estramustine and Neoplasm-Metastasis

To describe drugs used in the hormonal treatment (hormonotherapy) of prostate cancer.. Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned.. LHRH analogs and the antiandrogens remain the cornerstone in the treatment of locally advanced and metastatic prostate cancer. New therapeutic classes emerged recently (inhibitor of the synthesis of the androgen, the new antiandrogens) and allowed to grow again the limits of the hormone resistance and define the concept castration-resistant prostate cancer.. The hormonal treatment of the prostate cancer grew rich of new therapeutic classes which are going to change the medical care of the prostate cancer in the coming years and the urologist must play its full part.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Combined Modality Therapy; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Estrogens, Non-Steroidal; Flutamide; Gonadotropin-Releasing Hormone; Humans; Imidazolidines; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Nitriles; Oligopeptides; Phenylthiohydantoin; Prostatectomy; Prostatic Neoplasms

Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Hormones; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

As part of an extensive search of synergistic combinations of agents that demonstrate cytotoxic activity in tissue culture against prostate cancer cell lines, we have identified estramustine phosphate and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as active. Patients with hormone-refractory metastatic prostate cancer with good performance status were entered onto a phase I trial of this combination. Estramustine phosphate was given on a daily oral dosing schedule of 14 mg/kg; docetaxel was administered intravenously over 1 hour every 3 weeks. Prophylactic corticosteroids were administered to minimize taxane side effects. Four dose levels of docetaxel were studied: 40, 60, 70, and 80 mg/m2. Actual weight was used for dosing calculations. An intermittent docetaxel dose of 70 mg/m2 with estramustine phosphate at 12 mg/kg was determined to be a phase II dose and to allow repetitive dosing. Eight additional patients were entered at this dose level of docetaxel. In all patients, the limiting side effects were fatigue and leukopenia. Thromboembolic events also were seen in 16% of patients. In the first 17 patients treated in the phase I aspect of the study, the biochemical response rate was 82%, demonstrating greater than a 50% decline in prostate-specific antigen. Twenty-four percent had normalization of prostate-specific antigen. These early studies indicate that the combination of estramustine and docetaxel has activity in this population of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Docetaxel; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Taxoids

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prognosis; Prostatic Neoplasms; Suramin; Vinblastine

Hormonal treatment is effective for only a limited time in primary treatment of advanced prostate cancer, because of the development of hormone-resistant cells. It is unknown whether these cells were present in small numbers from the beginning or developed later by mutation of hormone-sensitive cells. Cytotoxic therapy has, up to now, mainly been used as second-line treatment when virtually all cells are hormone-resistant. Because 20% of all advanced prostate cancers do not respond to hormonal treatment even when given as primary therapy, hormone-resistant cells may have been present from the beginning. Trials using a combined hormonal and cytotoxic treatment as primary therapy would, therefore, be interesting. However, there is a lack of active compounds that do not show major toxicity. Estramustine phosphate (EMP) may be an exception. It is unusual because it combines hormonal and cytotoxic effects. Second-line treatment with chemotherapy has led to subjective improvement over a very short period of time only. EMP may be of benefit to patients who have had previous radiotherapy as it does not suppress the bone marrow. Although primary treatment of advanced prostate cancer with a combination of hormone and chemotherapy does not lead to a cure, it may extend time to progression, particularly in patients with poor prognostic factors at the onset. In future phase III studies, the role of prognostic factors must be further classified in order to obtain meaningful results.

Topics: Animals; Antineoplastic Agents; Estramustine; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms

The objective of this review is to explore different therapeutic options for metastatic adenocarcinoma of the prostate. Orchiectomy, estrogen therapy, synthetic LHRH analogs and possibly antiandrogens are equally effective frontline treatment modalities. Ketoconazole is indicated in emergency situations, but chronic use is prevented by serious idiosyncratic toxicity and by long term complications. Combined androgen blockade (CAB), with leuprolide (or tryptorelin) and flutamide is more effective than single modality treatment in patients capable of strict treatment compliance. Estramustine phosphate may be as effective as CAB and may be the frontline treatment of choice in sexually active patients. Institution of single modality treatment may be delayed until cancer becomes symptomatic. Controversy lingers over whether the institution of CAB at an earlier time may improve progression free survival (PFS) and survival. Research projects of immediate clinical relevance include: comparison of CAB and estramustine; determination of the optimal time for CAB; study of other forms of CAB; and phase II trials of new cytotoxic agents.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prostatic Neoplasms

