or without carcinoma using any manipulation of PSA.
Littrup et al39 have reported on evi152
dence that greater intervals between determination of PSA levels may enhance
cancer detection. Analyzing the results of
the American Cancer Society National
Prostate Cancer Detection Project, they
observed that PSA velocity greater than
1.0 ng/ml per year predicted cancer. Percent change in PSA was not useful.
The discrepancy between these observations may merely be a reflection of
biologic variation masking significant
change during short-term follow-up. This
might be attenuated with longer intervals
between PSA determinations. Pearson
and Carter,36 in a review of their Baltimore Longitudinal Aging study, demonstrated that in men with prostatic carcinoma, there was a transition from a linear to
an exponential phase of PSA velocity beginning 7.3 years before diagnosis in
those men with local regional disease and
9.2 years before diagnosis in men with
more-advanced malignancy. Komatsu et
al40 have recently demonstrated signifiCa—A cancer Journal for Clinicians
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Table 4
Factors Affecting Serum Prostate-Specific Antigen Level
Activity
Effect
Ambulation
Increase
Cystoscopy
Increase
Digital rectal examination
No effect
Exercise
Variable
Prostate biopsy
Increase
Prostatic massage
Increase
Prostate ultrasound
Variable
Reduction in androgen activity
Decrease
Sexual activity
Variable
Urethral instrumentation
Increase
1
.9
Specificity/Sensitivity
.8
Specificity
.7
Sensitivity
.6
.5
.4
.3
.2
.1
0
2
4
6
8
10
12
14
16
18
20
22
PSA Cutoff (ng/ml)
Fig. 2. The inverse relationship of prostate-specific antigen (PSA) sensitivity and specificity for
men undergoing ultrasound-guided prostate needle biopsy.
Vol. 45 No. 3 may/june 1995
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1.0
2.0
0.05
0.075
0.8
3.0
Sensitivity
4.0
0.6
0.1
6.0
0.15
0.4
PSA
0.3
0.2
PSAD
10.0
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
Fig. 3. Receiver operating characteristic curve of prostate-specific antigen (PSA) versus prostatespecific antigen density (PSAD). Note no enhancement of PSAD in the performance over PSA
alone. (Modified with permission from Brawer et al.44)
cant biologic variation in serum PSA levels. When specimens were drawn 15 to 183
days (mean 80 days) apart, 36.5 percent of
the patients showed an increase of more
than 20 percent, and 10 percent of patients
showed an increase of more than 0.75
ng/ml. I do not believe that current data
support using PSA velocity with the relatively short intervals between tests. Rather
a PSA level greater than 4.0 ng/ml should
be the indication for further evaluation.
PSA DENSITY
Another approach to enhancing the
specificity of the serum PSA assay is PSA
density (also known as PSA index). In
this analysis, the idea is to adjust for the
154
contribution of PSA from BPH by dividing the serum PSA level by the volume of
the prostate. Results with this technique
were published by Benson et al.41,42
Stamey et al5 had previously demonstrated the about 10-fold increase in PSA level
arising from carcinomas compared with
the PSA level for BPH, which provides a
basis for PSA density. Furthermore,
Babaian et al43 demonstrated clearly the
relationship of prostatic volume to serum
PSA levels. Benson et al made a significant contribution when they noted highly
significant stratification of men with and
without carcinoma by calculating PSA
density, initially by measuring prostate
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Table 5
Studies of Prostate-Specific Antigen Density
Biopsy
No. of
Patients
PSA
(ng/ml)*
Prosate
Volume (cc)*
Bazinet et al25,46
Positive
Negative
217
317
21.4 (29.6)†
9.1 (8.1)
37.6 (21.4)†
51.6 (27.3)
0.63 (0.86)†
0.21 (0.25)
Benson et al41
Positive
Negative
98
191
7.0 (1.7)†
6.8 (1.8)
28.9 (14.6)†
40.1 (20.2)
0.30 (0.15)†
0.21 (0.11)
Rommel et al29,47
Positive
Negative
612
1,394
15.5 (21.6)†
4.9 (4.7)
42.7 (27.2)†
47.0 (31.6)
0.47 (0.11)†
0.105 (0.09)
Brawer et al44
Positive
Negative
68
159
10.4 (11.7)†
5.2 (5.0)
40.5 (16.6)
42.6 (25.6)
0.29 (0.41)†
0.14 (0.14)
Mettlin et al48
Positive
Negative
171
650
12.0 (16.0)†
2.1 (2.3)
38.9 (16.4)†
33.5 (14.2)
0.35 (0.5)†
0.08 (0.09)
Author
Prostate-Specific
Antigen Density*
*Standard deviation indicated in parentheses.
