Comparison
of percent free prostate specific
antigen and prostate specific antigen density as
methods to enhance prostate specific antigen
specificity in early prostate cancer detection in
men with normal rectal examination and
prostate specific antigen between 4.1 and
10 ng/ml
Morote J, Raventos CX, Lorente JA, LopezPacios MA,
Encabo G, deTorres I, Andreu J Journal of
Urology, 1997, Vol 158, Iss2, pp 502-504
Univ Autonoma Barcelona, Vall Dhebron Hosp,
Dept Urol, E-08193 Barcelona, SPAIN
Purpose: We analyzed the behavior of prostate
specific antigen (PSA) density and percent free PSA
to enhance the specificity of PSA in the early
diagnosis of prostate cancer in men with normal
digital rectal examination and PSA serum level
between 4.1 and 10 ng./ml. Materials and Methods: PSA
serum level, PSA density and percent free PSA were
analyzed in 74 men with normal digital rectal
examination and PSA serum level between 4.1 and 10
ng./ml. All men underwent systematic prostate biopsy,
and the diagnosis was benign prostate hyperplasia in
52 and prostate cancer in 22. Furthermore, we
determined the decrease in unnecessary biopsies and
the cancer detection rate using 0.10 versus 0.15 as
cut points for PSA density, and 20 versus 25 as cut
points for percent free PSA. Results: In patients
with benign prostatic hyperplasia and prostate
cancer, respectively, the median PSA level was 6.7
and 7.0 ng./ml. (p > 0.05), median prostate volume
was 50 and 37 cc (p < 0.04), median PSA density
was 0.14 and 0.19 (p < 0.007) and median percent
free PSA was 18.9 and 10.1 (p < 0.005). Using PSA
density cut points of 0.15 and 0.10, the decrease in
negative biopsies was 53.8 and 36.5% with a
sensitivity of 86.4 and 90.9%, respectively. However,
using percent free PSA cut points of 20 and 25, the
decrease in negative biopsies was 36.5 and 26.9% with
a sensitivity of 77.3 and 95.5%, respectively.
Conclusions: Although both methods could minimize
unnecessary biopsies in men with normal digital
rectal examination and PSA serum level between 4.1
and 10 ng./ml., the percent free PSA was more
cost-effective since transrectal ultrasound was not
required. In this small series of symptomatic
patients a percent free PSA cut point of 25 could
detect at least 95% of prostate cancers and decrease
26.9% of negative biopsies.
Prevalence
and predictors of a positive
repeat transrectal ultrasound guided needle
biopsy of the prostate
NE Fleshner, M O'Sullivan, WR Fair Journal of
Urology, 1997,
Vol 158, Iss 2, pp 505-508
Fleshner NE, Mem Sloan Kettering Canc Ctr,
Urol Serv, New York,NY 10021 USA
Purpose: We determined the prevalence of and risk
factors for carcinoma in patients with 1 previously
negative prostate biopsy. Materials and Methods:
Transrectal ultrasound guided prostate needle
biopsies were repeated in 130 men. Risk factors
analyzed included age, pathological result of initial
biopsy, inter-biopsy interval, prostate specific
antigen (PSA), PSA density, PSA velocity, digital
rectal examination, abnormal transrectal ultrasound
and family history of prostate cancer. Results: A
total of 39 patients (30%) had positive biopsies for
cancer. Univariate analysis revealed that PSA more
than 20 ng./ml. And abnormal transrectal ultrasound
were more frequent in men with positive second
biopsies. Using multivariate logistic regression
analysis only PSA more than 20 ng./ml. Was a
significant risk factor (adjusted odds ratio 4.48,
95% confidence interval 1.02 to 20.1). We determined
the incidence of carcinoma in patients who represent
the lowest risk group as defined by PSA less than 10
ng./ml., PSA density less than 0.15 mg./ml./cm.(3),
PSA velocity less than 0.75, ng./ml. Per year, no
prostatic intraepithelial neoplasia plus negative
transrectal ultrasound, digital rectal examination
and family history. Of 21 patients who fit this
cohort 5 (23.8%) had carcinoma on repeat biopsy.
Conclusions: A significant false-negative rate for
initial transrectal ultrasound guided prostate
biopsies exists. Baseline risk in lowest risk
patients is sufficiently high such that one cannot
define a subset of patients for whom repeat biopsy is
unnecessary. We recommend repeat biopsy in all
patients who meet the criteria for a transrectal
ultrasound guided biopsy and in whom the initial
biopsy is negative.
Accelerated tumor proliferation rates
in
locally recurrent prostate cancer after
radical prostatectomy
JA Connolly, JC Presti, ML Cher, K Chew, K
Shinohara, PR Carroll
Journal of Urology, 1997, Vol 158, Iss 2, pp
515-518
Carroll PR, Univ Calif San Francisco, Dept
Urol, Sch Med, Program Urol Oncol, Mt Zion Canc Ctr,
U-575, San Francisco,CA 94143 USA
Purpose: We compared the growth rates of primary
cancer and prostatic fossa recurrence after radical
prostatectomy. Materials and Methods: Tumor
proliferative rates were studied in 26 patients with
biopsy proved prostatic fossa recurrences after
radical prostatectomy. Proliferation was calculated
in the prostatectomy specimens and in recurrent
cancer using Ki-67 antibody to detect dividing cells.
Results: Mean and median labeling indexes for radical
prostatectomy specimens were 2.96 and 2.51,
respectively. Labeling indexes in locally recurrent
tumors were significantly higher (mean 6.47, median
5.59, p < 0.001). The increase in labeling index
between parent and recurrent tumors was unrelated to
pathological staging at prostatectomy or interval
from radical prostatectomy. Conclusions: Tumors that
recur locally after radical prostatectomy appear to
have a higher proliferative rate compared to parent
tumors.
