Download Early detection of highgrade prostate cancer using digital rectal

BJUI
BJU INTERNATIONAL
Early detection of high-grade prostate cancer
using digital rectal examination (DRE) in men
with a prostate-specific antigen level of
<2.5 ng/mL and the risk of death
Jona A. Hattangadi, Ming-Hui Chen* and Anthony V. D’Amico†
Harvard Radiation Oncology Program, Boston, MA, *Department of Statistics, University of Connecticut, Storrs, CT,
and †Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA
Accepted for publication 19 April 2012
Study Type – Prognosis (inception
cohort)
Level of Evidence 2a
OBJECTIVE
• To determine whether detection of
high-grade prostate cancer while still
clinically localised on digital rectal
examination (DRE) can improve survival in
men with a normal prostate-specific
antigen (PSA) level.
PATIENTS AND METHODS
• From the Surveillance, Epidemiology and
End Results database, 166 104 men with
prostate cancer diagnosed between 2004
and 2007 were identified.
• Logistic regression was used to identify
factors associated with the occurrence of
palpable, PSA-occult (PSA level of <2.5 ng/
mL), Gleason score 8–10 prostate cancer.
• Fine and Gray’s and Cox multivariable
regressions were used to analyse whether
demographic, treatment, and
clinicopathological factors were associated
with the risk of prostate cancer-specific
INTRODUCTION
Before the use of PSA screening for prostate
cancer, DRE was the most sensitive method
of diagnosis [1]. Early prospective studies
suggested that screening for prostate cancer
with DRE was cost-effective and specific for
detection of more aggressive tumour [1,2].
And contrary to the notion that DRE is
highly subjective, studies have shown that
1636
What’s known on the subject? and What does the study add?
There is little data on the utility of digital rectal examination (DRE) as a diagnostic tool
in the era of prostate-specific antigen (PSA) testing. Using a population-based
database, we found that detection of prostate cancer while still localized among men
with high-grade PSA-occult disease may result in survival benefit.
mortality (PCSM) and all-cause mortality
(ACM), respectively.
RESULTS
• Both increasing age (adjusted odds ratio
[aOR] 1.02, 95% confidence interval (CI)
1.01–1.03; P < 0.001) and White race (aOR
1.26, 95% CI 1.03–1.54; P = 0.027) were
associated with palpable, Gleason 8–10
prostate cancer. Of 166 104 men, 685
(0.4%) had this subset of prostate cancer.
• Significant factors associated with risk
of PCSM included PSA level (adjusted
hazard ratio [aHR] 0.71, 95% CI 0.51–0.99;
P = 0.04), higher Gleason score (aHR 2.20,
95% CI 1.25–3.87; P = 0.006), and T3–T4 vs
T2 disease (aHR 3.11, 95% CI 1.79–5.41;
P < 0.001).
• Significant factors associated with risk
of ACM included age (aHR 1.03, 95% CI
there is little inter-observer variability when
the prostate is examined in a systematic
method [3,4]. More recent studies combining
DRE and PSA levels for screening have
shown that the sensitivity and accuracy of
DRE are improved when PSA values are
taken into account [5,6], and that DRE
is particularly relevant in the detection
of higher grade, clinically aggressive
disease [7]. As a result, active surveillance
©
1.01–1.06; P = 0.006), higher Gleason score
(aHR 2.05, 95% CI 1.36–3.09; P < 0.001),
and T3–T4 vs T2 disease (aHR 2.11, 95% CI
1.38–3.25, P < 0.001)
CONCLUSIONS
• Clinically localised disease on DRE
among men with PSA-occult high-grade
prostate cancer was associated with
improved PCSM and ACM, suggesting that
DRE in this cohort (older age and White
race) may have the potential to improve
survival.
KEYWORDS
digital rectal examination, PSA, high-grade
prostate cancer, SEER, disease-specific
death, prostate cancer
protocols dictate that finding palpable
disease on DRE during follow-up requires
ceasing surveillance and initiation of
treatment [8,9].
