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PubMed1981

Hormonal effects of different doses of estramustine phosphate (Estracyt) in patients with prostatic carcinoma.

Ten patients with previously untreated prostatic carcinoma were studied to evaluate the hormonal effects of different doses of estramustine phosphate (Estracyt). The drug was given by mouth in increasing doses; during the first month 70 mg daily, during the second 140 mg, during the third 280 mg and during the fourth and following months 560 mg. The following hormonal parameters were studied before the treatment and then once weekly during a period of four months: testosterone, dihydrotestosterone, androstenedione, cortisol, FSH and LH. The levels of the steroids were also re-assessed one to two years later. The patients were also followed clinically at regular intervals. Initial testosterone levels of approximately 20 nmol/l plasma were reduced to approximately 0.6 nmol/l already by the lowest Estracyt dose of 70 mg/day. No further decrease was obtained by a stepwise increase of doses up to 560 mg/day. The plasma levels of dihydrotestosterone, androstenedione, FSH and LH were also reduced significantly following the administration of the lowest daily Estracyt dose and then remained at that low level. Cortisol levels increased steadily during the four months of the study. After longterm treatment the hormonal indices were by and large the same as during the last initial treatment period. Initially, the clinical effect of the treatment was excellent. In 4 patients, however, the therapy had to be discontinued after some time, because of complicating oedema (2 patients) or refractoriness to therapy (2 patients). Three years after initiating the therapy 6 patients still were on Estracyt treatment. All of them were doing well subjectively. In 5 patients the prostatic cancer was in remission or at least stable. In one patient, however, skeletal metastases were progressing. In conclusion, Estracyt was found to possess a maximal hormonal (oestrogenic) effect already in doses far below those usually recommended.

Administration, Oral↗

PubMed1997

Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group.

Between 1984 and 1989, 197 patients with T1-4, NX, M1, G2-3 or G3 prostate cancer were randomized to treatment with 560 mg estramustine phosphate (EMP, Estracyt, Emcyt) or 3 mg diethylstilbestrol (DES) per day in a double blind study with stratification on presence or absence of cancer pain at start. A total of 194 patients were evaluated for efficacy of therapy. Time to progression (p = 0.054), to treatment failure (p = 0.036), cancer-specific survival (p = 0.068) as well as overall survival (p = 0.021) were longer in the DES group. There were more patients with prognostic parameters indicating bad prognosis in the EMP group. This trial was designed to study whether EMP had better effect than DES as the primary treatment of high-grade, disseminated prostate cancer. The results did not confirm this hypothesis. On the contrary, treatment with DES had relatively good effect on this very aggressive form of prostate cancer.

Antineoplastic Agents, Hormonal↗

PubMed1991

Modal DNA values and estramustine-binding protein (EMBP) as prognostic markers in prostatic cancer.

In this study, we have investigated the model DNA values and the expression of estramustine-binding protein (EMBP) in formalin-fixed and paraffin-embedded TUR specimens from 76 untreated patients with prostatic cancer. In addition, specimens from 13 patients were analyzed for tumour EMBP expression only. Ploidy was measured as diploid, tetraploid and non-tetraploid aneuploid or aneuploid in the near-diploid region. All patients had been referred during 1978-1981, and were subjected to TUR due to urinary obstruction. Survival data were obtained for all patients through March 1988. Statistical analyses were performed using a Cox's regression model with respect to survival and cause specific survival and correlated to the DNA pattern and the expression of EMBP. The existence of a near-diploid aneuploid cell population as well as poor differentiation grade were both statistically significantly correlated with poor survival. Near-diploid aneuploid cell lines were seen in 9/76 (12%) of the patients and were also seen in well differentiated cancers (4/17). The expression of EMBP was most abundant in the moderately differentiated cancers. However, all prostatic cancer specimens investigated were positive for the antigen. Patients with poorly differentiated carcinomas and high EMBP expression showed a tendency towards better prognosis than those with poorly differentiated carcinomas and low EMBP expression. The present patient material was, however, too small to show a statistically significant correlation between EMBP and survival.