Improved
survival in patients with locally
advanced prostate cancer treated
with radiotherapy and goserelin
M Bolla, D Gonzalez, P Warde, JB Dubois, RO
Mirimanoff, G Storme, J Bernier, A Kuten, C
Sternberg,
T Gil, L Collette, M Pierart
New England Journal of Medicine, 1997, Vol 337,
Iss 5, pp 295-300
Bolla M, Univ Hosp, Dept Radiotherapy, BP
217,
F-38043 Grenoble 9, FRANCE
Background We conducted a randomized, prospective
trial comparing external irradiation with external
irradiation plus goserelin (an agonist analogue of
gonadotropin-releasing hormone that reduces
testosterone secretion) in patients with locally
advanced prostate cancer. Methods From 1987 to 1995,
415 patients with locally advanced prostate cancer
were randomly assigned to receive radiotherapy alone
or radiotherapy plus immediate treatment with
goserelin. The patients had a median age of 71 years
(range, 51 to 80). Patients in both groups received
50 Gy of radiation to the pelvis over a period of
five weeks and an additional 20 Gy over an additional
two weeks as a prostatic boost. Patients in the
combined-treatment group received 3.6 mg of goserelin
(Zoladex) subcutaneously every four weeks starting on
the first day of irradiation and continuing for three
years; those patients also received cyproterone
acetate (150 mg orally per day) during the first
month of treatment to inhibit the transient rise in
testosterone associated with the administration of
goserelin. Results Data were available for analysis
on 401 patients. The median follow-up was 45 months.
Kaplan-Meier estimates of overall survival at five
years were 79 percent (95 percent confidence
interval, 72 to 86 percent) in the combined-treatment
group and 62 percent (95 percent confidence interval,
52 to 72 percent) in the radiotherapy group
(P=0.001). The proportion of surviving patients who
were free of disease at five years was 85 percent (95
percent confidence interval, 78 to 92 percent) in the
combined-treatment group and 48 percent (95 percent
confidence interval, 38 to 58 percent) in the
radiotherapy group (P<0.001). Conclusions Adjuvant
treatment with goserelin, when started simultaneously
with external irradiation, improves local control and
survival in patients with locally advanced prostate
cancer. (C) 1997, Massachusetts Medical Society.
Prostate
cancer:
Relative effects of demographic,
clinical, histologic, and MR imaging variables
on the accuracy of staging
DJ Getty, SE Seltzer, CMC Tempany, RM Pickett, JA
Swets, BJ McNeil
Radiology, 1997, Vol 204, Iss 2, pp 471-479
Getty DJ, Bbn Syst & Technol Corp,
10 Moulton St, Cambridge,MA 02138 USA
PURPOSE: To determine the effects on the accuracy
of staging prostate gland cancer of diagnostic
prediction rules based on demographic, clinical,
histologic, and magnetic resonance (MR) image
variables. MATERIALS AND METHODS: A total of 200
cases from four medical centers were evaluated by
nine radiologists experienced in MR imaging. The
accuracies of the four diagnostic variables (age,
prostate specific antigen level, Gleason tumor grade,
and MR imaging findings) were measured, both singly
and combined in a particular sequence, by calculating
the area index of the receiver operating
characteristic curve. RESULTS: The accuracy of
staging with single variables (age, 0.58; prostate
specific antigen level, 0.74; Gleason grade 0.73, MR
image findings, 0.74) increased as the variables were
optimally merged. The first two variables combined to
yield an accuracy of 0.74; the first three combined
to yield an accuracy of 0.81; and all four variables
resulted in an accuracy of 0.86. In a clinically
important subset of 69 cases for which antigen level
and Gleason grade together were inconclusive for the
purposes of staging, the addition of MR imaging
findings resulted in an increase in accuracy from
0.55 to 0.73. CONCLUSION: Optimal merging of
diagnostic test results yields an improvement in the
accuracy of prostate cancer staging.
Results of
3D conformal radiotherapy in
the treatment of localized prostate
cancer
N FukunagaJohnson, HM Sandler, PW McLaughlin,
MS Strawderman, KH Grijalva, KE Kish, AS Lichter
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 2, pp 311-317
FukunagaJohnson N, Univ Michigan Hosp,
Dept Radiat Oncol, Ann Arbor,MI 48109 USA
Purpose: 3D conformal radiotherapy (3D CRT) has
been shown to decrease acute morbidity in the
treatment of prostate cancer. Therapeutic outcome and
late morbidity data have been accumulating. To
evaluate the results of 3D CRT for the treatment of
prostate cancer, we analyzed the outcome of a large
series of patients treated with conformal techniques.
Material and Methods: From January 1987 through June
1994, 707 patients with localized prostate cancer
were treated with 3D CRT. Patients with
pathologically-confirmed pelvic lymph node
metastasis, treated with preirradiation (preRT)
androgen ablation, or treated post-prostatectomy were
excluded. All had CT obtained specifically for
treatment planning, multiple structures contoured on
the axial images, and beam's-eye view conformal beams
edited to provide 3D dose coverage. Median follow-up
is 36 mos; 70 patients have been followed longer than
5.5 Sears. Six hundred three had T1-T2 tumors. PreRT
prostate specific antigen (PSA) was available for 649
patients: median preRT PSA was 12.9 ng/ml, 209
patients had preRT PSA > 20 ng/ml. The median dose
of radiation was 69 Gy; 102 patients received greater
than or equal to 69 Gy. Biochemical failure was
defined as: 1) two consecutive PSA rises over 2.0
ng/ml if nadir PSA less than or equal to 2.0 ng/ml,
2) two consecutive PSA rises over nadir if nadir PSA
> 2.0 ng/ml, or 3) initiation of hormonal therapy
after RT. Complications were graded using the RTOG
system. Results: PreRT PSA and Gleason score emerged
as independent indicators of biochemical control
(bNED). Patients with preRT PSA > 10 had a
significantly worse bNED at 5 years than patients
with preRT PSA less than or equal to 10. Five-year
bNED was determined according to preRT PSA: PSA less
than or equal to 4, 88%; PSA > 4 less than or
equal to 10, 72%; PSA > 10 less than or equal to
20, 43%; and PSA > 20, 30%. Patients with Gleason
score greater than or equal to 7 also had a
significantly worse bNED than patients with Gleason
score < 7. Patients were divided into two
prognostic groups: a favorable group with PSA less
than or equal to 10, Gleason score < 7, and T1-T2
tumors, and an unfavorable group with PSA > 10,
Gleason score greater than or equal to 7 or T3-T4
tumors and studied for the effect of dose on bNED
status. The bNED at 5 years was 75% for the favorable
group and 37% for the unfavorable group. In addition,
a group that might be considered a surgical subset
was reviewed: patients with PSA less than or equal to
10, Gleason score less than or equal to 7, and T1-T2
tumors who were <70 years old. This subset had an
84% 5-year bNED rate and 98% 5-year overall survival.
Complications with the techniques used here are very
low: 3% risk at 7 years of Grade 3-4 complications
and 1% risk at 7 years of Grade 3 bladder
complications (no Grade 4). Conclusion: 3D CRT allows
for treatment of prostate cancers with a very low
risk of complications. Patients with relatively early
disease as defined by preRT PSA, Gleason score <
7, and T1-2 tumors and patients who are candidates
for radical prostatectomy have excellent 5-year bNED
rates. Patients with adverse prognostic factors have
a high risk of biochemical recurrence and are
candidates for innovative therapy. (C) 1997 Elsevier
Science Inc.
Induction
of apoptosis and altered
nuclear/cytoplasmic distribution of the
androgen receptor and prostate-specific
antigen by 1 alpha,25-dihydroxyvitamin
D-3 in androgen-responsive LNCaP
cells
TC Hsieh, JM Wu
Biochemical and Biophysical Research
Communications, 1997,
Vol 235, Iss 3, pp 539-544
Wu JM, New York Med Coll, Dept Biochem
Mol Biol, Valhalla,NY 10595 USA
In addition to suppressing prostate cell growth,
vitamin D also up-regulates the expression of
androgen receptor (AR) and prostate-specific antigen
(PSA). To study the mechanism involved in the control
of these proteins, LNCaP cells were treated with 10
nM 1 alpha,25-dihydroxyvitamin D-3 and separated into
cytosol and nuclear fractions. AR and PSA were
analyzed by western blot analysis. A second approach
involved incubating control and treated cells with
[H-3]R1881, fractionating the cells into the
cytosolic and nuclear components, and quantifying the
amount of radioactivity associated with the
respective fractions. Alternatively,
immunohistochemical assays were performed by staining
cells with cognate antibodies for AR and PSA, Both
biochemical and immunohistochemical analyses show
proportionately greater increased presence of AR in
the nucleus, accompanied by relatively reduced AR in
the cytosol, following treatment of LNCaP cells with
vitamin D-3. Surprisingly, PSA was found to be
present in the nuclear fraction in both control and
treated cells. These results suggest that vitamin D-3
promotes the translocation of AR from the cytosol to
the nucleus. The presence of PSA in the nucleus of
LNCaP cells raises the possibility of an autogenous
mode of control of PSA gene expression. (C) 1997
Academic Press.
Effects of
endocrine therapy on the
primary lesion in patients with prostate
carcinoma as evaluated by endorectal
magnetic resonance imaging
Nakashima J.; Imai Y.; Tachibana M.; Baba S.;
Hiramatsu K.; Murai M.
Cancer (USA) , 1997, 80/2 (237-241)
Dr. J. Nakashima, Department of Urology, Keio
University School of Medicine,
35 Shinanomachi, Shinjuku-ku, Tokyo 160 Japan
BACKGROUND. Little effort has been made at the
quantitative and qualitative evaluation of patients
with prostate carcinoma, including downsizing and
downstaging of the primary lesion, after conservative
therapy. The current study was undertaken to
investigate the qualitative and quantitative effects
of endocrine therapy on the primary prostate
carcinoma using magnetic resonance imaging (MRI).
METHODS. The primary prostate carcinoma was evaluated
by endorectal MRI approximately 4 months after the
initiation of endocrine therapy in 48 patients with
histologically confirmed prostate carcinoma detected
by endorectal MRI before therapy. RESULTS. The
volumes of the prostate gland, the carcinoma, and the
noncarcinomatous components were reduced to 60.2 plus
or minus 2.7%, 25.5 plus or minus 2.9%, and 83.2 plus
or minus 6.3% of their pretreatment volumes
respectively after endocrine therapy, indicating that
the tumors are more susceptible to endocrine therapy
than the nontumorous components. The number of
prostate carcinomas that demonstrated low signal
intensity compared with the normal peripheral zone on
T2-weighted images decreased after endocrine therapy
and the number of carcinomas with enhancement of
T1-weighted contrast-enhanced images increased after
therapy. Seven of the 48 patients underwent
downstaging after endocrine therapy, based on the
endorectal MRI evaluation. CONCLUSIONS. The results
of the current study suggest that downsizing and
occasionally downstaging of the carcinoma may occur
after endocrine therapy in patients with prostate
carcinoma. In addition, the androgen sensitivity of
the prostate carcinoma tissue is relatively high
compared with the residual noncancerous prostate
gland.
Ischemic
damage to the prostate
during cardiac surgery: A clinical
model
C Coker, RA Sherwood, T Crayford, F Saadeh,
D Mulvin, E Brakenbury, MJ Coptcoat
Prostate, 1997, Vol 32, Iss 2, pp 85-88
BACKGROUND. To determine if altered tissue
perfusion during cardiac surgery results in ischemic
tissue damage to the prostate, as suggested by a rise
in prostatic-specific antigen (PSA). METHODS.
Twenty-nine male patients undergoing elective
coronary artery bypass grafting were studied. Ten
male patients undergoing elective gastrointestinal
surgery served as controls. PSA levels were
determined preoperatively and six hourly intervals
postoperatively for 48 hr. All patients underwent
urethral catheterization at induction of anesthesia.
RESULTS. All patients (100%) who had undergone
cardiac bypass surgery showed rises in serum PSA
during 48 hr of postoperative follow-up. At the 6-hr
postoperative interval, the mean PSA was
significantly different from the mean baseline value
(paired two tailed Student's t test, P < 0.001) in
27 of the 29 (93%) patients. In contrast, the PSA
values in the 10 gastroenterological controls did not
change at 6 hr (P > 0.2) or during the next 48 hr.
One patient in the cardiac group showed a very marked
elevation in serum PSA of greater than 50 times
normal preoperative levels. CONCLUSIONS.
Statistically significant rises in PSA levels are
seen following coronary bypass surgery. This rise may
be caused by ischemic nontrauma related damage to the
prostate and suggests a possible pathophysiological
mechanism for the clinically episodic symptoms of
prostatism seen in elderly men. (C) 1997 Wiley-Liss,
Inc.
Prostate-specific antigen-detected
prostate cancer (stage T1c): an analysis
of whole-mount prostatectomy
specimens.
Douglas TH; McLeod DG; Mostofi FK;
Mooneyhan R; Connelly R; Moul JW; Sesterhenn IA
Prostate (UNITED STATES) Jun 15 1997, 32 (1)
p59-64,
Department of Surgery, Walter Reed Army Medical
Center,
Washington, DC 20307-5001, USA.
BACKGROUND: Clinical and pathological staging of
prostate cancer has been, and remains, problematic.
Since prostate-specific antigen (PSA)-detected tumors
are often discerned during "screening," what are
their significance? METHODS: We analyzed 67
consecutive patients with stage T1c prostate cancer
undergoing radical prostatectomy at our institution
from August 1, 1991-September 12, 1995, and who had
whole-mount specimen processing. Diagnosis was
determined in all cases by transrectal
ultrasound-guided biopsy. RESULTS: The mean age of
our patients was 63 years, and the mean PSA at time
of diagnosis was 8.6 ng/ml (median, 7.2 ng/ml). There
was organ-confined cancer in 31/67 (46%) patients;
17/67 (25%) had periprostatic fat infiltration, and
of these 5(7%) had seminal vesicle involvement.
Thirty-one of 67 (46%) had positive surgical margins.
Twenty-two (33%) had a Gleason sum of > or = 7 in
the final pathological specimen. Insignificant tumors
(dominant tumor volume < 0.20 cc) were found in
only 4 cases. Smaller tumors were more likely to be
found when the PSA was < 10 ng/ml. Multifocal
disease was found in 64/67 (96%) prostate specimens.
CONCLUSIONS: This study adds impetus to the growing
realization that nonpalpable prostate cancer,
detected because of elevated PSA, is rarely
insignificant. Our findings add further emphasis to
the fact that patients diagnosed by PSA elevation
have, for the most part, significant cancer that
should be treated aggressively.
Early
stage prostate cancer treated
with radiation therapy:
Stratifying an intermediate risk
group
JP Lattanzi, AL Hanlon, GE Hanks
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 3, pp 569-573
Lattanzi JP, Fox Chase Canc Ctr, Dept Radiat
Oncol,
7701 Burholme Ave, Philadelphia,PA 19111 USA
Purpose: This study identifies two early prostate
cancer populations within the T1/T2AB, Gleason 2-7,
pretreatment prostate specific antigen (PSA) 4-15
ng/ml grouping. By demonstrating different outcomes
we may be able to more appropriately select a
subgroup for whom adjuvant therapy trials or altered
treatment techniques are indicated. Materials and
Methods: One hundred forty-six patients with T1/T2AB,
Gleason score 2-7, PSA 4-15 ng/ml prostate cancer
were treated with external beam radiotherapy alone
from November 1987 to October 1993. The median
pretreatment PSA was 8.6 and the mean 8.7. Minimum
follow-up was 2 years with a median of 38 months
(mean 42 months, range 24-87). The median age was 70
years (range 58-83) and the median central axis dose
delivered was 7240 cGy (mean 7273, range 6541-7895
cGy). Eleven patients received conventional
radiotherapy while 135 were treated using conformal
techniques. As there is evidence that a low PSA nadir
is an early marker for long term biochemical control,
time to post treatment PSA < 1 ng/ml was
actuarially analyzed by Gleason score, pretreatment
PSA, radiation dose, stage, and the presence of
perineural invasion. Pretreatment PSA was the only
patient characteristic predictive of achieving a PSA
level < 1.0 ng/ml. Biochemical relapse free (bNED)
control (non rising PSA) was then compared for
patients above and below the approximate median
pretreatment PSA level of 8 ng/ml. BNED control rates
and the time to PSA <1.0 ng/ml were estimated
using Kaplan-Meier methodology, and differences in
bNED control and PSA <1.0 ng/ml according to PSA
level were evaluated using the log-rank test.
Results: Results from actuarial analysis revealed
that pretreatment PSA was the only significant
variable predictive of a PSA <1.0 ng/ml.
Ninety-eight percent of patients with pretreatment
PSA <8 achieved a PSA level <1.0 ng/ml within 3
years compared to 78% for patients with a PSA >8
ng/ml (p = 0.0003). BNED control for the two groups
separated at a pretreatment PSA of 8 ng/ml confirms a
favorable outcome, 88% bNED control at 5 years for
<8 ng/ml and 74% for a pretreatment PSA greater
than or equal to 8 ng/ml (p = 0.007 for overall curve
comparison). Conclusion: For early prostate cancer
patients (T1/T2AB, Gleason 2-7, pretreatment PSA
4-15) there is a significant break in bNED control
following external beam radiation at a pretreatment
PSA level of 8 ng/ml. Patients with pretreatment PSA
<8 have a very favorable bNED response with
radiation alone while those with a pretreatment PSA
8-15 have a significant decrease in bNED response.
The 27% failure rate at 5 years in the PSA 8-15 ng/ml
patients may justify altered treatment techniques or
clinical trials of adjuvant androgen deprivation in
this group. (C) 1997 Elsevier Science Inc.
