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vol. 12, No. 6, November/December
Society of Andrology
Response
Testosterone
Hyperplasia
NELSON
From
of Prostate
Volume,
Prostate-Specific
to Flutamide
in Men with Benign
N. STONE
AND
the Department
Tulane
1991
University
SANDA
of Urology,
Medical
Sinai
New
School
Orleans,
of Medicine,
ndrogen
therapy
has been
tients with benign
prostatic
directed
at shrinking
the enlarged
deprivation
hyperplasia
prostate
used
investigations
have
luteinizing
hormone-releasing
pounds
or cyproterone
acetate
androgen
deprivation.
what successful,
they
most patients.
This
steroidal
anti-androgen
evaluated
to treat
the effects
obstructive
The relationship
in men with BPH
were someand potency
in
between
prostate
was also investi-
gated.
Materials and Methods
Forty-three
patients with a history of symptomatic
BPH
sidered for entry into a randomized
clinical trial of the
ness of flutamide
for managing
BPH. Inclusion
criteria
This
at the
manuscript
Sixteenth
Correspondence
79-01
Broadway,
is derived
Annual
Meeting
to: Nelson
Room
A4-l,
from a lecture
of the
were
con-
effective-
included
presented on April 30, 1991
American
Society
N. Stone,
MD,
Elmhurst
Elmhurst,
New
York
and
*Cljnjcal
Laboratories,
of Andrology.
Hospital
urinary
symptoms
In addition,
confirmed
the
prostate
by
volumes
conventional
urologic
of all
-
of several
study evaluates
the effect
of the nonflutamide
on prostate
size, and PSA
and testosterone
levels.
volume
and PSA level
York,
patients were
determined
by planimetry
(Johnson
and Johnson
Model 520,
Corometrics,
Wallingford,
CT, 5-mHz
chair-mounted
radial
probe).
Before digital examination
of the prostate,
serum was
obtained
for PSA and testosterone
levels. Blood was drawn and
centrifuged,
and the serum was decanted and frozen at
80#{176}C.
All
specimens
were
analyzed
in one laboratory
(S.C.).
Prostatespecific antigen levels were determined
using a Hybritech#{174}(San
Diego, CA) enzyme
immunoassay,
and testosterone
levels were
determined
using
a solid-phase
iodine125 radioimmunoassay
in
unextracted
serum
based
on a testosterone-specific
antibody
kit
(Diagnostic
Product Corporation,
Los Angeles,
CA; normal range
=
270-1,070
ng/ml).
Patients were allowed to enter the double-blind
study
if they
met the entry criteria,
which included
a residual
urine volume
between
30 and 300 ml, maximum
uroflow
greater than 4 ml!
second but less than 15 mllsecond,
and adequate
performance
status. More details about entry
criteria and preliminary
efficacy
results
have
been previously
reported
(Stone,
1989). Twenty-two
patients (II treated with flutamide
and
11 treated with a placebo)
elected to enter this double-blind,
randomized
trial. All patients
gave their informed
consent.
Any patient with an abnormal
gland determined
by digital examination,
a PSA level greater than 4 ng/ml, or an abnormality
detected
by transrectal
sonography
was offered
prostate
needle
biopsy. All prostate biopsies were performed
transrectally
with a
spring-loaded
18-gauge needle (Biopty#{174},C. R. Bard, Covington,
GA) guided by ultrasound
(Bruel and Kjaer, Marlborough,
MA,
Model 1846 with the 8538 or 8551 probe).
Patients undergoing
biopsy were given an enema the night before and oral fluoroquinexamination.
is
(LHRH)
comfor achieving
While
these compounds
did cause loss of libido
New
Prostate
volume decreased
by 35% and PSA by 65% (P <
0.001)
within
6 months.
These changes
occurred
despite a
58.3% increase
in serum testosterone
levels (P <0.01).
Patients
treated with a placebo
experienced
no significant
changes.
Side
effects
were minimal,
and flutamide
was well tolerated.
These
data suggest
that androgen
deprivation
therapy
with flutamide
may be an effective
and safe treatment
for BPH.
Key words:
Treatment,
benign
prostatic
hyperplasia,
flutamide.
J Androl 1991 ;12:376-380.
pa-
(BPH),
and
gland.
However,
hormone
as a mechanism
York,
study.
minimal
data are available
from controlled
studies
on treatment response
or the effects
of these agents
on prostatespecific
antigen
(PSA)
and serum
testosterone
levels.
Previous
New
Louisiana.
ABSTRACT:
Patients
diagnosed
as having
benign
prostatic
hyperplasia
(BPH)
had determination
of prostate
volume
(PV),
prostate-specific
antigen
(PSA), and serum testosterone
before
consideration
for entry into a double-blind,
randomized
trial of
flutamide
(750 mg/day
for 6 months).
The mean PSA level for
these patients
(N = 43) was 7.6 ng/ml (range:
1.0 to 45.7), and
the mean PV was 76.8 cm3 (range: 24 to 198). Linear regression
analysis
demonstrated
a strong
correlation
between
the two (r
0.876, P <0.05).
Every 10 cm3 of prostate
volume
accounted
for 1.02 ng/ml
of PSA in the serum.
Twenty-two
patients
(11
treated
with flutamide,
11 with a placebo)
agreed
to enter the
A
and
J. CLEJAN*
Mt.
Center,
Antigen,
Prostatic
Center,
11373.
376
Stone and Clejan
Flutamide in Men with BPH
-
377
oline starting the day before and continuing
for 3 days following
biopsy.
A diagnosis
of prostate
cancer excluded
patients
from
entry into the study.
Twenty-two
patients agreed to participate
in the clinical
trial.
Biopsies
were done on 12; no evidence
of prostate
cancer was
found in any of these patients.
At the start of the study, patients
were given flutamide
tablets (250 mg/tid) or placebo tablets (250
mg/rid).
Drugs were administered
in a double-blind
fashion.
Patients were reevaluated
after 3 months by transrectal
ultrasound,
uroflowmetry,
and symptom
improvement.
Responders
were permitted to continue
drug treatment
for 3 more months. All patients
were taken off medication
after 6 months, and reevaluated
6 weeks
later. Patient follow-up
consisted
of serial measurements
of prostate volume,
and PSA and testosterone
levels. Correlations
were
determined
using linear regression
analysis and determination
of
significance
by one- or two-tailed
student’s
t test.
D
30
Results
y
a
Forty-three
men
with
an average
age of 68 years
51-84)
met the criteria
for entry
PSA level for these patients
was
45.7),
=
and
the mean
24-198).
Linear
strong
correlation
scribed
(r
prostate
prostate
P
PSA
0.05,
<
volume,
Fig
there
was
level
prostate
-3.2013
=
1.02
cm3
ng PSA
(range
a
de-
+ 0. 14024
PV
per
10 cm3
0
=
of 101 cm3 (range
=
54-198
cm3)
3 1-136
cm3, mean decrease
35%,
P
PSA
decreased
ng/ml
(range
during
from
=
the 6 months
prostate
volume
ng/mI,
volume
and PSA
level
=
between
taking
1.9-42)
=
65%,
There
was
4.6
ng/ml)
in the
in prostate
flutamide
PV
+ 0.858
(r
=
for every
19% decrease
10% decrease
in prostate
Serum
testosterone
Initially,
there
or placebo-treated
months,
the
crease
elevated
group
was
taking
(range
androgen
levels
=
was
also
flutamide
=
was
0.058,
was
Fig
to baseline
and
Lin=
3). Thus,
a corresponding
<
the fluafter
6
a rise
(range
a mean
0.01).
levels
VOLUME
(cc)
FiG. 1. Comparison
of prostate volume with prostate-specific
antigen (PSA) in men with benign prostatic
hyperplasia.
Every 10 cm3
of prostate accounts
for 1.02 ng/ml of (PSA).
after termination
of flutamide
therapy.
Despite
increased
testosterone
levels,
androgen
inhibition
was maintained
while
on flutamide,
as evidenced
by decreasing
prostate
and PSA values
(Fig
The patients
experienced
in
=
4).
minimal
toxicity
while
on flu-
tamide.
One (9%) suffered
diarrhea,
necessitating
the cessation
of therapy
for 2 weeks.
This patient
was restarted
(without
breaking
the blind) and slowly
brought
back to full
therapy
over
other episode.
comastia
in these
ng!dl
for
PROSTATE
size
between
%PSA
experienced
P
placebo
found.
determined
of 336
400-732)
9%-lll%,
returned
in
size
no difference
between
patients.
However,
levels
from
a mean
to 518 ng/dl (range
=
of 58.3%
P
in PSA, there
volume.
level
patients.
tamidetestosterone
250-597)
0.587,
200
0.001)
<
no change
ear regression
analysis
demonstrated
a correlation
these two variables,
described
by the equation:
0.522
to 3.8
P
73.5 cm3, post-treatment
level (initial
level
=
5.3
=
the decrease
in the patients
to 66 cm3 (range
0.001).
Serum
(range
150
ml of serum.
<
decrease
of treatment.
post-treatment
levels
ng/ml
mean
volume
(initial
=
73.4 cm3)
group (Fig 2).
A relationship
PSA
10.7
0.5-16,
100
50
of
In this group of patients,
11 men took 750 mg of flutamide per day for a minimum
of 6 months,
and 11 men took
a placebo
for 3 months.
