Bi-weekly epirubicin, etoposide and low-dose dexamethasone for hormone-refractory prostate cancer

BACKGROUND: Recent studies have demonstrated the efficacy and favorable toxicity profile of chemotherapy regimens given at lower doses and frequent intervals. The aim of our study was to evaluate the efficacy and toxicity of a bi-weekly chemohormonal regimen consisting of epirubicin, etoposide, and low-dose dexamethasone (EED) in patients with hormone-refractory prostate cancer (HRPC). METHODS: We treated a total of 32 patients who had failed hormonal therapy and antiandrogen withdrawal. Chemotherapy was given every 2 weeks and consisted of epirubicin (30 mg/m2 intravenously, day 1) and etoposide (50 mg/m2 orally, days 1-7). Dexamethasone (1.5 mg orally, every other day) was given continuously until disease progression. Twenty patients (63%) had received prior treatment with estramustine phosphate. Each patient's pain response was evaluated according to analgesic use. Toxicity was graded using the Common Toxicity Criteria (version 2.0). RESULTS: Prostate-specific antigen (PSA) levels showed a decline of 50% or greater in 16 of 32 patients (50%, 95% confidence interval [CI], 32-68%) with a median time to biochemical progression of 5 months (range, 4-9 months). The median survival for all patients was 10.5 months (range, 3-35 months). Four of 10 patients (40%) with measurable soft tissue lesions achieved partial response according to standard criteria. Eleven of 23 symptomatic patients (48%, 95% CI, 27-69%) experienced an improvement in pain with a median duration of 6 months. The regimen was tolerated well by the patients, with only four patients (12%) having grade 3 leukopenia. CONCLUSION: Chemohormonal EED regimen proved to be active and well-tolerated in patients with HRPC.     

Phase II study of epirubicin in advanced hormone-resistant prostatic carcinoma.

Twenty-nine patients with metastatic prostate cancer that had progressed following orchiectomy were treated with intravenous epirubicin 90 mg/m2 every 28 days. Their median age was 71 years (range 49-78) and the median Zubrod scale (WHO score) was 1. Two patients had soft tissue lesions, 20 had bone metastases and 7 had both. Tumour response was assessed according to the National Prostatic Cancer Project criteria. Of 29 patients, 11 (38%) achieved a partial remission. The median duration of response was 6 months and the median survival time of all patients was 9 months (range 2-27). It seemed that treatment with epirubicin was not associated with an increase in survival. Toxicity was moderate and consisted of alopecia and mild nausea/vomiting. There was no significant haematological toxicity and no clinical cardiotoxicity. It was concluded that epirubicin was active in hormone-resistant metastatic prostate cancer in approximately 33% of the patients.     

Chemohormonal therapy as primary treatment for metastatic prostate cancer: A randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist

BACKGROUND: The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer. METHODS: A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis. RESULTS: Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group. CONCLUSIONS: Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.     

Estramustine phosphate (Emcyt) as treatment for metastatic renal carcinoma

Sixteen patients completed an adequate trial of estramustine phosphate for the management of metastatic renal cell carcinoma. Although no patient showed a complete or partial response, 9 (56 per cent) had stabilization of disease for a median of 44 weeks. Toxicity was not severe, but intolerance to the drug may limit its widespread use.     

Effect of oral clodronate on bone pain

Although osteosclerotic metastases are characteristic of prostatic carcinoma, bone resorption is also accelerated. Since clodronate inhibits bone resorption and relieves bone pain, we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy. All patients received estramustine phosphate orally. Simultaneously they were randomly allocated to clodronate (36) and placebo (39) groups. Clodronate was given by mouth. The dose was 3.2 g for the first month, thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain. The use of analgesics stopped in 38% of patients on clodronate and in 18% on placebo which effect probably belongs to estramustine phosphate. Serum calcium concentration decreased more markedly in the clodronate group. Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups. No significant differences were seen in median survival or survival rates between the groups.     

Combination chemotherapy with paclitaxel,estramustine and carboplatin for hormone refractory prostate cancer

