The role of parenteral polyestradiol phosphate in the treatment of advanced prostatic cancer on the threshold of the new millennium

Orchiectomy and estrogens have been used for over 50 years in the treatment of advanced prostatic cancer. Although orchiectomy is a simple procedure, it may cause psychological stress. Oral estrogen therapy is as effective as orchiectomy in terms of cancer inhibitory effect, but its acceptance as primary hormonal treatment is overshadowed by an increased risk of cardiovascular complications. Parenteral estrogen, polyestradiol phosphate (PEP), is effective, but also associated with cardiovascular complications, although to a lesser extent. During the last 20 years, well tolerated luteinizing hormone releasing hormone (LHRH) analogues have been replacing orchiectomy and estrogens. Efforts have been made to increase the efficacy of the treatment by adding antiandrogens to LHRH analogues and also to orchiectomy (combined androgen blockade, CAB). However, the efficacy of LHRH analogues and CAB has not proved to be superior to that of simple orchiectomy and, moreover, they are expensive treatment modalities. Orchiectomy and LHRH analogues are associated with negative effects on bone mass and may cause osteoporosis, whereas PEP treatment has an opposite effect. Parenteral polyestradiol phosphate is still a cheap potential treatment for advanced prostatic cancer, but further studies should be conducted to establish its future role, e.g. combining acetylsalicylic acid to prevent cardiovascular complications.     

High dose polyoestradiol phosphate with and without acetosalicylic acid versus orchiectomy in the treatment of prostatic cancer. Finnprostate Group

The clinical efficacy of high dose (160 mg) polyoestradiol phosphate (PEP) was compared with that of orchiectomy in a prospective randomised multicentre study including 200 prostatic cancer patients. The effect of daily low dose (75 mg) acetosalicylic acid (ASA) on possible cardiovascular complications during the first 6 months of therapy was also evaluated. Oestrogen-treated patients had more progressions, but follow-up was too short to draw any definite conclusions on the efficacy of treatment. There was no cardiovascular mortality and there were no thromboembolic complications in any treatment group. It was concluded that parenteral high dose PEP is not associated with an increased risk of cardiovascular complications and there is no need for daily low dose ASA.     

Effects of orchiectomy and polyestradiol phosphate therapy on serum lipoprotein lipids and glucose tolerance in prostatic cancer patients

In 17 prostatic cancer patients, changes in the plasma lipoprotein pattern, including high density lipoprotein (HDL) subfractions, and in glucose tolerance were compared after 6 months on parenteral polyestradiol phosphate (PEP; Estradurin, 80 or 160 mg/month) with the respective changes in orchiectomized patients. In the estrogen group there was no change in the total serum cholesterol level, whereas in the orchiectomy group an increase of 10% was observed. Estrogen therapy resulted in a significant increase of serum HDL (11%) and HDL2 cholesterol (26%) levels; in the orchiectomy group these fractions remained unchanged. Estrogen therapy induced a significant decrease in total serum triglycerides (24%) and in low density lipoprotein triglycerides (27%); in the orchiectomy group reverse changes were observed. PEP treatment caused changes in the serum lipoprotein pattern, which apparently decreases the risk of atherosclerosis.     

Comparison of endocrine and radiation therapy in locally advanced prostatic cancer

151 patients with locally advanced prostatic cancer (T3-4 M0), representing 38% of the 404 cancer patients in a Finnish multicenter study, were randomly assigned to one of three treatment arms: orchiectomy, estrogens or radiotherapy. During the 4-year follow-up period there were no significant differences in the progression rates (appearance of metastases in bone scan) between the therapy groups. The frequency of thromboembolic and other cardiovascular complications was highest in the estrogen group (13/50 patients). In the radiotherapy group, 19 of 45 patients had bowel or bladder complications. On the other hand, orchiectomy has few, if any, complications. The high risk of complications associated with estrogens and radiotherapy has to be taken into consideration in the selection of treatment.     

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.     