Topics: Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Acid Phosphatase; Antineoplastic Agents; Bromocriptine; Castration; Combined Modality Therapy; Cyproterone; Estramustine; Estrogens; Fluorouracil; Humans; Lisuride; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation

Topics: Adenocarcinoma; Adrenalectomy; Aged; Animals; Castration; Cryosurgery; Estramustine; Estrogens; Growth Hormone; Hormones; Humans; Hypoglycemia; Hypophysectomy; Ketosteroids; Male; Middle Aged; Neoplasm Metastasis; Postoperative Complications; Prostatic Neoplasms; Recurrence; Remission, Spontaneous

To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).. 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).. The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).. Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.. CDR0000067865.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Interferons; Isotretinoin; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Survival Rate; Teratogens; Treatment Outcome; Vinblastine; Vinorelbine

The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC).. Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients.. A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients.. The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Taxoids; Vinblastine; Vinorelbine

To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer.. One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%.. The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04).. The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Belgium; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Time Factors; Treatment Outcome

We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease.. Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy.. Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events.. There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Estramustine; Humans; Ketoconazole; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Vinblastine

The aim of this study was to investigate prognostic factors of patients with metastatic hormone refractory prostate cancer (HRPC) under combined administration of personalized peptide vaccination and low-dose estramustine phosphate (EMP). From February 2001 to July 2004, 58 men with metastatic HRPC received the combination therapy of personalized peptide vaccination and low-dose EMP. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and survival times were also evaluated. The combination therapy was well tolerated with no major adverse effects. Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 29 of 37 (78%) patients and in 36 of 41 (88%) patients tested, respectively. A prostate-specific antigen decline of at least 50% occurred in 24% of patients. The median survival time was 17 months (95% confidence interval, 12-25 months). Cox proportional hazards analysis showed that a low number of lymphocytes (p = 0.0075, odds ratio 2.700), a negative immunological activity response after the vaccination (p = 0.0185, odds ratio 2.658), and poor performance status (p = 0.0347, odds ratio 2.569) were independent predictors of disease death. These encouraging results show the need for further evaluation of the combination of personalized peptide vaccination and low dose of EMP for metastatic HRPC patients.

Topics: Aged; Aged, 80 and over; Amino Acid Sequence; Antibody Formation; Cancer Vaccines; Combined Modality Therapy; Epitopes, T-Lymphocyte; Estramustine; Humans; Immunity, Cellular; Immunoglobulin G; Immunotherapy, Active; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Peptides; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; T-Lymphocytes, Cytotoxic; Treatment Outcome

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Epothilones; Estramustine; Fatigue; Humans; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Prostatic Neoplasms; Thrombosis

Additive antitumor effects could be achieved by combination of immunotherapy and cytotoxic agents with no or minimum suppression.. 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).. 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%.. These results encouraged the further evaluation of the combination of peptide vaccination and low-dose estramustine phosphate for metastatic HRPC patients.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Estramustine; Humans; Immunoglobulin G; Immunosuppression Therapy; Interferon-gamma; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Vaccines, Subunit

To describe the 5-year outcomes of patients with high-risk localized prostate cancer treated with neoadjuvant estramustine and vinblastine followed by concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT).. A total of 23 patients completed therapy consisting of two 8-week cycles of vinblastine, weekly as 4 mg/m2, followed by 8 weeks of concomitant chemotherapy and 3D-CRT. Estramustine was given daily at 10 mg/kg in three divided doses. 3D-CRT consisted of a total dose of 7560 cGy.. Assessable patients include 9 with Stage T3 or greater tumors and 5 with lymph node metastasis at diagnosis. All patients had a Gleason score 7 or greater. The median follow-up was 60 months. Of the 23 assessable patients, 15 (65%) experienced biochemical relapse by American Society for Therapeutic Radiology Oncology criteria. The median time to prostate-specific antigen relapse was 12 months (range 7 to 16). Five patients (22%) developed metastases. The median time to metastasis had not been reached by last follow-up. Of the 23 assessable patients, 11 (48%) received no additional therapy and had noncastrate testosterone levels. Six patients had no evidence of disease and 9 patients were receiving androgen blockade. Three patients died (one of prostate cancer and two of other diseases).. A substantial proportion of patients with unfavorable-risk localized prostate cancer achieved long-term disease control with estramustine and vinblastine and concurrent 3D-CRT, no significant long-term toxicities were seen and 48% underwent no further therapy after RT. These long-term findings support the continued study of chemotherapy combined with RT as a potential alternative to prolonged androgen deprivation.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Disease-Free Survival; Estramustine; Feasibility Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Risk; Survival Analysis; Testosterone; Treatment Outcome; Vinblastine

Early chemohormonal therapy in metastatic prostate cancer may offer an advantage by simultaneously targeting androgen-dependent and -independent clones. Hence, a phase II trial was conducted to evaluate the efficacy and toxicity of estramustine and etoposide in hormone-sensitive metastatic prostate cancer.. Eligibility consisted of untreated metastatic prostate cancer, adequate organ function, and a performance status of 0 to 2 by Zubrod criteria. A 21-day schedule of oral estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) was administered every 28 days. Hormonal therapy was allowed at the end of the protocol therapy. Toxicity was assessed weekly, PSA levels were assessed with each cycle, and objective response was evaluated every 3 cycles.. Twenty-one patients were enrolled (10 white, 11 black) with a median age of 59.5 years (range, 42-79 years), a median PSA of 338 ng/mL (range, 0.9-20,000 ng/mL), and a median Gleason score of 8 points. Ten patients had bone-only metastases, 11 had measurable disease, of whom 4 had visceral metastases. A total of 128 cycles were administered (median, 6 cycles). No dose reductions were required. Nineteen patients were able to be evaluated for response. Severe toxicities included thromboembolic events and anemia in 2 patients each and fatigue in 1 patient. There were no episodes of febrile neutropenia. Response was observed in 8 of 11 patients (73%) with measurable disease. Median PSA nadir after therapy was 0.45 ng/mL, and undetectable PSA (<0.1 ng/mL) was achieved in 4 patients. Median time to PSA progression was 16.65 months. At a median follow-up of 34 months, 18 patients were alive. The 1-, 2-, and 3-year overall survival rates were 90%, 82%, and 72% respectively. Median survival has not yet been reached.. The combination of estramustine and etoposide is well tolerated, and has promising activity in newly diagnosed metastatic prostate cancer.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Rate

The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC).. Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC.. Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life.. The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Estramustine; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Quality of Life; Remission Induction; Survival Analysis; Taxoids

The combination of paclitaxel, oral estramustine phosphate (EMP), and carboplatin (TEC) has shown antitumor activity in patients with castrate, metastatic prostate carcinoma. To improve the therapeutic efficacy and reduce the toxicity of TEC, the authors substituted intravenous (i.v.) EMP for oral EMP based on single-agent studies demonstrating an improved safety profile with i.v. EMP.. Patients with progressive, castrate, metastatic prostate carcinoma were treated with up to 6 4-week cycles of i.v. EMP (500-1500 mg/m(2) per week), paclitaxel (100 mg/m(2) per week), and carboplatin (target area under the curve = 6 mg/mL every 4 weeks).. Thirty patients were treated in 6 dose cohorts. Deep venous thrombosis occurred in 5 of 30 patients (17%). Other common Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria) toxicities included hepatic toxicity (23%) and leukopenia (24%). Posttherapy prostate specific antigen declines > 50% were seen in 18 of 30 patients (60%), and declines > 80% were seen in 15 of 30 patients (50%). Eleven of 17 patients (65%) with measurable soft tissue disease achieved a partial response. Four of 27 patients (15%) with osseous metastases demonstrated improvement on bone scan.. Intravenous EMP was administered safely with paclitaxel and carboplatin and produced clinical outcomes similar to the outcomes achieved with the TEC regimen. Substitution of i.v. EMP for the oral formulation was found to result in a lower incidence of severe nausea but increased hepatic toxicity.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carboplatin; Disease-Free Survival; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC).. Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles.. Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen.. Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Administration Schedule; Estramustine; Female; Humans; Microtubules; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival; Taxoids; Treatment Outcome; Venous Thrombosis