†
P<.05.
PSA: 8.0 ng/ml
Volume: 80 cc
PSAD: 0.1
PSA: 8.0 ng/ml
Volume: 40 cc
PSAD: 0.2
Fig. 4. Sampling concerns with prostate-specific antigen density (PSAD). Note that the carcinoma in the larger prostate (with a lower
PSAD) is more likely to be missed
tal ultrasound.42
We were interested in these observations and attempted to replicate the results.44 Unfortunately, we were unable to
match the performance of the reports by
Benson et al (Fig. 3). The PSA index
Vol. 45 No. 3 may/june 1995
(density) provided no increased utility
over PSA alone.
A number of possibilities exist for
the discrepancy between these studies.
Certainly, patient mix, differing ultrasound volume techniques, PSA assay
variability, as well as statistical analysis all
might contribute. Another factor is sampling (Fig. 4). If one assumes two men to
have an equivalent PSA level but widely
disparate gland volumes, a man with a
smaller prostate will have a higher PSA
density. Moreover, if each man has an
equal-volume carcinoma that is both
isoechoic (nonvisible on ultrasound) as
well as nonpalpable (T1c carcinoma),
then because of sampling considerations,
it is more likely that the cancer in the man
with the smaller gland will be identified.
Although the largest contribution to the
volume of the prostate gland is the transition zone where the minority of carcinomas arise, associated compression of the
peripheral zone and, most importantly,
lateral displacement may make sampling
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Table 6
Further Evaluation of Prostate-Specific Antigen Density
PSA Range
(ng/ml)
<4.0
No. of Carcinomas
/No. of Patients
Mean PSA
CAP/Ben
Mean PSAD
CAP/Ben
Mean Volume (cc)
CAP/Ben
59/328
2.3/1.9*
0.08/0.072
32.0/29.6
4.0 < PSA <10.0
89/271
6.3/6.2
0.20/0.16
37.9/48.5†
>10.0
92/66
36.2/29.1
1.15/1.03
41.8/66.0†
240/665
16.7/6.4†
0.53/0.20
37.9/40.9
0.2 - 220.0
†
*P<.05.
†
P<.01.
PSA = prostate-specific antigen; CAP = carcinoma present; Ben = benign.
of the peripheral-zone neoplasm more
difficult.45 This suggests that PSA density
enhancement in predicting cancer may be
spurious.
Table 5 summarizes five reports
from the literature in which PSA density
has been investigated. The reports by
Bazinet et al,25,46 Benson et al,41 and
Rommel et al29,47 demonstrate increased
stratification with PSA density. However,
in each study, the glands harboring malignancy were smaller than those without
disease in a statistically significant number. In our study44 as well as a study by
Mettlin et al,48 there was either no difference in the gland volumes or, in the case
of the experience of Mettlin et al, the cancer glands were actually larger.
Recently, we expanded our experience with PSA density, examining a series of 665 men undergoing systematic,
ultrasound-guided sector biopsy. As is
shown in Table 6, 240 men had carcinoma
detected. In this series, PSA density, unlike PSA, was useful in stratifying those
men with carcinoma in the PSA range of
4.0 to 10.0 ng/ml—the most important
subgroup for this experience. Again,
however, a statistically significant number
of men with carcinoma had smaller pros156
tates than those without. Until these issues
are resolved, I believe PSA density determination should not be used as the primary determinant for biopsy. Littrup et al39
have suggested that density determination
may have a role in a sequential decision
analysis approach to biopsy decision.
AGE-SPECIFIC PSA CUTOFF VALUES
Recently, considerable attention has been
directed to the idea of age-specific serum
PSA cutoff values. This concept stems
from the observation that PSA levels increase as men get older, suggesting that
the arbitrary use of any specific cutoff for
PSA level in men of all ages may be inappropriate. It should be noted that the use
of 4.0 ng/ml as the upper limit of normal
for the Hybritech assay was based on the
observation that in men apparently free
of prostatic disease, this value represented the 95 percent confidence interval.49
Oesterling et al50 and Dalkin et al51
noted that this definition was probably inappropriate for the upper limit of normal.
They used very well-characterized patient populations apparently free of carcinoma (as evidenced by either PSA level
less than 4.0 ng/ml and a normal DRE
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0.45
0.4
Positive Predictive Value
0.35
0.3
50-59
60-69
70
0.25
0.2
0.15
0.1
0.05
0
>2.5
>3.5
>4.0
>4.5
>6.5
PSA Cutoff (ng/ml)
Fig. 5. Positive predictive value for prostate-specific antigen (PSA) cutoffs of 2.5, 3.5, 4.0, 4.5,
and 6.5 ng/ml and different age groups in men undergoing ultrasound-guided prostate needle
biopsy. Note increasing yield with advancing age along with higher PSA cutoff levels.
and ultrasound or negative biopsy following abnormality on any of these tests) to
define what they termed “age-specific
cutoffs.” They reported the 95th percentile for each decade.50,51
Oesterling et al50 defined the agespecific reference range for serum PSA to
be 0.0 to 2.5 ng/ml for men aged 40 to 49
years, 0.0 to 3.5 ng/ml for men aged 50 to
59 years, 0.0 to 4.5 for men aged 60 to 69
years, and 0.0 to 6.5 for men aged 70 to 79
years. Furthermore, these authors concluded that using such age-specific cutoffs
would result in improved sensitivity for
younger men and improved specificity for
older men.
These observations are obvious.
Lowering the PSA cutoff will certainly allow an increased detection rate at the cost
of decreasing PPV, and increasing the
PSA cutoff will have the opposite effect
(Fig. 2). Figure 5 demonstrates this pheVol. 45 No. 3 may/june 1995
nomenon, using various age-specific cutoffs as suggested by Oesterling et al.50
Note that in addition to increase in PPV
with increasing PSA cutoffs, there is a
concomitant increase in cancer found as
men age—owing to the increased prevalence of prostate cancer.
Mettlin et al52 observed that among
156 cancers detected in the American
Cancer Society National Prostate Cancer
Detection Project, 35.3 percent of the patients had normal age-specific PSA cutoffs, whereas 64.7 percent of patients had
elevations. In contrast 27.5 percent of the
men with cancer had a PSA level less
than 4.0 ng/ml. This is an important cohort in which to study the efficacy of agespecific PSA cutoffs, owing to the fact
that PSA level was not an indication for
biopsy. It should be emphasized that in
this study the minimum age for entry was
55 years, thus potential enhanced sensi157
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Major Forms of PSA
2-Macroglobulin
PSA Complex
Free PSA
ACT
MG
PSA
PSA
PSA
1-Antichymotrypsin
PSA Complex
Fig. 6. Schematic of the major forms of
prostate-specific antigen (PSA) in the systemic
circulation. Note that 1-antichymotrypsin may
mask three of five PSA epitopes, and all currently identified epitopes are rendered nonvisible by conventional immunoassays in the 2macroglobulin complexed form.
Cancer Detected (percent)
100
Tandem
IMX
80
60
40
20
0
>4.0
>5.0
>6.0
PSA Cutoff (ng/ml)
Fig. 7. The percentage of cancers detected at
cutoffs of 4.0, 5.0, and 6.0 ng/ml using
Hybritech Tandem and Abbott IMX assays for
men with known prostate cancer. Note stepwise reduction in the yield at each level where
the IMX is used.
tivity with a PSA cutoff less than 4.0
ng/ml based on the age-specific cutoff
could not be ascertained.
To study the impact of the effect of
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A n t i g e n
age-specific cutoffs in men subjected to
early detection and screening, we compared the yield of our ultrasound-guided
needle biopsy with the cutoff of 4.0 ng/ml
for all ages and the age-specific cutoffs
from our screening cohort.53 The PPV we
applied is derived from men undergoing
ultrasound-guided biopsy for any indication, including an abnormality in PSA
(Fig. 5). Our screening study is based on
men aged 50 years and older; therefore,
the yield in a younger cohort cannot be
assessed. As anticipated, there is an agespecific cutoff enhancement in the PPV.
