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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.
Optimal dosing of ketoconazole (Keto) and
hydrocortisone (HC) leads to long responses in hormone
refractory prostate cancer.
Muscato JJ, Ahmann TA, Johnson KM, et al
Proc Am Soc Clin Oncol 13:229A, 1994.
No abstract.
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):2371-2376
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).
Harvey, WH and Bretton PR
Proc Am Soc Clin Oncol 13:255A, 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.
Kelly WK, Scher H, Bajorin D, et al
Proc Am Soc Clin Oncol 13:A710, 1994.
No abstract.
The in vitro localization of 3H-estradiol in human
prostatic carcinoma.
Sinha AA, Blackard CE, Doe RP, et al:
Cancer 31:682-8, 1973.
No abstract.
Hormonal effects in vitro on ribonucleic acid
polymerase in nuclei isolated from human prostatic
tissue.
Davies P, Griffiths K
J Endocrinol 59:367-368, 1973.
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.
Byer DP
Cancer 32:1126-30, 1973.
No abstract.
The Veterans' Administrative Cooperative Urological
Research Group studies of carcinoma of the prostate: a
review.
Blackard CE
Cancer Chemother Rep 59(Part 1):225-7, 1975.
No abstract.
Comparison of diethylstilbestrol, cyproterone
acetate and medroxyprogesterone acetate in the treatment of
advanced prostatic cancer: final analysis of a randomized
phase III trial of the European Organization for Research on
Treatment of Cancer Urological Group.
Pavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E,
Lardennois B, de Pauw M, Sylvester R
J Urol 1986 Sep;136(3):624-31
Patients with previously untreated category T3 to T4 Mo or
Ml prostatic cancer were allocated randomly to receive 250 mg.
cyproterone acetate per day, a loading dose of 500 mg.
medroxyprogesterone acetate intramuscularly 3 times weekly for
8 weeks followed by 100 mg. orally twice daily, or 1 mg.
diethylstilbestrol 3 times daily in a phase III trial
(protocol 30761) performed by the genitourinary tract
cooperative group of the European Organization for Research on
the Treatment of Cancer. Of 236 patients entered 210 were
eligible: 75 received cyproterone acetate, 71
medroxyprogesterone acetate and 64 diethylstilbestrol. Local
and distant tumor response, time to progression, survival and
toxicity were assessed. Patients treated with
medroxyprogesterone acetate had a less favorable course with a
shorter duration of survival and time to progression than
those treated with the other 2 drugs. There was no significant
difference between diethylstilbestrol and cyproterone acetate.
Cardiovascular side effects were reported more often in
patients treated with diethylstilbestrol than in those treated
with cyproterone acetate but severe and lethal cardiovascular
toxicity was relatively low in all groups. Other side effects
were negligible. Further studies are required to establish the
influence of effective hormonal treatment upon survival.
Haemostatic changes during hormone manipulation in
advanced prostate cancer: a comparison of DES 3 mg/day and
goserelin 3.6 mg/month.
Emtage LA, George J, Boughton BJ, Trethowan C, Blackledge
GR
West Midlands Cancer Research Campaign Clinical Trials Unit,
Department of Medicine, Queen Elizabeth Hospital, Birmingham,
U.K.
Eur J Cancer 1990 Mar;26(3):315-9
Two hundred and fifty patients were entered into a
randomized clinical study to compare the effectiveness of
goserelin (Zoladex) in depot formulation with diethyl
stilboestrol in locally advanced or metastatic prostate
cancer. In 22 patients from the two arms of the study regular
assessments were made of the effect of these hormone
treatments on the haemostatic system. Selection of those
patients with no recent surgical intervention and those on no
drugs liable to interfere with the haemostatic mechanism was
done at entry, in order to remove bias and achieve comparable
groups. Baseline comparison of the two treatment groups showed
no difference in clinical or biochemical measures of disease
extent or activity, including serum prostate specific antigen
(PSA) levels. There was a significant fall in plasma
antithrombin-III (AT-III) activity in the DES treated group
both from baseline and compared with the goserelin group. This
effect commenced within 1 month and was maintained until
monitoring ceased at 12 months. There was also a significant
increase of fibrinolytic activity in the DES treated patients
compared with those on goserelin. No divergence between the
two treatment groups was seen in any other haematological
parameters at baseline or on follow-up. A single AT-III
estimation was also performed on a larger group of 74 patients
at median follow-up time of 17 months (range 3-24). This
confirmed the difference noted in the original study group. In
the main study thrombotic episodes were noted in 13/126
patients treated with DES and 0/124 treated with goserelin (P
less than 0.001). These findings suggest that lowered AT-III
is the major factor through which DES affects the coagulation
mechanism, and that no such effect is seen with goserelin
treatment despite an equivalent therapeutic efficacy.
