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For Our Fathers
|
J.
Brantley Thrasher1, Jeoffrey
Deeths2, Charles Bennett3, Padmini Iyer4, Martin K. Dineen5,
Suoping Zhai6, William D. Figg7 and David G. McLeod8
1Section
of Urology, University of Kansas Medical Center, Kansas
City, Kansas; 2Nebraska Clinical Research
Center, Omaha, Nebraska; 3Division of Hematology/Oncology,
Northwestern University, Chicago, Illinois; 4Section
of Hematology/Oncology, Long Beach VA Medical Center,
Long Beach, California; 5Atlantic Urological
Association; 6,7National Institute of Health,
Bethesda, Maryland, 8Walter Reed Army Medical
Center, Washington, DC.
Welcome
to the Prostate Cancer Education Council's Article
Series: 2000 website.
Below
is the sixth in a series of six articles written
by a select panel of distinguished urologists
from across the nation. A new article will appear
each month and address topics related to advancements
in prostate cancer treatment, research, and prevention.
Informative sidebars will accompany each segment,
along with highlighted technical vocabulary hyperlinked
to a prostate cancer glossary,
creating an easily digestible format for consumers.
The
series is presented on behalf of the Prostate
Cancer Education Council (PCEC). Founded in 1988,
the PCEC is a consortium of physicians, health
educators, scientists, and patient advocates dedicated
to increasing prostate cancer awareness and knowledge.
This
article is provided by Dr. J. Brantley Thrasher,
William L. Valk Distinguished Professor and Chairman
of the Section of Urology at the University of
Kansas Medical Center in Kansas City, Kansas.
He is also the current Co-Director of the operating
room at the University of Kansas.
Dr.
Thrasher is a member of the Executive Board of
the Society of Urologic Oncology, a member of
the American Joint Committee on Cancer as a representative
of the Society of Urologic Oncology, and a consultant
to the American Urologic Association's Public
Media Committee. He is also a member of numerous
subspecialty societies, including the American
Urologic Association, the American College of
Surgeons, the Society for Basic Urologic Research,
and the Society of University Urologists.
Dr.
Thrasher completed a fellowship in his sub-specialty
of expertise, Urologic Oncology, at Duke University.
He has published numerous manuscripts covering
multiple urologic cancers and his basic urologic
research is centered on growth factors and the
regulation of prostate cancer growth. Dr. Thrasher
is also a principal investigator or collaborator
in several ongoing clinical oncology trials.
ABSTRACT
Background:
We performed a prospective randomized trial to compare
the efficacy and toxicity of a new dose (500 mg QD)
of flutamide
(FLT)
to the currently recommended dose (250 mg q8h)
in the treatment of advanced prostate cancer. Primary
endpoints used for comparisons were percent of patients
normalizing PSA,
time to normalization and percent changes from baseline.
Secondary endpoints were quality of life (QOL) and toxicity
differences.
Methods: From July 1995
to October 1999, 440 men aged 46-94 years (mean 71 years)
were randomized to receive either 500 mg QD
FLT
or 250 mg q8h
+ medical or surgical castration for 3 months. Patients
were included with confirmed M1
disease, documented PSA
recurrence, ECOG
status 0-2, PSA
>0.2 ng/mL,
no second neoplasm, no LFTs
>1.5x normal and no previous treatment. Laboratory values,
toxicity and QOL were evaluated at weeks 0, 4, 8 and
12 with bone scans evaluated at screening and week 12.
Pharmacokinetic
data were collected from 30 men at 7:00 AM prior to
their first dose of medication. Serum flutamide
and 2-hydroxyflutamide levels were measured and compared
between the two groups.
Results: Two hundred
twenty-five patients were randomized to the 500 mg QD
arm and 215 to the 250 mg q8h
arm. No differences were noted in mean age, race, severity
of disease, baseline PSA
level, or ECOG
status between the two groups. PSA
changes were not significantly different, 71% of the
500 mg patients and 75% of the 250 mg normalized their
PSA
by week 12 and percent change was 89% and 96%, respectively.
The treatment groups were not significantly different
with respect to incidence of adverse events with 71%
vs 68% in the 500 mg and 250 mg arm, respectively (p=0.337).
The mean post-dosing sample
size (sample obtained just prior to next dose) was 11
hours for the 250 mg q8h
dosing regimen and 25.7 hours for the 500 QD
dosing regimen. The mean plasma concentration of 2-hydroxyflutamide
for the 250 mg q8h
dose (0.88 µg/mL)
was higher than that for the 500 mg QD
dose (0.41 µg/mL).
Conclusions: Five hundred
mg of FLT
when combined with castration appears to be equally
effective in lowering serum PSA
and is not significantly more toxic than conventional
FLT
dosing. The use of 500 mg QD
instead of the standard 250 mg q8h
would result in a cost savings of 30%.
INTRODUCTION
| |
|
A
single 500 mg dose of flutamide may
result in a longer half-life of the
drug, though comparative dosing studies
have not been performed.
The
biological half-life of flutamide
and its active metabolite 2-hydroxyflutamide
may be very different than the serum
of these agents.
Patients
are only 40% compliant with a thrice-daily
dosing schedule of any drug, but are
83% compliant with BID and 90% compliant
with QD dosing.
The
objective of this trial was to compare
two doses of flutamide based on PSA
response with secondary endpoints
of quality-of-life and toxicity differences.
|
|
|
The
original pharmacokinetics
studies performed in humans on oral flutamide
and its active metabolite
2-hydroxyflutamide suggested that the elimination half-life
of 2-hydroxyflutamide was 4 to 6.6 hours and 8 to 22 hours
after a single oral dose of 250 and 500 mgs of flutamide,
respectively, in patients with prostate cancer.1
Although this early study suggested that a single 500
mg dose of flutamide
may result in a longer half-life
of the drug, comparative dosing studies have not been
performed. More recent data from animal studies suggests
that the biological half-life
of flutamide
and its active metabolite
2-hydroxyflutamide may be quite different than the serum
half-life
of these agents. In rats, the prostate continues to respond
to a dose of flutamide
for up to 96 hours.2
Furthermore, data from geriatric volunteers suggests that
patients are only 40% compliant with a thrice daily dosing
schedule of any drug but are 83% compliant with BID
and 90% compliant with QD
dosing.
This
data led to the development of a prospective randomized
trial comparing the efficacy and toxicity of a new dose
(500 mg QD)
of flutamide
to the currently recommended dose, 250 mg q8h,
in the treatment of advanced prostate cancer. The objective
of this trial was to compare two doses of flutamide
based on PSA
response with secondary endpoints of quality-of-life
and toxicity differences.
MATERIALS
AND METHODS
| |
|
From
mid 1995 to late 1999, 440 men with
an average age of 71 years were randomized
to receive either 500 mg QD FLT or
250 mg q8h + medical or surgical castration
for 3 months.
Patients
excluded from this trial included
those with hepatic or renal disease,
known hypersensitivity to drugs, metastatic
prostate cancer to the CNS or evidence
of spinal cord compression.
|
|
|
From
July 1995 to October 1999, 440 men aged 46-94 years (mean
71 years) were randomized to receive either 500 mg QD
of flutamide
or 250 mg q8h
plus medical or surgical castration for three months.
Patients were required to be >40 years of age with
de novo M+
or N+
prostate cancer or stage
T1-T4 with biochemical evidence of progression defined
as a PSA
>0.5 ng/mL
(for baseline PSA
< 2 ng/mL,
3 serial PSA
elevations a minimum of two weeks apart after nadir
had been reached; for baseline PSA
>2 ng/mL,
2 serial PSA
elevations a minimum of two weeks apart after nadir
had been reached) following definitive therapy (radical
prostatectomy or radiation therapy). All patients
were required to have a life expectancy of at least one
year, an ECOG
performance status of 0-2, no prior treatment for metastatic
prostate cancer, able to read and understand English,
and able to give informed consent. Patients were excluded
from the trial with hepatic
or renal
disease, known hypersensitivity to study drugs, metastatic
prostate cancer to the CNS
or evidence of spinal cord compression, LFTs
> 1.5x normal, creatinine
> 2 x normal, WBC
< 3000 cells/mm3, hematocrit
<30%, platelet
count <100,000 mm3, any other active
malignancy except nonmelanomatous skin cancer, any other
investigational drug used within 30 days of the screening
visit, or finasteride
within two weeks of the screening visit. Follow-up
visits were performed at weeks 0, 4, 8 and 12 (Table
I).
