Estramustine phosphate-hormone,chemotherapeutic agent,or both?

Estramustine phosphate, a combination steroid and alkylating agent, has been used for treatment of cancer of the prostate since 1969. We treated 32 patients with Stages C and D prostate cancer with this compound. Using the National Prostatic Cancer Project criteria of response, no patient achieved complete or partial objective response. Sixty-two per cent of the patients without prior hormonal manipulation and 12 per cent of those who were progressing following hormonal therapy met the criteria for a stable response. Both Stage C patients, 50 per cent of D1 and 28 per cent of D2 patients achieved disease stabilization for a mean duration of 14.8 months. There was no correlation between tumor grade and response to treatment. Fifty per cent of the patients whose elevated acid phosphatase declined remain stable, whereas 80 per cent in whom the acid phosphatase did not decline have progressed. Estramustine is effective in patients without prior hormonal manipulation. In those refractory to hormones, the prognosis is poor yet data exist to support the superiority of estramustine phosphate over conventional therapy.     

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.     

Estramustine phosphate with multiple cytotoxic agents in treatment of advanced prostatic cancer

Twenty-five patients with histologically proved adenocarcinoma of the prostate were divided into two groups and submitted to combination therapy with estramustine (Estracyt), cyclophosphamide (Cytoxan), 5-fluorouracil, and Cisplatin. Group A consisted of 10 patients newly diagnosed Stage D disease with no prior treatment. Group B consisted of 15 Stage D patients who had become hormonally unresponsive. Group A patients demonstrated an initial 100 per cent response rate including 70 per cent partial objective responses and 30 per cent stabilizations. Group B patients had a 46 per cent response with 39 per cent complete and partial responses and 6 per cent as stabilized. Toxicity was tolerable judged by the NPCP criteria. Both groups of patients are still under study for up to two years to determine if this therapy is superior to other traditional therapies.     

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.     

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.     

Current status of cytotoxic chemotherapy in hormone refractory prostate cancer

Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.     

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.     

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

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

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.     

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.     

Subsequent tumor analysis of 36 patients who have received intravesical mitomycin C for superficial bladder cancer

We studied 36 patients with stages O and A (Tis, Ta and T1) bladder cancer who had received 8 weekly doses of 30 or 40 mg. mitomycin C as definitive therapy. Of this group 16 had failed thiotepa therapy and 13 had grade III tumors (6 multifocal carcinoma in situ). The complete response rate at 12 weeks was 45 per cent (negative biopsy and cytology), while an additional 33 per cent had a partial response. Response did not correlate with tumor grade or stage. Patients who had failed thiotepa therapy were less likely to have a complete response, although the over-all response rate was identical to patients who had either not received prior chemotherapy or were not clear thiotepa failures. Followup of these patients indicates that the complete responders were benefited by this regimen since the subsequent recurrence rate was reduced when compared prior to initiation of mitomycin C. Most of these patients received monthly maintenance therapy.     

The use of estramustine and prednimustine versus prednimustine alone in advanced metastatic prostatic cancer patients who have received prior irradiation.

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9% of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.     

Estramustine phosphate (Emcyt) as treatment for metastatic renal carcinoma

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

Quality control of radiation therapy in multi-institutional randomized clinical trial for localized prostate cancer

The National Prostatic Cancer Project (NPCP) from 1978 through 1985 compared definitive radiation therapy for Stages B2, C, D1 lesions in those who received only radiation treatment to those who received two years of additional cyclophosphamide (Cytoxan) or estramustine phosphate (Emcyt) chemotherapy. Two hundred fifty-four patients were entered and 229 evaluated for compliance of the spatial localization of the prostate through review of the simulation and port films. In 78 per cent this was satisfactory, whereas in 12 per cent it was unsatisfactory, and another 10 per cent were not evaluable. The principle cause of an unsatisfactory rating was failure to adequately cover the prostatic target volume, especially the apex which was found to be variable in location. Routine use of retrograde urethrocystography is urged as part of the localization method in patients to receive definitive external beam radiation therapy for prostate cancer. The role and impact of quality assurance programs for radiotherapy in cooperative clinical study groups is reviewed and discussed.     

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.     

Hormonal chemotherapy for hormone-refractory prostate cancer

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.     

Phase II trial of doxorubicin in bidimensionally measurable prostatic adenocarcinoma

Intravenous doxorubicin (30 to 60 mg. per m.2 every 3 weeks) was administered to 52 patients with metastatic adenocarcinoma of the prostate, including 41 with bidimensionally measurable soft tissue lesions. Prior therapy in the measurable disease group included hormonal manipulation in 39 cases, irradiation in 39 and cytotoxic drugs in 19. In 39 of 41 adequately treated patients with soft tissue lesions only 2 (5 per cent, 95 per cent confidence limits 0 to 12 per cent) achieved a partial remission for 12 and 6 months, respectively, 3 had a minor response for 5, 4 and 3 months, respectively, and 1 had stabilization of disease for 4 months. Survival in this group was 16 months versus 5 months for patients with a mixed response and progression of disease. Of 11 patients with evaluable parameters only 1 had stabilization and 5 showed subjective improvement. Recognizing the patient selection bias and treatment schedule in this study, we believe that doxorubicin has marginal activity in soft tissue lesions in patients with advanced prostatic cancer.     

Immunological monitoring during combination of patient-oriented peptide vaccination and estramustine phosphate in patients with metastatic hormone refractory prostate cancer

BACKGROUND: Additive antitumor effects could be achieved by combination of immunotherapy and cytotoxic agents with no or minimum suppression. METHODS: Thirteen patients positive for human leukocyte antigen (HLA)-A24 or -A2 with metastatic hormone refractory prostate cancer (HRPC) who had failed to respond to the prior-peptide vaccination were entered in the combined peptide vaccination and estramustine phosphate. Conducted immune monitoring on those 13 patients were mainly peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by IFN-gamma productions and peptide-reactive IgG by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Grade 3 arrhythmia or cerebral infarction was observed in two cases, and Grade 1 or 2 dermatologic reaction at the vaccination sites was observed in all 13 cases. Eleven patients who received more than one cycle of treatment were eligible for immunological and clinical evaluation. There was no significant immunosuppression in most cases when the peptide and a half dose (280 mg/day) of estramustine were administrated, whereas severe immunosuppression was observed in the first two patients who received both the peptide and a full dose (560 mg/day) estramustine. Augmentation of peptide-specific CTL precursors or peptide-specific IgG was observed in 6 of 11 or 10 of 11 cases, respectively. Ten of 11 patients showed serum prostate-specific antigen (PSA) level decrease from the baseline including 8 patients with a serum PSA level decrease of > or =50%. CONCLUSIONS: These results encouraged the further evaluation of the combination of peptide vaccination and low-dose estramustine phosphate for metastatic HRPC patients.     

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.     

A phase II trial of estramustine and etoposide in hormone refractory prostate cancer: A Southwest Oncology Group trial (SWOG 9407)

BACKGROUND: The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS: Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy. RESULTS: Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS: This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.