Aged↗

PubMed2005

Prior estrogen therapy as a predictor of response to subsequent estramustine-based chemotherapy in patients with androgen-independent prostate cancer.

BACKGROUND: Hormone-refractory prostate cancer (HRPC) has modest response rates to second-line estrogenic agents such as diethylstilbestrol and the herbal product PC SPES. Estramustine phosphate (EMP) is a microtubule inhibitory agent with estrogenic properties commonly used in patients with metastatic HRPC. To determine whether previous response to second-line estrogen therapy would predict subsequent response to EMP-based chemotherapy, a retrospective study was conducted. PATIENTS AND METHODS: Patients with HRPC previously treated with second-line estrogenic therapy who subsequently received EMP-based chemotherapy were enrolled in a retrospective analysis. The progression of disease or response to treatment was determined with use of standard prostate-specific antigen (PSA) criteria and Response Evaluation Criteria in Solid Tumors. RESULTS: Seventy-eight patients were included in the analysis. Twenty-five patients with disease progression after receiving estrogen therapy received subsequent EMP-based chemotherapy. Overall, initial PSA response to any estrogen therapy was 54%. The overall PSA response to EMP-based chemotherapy was 60%, and the objective response was 36%. The PSA response to subsequent EMP-based chemotherapy was independent of patients having a previous response to estrogen therapy (70% vs. 53%; P = 0.68). The median overall survival for patients receiving estrogenic therapy and subsequent EMP-based chemotherapy was 12.7 months. CONCLUSION: Previous response to second-line hormonal maneuvers with estrogen therapy does not predict subsequent response to EMP-based chemotherapy.

Antineoplastic Agents, Hormonal↗

PubMed2001

[Clinical efficacy of leuprolide acetate and combined treatment with estramustine for advanced prostate cancer].

BACKGROUND/PURPOSE: Twenty-two institutes have organized Keio University Prostate Cancer Study Group to study clinical efficacy and safety of Leuprolide acetate (Leuplin) for the treatment of advanced prostate cancer (clinical stage D1 and D2). Cotreatment of Leuplin and Estramustine phosphate disodium (Estracyt) has been performed to investigate its clinical efficacy. MATERIALS AND METHODS: One hundred and two cases of advanced prostate cancer were treated either with Leuplin alone (group I), Leuplin and Estracyt (group II) or Estracyt alone (group III). After 12 weeks treatment, clinical effects against subjective symptoms (pain, voiding difficulty, performance status and body weight), serum testosterone level, tumor size and serum PSA level were examined to investigate short-term effect of each treatment. The treatment had been continued for 24 months and the treatment effects including progression free survival and overall survival were analyzed. RESULTS: Clinical efficacy after 12 weeks treatment were examined among 97 cases (group I; 35 cases, group II; 36 cases, group III; 26 cases). The background of those patients in each group was statistically equal. Treatment effects against subjective symptoms and serum testosterone level statistically revealed no significant difference among 3 groups. Treatment effects against primary tumor, bone metastatic lesion, lymphnode metastatic lesion and serum PSA level were investigated and anti-tumor effect was characterized by total efficacy rate (complete remission rate plus partial remission rate) of each treatment group. Treatment efficacy rates for each lesion and PSA demonstrated no statistical difference among 3 treatment groups. Total efficacy rate of group I, II and III were 88.2%, 84.0% and 78.3%, respectively, which statistically revealed no significant difference. Total efficacy rate of each group after completing 24 months treatment was; group I 80.0%, group II 55.6% and group III 83.3%, which statistically showed no significant difference among 3 treatment groups. The median day for progression free survival of group I, II and III were 661, 731 and 517, respectively. The overall survival rate of group I, II and III after completing 24 months treatment were 77.5%, 83.0% and 72.4%, respectively. Both progression free survival rates and overall survival rates revealed no significant difference among 3 groups. Side effects during 24 months treatment were seen in 8.6% of group I, 47.2% of group II and 26.9% of group III, and these occurrence rates were significantly different among the groups (p = 0.0013). CONCLUSION: Although number of the cases had not been able to continue the treatment for their side effects, the statistical characterization demonstrated that cotreatment of Leuplin and Estracyt had no greater treatment effect than monotreatment of each drug.

