Effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate on some proteins related to haemostasis in prostatic carcinoma patients

Twenty-four previously untreated patients with carcinoma of the prostate were prospectively randomized to one of the following treatments: (1) ethinyl oestradiol combined with polyoestradiol phosphate (EE/EP); (2) estramustine phosphate (EM); (3) bilateral orchiectomy. The effects on some plasma proteins related to haemostasis were studied by measuring the concentrations of alpha-1-antitrypsin, orosmmucoid, haptoglobin, antithrombin III, C1-inhibitor and von Willebrand’s factor before and 3 months after the start of treatment. Orchiectomy induced a reduction of alpha-1-antitrypsin and haptoglobin, while the other studied proteins were unaffected. It was found that both EE/EP and EM treatment induced significant decreases of orosomucoid, haptoglobin, antithrombin III and C1-inhibitor, while the same treatment increased the plasma concentration of alpha-1-antitrypsin. None of these treatments showed any influence on the plasma concentration of the von Willebrand factor. No differences were observed between EE/EP and EM for any of the studied proteins, suggesting comparable oestrogenic effects of these forms of treatment in patients with prostatic carcinoma. The findings are discussed in relation to the proposed difference in thromboembolic complications between EE/EP and EM treatments of prostatic carcinoma patients.     

Some effects of treatment with ethinyl oestradiol with or without polyoestradiol phosphate in patients with prostatic carcinoma

Eleven patients with prostatic carcinoma were treated with ethinyl oestradiol (Etivex) 50 micrograms three times daily with and 10 patients without 80 mg polyoestradiol phosphate (Estradurin) monthly. Both forms of treatment produced a significant decrease in the serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) and a significant increase in the testosterone-oestradiol-binding globuline (TeBg). Serum prolactin was significantly higher at 1, 3 and 6 months after treatment, in all patients studied, but the concentrations found at 12 and 18 months did not differ from those before treatment. One out of 10 patients treated with ethinyl oestradiol had congestive heart failure. Five out of 11 patients treated with ethinyl oestradiol-polyoestradiol phosphate had cardiovascular or liver complications. Three of the 5 had thromboembolic complications. It is concluded that ethinyl oestradiol given in combination with polyoestradiol phosphate, was not superior in decreasing serum testosterone when compared to ethinyl oestradiol given alone. Furthermore, the oestrogens used, elevated prolactin only, during the first 6 months of treatment. There were fewer complications using ethinyl oestradiol alone than when using ethinyl oestradiol combined with polyoestradiol phosphate.     

Orchiectomy versus oestrogen in the treatment of advanced prostatic cancer

The primary clinical efficacy of orchiectomy and the combination therapy of intramuscular polyoestradiol phosphate 80 mg monthly and oral ethinyl oestradiol 0.15 mg daily was evaluated by progression and cancer mortality rates in a series of 277 prostatic cancer patients representing part of the Finnprostate study. After a follow-up of 5 years there was a significant difference between the groups in terms of progression rate and prostatic cancer deaths. The oestrogen combination was more effective in delaying progression of the disease. The overall mortality rate was similar in both groups. About one-third of the patients were alive after 5 years.     

Direct inhibitory effects of natural and synthetic oestrogens on testosterone release from human testicular tissue in vitro

Human testicular slices were incubated in vitro in order to examine the direct effects of natural and synthetic oestrogens on testosterone secretion. In the presence of human chorionic gonadotrophin (10 IU per ml), oestradiol-17 beta (1 or 10 micrograms per ml) and ethinyl oestradiol (0.1, 1 or 10 micrograms per ml) inhibited testosterone release into the media in a dose dependent manner. The addition of estramustine phosphate, estromustine, diethylstilboestrol or diethylstilboestrol diphosphate in comparable concentrations produced no significant effects on testosterone release.     