Enhancement of prostate tumor volume
definition with intravesical contrast:
A three-dimensional dosimetric
evaluation
R Sharma, M Duclos, PJ Chuba, F Shamsa, JD
Forman
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 3, pp 575-582
prostate cancer; intravesical contrast;
three-dimensional treatment planning
Pergamon-Elsevier Science Ltd,
The Boulevard, Langford Lane, Kidlington, Oxford,
England OX5 1GB
Purpose: To assess the impact of intravesical
contrast during computed tomography (CT) simulation
on prostate tumor volume definition and dose
distribution. Methods and Materials: Sixteen patients
with localized adenocarcinoma of the prostate
underwent CT-based virtual simulation in preparation
for definitive radiotherapy, Patients were
immobilized with a foam cradle and an initial CT was
performed after oral but without intravesical
contrast (noncontrast scan), A second scan was
performed following administration of intravesical
contrast (contrast scan), Beam apertures were
designed on the noncontrast scans and digitized into
the contrast scan file, Beam apertures were also
designed on the contrast scans, Isodose plans were
generated for several beam apertures and
arrangements. Results: There was enhanced
visualization of the prostate at the cephalad portion
of the field for 15 of the 16 cases, The mean
differences between the noncontrast and contrast
volumes was significant (p = 0.0001), The mean
percent underdosage to the prostate ranged from 3.9%
to 18.6%, depending upon the target volume and beam
arrangement. Conclusion: This study demonstrates the
necessity of using intravesical contrast for defining
the location of the prostate during CT simulation,
The underestimation of the extent of the prostate
when omitting intravesical contrast leads to
significant underdosage, The value of intravesical
contrast is most evident when small (prostate only)
conformal fields are used. (C) 1997 Elsevier Science
Inc.
Arachidonic acid stimulates prostate
cancer
cell growth: Critical role of
5-lipoxygenase
J Ghosh, CE Myers
Biochemical and Biophysical Research
Communications,
1997 Vol 235, Iss 2, pp 418-423
Ghosh J, Univ Virginia, Ctr Canc, POB 334,
Charlottesville,VA 22908 USA
Arachidonic acid (5,8,11,14-eicosatetraenoic
acid), a member of the omega-g poly-unsaturated fatty
acids, was found to be an effective stimulator of
human prostate cancer cell growth in vitro at
micromolar concentrations, Selective blockade of the
different metabolic pathways of arachidonic acid
(e.g. Ibuprofen for cyclooxygenase, SKF-525A for
cytochrome P-450, baicalein and BHPP for
12-lipoxygenase, AA861 and MK886 for 5-lipoxygenase,
etc.) revealed that the growth stimulatory effect of
arachidonic acid is inhibited by the 5-lipoxygenase
specific inhibitors, AA861 and MK886, but not by
others. Addition of the eicosatetraenoid products of
5-lipoxygenase (5-HETEs) showed stimulation of
prostate cancer cell growth similar to that of
arachidonic acid, whereas the leukotrienes were
ineffective, Moreover, the 5-series of
eicosatetraenoids could reverse the growth inhibitory
effect of MK886. Finally, prostate cancer cells fed
with arachidonic acid showed a dramatic increase in
the production of 5-HETEs which is effectively
blocked by MK886. These experimental observations
suggest that arachidonic acid needs to be metabolized
through the 5-lipoxygenase pathway to produce 5-HETE
series of eicosatetraenoids for its growth
stimulatory effects on human prostate cancer cells.
(C) 1997 Academic Press.
Induction of cyclo-oxygenase-2 mRNA
by
prostaglandin E-2 in human prostatic carcinoma
cells.
Tjandrawinata RR, Dahiya R, HughesFulford M
Br J Cancer 1997 APR;75(8):1111-1118
HughesFulford M, Vet Affairs Med Ctr, Lab Cell
Growth 151F,
4150 Clement St, San Francisco,CA 94121 USA
Prostaglandins are synthesized from arachidonic
acid by the enzyme cyclo-oxygenase. There are two
isoforms of cyclo-oxygenases: COX-I (a constitutive
form) and COX-2 (an inducible form). COX-2 has
recently been categorized as an immediate-early gene
and is associated with cellular growth and
differentiation. The purpose of this study was to
investigate the effects of exogenous
dimethylprostaglandin E-2 (dmPGE(2)) on prostate
cancer cell growth. Results of these experiments
demonstrate that administration of dmPGE(2) to
growing PC-3 cells significantly increased cellular
proliferation (as measured by the cell number), total
DNA content and endogenous PGE(2) concentration.
DmPGE(2) also increased the steady-state mRNA levels
of its own inducible synthesizing enzyme, COX-2, as
well as cellular growth to levels similar to those
seen with fetal calf serum and phorbol ester. The
same results were observed in other human cancer cell
types, such as the androgen-dependent LNCaP cells,
breast cancer MDA-MB-134 cells and human colorectal
carcinoma DiFi cells. In PC-3 cells, the dmPGE(2)
regulation of the COX-2 mRNA levels was both time
dependent, with maximum stimulation seen 2 h after
addition, and dose dependent on dmPGE(2)
concentration, with maximum stimulation seen at 5 mu
g ml(-1). The non- steroidal anti-inflammatory drug
flurbiprofen (5 mu M), in the presence of exogenous
dmPGE(2), inhibited the up- regulation of COX-2 mRNA
and PC-3 cell growth. Taken together, these data
suggest that PGE(2) has a specific role in the
maintenance of human cancer cell growth and that the
activation of COX-2 expression depends primarily upon
newly synthesized PGE(2), perhaps resulting from
changes in local cellular PGE(2) concentrations.
Mitoxantrone: A review of its
pharmacology
and clinical efficacy in the management of
hormone-resistant advanced prostate
cancer.