Aged↗

PubMed1999

Detection of chromosome loss and gain induced by griseofulvin, estramustine, and vanadate in binucleated lymphocytes using FISH analysis.

Cytochalasin B-blocked binucleated human lymphocytes from a healthy male donor were used to detect micronucleus induction and other aneuploidy events (chromosome loss and gain) after treatment with griseofulvin (GF), estramustine (EM), and sodium orthovanadate (Na(3)VO(4)). A two-color FISH was performed by using centromeric probes for chromosome 2 (FITC labeled) and the X chromosome (TRITC labeled) to measure chromosome loss and gain events in binucleated cells. GF induced mainly aneuploid binucleates involving the X chromosome, but this was not associated with preferential loss of one of the two chromosomes. EM preferentially induced aneuploidy of chromosome 2, and Na(3)VO(4) of the X chromosome. Our results indicate that chromosome malsegregation events (chromosome loss and/or gain) are probably not randomly induced, suggesting that different mechanisms leading to aneuploidy may be either chromosome-dependent or compound- and dose- related.

Aneuploidy↗

PubMed2000

[Clinical evaluation of estramustine phosphate and vinblastine in patients with hormone-refractory prostate cancer].

We evaluated the efficacy of the combination of estramustine phosphate and vinblastine in 13 patients with hormone-refractory prostate cancer. Of 12 patients with an elevated prostate specific antigen (PSA) level at the start of treatment, 5 (42%) had a greater than 50% decrease in PSA level. In a patient with cervical and mediastinal lymph node metastases, about a 57% decrease was observed in bidimensional measurement. Side effects were mild and manageable. The survival rate was not significantly different between patients who showed a greater than 50% decrease in PSA levels or regression of lymph node metastases versus the other patients.

Aged↗

PubMed2004

[Potentiation of focal ultrasound treatment of prostate adenocarcinoma by concomitant chemotherapy with estramustine phosphate and paclitaxel].

STUDY OBJECTIVES: To demonstrate a synergistic action between high intensity focal ultrasound (HIFU) and combination chemotherapy with paclitaxel and estramustine phosphate (EMP) on a prostate cancer model. MATERIAL AND METHODS: The animal model used in this study was the Copenhagen rat and the tumour model is a Dunning R 3327-AT 2 hormone-independent prostatic adenocarcinoma cell line. Chemotherapy was administered once a week for 4 weeks according to 2 modalities: low-dose with paclitaxel 2 mg/kg/day, 1 day per week and EMP 50 mg/kg/day, 3 days per week; or high-dose with paclitaxel 3 mg/kg/day, 1 day per week and EMP 75 mg/kg/day, 3 days per week. Treatment with HIFU was performed at the second week and only 55% of the tumour volume was treated. The study was conducted on 42 rats divided into 6 arms: Control, HIFU, low-dose paclitaxel-EMP, high-dose paclitaxel-EMP, HIFU + low-dose paclitaxel-EMP and HIFU + high-dose paclitaxel-EMP. Study endpoints were the course of tumour volume and animal survival. RESULTS: After two weeks of treatment, a statistically significant difference for tumour volume was observed between the various arms of the study (p < 0.0001). The HIFU-chemotherapy arm and, to a lesser degree, the chemotherapy only arm, presented the lowest tumour progression. CONCLUSION: The combination of HIFU + paclitaxel-EMP is more effective than treatment with HIFU alone or paclitaxel-EMP alone on growth of the Dunning tumour, right from the first weeks of treatment.

Adenocarcinoma↗

PubMedDate not supplied

Docetaxel, estramustine and prednisone for hormone-refractory prostate cancer: a single-center experience.

