Serum PSA Concentration Is Powerfull Predictor of Acute Urinary Retension and Need For Surgery in Men With BPH
Serum PSA Concentration Is Powerfull Predictor of Acute Urinary Retension and Need For Surgery in Men With BPH
Serum PSA Concentration Is Powerfull Predictor of Acute Urinary Retension and Need For Surgery in Men With BPH
CME ARTICLE
ABSTRACT
Objectives. Prostate-specific antigen (PSA) is produced exclusively in the prostate gland and is currently the
most useful clinical marker for the detection of prostate cancer. In this report, we examine whether serum
PSA is also a predictor of important benign prostatic hyperplasia (BPH)-related outcomes, acute urinary
retention (AUR), and the need for BPH-related surgery.
Methods. Three thousand forty men were treated with either placebo or finasteride in a double-blind,
randomized study of 4-year duration. Serum PSA was measured at baseline, and baseline prostate volume
was measured in a 10% subset of 312 men. Probabilities and cumulative incidences of AUR and BPH-related
surgery, as well as reduction in risk of events with finasteride, were calculated for the entire patient
population, stratified by treatment assignment, baseline serum PSA, and prostate volume.
Results. The risk of either needing BPH-related surgery or developing AUR ranged from 8.9% to 22.0%
during the 4 years in placebo-treated patients stratified by increasing prostate volume and from 7.8% to
19.9% when stratified by increasing serum PSA. In comparison with symptom scores, flow rates, and
residual urine volume, receiver operating characteristic curve analyses showed that serum PSA and prostate
volume were the most powerful predictors of spontaneous AUR in placebo-treated patients (area under the
curve 0.70 and 0.81, respectively). Finasteride treatment reduced the relative risk of needing surgery or
developing AUR by 50% to 74% and by 43% to 60% when stratified by increasing prostate volume and
serum PSA, respectively.
Conclusions. Serum PSA and prostate volume are powerful predictors of the risk of AUR and the need for
BPH-related surgery in men with BPH. Knowledge of baseline serum PSA and/or prostate volume are useful
tools to aid physicians and decision makers in predicting the risk of BPH-related outcomes and choosing
therapy for BPH. UROLOGY 53: 473480, 1999. 1999, Elsevier Science Inc. All rights reserved.
lar-epithelial hyperplasia can be found in approximately 60% of men in their 60s, and 80% of men in
their 80s. Although not all these men require treat-
Medical Center, Boston, Massachusetts; Case Western Reserve University, Cleveland, Ohio; Department of Medicine, Mercy Hospital
and Medical Center, San Diego, California; and Departments of Biostatistics and Clinical Research, Endocrinology and Metabolism,
Merck Research Laboratories, Rahway, New Jersey
Reprint requests: Claus G. Roehrborn, M.D., Department of Urology, University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Boulevard, J8-130, Dallas, TX 75235-9110
Submitted: October 13, 1998, accepted (with revisions): November 10, 1998
0090-4295/99/$20.00
PII S0090-4295(98)00654-2 473
STUDY DESIGN
The study was approved by the institutional review boards
at all 95 participating centers, and all men gave written informed consent. After a 1-month single-blind placebo lead-in,
men were randomly assigned to receive placebo or 5 mg of
finasteride (Proscar, Merck and Co., Inc., West Point, Pa)
daily. Symptoms, bothersomeness, adverse events, and urinary flow rates were assessed every 4 months.8 Serum PSA was
measured every 4 months in the first year and then every 8
months at a central laboratory. Physical examination and routine hematologic and serum chemistry tests were performed
yearly. Magnetic resonance imaging was performed at baseline
and then yearly in a subset of participants at 13 centers (n 5
312). All magnetic resonance images were read by a central
radiologist unaware of the treatment allocation and time of
imaging (ie, base line or follow-up). Additional details on
study design have previously been described.8
AUR and surgery for BPH were predefined secondary end
points. An Endpoint Committee, whose members were unaware of the treatment assignment, reviewed all documentation relating to episodes of AUR and all prostate surgeries for
BPH, excluding surgery for prostate cancer. The Endpoint
Committee classified episodes of AUR as spontaneous versus
precipitated (when contributing factors such as a cerebrovascular accident, urinary tract infection, surgery, anesthesia, and
ingestion of alpha-sympathomimetic drugs or anticholinergics were identified).
Complete data on outcomes, including 4-year follow-up
information for men who had discontinued treatment, were
available for 92% of the men randomized. In the other 8%,
complete information was available until discontinuation of
the medication or up to the 6-month follow-up assessment
after discontinuation.
STATISTICAL ANALYSIS
The effect of baseline prostate volume and serum PSA on the
risk of a BPH-related outcome (developing AUR and need for
BPH-related surgery) were assessed by dividing patients into
tertiles of baseline prostate volume and baseline serum PSA
and calculating the risk of developing an outcome by lifetable, time-to-first event analysis, and Fishers exact test for
UROLOGY 53 (3), 1999
TABLE I.