Wiseman LR, Spencer CM
Drug Aging 1997 JUN;10(6):473-485LA - English
Wiseman LR, Adis Int Ltd, 41 Centorian Dr,
Private Bag 65901, Auckland 10, NEW ZEALAND
The antineoplastic agent mitoxantrone in
combination with a corticosteroid (either prednisone
or hydrocortisone) hasshown clinical efficacy as
palliative treatment for a proportion of patients
(about 35 to 40%) with hormone-resistant advanced
prostate cancer; a disease which predominantly
affects elderly men and for which few systemic
treatment options are available. Palliative
end-points including pain relief decreased analgesic
use and reduced prostate specific antigen levels (a
marker of tumour response) are reached in a greater
percentage of patients receiving combination therapy
than corticosteroid alone. In addition, there are
generally greater improvements in quality-of-life
parameters in mitoxantrone recipients. However,
combined treatment offers no survival advantage over
corticosteroid monotherapy.Neutropenia is the most
common toxicity associated with mitoxantrone therapy
and may necessitate dosage reduction in some
patients. Otherwise, mitoxantrone generally has a
more favourable tolerability profile than has been
established for other cytotoxic agents such as
doxorubicin with regard to acute adverse events (e.g.
Nausea/vomiting, anorexia, constipation, alopecia,
malaise/fatigue, oedema) and cardiac toxicity.In
conclusion, administration of mitoxantrone plus a
corticosteroid can provide palliation for some
elderly patients with hormone-resistant advanced
prostate cancer, and is thus a valuable first-line
treatment for this indication.
Molecular and cellular biology of
prostate cancer.
Lalani EN, Laniado ME, Abel PD
Cancer Metastasis Rev 1997 JUN;16(1-2):29-66
Lalani EN, Hammersmith Hosp, Royal Postgrad Med
Sch, Dept
Histopathol, du Crane Rd, London W12 0NN,
ENGLAND
Prostate cancer is an enigmatic disease. Although
prostatic-intraepithelial neoplasia appears as early
as the third decade and as many as 80% of 80 year old
men have epithelial cells in their prostate that fit
the morphological criteria for cancer, only about 10%
of men will ever have the clinical disease and less
than 3% will die from it. There have been no
significant proven interventions which have al tered
the natural history of the disease since hormone down
regulation was introduced in the 1940s and new
research has been poorly supported. There is however
an urgent need to develop new criteria to distinguish
those patients with localised disease who will
benefit from intervention from those that do not
require it or who will have occult extra prostatic
metastases. Similarly, there is an urgent need to
develop new treatments for those in wham the disease
is extra- prostatic and therefore incurable by
conventional treatments. This review covers the
latest developments in epidemiology, cellular and
molecular biology including new areas such as ion
channels in the field of prostate cancer.
Antiproliferative effect of Pygeum
africanum
extract on rat prostatic
fibroblasts.
Yablonsky F, AU - Nicolas V, Riffaud JP, Bellamy
F
J Urol 1997 JUN;157(6):2381-2387
Yablonsky F, Labs Debat, Grp Fournier, 153 Rue
Buzenval, F
92380 Garches, FRANCE
The effect of a Pygeum africanum extract
(Tadenan(R)) (Pa), used in the treatment of
micturition disorders associated with BPH, has been
examined on the proliferation of rat prostatic
stromal cells stimulated by different growth factors.
EGF, bFGF, and IGF-I but not KGF are mitogenic for
prostatic fibroblasts in culture. Pygeum africanum
inhibits both basal and stimulated growth with IC50
values of 4.5, 7.7 and 12.6 mu g./ml. For EGF, IGF-I
and bFGF, respectively, compared to 14.4 mu g./ml.
For untreated cells, the inhibition being stronger
towards EGF. Pygeum africanum inhibited the
proliferation induced by TPA or PDBu in a
concentration-dependent manner with IC50 values of
12.4 and 8.1 mu g./ml. Respectively. The
antiproliferative effects of Pa were not ascribed to
cytotoxicity. These results show that Pygeum
africanum is a potent inhibitor of rat prostatic
fibroblast proliferation in response to direct
activators of protein kinase C, the defined growth
factors bFGF, EGF and IGF-I, and the complex mixture
of mitogens in serum depending on the concentration
used. PKC activation appears to be an important
growth factor-mediated signal transduction for this
agent. These data suggest that therapeutic effect of
Pygeum africanum may be due at least in part to the
inhibition of growth factors responsible for the
prostatic overgrowth in man.
Flutamide withdrawal plus
hydrocortisone
resulted in clinical complete response
in a patient with prostate
carcinoma.
Figg WD, Kroog G, Duray P, Walther MM, Patronas N,
Sartor O, Reed E
Cancer 1997 MAY 15;79(10):1964-1968
Figg WD, NCI, Med Branch, Bldg 10, Room
5A01,
9000 Rockville Pike, Bethesda,MD 20892 USA
BACKGROUND. Combined androgen blockade plus (CAB)
(medical or surgical castration plus antiandrogen
therapy) is considered by many to be the optimal
endocrine maneuver for patients with metastatic
prostate carcinoma. When progression occurs after
CAB, the discontinuation of the antiandrogen is
recommended. The authors present a patient that had a
clinical complete response to flutamide withdrawal
plus hydrocortisone that, at last follow-up, had been
maintained for more than 46 months. METHODS. A
71-year-old man with a positive family history of
prostate carcinoma presented in 1989 with urinary
frequency and a suspicious digital rectal
examination. He was found to have a poorly
differentiated adenocarcinoma (Gleason 4+4). He was
started on CAB and his prostate specific antigen
(PSA) concentration declined from 96 ng/mL to the
normal range and was maintained for the next 24
months. In 1991 his PSA began to rise, and reached 64
ng/mL by 1993. The patient was enrolled on a clinical
trial that discontinued the flutamide administration
and hydrocortisone was initiated. RESULTS. Physical
examination at the time of enrollment was
unremarkable. His PSA declined to below the limits of
detection after this maneuver and at last follow-up
had been maintained there for more than 46 months. In
1995, the patient underwent a repeat biopsy of the
prostate and all six tissue cores were negative for
carcinoma. At last follow-up in December 1996, the
patient had no evidence of disease and was being
followed routinely; however, the authors were
continuing treatment with testicular suppression
(leuprolide) plus hydrocortisone. CONCLUSIONS. The
authors believe the residual androgens and steroids
produced by the adrenal cortex play a meaningful role
in prostate carcinoma cell proliferation. Based on
this case and data from trials supporting the
activity of flutamide withdrawal plus adrenal
suppression, it appears reasonable to evaluate
prospectively the discontinuation of antiandrogen
versus antiandrogen withdrawal plus adrenal
suppression in individuals failing CAB. (C) 1997
American Cancer Society.