PURPOSE: The activity of estramustine phosphate is synergistic with paclitaxel against hormone refractory prostate cancer. Moreover, the single agent activity of carboplatin has demonstrated a 17% response rate in measurable disease. Therefore, we conducted a prospective trial to establish more effective chemotherapy consisting of paclitaxel, estramustine phosphate and carboplatin for hormone refractory prostate cancer. MATERIALS AND METHODS: The study included 32 patients with hormone refractory prostate cancer. Prior chemotherapy was accepted. Patients were treated with 100 mg./m.2 paclitaxel intravenously weekly, 10 mg./kg. estramustine phosphate orally daily and carboplatin intravenously to an area under the curve of 6 on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Of the 32 patients 30 were assessable for response. A median of 7 consecutive cycles was administered per patient. Ten patients had received prior cytotoxic chemotherapy. Levels of prostate specific antigen decreased by greater than 50% in 100% of patients and by greater than 90% in 56.7%. Partial response was obtained in 61.1% of measurable lesions. Consumption of medication for cancer induced pain was reduced in 89.5% of patients. Tumor volume reduction and/or antitumor therapeutic effects were exhibited in 81.0% of patients with positive biopsy. At a median followup of 48 weeks median time to progression was 48 weeks and median overall survival was 95 weeks. Two patients suffered myocardial infarction and hepatic insufficiency, respectively, and discontinued treatment during the first cycle. Major toxicities were grade 3 or 4 anemia in 59.4% of patients, leukopenia in 37.5%, thrombocytopenia in 28.1% and neuropathy in 12.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. CONCLUSIONS: Paclitaxel, estramustine phosphate and carboplatin chemotherapy was extremely effective for hormone refractory prostate cancer. Although hematological and neurotoxicity were modest, this therapy may be more manageable with lower doses.     

Sequentially alternating hormone chemotherapy with high-dose medroxy-progesterone acetate and low-dose epirubicin for the treatment of hormone-resistant metastatic prostatic cancer

Thirty patients with hormone-resistant metastatic progressive prostatic carcinoma were treated with sequentially alternating hormone chemotherapy. They were given 1,000 mg medroxyprogesterone acetate (MPA) orally for 26 days followed by intravenous doses of 25 mg/m2 epirubicin weekly for 4 weeks. The median duration of the treatment was 29 weeks (range 8-84). In 2 patients a more than 50% reduction in the size of measurable lymph node metastases was observed and in 2 others skeletal metastases decreased. Serum acid phosphatase normalized in 6 patients. Twenty-five patients achieved a subjective response (median duration 24 weeks; range 4-76 weeks). Median survival from the start of treatment (30 +/- 16 weeks) was unrelated to the achievement of subjective response. Normalization of serum acid phosphatase and a more than 50% reduction in serum alkaline phosphatase correlated with the achievement of a subjective response. Toxicity was generally mild, but in 1 case therapy was discontinued because of suspected cardiotoxicity. Sequentially alternating high-dose MPA low-dose epirubicin hormone chemotherapy has a marginal objective effect but a good subjective effect on progressing hormone-resistant prostatic cancer.     

An evaluation of high-doses ketoconazole with hydrocortisone substitution in hormone-refractory prostate cancer

We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal biosynthesis, for treating patients with progression of hormone-refractory prostate cancer. The study comprised 35 patients with progressive disease despite salvage treatment with estramustine with or without vinblastine. Treatment consisted high-doses ketoconazole (400 mg three times daily) and hydrocortisone substitution. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint of the study was PSA response to applied therapy. Of the 35 patients, 18 (51.4%) showed a decrease in PSA 50% with a median duration of 30 weeks (range 6-60 weeks). A PSA reduction 50% was seen in 15 of 31 patients (48.4%) with established metastasis. Twelve patients (34.2%), all of whom had metastasis, exhibited a PSA decrease 80% with median duration of 9 months (range 3-48 months). The median time to progression was 6.3 months (range 0-27 months) and the median survival time was 12.5 months (range 3-48 months). Twelve (34.3%) reported toxicity related to ketoconazole, whereas no patients required discontinuation of therapy. It is apparent from this study that a reasonable percentage of patients failing salvage chemotherapy (estramustine with or without vinblastine) respond favorably to high-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trail of ketoconazole should be considered when progression of PSA occurs, following initial hormonal androgen deprivation.     

Evaluation of adjuvant estramustine phosphate,cyclophosphamide and observation only for node-positive patients following radical prostatectomy and definitive irradiation

In 1978 the National Prostate Cancer Project launched two protocols evaluating adjuvant therapy following surgery (Protocol 900) or irradiation (Protocol 1,000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy. Following definitive treatment, patients were randomized to either cyclophosphamide 1 gram/m²-IV every 3 weeks for 2 years, estramustine phosphate 600 mg/m²-po daily for up to 2 years, or to observation only. Patient accession closed in 1985 and includes 184 to Protocol 900 (170 evaluable) and 253 to Protocol 1,000 (233 evaluable). Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900, 63% in Protocol 1,000. Median progression-free survival (PFS) for patients with nodal involvement in Protocol 1,000 receiving estramustine phosphate adjuvant was longer (37.3 mo) compared to cyclophosphamide (30.9 mo) and to no treatment (20.9 mo). Median PFS for patients with limited nodal disease in Protocol 1,000 was longer (39.9 mo), regardless of adjuvant, compared to extensive nodal disease (20.7 mo). However for patients with extensive nodal involvement, those receiving adjuvant estramustine phosphate experienced a significantly longer median PFS (32.8 mo) compared to adjuvant cyclophosphamide (22.7 mo) and no adjuvant (12.9 mo). We conclude that adjuvant estramustine phosphate is of benefit in prostate cancer patients with extensive pelvic node involvement receiving irradiation as definitive treatment. © 1996 Wiley-Liss, Inc.     