Efficacy of orchiectomy versus high dose polyoestradiol phosphate (160 mg) in relieving infravesical obstruction in patients with prostatic cancer

Post voiding residual urine volume (78 patients) and maximum urinary flow rate (59 patients) were measured in prostatic cancer patients treated by orchiectomy or oestrogen (polyoestradiol phosphate 160 mg i.m. monthly) to compare the effects of these endocrine treatments on bladder outlet obstruction caused by prostatic carcinoma. The relieving effect of orchiectomy seemed to be more apparent than that of high dose oestrogen during the first six months of therapy.     

Uptake of estramustine phosphate (estracyt) metabolites in prostatic cancer

Plasma and tumour concentrations of estramustine, estromustine, estradiol and estrone, the major metabolites of estramustine phosphate (estracyt), were determined in patients with prostatic carcinoma treated between one and nine years with repeated oral doses of estracyt (560 to 840 mg./day). The last dose was given 12 to 16 hours before sampling. The binding of radioactive estramustine and estromustine was determined in the tumour tissue to examine the possible role of estramustine-binding protein for the accumulation of these metabolites into the tumour. Comparison was made with benign prostate hyperplastic tissue from untreated patients. Estromustine was the main metabolite in plasma as well as in the tumour (range 235 to 450 and 205 to 485 ng./gm., respectively), whereas estramustine (20 to 45; 95 to 370), estrone (62 to 140; 63 to 160) and estradiol (8 to 15; 7 to 36) were found in lower concentrations. Interestingly the concentration of estramustine was as an average six times higher in the tumour than in plasma contrasting with the other metabolites which were present in equal amounts of the two localities. Binding of 3H-estramustine and 3H-estromustine was two to three times higher in the tumour than in benign hyperplastic tissue and negligible in plasma samples. The present study is the first where substantial amounts of cytotoxically active estramustine and estromustine are demonstrated in tumour tissue from estracyt treated patients. Our findings suggest a mechanism for selective uptake of these metabolites in prostatic cancer (estramustine-binding protein). The uptake and binding of estramustine and estromustine in the tumour may account for the clinical effects of estracyt in prostatic carcinoma.     

Treatment of stage D hormone-resistant carcinoma of the prostate with estramustine phosphate.

We report on 51 patients with hormone-resistant, stage D prostatic carcinoma who were treated with estramustine phosphate and followed for at least 6 months. Of the 51 patients 5 (10 per cent) had a partial objective response, 30 (59 per cent) remained stable and 16 (31 per cent) had progression of the disease. All of those patients who had a partial response or remained stable also experienced subjective improvement as judged by relief of pain and performance status. Approximately 8 per cent of the patients will be unable to take estramustine phosphate because of intolerable gastrointestinal side effects.     

The influence of treatment with estrogens and estramustine phosphate on platelet aggregation and plasma lipoproteins in non-disseminated prostatic carcinoma

The treatment of prostatic carcinoma with estrogens is associated with an increased risk of cardiovascular as well as thromboembolic complications. In the present study, patients harboring highly or moderately differentiated prostatic carcinoma without signs of metastases were treated with either polyestradiolphosphate + etinylestradiol, estramustine phosphate or given no treatment. Subsequently, these patients were investigated regarding factors (platelet aggregation, plasma and platelet phospholipid composition and lipoprotein patterns) that might contribute to increased thrombogenesis and cardiovascular risk. The results indicate the presence of increased in vitro platelet aggregation in patients treated with polyestradiolphosphate + etinylestradiol compared to those treated with estramustine phosphate or given no treatment. A possible relationship between the availability of arachidonic acid in platelet membrane phospholipids and in vitro platelet aggregation is suggested. On the other hand the alterations in plasma lipoproteins observed during treatment are generally considered positive from an atherogenic point of view and do not seem relevant to the elevated incidence of cardiovascular disease in these patients.     

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.     

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.     

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.     

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.     

Prostatic cancer. Transcortin levels during treatment with estramustine phosphate.

Plasma transcortin and cortisol levels, which are significantly elevated by estrogens, were determinied in a group of patients with prostatic cancer who were on estramustine phosphate (Estracyt) therapy. In a series of 44 male patients studied transcortin and corticol levels became elevated above normal and were maintained at these high levels as long as the patients were on estramustine phosphate therapy. The levels observed in this study may serve as reliable indices to monitor patients who are on this drug.     

