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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.
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.
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.
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.
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, Gagliardi V
Clin Endocrinol (Oxf) 1973 Apr;2(2):101-9
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 the
discontinuation of flutamide in patients with stage D2
prostate cancer.
Figg WD, Sartor O, Cooper MR, Thibault A, Bergan RC, Dawson
N, Reed E, Myers CE
Pharmacology Branch, National Cancer Institute, Bethesda,
Maryland, USA.
Am J Med 1995 Apr;98(4):412-4
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.
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 diethylstilbestrol 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.
Anti-androgen activation of mutant androgen
receptors from androgen-independent prostate cancer.
Clin Cancer Res 3:1383, 1997.
No abstract.
The proliferative effect of "anti-androgens" on the
androgen-sensitive human prostate tumor cell line LNCaP.
Endocrinology 126:1457, 1990.
No abstract.
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.
A novel and rapid treatment for advanced prostatic
cancer.
J Urol 130:152-3, 1983.
No abstract.
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.
Ketoconazole: a possible direct cytotoxic effect on
prostate carcinoma cells.
Eichenberger T, Trachtenberg J, Toor P, Keating A
Division of Urology, Toronto General Hospital, Ontario,
Canada.
J Urol 1989 Jan;141(1):190-1
Ketoconazole has been recently used in the treatment of
advanced prostatic cancer and is believed to exert its effect
by inhibition of androgen production. In order to determine
whether ketoconazole exerts an additional direct cytotoxic
effect on prostate cancer cells, we studied its effect on
human hormone-independent prostate cancer cell lines (PC-3 and
DU-145) in an in vitro clonogenic tumor assay. We showed that
clinically achievable doses of ketoconazole caused greater
than 90% suppression of tumor colony growth.
Ketoconazole effectively reverses multidrug
resistance in highly resistant KB cells.
Siegsmund MJ, Cardarelli C, Aksentijevich I, Sugimoto Y,
Pastan I, Gottesman MM
Laboratory of Molecular Biology, DCBDC, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
20892.
J Urol 1994 Feb;151(2):485-91
The antifungal agent ketoconazole was found to overcome
resistance to vinblastine and doxorubicin in multidrug
resistant KB-V1 cells in vitro. These cells are several
hundred-fold more resistant than the parental cell line
KB-3-1. Ketoconazole had little or no effect on the parental
KB-3-1 cells. The concentrations used to overcome drug
resistance in vitro have already been safely used in vivo for
treatment of fungal infections and in the monotherapy of
hormone independent prostate carcinomas to block adrenal
androgen production. Because of a possible beneficial effect
of a combination of ketoconazole and a chemotherapeutic drug
in multidrug resistant cancers, we examined a panel of 11
prostate carcinoma tissues for the expression of the MDR1 gene
by an RNA-PCR assay. MDR1 expression was detectable, albeit at
low levels, in 8 of the 11 tumors, suggesting a possible role
of this gene in the drug resistance of prostate carcinomas.
Our data suggest that ketoconazole might be useful in
overcoming multidrug resistance in concentrations that are
achievable in humans.
Long-term experience with high dose ketoconazole
therapy in patients with stage D2 prostatic carcinoma.
Pont A
J Urol 1987 May;137(5):902-4
The antifungal drug ketoconazole has been shown to block
testosterone synthesis. High dose ketoconazole therapy was
given to 17 patients with previously untreated stage D2
prostatic cancer. Rapid relief of pain occurred in 15 patients
with significant pain. Prostatic acid phosphatase levels
normalized or decreased in all patients. Bone scan scores were
stable or improved. Two patients remain on therapy for more
than 30 months. The remainder have ceased treatment owing to
subsequent progressive disease (5 patients), side effects (6)
or noncompliance. Eleven patients who had relapse after
previous endocrine ablative therapy were treated with
ketoconazole. Subjective responses were frequent but long-term
objective responses were rare. There was a high incidence of
side effects, particularly nausea. Ketoconazole may have
limited usefulness as initial therapy in patients with
endocrine responsive advanced prostatic cancer. The drug can
be palliative in some patients who have failed previous
therapeutic modalities. Analogues of the drug should prove to
have better efficacy and fewer side effects.
Ketoconazole retains activity in advanced prostate
cancer patients with progression despite flutamide
withdrawal.