Safety and efficacy of docetaxel,estramustine phosphate and hydrocortisone in hormone‐refractory prostate cancer patients

Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone‐refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate‐specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3–4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4–5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.     

A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.     

Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer

OBJECTIVES: Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer. METHODS: From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2). RESULTS: A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months. CONCLUSIONS: The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.     

Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancer

A total of 42 patients with hormone-refractory prostate cancer received E-E therapy. Oral estramustine phosphate (EMP) was administered twice daily for a total daily dose of 560 mg every day and oral etoposide (E-E therapy, 50 mg/body/day) was given on days 1-21 and stopped on days 22-35. Treatment was continued until the disease progression was confirmed radiographically or PSA had increased from base line of at least 25%. The median follow-up period after E-E therapy was 77.4 months (range : 12.5 to 122.3). Nineteen patients (43%) achieved a PSA decrease of 50% or greater. The median survival time of the patients who had a decrease of 50% or greater in the PSA value (PSA responder) was 29.3 months and the patients who did not (PSA non-responder) was 14.1 months (p = 0.01). There were no significant differences between PSA responders and non-responders when taking into account variables. Excluding those patients with only PSA elevation, the survival time was 14.9 months with no significant difference between PSA responders and non-responders. The toxicities (grade 3 or more) were identified as anemia, leukocytopenia thrombocytopenia, cardiovascular events, and gastrointestinal and hepatic disorders, which occurred in 0, 5, 2, 2, 14, and 2% of the patients, respectively. E-E therapy was considered to be an active oral regimen and well-tolerated for outpatients with hormone-refractory prostate cancer in Japanese patients.     

Quality of life assessment in patients with hormone-resistant prostate cancer treated with epirubicin or with epirubicin plus medroxy progesterone acetate - is it feasible?

OBJECTIVES: The optimal palliative treatment in patients with advanced hormone-resistant prostate cancer (AHRPC) is still under investigation. We studied the effect of epirubicin, alone or combined with medroxy progesterone acetate (MPA), in this particular patient group. The aim of the study was to investigate the feasibility of quality of life (QOL) measurement and to ascertain whether MPA added to epirubicin produces a better QOL than epirubicin alone. METHODS: Of 28 randomized patients with symptomatic AHRPC, 26 were eligible for the study. Fourteen of them received epirubicin (100 mg/m(2) i.v.) every 3 weeks in combination with an oral dose of 500 mg of MPA twice daily. Twelve patients received epirubicin alone. For the QOL assessment, the Rotterdam Symptom Checkliste was used. Toxic side effects of chemotherapy were assed by the WHO criteria. Subjective responses included performance status and pain score. RESULTS: Compliance in completing QOL questionnaires was high (87.5%). In none of the QOL domains studied did any of the patients, irrespective of their treatment, experience an improvement in their QOL. Moreover, after 12 and 24 weeks, patients in both treatment arms experienced a significant worsening of physical symptom distress when compared to study entry. Toxicity was moderate to severe. A biochemical response (drop in prostate-specific antigen of more than 50%) was observed in 5 out of 26 patients (19.1%) and a subjective response in 7 out of 26 patients (26.9%). The median survival for all patients was 30 weeks. There was no statistically significant difference between the two arms. Performance status and the global QOL as judged by the patients themselves were associated with the duration of survival. No relation was found between the initial observed subjective response and survival. CONCLUSIONS: The feasibility of measuring QOL in patients with symptomatic AHRPC is demonstrated in the present study. Subjective and biochemical responses were observed in both treatment arms, but these were not translatable as improved measured QOL domains.     

Chemotherapy agents and timing of chemotherapy in prostate cancer management

In 2005, it is estimated that more than 30,000 men will die from metastatic hormone-refractory prostate cancer. For decades, no chemotherapeutic agent demonstrated a survival benefit in these patients, although two randomized clinical trials demonstrated a clear palliative benefit using mitoxantrone combined with a corticosteroid. However, beginning in 1999, a series of phase-2 trials were performed using docetaxel, either as a single agent or in combination with estramustine. Preliminary data implied a survival improvement, with median survivals reported to be 14 to 23 months. Prostate-specific antigen levels dropped by more than 50% in 38% to 48% of patients treated with docetaxel. These findings were confirmed in two phase-3 randomized trials in which docetaxel with and without estramustine have demonstrated a survival benefit using chemotherapy in the treatment of hormone-refractory prostate cancer.     

