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Combination of screening and preoperative endocrine
therapy: the potential for an important decrease in prostate
cancer mortality.
Labrie F, Cusan L, Gomez JL, Diamond P, Candas B
Prostate Cancer Research Unit, CHUL Research Center, Le
Centre Hospitalier de l'Universite Laval, Quebec,
Canada.
J Clin Endocrinol Metab 1995 Jul;80(7):2002-13
Prostate cancer is the second cause of cancer death in men
in the Western world; its medical and social impact is
comparable to that of breast cancer in women. Although it is
well recognized that early treatment is the only possibility
for reducing the high rate of death from prostate cancer,
screening and even early treatment are controversial issues
due mainly to arguments based upon old literature and lack of
awareness of the significant advances recently made in this
field. As it is well known that surgical removal of
organ-confined prostate cancer cures the disease, and it has
been demonstrated that annual screening with prostate-specific
antigen coupled with digital rectal examination followed, when
indicated, by transrectal ultrasonography of the prostate more
than doubles the proportion of organ-confined disease,
screening alone offers the possibility of at least doubling
the number of patients curable from prostate cancer or the
potential for a cure to an estimated 45% of prostate cancer
patients compared to a maximum of 20% in the absence of
screening. It is important to mention that screening does not
detect small and insignificant cancers, especially when random
biopsies are not performed routinely. The critical volume of
prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in
diameter, if spherical. Such a tumor should increase serum
prostate-specific antigen by 0.5 ng/mL. Contrary to the belief
that screening detects cancers that are too small, the fact is
that screening detects prostate cancer too late or nonorgan-
or nonspecimen-confined cancer in 35-50% of cases. There is,
thus, a narrow window when prostate cancer can be detected at
a curable stage, and even the best available screening
techniques cannot succeed in all cases. It should be mentioned
that the recent improvements of the technique of radical
prostatectomy have markedly improved the acceptability of
surgery. Concerning the recent publicity related to watchful
waiting, it is essential to indicate that all such reports
support the notion that prostate cancer grows slowly, but
steadily and irremediably, with increasing malignancy and risk
of distant metastases and death if sufficient time is allowed.
Another serious limitation of watchful waiting is that the
available prognostic factors have a large margin of error and
cannot predict with certainty the rate of progression of the
tumor.
Diagnosis of advanced or noncurable prostate cancer
can be practically eliminated by prostate-specific
antigen.
Labrie F, Candas B, Cusan L, Gomez JL, Diamond P, Suburu R,
Lemay M
Prostate Cancer Clinical Research Unit, CHUL Research Center,
Quebec, Canada.
Urology 1996 Feb;47(2):212-7
OBJECTIVES: To determine the percentage of localized and
potentially curable prostate cancers diagnosed at follow-up
screening visits compared with the first screening visit.
METHODS: Within the context of a prospective screening
study performed in randomly chosen men aged between 45 and 80
years, up to 6-year follow-up screening visits have been
performed with serum prostate-specific antigen (PSA)
measurement and digital rectal examination (DRE) followed by
transrectal ultrasonography of the prostate when PSA or DRE is
abnormal.
RESULTS: Of the 117 prostate cancers diagnosed at 14,554
annual follow-up visits, only 1 cancer (0.9%) was metastatic
compared with 8% (26/322) at 8029 first visits. Moreover, 97%
of the cancers detected at follow-up visits could be
identified by PSA alone compared with 86% at first visit. The
incidence of 0.8% per year during 15 years of screening
between the ages of 55 and 70 years would diagnose localized
prostate cancer in 12% of the population, a value not too
different from the 10% diagnosed with prostate cancer during
life-time in the absence of screening.
CONCLUSIONS: The present data show that annual screening
with PSA diagnoses clinically localized prostate cancer in
more than 95% of cases, thus almost completely eliminating the
diagnosis of metastatic prostate cancer. Moreover, the number
of prostate cancers diagnosed is not significantly increased
by screening.
Evaluation of prostAsure index in the detection of
prostate cancer: a preliminary report.
Babaian RJ, Fritsche HA, Zhang Z, Zhang KH, Madyastha KR,
Barnhill SD
Department of Urology, University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA.
Urology 1998 Jan;51(1):132-136
OBJECTIVES: Although prostate-specific antigen (PSA) has
revolutionized the detection of prostate cancer, it has
definite limitations with respect to its clinical sensitivity
and specificity. Because a substantial number (20% to 40%) of
men undergoing radical prostatectomy have a PSA level of 4.0
ng/mL or less, any new test offering diagnostic improvement
must perform well in patients whose PSA level is less than or
equal to 4.0 ng/mL, as well as in patients whose PSA is
greater than 4.0 ng/mL. The performances of two tests, the
ProstAsure index and the percent free PSA test, were evaluated
in detecting cancer.
METHODS: We retrospectively analyzed serum samples from 225
men who were grouped into three categories: 94 men who had a
normal digital rectal examination and a serum PSA level of 4.0
ng/mL or less, 77 men who were clinically suspected of having
benign prostatic hyperplasia (BPH) with a serum PSA level of
4.0 ng/mL or less, and 54 men with localized prostate cancer.
The PSA assays were performed using the Hybritech and Tosoh
assays and the ProstAsure index was determined by Global
Health Net, Savannah, Ga. Receiver operator characteristic
(ROC) curves were constructed to evaluate the performance of
these two tests, and the areas under the curve were compared
for significance.
RESULTS: The sensitivity and specificity of detecting
prostate cancer using ProstAsure were 93% and 81%,
respectively. Using a cutoff value of 15%, the sensitivity and
specificity of detecting cancer for percent free PSA were 80%
and 74%, respectively (sensitivity increased to 93% and
specificity to 59% for free PSA at 19%). In men with a total
serum PSA level of 4.0 ng/mL or less, ProstAsure had a lower
false-positive rate compared to free PSA level at 19% for men
with or without clinical BPH as well as for men without
clinical BPH using a 15% free PSA threshold. ProstAsure left
fewer cancers undetected (7%) compared to free PSA at the 15%
cutoff (20%).
CONCLUSIONS: In this study of selected men, ROC curve
analysis shows a statistically significant advantage in
performance (P = 0.0023) for the ProstAsure index compared to
free PSA in detecting prostate cancer.
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
Division of Urologic Surgery, Department of Surgery,
Washington University School of Medicine, St. Louis, Mo 63110,
USA.
JAMA 1997 May 14;277(18):1452-5
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 harmless). 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.
Prospective longitudinal evaluation of men with
initial prostate specific antigen levels of 4.0 ng./ml. or
less.
Harris CH, Dalkin BL, Martin E, Marx PC, Ahmann FR
Section of Urology, University of Arizona College of Medicine
and Tucson Veterans Affairs Medical Center, USA.
J Urol 1997 May;157(5):1740-3
PURPOSE: We evaluated the 3-year longitudinal changes in
serial serum prostate specific antigen (PSA) levels in men
with an initial PSA of 4.0 ng./ml. or less and no suspicion of
prostate cancer.
MATERIALS AND METHODS: A total of 760 men with an initial
PSA of 4.0 ng./ml. or less plus a normal or suspicious digital
rectal examination and a benign prostate biopsy was enrolled
into an every 4-month PSA monitoring study.
RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml.
or less only 3 (0.5%) had a persistently abnormal PSA for 3
years and 1 cancer (0.2%) was detected, and 48 men had a PSA
velocity of 0.8 ng./ml. per year or more at year 1 but only 1
(2%) had a persistent rate of increase (2.4 ng./ml. per year)
at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85
had an abnormal PSA but only 37 (43%) met the criteria for
biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the
201 men 24 had a PSA velocity of 0.8 ng./ml. Per year or more
at year 1 but only 4 had persistence for 3 years. All 4 men
had cancer but they were identified as at high risk by PSA
criteria.
CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at
low risk for an abnormal PSA or cancer within 3 years and
annual monitoring may not be necessary. However, annual
monitoring is clinically useful in men with an initial PSA of
2.1 to 4.0 ng./ml. Also, serial monitoring with interval
testing in men whose PSA becomes greater than 4.0 ng./ml. is
beneficial in identifying a high risk group requiring biopsy.
Finally, PSA velocity did not add further to cancer detection
in this population.
Systematic 5 region prostate biopsy is superior to
sextant method for diagnosing carcinoma of the prostate.
Eskew LA, Bare RL, McCullough DL
Department of Urology, Bowman Gray School of Medicine of Wake
Forest University, Winston-Salem, North Carolina, USA.
J Urol 1997 Jan;157(1):199-202; discussion 202-3
PURPOSE: The number of patients undergoing prostate biopsy
has dramatically increased due to prostate specific antigen
screening. The low specificity of this screening tool requires
prostate biopsy for diagnosis of prostate cancer. The sextant
biopsy technique has been used widely with success in
diagnosing carcinoma of the prostate. However, concern has
arisen that the original sextant method may not include an
adequate sampling of the prostate. For many years we have used
a method of prostate biopsy that, in addition to sextant
biopsies, takes additional biopsies in a systematic fashion,
which we call the 5 region prostate biopsy. We conducted a
prospective study to determine if our 5 region prostate biopsy
technique significantly increases the chances of finding
carcinoma of the prostate compared to the sextant biopsy
technique.
MATERIALS AND METHODS: A total of 119 patients underwent
transrectal ultrasound guided needle biopsy of the prostate.
In addition to sextant biopsies, cores were taken from the far
lateral and mid regions of the gland. Pathological findings of
the additional regions were compared to those of the sextant
regions.
RESULTS: Of the 48 patients with prostate cancer 17 (35%)
had carcinomas only in the additional regions, which would
have remained undetected had the sextant biopsy technique been
used alone (p < 0.05). Of these additional cancers 83% had
Gleason scores of 6 or more.
CONCLUSIONS: We introduce the 5 region technique of
prostate biopsy as a means of significantly increasing the
diagnostic yield of prostate biopsy in finding carcinoma of
the prostate. We have found this technique to be safe,
efficacious and superior to the sextant method of biopsy in
identifying prostate cancer at an early but significant stage.
The greatest use of the 5 region biopsy technique is in
patients who have prostate specific antigen levels between 4
and 10 ng./ml.
Heterogeneity of prostate cancer in radical
prostatectomy samples.
Aihara M, Wheeler TM, Ohori M and Scardino PT
Urology 43:60-4, 1994.
OBJECTIVE. To understand the morphologic and spatial
relationships of the various grades of prostate cancer, we
investigated whether poorly differentiated cancer usually
arises within the center of a large, well-differentiated tumor
or more often forms the periphery or leading edge of the
tumor.
METHODS. In a series of one hundred and one completely
sectioned whole-mount radical prostatectomy specimens removed
from patients with clinical Stage T2 prostate cancer, we
mapped the distribution of each of the five Gleason grades and
assessed their frequency, proportion, and spatial
distribution.
RESULTS. The average number of different grades present in
our patients was 2.7 (range 1-5). Over 50 percent of the
prostates contained at least three different grades of cancer.
The number of different Gleason grades present increased
significantly with increasing tumor volume (p < 0.0001).
Only 10 percent of the index cancers (largest tumor present)
were composed of a single grade and these cancers were small
(0.02-1.7 cm3). Among cancers with multiple grades, the most
common finding (53%) was a high-grade cancer present within
the core of a larger, more well-differentiated tumor; however,
the opposite pattern, low-grade cancer present within a larger
poorly differentiated cancer, was also common (30%) and
predominated in very large cancers (> 10 cm3).
CONCLUSION. Small prostate cancers are often composed of a
single grade, usually Gleason grade 2 or 3. But most palpable
cancers contain multiple grades which are arranged in
heterogeneous and unpredictable geographic
interrelationships.
The dedifferentiation of prostate carcinoma.
Brawn PN
Cancer 1983 Jul 15;52(2):246-51
Fifty-four patients with prostate carcinoma, each having 2
TURP (transurethral resection of the prostate) procedures
separated by 3 to 11 years, were studied to determine whether
the histologic appearance of prostate carcinoma remains the
same for the life of the host or whether the histological
appearance changes with time. Using the M. D. Anderson (MDAH)
method of grading prostate carcinoma, 19 of 26 (73%) Grade 1
lesions, 9 of 12 (75%) Grade 2 lesions, and 7 of 8 (88%) Grade
3 lesions dedifferentiated into another grade at the time of
the 2nd TURP. Eight cases that were Grade 4 at the time of the
1st TURP, remained Grade 4 lesions at the time of the 2nd
TURP. Although 10 Grade 1, Grade 2, and Grade 3 lesions did
not change grades, 8 of these 10 cases were less
differentiated at the time of the second TURP than they were
at the time of the first TURP. Furthermore, no Grade 1 lesions
demonstrated evidence of metastases, but 19% of Grade 2
lesions, 55% of Grade 3 lesions, and 80% of Grade 4 lesions
demonstrated evidence of metastases. This study suggests that
the usual course of prostate carcinoma is dedifferentiation
and that with dedifferentiation, the likelihood of metastases
increases.
A model to study c-myc and v-H-ras induced prostate
cancer progression in the Copenhagen rat.
Lehr JE, Pienta KJ, Yamazaki K, Pilat MJ
University of Michigan Comprehensive Cancer Center, Ann Arbor
48109-0946, USA.