Other studies have questioned the role of
DRE [10], or omitted DRE altogether in
prostate cancer screening [11]. The recent
American Cancer Society guidelines on
prostate cancer screening recommended
2 0 1 2 B J U I N T E R N A T I O N A L | 11 0 , 1 6 3 6 – 1 6 4 1 | doi:10.1111/j.1464-410X.2012.11354.x
DRE DETECTED HIGH-GRADE PROSTATE CANCER AND THE RISK OF DEATH
that DRE be considered an option rather
than a necessary adjunct to PSA testing [12].
However, PSA testing as a screening tool has
come under increased scrutiny recently,
because of differing results from
randomised trials [13,14], and the potential
for unnecessary evaluation, detection and
treatment [15]. Thus the role of DRE should
be re-examined to determine if men can be
identified in whom DRE can provide earlier
detection and therefore be potentially
lifesaving.
There is little data on the utility of DRE as a
clinical diagnostic tool in the PSA era,
particularly in cases of high grade disease
where low PSA levels due to hypogonadism
[16,17], dedifferentiation [18], or
medications that lower PSA, e.g. 5α
reductase inhibitors [19] make the PSA test
unreliable. Therefore, we used a populationbased database to examine whether
detection of high-grade prostate cancer
while still clinically localised on DRE can
improve survival in men with a low PSA
level.
PATIENTS AND METHODS
Data were obtained from the Surveillance,
Epidemiology, and End Results (SEER)
database [20,21], which includes patients
with cancer reported by 17 tumour registries
since 2000. The SEER programme captures
≈97% of incident cancers and the 17
tumour registries cover ≈26% of the USA
population [20,21]. Registries collect
information on demographics, date of
diagnosis, tumour characteristics, surgical
treatment, radiation therapy, vital status,
follow-up, and cause of death. Pretreatment PSA levels (ng/mL) were collected
from 2004 to 2007 in a recent release of
SEER data [21].
value of <2.5 ng/mL was chosen, as it is
below the standard threshold PSA level for
further evaluation in prostate cancer
screening [8,12]. Gleason score was obtained
from the biopsy report if the patient did
not undergo radical prostatectomy (RP),
and was obtained from the surgical
pathology report if the patient underwent
RP.
Demographic, clinical and pathological
factors, along with patient follow-up and
determination of cause of death were
extracted from the database. This study was
determined to be exempt from review by the
Institutional Review Board of the DanaFarber Cancer Institute/Brigham and
Women’s Hospital.
COMPARISON OF BASELINE CLINICAL
CHARACTERISTICS AMONG STUDY COHORT
Patient and clinical factors were compared
stratified by DRE-based clinically localised
(T2) or extraprostatic disease (T3, T4). Race
was White, Black, or Other Race (including
American Indian, Native Alaskan, East Asian,
South Asian, Southeast Asian and Pacific
Islander populations). Because of small
numbers in the Other Race category,
patients from Other and Black race were
grouped for analyses. Curative treatment
included RP and external beam radiation
therapy approaches. Non curative
approaches included active surveillance, and
non-radiation, non-RP approaches, e.g. laser
ablation, TURP, and primary hormonal
therapy. The distribution of continuous
variables including age, PSA level and
follow-up were compared using the
Wilcoxon two-sample test and categorical
variables were compared using a chi-square
metric.
PREDICTORS OF PROSTATE CANCER-SPECIFIC
MORTALITY (PCSM) AND ALL-CAUSE
MORTALITY (ACM)
Univariable and multivariable Fine and
Gray’s and Cox regression analyses were
used to identify whether the risk of PCSM
and ACM, respectively, were associated with
clinical T-category (T2 vs T3,T4), adjusting
for age at diagnosis (continuous), race (Black
or Other vs White), year of diagnosis
(continuous) and known prognostic factors
including Gleason score (8 vs 9–10), PSA
level (continuous), and treatment (curative
vs non-curative). For these analyses, time to
event was measured from date of diagnosis.
PSA levels was log-transformed for all
analyses to ensure normal distribution.
Unadjusted and adjusted hazard ratios (aHR)
for PCSM and ACM with associated 95% CIs
were calculated for each covariate. This
analysis was repeated for the subset of men
who did not undergo RP (Gleason score was
based on biopsy only).
ESTIMATES OF PCSM AND ACM
Estimates of PCSM and ACM stratified by
T-category on DRE (T2 vs T3,4) were
calculated using cumulative incidence and
Kaplan–Meier methodology, respectively.