Hormone therapy for prostate cancer: results of the
Veterans Administrative Cooperative Urological Research Group
studies.
Byer DP and Corle DK
NCI Monogr 7:165-70, 1988.
No abstract.
Hormonal therapy of prostatic cancer.
Scott WW, Menon M and Walsh PC
Cancer 47(7 suppl):1929-36, 1980.
No abstract.
Clinical efficacy of Diethylstilbestrol treatment
in post-orchiectomy progressive prostate cancer.
Jazieh AR, Munshi NC, Muirhead M and Ross SW
Proc Am Assoc Cancer Res 35:233A, 1994.
No abstract.
A phase II trial of oral diethylstilbesterol as a
second-line hormonal agent in advanced prostate cancer.
Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta
KJ
University of Michigan Comprehensive Cancer Center, Division
of Hematology/Oncology, University of Michigan School of
Medicine, Ann Arbor, USA.
Urology 1998 Aug;52(2):257-60
OBJECTIVES: To test the use of 1 mg/day of oral
diethylstilbesterol (DES) as a treatment for patients with
advanced prostate cancer who had failed primary hormonal
therapy. Approximately 40,000 men this year will experience
first-line hormonal therapy failure for their metastatic
prostate cancer. At this time there is no standard therapy for
men whose first-line hormonal manipulation has failed. This
clinical problem has been exacerbated by the use of
prostate-specific antigen (PSA) as a proved biomarker to
follow disease progression. Patients who are experiencing
hormonal therapy failure now present with a rising PSA, and
virtually all are asymptomatic. The dilemma of how to treat
these patients represents a new clinical problem for the
medical oncologist and urologist that needs to be
answered.
METHODS: We conducted a Phase II trial of oral DES in 21
patients. Patients were followed for response by PSA criteria
and toxicity. A decrease in two serial measurements of PSA of
greater than 50% from baseline was judged to be a partial
response.
RESULTS: Nine of 21 patients achieved a PSA response (43%
response rate with 95% confidence intervals of 22% to 64%)
leading to early cessation of this Phase II trial. Eight of 13
patients (62%) who had only one prior hormone manipulation
that failed demonstrated a PSA response, whereas only 1 of 8
patients (13%) who had received two or more hormone treatments
responded (P = 0.07). The median follow-up is 82 weeks (range
8 to 122) among 16 surviving patients. The survival rate at 2
years is 63% (95% confidence interval 41% to 99%).
CONCLUSIONS: DES appears to be an active agent for
second-line hormone therapy for metastatic prostate cancer.
Because it has been taken off the market for economic reasons,
DES should be considered for development under the orphan drug
strategy.
Clinical trial of massive stilboestrol diphosphate
therapy in advanced carcinoma of the prostate.
Colapinto V and Aberhart C
Br J Urol 33:171, 1961.
No abstract.
Effect of stilboestrol and testosterone on the
incorporation of 75selenomethionine by prostatic carcinoma
cells.
Ferro MA, Heinemann D, Smith PJ, Symes MO
Department of Urology, University of Bristol, Royal
Infirmary.
Br J Urol 1988 Aug;62(2):166-72
Controversy still exists as to whether oestrogens exert a
direct effect on the prostatic cell. Incorporation of
75Selenomethionine (SeM) was used as a measure of protein
synthesis by prostatic carcinoma cells in vitro to investigate
the action of hormones on prostatic carcinoma cells in tissue
culture. Stilboestrol (DES) and stilboestrol diphosphate
(Honvan) inhibited protein synthesis in a proportion of
patients, while testosterone was stimulatory. A similar effect
was noted in cells from patients with benign hyperplasia
(BPH). This work confirms that oestrogens have a direct
inhibitory effect on prostatic cells at high concentrations
which can be attained in patients given intravenous
stilboestrol diphosphate.