BACKGROUND: The results of chemotherapy in patients with advanced, hormone-refractory prostate cancer (HRPC) have been disappointing. Mitoxantrone has been used in the past for palliation, but it does not prolong survival. It was recently demonstrated that docetaxel is able to improve median survival as compared to mitoxantrone. We, therefore, wanted to evaluate a docetaxel-based regimen, with regard to efficacy and tolerability, in men with HRPC at our institution. PATIENTS AND METHODS: Patients with progressive HRPC (new metastatic lesions or PSA progression) and no prior cytotoxic chemotherapy received the following treatment administered in 21-day cycles: 280 mg estramustine three times daily on days 1 to 5 and 7 to 11, 70 mg docetaxel per square meter of body surface area on day 2, and 10 mg prednisone once daily throughout the course. After four cycles, the patients were re-evaluated via PSA, blood counts, CT and bone scans. If no progression had occurred, two more cycles were given. Objective response rates, post-treatment declines in serum PSA levels, as well as side-effects, were recorded. RESULTS: Thirty-nine patients with HRPC (age range 43-79 years, average 65 years) were enrolled after informed consent. The median PSA in this cohort was 144 (1.5-3030) ng/ml. The percentage of patients with bone and lymph node metastases was 82% and 61.5%, respectively. During an average follow-up period of 11 months, 20 patients (64.5%) showed a response to therapy, including a complete (CR), partial (PR) or mixed (MR) response, stable disease (SD) of metastatic lesions, or a PSA response. A post-therapeutic decrease of serum PSA levels of >25%, >50% and >75% occurred in 26.1%, 21.7% and 26.1% of patients, respectively. Lymph node metastases responded better to therapy (73%) than bone metastases (42%). Regarding toxicity, the regimen was generally well tolerated. Only three patients showed adverse events (one grade 4 neutropenia, one dermatological and one as a result of pain), which led to therapy withdrawal. Minor adverse events included nausea, alopecia and fatigue. No cardiovascular events were reported. CONCLUSION: Although the patients included in the present study had advanced disease, responses were promising and toxicity was tolerable. These preliminary data support the findings of recently published studies and suggest that docetaxel-based chemotherapy is going to play an important role as a regimen for patients with HRPC.

Adenocarcinoma↗

PubMed2006

Repeated massive tongue swelling due to the combined use of estramustine phosphate and angiotensin-converting enzyme inhibitor.

A 70-year-old man presenting with a chief complaint of tongue swelling had been diagnosed with prostate cancer 1 year earlier. He had been on an oral angiotensin-converting enzyme inhibitor (ACE) inhibitor for hypertension for 20 years. Two months before the first of 4 episodes of tongue swelling within a period of 40 days, he had been prescribed oral estramustine phosphate (EMP) for the prostate cancer. He was admitted to our hospital for the evaluation after massive swelling of the tongue and epiglottis which necessitated tracheotomy. Food allergies, allergic reactions to environmental factors, and hereditary angioneurotic edema were excluded. Massive swelling of the tongue and epiglottis disappeared completely after EMP was discontinued. We concluded that angioedema was induced by EMP used concurrently with the ACE inhibitor.

Aged↗

PubMedDate not supplied

Effects of antimicrobial drugs on the cytotoxicity of epirubicin, bleomycin, estramustine and cisplatin.

The effect of concomitant treatment with different antibiotics on the cytotoxicity of epirubicin, bleomycin, estramustine and cisplatin was studied in vitro on fibroblasts (V79) and two cancer cell lines (colon cancer HT29 and lung cancer P31). The cell lines were propagated under standard tissue culture conditions and evaluated as the number of surviving cell clones in comparison to untreated controls. Fifteen commonly used antibiotics were tested and thirteen of these were found to modify the cytotoxic effect in one or several of the combinations tested. One antibiotic agent could affect the toxicity of different cytostatics in opposite directions and there were marked differences between the cell lines tested. Only in one of the situations, the combination of bleomycin and ceftazidim, did the antibiotic cause opposite effects on the toxicity of a cytostatic when comparing fibroblasts and carcinoma cells. A most impressive observation was the pronounced increase in cisplatin-induced cytotoxicity by amphotericin B. In conclusion, the results suggest that antibiotics can interact with the cytotoxicity of antitumoral drugs but that the feature of this interaction is seemingly an erratic phenomenon. Further studies are certainly justified, especially regarding the effects of amphotericin B and its mechanisms in enhancing the cytotoxicity of cisplatin.