These estimates were compared using a
Gray’s k-mean test and log-rank test,
respectively. All statistical tests were
two-sided and a two-sided P < 0.05 was
considered to indicate statistical
significance. R version 2.12.0 software (R
Foundation for Statistical Computing,
Vienna, Austria) was used for all calculations
pertaining to Gray’s k-mean P value and
Fine and Gray’s regression. SAS version 9.3
software (SAS Institute, Cary, NC) was used
for all remaining calculations.
RESULTS
We identified 166 104 men with nonmetastatic prostate cancer who were
diagnosed from 1 January 2004 to 31
December 2007 when PSA data was
available. All patients had prostate cancer as
their first and only cancer diagnosis, and
cancer diagnosis not obtained through
death certificate or autopsy. We next
selected a subset of patients with PSAoccult (<2.5 ng/mL), clinically significant
high-grade (Gleason score 8–10) and
palpable (American Joint Committee on
Cancer [AJCC] T2–T4) prostate cancer. A PSA
©
2012 BJU INTERNATIONAL
PREDICTORS OF HIGH GRADE, PSA-OCCULT
PROSTATE CANCER
Univariable and multivariable logistic
regression analyses were used to identify
predictors of high-grade, PSA-occult,
clinically palpable disease. Covariates
examined included age (continuous), race
(Black and Other vs White), and year of
diagnosis (continuous). Odds ratios (ORs)
and associated 95% CIs were generated,
with two-sided P values from the chi-square
test.
BASELINE CHARACTERISTICS OF THE STUDY
COHORT AT DIAGNOSIS
Baseline characteristics of the study cohort
(685 patients) are shown in Table 1,
stratified by clinically localised (T2) vs
extraprostatic (T3, T4) T stage. Patients
with T2 tumours were significantly older
than those with T3–T4 tumours (median
age 69 vs 65 years, P < 0.001). Those
presenting with more advanced T3–T4 stage
had a significantly higher proportion of
1637
HATTANGADI ET AL.
Gleason 9–10 prostate cancer (63.6 vs
35.7%, P < 0.001). Significantly more
patients with T3–T4 tumours underwent
curative treatment (definitive surgery or
radiation) than men with T2 tumours
(P < 0.001). There was no significant
difference among the distribution of years
of diagnosis (P = 0.14) or median follow-up
(P = 0.94).
TABLE 1 Baseline characteristics of the 685 men in the study cohort with PSA levels of <2.5 ng/mL,
Gleason score 8–10 and AJCC T-category 2, 3, or 4 prostate cancer stratified by the AJCC
Tumour-category
Of 166 104 men, 685 (0.4%) had a PSA level
of <2.5 ng/mL, Gleason score 8–10, and
AJCC T-stage T2–T4 prostate cancer. As
shown in Table 2, increasing age was
significantly associated with the occurrence
of this cohort (adjusted OR [aOR] 1.02, 95%
CI 1.01–1.03, P < 0.001) as was White race
when compared with Black or Other Race
(aOR 1.26, 95% CI 1.03–1.54, P = 0.027). The
median (interquartile range [IQR]) age for
White and Black or Other Race men were
68 (61–75) years and 66 (60–73) years,
respectively.
Characteristic
N
Median (IQR):
Age at diagnosis, years
PSA, ng/mL
N (%):
Gleason score:
8
9–10
Race
White
Black
Other
Treatment:
Curative (surgery or RT)
Non-curative
Year of diagnosis:
2004
2005
2006
2007
Median (IQR) follow-up, years
FACTORS ASSOCIATED WITH INCREASED
RISK OF PCSM AND ACM
RT, radiation therapy; percentages may not add up to 100 because of rounding. *Two-sided Wilcoxon
two-sample test; †chi-square test; ‡log-rank test.