Selective regional chemotherapy of unresectable hepatic tumours using lipiodol.

Over a 30 month period from 1987 to 1990, selective hepatic cannulation under fluoroscopic control was performed in 57 consecutive patients with primary and secondary malignancies of the liver. Fifty-three patients were subsequently treated using intra-arterial Lipiodol emulsified with epirubicin. The tumours treated were hepatocellular carcinoma (n = 35), metastatic adenocarcinoma (n = 14), intrahepatic cholangiocarcinoma (n = 3) and leiomyosarcoma (n = 1). For hepatocellular carcinoma the cumulative survival was 38% at one year; the median survival was 12.2 months for Stage I, 6.3 months for Stage II and 0.9 months for Stage III tumours. In metastatic disease the cumulative survival was 63% at one year. These data suggest that targeted intra-arterial chemotherapy with Lipiodol-epirubicin is a useful palliative therapy for patients with Stage I and II HCC, and that a controlled trial of this treatment should be undertaken.     

Intermittent oral hormonal chemotherapy using estramustine phosphate and etoposide for the treatment of hormone-refractory prostate cancer

Seventeen patients were given lower dose and intermittent oral administration of estramustine phosphate (6 mg/kg/day) and etoposide (30 mg/m2/day) for 7 days. Then administration was discontinued for 7 days. This administration cycle was repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. Fifteen of the 17 patients were finally evaluated for PSA response. Overall, the pretreatment PSA levels were lowered at least 50% from baseline in 7 (47%) of the 15 patients. The median survival was 65 weeks. Five of the 17 patients complained of anorexia or nausea during the treatment, but none of them showed over grade 2 anorexia, none requiring transfusion or hospitalization. None of the patients showed edema, deep venous thrombosis, thrombocytopenia, anemia or myocardial infarction. Because of its rare and mild adverse effects, this intermittent administration of oral estramustine and oral etoposide may be a useful and secure regimen for hormone refractory prostate cancer.     

激素抵抗性前列腺癌(附39例报告)

目的探讨激素抵抗性前列腺癌的诊断和治疗,以提高其诊治水平。同时比较中国人和欧美人激素抵抗性前列腺癌生存期的差异。方法回顾性分析1995年6月～2004年10月39例激素抵抗性前列腺癌患者的临床资料。结果确诊激素抵抗性前列腺癌时,38例血PSA值较最低点均有不同程度升高,血PSA值0．2ng/ml～200ng/ml,平均(51．16±54．71)ng/ml,其中有4例血PSA值一直在4ng/ml以下,升高很少,主要靠转移灶来诊断。化疗是主要的治疗方法,常用的有磷酸雌二醇氮芥,磷酸雌二醇氮芥 足叶乙甙,环磷酰胺 足叶乙甙,磷酸雌二醇氮芥 环磷酰胺等。PSA有效率为44．4%～57．8%,平均有效时间3,8月～7．5月,软组织灶有效率为28．6%～50%。39例中已死亡21例,这21例诊断激素抵抗性前列腺癌后,中位生存期为16个月。结论绝大多数激素抵抗性前列腺癌患者可用PSA诊断和随访,但极少数患者PSA变化很小,需用癌灶和症状来随访。化疗是治疗激素抵抗性前列腺癌的主要方法,有一定的疗效。本组患者生存时间似较欧美患者长。     

Extended therapy of stage D carcinoma of the prostate with oral estramustine phosphate.

We treated 50 patients with stage D carcinoma of the prostate with 15 mg. per kg. per day oral estramustine phosphate for 3 to 24 months. We are able to evaluate 44 patients. Objective remissions were induced in 8 of the 44 patients (19 per cent) and subjective remission occurred in all objective responders and in 7 additional patients for a subjective response of 15 of 44 (36 per cent). No hematologic or renal toxicity was encountered. Transient nausea occurred early in half of the patients and was dose limiting in 3 patients. One case of hepatic toxicity was seen. Oral estramustine phosphate is well tolerated and long-term therapy is feasible.     

The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin

Thirty previously untreated patients with carcinoma of the prostate were prospectively randomised to one of the following treatments: ethinyl oestradiol (Etivex) combined with polyoestradiol phosphate (Estradurin); estramustine phosphate (Estracyt); bilateral orchiectomy. Oestrogenic effects were measured by blood levels of pregnancy zone protein, sex hormone binding globulin, LH, FSH and prolactin. During a follow-up period of 6 months, estramustine phosphate and ethinyl oestradiol/polyoestradiol phosphate induced comparable changes in these proteins, suggesting comparable oestrogenic effects of these two forms of treatment in patients with prostatic carcinoma.