However, a reduction in the number of
cancers that would be detected in the
screening population was found. The detection rate was 5.3 percent using 4.0
ng/ml and 4.1 percent using age-specific
cutoffs.
In an attempt to estimate the impact
of this difference in a population of
screened men, we analyzed the potential
years saved by applying the standard US
life table estimates. To give age-specific
cutoffs all the benefit, in our simplistic
model, we assumed that all cancers detected would be cured, that the men tested have a normal life expectancy, and
that the life expectancy for each man in
an age group was the same (i.e., a 59year-old man was assumed to have the
life expectancy of a 50-year-old man).
Moreover, we assumed that there was no
treatment-related mortality and that
missing a carcinoma would have no deleterious effect on our artificial society.
Based on 1,208 men from our
screening population, we estimated that
for this population 1,042 life years would
be saved if 4.0 ng/ml was selected as a cutoff and 856 life years would be saved if
age-specific cutoffs were used.
Other authors have also investigated
age-specific cutoffs.52,54 Catalona et al54
noted that the optimum balance of sensitivity and specificity for men older than 70
years was 5.0 ng/ml, as opposed to 4.0
ng/ml. However, they cautioned that widespread recognition of increasing unfavorCa—A cancer Journal for Clinicians
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Table 7
Prostate Markers of Malignant Potential
Grade
Clinical stage
Pathologic stage
Tumor volume
Prostatic acid phosphatase
Prostate-specific antigen
DNA ploidy
Nuclear morphometry
Neovascularity
Oncogenes
Tumor suppresser genes
Invasion markers (cathepsin, collagenase)
Adherens
Basement membrane (collagen)
Growth factors
able pathology with elevation in serum
PSA makes the cutoff unwarranted.
It has been suggested that the increased specificity (and resulting decrease in sensitivity) associated with increasing PSA cutoffs is nevertheless
reasonable in older men who may derive
little benefit from early detection of prostatic carcinoma. It is my contention that
it is more reasonable to identify this
quandary prior to testing and actually not
perform screening in such patients rather
than apply a less sensitive cutoff to avoid
the dilemma of what to do with a man
with a more-limited life expectancy in
whom prostate cancer is detected. Obviously, an absolute upper age limit for
prostate cancer screening or early detection is inappropriate. However, most authorities would limit this in asymptomatic
men to those with a greater than 10-year
life expectancy.
Vol. 45 No. 3 may/june 1995
PSA FORMS
Another potential approach to enhancement of the specificity of serum PSA assays is the recognition that PSA circulates
in at least three molecular forms—free
PSA; PSA complexed with 2-macroglobulin; and the major form, PSA complexed with 1-antichymotrypsin.55-58 Figure 6 shows these three forms and the
masking of the epitopes recognized by
the antibodies in conventional serum assays for PSA. Free PSA has five epitopes
available. In general free PSA represents
the minority of identifiable PSA in the
systemic circulation. PSA complexed to
1-antichymotrypsin constitutes roughly
90 percent of the identifiable PSA in the
systemic circulation. Note that three of
the epitopes potentially available on free
PSA are masked by this protein. Finally,
PSA that is complexed to 2-macroglobulin has no epitopes available to the anti159
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P r o s t a t e - S p e c i f i c
bodies employed in current assays.
The recognition that free PSA
makes up a greater proportion of the total serum PSA in men without prostate
cancer has generated considerable enthusiasm. Lilja et al59 studied 89 men and
measured the ratio of free PSA to total
PSA or free PSA to complexed PSA
measured by an investigational assay at
cutoffs giving a sensitivity of 90 percent.
They observed that total PSA revealed a
specificity of 32 to 43 percent. In contrast
the specificity was 64 to 68 percent if the
ratio was used.
Stamey et al60 used gel chromatography from highly characterized patients
with and without carcinoma. They noted
that the total serum PSA recognized by
several commercial assays was 88 to 98
percent complexed with 1-antichymotrypsin in all patients with carcinoma.
Ten men with BPH had 73 to 84 percent
complexed with 1-antichymotrypsin.
Further work is obviously essential to
demonstrate whether increased specificity will be associated with examining the
ratio of free to total or free to complexed
PSA.
PSA Assay Variability
There are currently six assays available
for PSA determination in the United
States, including Pros-Check PSA Assay
(Yang Laboratories, Belvue, Wash.); the
Tandem-E PSA, Tandem-R PSA, and
TOSOH assays (Hybritech Inc., San
Diego, Calif.); the IMX PSA Assay (Abbott Laboratories, North Chicago, Ill.);
and the recently improved ACS assay
(CIBA Corning, Norwood, Mass.). The
Pros-Check assay is a conventional polyclonal radioimmunoassay. The Hybritech
assays employ the Tandem monoclonalmonoclonal technology, either by a radioimmunoassay format (Tandem-R) or
immunoenzymatic format (Tandem-E).
The TOSOH assay employs the Hybritech monoclonal assays in an automated
format. The IMX and ACS assays em160
A n t i g e n
ploy polyclonal-monoclonal technology
with microparticle-capture enzyme immunoassay or chemolumenescent formats, respectively. In Europe and elsewhere, 30 or more assays are currently
available.
Owing to the importance of knowing
whether there are differences between
assays, we have begun a series of comparisons.61,62 We examined 266 random sera
from our archival bank and ran three lots
of the Abbott IMX assay versus three lots
of the Hybritech Tandem-E assay according to the manufacturer’s specifications.
Each serum was assayed in all lots on the
same day with only one freeze/thaw. We
noted significant lot-to-lot variation with
the IMX assay.
Regression among the three Tandem-E lots had calculated slopes of 1.003,
1.033, and 1.037 (proportional bias of 0.3
to 3.7 percent). Regression of the results
from the three IMX lots demonstrated
between-lot slopes of 1.011, 1.098, and
1.109 (proportional bias of 1.1 to 10.9 percent).61 This indicates significant lot-to-lot
variability with the IMX assay.
Over the range of 2.0 to 10.0 ng/ml,
the overall bias was a 13 percent lower
reading with the IMX assay. Figure 7
demonstrates the percentage of men with
an established diagnosis of cancer who
exceeded the threshold for various cutoffs with the Tandem or IMX assay. For
each PSA cutoff, there was a stepwise reduction in yield with the IMX assay.
It is recognized that the IMX assay
preferentially identifies the free form of
PSA. For example, Stamey et al60 demonstrated that the IMX assay reads PSA
complexed with 1-antichymotrypsin at a
significantly lower value than the Tandem-R assay, but it detects the uncomplexed PSA at a higher value than the
Tandem-R assay. The authors concluded
that because 90 percent or more of the
serum PSA in cancer patients is in the
complexed form, the overall effect is a decreased value for the IMX with respect to
Tandem-R.
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This may result from epitopic shielding as described above, making the free
PSA more readily identifiable by the antibodies employed by the IMX assay compared with the so-called equimolar response of the Tandem assay, where both
the free PSA and PSA complexed with
1-antichymotrypsin are equally identified. Moreover, the rapid-format technique of the IMX assay may preferentially allow higher signal from the free
compared with the complexed form of
PSA, owing to diffusion effects.
PSA Standardization
Recently, the Second Annual Stanford
PSA Standardization Conference was
held.63 Under the leadership of Dr.
Thomas Stamey, significant strides have
been made toward creating an international standard for serum PSA assays.
Given the rapid proliferation of available
commercial assays, this is obviously of
paramount importance. By providing a
standard calibrator determined by mass
weight of PSA, it is hoped that the various
manufacturer’s assays will be more directly comparable. It was decided at the conference that a standard calibrator with 10
percent free PSA and 90 percent complexed PSA would be most appropriate.63
The Stanford group has shown that
the use of this calibrator makes PSA assays of various manufacturers more comparable.63 While the 10 to 90 ratio may be
appropriate for many patients undergoing
PSA testing, we have observed a free
PSA range of six to 32 percent in men
with prostate cancer and a free PSA range
of six to 35 percent in men with negative
biopsies (unpublished observations). Obviously, further inquiry in this important
area is necessary and is under way.
The Need for Repeat Biopsy
One of the many unknowns surrounding
the diagnosis of prostate cancer is how to
evaluate the man with an abnormality on
Vol. 45 No. 3 may/june 1995
1 9 9 5 ; 4 5 : 1 4 8 - 1 6 4
DRE or an elevation in serum PSA who
has a negative biopsy. Little data exist to
offer guidelines on who should undergo
further evaluation.