Pharmacokinetics
Data
| |
|
Pharmacokinetics
testing was done on a subpopulation
of patients from Madigan Army Medical
Center and Walter Reed Army Medical
Center.
|
|
|
Pharmacokinetics
testing was done on a small subpopulation of patients
who agreed to participate from two institutions, Madigan
Army Medical Center and Walter Reed Army Medical Center.
A total of 30 patients gave informed consent for serum
samples at 7:00 AM prior to their first morning dose.
2-hydroxyflutamide plasma concentrations were then determined
by high performance liquid
chromatography using a modification of a published
method.3
In brief, 3 ml methylene chloride were added to 0.5 cc
of plasma and vortexed for 60 seconds. The samples were
centrifuged at 3,000 rpm for 15 minutes at 4oC.
The aqueous phase was removed and the organic layer decanted
into glass tubes and evaporated to dryness under nitrogen.
The sample was reconstituted with 200 µl
mobile phase and vortexed. One hundred and fifty microliters
was injected into a Water C18 uBondapak column. The mobile
phase was methanol:water 60:40 (v/v) with a flow rate
of 1 ml/min. 2-hydroxyflutamide had a eluting time of
4 min and was detected using ultraviolet absorbance at
280 nm. The peak area was used for quantification against
an external standard of 2-hydroxyflutamide in methanol.
The assay has a lower limit of detection of 0.03 µg/mL.
Statistical
Methods
| |
|
All
between-group comparisons used two-tailed
test procedures; the groups were compared
with respect to age, baseline PSA
and baseline quality of life measurements
using Analysis of Variance and with
respect to race (% of Caucasian patients)
and baseline PSA (% of patients with
normal PSA) using Cochran-Mantel-Haenszel
tests.
Percent
of patients with normal PSA, change
from baseline PSA, percent change
from baseline PSA, general quality
of life, and urinary quality of life
were each measured at weeks 4, 8,
and 12.
|
|
|
All
between-group comparisons used two-tailed test procedures,
with a 0.05 level of significance (a=0.05) to test a null
hypothesis of no difference between the treatment groups
(500 QD,
250 q8h).
The groups were compared with respect to age, baseline
PSA
and baseline quality of life measurements using Analysis
of Variance and with respect to race (% Caucasian patients)
and baseline PSA
(% of patients with normal PSA)
using Cochran-Mantel-Haenszel
tests. The following efficacy endpoints were measured
at weeks 4, 8 and 12:
- percent of patients with normal PSA
- change from baseline PSA
- percent change from baseline PSA
- general quality of life
- urinary quality of life
Cochran-Mantel-Haenszel
tests were used for the analyses of percent of patients
with normal PSA.
Wilcoxon rank sum tests were used for the analyses of
change and percent change from baseline PSA.
Analysis of Variance was used to compare the treatment
groups with respect to quality-of-life measurements.
RESULTS
| |
|
When
225 patients were randomized to the
500 mg QD arm and 215 to the 250 mg
q8h arm, no differences were noted
in the mean age, race, severity of
disease, baseline PSA level, or ECOG
status between the two groups.
One-hundred-ninety-one
patients in the 500 mg QD arm and
197 in the 250 mg q8h arm had complete
information and were available for
comparison at the end of the study.
The
treatment groups were not substantially
different with respect to incidence
of adverse events, which were categorized
as possibly, probably, or definitely
related to study drug with 71% reporting
at least one event in the 500 mg arm
and 68% reporting at least one event
in the 250 mg arm (p=0.337).
|
|
|
Two
hundred and twenty-five patients were randomized to the
500 mg QD
arm and 215 to the 250 mg q8h
arm. One hundred and ninety-one patients in the 500 mg
QD
arm and 197 in the 250 mg q8h
arm had complete information and were available for comparison
at the end of the study. The list of reasons for patients
who were excluded from the analysis (including patients
who withdrew from the trial with no PSA
information and patients who had missing PSA
information at baseline) is outlined
in Table II. The majority of laboratory
abnormalities were mild elevation of transaminases
while the toxicities were primarily diarrhea. No differences
were noted in the mean age, race, ECOG
performance status, severity of disease or baseline PSA
levels between the two groups
(Table III). PSA
changes were not significantly different, 71% of the 500
mg patients and 75% of the 250 mg normalized their PSA
by week 12 and percent change was
89% and 96%, respectively (Table IV).
The treatment groups were not significantly different
with respect to the incidence of adverse events, which
were categorized as possibly, probably, or definitely
related to the study drug with 71% reporting at least
one event in the 500 mg arm and 68% reporting at least
one event in the 250 mg arm (p=0.337)
(Table V). No significant differences
were noted between the two groups with regard to any of
the QOL domains.
Pharmacokinetics
| |
|
The
mean post-dosing sample size (sample
obtained just prior to next dose)
was 11 hours for the 250 mg q8h dosing
regimen and 25.7 hours for the 500
QD dosing regimen.
|
|
|
The
minimum steady-state plasma concentrations
of 2-hydroxyflutamide for 30 patients are listed in Table
VI. The mean post-dosing sampling time (sample obtained
just prior to next dose) was 11 hours for the 250 mg q8h
dose level and 25.7 hours for the 500 mg QD
dose level. The mean plasma concentration of 2-hydroxyflutamide
for the 250 mg q8h
dose level (0.88 ug/ml) was higher than that for the 500
mg QD
dose level (0.41 µg/mL).
DISCUSSION
| |
|
Heretofore,
there have been no studies comparing
variable doses of FLT for advanced
prostate cancer.
When
combined with castration, 500 mg of
FLT appears to be equally effective
in lowering serum PSA and is not much
more toxic than conventional FLT dosing.
The
reduction of cost associated with
500 mg QD dosing vs. 250 mg q8h is
significant; the use of four capsules
per day vs. six per day reduces the
cost by 30%.
|
|
|
Heretofore,
there have been no studies comparing variable doses of
FLT
for advanced prostate cancer. Recent animal data suggesting
the biological half-life
of the drug may be quite different than the serum half-life
led to the development of this trial. Our data suggests
500 mg QD
of FLT
combined with castration is equally effective in lowering
serum PSA
when compared to conventional FLT
dosing. Previous studies have brought into question the
use of PSA
as a surrogate endpoint primarily because PSA
differences were noted between comparison arms early in
the trial but this did not equate to differences in survival.4
Our data revealed no significant differences between comparison
groups in PSA
changes and, thus, we would not expect differences in
survival after long-term follow-up. However, only long-term
follow-up will definitely answer the question. Equally
important in this trial was the question of differences
in toxicities with 500 mg QD
FLT
compared to conventional dosing. We found no significant
differences between the two groups relative to toxicities.
Diarrhea was slightly more common in the 500 mg QD
arm at 18% compared with 14% in the 250 mg q8h
arm, although the difference was not significant. However,
these data may shed some light on the etiology of diarrhea
in patients receiving flutamide.
Our study suggests the diarrhea is due to peak serum levels
of the drug since the 500 mg QD
patients experienced a higher incidence of the side effect.
Finally, a significant benefit of 500 mg QD
dosing vs 250 mg q8h
is a reduction in cost. The use of 4 capsules per day
vs 6 capsules reduces the cost by 30%. This would make
flutamide
used in combination therapy the least expensive nonsteroidal
antiandrogen
presently available in the United States.
ACKNOWLEDGMENTS
- Mitchell
C. Benson, M.D., Columbia Presbyterian Medical Center
- L.
Dean Knoll, M.D., Center for Urological Treatment
and Research
- Roy
Berger, M.D., North Shore Hematology-Oncology Associates
PC
- Nabil
Bissada, M.D., Professor of Urology, MUSC, Hollings
Cancer Center
- Stanley
Brosman, M.D., Santa Monica Urological Group
- Seck
Chan, M.D., Pan Pacific Research
- Robert
Feldman, M.D., Urology Specialists, PC
- John
Forrest, M.D., Urologic Specialists of Oklahoma Research
Center
- Wallace
Gibbons, M.D., Wenatchee Valley Clinic
- Marc
Gittelman, M.D., South Florida Medical Research
- Michael
D. Bagg, M.D., William Beaumont Army Medical Center
- Perry
B. Hudson, M.D., Department of Veterans Affairs -
Bay Pines, FL
- James
Roberts, M.D., San Diego Navy Medical Center
- Thomas
Keane, M.D., Emory Clinic-Winship Cancer Center
- Alee
S. Koo, M.D., Western Clinical Research, Inc.
- Leo
Kusuda, M.D. (P.I.), Portsmouth Naval Medical Center
- James
McMurray, M.D., Medical Affiliated Research Center
- Glen
Mills, M.D., LSU Medical Center
- Bill
See, M.D., University of Iowa Hospitals and Clinics
- Douglas
Soderdahl, M.D., Eisenhower Army Medical Center
- Christopher
Steidle, M.D., Northcast Indiana Urology
- Martha
Terris, M.D., Palo Alto Veterans Administration Health
Care System
Please
address all correspondence to:
J. Brantley Thrasher, M.D.
Valk Professor and Chairman
Section of Urology
University of Kansas Medical Center
3901 Rainbow Boulevard
Kansas City, KS 66160-7390
Phone (913) 588-6152
Fax (913) 588-7625
E-mail bthrasher@kumc.edu
REFERENCES
- Schulz
M, Schmoldt A, Donn F, Becker H. The
pharmacokinetics of flutamide and its major metabolites
after a single oral dose and during chronic treatment.
Eur J Clin Pharmacol. 1988;34(6):633-36.
- Personal
communication - F. Labrie.
- Asade
RH, Prizont L, Muino JP, Tessler J. Steady-state
hydroxyflutamide plasma levels after the administration
of two dosage forms of flutamide. Cancer Chemother
Pharmacol. 1991;27(5):401-405.
- Eisenberger
MA, Blumenstein BA, Crawford ED, et al. Bilateral
orchiectomy with or without flutamide for metastatic
prostate cancer. N Eng J Med. 1998;339(15):1036-42.
| Table
I. Study Calendar (back to
article) |
| |
Screening* |
Time 0** |
Wk4 |
Wk 8 |
Wk
12 |
| Physical |
|
|
|
|
|
| History/physical/neuro
exam |
|
|
|
|
|
| Weight,
vital signs |
x |
x |
x |
x |
x |
| ECOG
performance rating |
|
|
|
|
|
| Bone
pain scale |
|
x |
x |
x |
x |
| Toxicity
notation |
|
x |
x |
x |
x |
| |
|
|
|
|
|
| Laboratory/Tests |
|
|
|
|
|
| CBC |
x |
x |
x |
x |
x |
| Creatinine |
x |
x |
x |
x |
x |
| SGOT/SGPT/bilirubin |
x |
x |
x |
x |
x |
| Alkaline
phosphatase |
|
x |
|
|
x |
| PSA |
x |
x |
x |
x |
x |
| Serum
testosterone |
|
x |
|
|
x |
| Bone
scans |
x |
|
|
|
x |
| |
|
|
|
|
|
| Quality
of Life! |
|
|
|
|
|
| Patient |
|
x |
x |
x |
x |
| |
|
*Pre-study |
| **Point
at which treatment is initiated, is considered (Time
0) |
|
! HR-QOL questionnaire - EORTC instrument |
| Table
II: List of Reasons for Discontinuation* and Missing
PSA Values at Baseline
(back to article) |
| Reason |
500
QD
(n=34) |
250
q8h
(n=18) |
| Discontinuation* |
26 |
8 |
| AE:
lab abnormality |