Prostate
volume
decreased
from a
mean
3.201
U
size,
for every
.
=
demonstrated
and
1). Thus,
was
76.8
analysis
PSA
by the equation:
0.876,
=
volume
0.140x
0.876
p e 0.05
0
0
into the study.
The mean
7.6 ng/ml (range
=
1.0-
regression
between
(range
-
-
10
2 weeks.
He completed
Four patients
(36%)
that resolved
completely
patient
(9%) noted a mild decrease
complained
of decreased
libido.
the study without
anexhibited
minor
gyneat study
termination.
in potency;
One
no patients
Discussion
in-
These
6 weeks
Prostatic
treated
enlargement
is probably
the most common
by the urologist,
and makes
up the bulk
disease
of most
Journal of Andrology
378
% Of Baseline
November/December
.
1991
Value
FIG.
2. Decrease
in prostate
volume
antigen
(PSA) in patients (N = 11) with benign prostatic
hyperplasia who took flutamide for 6 months.
Prostate
size decreased
from a mean of
101 cm3 (range:
54 to 198) to 66 cm3
(range: 31 to 136 cm3), resulting
in a mean
decrease
of 35% (P < 0.001).
PSA decreased from a mean of 10.7 ng/ml (range:
1.9 to 42) to 3.8 ng/ml (range: 0.5 to 16),
resulting
in a mean decrease
of 65% (P <
0.001).
and prostate-specific
2
1
3
4
5
6
Months on flutamide
urologic
performed
practices.
Upward
of 400,000
prostatectomies
each year in the United
States,
with a direct
of over
one billion
Surgical
leading
treatment
reimbursement
fey,
1990).
surgical
currently
dollars
per year
of prostatic
enlargement
paid by Medicare
It is no wonder
that
alternatives
to the
under
investigation.
Medical
dynamic
Decrease
(Holtgrewe
therapy
for
or the static
in muscular
1988).
is the second
(Carter
and Cof-
several
surgical
standard
and
non-
prostatectomy
are
BPH
strives
to reduce
either
the
of the obstructing
tissue.
first studied
by Caine with
the use of phenoxybenzamine,
and more
with the selective
alpha receptor
blocker
Reduction
accomplished
recently
terazosin
of the static component
by androgen
deprivation
cause
White
prostate
noted
deprivation
gland
several
therapy
shrinkage
positive
has
long
been
known
in men with BPH.
responses
following
vation
therapy
administration
tency.
Peters
and Walsh,
oral anti-androgen
finasteride
have
more
and
Caine first reported
BPH (Caine,
1986).
attractive
the
minimal
effects
of the
on
on the use of flutamide
A dose of 350 mg/day
ease
was
was
no objective
some
po-
for managing
was used for a
report
improvement
in
urine symptoms.
The current
study demonstrated
that flutamide,
when given for 6 months
at a dose of 750 mg/day,
resulted
in a mean decrease
in prostate
size of 35%.
Prostate-specific
antigen
is a single-chain
glycoprotein
localized
to prostatic
(Killian
et al,
et al, 1981).
Several
relationship
between
in patients
who
epithelial
1985;
cells
Liedtke
lining
and
study,
Babian
(1987).
acini
1984;
reports
have sought
to quantitate
PSA and BPH. Stamey
measured
underwent
open
prostatectomy
and
and
Nadji
the
PSA
trans-
of the prostate
(TURP)
for BPH.
Using
he found 0.29 ng/ml per gram of tissue for
and measured
et a!, 1989).
(Babian
et al,
gram
of tissue
from
BPH
for
with
PSA levels before
and after therThe mean initial prostate
volume
of 87.6 g and the mean
initial
serum
ng/ml compares
favorably
to the current
also found a direct relationship
between
tate volume
the
Batjer,
leuprolide,
apy (Levine
of oral
and
there
there
to
Cabot and
orchiec-
libido
size,
the open procedure,
and 0.31 ng/ml per
TURP
(Stamey
et al, 1987).
Levine
et al treated
12 men suffering
1987).
The introducflutamide
and the 5-a
made androgen
depri-
because
Although
in prostate
of
tomy for enlarged
prostates
(Cabot,
1896; White,
1895).
More recently,
the use of chemical
castration
with LHRH
agonists
has exhibited
similar
results
(Bosch
et a!, 1989;
Gabrilove,
1987;
tion of the potent
reductase
inhibitor
of 3 months.
on changes
urethral
resection
the Yang assay,
by Lepor
(Caine,
therapy.
Androgen
period
ducts
component
tone was
1986; Lepor,
1990).
obstruction
has been
et al,
are
cost
1990).
The
PSA level of 11.5
study.