Quality of life and treatment outcomes:
Prostate carcinoma patients' perspectives
after prostatectomy or radiation
therapy.
ShraderBogen CL, Kjellberg JL, McPherson CP,
Murray CL
Cancer 1997 MAY 15;79(10):1977-1986
ShraderBogen CL, Healthsyst Minnesota, Inst
Res
Educ, 3800 Pk Nicollet Blvd, 2 S,
Minneapolis,MN 55416 USA
BACKGROUND. Of the estimated 317,000 men in the
United States diagnosed with prostate carcinoma in
1996, 57% will have localized disease, and their
5-year relative survival rate will be 98%. Limited
information exists on patient- reported quality of
life (QOL) and the incidence and severity of
treatment-related side effects. The purpose of this
study was to identify and compare patients' self-
reported QOL and treatment side effects 1-5 years
after radical prostatectomy or radiotherapy. METHODS.
Data collection for this cross-sectional study
included a mailed, self-administered survey with
three parts: a demographic survey, the Functional
Assessment of Cancer Therapy-General (FACT-G), and a
newly developed Prostate Cancer Treatment Outcome
Questionnaire (PCTO-Q). The FACT-G measured the
effect of prostate carcinoma on overall QOL in the
two treatment groups. The PCTO-Q assessed the
patients' perceptions of the incidence and severity
of specific changes in bowel, urinary, and sexual
functions. The test-retest reliability of the PCTO-Q
in a pilot study was 91.2%. RESULTS. Two hundred
seventy-four eligible men completed the
questionnaires; 132 (48%) reported having undergone
prostatectomy and 142 (52%) reported having undergone
radiotherapy. After age adjustment, the radiotherapy
group reported more bowel dysfunction (P = 0.001),
whereas the prostatectomy group reported more urinary
problems (P = 0.03) and more sexual dysfunction (P =
0.001). Scores for the FACT-G were similar in the two
treatment groups. CONCLUSIONS. Men undergoing
treatment for clinically localized prostate carcinoma
continue to experience difficulty long after
treatment. In this study, the prostatectomy group
fared worse in regard to sexual and urinary
functions, whereas the radiotherapy group experienced
more bowel dysfunction. Survivor-reported QOL and
treatment outcomes can assist physicians in
counseling patients in the selection of the preferred
course of treatment. (C) 1997 American Cancer
Society.
Prostate
cancer detection in men with
serum PSA concentrations of 2.6 to 4.0 ng/mL
and benign prostate examination:
Enhancement of specificity with
free PSA measurements.
Catalona WJ Smith DS Ornstein DK
JAMA 1997 MAY 14;277(18):1452-1455
Catalona WJ, Washington Univ, Sch Med, Dept
Surg,
Div Urol Surg, 4960 Childrens Pl,
St Louis,MO 63110 USA
Objective.-To determine the detection rate of
prostate cancer in a screening population of men with
prostate- specific antigen (PSA) concentrations of
2.6 to 4.0 ng/mL and a benign prostate examination,
to assess the clinicopathological features of the
cancers detected, and to assess the usefulness of
measuring the ratio of free to total PSA to reduce
the number of prostatic biopsies. Design.-A
community-based study of serial screening for
prostate cancer with serum PSA measurements and
prostate examinations. Setting.-University medical
center. Subjects.-A total of 914 consecutive
screening volunteers aged 50 years or older with
serum PSA levels of 2.6 to 4.0 ng/mL who had a benign
prostate examination and no prior screening tests
suspicious for prostate cancer, 332 (36%) of whom
underwent biopsy of the prostate. Main Outcome
Measures.-Cancer detection rate, clinical and
pathological features of cancers detected, and
specificity for cancer detection using measurements
of percentage of free PSA. Results.-Cancer was
detected in 22% (73/332) of men who underwent biopsy.
All cancers detected were clinically localized, and
81% (42/52) that were surgically staged were
pathologically organ confined. Ten percent of the
cancers were clinically low-volume and low-grade
tumors, and 17% of those surgically staged were
low-volume and low- grade or moderately low-grade
tumors (possibly harm less). Using a percentage of
free PSA cutoff of 27% or less as a criterion for
performing prostatic biopsy would have detected 90%
of cancers, avoided 18% of benign biopsies, and
yielded a positive predictive value of 24% in men who
underwent biopsy. Conclusions.-There is an
appreciable rate of detectable prostate cancer in men
with serum PSA levels of 2.6 to 4.0 ng/mL. The great
majority of cancers detected have the features of
medically important tumors. Free serum PSA
measurements may reduce the number of additional
biopsies required by the lower PSA cutoff.
Prostate-specific antigen failure
despite
pathologically organ-confined and
margin-negative prostate cancer:
The basis for an adjuvant therapy
trial.
DAmico AV, Whittington R, Malkowicz SB, Schultz
D,
Tomaszewski JE, Wein A,
J Clin Oncol 1997 APR;15(4):1465-1469
DAmico AV, Harvard Univ, Sch Med, Joint Ctr
Radiat Therapy,
330 Brookline Ave, Boston,MA 02215 USA
Purpose: A multivariable analysis to evaluate the
potential clinical and pathologic factors that
predict for early biochemical failure in patients
with pathologically organ-confined and
margin-negative disease was performed to define
patients who may benefit from adjuvant therapy.
Patients and Methods: Three hundred forty-one
prostate cancer patients treated with a radical
retropubic prostatectomy between January 1989 and
June 1995 and found to have pathologically
organ-confined and margin-negative disease comprised
the study population. A logistic regression
multivariable analysis to evaluate the predictive
value of the preoperative prostate-specific antigen
(PSA) level, pathologic (prostatectomy) Gleason
score, and pathologic stage on PSA failure occurring
during the first postoperative year was performed.
Results: Predictors of PSA failure during the first
postoperative year in patients with pathologically
organ- confined disease included pathologic Gleason
score greater than or equal to 7 (P = .0007) and
preoperative PSA level greater than 10 (P .0001).
Corresponding 3-year freedom- from-PSA-failure rates
for these pathologic organ-confined patients with
both, one, or neither of these factors were 60%, 75%
to 84%, and 95%, respectively (P .0001). Conclusion:
Prostate cancer patients with pathologically
organ-confined and margin-negative disease and a
preoperative PSA level greater than 10 ng/mL or a
pathologic Gleason score greater than or equal to 7
have significant decrements in short-term
PSA-failure-free survival. Therefore, these patients
should be considered for adjuvant therapy in the
setting of a phase III clinical trial. (C) 1997 by
American Society of Clinical Oncology.
Family
history of prostate cancer in
patients with localized prostate cancer:
An independent predictor of treatment
outcome.
Kupelian PA, Kupelian VA, Witte JS, Macklis R,
Klein EA,
J Clin Oncol 1997 APR;15(4):1478-1480
Kupelian PA, Cleveland Clin Fdn, Dept Radiat
Oncol,
Desk T28, Cleveland,OH 44195 USA
Purpose: To determine if familial prostate cancer
patients have a less favorable prognosis than
patients with sporadic prostate cancer after
treatment for localized disease with either
radiotherapy (RT) or radical prostatectomy (RP).
Patients and Methods: One thousand thirty-eight
patients treated with either RT (n = 583) or RP (n =
455) were included in this analysis, These patients
were noted as having a positive family history if
they confirmed the diagnosis of prostate cancer in a
first-degree relative, The outcome oi: interest was
biochemical relapse-free survival (bRFS). We used
proportional hazards to analyze the effect of the
presence of family history and other potential
confounding variables (ie, age, treatment modality,
stage, biopsy Gleason sum [GS], and initial
prostate-specific antigen [iPSA] levels) on treatment
outcome. Results: Eleven percent of all patients had
a positive family history, The 5-year bRFS rates for
patients with negative and positive family histories
were 52% and 29%, respectively (P .001). The
potential confounders with bRFS rates were iPSA
levels, biopsy GS, and clinical tumor stage;
treatment modality and age did not appear to be
associated with outcome. After adjusting for
potential confounders, family history of prostate
cancer remained strongly associated with biochemical
failure. Conclusion: This is the first study to
demonstrate that the presence of a family history of
prostate cancer correlates with treatment outcome in
a large unselected series of patients. Our findings
suggest that familial prostate cancer may have a more
aggressive course than nonfamilial prostate cancer,
and that clinical and/or pathologic parameters may
not adequately predict this course. (C) 1997 by
American Society of Clinical Oncology.
Phase II
trial of suramin, leuprolide,
and flutamide in previously untreated
metastatic prostate cancer.
Dawson NA, Figg WD, Cooper MR, Sartor O, Bergan
RC,
Senderowicz AM, Steinberg SM,
Tompkins A, Weinberger B, Sausville EA, Reed E,
Myers CE,
J Clin Oncol 1997 APR;15(4):1470-1477
Dawson NA, Walter Reed Army Med Ctr,
Washington,DC 20307 USA
Purpose: To assess the efficacy and toxicity of
suramin, hydrocortisone, leuprolide, and flutamide in
previously untreated metastatic prostate cancer.
Patients and Methods: patients with stage D2 and
poor- prognosis stage D1 prostate cancer were given
suramin on a pharmacokinetically derived dosing
schedule to maintain suramin concentrations between
175 and 300 mu g/mL. Additionally, all patients
received flutamide 250 mg orally three times daily,
initiated on day 1 and continued until disease
progression; depot leuprolide 7.5 mg intramuscularly
begun on day 5 and repeated every 4 weeks
indefinitely; and replacement doses of
hydrocortisone. Results: Fifty patients were entered
onto the study: 48 with stage D2 and two with stage
D1 disease, The median age was 59 years (range, 42 to
79) and 31 patienf 5 had a Karnofsky performance
status (KPS) of 100%. Forty-five patients had bone
metastases and 25 had measurable soft tissue disease,
Forty-one (82%) had severe disease. The overall
response rate in 49 assessable patients was three
complete responses (CRs) and 30 partial responses
(PRs) for an overall response rate of 67%, Eighteen
patients have died, The median survival time has not
been reached, with a median potential follow-up
duration of 44 months. Grade 3 to 4 toxicity was seen
in 38% of patients and was predominantly hematologic
and reversible. Conclusion: The high response rate
and prolonged survival in a poor-prognosis group of
patients with metastatic prostate cancer warrant a
phase III randomized comparison of this regimen
versus hormonal therapy alone, Toxicity was moderate
and reversible.
The antiandrogen withdrawal
syndrome.
Wirth MP, Froschermaier SE
Urol Res 1997 APR;25:S67-S71
Wirth MP, Tech Univ Dresden, Dept Urol,
Fetscherstr 74, D 01307 Dresden, GERMANY
In 1989 the unanticipated agonist effect of
antiandrogens on LNCaP prostate cancer cells was
detected. A ''flutamidewithdrawal syndrome'' was
first described by Kelly andScher [15], who reported
a decrease in serum prostate-specific antigen (PSA)
levels after the removal offlutamide from the
treatment regimen. In the last fewyears the
paradoxical response to antiandrogens has alsobeen
reported for bicalutamide, chlormadinone acetate
andothers. Therefore the name of the syndrome has
changed to''antiandrogen withdrawal syndrome.''
Several reasons suchas mutations in the androgen
receptor or a directstimulatory effect of the
antiandrogen for this effecthave been discussed, but
the exact molecular mechanismremains unclear.
However, in patients with hormonallyrelapsed prostate
cancer, a trial of ''withdrawaltherapy'' is required
prior to the initiation of toxictherapies.
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