Treatment of prostatic cancer: effects on serum lipoproteins and the cardiovascular system

We studied 32 patients with prostatic cancer before, and after 1 and 6 months of treatment with orchiectomy, estramustine phosphate or conventional estrogens (polyestradiol phosphate plus ethinyl estradiol). Lipid metabolism was evaluated by lipoprotein analysis and the intravenous fat tolerance test. Effects on the cardiovascular system were studied by exercise electrocardiography, blood volume estimation and thoracic electrical impedance measurement, a sensitive method to detect early signs of fluid retention. Present treatment programs for prostatic cancer seem to result in effects on lipoprotein metabolism that probably are of minor importance for the development of atherosclerotic manifestations. Measurement of thoracic impedance may be of value to detect fluid retention in individual patients.     

Cardiovascular complications of estrogen therapy for nondisseminated prostatic carcinoma. A preliminary report from a randomized multicenter study

In a prospective multicenter study, 244 men with highly or moderately differentiated prostatic cancer in stage I, II or III (VACURG) were consecutively randomized to three groups of treatment: Group A (77 patients) received polyestradiol phosphate (Estradurin, Leo) 80 mg i.m. every fourth week + ethinyl estradiol (Etivex, Leo) 150 micrograms daily, group B (72 patients) estramustine phosphate (Estracyt, Leo) 280 mg twice daily, and group C (76 patients) no therapy. Only men without current or previous other malignancy and without cardiovascular disease were admitted to the study. After 4 1/2 years 125 of the 244 patients had left the study, 9 because of cancer progression (stage IV, VACURG). The most serious complications were cardiovascular, including ischemic heart disease, cardiac decompensation, cerebral ischemia and venous thromboembolism, which occurred in 24 patients from group A and 9 from group B as compared to only one patient in group C. The subgroup superficial or deep venous thrombosis comprised 11 group A and 2 group B patients. Estrogens (E + e) offered as palliative treatment to patients with non-generalized prostatic carcinoma is burdened with a high incidence of serious cardiovascular complications.     

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.     

Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen.

BACKGROUND: The present pilot study tested the clinical performance of a new pharmacokinetically guided dosing regimen of parenteral estrogen in patients with advanced prostatic carcinoma. The aim was to accelerate endocrine effects and to avoid cardiovascular side effects. METHODS: Seventeen patients were randomized to intramuscular injections of 240 mg polyestradiol phosphate (PEP) every second week for the first 8 weeks (five doses), followed by a maintenance dose of 240 mg every month; and 16 patients were randomized to bilateral orchidectomy. The estrogen dosing was calculated by pharmacokinetic modelling to achieve a rapid increase in serum estradiol and thereby a fast decrease in testosterone. RESULTS: The predicted increment in serum estrogen was achieved, together with a subsequent decrease in testosterone in the PEP group. In addition, there were no signs of an increased cardiovascular morbidity. This was probably due to a minimal estrogenic influence on the liver and was reflected by unchanged levels of coagulation factor VII. Clinical effects, during the first 2 years of treatment, were similar in the two treatment arms, with 12 patients in the orchidectomy group and 14 patients in the PEP group responding to treatment. CONCLUSIONS: The present parenteral regimen is an efficient and time-saving estrogen regimen with a favorable side-effect profile. PEP seems to offer a potential for revival of the most cost-effective endocrine treatment of cancer of the prostate, i.e., estrogen.     

Cardiovascular and all-cause mortality in prostatic cancer patients treated with estrogens or orchiectomy as compared to the standard population

Four hundred and seventy-seven prospectively randomized patients with prostatic carcinoma were treated with a combination of intramuscular polyestradiol phosphate (PEP) and oral ethinyl estradiol, with intramuscular PEP alone, or with orchiectomy. The cardiovascular and all-cause mortality of the two estrogen therapy modalities and orchiectomy were compared with those of the Finnish male population in general. The age-standardized rate ratios (approximately relative risk) for cardiovascular mortality and for all-cause mortality were 1.51 and 2.31 in the combination estrogen therapy group, 0.17 and 1.50 in the PEP monotherapy group, and 0.78 and 1.78 in the orchiectomy group, respectively. Further mortality rates by cause for all three treatment groups were standardized for age using the age-specific person-years at risk as standard. Age-standardized mortality from cardiovascular diseases was very low in the PEP group, as compared to other treatment modalities, and the mortality rates for prostatic cancer were about equal in all three treatment groups. It is concluded that intramuscular PEP monotherapy is associated with low cardiovascular mortality and with an all-cause and prostatic cancer mortality equal to orchiectomy.     

A randomized study on hormone-resistant prostatic cancer: estramustine phosphate versus low dose epirubicin with or without medroxyprogesterone acetate. A Norwegian multicenter study

A prospective randomized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer. A total of 79 patients were included. One group was treated with estramustine phosphate, another with Epirubicin plus Medroxyprogesterone acetate (MPA), while the third arm consisted of Epirubicin plus placebo. Best palliation was obtained by the combination of Epirubicin and MPA. This combination also seemed to be associated with the longest response duration.     

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.     

Evidence for a non-estrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo.

Estramustine is one of the main metabolites of estramustine phosphate (EstracytR), a drug used in the treatment of advanced prostatic cancer. In the present study the hormone independent human prostatic carcinoma cell line DU 145 implanted subcutaneously in nude mice (NMRI) was used to investigate the mode of action of estramustine in vivo. Metaphase arrest was found in mice treated with estramustine intraperitoneally, 200 and 400 micrograms daily for 2 weeks, 5 days a week. A significant dose dependent decrease in the number of anaphase figures was found. A 7 to 8 fold increase in the number of abnormal metaphases, i.e., highly contracted and unaligned chromosomes, was found. Uptake and retention of 3H-estramustine was found in tumour tissue. No increase in the mitotic index or the number of abnormal metaphases was found in animals treated with polyestradiol phosphate (EstradurinR). This is the first time evidence has been presented demonstrating the anti-mitotic effect of estramustine in vivo.     

Prospective evaluation of hot flashes during treatment with parenteral estrogen or complete androgen ablation for metastatic carcinoma of the prostate.

PURPOSE: We evaluated the incidence and frequency of, and distress due to hot flashes after castration therapy with polyestradiol phosphate and complete androgen ablation. MATERIALS AND METHODS: A total of 915 men with metastatic prostate carcinoma enrolled in the Scandinavian Prostatic Cancer Group-5 trial study were randomized to intramuscular injections of 240 mg. Polyestradiol phosphate every 2 weeks for 8 weeks followed by monthly subcutaneous injections or complete androgen ablation, that is bilateral orchiectomy or 3.75 mg. of the gonadotropin-releasing hormone analog triptorelin monthly combined with 250 mg. of the antiandrogen flutamide 3 times daily. The incidence and frequency of, and distress due to hot flashes were recorded at regular intervals using a questionnaire. RESULTS: Of the 915 men 901 were evaluated at a median followup of 18.5 months. The incidence of hot flashes was 30.1% and 74.3% in the polyestradiol phosphate and complete androgen ablation groups, respectively (p <0.001). In the polyestradiol phosphate group the frequency of and distress due to hot flashes were significantly lower than in the androgen ablation group. There was complete relief from hot flashes in 50% of the men on polyestradiol phosphate during followup compared with none on androgen ablation. The incidence of hot flashes did not differ in men with and without tumor progression. CONCLUSIONS: Endocrine treatment with polyestradiol phosphate induced fewer and less distressing hot flashes than complete androgen ablation. Flashes also disappeared to a greater extent during polyestradiol phosphate than during androgen ablation. The data in this study enable us to provide thorough individual information to patients on the risk and grade of expected distress and duration of hot flashes during polyestradiol phosphate or complete androgen ablation treatment.     

Adrenocortical function in prostatic cancer patients: effects of orchidectomy or different modes of estrogen treatment on basal steroid levels and on the response to exogenous adrenocorticotropic hormone

Basal serum levels and ACTH-induced increments ('delta-values') of dehydroepiandrosterone (DHA) and its sulfate (DHAS), 4-androstene-3,17-dione (A-4), 17 alpha-hydroxyprogesterone (17-OHP), cortisol and testosterone and serum albumin levels were studied in patients with prostatic cancer before treatment and after orchidectomy or during estrogen treatment (intramuscular polyestradiol phosphate during the first 3 months, followed by another 3 months with additional oral ethinyl estradiol). Orchidectomy as well as single drug intramuscular or oral + intramuscular estrogens exerted a similar suppressive effect on basal levels of A-4 and 17-OHP. Orchidectomy caused a slight decrease in basal DHAS, while combined oral + intramuscular estrogens caused a pronounced decrease in basal DHAS and also in DHA. Single drug intramuscular estrogens did not affect basal DHA or DHAS levels. Increased basal cortisol levels appeared during combined oral + intramuscular estrogen therapy. delta DHA and delta A-4 values were unaffected by endocrine treatment, but delta 17-OHP and delta cortisol increased slightly after orchidectomy and during estrogen therapy. Significantly decreased albumin levels were only observed during combined oral + intramuscular estrogen treatment. Determination of estriol, which is a major metabolite of estradiol originating from polyestradiol phosphate, revealed significantly higher estriol levels during combined oral + intramuscular estrogen treatment than during single drug intramuscular estrogen therapy, indicating an increased induction of hepatic 16 alpha-hydroxylase activity. The pronounced decreases in DHAS and also in DHA during combined oral + intramuscular estrogen treatment are probably another reflexion of the liver side effects of oral estrogens.     

Results of another trial of chemotherapy with and without hormones in patients with newly diagnosed metastatic prostate cancer

From July, 1980, to June, 1983, 319 patients with newly diagnosed metastatic prostatic cancer were randomized to one of three treatment protocols: diethylstilbestrol (DES) or bilateral orchiectomy, cyclophosphamide plus 5-fluorouracil plus DES, and estramustine phosphate (Emcyt). Ninety-three per cent of 296 patients were eligible for evaluation. This report shows no difference in survival, disease-free progression time, or status regarding pain at entry. Other prognostic factors failed to reveal any difference within any of the treatment protocols.     

Single-drug parenteral estrogen treatment in prostatic cancer: a study of two maintenance-dose regimens

Treatment of 17 patients with prostatic cancer with 320 mg polyestradiol phosphate (PEP) as intramuscular injections every fourth week suppressed serum testosterone (T) values to orchidectomy levels within 1 month, and serum estradiol-17 beta (E2) rose to a mean level of 2,456 pmol/liter after 6 months. Following 6 months of treatment, the PEP dose was reduced to 80 mg/4 weeks in 9 and 160 mg/4 weeks in eight patients. Mean T levels, increased significantly after dose reduction in both groups and were above the upper orchidectomy limit at 1 month after dose reduction in the 80 mg group. Mean T levels, however, remained below this level at 5 months in the 160 mg group. Dose reduction caused a rise in gonadotropin levels in the 80 mg but not in the 160 mg group. While 320 mg/4 weeks may be a suitable initial dosage, doses less than or equal to 160 mg/4 weeks are insufficient as maintenance dosages if orchidectomy values of T are required.     

Steroid-sensitive proteins, growth hormone and somatomedin C in prostatic cancer: effects of parenteral and oral estrogen therapy

The effects of parenteral and parenteral plus oral estrogen therapy on the serum levels of sex hormone binding globulin (SHBG), pregnancy-associated alpha 2-macroglobulin (alpha 2-PAG), growth hormone (GH), and somatomedin C (SmC) were studied in 26 patients with prostatic cancer. Intramuscular polyestradiol phosphate treatment, yielding a mean serum level of estradiol-17 beta of 1,446 pM and a mean testosterone level of 4.5 nM, had no significant effects on alpha 2-PAG, GH, and SmC and increased SHBG levels only marginally. Combined treatment with intramuscular polyestradiol phosphate and oral ethinyl estradiol greatly increased SHBG and alpha 2-PAG levels and caused elevated GH and decreased SmC levels. The route of estrogen administration is probably of major importance for the hormonal effects on hepatic activity as reflected by SHBG and alpha 2-PAG levels. Bypassing the portal circulation might be advantageous with respect to liver-related side effects of estrogen therapy. GH and SmC might act as mediators of estrogen effects on the human liver.     

Relationship of prior hormonal therapy to subsequent estramustine phosphate treatment in advanced prostatic cancer

The relationship of prior hormonal therapy to subsequent response on estramustine phosphate (Estracyt) was examined in 107 patients with advanced prostatic cancer treated in two different Phase II chemotherapy trials. In both trials patients with the longest prior hormonal treatment were the least likely to respond to estramustine phosphate. Patients in the series from the National Prostatic Cancer Project with a response classification to prior hormonal therapy had only a 26 per cent response to subsequent estramustine phosphate therapy, whereas 40 per cent of those with no prior response to hormonal therapy responded to estramustine phosphate. This latter group had the shortest average disease duration from diagnosis. The sample of prostate cancers studied appeared to include groups that were sensitive to both hormones and cytotoxic activity as well as to either of these two alone. These data support the contention that estramustine phosphate may act both as an estrogenic and a cytotoxic agent.     

Estramustine phosphate (Estracyt®) in the treatment of prostatic carcinoma

This review presents the most important hormonal, cytotoxic and pharmacokinetic properties of estramustine phosphate. Furthermore the results of randomized Phase III trials are described in patients with hormone refractory prostatic cancer with and without previous irradiation. Several randomized studies are reported with Estracyt^® also in the primary treatment of this disease.     

The effect of estramustine phosphate on prostatic cancer estimated by transrectal ultrasonotomography

Transrectal Ultrasonotomography was performed in 44 patients with prostatic cancer before, during, and after estramustine phosphate (Estracyt®) administration. In 75.7% of 37 previously untreated patients, the deformity of the horizontal section of the prostate with prostatic cancer was corrected considerably, while in 89.2%, prostatic weight was remarkably reduced. In 57.1% of seven previously treated patients, appreciable changes were also observed in the shape and weight of the prostate. We concluded that estramustine phosphate was effective not only for untreated prostatic cancer, but also, at least in some degree, for relapsed cases.     

Androgens during different modes of endocrine treatment of prostatic cancer

Summary Serum levels of testosterone (T), 17-hydroxyprogesterone (17OHP), 4-androstene-3,17-dione (A-4), dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS) and cortisol were measured before and after 6 months of treatment in prostatic cancer patients treated by orchidectomy (ORX) or with oral+parenteral estrogens (OE), single parenteral estrogens (PE; 160 or 320 mg polyestradiol phosphate i.m. every fourth week), estramustine phosphate (ECYT) or LHRH agonist without (LHRH) or with (LHRH-F) flutamide. Castration values of T and 170HP were reached in all types of treatment (PE at the higher dose). A-4 levels were suppressed by all treatment regimens except ECYT; DHA by OE and LHRH-F and DHAS by ORX, OE and LHRH-F. The most pronounced suppression was found in the LHRH-F group. Cortisol levels were markedly increased by OE and ECYT. The observed effects on the adrenal androgens A4, DHA and DHAS and on cortisol probably reflect different degrees of liver interaction rather than interaction with adrenocortical steroid synthesis.Part of this paper was presented at the 6th Congress of the European Society for Urological Oncology and Endocrinology, May 2–4, 1988, Innsbruck, Austria     

Primary orchiectomy versus estrogen therapy in advanced prostatic cancer--a randomized study: results after 7 to 10 years of followup

Of 163 new consecutively diagnosed cases of advanced (T3-4 M0 or T04M1) prostatic cancer 13 had contraindications for estrogen treatment, and the remainder were randomized to orchiectomy (76) or to estrogen treatment (74), consisting of 150 micrograms ethinyl estradiol daily and 80 mg. polyestradiol monthly. During the followup period of 7 to 10 years disease progression was noted in 27 patients (36%) treated with estrogen and 39 (51%) orchiectomized patients. The free of progression survival rate was significantly better (less than 0.05) among the estrogen treated patients but the over-all survival rates after orchiectomy and estrogen treatment were almost identical. A significantly higher frequency of cardiovascular side effects was noted in the estrogen group (23 cases) compared to the orchiectomy group (4 cases). Therefore, estrogen treatment in this form cannot be recommended for the palliative treatment of prostate cancer.     

Effect of estramustine phosphate on free androgens. A comparative study of the effect of orchiectomy and estramustine phosphate on free androgens in patients with prostatic cancer

Total serum testosterone, serum testosterone binding globulin and free androgen index were determined before and during treatment in 14 patients with previously untreated disseminated prostatic cancer. Six patients received estramustine phosphate and six other patients underwent orchiectomy. Two further patients received estramustine phosphate because of tumor progression one and two years after orchiectomy. The result of the study indicates that estramustine phosphate is significantly more effective than orchiectomy in eliciting low levels of free androgens. This complete androgen ablation is produced by a depression of total testosterone and a concomitant increase of total serum testosterone binding globulin which yields a free androgen index an average 4.6 times lower in estramustine phosphate treated patients than in patients who underwent orchiectomy.     

Estramustine phosphate in secondary hormone-resistant carcinoma of the prostate

In this retrospective study, 71 patients with secondary hormone-refractory prostatic carcinomas were treated with estramustine phosphate (EMP), at three different dosages (280, 560, 840 mg orally). All patients were completely followed up until cancer-induced death. In 12 cases of further progression polychemotherapy was administered. As this was not a randomized study, an analysis of statistical significance was not performed. The higher dosages of EMP caused an extended progression-free interval accompanied by an equally considerable alleviation of carcinoma-induced pain. The overall survival time was not influenced by subsequent polychemotherapy. An elevation of liver function parameters was observed in 5 patients. One of these patients died of toxic liver damage, possibly therapy-related, on the basis of a preexisting cirrhosis. Cardiovascular side effects were not observed. With regard to survival time, the positioning of polychemotherapy as a third-line treatment for prostatic cancer should be examined critically. Before administration of high-dose EMP, it is mandatory to control liver functions carefully.