Download Prostate-specific antigen (PSA) and PSA velocity for prostate cancer

Original Article
PSA AND PSA VELOCITY FOR MEN AGED <50 YEARS
SUN
ET AL.
Many of the papers in this section
are specifically related to the
complexities of PSA testing and
prostatic biopsy. Increasingly PSA
testing has become a constituent
part of urological practice, and
although most would maintain that
its is the best urological marker for
prostate cancer that we have, its
failings have led us to examine its
performance in microscopic detail,
to help us to use it better for
detecting prostatic cancer.
Prostate-specific antigen (PSA) and
PSA velocity for prostate cancer
detection in men aged <50 years
Leon Sun, Judd W. Moul, James M. Hotaling,
Edward Rampersaud, Phillipp Dahm, Cary Robertson,
Nicholas Fitzsimons, David Albala and Thomas J. Polascik
Division of Urology and Duke Prostate Center, Department of Surgery, Duke
University Medical, Center, Durham, NC, USA
Accepted for publication 6 October 2006
OBJECTIVE
In the same way, high-grade
prostatic intraepithelial neoplasia
has become important in our
understanding of the progression
of the pathology of prostate
cancer. Several papers in this
section re-emphasise the
importance of this finding, and
suggest that it remains a highly
significant indicator of the likely
development of prostate cancer.
To identify threshold values of prostatespecific antigen (PSA) levels and PSA velocity
(PSAV) to optimize the assessment of the risk
of prostate cancer in young men, as prostate
cancer is detected increasingly in men aged
<50 years.
PATIENTS AND METHODS
Data for a group of 12 078 men, including
1622 with prostate cancer, were retrieved
from the Duke Prostate Center Database.
Based on the latest date for a PSA assay, these
men were divided into two age groups of <50
and ≥50 years, with 904 and 11 174 men in
each group, respectively. Receiver operating
characteristic curves (ROC) of PSA and PSAV
were calculated and the cancer risk was
assessed.
showed a breakpoint at a PSA level of 2.3 ng/
mL and a PSAV of 0.60 ng/mL/year for men
aged <50 years. Both the sensitivity and
specificity in the younger group at a PSA level
of 2.5 ng/mL were higher than in the older
group.
CONCLUSIONS
In men aged <50 years the operating
characteristics of PSA are more sensitive and
specific than in older men. Diagnostic PSA
levels in men aged <50 years are significantly
lower than suggested by guidelines. Using a
2.0–2.5 ng/mL PSA level threshold for biopsy
in men aged <50 years and a PSAV threshold
lower than the traditional 0.75 ng/mL/year is
reasonable in contemporary practice. Further
studies are warranted to validate these
thresholds.
KEYWORDS
RESULTS
The prevalence of prostate cancer was 4.4%
(40 men) for men aged <50 years and 14.2%
(1582 men) for men aged ≥50 years. For the
group with cancer the median PSA in men
aged <50 years was significantly lower than
that in men aged ≥50 (1.3 vs 6.3 ng/mL,
P < 0.001). ROC curves of PSA and PSAV
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2 0 0 7 B J U I N T E R N A T I O N A L | 9 9 , 7 5 3 – 7 5 7 | doi:10.1111/j.1464-410X.2006.06682.x
PSA velocity, age-adjusted PSA levels,
sensitivity, specificity
INTRODUCTION
The use of PSA as a screening tool has
revolutionized the detection of early-stage
prostate cancer [1]; since the advent of PSA
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S U N ET AL.
TABLE 1 Demographics, PSA level and PSAV in different age groups (12 078, including 40 and 1582 men who were diagnosed with prostate cancer in those aged
<50 years and ≥ 50 years, respectively)
Variable
Median (IQR) age, years
Caucasian, n (%)†
African-American, n (%)†
Other ethnic group, n (%)†
Median (IQR) PSA, ng/mL
No. with PSAV ≥ 0 ng/mL/year‡
Median (IQR) PSAV, ng/mL/year‡
<50 years
No cancer
46.3 (43.3–48.4)
700
155
9
0.7 (0.4–1.0)
413 (47.8)
0.15 (0.07–0.32)
Cancer
48.1 (45.0–49.0)
31 (4.2)
8 (4.9)
1
1.3 (0.7–2.7)
21 (52.5)
1.83 (0.28–8.54)
≥50 years
No cancer
65.7 (58.3–72.8)
7716
1827
49
5.1 (0.9–7.1)
4965 (51.8)
0.25 (0.1–0.48)
Cancer
69.4 (63.3–74.7)
1258 (14.1)
319 (14.9)
5
6.3 (3.5–12.3)
1086 (68.6)
1.78 (0.69–5.19)
P*
<0.001
<0.001
0.102
*Mann–Whitney U-test of cancer groups between the age groups. IQR, interquartile range, 25th–75th percentile. †% over the total cases in the corresponding
group. ‡From cases with a PSAV of ≥0.
testing the median age of diagnosis has
decreased substantially and it has been
confirmed that being younger at diagnosis
is an independent predictor of a better
prognosis [2,3]. While as few as 25% of men
with a PSA level of 4–10 ng/mL have prostate
cancer, up to 25% of men with a PSA of
<4 ng/mL will have prostate cancer [4–6]. This
poor specificity prompted the introduction
of age-adjusted PSA level thresholds [7].
Younger men have lower PSA values,
prompting some, e.g. Oesterling et al. [7] and
Moul et al. [8], to suggest that the upper limit
of normal PSA in men aged 40–49 years is 2.5
and 2.0 ng/mL, respectively.
Smith and Catalona [9] showed that the
vast majority of tumours detected through
PSA screening are clinically significant.
Clinically significant prostate cancer
implies that the treatment of these
tumours will directly affect either the
quality or length of the patient’s life. The
question of clinically significant cancer is
usually an issue in older patients, as
many die from causes unrelated to their
prostate cancer. This has led us and
others to hypothesise that lowering PSA
level thresholds in men aged <50 years
would result in increased detection and
treatment of early-stage prostate cancer that
would potentially affect the length of their
lives. Furthermore, as the incidence of BPH
increases from 9% in men aged <60 years to
17% in men aged >60, screening younger
men should result in fewer false-positive
results [10].
The objective of the present study was to
identify PSA kinetic data and optimized
754
screening variables that could be used to
recognize clinically significant prostate cancer
in young men.
PATIENTS AND METHODS
A group of 12 078 men (aged 40–96 years)
with at least two PSA tests within a 2-year
period were retrieved from the Duke Prostate
Center outcomes database, that contains data
for >14 000 patients with prostate cancer and
>1.5 million associated clinical records; 904 of
these men were aged <50 years and 12 074
were aged >50 years. For the group with
prostate cancer, PSA values drawn within
2 years before the first positive biopsy were
included. Patients with either a negative
biopsy or no known history of prostate cancer
were included in the no-cancer arm. It was
important to include these patients, as
their PSA values and velocities served as the
controls for the patients who had positive
biopsies. PSA velocity (PSAV) was calculated
as the slope of the linear regression line of all
PSA values over time [5]. All PSA values after
diagnosis were excluded from the dataset, as
were all men who did not have at least two
PSA values within 2 years and were not aged
≥40 years. Men were stratified into two age
groups, i.e. <50 and ≥50 years, based on their
age at the time of the most recent PSA test.
Receiver operating characteristic (ROC) curves
were calculated and used to analyse the
sensitivity and specificity of PSA and PSAV for
detecting prostate cancer in men aged <50
and ≥50 years. The ROC curve break-points
served to establish the new PSA level and
PSAV thresholds for young men. The positive
predictive value (PPV) was calculated by
dividing the number of cancers detected by
the number of all men meeting the criteria
being evaluated. Finally, we compared the
number of cancers detected between the old
and new criteria.
Results were considered statistically
significant with a two-sided α of <0.05. The
Mann–Whitney U-test was used to determine
P values, as the data had a non-Gaussian
distribution. Chi-square tests were used to
evaluate the racial composition of each
cohort and the percentiles.
RESULTS
Among the 12 078 men in the study, 1622
(13.9%) were diagnosed with prostate cancer
by prostatic needle biopsy. Of the 904 men
aged <50 years, 40 were diagnosed with
cancer (4.4%), with a median age of
48.1 years. Of these men, four had a family
history of prostate cancer and six had an
abnormal DRE. The distribution of race in the
groups with cancer aged <50 and ≥50 years
were similar (Table 1).
The median age at last PSA sampling was
substantially younger for those aged ≥50 and
with no cancer than for those with cancer (66
vs 69 years). This was also the trend in men
aged <50 years with no cancer, with a median
age of 46, vs 48 years in the group with
cancer (Table 1).
For men aged ≥50 years and no cancer the
median PSA and PSAV were 5.1 ng/mL and
0.25 ng/mL/year, respectively, vs 6.3 ng/mL
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PSA AND PSA VELOCITY FOR MEN AGED <50 YEARS
100
100
80
80
60
40
AUC: 0.872 (<50 years)
AUC: 0.819 (≥50 years)
P < 0.0001
20
0
0
20
40
60
80
100-specificity (PSA)
Sensitivity, %
Sensitivity, %
FIG. 1. PSA level (left) and PSAV (right) were better predictors of prostate cancer in young men.
100
60
40
AUC: 0.836 (<50 years)
AUC: 0.812 (≥50 years)
P < 0.0001
20
0
0
20
40
60
80
100-specificity (PSAV)
100
TABLE 2 The sensitivity and specificity of PSA level and PSAV between the age groups
<50 years
Variable
Sensitivity, %
PSA level, ng/mL
1.0
85.0
2.0
75.0
2.5
73.8
3.0
68.8
4.0
61.3
PSAV, ng/mL/year
0.10
95.2
0.20
85.7
0.30
71.4
0.40
71.4
0.50
71.4
0.60
71.4
0.70
66.7
0.75
66.7
Specificity, %
≥50 years
Sensitivity, %
Specificity, %
73.6
92.2
94.1
95.9
97.7
89.3
83.4
81.0
78.3
71.3
39.8
65.5
72.7
77.8
85.2
41.0
62.1
73.2
78.8
81.7
83.7
85.6
86.3
95.0
91.2
88.6
86.2
82.4
78.6
74.6
73.4
26.1
44.1
54.8
62.0
67.7
71.6
75.6
77.1
©
Cancer
No
cancer
21
413
≥50 (PSAV ≥0)
PSA level thresholds
<50
1086
4965
40
864
≥50
1582
9592
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Cancers
detected, %
Non-cancers
biopsied, %
PPV, %
≥0.60
≥0.70
≥0.75
≥0.75
15 (71.4)
14 (66.7)
14 (66.7)
797 (73.4)
68 (16.5)
59 (14.3)
56 (13.6)
1139 (22.9)
18.1
19.2
20.0
41.2
≥2.0
≥2.5
≥3.0
≥4.0
≥4.0
30 (75.0)
30 (75.0)
28 (70.0)
25 (62.5)
1135 (71.7)
69 (8.0)
52 (6.0)
37 (4.3)
21 (2.4)
1451 (15.1)
30.3
36.6
43.1
54.3
43.9
Threshold
ROC curves were constructed for PSA and
PSAV, and the area under the curve was
greater for men aged <50 years than for
those aged ≥50 years, for both PSA and PSAV
(Fig. 1, P < 0.001). Break-points in the PSA
and PSAV curves (arrows, Fig. 1) were used
to guide the determination of the new ranges
for cancer biopsy in men aged <50 years, at
2.0–2.5 ng/mL for PSA and 0.2–0.6 ng/mL/
year for PSAV.
The sensitivity and specificity for the
traditional PSA level threshold of 4.0 ng/mL
was 61.3% and 97.7%, respectively, for
men aged <50 years, and 71.3% and
85.2%, respectively, for men aged
≥50 years (Table 2). The sensitivity and
specificity for the traditional PSAV threshold
of 0.75 ng/mL/year was 66.7% and 86.3%,
respectively, for men aged <50 years, and
73.4% and 77.1%, respectively, for men aged
≥50 years (Table 2). The sensitivity and
specificity for a PSA level of 2.0–2.5 ng/mL
in men aged <50 years were 73.8–75% and
92.2–94.1%, and for a PSAV of 0.2–0.6 ng/mL/
year was 71.4–85.7% and 62.1–83.7%,
respectively.
TABLE 3 The performance of PSA level (ng/mL) and PSAV (ng/mL/year) thresholds in the two age groups
Age group, years
PSAV thresholds
<50 (PSAV ≥0)
and 1.78 ng/mL/year in the group with cancer
(P < 0.05, Table 1). For men aged <50 years
the PSA and PSAV were 0.7 ng/mL and
0.15 ng/mL/year, respectively, in men with no
cancer, vs 1.3 ng/mL and 1.83 ng/mL/year in
those with cancer (P < 0.05, Table 1). Notably,
1.83 ng/mL/year is well above the PSAV
threshold established by Carter et al. [5]
of 0.75 ng/mL/year, but the PSA value
(1.3 ng/mL) is still well below the current
AUA guideline of 4.0 ng/mL.
Table 3 shows the performance of the new
and traditional PSA level thresholds for cancer
detection in men aged <50 years. Among the
40 men aged <50 years diagnosed with
cancer, a third of them were below the
traditional PSAV threshold of 0.75 ng/mL/year
and 38.5% were below the current PSA level
threshold of 4.0 ng/mL. For men aged
≥50 years the traditional PSAV threshold
missed only 27.6% of cancers and the PSA
level threshold missed 29.3%. The PPV for the
traditional PSAV threshold was 41.2% for the
older men and 20% for younger men, whereas
for a PSA level of 4.0 ng/mL it was 43.9% for
older men and 54.3% for younger men. Using
a PSA level threshold of ≥2.5 ng/mL and PSAV
threshold of ≥0.60 ng/mL/year for younger
men, an additional six men with cancer
were detected and only 11 were missed, with
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S U N ET AL.
a PPV of 18.1% for a PSAV of ≥ 0.60 ng/mL/
year and PPV of 36.6% for a PSA level of
≥2.5 ng/mL (Table 3). However, only one
additional man with cancer was detected
using the new PSAV criteria, compared with
the traditional one.
DISCUSSION
Recent work has cast doubt on the existence
of a true PSA level threshold for biopsy [11].
Others have indicated that many men with
cancer actually have PSA values of <4.0 ng/
mL [6]. Regardless of the current views
questioning the validity of PSA, its impact is
undeniable [3,12]. PSA remains the best
prostate cancer-screening tool currently
available, and the standard against which
all others are judged. As the ‘baby-boom’
generation reaches its peak years for prostate
cancer it is imperative that urologists use PSA
judiciously and effectively to minimize the
economic impact on an already overburdened
healthcare system, and maximize its
effectiveness to detect and treat early-stage
and clinically significant prostate cancer.
In the present study we explored whether
lowering the current PSA level threshold and
using PSA kinetics at 40 years instead of
50 years old would lead to the detection of
more curable prostate cancer.
There are three main reasons that make PSA
screening with a lowered threshold useful in
men aged 40–49 years. First, the incidence of
BPH is lower in young men [4]. Second, PSA
screening in younger men is more likely to
detect men with curable, clinically localized
cancer. Finally, younger men are less likely to
have significant medical comorbidities and
more likely to opt for definitive treatments
such as surgery.