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

OBJECTIVE: To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular events. MATERIAL AND METHODS: In total, 910 eligible patients with T0-4, NX, M1, G1-3 prostate cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg i.m. per month or on an optional basis bilateral orchidectomy. RESULTS: At this final evaluation of the trial 855 of the 910 patients were dead. There was no difference between the treatment groups in terms of biochemical or clinical progression-free survival or in overall or disease-specific survival. There was no difference in cardiovascular mortality, but a significant increase in non-fatal cardiovascular events in the PEP arm (p<0.05) predominantly caused by an increase in ischemic heart and heart decompensation events. There were 18 grave skeletal events in the CAD group but none in the PEP group (p=0.001). CONCLUSIONS: PEP has an anticancer efficacy equal to CAD and does not increase cardiovascular mortality in metastasized patients, but carries a significant risk of non-fatal cardiovascular events, which should be balanced against the skeletal complications in the CAD group. It is feasible to use Estradurin in the primary or secondary endocrine treatment of metastasized patients without prominent cardiac risk factors and especially those with osteoporosis.     

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.     

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.     

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer -- Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

OBJECTIVE: In the mid-1980s, interest in parenteral estrogen therapy for prostate cancer was renewed when it was found that it influenced liver metabolism only marginally and had very few cardiovascular side-effects. In this study high-dose polyestradiol phosphate (PEP; Estradurin) was compared to combined androgen deprivation (CAD) for the treatment of patients with metastatic prostate cancer. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular side-effects. MATERIAL AND METHODS: A total of 917 patients with T0-4, NX, M1, G1-3 prostate cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter once a month or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg per month i.m. or, on an optional basis, bilateral orchidectomy. A total of 556 patients had died at the time of this analysis. RESULTS: There was no difference between the treatment arms in terms of time to biochemical or clinical progression and overall or disease-specific survival. There was no increase in cardiovascular mortality in the PEP arm. The PEP group had a higher prevalence of cardiovascular disease prior to the study and a significantly higher incidence of non-fatal ischemic heart events and heart decompensation during the study. CONCLUSIONS: PEP has an equal anticancer efficacy to CAD and does not increase cardiovascular mortality. Final evaluation of cardiovascular morbidity is awaiting further analysis and follow-up. PEP is considerably cheaper than CAD.     

Endocrine treatment of prostatic cancer

Data are drawn from the pertinent literature supporting diethylstilbestrol for initial endocrine treatment of advanced prostatic cancer. When diethylstilbestrol is given in a dosage of 2 mg daily, the risk of cardiovascular complications is low. Bilateral orchiectomy is reserved for high-risk patients or those intolerant of estrogen. To prevent possible complications of uncontrolled tumor growth and perhaps to increase survival time, endocrine treatment of advanced prostatic cancer should be started early.     

Patients at high risk of cardiovascular complications in oestrogen treatment of prostatic cancer

The aim of this study was to predict cardiovascular complications in patients with prostatic cancer treated with oestrogen. A randomised prospective study of oestrogen therapy versus orchiectomy was performed. Patients with pre-existing cardiovascular morbidity were excluded (16%). Prior to the initiation of therapy, patients were subjected to exercise stress tests, physiological evaluation of peripheral circulation, blood volume estimation, chest X-ray, blood test, including hormones, lipoproteins, and antithrombin III, and a physical examination and history by a cardiologist. The oestrogen treatment and the orchiectomy group did not differ with regard to these pretreatment variables; 25% of the patients given oestrogen therapy had cardiovascular complications during the initial treatment year compared with none in the orchiectomy group. Three statistical discriminating techniques were employed and they allowed us to identify 2 strong discriminating variables for cardiovascular complications if oestrogen therapy is instituted in patients with prostatic cancer but without overt clinical cardiovascular disease. These 2 discriminators were luteinising hormone (LH) and ST-segment depression during exercise. This means that a patient with ST-segment depression during an exercise test and/or a high luteinising hormone concentration should not be treated with oestrogen.     