FACTORS ASSOCIATED WITH AN INCREASED
ODDS OF A PSA LEVEL OF <2.5 NG/ML AND
PALPABLE GLEASON 8–10 PROSTATE CANCER
After a median (IQR) follow-up period of
2.9 (1.9–4.1) years, 109 men (15.9%) died
and 61 men (8.9%) died from prostate
cancer. As shown in Table 3, increasing PSA
level was associated with a lower risk of
PCSM (aHR 0.71, 95% CI 0.51–0.99, P =
0.04). Gleason score 9–10 vs 8 (aHR 2.20,
95% CI 1.25–3.87, P = 0.006), T3–T4 vs T2
(aHR 3.11, 95% CI 1.79–5.41, P < 0.001) and
non-curative compared with curative
treatment (aHR 5.87, 95% CI 3.23–10.7, P <
0.001) were associated with a significantly
higher risk of PCSM.
Increasing age (aHR 1.03, 95% CI 1.01–1.06,
P = 0.006), Gleason score 9–10 vs 8 (aHR
2.05, 95% CI 1.36–3.09, P < 0.001), T3–T4 vs
T2 (aHR 2.11, 95% CI 1.38–3.25, P < 0.001)
and non-curative vs curative treatment (aHR
3.74, 95% CI 2.39–5.87, P < 0.001) were
associated with an increased risk of ACM as
shown in Table 4.
RISK OF PCSM AND ACM BY AJCC T-STAGE
Estimates of PCSM and ACM were
significantly higher for men with clinical T3
or T4 vs T2 disease (P < 0.001 for PCSM and
1638
T2
479
T3, T4
206
69 (62–76)
1.5 (1–2)
P
65 (58–71)
1.5 (1–2)
<0.001*
0.92*
0.001†
308 (64.3)
171 (35.7)
75 (36.4)
131 (63.6)
401 (83.7)
42 (8.8)
36 (7.5)
170 (82.5)
26 (12.6)
10 (4.9)
371 (77.5)
108 (22.6)
182 (88.4)
24 (11.7)
0.16†
0.001†
0.14†
137 (28.6)
99 (20.7)
106 (22.1)
137 (28.6)
2.83 (1.83–4.08)
62 (30.1)
41 (19.9)
59 (28.6)
44 (21.4)
2.92 (2.08–4.08)
0.94‡
TABLE 2 Univariable and multivariable logistic regression analyses providing the odds for clinical
factors of being diagnosed with a PSA level of <2.5 ng/mL, Gleason score 8–10 and AJCC T-category 2,
3, or 4 prostate cancer
Clinical factor
Age at diagnosis, years (continuous)
Race:
Black or Other
White
Year of diagnosis (continuous)
Univariable analysis
OR (95% CI)
P
1.02 (1.01–1.03)
<0.001
Multivariable analysis
aOR (95% CI)
P
1.02 (1.01–1.03)
<0.001
1.00 Ref
1.28 (1.04–1.56)
0.93 (0.87–1.00)
1.00 Ref
1.26 (1.03–1.54)
0.94 (0.88–1.00)
Ref
0.018
0.04
Ref
0.027
0.06
Ref, reference.
P = 0.027 for ACM) as shown in Figs 1 and
2, respectively. Estimates of PCSM at 3 years
were 15.8% (95% CI 10.6–21.7) for men
with T3–T4 disease, compared with 5.9%
(95% CI 3.9–8.6) for men with T2 prostate
cancer. These respective estimates were
21.5% (95% CI 15.9–28.7) and 14.5% (95%
CI 11.2–18.7) for ACM.
RISK OF PCSM AND ACM BY AJCC T-STAGE
AMONG MEN WITH BIOPSY-ONLY
GLEASON SCORES
Within the study cohort, 414 men did not
undergo RP, and thus their Gleason score
was based on biopsy findings only. Among
these 414 men, there were 97 deaths, 53
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2012 BJU INTERNATIONAL
DRE DETECTED HIGH-GRADE PROSTATE CANCER AND THE RISK OF DEATH
TABLE 3 Univariable and multivariable Fine and Gray’s regression analyses providing the risk of PCSM for each clinical factor
Clinical factor
Age at diagnosis, years (continuous)
Log PSA, ng/mL (continuous)
Gleason score:
8
9–10
Race:
Black or Other
White
AJCC T-stage:
T2
T3, T4
Treatment:
Curative (surgery or RT)
Non-curative
Year of diagnosis (continuous)
Number of
men (n = 685)
685
685
Number of
events (n = 61)
61
61
Univariable analysis
HR (95% CI)
1.02 (0.98–1.06)
0.68 (0.50–0.91)
383
302
17
44
1.00 Ref
3.38 (1.94–5.90)
Ref
<0.001
1.00 Ref
2.20 (1.25–3.87)
Ref
0.006
114
571
12
49
1.00 Ref
0.83 (0.44–1.56)
Ref
0.56
1.00 Ref
1.08 (0.54–2.17)
Ref
0.82
479
206
30
31
1.00 Ref
2.43 (1.48–4.01)
Ref
<0.001
1.00 Ref
3.11 (1.79–5.41)
Ref
<0.001
553
132
685
29
32
61
1.00 Ref
5.26 (3.20–8.64)
0.79 (0.61–1.02)
Ref
<0.001
0.07
1.00 Ref
5.87 (3.23–10.7)
0.87 (0.67–1.13)
Ref
<0.001
0.28
P
0.27
0.009
Multivariable analysis
aHR (95% CI)
P
1.00 (0.97–1.03)
0.98
0.71 (0.51–0.99)
0.04
Ref, reference.
