estramustine and Vomiting

What's known on the subject? and What does the study add? Estramustine phosphate has anti-tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as docetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low-molecular-weight heparin support its use as a second-line treatment in hormone-resistant prostate cancer.. •  Estramustine phosphate is a nitrogen mustard derivative of estradiol-17β-phosphate and has anti-tumour properties. •  Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.. •  Relevant clinical studies using chemotherapy combinations including estramustine are discussed. •  Efficacy and safety outcomes are summarized.. •  Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine. •  Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.. •  The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low-molecular-weight heparins support the use of estramustine as an effective second-line treatment strategy in hormone-resistant prostate cancer. •  These promising findings warrant further investigation in a randomized clinical trial.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Nausea; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Taxoids; Thromboembolism; Treatment Outcome; Vomiting

Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cross-Over Studies; Dose-Response Relationship, Drug; Estramustine; Follow-Up Studies; Humans; Lymphopenia; Male; Middle Aged; Nausea; Orchiectomy; Peptides; Prostatic Neoplasms; Skin Diseases; Survival Analysis; Treatment Outcome; Vomiting

To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP).. A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment.. The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2).. High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Fatigue; Humans; Hypotension; Infusions, Intravenous; Liver; Male; Middle Aged; Nausea; Pain; Prostatic Neoplasms; Thrombosis; Vomiting

The antiemetic effect of prednisolone on nausea/vomiting was investigated in 67 patients with advanced prostatic cancer and a performance status of < or = 2. The study was a double-blind, placebo-controlled, randomized trial with a parallel group design. The objective was to compare the incidence and severity of nausea/vomiting between the two groups. Prednisolone or placebo was given twice daily for 3 weeks with the dose decreased during the third week from 15 mg/day to 10 mg for 3 days and finally to 5 mg/day during the last 4 days. EMP was given as two 140 mg capsules daily for 3 days at the beginning, then as four capsules for 4 days followed by six capsules for 21 days. Areas under curves (AUCs) for nausea and for nausea/vomiting scores were calculated based on the patient's diary notes: nausea (0-3), vomiting (0-6), nausea/vomiting (0-9). Control of emesis in terms of complete, moderate or poor control was registered. Pretreatment characteristics were evenly balanced. The results indicated that no statistical differences between the two groups of patients were present in AUCs for weeks 1-3 or weeks 1-4. We conclude that it was not possible to demonstrate a significant antiemetic efficacy of prednisolone. However, in all but one case the patients in the prednisolone group could be treated for at least 3 weeks without any major incidents of nausea/vomiting.

Topics: Aged; Antiemetics; Antineoplastic Agents, Alkylating; Area Under Curve; Double-Blind Method; Estramustine; Humans; Male; Nausea; Prednisolone; Prostatic Neoplasms; Treatment Outcome; Vomiting

Estramustine phosphate (EMP) is thought to form a chemical link between estradiol and non-nitrogen mustard. An estramustine-binding protein has been isolated in prostate, breast, and brain cancers as well as in malignant melanoma cells. Estramustine phosphate's ability to bind to microtubular-associated proteins and to interfere with mdr-mediated drug efflux are thought to result in its enhancement of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) activity in cell lines and in its ability to affect hormone-resistant prostate cancer. This phase I study administered combined paclitaxel and EMP to 25 women with ovarian, breast, and other tumors and assessed efficacy and toxicity. Estramustine phosphate was administered at two dose levels, 900 or 1,200 mg/m2 daily on days 1, 2, and 3 in 3-week cycles. On day 3, paclitaxel (150, 180, 210, or 225 mg/m2) was given concomitantly by 3-hour infusion. Therapeutic effects were noted in all patients. Partial responses were noted in three of eight patients with breast cancer who had failed to improve on paclitaxel alone. Three other patients experienced prolonged stable disease. Only moderate toxicities were noted until EMP levels of 1,200 mg/m2 were reached. At these dose levels, gastrointestinal toxicities became more prominent. The addition of EMP to paclitaxel allowed patients to receive paclitaxel for longer periods, and may have enhanced the therapeutic effects of paclitaxel. If so, the mechanisms of such enhancement warrant investigation. The two drugs may work on different aspects of microtubular function, for example, or may reduce efflux of paclitaxel in P-glycoprotein overexpressed tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Estramustine; Fatigue; Female; Humans; Middle Aged; Nausea; Ovarian Neoplasms; Paclitaxel; Treatment Outcome; Vomiting

A prospective randomized trial for metastatic prostatic cancer in 220 patients who were refractory to hormone therapy was conducted by the National Prostatic Cancer Project from 1984 to 1985. As of July, 1986, the evaluation of these patients reflected no difference in response to either estramustine phosphate (Emcyt) or flutamide. Toxicities were minimal, and the observed survival and progression-free survival intervals were noteworthy in view of the overall prospects for such patients. Future studies dealing with specific quality of life issues seem to be indicated by our results.

Topics: Anilides; Carcinoma; Clinical Trials as Topic; Estramustine; Flutamide; Hematologic Diseases; Humans; Male; Nausea; Nitrogen Mustard Compounds; Prospective Studies; Prostatic Neoplasms; Random Allocation; Vomiting

In May 1978, the National Prostatic Cancer Project Treatment Subgroup activated its first clinical trial evaluating adjuvant chemotherapy (Protocol 900). This protocol is a comparison of long-term adjuvant chemotherapy with cyclophosphamide, estramustine phosphate, or no additional treatment in patients with definitive surgical therapy for adenocarcinoma of the prostate. To date, 128 patients have been entered with an entry rate of approximately 2.2 patients per month. One hundred five patients form the basis of this report, with 96 patients still on active therapy. Estramustine phosphate has been administered at a dose of 600 mg/m2 orally daily in three divided doses. The cyclophosphamide is administered 1 g/m2 intravenously every 3 weeks. Results are still preliminary; only two evaluable patients have died. Approximately two-thirds of patients entered have had negative lymph nodes. Recurrent disease has been documented in 15 patients, including eight receiving cyclophosphamide, three receiving estramustine phosphate, and four on the no-treatment arm. The recurrence rate has been disproportionately high (50%) in patients receiving cryosurgery rather than radical prostatectomy (12%). Maximum survival has reached 241 weeks. Side effects have consisted of leukopenia in patients receiving cyclophosphamide (56%), and nausea and vomiting with cyclophosphamide (85%), and estramustine phosphate (36%). This study continues with patient entries now over one-half of the number anticipated in the original study design.

Topics: Adenocarcinoma; Adult; Aged; Cardiovascular Diseases; Clinical Trials as Topic; Combined Modality Therapy; Cryosurgery; Cyclophosphamide; Estramustine; Follow-Up Studies; Humans; Leukopenia; Lymph Node Excision; Male; Middle Aged; Multi-Institutional Systems; Nausea; Nitrogen Mustard Compounds; Prognosis; Prostatectomy; Prostatic Neoplasms; Random Allocation; Vomiting

Experiences resulting from Emcyt therapy in patients with both newly diagnosed and hormone refractory advanced prostate cancer, as well as on adjuvant to surgery or radiotherapy in earlier disease are presented. Data from trials of the National Prostatic Cancer Project (NPCP) and a series from Roswell Park Memorial Institute (RPMI) were divided into short-term (up to twenty weeks and up to fifty-two weeks in adjuvant trials) and long-term therapy. Baseline disease and patient characteristics and toxicities encountered in these two treatment-duration groups were compared. Patients in a more favorable health or disease status and/or responded to therapy were more frequently in the long-term group. Patients in the long-term group tended to have higher over-all incidences of toxicity; and although many had occurrences begin as early as those in the short-term group, they were able to tolerate the therapy for relatively long periods. The agent is thus both effective and can be given safety for long periods of time.

Topics: Acid Phosphatase; Alkaline Phosphatase; Anorexia; Cardiovascular Diseases; Clinical Trials as Topic; Diarrhea; Drug Administration Schedule; Estramustine; Humans; Male; Nausea; Neoplasm Staging; Nitrogen Mustard Compounds; Probability; Prostatic Neoplasms; Time Factors; Vomiting

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

Topics: Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Nausea; Nitrogen Mustard Compounds; Probability; Prostatic Neoplasms; Vincristine; Vomiting

Estracyt(R) is an antimitotic drug used for the treatment of prostate cancer, and its most common adverse effects are nausea and vomiting. In this study, we investigated the effect of a 5-HT3 receptor antagonist, granisetron, on emesis induced in ferrets by estramustine phosphate sodium (EMP), the active ingredient of Estracyt. To clarify the mechanism of action of EMP-induced emesis, we also investigated the effect of EMP on the release of serotonin (5-HT) in the isolated rat ileum. EMP (3 mg/kg, per os) induced 75.3+/-10.2 retching episodes and 7.5+/-1.3 vomiting episodes during a 2-h observation period. The latency to the first emetic response was 58.0+/-13.5 min. Granisetron (0.1 mg/kg, per os) administered 1 h before the administration of EMP reduced the number of EMP-induced retching and vomiting episodes to 1.3+/-1.3 and 1.0+/-1.0, respectively, and prolonged the latency by a factor of almost two. EMP (10-5 and 10-4 M) increased 5-HT release from isolated rat ileum, and 10 -7 M granisetron almost completely inhibited the increase induced by 10-4 M EMP. These results suggest that EMP induces nausea and vomiting via 5-HT release from the ileum, and that 5-HT3 receptor antagonists may be useful to prevent gastrointestinal adverse effects that occur during treatment with Estracyt.

Topics: Animals; Antiemetics; Antineoplastic Agents, Alkylating; Estramustine; Ferrets; Granisetron; Male; Rats; Vomiting

Estramustine phosphate, an anti-prostatic cancer agent, was investigated on eleven patients to evaluate the efficacy in a treatment of advanced breast cancers. The daily dose of medication was 840 mg. According to criteria of Japan Society for Cancer Therapy, none was assessed as CR, three as PR, four as NC and PD. The response rate was 27.3%. There was no differences in response rates among estrogen receptor status. A favourable response was observed in postmenopausal patients but no response in premenopausal, as well as a good response in lesions of soft tissue and lung, a poor response in lesions of liver and bone. As to toxicity of estramustine phosphate, gastrointestinal disorders such as nausea, vomiting and diarrhea were noted frequently during the treatment, and a long term administration was not able to perform in premenopausal patients because of vaginal bleeding and discharge, and pain in breast. The estramustine phosphate therapy for advanced breast cancers was regarded as one of modalities for a treatment of postmenopausal patients as a second line therapy. This is the first report in Japan discussing the efficacy of estramustine phosphate for a treatment of breast cancer.

Topics: Administration, Oral; Adult; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Estramustine; Female; Humans; Leukorrhea; Menopause; Middle Aged; Nausea; Nitrogen Mustard Compounds; Receptors, Estrogen; Vomiting

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.

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Nausea; Nitrogen Mustard Compounds; Prostatic Neoplasms; Vomiting

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: Chlorambucil; Estramustine; Hematopoiesis; Humans; Male; Nausea; Prednimustine; Prostatic Neoplasms; Vomiting