The aim of this study was to determine the safety and activity of vinorelbine in combination with estramustine in men with androgen-independent metastatic prostate cancer.. Twenty-five men with androgen-independent metastatic prostate cancer were treated with the combination of vinorelbine and estramustine. Vinorelbine 25 mg/m(2) was administered by intravenous bolus on Days 1 and 8. Estramustine 140 mg was administered three times a day by mouth on Days 1 through 14. Treatment was repeated every 21 days.. A total of 132 cycles of treatment were administered. The median number of cycles per patient was 5 (range: 1-16). Mild Grade 1 or 2 gastrointestinal toxicity and fatigue were the most common adverse effects. Hematologic toxicity was minimal. Treatment resulted in a sustained > 50% decrease in serum prostate-specific antigen (PSA) in 6 of 25 patients (24% of patients; 95% confidence interval (CI) 9-45%). The median duration of PSA response was 10 weeks (range: 3-39 weeks). Of the five men with bidimensionally measurable disease, none achieved a complete or partial response. There were no documented improvements in post-treatment bone scans. Median overall survival time was 14.1 months.. The combination of vinorelbine and estramustine is a well-tolerated and modestly active regimen in men with androgen-independent metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Survival Analysis; Vinblastine; Vinorelbine

Thirty-one patients with progressive metastatic prostate cancer refractory to first- or second-line hormonal therapy were treated with a combination of daily oral estramustine phosphate (600 mg) and weekly intravenous doxorubicin (20 mg/m2). Eighteen (58%) patients demonstrated a biologic response with a 50% or more serum prostate-specific antigen decline. The median duration of biologic response was three months. Five (45%) of the 11 patients with measurable lesions achieved a partial response in liver or retroperitoneal lymph nodes. The median duration of these objective responses was four months. Of 22 patients who required analgesics at the onset of the study, six (27%) achieved a significant reduction of pain. The combination of doxorubicin and estramustine phosphate was tolerated on an outpatient schedule. The occurrence of severe toxicities required suspension of therapy in six patients. At the end of the observation time, all patients but one had died, 29 of progressive prostatic cancer and one of toxicity. The median survival time from the onset of chemotherapy was 12 months. The administration of weekly doxorubicin with phosphate estramustine appears to be a safe combination for those patients with hormone-resistant prostate cancer who require chemotherapy. The benefit of chemotherapy should be investigated using relevant quality-of-life criteria in future trials.

Topics: Adult; Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Analysis

72 patients with hormone resistant, progressing prostatic cancer completed a self-administered questionnaire to assess subjective morbidity and quality of life before they were entered into a phase III trial of estramustine (34) vs. mitomycin (38). At least one post-treatment assessment was available in 43 patients. This considerable degree of non-compliance is explained by practical problems related to completion and collection of the questionnaires in these rapidly deteriorating patients. Doctors underestimated subjective morbidity (pain, decreased performance status, nausea) in 30-50% of the cases. Decreased functional status, fatigue and pain were identified as the most frequent major morbidities before study entry. In most patients, treatment did not reduce this morbidity. The routine application of self-administered quality of life questionnaires has considerable practical problems but yields clinically worthwhile information about subjective morbidity. Simple but relevant monitoring of subjective morbidity by the patient should be mandatory in cancer trials where palliation is a major endpoint.

Topics: Attitude of Health Personnel; Attitude to Health; Drug Resistance; Estramustine; Hormones; Humans; Male; Mitomycins; Neoplasm Metastasis; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires

The results of orchiectomy + flutamide (n = 28) versus orchiectomy + estramustine (n = 27) in the initial therapy of advanced prostatic cancer were compared in a prospective randomized study. The minimum observation period was one year. In the group orchiectomy + flutamide the incidence of side effects was 25%, the response rate (complete + partial remission) was 28% and the progression rate was 18%. 5 patients (18%) died within the first year. In the group orchiectomy + estramustine the incidence of side effects was 22%, the response rate (complete + partial remission) was 29% and the progression rate was 33%. 2 patients (7%) died within 1 year of treatment. There is no significant difference either in the response rate or the progression rate between the two groups.

Topics: Aged; Aged, 80 and over; Anilides; Clinical Trials as Topic; Combined Modality Therapy; Estramustine; Flutamide; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Orchiectomy; Prospective Studies; Prostatic Neoplasms; Random Allocation

Topics: Castration; Clinical Trials as Topic; Cyproterone; Diethylstilbestrol; Estramustine; Humans; Male; Medroxyprogesterone; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

Topics: Aged; Cisplatin; Clinical Trials as Topic; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prognosis; Prostatic Neoplasms; Random Allocation