Parameter
Age (yr)
Quasi-AUA symptom score*
Peak flow rate (mL/s)
Prostate volume (mL)
First tertile (1441)
Second tertile (4257)
Third tertile (58150)
Serum PSA (ng/mL)
First tertile (0.21.3)
Second tertile (1.43.2)
Third tertile (3.312.0)
Finasteride
Mean 6 SD
6
6
6
6
6
6
6
6
6
6
6
1503
1503
1196
155
45
60
50
1498
511
514
473
64
15
11
55
32
49
81
2.8
0.9
2.2
5.4
7
6
4
26
6
5
29
2.1
0.3
0.6
1.7
Mean 6 SD
6
6
6
6
6
6
6
6
6
6
6
1513
1513
1208
157
59
44
54
1512
472
536
504
64
15
11
54
33
47
82
2.8
0.8
2.2
5.4
6
6
4
25
6
5
22
2.1
0.3
0.6
1.7
Prostate volume was only measured in approximately 10% of patients in 13 of the participating centers.
RESULTS
At baseline, men assigned to finasteride and placebo were similar in terms of age, demographics,
symptom severity, peak flow rate, prostate volume,
and serum PSA (Table I). Baseline characteristics
of the subset with prostate volume measurements
were similar to those in the entire study group.
The overall incidence of AUR was 7% with placebo and 4% with finasteride (spontaneous AUR
4% with placebo and 1% with finasteride; precipitated AUR 3% with placebo and 2% with finasteride) and of BPH-related surgery, 10% in men
taking placebo and 5% in men taking finasteride.8
The incidence of AUR or surgery increased from
8.9% to 22.0% from the first to the third tertile of
baseline prostate volume for placebo-treated patients; it remained relatively stable between 5.1%
and 5.6% for finasteride-treated patients (Fig. 1A).
As a result, the risk reduction with finasteride increased from 50% in the smallest to 74% in the
largest prostate volume tertile. When stratified by
UROLOGY 53 (3), 1999
FIGURE 1. Four-year incidences of either AUR or BPHrelated surgery in patients treated with placebo or finasteride, stratified in tertiles by (A) baseline prostate
volume (subset of 10% of patients) or (B) baseline serum PSA. Arrows denote reduction in risk by the logrank test. One placebo patient had a prostate volume
of 222.
Figure 2 displays Kaplan-Meier curves for the incidence of AUR or surgery for patients treated with
placebo or finasteride, stratified by baseline PSA.
Patients in the lowest tertile of serum PSA (0.0 to
1.3 ng/mL) had the lowest risk of either one of the
events, and the benefit of finasteride over placebo is
minimal for the first 2 years. In this tertile, the overall 4-year relative risk for finasteride- versus placebo-treated patients is 0.57 (95% confidence interval
[CI] 0.35 to 0.95), with a 43% risk reduction (P 5
0.030; Fig. 2A). For patients in the second tertile
(serum PSA between 1.4 and 3.2 ng/mL), the 4-year
476
tate volume in men with BPH10 has led us to consider that PSA may also predict those men at
increased risk of developing AUR or needing BPHrelated surgery.
In the longitudinal community-based Olmsted
County study,3 it had been shown that men with
prostate volumes greater than 30 mL by transrectal
ultrasound had almost four times the odds of exUROLOGY 53 (3), 1999
periencing AUR compared with those with prostate volumes less than 30 mL. The tertile analysis
(Fig. 1) presented here demonstrates a very strong
relationship between baseline prostate volume and
serum PSA in predicting the incidence of BPH-related surgery or AUR during 4 years. The significant
increase in the risk of experiencing these complications with placebo treatment is nearly completely obliterated with finasteride treatment. This
phenomenon leads to a greater benefit of finasteride over placebo in men with either larger prostate volumes or higher baseline PSA in avoiding
these complications. About 1 of 5 patients in the
highest tertiles are likely to experience either AUR
or surgery for BPH, and the risk reduction with
finasteride treatment is 74% (based on prostate
volume) and 60% (based on serum PSA).
A second important question for clinicians is
whether the risk increases over time of observation. In fact, in placebo-treated patients, the cumulative risk increases in a linear fashion for all three
serum PSA tertiles (Fig. 2). With the exception of
the lowest PSA tertile, where there is no apparent
benefit of finasteride over placebo in the first 2
years (Fig. 2A), the difference in risk between
treatment groups in the two higher tertiles (greater
than 1.3 ng/mL) becomes evident as early as the
first follow-up visit at 4 months (Figs. 2B and C).
Physicians may have different thresholds regarding their use of preventive healthcare measures.
Figure 3 provides a graphic assessment to aid in
this decision. The cumulative incidence of spontaneous AUR for placebo-treated patients increases
dramatically with serum PSA levels above approximately 1.3 ng/mL. In fact, although the cumulative risk for all patients is approximately 4% or 1 in
25 men in 4 years, it reaches 9% or nearly 1 in 10
patients for those with a PSA greater than 4.0
ng/mL at baseline (Fig. 3A). At the same time, the
risk remains unchanged for the entire serum PSA
spectrum for finasteride-treated patients. Similar
observations hold true for the cumulative risk of
both spontaneous and precipitated AUR and BPHrelated surgery (Figs. 3B and C).