Small EJ, Baron AD, Fippin L, Apodaca D
Department of Medicine, University of California, San
Francisco Cancer Center 94115, USA.
J Urol 1997 Apr;157(4):1204-7
PURPOSE: We tested the hypothesis that certain patients
with hormone refractory prostate cancer retain hormonal
sensitivity even after progression following antiandrogen
withdrawal. The efficacy of ketoconazole and hydrocortisone in
this patient population was evaluated.
MATERIALS AND METHODS: A total of 50 consecutive patients
with advanced prostate cancer received ketoconazole and
hydrocortisone at progression after antiandrogen withdrawal.
Prostate specific antigen (PSA) response was defined as
greater than a 50% decrease in PSA from baseline that was
maintained for at least 8 weeks.
RESULTS: Overall, of 48 evaluable patients 30 (62.5%, 95%
confidence interval 47.3 to 76.1%) had greater than a 50%
decrease in PSA, while 23 (48%) had greater than an 80%
decrease. The median duration of response was 3.5 months but
23 of 48 patients continue to exhibit a response, ranging from
3.25 to 12.75 or more months. The ketoconazole response rate
in patients with no response to prior antiandrogen withdrawal
was not different from that in patients with such a response
(65 versus 40%, p = 0.35). Toxicity was mild. Grade 1 or 2
nausea, fatigue, edema, hepatotoxicity and rash occurred in
10.4 (5 of 48), 6.25, 6.25, 4.2 and 4.2% of patients,
respectively, and anorexia occurred in 2%.
CONCLUSIONS: Failure to respond to antiandrogen withdrawal
does not identify patients with truly hormone refractory
disease. Ketoconazole retains significant activity in this
setting and is extremely well tolerated.
Simultaneous antiandrogen withdrawal and treatment
with ketoconazole and hydrocortisone in patients with advanced
prostate carcinoma.
Small EJ, Baron A, Bok R
University of California-San Francisco Cancer Center,
University of California 94115, USA.
Cancer 1997 Nov 1;80(9):1755-9
BACKGROUND: Although antiandrogen withdrawal has moderate
efficacy in patients with hormone refractory prostate
carcinoma (HRPC), the effect of the simultaneous suppression
of adrenal androgens with ketoconazole at the time of
antiandrogen withdrawal is not known.
METHODS: Twenty consecutive patients with HRPC who had
developed progressive disease despite combined androgen
blockade were treated with antiandrogen withdrawal and
simultaneous ketoconazole as a means of inhibiting adrenal
steroid production. Prostate specific antigen (PSA) response
was defined as a > 50% fall in PSA from baseline that was
maintained for at least 8 weeks.
RESULTS: Ten patients had established metastatic disease, 2
had high PSAs and no imaging studies (PSA of 70 and 160 ng/mL,
respectively), 3 had microscopically positive lymph nodes and
serologic progression, and 5 had serologic progression alone.
Overall, of 20 evaluable patients, 11 (55%) had a > 50%
fall in PSA (95% confidence interval [CI], 31.5-76.9%). The
median PSA response duration was 8.5 months (95% CI, 7-17
months). The median survival was 19 months. Toxicity was mild,
with Grade 1 and 2 nausea and emesis in 15% of patients, Grade
1 fatigue in 10% of patients, and reversible Grade 1 or 2
hepatotoxicity in 10% of patients. Mild skin toxicity was
observed in 20% of patients.
CONCLUSIONS: The addition of ketoconazole and
hydrocortisone to antiandrogen withdrawal appears to increase
the PSA response proportion observed with antiandrogen
withdrawal alone. Toxicity is mild.
Phase II study of ketoconazole combined with weekly
doxorubicin in patients with androgen-independent prostate
cancer.
Sella A, Kilbourn R, Amato R, Bui C, Zukiwski AA, Ellerhorst
J, Logothetis CJ
Department of Genitourinary Medical Oncology, University of
Texas M.D. Anderson Cancer Center, Houston 77030.
J Clin Oncol 1994 Apr;12(4):683-8
PURPOSE: A phase II clinical trial was performed to assess
the antitumor activity and toxicity of ketoconazole in
combination with doxorubicin (Adriamycin; Adria Laboratories,
Columbus, OH) in patients with androgen-independent prostate
cancer (AI PCa).