Patients with advanced prostate carcinoma that had been stabilized by orchiectomy (ORCH) or hormone therapy for at least 3 months, were randomized to either diethylstilbestrol (DES) alone or DES plus Cytoxan or DES plus Emcyt. A total of 188 patients were randomized between July, 1976 and February, 1982 of which 161 were evaluable for objective response to treatment. Objective response rates, response duration, or survival experiences were not demonstrably different between treatment arms, either for all patients or within good or poor prognosis groups determined by initial pain or acid phosphatase level. Subjective improvements in performance status were small for each treatment. Pain relief was somewhat greater in the chemotherapy-hormone combinations than in the DES/ORCH, but the advantage was not statistically significant. Side effects were primarily nausea and vomiting and leukopenia, mostly in the DES + Cytoxan arm. The duration of stabilization prior to entry did not influence response overall, although there were opposing trends within each of the two chemotherapy arms. The premise for combining antitumor agents with hormones before hormone failure is still felt to be a more logical approach than waiting for the ultimate hormone failure, and a combination of hormones plus two antitumor agents is being evaluated in a subsequent ongoing trial where a more rigid design limits the duration of the preentry period of hormone stabilization.

Topics: Aged; Castration; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

A controlled, randomized trial of estramustine phosphate versus stilbestrol has been conducted in patients with previously untreated adenocarcinoma of the prostate. Both drugs were equally effective in decreasing serum testosterone and acid phosphatase levels. No therapeutic advantage of estramustine over stilbestrol was noted. At 3 months, 50% of tumours treated with stilbestrol had regressed compared with 36% treated with estramustine, at 1 year the rates were 50% and 21% respectively and at 2 years 50% and 9%. However, there was no difference in objective stabilization and regression rates between the two groups or in therapeutic failure rates.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prolactin; Prostatic Neoplasms; Random Allocation; Testosterone

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.

Topics: Adult; Aged; Clinical Trials as Topic; Estramustine; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Sex Factors

A preliminary report is presented of prospective, randomized study with continuous and intermittent oral Estracyt treatment in patients with prostatic carcinoma. It seems that the therapeutic effect of intermittent treatment is as favorable as continuous therapy. Side effects and costs are lower with intermittent therapy.

Topics: Drug Administration Schedule; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitrogen Mustard Compounds; Prostatic Neoplasms

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 percent 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.

Topics: Drug Therapy, Combination; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

In Roswell Park Memorial Institute, between 1969 and 1974, a total of 32 patients with widespread metastasized carcinoma of the prostate were treated with oral Estracyt. Objectively demonstrable remissions were achieved in eight patients (8/32 equals 25%). Subjective improvement of their general condition was experienced by 15 patients (15/32 equals 47%). The toxicity of Estracyt manifests itself with gastrointestinal disorders, which in most cases are amenable to anti-emetic treatment.

Topics: Administration, Oral; Aged; Clinical Trials as Topic; Drug Evaluation; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Palliative Care; Prostatic Neoplasms

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. The current guidelines recommend extended pelvic lymph node dissection (e-PLND) for selected intermediate- and high-risk patients treated with RP. However, the indications, optimal extent, and therapeutic benefits of e-PLND remain unclear. The aim of this study was to assess whether e-PLND confers an oncological benefit for high-risk Pca compared to neoadjuvant luteinizing hormone-releasing hormone and estramustine (LHRH + EMP). The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at four institutes between March 2000 and December 2014. In the e-PLND group, we identified 238 high-risk Pca patients who underwent RP and e-PLND, with lymphatic tissue removal around the obturator and the external iliac regions, and hypogastric lymph node dissection. The neoadjuvant therapy with limited PLND (l-PLND) group included 280 high-risk Pca patients who underwent RP and removal of the obturator node chain between September 2005 and June 2014 at Hirosaki University. The outcome measure was BRFS. The 5-year biochemical recurrence-free survival rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9 and 54.7%, respectively (P < 0.0001). The operative time was significantly longer in the e-PLND group compared to that of the neoadjuvant therapy with l-PLND group. Grade 3/4 surgery-related complications were not identified in both groups. Although the present study was not randomized, neoadjuvant LHRH + EMP therapy followed by RP might reduce the risk of biochemical recurrence.

Topics: Aged; Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Estramustine; Gonadotropin-Releasing Hormone; Humans; Lymph Node Excision; Lymph Nodes; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prostatic Neoplasms; Retrospective Studies; Risk Factors

Chemotherapy is indicated in metastatic castration-refractory prostate cancer. It aims at alleviating symptoms and increasing survival, without impairing quality of life. Docetaxel is considered as the reference treatment in this indication. However, several studies demonstrated the relevance of associating estramustin with docetaxel, due to the synergistic effect of the combination and the action of estramustin on resistance mechanisms. Moreover, the addition of estramustin to chemotherapy demonstrated a survival benefit for patients. Thrombotic events are frequent in patients with advanced prostate cancer and estramustine is known to increase the risk. Optimization of treatment requires a thorough assessment of the individual risk in each patient as well as the prescription of an anti-thrombotic prophylaxis, which should be currently based on low molecular weight heparin.

Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Chemotherapy has emerged as a standard treatment in patients with castration-refractory prostate cancer (CRPC). Consensus criteria are available to define response in CRPC as at least a 50% decline in serum prostate-specific antigen (PSA) confirmed 4 weeks later. The objective of this work was to study early serum PSA changes in patients under chemotherapy and to correlate these changes with subsequent response assessment.. Serum PSA levels were monitored every 3 weeks in 79 patients with CRPC treated with chemotherapy and a time course of serum PSA levels was obtained. Correlation with response was studied.. According to consensus criteria, 21 (40%) and 20 (38%) patients achieved a PSA response and stabilization, respectively, after first-line chemotherapy. Among patients who achieved either a response or a stabilization, 8 of 41 (20%) had a serum PSA rise during the first 8 weeks of chemotherapy, followed by a subsequent decline in serum PSA. The same observation was made in patients receiving second-line chemotherapy: 6 of 20 patients achieving a response or stabilization had an initial serum PSA rise. The postchemotherapy increase in serum PSA could reach more than twice the baseline value. The duration of the PSA surge ranged from 1 to 8 weeks. When considering responders only, 6 of 30 (20%) had a postchemotherapy serum PSA surge, followed by a drop.. Postchemotherapy PSA surges occur not infrequently in patients with CRPC who respond to chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Estramustine; Gonadotropin-Releasing Hormone; Humans; Kinetics; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Sesquiterpenes; Syndrome; Taxoids; Treatment Outcome

Prostatic carcinoma metastasizing to the penis is rare. A case of adenocarcinoma of the prostate with metastases to the penile shaft and glans penis is presented.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Estramustine; Humans; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Orchiectomy; Penile Neoplasms; Prostate-Specific Antigen; Prostatic Neoplasms

Early diagnosis and monitoring of progression for relapsed prostatic carcinoma after primary treatment is necessary, and early intervention recommended. This has now been made possible with rising prostate-specific antigen levels as an indication of the endpoint of treatment failure. Patients with relapsed disease can be divided into three groups: those relapsing following curative treatment with surgery or radiotherapy with local or distant metastases; patients who have been treated with primary hormonal palliative therapy or combination hormonal-chemotherapy relapsing after the first palliative treatment, and patients relapsing after all acceptable therapies for the treatment of prostate cancer. The management of these groups of patients is discussed.

Topics: Androgen Antagonists; Antineoplastic Agents; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.

Topics: Adenocarcinoma; Adrenal Glands; Animals; Aromatase Inhibitors; Body Weight; Chlorobenzenes; Estradiol; Estramustine; Hypophysectomy; Male; Neoplasm Metastasis; Neoplasms, Experimental; Orchiectomy; Organ Size; Prostatic Neoplasms; Pyrimidines; Pyrrolidines; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis; Thiophenes

In this paper the authors review the completed and current EORTC Genitourinary Group trials for metastatic carcinoma of the prostate. In terms of time to progression and length of survival, there is no significant difference between any of the effective endocrine treatments that have been studied. The statistical analysis of the different variables used in trials 30,761 and 30,762 determines three risk groups of patients. There is no need for very special laboratory investigations to establish a prognosis. Orchiectomy is the cheapest and safest endocrine treatment in metastatic carcinoma of the prostate.

Topics: Androgen Antagonists; Carcinoma; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Europe; Gonadotropin-Releasing Hormone; Hormones; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms

Prostata cancer is one of the most dangerous tumours occurring in the older man. No general accepted therapy has existed up to now. In this study we were engaged on the pharmacokinetics of fosfestrol (Honvan) after oral administration. Its active principle is E-diethylstilbestrol (E-DES), the main metabolite. 250-1600 ng/ml E-DES are measurable after 60-110 min in the plasma of 11 patients suffering from metastatic prostata cancer who have been administered 360 mg fosfestrol orally. This range is equivalent to E-DES concentrations in plasma of 1-4 x 10(-6) mol/l. Thus that E-DES concentration range (5 x 10(-6) mol/l) is nearly attained for a short time to the concentration which hinders the mitosis of human breast cancer cells. Surprisingly similar but not higher concentration - time courses may be measured after a bolus infusion of 360 mg fosfestrol (lasting 45 min). Furthermore, E-DES-glucuronide, E-DES-sulphate and the mixed E-DES-glucuronide-sulphate could be observed in plasma after oral administration. In spite of the high sensitivity of the analytical method (limit of detection for fosfestrol 0.1 micrograms/ml and for E-DES and its mono-conjugates 2-5 ng/ml) neither fosfestrol nor E-DES-monophosphate are detectable in plasma due to the biotransformation of fosfestrol, which is already metabolized by the enzymes of the gut wall. Both phosphates only exist in plasma after intravenous infusion. Further investigations are linked with the question if phase II-conjugates of E-DES can eventually be prodrugs delivering E-DES by cleavage of the ester bonds.

Topics: Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents; Biological Availability; Biotransformation; Carcinoma; Chemical Phenomena; Chemistry; Diethylstilbestrol; Estramustine; Estrogens; Humans; Ketoconazole; Male; Middle Aged; Neoplasm Metastasis; Pituitary Hormone-Releasing Hormones; Prostatic Neoplasms; Protein Binding

A patient with metastatic prostate cancer is described where treatment with Adriamycin (doxorubicin) and estramustine produced severe hypophosphatemia (serum phosphate level, 1.2 mg/dl), which was reversible when treatment was discontinued. Previous studies have shown no effect of Adriamycin on serum phosphate levels. A retrospective study of serial serum chemistry values was done in 15 patients treated with estramustine. A significant fall in the serum phosphate level (mean, 0.8 +/- 0.3 mg/dl) was observed during the first 6 weeks of treatment. When compared with similar patients treated with bilateral orchiectomy, estramustine-treated patients had lower levels of serum calcium, fractional excretion of calcium, serum phosphate, and renal tubular threshold for phosphate reabsorption (TmPO4/GFR). Qualitatively similar but quantitatively smaller effects were also seen in a group of patients treated with diethylstilbestrol (DES) in a dose of 1 to 3 mg daily. Estramustine appears to have significant effects on bone mineral metabolism, particularly on renal phosphate handling resulting in significant hypophosphatemia. This is probably due to an estrogenic effect.

Topics: Adenocarcinoma; Bone and Bones; Calcium; Creatinine; Diethylstilbestrol; Estramustine; Estrogens; Humans; Kidney; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Orchiectomy; Phosphates; Prostatic Neoplasms

Current management techniques for metastatic prostatic cancer have given rise to controversies regarding the optimal timing, form, and degree of androgen deprivation. Low-dose diethylstilbestrol (DES) or orchiectomy decrease serum testosterone levels while posing less cardiovascular risk than high-dose DES. LH-RH analogues, such as leuprolide or buserelin, also inhibit testosterone production. Some studies suggest that some tumor cells may be relatively, rather than absolutely, androgen dependent. This has been the rationale for the combined use of a pure antiandrogen and an LH-RH agonist. Unfortunately, while this combination has been found effective in previously untreated patients, it has not been equally effective in those who have undergone prior therapy and demonstrated disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Castration; Cyclophosphamide; Diethylstilbestrol; Estramustine; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Antineoplastic Agents; Castration; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

The effects of estramustine phosphate (EMP) and diethylstilbestrol (DES) on natural killer (NK) cell activity, tumor growth, and artificial metastases were investigated in male C57BL/6 mice. Kinetic analysis and studies at the single-cell level indicated that EMP did not influence the number of NK cells but interfered with their lytic activity thereby reducing the actual killer capacity. NK cells from EMP-exposed animals responded normally to the interferon inducer Poly I:C which restored NK activity to control levels. Spleen cells from DES-treated animals had lytic activity comparable to that of control animals. However, more detailed analysis showed that DES reduced the number of lymphocytes able to recognize target cells, while the individual NK cell had an increased lytic activity and recycling capacity. Moreover, NK cells from DES-treated animals were refractory to poly-I:C stimulation, suggesting that they were prestimulated in vivo. The pertubations of the NK cell system induced by both EMP and DES were reversible and normalization of NK activity was reached within a week. The incidence of tumor takes after subcutaneous inoculation of the syngeneic Lewis lung carcinoma was increased in EMP as well as DES-treated animals. Artificial lung metastasis produced by intravenous injection of the same tumor was increased in EMP but not in DES-exposed animals.