TABLE 4 Univariable and multivariable Cox regression analyses of factors providing the risk of ACM for each clinical factor
Clinical factor
Age at diagnosis, years (continuous)
Log PSA, ng/mL (continuous)
Gleason score:
8
9–10
Race:
Black or Other
White
AJCC T-stage
T2
T3, T4
Treatment:
Curative (surgery or RT)
Non-curative
Year of diagnosis (continuous)
Number of men
(n = 685)
685
685
Number of events
(n = 109)
109
109
Univariable analysis
HR (95% CI)
1.06 (1.03–1.08)
0.86 (0.67–1.10)
P
<0.001
0.22
Multivariable analysis
aHR (95% CI)
P
1.03 (1.01–1.06)
0.006
0.90 (0.69–1.17)
0.42
383
302
36
73
1.00 Ref
2.73 (1.83–4.07)
Ref
<0.001
1.00 Ref
2.05 (1.36–3.09)
Ref
<0.001
114
571
15
94
1.00 Ref
1.32 (0.76–2.27)
Ref
0.32
1.00 Ref
1.41 (0.81–2.45)
Ref
0.22
479
206
66
43
1.00 Ref
1.54 (1.05–2.25)
Ref
0.029
1.00 Ref
2.11 (1.38–3.25)
Ref
<0.001
553
132
685
59
50
109
1.00 Ref
4.36 (2.99–6.36)
0.77 (0.63–0.95)
Ref
<0.001
0.01
1.00 Ref
3.74 (2.39–5.87)
0.84 (0.69–1.04)
Ref
<0.001
0.10
Ref, reference.
(55%) from prostate cancer. Men with
locally advanced compared with clinically
localised disease on DRE (T3, T4 vs T2) had a
statistically significant increased risk of
PCSM (aHR 3.59, 95% CI 2.07–6.24, P <
0.001) and ACM (aHR 2.50, 95% CI
1.61–3.88, P < 0.001).
©
2012 BJU INTERNATIONAL
DISCUSSION
Whether DRE alone has the ability to
decrease the risk of PCSM by providing
earlier detection of high-grade prostate
cancer, when the PSA level is <2.5 ng/mL,
remains unknown. In the present study,
using population-based data, we found that
men most likely to be diagnosed with
high-grade, PSA-occult, clinically palpable
prostate cancer were older and of White
race. We also found that the detection of
prostate cancer while locally advanced as
compared with clinically localised was
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HATTANGADI ET AL.
FIG. 1. Cumulative incidence estimates of PCSM
stratified by clinically localised (T2) or locally
advanced (T3, T4) prostate cancer as per DRE
(Gray’s k-mean test, P < 0.001).
50
PCSM, %
T3, 4
T2
40 P < 0.001
30
20
10
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Time after diagnosis, years
206 202 195 175 136 103 79 59 41 18
479 471 458 393 305 248 195 154 106 57
Number at Risk
FIG. 2. Kaplan–Meier estimates of ACM stratified
by clinically localised (T2) or locally advanced
(T3, T4) prostate cancer as per DRE (log-rank test,
P = 0.027).