Cell Mol Biol (Noisy-le-grand) 1998
Sep;44(6):949-59
Normal rat prostate epithelial cells (EPYP-1) were isolated
and immortalized with the Simian Virus-40 (SV40) large
T-antigen, and transfected with the v-H-ras (EPYP-1-ras) and
the c-myc oncogenes (EPYP-1-myc; EPYP-1-ras-myc) to serially
create a step-wise model of tumor development in the rat
prostate. Pronounced morphological differences were observed
between EPYP-1 and the transfected sublines. The immortal
epithelial cells (EPYP-1) maintained a cuboidal shape with
orderly, contact mediated inhibition of growth. Oncogene
transfected clones displayed a spindle shaped structure with
multiple overlapping pseudopodia. Transfected cells also
exhibited a greater degree of dysplasia, loss of contact
inhibition growth and the upregulation of an epithelial tumor
marker, cytokeratin-18. All cells exhibited anchorage
independent and androgen independent growth. In vivo, EPYP-1
cells and EPYP-1-myc and formed slowly growing non-metastatic,
benign tumors in immune compromised mice, while EPYP-1-ras and
EPYP-1-ras-myc transfected cells produced rapidly growing,
malignant tumors in similar animals. This model augments the
hypothesis that tumor initiation and progression can be caused
by as few as two discrete genetic events. In addition, the
"normal" rat prostate epithelium and transfected daughter cell
lines represent a tumor model system with distinct, well
understood genetic alterations: activation of ras and myc.
This model will be a valuable addition to the current cell
lines used in the investigation of prostate cancer
carcinogenesis.
Oncogene overexpression in human prostate cancer
cell lines.
Yamazaki H, Sinha BK
Proc Annu Meet Am Assoc Cancer Res 34:A2309,
1993.
No abstract.
Expression of the protooncogene bcl-2 in the
prostate and its association with emergence of
androgen-independent prostate cancer.
McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW,
Hsieh JT, Tu SM, Campbell ML
Department of Molecular Pathology, University of Texas M.D.
Anderson Cancer Center, Houston 77030.
Cancer Res 1992 Dec 15;52(24):6940-4
The significance of apoptosis in relation to the
development and progression of prostate cancer remains largely
undefined. bcl-2 is an oncogene that functions by overriding
apoptosis. bcl-2 expression was localized to the basal
epithelial cells in the normal human prostate with the use of
immunohistochemistry. Androgen-dependent and
androgen-independent prostate carcinomas were evaluated
immunohistochemically for bcl-2 expression. bcl-2 was
undetectable in 13 of 19 cases of androgen-dependent cancers.
In contrast, androgen-independent cancers displayed diffuse,
high levels of bcl-2 staining (P < 0.01). In rats,
steady-state levels of bcl-2 mRNA, assessed by S1 assays,
reached maximum levels 10 days following castration. Addition
of exogenous testosterone with, or without, flutamide
demonstrated that the increased bcl-2 Mrna resulted from
androgen ablation. Our findings indicate that bcl-2 expression
is augmented following androgen ablation and is correlated
with the progression of prostate cancer from androgen
dependence to androgen independence.
p53 is mutated in a subset of advanced-stage
prostate cancers.
Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred
DC
Department of Molecular Biology, Canji, Inc., San Diego,
California 92121.
Cancer Res 1993 Jul 15;53(14):3369-73
Inactivation of p53, a tumor suppressor gene, contributes
to the genesis and/or progression of a substantial fraction of
all human cancers, including > or = 50% of breast, lung,
and colon carcinomas. Mutated p53 alleles typically contain
missense single-base substitutions within exons 5-8 and encode
abnormally stable p53 proteins that accumulate to high levels
in tumor cell nuclei. To evaluate the frequency, type, and
clinical significance of p53 mutation in human prostate
cancer, archival tumor material from 150 prostate cancer
patients was examined by immunohistochemistry (IHC) with
anti-p53 antibodies. Abnormal nuclear p53 accumulation (IHC)
was observed in 19 tumors (12.7%) and was strongly related to
disease stage (23% of 69 stage III or IV tumors were IHC+
versus 4% of 74 stage 0-II tumors; P < 0.001, Fisher's
exact test). The methods of polymerase chain reaction,
single-strand conformational polymorphism, and direct
sequencing were used to identify mutations, predominantly
missense single-base substitutions in exons 5, 7, or 8 in 9 of
14 IHC+ cases but in none of 20 IHC- cases; 5 of these
mutations were G:C-->A:T transitions at CpG dinucleotides.
These data indicate that mutated p53 alleles are quite
uncommon in early prostate cancers but are found in 20-25% of
advanced cancers, suggesting a role for p53 mutation in the
progression of at least a subset of prostate cancers.
A mutation in the ligand binding domain of the
androgen receptor of human LNCaP cells affects steroid binding
characteristics and response to anti-androgens.
Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G,
Berrevoets C, Claassen E, van Rooij HC, Trapman J, Brinkmann
AO, Mulder E
Department of Biochemistry II, Erasmus University Rotterdam,
The Netherlands.