Babian
et al
PSA level and prosdata
from
the current
as well as the data reported
by Levine
et al and
et al, differ
from those
reported
by Stamey
et al
The work by Stamey
et a! relied on resected
tissue,
and took no consideration
of either
unresected
BPH or remaining
peripheral
zone tissue.
Our data, which
reflect
an
in vivo determination
of the relationship
between
the prostate
and PSA, suggest
a 10:1
The fact that this correlation
ratio between
is not perfect
these
has
two.
been pre-
Stone and Clejan
-
Flutamide in Men with BPH
379
70
0
60
50
%dPV
%dPSA
U
_-_
C
a
0
40
U
I-
a
IU
a
C
a
0
y = 0.522x
=
+
0.858
0.587
p = 0.058
20
FL UT AMIDE
0
TIME
weeksl
0
FIG. 4. Percent
10
1 00
90
specific
treated
antigen
change
in serum
(%dPSA),
with flutamide
and
testosterone
prostate
for 6 months
(%dT),
volume
prostate-
(%dPV)
and no treatment
in men
for 6 weeks
(P
<0.05).
PSA
%
Thus,
for every
19% decrease
in serum
a corresponding
10% decrease
in prostate
FIG. 3. Correlation
of percent change in prostate
volume
(PV)
and prostate-specific
antigen (PSA) in men treated with flutamide
for
6 months.
For every 19% decrease
in PSA, there was a corresponding
10%
decrease
in
PV.
For
example,
volume
expect
of
a patient
100
a 10 cm3
cm3
presenting
and
a PSA
decrease
with
level
viously
reported
treated
with
a correlation
ithelial
and
culties
(Weber
et a!,
1989).
Seven
the LHRH
nafarelin
acetate
was found.
Morphometric
stromal
content
highlighted
in trying
to use
PSA
levels
patients
were
for 6 months,
and
analysis
of the epsome of the diffi-
as a marker
for
BPH.
Despite
this evidence,
the potential
exits for using
levels to monitor
the success
of androgen
deprivation
PSA
ther-
amounts
of epithelium
larly evident
are far from
and
in the current
the line (Fig
an initial
of
in prostate
ng/ml drop in serum PSA. However,
formula
still needs to be determined
stroma
study,
3).
PSA, there was
volume
(Fig 3).
size
for
present.
as some
This
this.
Six months
of
enough
for complete
therapy
blockade.
with flutamide
Conversely,
can be successfully
The
decreasing
ished
PSA
gland
shrinkage
levels,
monitored
prostate
by serial
size correlated
and allowed
by calculating
of the therapy
PSA
measurements.
well
with
for the estimation
the percent
of PSA
the diminof prostate
decrease.
points
may not be
it is possible
control
(Weber
et a!, 1989).
treatment,
some patients
still
that the effectiveness
1.9
Prostate-specific
antigen
levels did not decrease
to zero
in all patients.
There
are several
possible
explanations
for
1972).
suggest
would
is particu-
of the data
that flutamide,
although
a potent
anti-androgen,
totally abolish
androgen
activity.
Weber et a! also
that PSA expression
may not be completely
under
data
every
the exact utility of this
because
of the variable
apy for BPH.
The current
study used flutamide,
a nonsteroidal
anti-androgen
that competes
with dihydrostestosterone (DHT)
for cytosol
androgen
receptor
sites (Neri et al,
Our
prostate
10 ng/ml
Despite
produced
does not
suggested
androgen
6 months
of LHRH
PSA, as evidenced
by serum
measurements
and immunohistochemical
staining. However,
that study did not control
for adrenal
androgens, which may have contributed
to androgen
expression.
Journal of Andrology
380
Gabrilove
Evidence
for minimal
androgen
activity
and PSA expression was recently
reported
by Geller
(Geller,
1990).
Obviously,
more data are needed
to resolve
this issue.
Initial studies
with
cancer
raised
concerns
rum
testosterone
tive
blockade
flutamide
because
levels
in the
overcoming
androgen
Binding
of flutamide
hypothalamus
leads
receptor
the
(Neri
of high
(HeIlman
et a!, 1979;
rent study,
treatment
Poyet
with
testosterone
Heilman
use
65%
and prostate
levels will further
of flutamide,
and
whether
volume
increase
such
promise
successful
treatment,
still need
In summary,
this study demonstrates
to be studied.
a relationship
tween
with
PSA
and
prostate
size
in patients
BPH.
Role
Frotscje
HA,
Evans
RB.
correlation
specific
clinical
antigen
application.
and
J Clin
Lab
Ri,
Griffiths
nign
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size
and
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AT.
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urodynamic
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by androgen
parameters.
question
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J Urol.
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The
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Information:
the United
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an irnmu-
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op-
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