50
ACM, %
T3, 4
T2
40 P = 0.027
30
20
10
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Time after diagnosis, years
206 202 195 175 136 103 79 59 41 18
479 471 458 393 305 248 195 154 106 57
Number at Risk
associated with a three-fold increase in risk
of PCSM and a two-fold increase in risk of
ACM. The clinical significance of these
findings are that DRE as a screening tool
may have the ability to decrease both PCSM
and ACM particularly in men of older age
and White race, whom have a higher
likelihood of harbouring high-grade prostate
cancer despite a normal PSA level.
Several points require further consideration.
First, it is well-established in the published
literature that testosterone levels are lower
among White than Black men, and that
testosterone levels decline with advancing
age for the vast majority of men [22,23]. In
addition, basal testosterone levels and PSA
1640
levels are highly correlated [24–26].
Therefore, it is not unexpected that
PSA-occult, high-grade, clinically palpable
prostate cancers were most likely to be
diagnosed in White, elderly men. Given that
DRE results may affect survival in older
Caucasian men with low PSA levels, this
may support the idea of annual DRE in
healthy men even beyond the age of 70
years, when screening for prostate cancer is
more controversial [12].
Second, a declining PSA level was associated
with a significantly increased risk of PCSM
in the present cohort. This correlation
between low serum PSA levels and
high-grade prostate cancer has been shown
in other studies [18,27,28], and may reflect
the decrease in PSA production due to
hypogonadism [29] or from dedifferentiated
high-grade prostate cancer cells [30]. The
biological mechanism to explain this later
phenomenon remains unclear. As patients
with high-grade tumours may produce less
PSA per gram of tumour [18], this subset of
men may benefit from earlier detection with
a DRE than what PSA can afford.
There are several potential limitations to the
present study. First, the study cohort
comprised <1% of men with non-metastatic
prostate cancer within the SEER database in
the study period. So, while a survival benefit
may be attained through the use of DRE in
the present cohort, the absolute number of
men is small. However, death rates from
prostate cancer in the present cohort were
substantial, particularly in men detected late
with locally advanced (3-year PCSM 15.8%)
as compared with localised prostate cancer
(5.9%), respectively. Therefore, while the
absolute numbers of men who may benefit
are small, the potential impact of early
detection is large. Second, the median
follow-up was relatively short, at <3 years.
But given the aggressive nature of disease
in the subset of patients with PSA-occult,
high-grade, clinically palpable prostate
cancer, a survival benefit was seen in men
diagnosed when their cancer was still
clinically localised. Third, Gleason scores
based on biopsies may differ from those
after RP, with possible upgrading and
downgrading. To address this, we
additionally analysed the subset of men who
did not undergo RP, thus their Gleason
scores were based only on biopsy specimens.
Among this subset of men, locally advanced
compared with clinically localised prostate
cancer on DRE (T3, T4 vs T2) was still
associated with a significantly higher risk of
PCSM and ACM. Finally, the present study is
retrospective and does not systematically
validate the use of DRE in the study cohort
but provides evidence of a significant
association between early detection based
on the DRE and a reduction in risk of PCSM.
In conclusion, despite the potential
limitations, it appears that the detection of
prostate cancer when it is clinically localised
as compared with locally advanced, among
men with high-grade PSA-occult disease,
may result in a survival benefit. These
findings highlight the potential importance
of DRE for the small but identifiable cohort
of aging White men with declining
testosterone levels where PSA lacks clinical
utility.
ACKNOWLEDGMENTS
Dr Leon Sun, Surveillance Research Program,
National Cancer Institute, Bethesda, MD,
USA.
CONFLICT OF INTEREST
None declared.
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DRE DETECTED HIGH-GRADE PROSTATE CANCER AND THE RISK OF DEATH
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Correspondence: Jona Hattangadi, Brigham
and Women’s Hospital, Department of
Radiation Oncology, 75 Francis St, L-2 Level,
Boston, MA 02215, USA.
e-mail: [email protected]
Abbreviations: ACM, all-cause mortality;
AJCC, American Joint Committee on Cancer;
(a)HR, (adjusted) hazard ratio; IQR,
interquartile range; (a)OR, (adjusted) odds
ratio; PCSM, prostate cancer-specific
mortality; RP, radical prostatectomy;
SEER, Surveillance, Epidemiology, and End
Results.
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