estramustine and ixabepilone

Estramustine, an agent with both hormonal and non-hormonal effects in men, is supposed to be effective in treating castration-resistant prostate cancer. However, previous studies have reported conflicting results. We conducted this meta-analysis to evaluate the efficacy and toxicity of additional estramustine to chemotherapy.. Data sources including PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. Prostate specific antigen (PSA) response, overall survival, and grade 3 to 4 toxicity were analyzed.. Seven randomized controlled trials, a total of 839 patients, were enrolled. The pooled odds ratio for PSA response was 3.02 (95% CI=1.69-5.39, P=.0002); the pooled hazard ratio for overall survival was .95 (95% CI=.80-1.14, P=.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI=1.05-14.45, P=.04) and 2.22 (95% CI=1.15-4.30, P=.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P>.05).. According to this meta-analysis, chemotherapy with additional estramustine increased the PSA response rate. However, it increased the risk of grade 3 or 4 adverse effects such as nausea/vomiting and cardiovascular events, and the overall survival was not improved for castration-resistant prostate cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Combined Modality Therapy; Docetaxel; Epirubicin; Epothilones; Estramustine; Fatigue; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Orchiectomy; Paclitaxel; Peripheral Nervous System Diseases; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

2004 was a critical year for advances in prostate cancer treatment. The results from two pivotal multicenter phase III randomized studies are the first to demonstrate a survival benefit associated with chemotherapeutic treatment interventions in patients with hormone-refractory prostate cancer. This review will focus on an interpretation of the data from these two studies, the emerging role for chemotherapy in 2005 and beyond, and ongoing areas of clinical research.. Phase I and II studies have demonstrated biochemical and objective responses achieved with docetaxel-based chemotherapy in men with hormone-refractory prostate cancer. Two pivotal phase III clinical trials, TAX 327 and SWOG 9916 have demonstrated a survival advantage of docetaxel-based chemotherapy over mitoxantrone. Novel targeted therapies under investigation include calcitriol, growth factor-targeted agents, epothilones and others.. We now have a new standard of care for men with metastatic hormone-refractory prostate cancer. Further investigation of docetaxel-based regimens in earlier clinical states of disease is warranted and may demonstrate greater clinical benefit. Additional chemotherapy agents are being studied, and may also add to the future armamentarium available for prostate cancer. The enrolment of patients into these studies is critical to the ongoing evolution of prostate cancer management.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Calcitriol; Calcium Channel Agonists; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epothilones; Estramustine; Humans; Male; Mitoxantrone; Multicenter Studies as Topic; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Epothilones; Estramustine; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

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

Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer.. Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks.. Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%).. The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bone Neoplasms; Castration; Dose-Response Relationship, Drug; Epothilones; Estramustine; Humans; Male; Maximum Tolerated Dose; Microtubules; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Epothilones and taxanes interfere with microtubule function. Ixabepilone, which is an epothilone-B analog, has activity against taxane-resistant cell lines and as first-line therapy for men with hormone-refractory prostate carcinoma (HRPC). Clinical cross-resistance of ixabepilone and taxanes in HRPC is unknown.. Records were evaluated retrospectively from patients with HRPC who were treated on a randomized Phase II trial of ixabepilone with or without estramustine and who subsequently received taxane chemotherapy. Posttherapy declines in prostate-specific antigen (PSA) levels and time to PSA progression were defined by consensus criteria. The median survival was evaluated by using the Kaplan-Meier method.. Forty-nine patients who received ixabepilone with estramustine (28 patients) or without estramustine (21 patients) subsequently received second-line taxane therapy. Second-line PSA declines > or = 50% were achieved by 51% of patients (95% confidence interval [95% CI], 33-66%). Second-line PSA declines > or = 50% were achieved by 61% of patients (95% CI, 42-78%) who achieved a first-line PSA decline > or = 50% with ixabepilone, compared with 33% of patients (95% CI, 13-59%) who did not (P = 0.08). Patients who discontinued first-line ixabepilone treatment for disease progression were less likely to achieve a PSA decline > or = 50% in response to second-line, taxane-based therapy compared with patients who discontinued for toxicity or patient preference (36% vs. 71%; P = 0.01).. Second-line taxane chemotherapy after ixabepilone resulted in a substantial frequency of PSA declines. Although patients with ixabepilone-refractory disease were less likely to respond to second-line taxane chemotherapy, 36% did achieve a PSA response. These findings were consistent with incomplete clinical cross-resistance between the taxanes and the epothilones.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome