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.

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.

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.

Muscato JJ, Ahmann TA, Johnson KM, et al
Proc Am Soc Clin Oncol 13:229A, 1994.

No abstract.

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.

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.

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.

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.

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).

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.

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.

Harvey, WH and Bretton PR
Proc Am Soc Clin Oncol 13:255A, 1994.

No abstract.

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.

Kelly WK, Scher H, Bajorin D, et al
Proc Am Soc Clin Oncol 13:A710, 1994.

No abstract.

Sinha AA, Blackard CE, Doe RP, et al:
Cancer 31:682-8, 1973.

No abstract.

Davies P, Griffiths K
J Endocrinol 59:367-368, 1973.

No abstract.

Lasnitzki I
J Steroid Biochem 11:625-630, 1979.

No abstract.

Byer DP
Cancer 32:1126-30, 1973.

No abstract.

Blackard CE
Cancer Chemother Rep 59(Part 1):225-7, 1975.

No abstract.

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.

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.

Byer DP and Corle DK
NCI Monogr 7:165-70, 1988.

No abstract.

Scott WW, Menon M and Walsh PC
Cancer 47(7 suppl):1929-36, 1980.

No abstract.

Jazieh AR, Munshi NC, Muirhead M and Ross SW
Proc Am Assoc Cancer Res 35:233A, 1994.

No abstract.

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.

Colapinto V and Aberhart C
Br J Urol 33:171, 1961.

No abstract.

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.

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.

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.

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.

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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