Currently, there are few data on PSA
screening in men aged <50 years. The idea of
lowering the PSA level threshold was explored
previously, Oesterling et al. [11] proposed agespecific PSA level thresholds for men aged
40–49 years of 2.5 ng/mL for Caucasians
and 2.0 ng/mL for African-Americans. Many
others suggested that lowering the PSA level
threshold for biopsy, in addition to lowering
the screening age, might be advantageous
[2,3,6,13]. Although PSA should be viewed as
a continuum on which to judge prostate
cancer [10], most urologists still rely on firm
thresholds or a reasonable range for PSA
screening.
756
Using the ROC curves to examine PSA level
and PSAV in men aged <50 years, it is clear
that although the area under the curve
was higher for this cohort, the traditional
thresholds for cancer biopsy are inadequate
and miss a significant proportion of men with
cancer (Fig. 1 and Table 2). Further, there
is a breakpoint in the curve at 2.3 ng/mL,
indicating that that 2.0–2.5 ng/mL for PSA in
this age group would be more reasonable, as
this PSA value maximizes the sensitivity and
specificity in men aged <50 years and
detected an additional five (12.5%) with
cancer, whereas the PSAV value only detected
one additional man with cancer (Fig. 1 and
Table 2).
The data used in the present study were from
Duke Urology clinic, rather than from a ‘pure’
population-based study. Interestingly, the
median PSAV for men aged <50 years with
cancer was 1.83 ng/mL/year, well above the
traditional PSAV threshold and similar to that
of men aged ≥50 year (1.78 ng/mL/year) but
the breakpoint in the ROC curve was 0.60 ng/
mL/year. The high median PSAV suggests that
current PSAV thresholds might be adequate or
that we have a selection bias toward men
with aggressive prostate cancer in this
population not regularly subjected to PSA
screening, and are probably missing men with
less advanced disease. To characterize PSAV
kinetics, the study included men with two or
more PSA estimates, without counting the
men with one PSA value and diagnosed with
prostate cancer (hence, PSAV >0). These
limitations could affect the ability to
generalize these findings to the overall
population. Information from a DRE and the
family history in men aged ≥50 years was
unavailable. This information is vital to future
studies, as it is likely that most men aged
<50 years diagnosed with prostate cancer
were initially detected by a DRE. Thus, by
examining only this cohort of men the data
might be skewed towards young men with
more aggressive cancer.
Further, the new thresholds significantly
decreased the PPV from 20% to 18.1% for
PSAV, and 54.3% to 36.6% for PSA. This
suggests that in the future an optimized PSAV
threshold could provide a better screening
tool than simply lowering the PSA level
threshold, as it does not lower the PPV as
much, but further studies with larger groups
of men with prostate cancer and aged
<50 years are needed to define the role of
PSAV in this cohort.
In conclusion, PSA level and PSAV patterns in
men aged <50 years are different from those
in men aged ≥50 years. Diagnostic PSA levels
in men aged <50 are much lower than the
guidelines suggested by the AUA. Using a PSA
level threshold of 2.0–2.5 ng/mL for biopsy in
men aged <50 years is advised, as is lowering
the PSAV threshold to ≤0.60 ng/mL/year in
this group. Further studies on men aged <50
years are warranted to validate the thresholds
and ranges proposed.
ACKNOWLEDGEMENT
The authors greatly appreciate the data
support from Howard Shang and his team,
Duke Business Information Services, Mr
Matthew Harker and his team, Duke
Department Surgery IT Services, and Ms.
Eileen Morgan and her team, Duke Tumor
Registry.
CONFLICT OF INTEREST
None declared. Source of funding: NIH ROI
CA104976-01.
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Correspondence: Judd W. Moul, Professor and
Chief, Division of Urologic Surgery and Duke
Prostate Center, Duke University Medical
Center, PO Box 3707, Durham, NC 27710, USA.
e-mail: [email protected]
Abbreviations: PSAV, PSA velocity; PPV,
positive predictive value; ROC, receiver
operating characteristic (curve).
757