estramustine and Alopecia

Treatment options for patients with hormone refractory prostate cancer (HRPC) showed unsatisfactory outcomes. Docetaxel-based combinations could offer more promising and tolerated results. A phase II trial was conducted with the combination of zoledronic acid, docetaxel and estramustine. Eligibility consisted of metastatic prostate adenocarcinoma with objective progression or rising prostate specific antigen levels (PSA) despite androgen deprivation therapy. Zoledronic acid was given at a dose of 4 mg on day 1, docetaxel (25 mg/m2) on days 1, 8 and 15, and estramustine orally at 140 mg two times daily on days 1 to 21 of a 28-day cycle. Twenty-seven patients were enrolled between October 2002 and November 2004. Median age was 68 years (53-83 years). A total of 124 cycles were administered with a median of 4.6 cycles per patient (1-8 cycles). The major toxicities were grades 1 to 3 anemia (55%), fatigue (15%), alopecia (11%) and hypocalcemia (11%). Two patients presented with deep venous thrombosis and died from pulmonary embolism. Another third patient died from Stevens-Johnson syndrome and grade 4 hepatic toxicity. Out of the 25 patients assessed for efficacy, 13 (52%) had a biologic response (>50% PSA decline). Three (21%) patients among the 14 with measurable disease had objective response: 1 complete response (CR) and 2 partial responses (PR). Response duration was 2 months for PR and 4 months for CR. A total of 12 patients (48%) experienced clinical benefit with pain reduction. This combination seemed effective; however toxic deaths especially from venous thrombosis counterbalanced the advantage of this regimen.

Topics: Administration, Oral; Aged; Aged, 80 and over; Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Diphosphonates; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Fatigue; Humans; Hypocalcemia; Imidazoles; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Thrombocytopenia; Time Factors; Treatment Outcome; Zoledronic Acid

We previously developed a novel and effective therapy for hormone-refractory prostate cancer using the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced, hormone-refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays, and then demonstrated their effectiveness in a phase I-II clinical trial, where they were shown to produce a 50% complete and partial response rate in patients with bidimensionally measurable disease. In preclinical studies, we had demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Expanding these investigations, we determined that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule inhibitor, interacts with estramustine and etoposide, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cells. These studies led us to conduct a phase II clinical trial of paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer. Preliminary results demonstrate that this is an active regimen, with 57% of patients demonstrating a response to therapy as measured by a decrease in pretreatment prostate-specific antigen levels of greater than 50%.

Topics: Adenocarcinoma; Administration, Oral; Alopecia; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; DNA Replication; DNA, Neoplasm; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Estramustine; Etoposide; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Microtubules; Nuclear Matrix; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Remission Induction; Tumor Cells, Cultured

Docetaxel is an effective agent for the treatment of androgen-independent prostate cancer (AIPC). Its combination with estramustine phosphate (EMP) has shown promising results in AIPC but the toxicity remains considerable. In an effort to minimize toxicity, we designed an every-2-week docetaxel administration regimen with a 3-day low-dose EMP regimen. Patients with bone metastases also received zoledronic acid.. A total of 54 patients with AIPC received docetaxel at 45 mg/m2 and EMP (140 mg orally every 8 hours for nine doses) every 2 weeks. Zoledronic acid was administered at 4 mg every 28 days.. Of the 49 assessable patients, 22 (45%, 95% confidence interval [CI] 31% to 60%) had a prostate-specific antigen response. Of 24 patients with measurable disease, 9 (38%, 95% CI 19% to 59%) had a response to therapy (one complete response and eight partial responses). The median time to progression was 4.4 months (95% CI 2.7 to 6), and overall survival was 13.3 months (95% CI 9 to 17.6). Toxicity was mild, with only 5 cases of grade 3 or 4 toxicity. The pain score improved by 1 point in 21 (54%) of 39 symptomatic patients, and 14 (40%) of 38 patients who used analgesics discontinued analgesic consumption by the end of treatment.. The combination of an every-2-week regimen of docetaxel, EMP, and zoledronic acid is an effective, well-tolerated regimen that results in symptomatic improvement in a significant proportion of patients with AIPC.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alopecia; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Diphosphonates; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Imidazoles; Life Tables; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Neutropenia; Orchiectomy; Pain; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, High-Energy; Remission Induction; Survival Analysis; Taxoids; Treatment Outcome; Zoledronic Acid

Although treatment of hormone-refractory prostate cancer (HRPC) is difficult, a single-agent weekly dose of docetaxel has been reported as a promising regimen for patients with HRPC. The purpose of this study was the investigation of the efficacy of docetaxel for Japanese patients with HRPC.. Ten patients with HRPC were treated with weekly docetaxel at Tsukuba University Hospital and were evaluated for the responses with respect to serum prostate-specific antigen (PSA), tumor size and survival. Considering the ethnic balance, the dose of docetaxel was reduced to 30 mg/m(2) weekly compared with 36 mg/m(2) in the study reported previously.. A biochemical response (>50% decrease in PSA) was observed in five patients (56%; 5/9) with an average time to progression of 4.5 months. In two partial responders as determined by PSA, respective metastatic lesions in bone and soft tissue were also improved. The estimated median survival duration was 6 months. Most of these responses were accompanied by a significant reduction in the requirement for analgesic agents. No severe toxicity of this regimen was observed, except for gastric ulcer in one patient who was excluded from the evaluation.. Weekly administration of docetaxel as a single agent was associated with a high rate of PSA reduction. This treatment is feasible for patients with HRPC, even those who have a poor performance status and extensive prior treatments.

Topics: Aged; Alopecia; Anorexia; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Feasibility Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Soft Tissue Neoplasms; Taxoids