Treatment of advanced carcinoma of the prostate with estramustine phosphate.

Estramustine phosphate has been useful in the treatment of advanced carcinoma of the prostate. Objective remissions were obtained with this therapy in 6 of 17 patients (35 per cent). The results presented herein indicate that the clinical response is to a certain extent caused by an estrogen effect, which was clearly demonstrable in a previously untreated patient. A specific cytostatic effect of estramustine phosphate, which is not yet clearly explained, may be responsible for remissions in some patients who have become resistant to conventional hormonal treatment.     

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.     

Oestrogen in the treatment of prostatic carcinoma. What is the safe and effective dose of ethinyloestradiol?

The treatment of prostatic carcinoma with diethylstilboestrol (DES) and ethinyloestradiol (Lynoral) has become less popular since the introduction of new forms of treatment such as antiandrogens, estramustine phosphate and LHRH analogues. One of the reasons for this decline in popularity is the risk of cardiovascular side effects during treatment with oestrogens. In the literature, different dosages of DES and ethinyloestradiol are recommended and different rates of cardiovascular side effects are reported. In a prospective study, 18 patients were treated with ethinyloestradiol 0.05 mg/day. In most cases this lowered the plasma testosterone permanently below castrate level during therapy. Also, because the acid phosphatase returned to normal in almost all patients, this treatment seemed adequate. In 4 patients the treatment was stopped because of side effects, in 3 of these because of cardiovascular complications. The cardiovascular side effect at this dose are considerable (29%) but comparable rates are reported in some studies following placebo treatment of patients with prostatic carcinoma.     

Effect of estramustine phosphate on plasma testosterone during treatment of carcinoma of prostate

Estramustine phosphate administered orally at 900 mg. daily depressed plasma testosterone levels in 10 consecutive patients who had previously been treated with estrogen hormones and/or orchiectomy and who were all in relapse from carcinoma of the prostate. Approximately one half of the patients responded to the treatment clinically. The decrease in plasma testosterone did not correlate with the clinical response. The clinical effect of estramustine phosphate may be due to decreased plasma testosterone levels, inhibition of 5-alpha reductase activity, and a local cytotoxic effect.     

Testosterone metabolism in patients with advanced carcinoma of the prostate: A comparative in vivo study of the effect of oestrogen and anti-prolactin

Summary In the light of the high incidence of cardiovascular side effects with oestrogen therapy in patients with prostatic cancer, other medications altering androgen metabolism are under investigation. The influence of the anti-prolactin bromocriptine (CB154) on plasma kinetics of testosterone and on endogenous hormones was studied and compared with the effect of ethinyl oestradiol in 25 patients with prostatic carcinoma. Bromocriptine significantly suppressed both prolactin and testosterone, inhibited the transfer of androgen from the inner pool into the deep compartment and favoured its degradation. Ethinyl oestradiol decreased testosterone, LH and FSH, and prolonged the biological half-life of testosterone. The effects of bromocriptine on androgen metabolism might be of therapeutic value in patients with prostatic carcinoma.     

The treatment of oestrogen-escaped carcinoma of the prostate with estramustine phosphate.

30 patients with oestrogen-escaped carcinoma of the prostate have been treated with estramustine phosphate (Estracyt). 27% showed a partial objective response and 33% had a subjective response. The terms used for defining a response are challenged and it is recommended that comparative controlled trials are necessary to judge the place of this drug in the management of advanced prostatic cancer.     

Hormone-resistant metastatic prostate cancer. Comparisons between estramustine phosphate and low-dose epirubicin treatments.

We compared the effect and toxicity of estramustine phosphate and weekly low-dose epirubicin in a prospective randomized trial in 41 patients with metastatic prostate cancer refractory to hormonal manipulation. No significant difference between treatment modalities was seen. Palliation was reached in over 60% of patients. The median survival was 15 months in both groups. Toxicity was mild. Further, we investigated the effect of epirubicin after the failure of preceding estramustine phosphate therapy in additional 20 patients. Pain relief was achieved in 50% of these patients. The median survival was 10 months. Toxicity was acceptable.