We reported on 100 men who underwent repeat prostate needle biopsy after
initial negative biopsy.64 Carcinoma was
detected in 20 men. Cancer was found in
four of 17 (23.5 percent) who had atypia
on the initial biopsy, five of 14 (35.7 percent) who had PIN, and 10 of 69 (14.5
percent) who had neither of these suspicious findings on the initial biopsy. Unfortunately, PSA levels or PSA velocity
did not offer statistically significant stratification of who had carcinoma on the repeat biopsy. Clearly, these data indicate
that men with an initial biopsy revealing
PIN or atypia should undergo repeat
biopsy. In addition, despite lack of definitive evidence, a man with a rapidly rising
PSA, or a grossly abnormal DRE, and a
benign biopsy may well be a candidate
for repeat biopsy.
Screening Issues
Considerable controversy surrounds the
entire issue of screening or early detection of prostatic carcinoma. Certainly
valid arguments against screening can be
made, based on scientific issues (e.g.,
length- and lead-time bias and the problem of overdetection) and ethical issues
(e.g., commitment of significant resources
that might be better used elsewhere), as
well as legal concerns.
Feightner65 reviewed the recommendation of the Canadian Task Force on the
Periodic Health Examination against the
use of PSA for population-based screening. He stated that given the absence of
proof of definitive therapy, including radiation therapy and radical prostatectomy, in controlling or decreasing prostate
cancer-specific mortality, widespread
screening cannot be recommended.
Woolf66 analyzed the appropriateness of
PSA screening employing four criteria:
burden of suffering, effectiveness of
161
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screening, potential harms of screening,
and economics of screening. He cautioned that while the burden of suffering
with carcinoma is obvious, currently
there are no data to suggest that screening is effective in reduction of cancer-related mortality.
A number of important trials are being conducted, yet the rising rate of
prostate cancer incidence and mortality
makes early detection and attempts at curative therapy the standard of care in
most settings. The Prostate, Lung, Colon,
and Ovarian trial67 will attempt to demonstrate the benefit of early detection of
prostatic carcinoma, using DRE and
PSA. Although this study is hampered by
the fact that no therapeutic approach is
mandated and the screening interval may
be too short, the biggest problem may be
identification and maintenance of a control (nontested) population.
The Prostate Intervention Versus
Observation Trial is currently under way
to investigate whether radical prostatectomy is effective in reducing cancer mortality.68 This study, which will randomize
2,000 men to radical prostatectomy versus observation, will in effect ultimately
prove or disprove the utility of early detection efforts. If curative therapy prolongs life, the efficacy of efforts to detect
earlier cancers will almost certainly be realized. However, if treatment is shown to
be ineffective without advances in our
therapeutic armamentarium, emphasis
on early detection will decrease.
It is likely that even with the opportunity of universal screening, not every
man would undergo such testing. Never-
theless, the economic implications are
staggering. In addition, we may diagnose
cancer in many men unlikely to derive
benefit. In my opinion, the most critical
issue in prostate cancer today is the development of reliable markers of malignant potential. Table 7 depicts a partial
listing of some of the markers currently
available.
Ultimately, it is the primary care
provider who must make the decision
whether the early detection of prostate
cancer will enhance his or her patient’s
well-being. Given such parameters as patient age, intercurrent illness, social situation, and patient desires, the primary
physician is well suited to counsel the patient with regard to benefits as well as potential risks that might arise from early
detection efforts. If, after such counsel, it
is determined that the patient will derive
benefit from early detection of prostatic
carcinoma, then a carefully performed
DRE with an attempt to identify subtle
changes, such as minimal induration or
perhaps even asymmetry, should be carried out and serum PSA measured. In my
opinion, any abnormality on DRE or a
serum PSA level greater than 4.0 ng/ml
should be an indication for referral to a
urologist. I do not believe that the current
data support the use of PSA velocity,
PSA density, age-specific PSA cutoffs, or
PSA isoform levels to determine who
should undergo further testing (i.e., biopsy). If, however, the primary provider and
patient feel that no benefit is to accrue by
early detection efforts, then no testing
CA
should be performed.
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