Bioavailability, distribution and pharmacokinetics
of diethystilbestrol produced from stilphostrol.
Abramson FP, Miller HC Jr
J Urol 1982 Dec;128(6):1336-9
The kinetic behavior of diethylstilbestrol (DES) produced
from stilphostrol has been studied in man, dog and rat. A
sensitive and selective assay for DES in plasma and tissues
has been developed with the use of gas chromatographic
separation and mass spectrometric detection. In patients with
prostate cancer, the plasma concentrations of DES produced by
1,000-mg. infusions of stilphostrol are 1,500 times the DES
concentrations produced by conventional oral DES doses. The
pharmacokinetics of DES show 2 separate phases; 1 with a t1/2
of approximately 1 hour, another with a t1/2 of approximately
a day. In rats, stilphostrol does not selectively liberate DES
in the prostate compared to dosing with DES itself. In dogs, a
50-mg. tablet of stilphostrol was bioequivalent to 40 mg. of
DES taken orally. Some of these data support the idea that the
high DES concentrations produced by stilphostrol infusions
underlie in its ability to produce objective responses in
patients refractory to conventional oral DES therapy.
High-dose intravenous estrogen therapy in advanced
prostatic carcinoma. Use of serum prostate-specific antigen to
monitor response.
Ferro MA, Gillatt D, Symes MO, Smith PJ
Department of Urology, Bristol Royal Infirmary, United
Kingdom.
Urology 1989 Sep;34(3):134-8
High-dose intravenous estrogen therapy was shown to be
effective in relieving bone pain due to metastatic disease in
22 of 29 (75.9%) men with advanced hormone-resistant prostate
cancer. This clinical response was accompanied by significant
falls in serum prostate-specific antigen (PSA) levels in 13
(44.8%) patients. It is suggested that this clinical benefit
is due to a direct inhibitory effect of estrogen on prostate
cancer cells.
High-dose continuous-infusion fosfestrol in
hormone-resistant prostate cancer.
Droz JP, Kattan J, Bonnay M, Chraibi Y, Bekradda M, Culine
S
Department of Medicine, Institut Gustave-Roussy, Villejuif,
France.
Cancer 1993 Feb 1;71(3 Suppl):1123-30
BACKGROUND. The initial treatment of advanced-stage
prostate cancer is total androgen deprivation. Autonomous
proliferation of primarily or secondarily hormonal
unresponsive cells may explain the development of
hormone-refractory status. The median survival of patients
with hormone-resistant disease is short; there is no standard
regimen of chemotherapy.
METHODS. Fosfestrol or diethylstilbestrol diphosphate and
its metabolites have cytotoxic activity in hormone-refractory
prostatic cell lines. Pharmacokinetic studies have shown that
fosfestrol metabolites have a short half-life that supports
the use of long-term infusion in the clinic.
RESULTS. A review of the literature shows that high-dose
fosfestrol induces no objective response, a greater than 50%
tumor marker decrease in 50% of patients, a subjective
improvement in 75% of patients, and cardiovascular
complications in 5% of patients. The median survival time of
patients is 5 months after the onset of treatment.
CONCLUSIONS. An exact evaluation of the role of high-dose
estrogens requires additional investigation.
Use of intravenous stilbestrol diphosphate in
patients with prostatic carcinoma refractory to conventional
hormonal manipulation.
Ferro MA
Huddersfield Royal Infirmary, West Yorkshire, England.
Urol Clin North Am 1991 Feb;18(1):139-43
The patient presenting with severe bone pain after primary
hormonal therapy, with vertebral collapse, or with uremia
resulting from ureteric obstruction should be considered for
intravenous stilbestrol diphosphate therapy. The urologist can
expect early marked improvement in the patients' mobility and
pain, with a reduction in analgesic requirements, from a
single 7-day course of treatment. In addition, the drug is
inexpensive and free of the side effects commonly associated
with cytotoxic therapy. Accurate monitoring of the response is
possible with serum prostate-specific antigen measurements,
which also enable further therapy to be planned
efficiently.
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