The ROC curve analyses show a trend toward a
reduction in the predictive power of many baseline
parameters with finasteride therapy when compared with placebo. This is not unexpected as therapy with finasteride significantly interferes with
the natural history of the disease process. For
spontaneous AUR, the purest outcome in terms of
being the least likely to be influenced by either the
patient or physician, both prostate volume (AUC
0.81) and serum PSA (AUC 0.70) are the most
powerful predictors in the placebo-treated patients
(Fig. 4C). That serum PSA and prostate volume are
both similarly significant predictors of outcomes is
477
TABLE II. Area under the curve 6 standard error values for ROC
curves for several baseline parameters for spontaneous acute
urinary retention and prostate-related surgery
Parameter
Spontaneous AUR
Serum PSA
Prostate volume
Peak flow rate
Residual urine volume
Quasi-AUA symptom score
Bothersomeness score
Age
Surgery
Serum PSA
Prostate volume
Peak flow rate
Residual urine volume
Quasi-AUA symptom score
Bothersomeness score
Age
Finasteride
Placebo
P Value*
0.53
0.67
0.67
0.46
0.49
0.47
0.57
6
6
6
6
6
6
6
0.06
0.04
0.06
0.07
0.06
0.07
0.06
0.70
0.81
0.62
0.56
0.55
0.58
0.53
6
6
6
6
6
6
6
0.03
0.11
0.04
0.04
0.04
0.04
0.04
0.012
0.665
0.510
0.224
0.440
0.168
0.562
0.59
0.49
0.59
0.52
0.60
0.55
0.60
6
6
6
6
6
6
6
0.03
0.09
0.04
0.03
0.03
0.03
0.03
0.62
0.63
0.57
0.60
0.59
0.60
0.57
6
6
6
6
6
6
6
0.02
0.08
0.03
0.02
0.02
0.02
0.03
0.461
0.213
0.692
0.046
0.761
0.197
0.507
KEY: ROC 5 receiver operating characteristic; AUR 5 acute urinary retention; PSA 5 prostate-specific antigen; QuasiAUA 5 adaptation of American Urological Association symptom score.
* Represents the between-group P value.
disease by shrinking the prostate gland and preventing further measurable growth. In fact, to
make predictions about the risk of surgery and/or
AUR once treatment is initiated is less important
than to be able to give patients and healthcare providers information before a treatment decision regarding possible future BPH-related outcomes.
Several limitations of our study need to be recognized. First, even though it is the longest BPH trial
ever conducted, in the lifespan of a patient with
BPH it still covers only a fraction of the entire duration during which the patient is at risk. Extrapolations of the data over extended periods have to be
undertaken with great caution. Second, all patients
in this study had to have an enlarged prostate by
DRE at baseline to be eligible for participation. Despite the stratification by PSA levels and the strong
clinical correlation between serum PSA and prostate volume, we cannot state with certainty that
similar results would be obtained in a cohort of
men not selected for enlarged prostate glands.
Prostate volume and serum PSA are good candidate parameters to aid in the individualized discussion that takes place between patients and physicians
before initiation of therapy for BPH. Finasteride
decreases the risk of developing a BPH-related outcome by approximately half in all subgroups examined. However, the absolute risk of having an outcome is substantially different across the different
levels of PSA and prostate volume. Risk is viewed
differently by patients, physicians, and administrators. The data provided in this report should be
helpful to all parties involved in the decision of
UROLOGY 53 (3), 1999
FIGURE 4. ROC curve analyses for the ability of baseline serum PSA to predict (A) the need for BPH-related
surgery, (B) both spontaneous or precipitated AUR, and
(C) spontaneous AUR only for patients treated with
placebo or finasteride.
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APPENDIX
The PLESS Study Group includes (in alphabetical order):
A. Aigen, P. Albertsen, R. Anderson, G. Andriole, S. Auerbach,
M. Bamberger, J. Bannow, W. Barzell, D. Bergner, J. Bonilla,
R. B. Bracken, W. Brannan, W. Bremner, T. Brown, R. Bruskewitz, R. Castellanos, S. Childs, K. S. Coffield, T. Cook, C. Cox,
E. D. Crawford, B. Dalkin, R. W. deVere White, G. Drach,
H. Epstein, C. Ercole, D. Falcone, D. Finnerty, W. Fitch,
M. Flanagan, J. Fowler, H. Fuselier, D. Garvin, J. Geller,
R. Gibbons, P. Gilhooly, M. Gittelman, S. Glickman, J.
Gottesman, T. Gray, J. Grayhack, H. Guess, L. Harrison, W.
Hellstrom, R. Herlihy, G. B. Hodge, Jr., H. L. Holtgrewe, R.
Huben, P. Hudson, C. L. Jackson, E. Johnson, D. Kadmon,
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480