Biochem Biophys Res Commun 1990 Dec
14;173(2):534-40
LNCaP prostate tumor cells contain an abnormal androgen
receptor system. Progestagens, estradiol and anti-androgens
can compete with androgens for binding to the androgen
receptor and can stimulate both cell growth and excretion of
prostate specific acid phosphatase. We have discovered in the
LNCaP androgen receptor a single point mutation changing the
sense of codon 868 (Thr to Ala) in the ligand binding domain.
Expression vectors containing the normal or mutated androgen
receptor sequence were transfected into COS or Hela cells.
Androgens, progestagens, estrogens and anti-androgens bind the
mutated androgen receptor protein and activate the expression
of an androgen-regulated reporter gene construct (GRE-tk-CAT).
The mutation therefore influences both binding and the
induction of gene expression by different steroids and
antisteroids.
Plasma testosterone and androstenedione after
orchiectomy in prostatic adenocarcinoma.
Sciarra F, Sorcini G, Di Silverio F, et al:
Clin Endocrinol 2:101-109, 1973.
No abstract.
Adrenal androgens predict for early progression to
flutamide withdrawal in patients with androgen-independent
prostate carcinoma.
Herrada J, Hossan B, Amato R, et al:
Proc Am Soc Clin Oncol 13:237, 1994.
No abstract.
Flutamide withdrawal syndrome: its impact on
clinical trials in hormone-refractory prostate cancer.
Scher HI, Kelly WK
Department of Medicine, Memorial Sloan-Kettering Cancer
Center, New York, NY 10021.
J Clin Oncol 1993 Aug;11(8):1566-72
PURPOSE: To evaluate the effect of discontinuation of the
antiandrogen, flutamide, in patients with metastatic prostate
cancer who are progressing on hormonal therapy.
PATIENTS AND METHODS: Thirty-six patients with progressive
disease on hormonal treatment that included flutamide had
discontinuation of the antiandrogen. Thirty-five (95%) had
progressive increases in prostate-specific antigen (PSA)
levels, despite castrate levels of testosterone. Twenty-five
patients (69%) were treated with combined androgen blockade
(orchiectomy or gonadotropin-releasing hormone [GnRH] analog
plus flutamide) as initial therapy and 11 (31%) were started
on monotherapy alone. Patients who had not undergone a
previous orchiectomy were continued on the GnRH analog.
Patients were monitored clinically and with serial PSA
measurements, radionuclide scans, and radiographs as indicated
to assess response.
RESULTS: Considering the 35 patients with increasing PSA
values, 10 (29%) showed a significant decline (> or = 80%
in seven, and > or = 50% in three) in PSA from baseline.
All 10 had received combined androgen blockade as initial
therapy. The duration of decline was short (median, 5+ months;
range, 2 to 10+), but was associated with improvement in
clinical symptoms, while one patient had a partial response in
an epidural mass with parallel decline in PSA. None of the
patients started on single hormone therapies responded.
CONCLUSION: Discontinuation of flutamide was associated
with a significant decrease in PSA values in 10 of 25 patients
(40%; 95% confidence interval, 21% to 59%) and clinical
improvement in a subset of patients who had an initial
response, but later progressive disease on combined androgen
blockade. A trial of flutamide withdrawal should be considered
in patients progressing on total androgen blockade before the
initiation of more toxic therapies. It is likely that
flutamide withdrawal has contributed to the observed responses
in phase II trials of both second-line hormonal therapies and
new cytotoxic agents. Future phase II trials in
hormone-refractory prostatic cancer must control for this
observation, and insure that progression off flutamide is
documented before initiation of alternative treatment.
Prostate specific antigen decline following
discontinuation of flutamide in patients with stage D2
prostate cancer.
Figg WD, Sartor O, Cooper MR, et al:
Pharmacology Branch, National Cancer Institute, Bethesda,
Maryland, USA.
Am J Med 98:412-14, 1995.
No abstract.
The antiandrogen withdrawal syndrome. Experience in
a large cohort of unselected patients with advanced prostate
cancer.
Small EJ, Srinivas S
Department of Medicine, University of California, San
Francisco, Mt Zion/UCSF Cancer Center 94115, USA.
Cancer 1995 Oct 15;76(8):1428-34
BACKGROUND. Flutamide withdrawal has been reported to be
therapeutically efficacious for patients with
hormone-refractory prostate cancer, with a reported prostate
specific antigen (PSA) response rate of 29%.
METHODS. To evaluate the results of flutamide withdrawal in
a large group of unselected patients, the medical records of
107 consecutive patients with metastatic prostate cancer who
developed progressive disease while receiving flutamide
therapy were reviewed retrospectively. Flutamide withdrawal
was undertaken at the time of disease progression.
RESULTS. Eighty-two patients were evaluable. Of these,
three had a > 80% fall in PSA value, and another nine had a
> 50% decrease, for a response proportion of 14.6% (95%
confidence interval 7.8%-24.2%). The median response duration
was 3.5 months (range, 1-12+ months). Eight of patients
treated with combined androgen blockade at the time of
diagnosis of metastatic disease had a response (14%), whereas
4/25 responses (16%) were noted in patients in whom flutamide
was added later, at the time of first progression. When
patients who responded were compared with patients who did not
respond, there was not a significant difference in age,
pretreatment PSA level, type of gonadal androgen deprivation,
or the likelihood of prior combined androgen blockade versus
late addition of flutamide. The duration of prior therapy with
flutamide was longer in patients who responded (21.5 vs. 12.0
months).
CONCLUSIONS. These findings confirm the flutamide
withdrawal phenomenon in a large group of unselected patients,
although its frequency is not as high as previously reported.
In contrast to earlier reports, whether patients have had
initial hormonal therapy with combined androgen blockade or
monotherapy does not appear to be predictive of the likelihood
of response to antiandrogen withdrawal.
Prostate-specific antigen decline after casodex
withdrawal: evidence for an antiandrogen withdrawal
syndrome.
Small EJ, Carroll PR
Department of Medicine, University of California, San
Francisco.
Urology 1994 Mar;43(3):408-10
OBJECTIVE. To evaluate the relationship between
antiandrogen withdrawal and change in prostate-specific
antigen (PSA) when the antiandrogen in question is other than
flutamide.
METHODS. Presented is a case of a patient in whom the
antiandrogen casodex was discontinued after clinical
progression despite combined androgen blockade.
RESULTS. A transient decline in serum PSA was observed
after casodex withdrawal.
CONCLUSIONS. The relationship between antiandrogen
withdrawal and a change in PSA may be a general phenomenon,
not unique to flutamide.
A double-blind assessment of antiandrogen
withdrawal from Casodex (C) or Eulexin (E) therapy while
continuing luteinizing hormone releasing hormone analogue
(LHRH-A) therapy for patients (Pts) with stage D2 prostate
cancer (PCA).
Small EJ, Schelhammer P, Venner P, et al:
Proc Am Soc Clin Oncol 15:255A, 1996.
No abstract.
Dramatic PSA decline in response to discontinuation
of megestrol acetate in advanced prostate cancer; expansion of
the antiandrogen withdrawal syndrome.
Dawson NA and McLeod DG
J Urol 153:1956-7, 1995.
No abstract.
Complete remission of hormone refractory
adenocarcinoma of the prostate in response to withdrawal of
diethylstilbestrol.
Bissada NK, Kaczmarek AT
Department of Urology, Medical University of South Carolina,
Charleston, USA.
J Urol 1995 Jun;153(6):1944-5
The phenomenon of regression of adenocarcinoma of the
prostate after the withdrawal of antiandrogens is well
documented. However, to our knowledge we report the first case
of durable complete remission of hormone refractory prostate
cancer after cessation of diethylstilbestrol. The drug was
discontinued because the patient had disease progression while
on diethylstilbestrol and withdrawal resulted in durable
remission. In more than 3 years of followup since
discontinuing diethylstilbes trol there has been no evidence
of clinical or biochemical recurrence.
Mutant androgen receptor detected in an
advanced-stage prostatic carcinoma is activated by adrenal
androgens and progesterone.
Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr
C, Eberle J, Bartsch G, Klocker H
Department of Urology, University of Innsbruck,
Austria.
Mol Endocrinol 1993 Dec;7(12):1541-50
Structural changes of the androgen receptor (AR) may
contribute to the development of resistance to endocrine
therapy in prostatic carcinoma. We have isolated AR cDNA
fragments from seven tumor specimens derived from patients
with advanced metastatic prostatic tumors. In one specimen
obtained from a patient who failed to respond to endocrine and
cytotoxic therapy we have detected a point mutation in the
hormone-binding domain of the receptor. This AR mutation is a
guanine-to-adenine transition at nucleotide 2671 that leads to
substitution of methionine for the wild type valine at
position 715. It is a somatic mutation because it was not
present in the AR genomic DNA fragments isolated from
prostatic and testicular tissues of the same patient. The
mutant AR was recreated in an expression vector and
transiently expressed in COS-7 and CV-1 cells. Hormone-binding
assays revealed that the mutant receptor does not differ from
the wild type receptor in its ability to bind androgen. The
dissociation constant for the synthetic androgen mibolerone
was 3 nM for both receptors. There was also no significant
difference in binding of other steroids and nonsteroidal
antiandrogens as revealed by competition binding assays.
However, transfection experiments to determine the
trans-activation potential of the mutant receptor produced
differences in the action of this receptor compared to the
wild type receptor. Dihydrotestosterone and the synthetic
androgens methyltrienolone (R1881) and mibolerone were equally
proficient in conferring trans-activation activity to both the
mutant and wild type receptors. Adrenal androgens such as
dehydroepiandrosterone and androstenedione, as well as
progesterone mediated a higher trans-activation through the
mutant than through the wild type receptor. These data
demonstrate that the exchange of a single valine into
methionine at position 715 in the AR promoters
trans-activation not only by testicular but also by adrenal
androgens and progesterone. This pattern of ligand-dependent
trans-activation may have significance in the process
controlling the progression of prostatic carcinoma.
Mutation of the androgen-receptor gene in
metastatic androgen-independent prostate cancer.
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE,
Ogata GK, Keer HN, Balk SP
Department of Medicine, University of Massachusetts Medical
Center, Worcester, USA.
N Engl J Med 1995 May 25;332(21):1393-8
BACKGROUND. Metastatic prostate cancer is a leading cause
of cancer-related death in men. The rate of response to
androgen ablation is high, but most patients relapse as a
result of the outgrowth of androgen-independent tumor cells.
The androgen receptor, which binds testosterone and stimulates
the transcription of androgen-responsive genes, regulates the
growth of prostate cells. We analyzed the androgen-receptor
genes from samples of metastatic androgen-independent prostate
cancers to determine whether mutations in the gene have a role
in androgen independence.
METHODS. Complementary DNA was synthesized from metastatic
prostate cancers in 10 patients with androgen-independent
prostate cancer, and the expression of the androgen-receptor
gene was estimated by amplification with the polymerase chain
reaction. Exons B through H of the gene were cloned, and
mutations were identified by DNA sequencing. The functional
effects of the mutations were assessed in cells transfected
with mutant genes.
RESULTS. All androgen-independent tumors expressed high
levels of androgen-receptor gene transcripts, relative to the
levels expressed by an androgen-independent prostate-cancer
cell line (LNCaP). Point mutations in the androgen-receptor
gene were identified in metastatic cells from 5 of the 10
patients examined. One mutation was in the same codon as the
mutation found previously in the androgen-independent
prostate-cancer cell line. The mutations were not detected in
the primary tumors from of the two patients. Functional
studies of two of the mutant androgen receptors demonstrated
that they could be activated by progesterone and estrogen.
CONCLUSIONS. Most metastatic androgen-independent prostate
cancers express high levels of androgen-receptor gene
transcripts. Mutations in androgen-receptor genes are not
uncommon and may provide a selective growth advantage after
androgen ablation.
Anti-androgen activation of mutant androgen
receptors from androgen-independent prostate cancer.
Fenton M-A, Shuster TD, Feris A, Taplin M-E, Kolvenbag G,
Bubley GJ and Balk SP:
Clin Cancer Res 3:1383, 1997.
No abstract.
The proliferative effect of "anti-androgens" on the
androgen-sensitive human prostate tumor cell line LNCaP.
Olea N, Sakabe K, Soto AM, Sonnenschein C
Tufts University Health Science Schools, Department of
Anatomy and Cellular Biology, Boston, Massachusetts
02111.
Endocrinology 1990 Mar;126(3):1457-63
The effect of steroidal and nonsteroidal "anti-androgens"
on the proliferative capacity of androgen-sensitive LNCaP-FGC
human prostate tumor cells in culture was studied using
charcoal-dextran stripped human serum-supplemented media.
Cyproterone and medroxyprogesterone acetates, flutamide,
hydroxyflutamide, and anandron (R23908) were administered
alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M.
Results indicated that although medroxyprogesterone induced
maximal proliferation at 3 X 10(-9) M, the other
"anti-androgens" (with the exception of flutamide that was
ineffective) were effective at 3 X 10(-8) M and higher
concentrations; the amplitude of the proliferative response by
these compounds was comparable to that elicited by
estradiol-17 beta (3 to 5-fold over control). None of the
anti-androgens tested triggered the shutoff effect
characteristic of androgen action. When 3 X 10(-10) M DHT and
the above mentioned anti-androgens were administered
simultaneously, a synergistic pattern was seen; on the
contrary, 3 X 10(-8) M DHT cancelled the proliferative effect
of each of the anti-androgens when administered
simultaneously. The relative binding affinity of these
anti-androgens to androgen receptors present in LNCaP-FGC
cells did not correlate well with their proliferative
efficiency. The data collected were interpreted within the
premises of the negative control hypotheses for the regulation
of cell proliferation in metazoans. Within those premises,
results became compatible with the notion that first,
"anti-androgens" elicited the proliferation of
androgen-sensitive cells by neutralizing the effect of a
serum-borne inhibitor (androcolyone-I); this event seems not
to be mediated by androgens receptors. Second, anti-androgens
did not trigger a proliferative shutoff response like
androgens do, i.e. the proliferative pattern induced by
anti-androgens was comparable to that elicited by estrogens
and progestins. Third, when administered simultaneously with 3
X 10(-10) M DHT, anti-androgens behaved synergistically.
Fourth, the DHT-induced shutoff effect consistently overrode
the proliferative effect generated by anti-androgens and
estrogens when added alone. Finally, taken together these
results raise important questions regarding the therapeutic
role of anti-androgens in prostate cancer.
High dose bicalutamide for androgen independent
prostate cancer: effect of prior hormonal therapy.
Joyce R, Fenton MA, Rode P, Constantine M, Gaynes L,
Kolvenbag G, DeWolf W, Balk S, Taplin ME, Bubley GJ
Department of Medicine, Harvard Medical School, Boston,
Massachusetts, USA.
J Urol 1998 Jan;159(1):149-53
PURPOSE: A pilot study of the antiandrogen bicalutamide at
150 mg. a day for androgen independent prostate cancer was
performed. This study was based on the possibility that
androgen independent cases might display responses to
additional hormonal agents.
MATERIALS AND METHODS: The study included 31 androgen
independent cases with an increasing prostate specific antigen
(PSA) and progressive disease. PSA measurements were used as
the primary method of assessing response. However, PSA decline
was also correlated with clinical status.
RESULTS: Seven patients demonstrated PSA declines of
greater than 50% for 2 months or more, for an overall response
rate of 22.5%. Responses were observed almost exclusively in
patients treated with long-term flutamide as part of a
complete androgen blockade regimen (43% response rate) in
contrast to patients treated with androgen deprivation without
flutamide (6% response rate). Of the 7 PSA responding patients
bicalutamide resulted in a significant improvement in
performance status and a decrease in analgesic requirement in
4 and 3 remained asymptomatic. Bicalutamide at 150 mg. a day
was well tolerated, with the most frequent side effect being
mild exacerbation of hot flashes.
CONCLUSIONS: Bicalutamide at this dose is modestly
effective for some patients with androgen independent prostate
cancer, particularly for those previously treated with
long-term flutamide. This study indicates that previous
antiandrogen therapy alters the response to subsequent
hormonal agents.
Ketoconazole: a novel and rapid treatment for
advanced prostatic cancer.
Trachtenberg J, Halpern N, Pont A
J Urol 1983 Jul;130(1):152-3
Ketoconazole is an orally administered broad-spectrum
antifungal agent that acts through the inhibition of the
steroid synthetic pathways. At high doses in humans
ketoconazole can lower rapidly serum testosterone and maintain
it in the castrate range with frequent administration. This
property suggested that ketoconazole might be useful in the
treatment of prostatic cancer. We report a case of prostatic
cancer in which ketoconazole resulted in rapid and sustained
reduction in serum androgens as well as rapid induction of a
clinical remission. Ketoconazole may be a valuable agent in
the treatment of prostatic cancer.
Synergistic effect of ketoconazole and
antineoplastic agents on hormone-independent prostatic cancer
cells.
Eichenberger T, Trachtenberg J, Chronis P, Keating A
Division of Urology, Toronto General Hospital, Ontario.
Clin Invest Med 1989 Dec;12(6):363-6
Ketoconazole has been recently used in the primary
treatment of patients with metastatic cancer of the prostate
and is identified as a potent inhibitor of cytochrome
P450-dependent adrenal and testicular androgen production. The
drug has also shown activity in patients failing conventional
hormonal manipulation. We subsequently showed that
ketoconazole in vitro has a direct cytotoxic effect on human
androgen-independent prostatic cancer cell lines. In order to
better define the possible role of ketoconazole on
hormone-independent prostatic cancer, we incubated the cells
from human androgen-independent prostatic cancer lines in a
methylcellulose tumour colony assay with different doses of
the drug and increasing doses of conventional cytotoxic agents
(etoposide, bleomycin, vinblastine, methotrexate, and
teniposide). We demonstrated synergistic suppression of
prostate cancer clonogenic cell growth by ketoconazole in the
presence of vinblastine or etoposide. This observation may
assign a new and important role for ketoconazole as part of
combination chemotherapy in the treatment of patients with
advanced prostatic cancer.
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