Cardiovascular complications in patients with advanced prostatic cancer treated by means of orchiectomy or polyestradiol phosphate

OBJECTIVE: To evaluate the cardiovascular (CV) complications associated with orchiectomy (OE) and parenteral polyestradiol phosphate (PEP) therapy (240 mg/month), taking into account the effect of pretreatment diseases and pretreatment medication. MATERIAL AND METHODS: A total of 244 T3-4 M0 patients and 200 T1-4 M1 patients were randomized to either OE or PEP therapy. The two groups of patients were analyzed separately. The follow-up period was 36 months. The effect of pretreatment vascular and other diseases and pretreatment medication which may be associated with a risk of CV complications was evaluated. RESULTS: In the T3-4 M0 patients, the treatment (PEP versus OE) and the presence of pretreatment vascular diseases were statistically significantly associated with a risk of CV complications (p=0.01 and 0.003, respectively). In the T1-4 M1 patients, such an association was not found. No association was observed between pretreatment medication and CV complications. There was no difference in progression-free time between the therapy groups in either the T3-4 M0 or T1-4 M1 patients. CONCLUSION: In patients with locally advanced prostatic cancer, PEP therapy is associated with a statistically significantly higher risk of CV complications compared to OE.     

Effectiveness of castration versus intravenous estrogen therapy in producing rapid endocrine control of metastatic cancer of the prostate

Nine men with histologically confirmed stage D cancer of the prostate were evaluated with serial serum testosterone levels after being treated with bilateral orchiectomy or intravenous estrogen. Bilateral orchiectomy produced castrate serum testosterone levels (less than or equal to 50 ng. per 100 ml.) within 2 to 6 hours (mean 3 hours) after surgery. Intravenous estrogen therapy did not consistently produce castrate serum testosterone levels immediately but did significantly decrease testosterone within 12 hours after infusion. Both forms of therapy are safe, produce a clinically effective response and offer advantages for patients with advanced prostatic cancer.     

Metastatic prostate cancer

Summary For decades the palliation of prostate cancer has centered around hormonal manipulation using orchiectomy or estrogen administration. Newer modalities, such as LHRH agonists and nonsteroidal antiandrogens, are now available. Patients receiving combination therapy enjoy superior progression-free and median survival rates.     

Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy

BACKGROUND: The aim of the study was to evaluate overall and prostate cancer (PCa) specific survival with special attention to cardiovascular (CV) mortality in patients primarily treated by parenteral polyestradiol phosphate (PEP) 240 mg/month or with orchiectomy (OE), taking into account the effect of pretreatment diseases and medication, and later PCa therapies. METHODS: The present Finnprostate 6 study (10-year follow-up) consisted of 244 patients with locally advanced PCa (T3-4 M0) and 200 patients with metastatic PCa (T1-4 M1). Patients were randomized to OE or PEP therapy. The T3-4 M0 and T1-4 M1 patients were analyzed separately. RESULTS: There was no difference in overall or PCa specific survival between the primary therapy groups in T3-4 M0 or T1-4 M1 patients. In the T3-4 M0 patients the primary treatment (PEP vs. OE) was statistically significantly associated with a risk of CV deaths (P = 0.001). Such an association was not found in the T1-4 M1 patients. CONCLUSIONS: The primary PEP and OE therapies are equal in terms of overall and PCa specific survival in patients with T3-4 M0 or T1-4 M1 disease. In T3-4 M0 patients PEP increases the risk of CV deaths compared to OE but not in T1-4 M1 patients.     

Effect of parenteral oestrogen on the coagulation system in patients with prostatic carcinoma

Patients with prostatic carcinoma on oral oestrogen therapy have an altered coagulation system and suffer cardiovascular side effects. Oestrogens--especially oral oestrogens--are potent inducers of liver synthesised proteins, including coagulation factors. We have assessed the effect of non-oral oestrogen on the coagulation system in patients with prostatic carcinoma. Twelve patients were given monthly intramuscular injections of 320 mg polyoestradiol phosphate (PEP). No additional oestrogens were given. No change was found in any of the coagulation factors, including factor VII, with the exception of a significant decrease in antithrombin III. No patient, including 38 patients treated with PEP, had any cardiovascular complications after a mean follow-up period of 12.9 +/- 0.7 months; 76% of the patients responded to treatment. Parenteral administration of oestrogen caused a less marked change in the coagulation system than oral administration and should be the treatment of choice for prostatic carcinoma.     