PATIENTS AND METHODS: Thirty-nine consecutive patients
whose disease progressed following castration were treated
with oral ketoconazole (1,200 mg) daily and Adriamycin (20
mg/m2 in a 24-hour infusion) once weekly. Antitumor activity
was assessed by the level of prostatic-specific antigen (PSA)
decline.
RESULTS: PSA levels decreased > or = 50% from baseline
in 21 (55%; 95% confidence interval, 38% to 71%) of 38
assessable patients. We observed partial responses (PRs) in
seven (58%) of 12 patients with measurable soft tissue disease
(in the lung, lymph nodes, and liver). Two patients with
history of atherosclerotic heart disease had a sudden cardiac
death. Serious toxic reactions included grade III to V
stomatitis and grade III to IV acral erythema in 11 patients
(29%), and grade III to IV anal and urethral mucositis in five
patients (13%). Grade III to IV neutropenia occurred in 11
patients (29%). Seventeen patients (45%) required
hospitalization for complications. Fifteen patients (39%)
developed hypokalemia, and 24 patients (63%) developed
clinical adrenal insufficiency.
CONCLUSION: The combination of ketoconazole and Adriamycin
has a 55% PSA response rate in patients with AI PCa and is
worthy of additional study. This treatment results in frequent
adrenal insufficiency. Therefore, future studies should
incorporate routine corticosteroid replacement. The cardiac
complications caused by this combination should be studied
further before it is widely used.
Phase II trial of alternating weekly chemohormonal
therapy for patients with androgen-independent prostate
cancer.
Ellerhorst JA, Tu SM, Amato RJ, Finn L, Millikan RE, Pagliaro
LC, Jackson A, Logothetis CJ
Department of Genitourinary Medical Oncology, The University
of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,
USA.
Clin Cancer Res 1997 Dec;3(12 Pt 1):2371-6
Two distinct regimens of weekly chemotherapy for
hormone-refractory prostate cancer were combined in an
alternating schedule and tested in a Phase II trial to
determine efficacy and toxic effects. Forty-six patients with
hormone-refractory prostate cancer and rising
prostate-specific antigen (PSA) levels entered the trial.
Therapy consisted of doxorubicin (20 mg/m2/week) plus oral
ketoconazole (400 mg three times a day) given at weeks 1, 3,
and 5 and vinblastine (5 mg/m2/week) plus oral estramustine
(140 mg three times a day) given at weeks 2, 4, and 6. No
therapy was given at weeks 7 and 8. Replacement doses of
hydrocortisone were administered throughout treatment to
counteract potential adrenal insufficiency secondary to the
ketoconazole. In 67% of patients (31 of 46), the PSA declined
by 50% or greater for a minimum duration of 8 weeks (95%
confidence interval, 52-80%). Among the 16 patients with
measurable soft tissue disease, there were 12 responses (75%;
95% confidence interval, 47-92%). The median duration of
response was 8. 4 months (1.8-14.9). The median survival for
the entire group was 19 months. The median survival of PSA
responders has not been reached, whereas that of nonresponders
was 13 months (P = 0.010). Seventy-six percent of symptomatic
patients noted improvement. Hematological toxicity was modest
and was managed without growth factors. Peripheral edema (49%)
and deep venous thrombosis (18%) were the most common
nonhematological toxicities. The alternating weekly regimen of
chemohormonal therapy is active for hormone-refractory
prostate cancer, providing a high rate of symptom control,
soft tissue response, and PSA decline.
Effects of an acidic beverage (Coca-Cola) on
absorption of ketoconazole.
Chin TW, Loeb M, Fong IW
Department of Pharmacy, St. Michael's Hospital, Toronto,
Canada.
Antimicrob Agents Chemother 1995
Aug;39(8):1671-5
Absorption of ketoconazole is impaired in patients with
achlorhydria. The purpose of this study was to determine the
effectiveness of a palatable acidic beverage (Coca-Cola
Classic, pH 2.5) in improving the absorption of ketoconazole
in the presence of drug-induced achlorhydria. A prospective,
randomized, three-way crossover design with a 1-week wash-out
period between each treatment was employed. Nine healthy
nonsmoking, nonobese volunteers between 22 and 41 years old
were studied. Each subject was randomized to receive three
treatments: (A) ketoconazole 200-mg tablet with water
(control), (B) omeprazole (60 mg) followed by ketoconazole
(200 mg) taken with water, and (C) omeprazole (60 mg) followed
by ketoconazole (200 mg) taken with 240 ml of Coca-Cola
Classic. The pH values of gastric aspirates were checked after
omeprazole was administered to confirm attainment of a pH of
> 6. Multiple serum samples were obtained for measurements
of ketoconazole concentrations by high-pressure liquid
chromatography. The mean area under the ketoconazole
concentration-time curve from zero to infinity for the control
treatment (17.9 +/- 13.1 mg.h/liter) was significantly greater
than that for treatment B (3.5 +/- 5.1 mg.h/liter; 16.6% +/-
15.0% of control).
Treatment of metastatic prostatic cancer with
low-dose prednisone: evaluation of pain and quality of life as
pragmatic indices of response.
Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart
L, Rider W
Princess Margaret Hospital, Toronto, Ontario, Canada.
J Clin Oncol 1989 May;7(5):590-7
Thirty-seven men with symptomatic bone metastases from
prostate cancer that had progressed following earlier
treatment with estrogens and/or orchidectomy were treated with
low-dose prednisone (7.5 to 10 mg daily). The rationale for
this treatment was that some patients might still have
hormone-sensitive disease that was stimulated by weak
androgens of adrenal origin, and that these androgens could be
suppressed by prednisone through its negative feedback on
secretion of adrenocorticotrophic hormone (ACTH). Response to
treatment was assessed by requirement for analgesics, by the
McGill-Melzack pain questionnaire, and by a series of 17
linear analog self-assessment (LASA) scales relating to pain
and to various aspects of quality of life. Fourteen patients
(38%) had improvement in indices used to assess pain at 1
month after starting prednisone, and seven patients (19%)
maintained this improvement for 3 to 30 months (median, 4
months). Reduction in pain was associated with improvement in
other dimensions of quality of life, and in the scale for
overall well-being. Prednisone treatment led to a decrease in
the concentration of serum testosterone in seven of nine
patients where it was not initially suppressed below 2 nmol/L,
and caused a decrease in serum levels of androstenedione and
dehydroepiandrosterone sulfate in more than 50% of patients.
Symptomatic response was associated with a decrease in serum
concentration of adrenal androgens. We conclude that (1)
low-dose prednisone may cause useful relief of pain in some
patients with advanced prostatic cancer; (2) relief of pain
was associated with suppression of adrenal androgens; and (3)
measures of pain and quality of life can be used to assess
possible benefits of systemic therapy in patients with
metastatic prostate cancer.
Chemotherapy with mitoxantrone plus prednisone or
prednisone alone for symptomatic hormone-resistant prostate
cancer: a Canadian randomized trial with palliative end
points.
Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore
MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy
KC
Department of Medicine, Princess Margaret Hospital, Toronto,
Canada.
ian-tannock@pmh.toronto.on.ca
J Clin Oncol 1996 Jun;14(6):1756-64
PURPOSE: To investigate the benefit of chemotherapy in
patients with symptomatic hormone-resistant prostate cancer
using relevant end points of palliation in a randomized
controlled trial.
PATIENTS AND METHODS: We randomized 161 hormone-refractory
patients with pain to receive mitoxantrone plus prednisone or
prednisone alone (10 mg daily). Nonresponding patients on
prednisone could receive mitoxantrone subsequently. The
primary end point was a palliative response defined as a
2-point decrease in pain as assessed by a 6-point pain scale
completed by patients (or complete loss of pain if initially 1
+) without an increase in analgesic medication and maintained
for two consecutive evaluations at least 3 weeks apart.
Secondary end points were a decrease of > or = 50% in use
of analgesic medication without an increase in pain, duration
of response, and survival. Health-related quality of life was
evaluated with a series of linear analog self-assessment
scales (LASA and the Prostate Cancer-Specific Quality-of-Life
Instrument [PROSQOLI]), the core questionnaire of the European
Organization for Research and Treatment of Cancer (EORTC), and
a disease-specific module.
RESULTS: Palliative response was observed in 23 of 80
patients (29%; 95% confidence interval, 19% to 40%) who
received mitoxantrone plus prednisone, and in 10 of 81
patients (12%; 95% confidence interval, 6% to 22%) who
received prednisone alone (P = .01). An additional seven
patients in each group reduced analgesic medication > or =
50% without an increase in pain. The duration of palliation
was longer in patients who received chemotherapy (median, 43
and 18 weeks; P < .0001, log-rank). Eleven of 50 patients
randomized to prednisone treatment responded after addition of
mitoxantrone. There was no difference in overall survival.
Treatment was well tolerated, except for five episodes of
possible cardiac toxicity in 130 patients who received
mitoxantrone. Most responding patients had an improvement in
quality-of-life scales and a decrease in serum
prostate-specific antigen (PSA) level.
CONCLUSION: Chemotherapy with mitoxantrone and prednisone
provides palliation for some patients with symptomatic
hormone-resistant prostate cancer.
Response of hormone resistant prostate cancer to
dexamethasone (dex) by weekly intravenous (IV) injection:
Improvement in performance status (PS), bone pain and
reduction in prostate specific antigen (PSA).
Proc Am Soc Clin Oncol 13:255A, 1994.
No abstract.
Prostate specific antigen levels and clinical
response to low-dose dexamethasone for hormone refractory
prostate carcinoma.
Proc Am Soc Clin Oncol 13: 235A, 1994.
No abstract.
Prostate specific antigen levels and clinical
response to low dose dexamethasone for hormone-refractory
metastatic prostate carcinoma.
Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC,
Richardson RL
Department of Family Medicine, Mayo Clinic, Rochester,
Minnesota 55905, USA.
Cancer 1995 Jul 1;76(1):96-100
BACKGROUND. It has been suggested that suppression of
adrenal androgens may provide benefit to patients with
metastatic prostate cancer refractory to initial hormonal
therapy (e.g., orchiectomy).
METHODS. The records of 38 patients with metastatic
prostate cancer that had progressed after orchiectomy who were
placed subsequently on low dose dexamethasone (DXM) with no
other concurrent therapy (36 patients received 0.75 mg twice
daily and two received 0.75 mg three times daily) were
reviewed. Symptomatic status, prostate specific antigen (PSA)
measurements, and available radiographic assessments were
recorded. Bone scans were reviewed by an independent, blinded
evaluator.
RESULTS. Symptomatic improvement was experienced by 24
patients (63%), 20 (83%) of whom also had decreases in PSA.
Prostate specific antigen values decreased in 30 patients
(79%) with decreases 50% or greater and 80% or greater in 23
(61%) and 13 (34%) patients, respectively. Of the 23 patients
with PSA decreases 50% or greater, 8 (35%) had radiographic
evidence of disease regression, 5 (22%) were stable, 7 (30%)
had disease progression, and 3 (13%) did not have serial
radiographic exams. Flutamide was discontinued shortly before
DXM treatment for 2 of the 23 patients.
CONCLUSIONS. Low dose DXM may produce important symptomatic
improvement and decreased PSA levels in the majority of
patients with hormone-refractory prostate cancer. In addition,
a substantial percentage of those patients with decreases in
PSA also will have radiographic evidence of disease
regression. These results suggest the need for additional
prospective controlled studies of DXM as a therapy for
hormone-refractory prostate cancer.
The contribution of hydrocortisone to the observed
response proportions of suramin.
Proc Am Soc Clin Oncol 13:A710, 1994.
No abstract.
The in vitro localization of H 3 estradiol in human
prostatic carcinoma. An electron microscopic autoradiographic
study.
Sinha AA, Blackard CE, Doe RP, Seal US
Cancer 1973 Mar;31(3):682-8
No abstract.
Hormonal effects in vitro on ribonucleic acid
polymerase in nuclei isolated from human prostatic
tissue.
Davies P, Griffiths K
J Endocrinol 1973 Nov;59(2):367-8
No abstract.
Metabolism and action of steroid hormones on human
benign prostatic hyperplasia and prostatic carcinoma grown in
organ culture.
Lasnitzki I;
J Steroid Biochem 11:625-630, 1979.
No abstract.
The Veterans' Administrative Cooperative Urological
Research Group's studies of cancer of the prostate.
Cancer 32:1126-30, 1973.
No abstract.
The Veterans' Administrative Cooperative Urological
Research Group studies of carcinoma of the prostate: a
review.
Cancer Chemother Rep 59(Part 1):225-7, 1975.
No abstract.
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