Amphotericin B↗

PubMedDate not supplied

Expression and partial characterization of estramustine-binding protein (EMBP) in human breast cancer and malignant melanoma.

The expression of the estramustine/estromustine-binding protein (EMBP) in human mammary cancer and malignant melanoma was examined by immunochemical methods and compared with that in endometrial and ovarian cancers. By RIA measurements, EMBP was detected in 6/17 mammary cancers (range 11.3-2,660 ng/g tissue) and 2/3 malignant melanomas (618 and 1,240 ng/g), whereas endometrial (n = 6) and ovarian (n = 3) cancers exhibited non-detectable levels. In breast cancer, EMBP-expressing tumours were all estrogen receptor-negative, suggesting an inverse correlation between EMBP and hormone responsiveness of the tumour. Biochemical characterization revealed properties of EMBP in mammary tumours and melanomas almost identical to those for EMBP purified from rat ventral prostate: i.e. surface-charge distribution by Mono Q/FPLC ion-exchange chromatography, a molecular weight of 50,000 by gel filtration, and a subunit composition by Western blot analysis under denaturing conditions. Finally, the EMBP immunoreactivity was confined to the cytoplasm of malignant cells in breast cancer and melanoma sections by immunohistochemical examination. This is the first study that demonstrates EMBP in mammary cancer and malignant melanoma. Our findings suggest that a mechanism for selective uptake of cytotoxic estramustine and estromustine is prevailing in these malignancies and that monitoring of EMBP in biopsy samples will be of value in defining patients who may benefit from Estracyt treatment.

Breast Neoplasms↗

PubMed1991

The present role of estramustine phosphate in advanced prostate cancer.

With estramustine phosphate the clinician has the possibility to ensure complete hormonal as well as cytotoxic control of advanced prostate cancer with a single drug. EMP is considered as a first choice for treatment of hormone refractory prostate cancer. It is at least as effective as conventional chemotherapy, yet less aggressive with regard to its toxicity profile. EMP is particularly useful in patients with limited bone marrow reserve, e.g. in case of prior or associated radiotherapy. As to the use of EMP in primary treatment, more information is required before we can define with certainty subgroups of patients who would benefit more from an early course of EMP than from other hormonal therapy. The existing data point in the direction of poorly differentiated tumors, patients with bone pain and poor prognosis. EMP treatment is associated with an increased risk of cardiovascular morbidity. This should be avoided as much as possible by proper selection of patients or by prophylaxis. Gastro-intestinal side effects, such as nausea, diarrhea and anorexia are dose-dependent. These adverse events tend to interfere with compliance at dosages over 560 mg/day. Dosage modifications or an anti-emetic may help. The intravenous administration of EMP offers the possibility for high loading doses at a substantially reduced risk for cardiovascular and gastrointestinal side effects.

Antineoplastic Agents↗

PubMed1990

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.

Administration, Oral↗

PubMed1990

[Clinical study of estramustine phosphate disodium (Estracyt) on prostatic cancer--results of long-term therapy for 38 patients with prostatic cancer].

Estramustine phosphate disodium (Estracyt) was used in the treatment of 38 patients with prostatic carcinoma for at least 1 year. Of these patients 37 patients were treated with Estracyt as primary treatment and 1 patient had been treated with another antiandrogenic therapy before the Estracyt treatment. Estracyt was given orally in a dose of 560 mg/day in divided oral doses. The clinical evaluation was done for the change of PAP, the relapse rate, the survival rate and the side effect. Among 22 cases which had shown abnormally high PAP values before the treatment started, the values decreased or normalized in 21 cases (95.5%) in the first year of administration of Estracyt. In 6 cases, however, the values increased again in the second year or later. Relapse was observed in 10 (26.3%) out of 38 cases. Relapse rate was 2.6%, 51.7%, and 51.7%, at the first, third, and fifth year, respectively. Survival rate was 97.4% at the first year, 88.5% at the third year, and 68.8% at the fifth year for the follow-up study. Side effects were observed in 14 (36.8%) out of 38 cases. The main side effect was gynecomastia. Gastro-intestinal disturbance and edema were also observed. However, there were only 2 cases (5.2%) in which administration of Estracyt had to be discontinued.