Inability of complete androgen blockade to increase survival of patients with advanced prostatic cancer as compared to standard hormonal therapy

It has been proposed that early treatment of patients with advanced prostatic cancer by surgical or medical orchiectomy when combined with a direct acting antiandrogen will result in a more complete form of androgen blockade, thereby increasing response and survival rates compared to orchiectomy alone. We treated 55 patients with previously untreated advanced prostatic cancer by bilateral orchiectomy and additional administration of 50 mg. of the direct acting antiandrogen cyproterone acetate orally per day. Therefore, these patients have undergone a combination therapy that meets the requirements of the proposed complete androgen blockade. All 22 patients with metastases at hospitalization died during the first 4 years of treatment. Among the 33 patients without clinical evidence of metastases at hospitalization 18 were alive after 5 years. Retrospectively, the direct observed 5-year survival rate for the patients treated with a complete androgen blockade did not show any advantage compared to reported data with orchiectomy alone.     

Treatment of advanced prostatic cancer

Many treatment modalities are available to patients with disseminated adenocarcinoma of the prostate. Although no single therapeutic approach can be advocated for all patients at the present time, delay of endocrine manipulation until the onset of symptoms is the recommended approach because it maintains the most normal lifestyle in these patients. With the onset of symptoms such as bone pain or urinary retention, or perhaps as disease progression becomes apparent, orchiectomy is recommended to patients with increased cardiovascular risks as well as to those patients who are judged irresponsible in taking oral estrogens. A dose of 1 mg of diethylstilbestrol three times daily achieves a castrate level of serum testosterone and may not increase cardiovascular mortality. Because of the relative safety and lack of side effects, GnRH analogues represent an alternative treatment in selected patients, particularly in those who refuse orchiectomy or have an increased risk of developing cardiovascular complications. Hormonal manipulation with androgen deprivation remains the cornerstone of treatment and provides clinical remission in the majority of patients with advanced prostate cancer. The prognosis is poor once tumor has recurred. Several secondary forms of endocrine therapy are available, but it would help to be able to select those patients with hormonally sensitive tumors that would respond favorably to these modalities. Transurethral surgery and radiotherapy are effective in palliating patients with bladder outlet obstruction and bony metastases unresponsive to hormonal therapy. Nonhormonal cytotoxic agents are available, but well-controlled studies are required to determine the value of specific agents, whether used alone or in combination.     

Treatment of prostatic cancer with LH-RH analogues

Twenty-one of 32 patients with locally advanced prostatic cancer (stage C) were treated with the LH-RH analogue Buserelin for 7-19 months. After an initial sequence of subcutaneous injections, treatment was continued with intranasal spray application (three daily doses of 400 μg each) which ensured maintenance of serum testosterone within the range seen in castrated men. To evaluate the response of the primary tumor to Buserelin, cytological regression was established for all patients by fine-needle aspiration biopsy every 3 months. The cytological results corresponded with those of DNA analyses of single-cell cytophotometry showing a statistically significant drop of the grade of aneuploidy or polyploidy when the prostatic carcinoma responded positively to Buserelin therapy. Seventeen of 21 patients treated with the potent LH-RH analogue showed good therapy response. Four patients with no cytological signs of tumor regression received secondary treatment with estramustin phosphate because of hormone resistence. One patient had to be crossed over to cyclophosphamide, the third drug, for clinical progression after 15 months. Essential side effects have not been observed. Continuous treatment of locally advanced prostatic cancer with Buserelin, combined with close control of the patient, offers not only a real alternative to surgical castration–as the patient is spared the psychical stress of orchiectomy–but also to estrogen therapy with its risk of cardiovascular side effects.     

Advanced Prostate Cancer: Hormones and Beyond

Bilateral orchiectomy became the “gold standard” treatment option for advanced prostate cancer following the Nobel Prize winning study by Huggins and Hodges in 1941. Almost 40 yr later, the combination of a nonsteroidal antiandrogen with castration-based treatment (combined androgen blockade [CAB]) was proposed to offer superior response and survival compared with castration alone. However, 25 yr and many randomised studies later, the benefit of CAB remains controversial. Here, we present a clinical scenario that describes a patient with advanced prostate cancer and we review the available treatment options. The first part of the article focuses on androgen-dependent disease, comparing castration (surgical or medical) to either Casodex™ (bicalutamide) 150 mg monotherapy or CAB. In the CAB setting, Casodex 50 mg combined with castration-based therapy is calculated to reduce the rate of all-cause mortality by an estimated 20% compared with castration alone. The second part of the article describes treatment options for androgen-independent prostate cancer, including alternative forms of hormonal therapy, such as oestrogen therapy and ketoconazole- and docetaxel-based chemotherapy.