4 |
3 |
| AE:
toxicity |
3 |
1 |
| AE:
other |
9 |
1 |
| Disease
progression |
1 |
0 |
| Failure
to return |
2 |
0 |
| Protocol
violation |
2 |
2 |
| Other |
5 |
1 |
| Missing
PSA information at Baseline |
8 |
10 |
|
*No PSA information |
| Table
III. Demographic and Disease Characteristics
(back to article) |
| Characteristic |
500
QD>
(n=225) |
250
q8h
(n=215) |
p-value |
| Age |
|
|
0.342 |
| Mean
+ S.D |
71.5+8.14 |
70.7+7.94 |
|
| Median |
72 |
71 |
|
| Range |
48-89 |
46-94 |
|
| |
| Race |
|
|
0.512 |
| Caucasian |
156
(69.3%) |
154
(71.6%) |
|
| Black |
54 (24.0%) |
50 (23.3%) |
|
| Asian |
6 (2.7%) |
3 (1.4%) |
|
| Hispanic |
8 (3.6%) |
5 (2.3%) |
|
| Other |
1 (0.4%) |
3 (1.4%) |
|
| |
| ECOG
Performance Status |
|
|
0.938 |
| Missing |
0 (0.0%) |
1 (0.5%) |
|
| Normal
activity |
139
(61.8%) |
132
(61.4%) |
|
| Light
work |
65 (28.9%) |
62 (28.8%) |
|
| No
work |
21 ( 9.3%) |
20 ( 9.3 %) |
|
| Table
IV: Percent Change from Baseline PSA (back
to article) |
| Week |
500
QD |
250
q8h |
p-value |
| |
|
|
|
| Week
4 |
(n=203) |
(n=197) |
|
| Mean
+ S.D. |
-85.3
+ 26.3 |
-86.9
+ 25.4 |
0.278 |
| Median |
-93.0 |
-94.0 |
|
| Range |
(-100,89) |
(-100,134) |
|
| |
|
|
|
| Week
8 |
(n=191) |
(n=189) |
|
| Mean
+ S.D. |
-91.1
+ 26.7 |
-94.5
+ 15.4 |
0.200 |
| Median |
-98.0 |
-98.0 |
|
| Range |
(-100,129) |
(-100,44) |
|
| |
|
|
|
| Week
12 |
(n=191) |
(n=197) |
|
| Mean
+ S.D. |
-88.9
+ 40.6 |
-95.7+13.1 |
0.092 |
| Median |
-99.0 |
-99.0 |
|
| Range |
(-100,219) |
(-100,35) |
|
| Table
V. Incidence of Adverse Events
(back to article) |
| Adverse
Event |
500
QD
(n=225) |
250
q8h
(n=215) |
p-value |
| Hot
flushes |
78
(34.7%) |
78
(36.3%) |
0.737 |
| Diarrhea |
41
(18.2%) |
31
(14.4%) |
0.245 |
| Anemia |
20
( 8.9%) |
20
( 9.3%) |
0.949 |
| Nausea |
17
( 7.6%) |
21
( 9.8%) |
0.444 |
| SGOT
increased |
20
( 8.9%) |
17
( 7.9%) |
0.772 |
| Fatigue |
11
( 4.9%) |
18
( 8.4%) |
0.108 |
| Constipation |
10
( 4.4%) |
7 ( 3.3%) |
0.494 |
| Vomiting |
8 ( 3.6%) |
9 ( 4.2%) |
0.614 |
| Pain |
10
( 4.4%) |
3 ( 1.4%) |
0.053 |
| Urinary
tract infection |
5 ( 2.2%) |
8 ( 3.7%) |
0.353 |
| Bone
pain |
7 ( 3.1%) |
6 ( 2.8%) |
0.848 |
| Insomnia |
4 ( 1.8%) |
7 ( 3.3%) |
0.380 |
| Dizziness |
7 ( 3.1%) |
3 ( 1.4%) |
0.206 |
| Table
VI. Pharmacokinetics Data for a Subset of 30 Patients
(back
to article) |
| Dose |
Number |
Postdose(h) |
Conc.(ng/ml) |
Dose |
Number |
Postdose(h) |
Conc.(ng/ml) |
|
|
|
|
|
|
|
|
|
| 250
mg QD |
|
|
|
500
mg QD |
|
|
|
| (n=14) |
38013 |
10.5 |
1642 |
(n=16) |
38016 |
25.5 |
214 |
| |
38014 |
11.75 |
237 |
|
38019 |
20.75 |
574 |
| |
38017 |
9.25 |
835 |
|
38023 |
24.75 |
261 |
| |
38018 |
6.73 |
907 |
|
38024 |
27 |
1596 |
| |
38021 |
9.5 |
1169 |
|
38025 |
25.66 |
448 |
| |
38026 |
12.5 |
1200 |
|
38028 |
-- |
449 |
| |
38027 |
21.25 |
741 |
|
3871 |
24.25 |
172 |
| |
38029 |
11.25 |
1088 |
|
3875 |
26.33 |
405 |
| |
3869 |
9 |
790 |
|
38001 |
27.7 |
173 |
| |
3867 |
10 |
283 |
|
38002 |
26 |
152 |
| |
38004 |
10.75 |
405 |
|
38003 |
26.58 |
752 |
| |
38005 |
12.25 |
873 |
|
38007 |
25.67 |
155 |
| |
38008 |
9.92 |
1237 |
|
38006 |
|