Adenocarcinoma↗

PubMedDate not supplied

The effect of estramustine on microtubuli is different from the direct action via oxygen radicals on DNA and cell membrane.

Estramustine (EM), a complex between estradiol-17 beta and nornitrogen mustard, is commonly used in the treatment of prostatic cancer. The exact mechanism of action is unknown but has previously been considered to be mediated through non-DNA targets, specifically with the mitotic spindle, and to be related to the intact EM complex. In the present study, using different cell-systems (monocyte phagocytosis transformed fibroblasts, colon cancer cells), the EM cytotoxicity was also found to involve direct interaxtion with DNA and cell membranes. The interaction with DNA was shown by a DNA precipitation assay using 3H- and 14C- thymidine, and the cell membrane damage by using 86Rb- accumulation as a sensitive marker for active potassium uptake. EM effects in the fibroblasts were inhibited by various metal chelators and radical scavengers. Involvement of free oxygen radicals was further indicated in a cell-free system with an oxygen electrode. The EM inhibition of monocyte phagocytosis was related to the engulfment, and was not at all influenced by radical scavengers. In contrast to EM, neither of its components alone, or together, affected monocyte engulfment. Finally, it was shown that the colon cancer cell-line HT-29 was resistant to both of the two suggested and separate mechanisms for EM toxicity: an interaction with the microtubuli system by the intact EM complex and a more unspecific action mediated by free-oxygen radicals.

Animals↗

PubMed1988

Antiinvasive activity of estramustine on malignant MO4 mouse cells and on DU-145 human prostate carcinoma cells in vitro.

Estramustine (EM) is a conjugate of estradiol and nor-nitrogen mustard (nor-HN2), which is effective in the treatment of prostate cancer. We have compared the effect of EM with that of the known microtubule inhibitor vinblastine (VLB) on the following functions of malignant MO4 mouse cells and of DU-145 human prostate cancer cells in vitro: directional migration, invasion; and the organization and the assembly/disassembly equilibrium of microtubule complexes. The circular area covered by cells migrating from an aggregate explanted on a solid substrate was taken as an index of directional migration. Invasion was studied through confrontation of MO4 or DU-145 cells with fragments of embryonic chick heart in organ culture. Microtubules were investigated immunocytochemically and through immunodetection on protein blots. VLB and EM inhibited directional migration and invasion of MO4 and DU-145 cells in a dose-dependent manner; equimolar combinations of estradiol plus nor-nitrogen mustard did not mimic these effects. At anti-invasive concentrations VLB led to partial disassembly of microtubule complexes, whereas EM resulted in an abnormal pattern of microtubule complexes without alteration of the overall assembly/disassembly equilibrium. Combined treatment with VLB and EM resulted in an enhanced VLB effect, namely complete disassembly. In all tests DU-145 cells were more sensitive to both VLB and EM than were MO4 cells, and the effects were less reversible. The present experiments showed that EM shares an anti-invasive activity with other microtubule inhibitors.

Animals↗

PubMed1986

[Clinical effects of estramustine phosphate disodium (Estracyt) on prostatic cancer].

Estramustine phosphate disodium (Estracyt) was used in the treatment of 40 patients with prostatic carcinoma. Of these 20 patients 18 were treated with Estracyt as primary treatment and 22 had been treated with diethyl stilbestrol dephosphate and/or bilateral orchiectomy for more than 4 months before the Estracyt treatment. The drug was given orally in a dose of 560 mg/day in 2 divided oral doses. The clinical evaluation was done after 3 months treatment. The response in subjective symptoms and objective signs were documented and evaluated according to 5 criteria. In this study, Estracyt showed 80% improvement of dysuria, 60% of nykturia, 35% of pain and 55% of general condition. In objective signs, it showed 52.5% improvement of size of the prostate, 42.5% of consistency and 70% of residual urine. It would be emphasized that Estracyt had almost equal efficacy in both the primary treatment group and secondary treatment group. As side effects of this drug, gynecomastia, gastro-intestinal disturbance, angina pectoris like chest pain were observed.

Drug Evaluation↗