Topics: Animals; Cytotoxicity Tests, Immunologic; Diethylstilbestrol; Disease Susceptibility; Estramustine; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Nitrogen Mustard Compounds; Spleen

Topics: Bone Neoplasms; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Castration; Diethylstilbestrol; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Palliative Care; Prostatic Neoplasms; Time Factors

Since the introduction of estrogen treatment of prostatic carcinoma in 1941 this treatment has been considered the treatment of choice until recently, when both conventional cytotoxic compounds and hormone cytotoxic agents have been used. Preliminary results are in many aspects very promising (Jönsson, Högberg & Nilsson, 1977). However, controlled randomized series are badly needed to give a final answer how to proceed. So far chemotherapy has been given only for palliation but new approaches and combined treatment modalities might point forward to a treatment that, hopefully, will cure prostatic carcinoma especially if the treatment is started in the very early stages.

Topics: Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Ninety patients with poorly differentiated prostatic carcinoma have been treated with Estramustine phosphate (Estracyt). Seventeen of them had clinically metastases and had had no previous therapy. Seventy-three were initially given oestrogens and/or irradiation. Objective response was observed in 59%. The best effect was seen in patients primarily untreated.

Topics: Acid Phosphatase; Bone Neoplasms; Estramustine; Humans; Lymphatic Metastasis; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Pain; Prostatic Neoplasms

Estracyt, a conjugate of an alkylating agent with an oestrogenic sterol, was given in a dose of 420 mg daily to a group of 44 postmenopausal patients with very advanced breast carcinoma. Thirty-eight of these were in relapse following chemotherapy and 32 had evidence of distant metastases. Seventeen patients had an objective response and marked or complete alleviation of symptoms, four others had a useful symptomatic response but no beneficial effect was observed in the remainder. Three who had shown no response to previous oestrogen therapy also failed to respond to Estracyt as did all nine patients with hepatic metastases. Oestrogen receptor status and age within the postmenopausal group seemed to have no bearing on the result. Side-effects were minimal with nausea in 18 patients but in only two did this necessitate withdrawal of the drug. Bone marrow depression did not occur. Changes in acute-phase reactant proteins suggested that part of the Estracyt was de-esterified in the liver liberating oestrone but the low incidence of vaginal haemorrhage and the recalcification of bony metastases suggested that on the whole Estracyt behaves as an anti-oestrogen as well as an antimitotic.

Topics: Aged; Breast Neoplasms; Estramustine; Female; Humans; Menopause; Middle Aged; Nausea; Neoplasm Metastasis; Palliative Care; Receptors, Estrogen; Time Factors

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.

Topics: Chlorambucil; Drug Therapy, Combination; Estramustine; Humans; Male; Nausea; Neoplasm Metastasis; Nitrogen Mustard Compounds; Pain; Prednisolone; Prostatic Neoplasms; Vomiting

Topics: Diethylstilbestrol; Drug Administration Schedule; Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Bone Neoplasms; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Radiography; Remission, Spontaneous

40 patients with prostatic carcinoma were treated with parenteral and/or oral Estracyt (estramustine phosphate) until 55 months. Metastases were present in 37 patients (stage D). 35 of the 40 patients developed metastases in spite of estrogen therapy and/or orchidectomy. Diminution of metastasic bone pain as well as improvement of hydroureteronephrosis was frequently observed. Paraplegia secondary to metastatic disease improved in 1 case for 6 months. Side effects were relatively rare and were mainly gastrointestinal. A possible hepatotoxic action of the compound has been pointed out previously. On the basis of our studies Estracyt is recommended in the treatment of primary estrogen resistent prostatic carcinoma and in metastatic carcinoma of the prostate not responding to conventional antiandrogenic therapy anymore.

Topics: Administration, Oral; Aged; Bone Neoplasms; Carcinoma; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; Estramustine; Estrogens; Humans; Injections, Intravenous; Long-Term Care; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate has been used as primary treatment in 38 patients with advanced prostatic carcinoma. Of these 38 patients 36 responded objectively to treatment, regression occurring in 10 patients with soft tissue metastases, 3 with pulmonary metastases and 3 with bony metastases. Primary cytotoxic treatment in patients with far advanced prostatic carcinoma is advocated and a randomized clinical study is suggested.

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Administration, Oral; Aged; Drug Evaluation; Estradiol; Estramustine; Humans; Injections, Intravenous; Male; Mechlorethamine; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

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.

Topics: Aged; Castration; Estramustine; Estrogens; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms