Progressive Hormone-refractory Prostate Cancer Research Articles

High activity rhenium-186 hydroxyethylidene diphosphonate (HEDP) with autologous peripheral blood stem cell (PBSC) transplant: A novel treatment strategy in hormone refractory prostate cancer metastatic to bone

4562 Background: Bone marrow is the dose-limiting organ for bone seeking radionuclide therapy of bone metastases from prostate cancer. This prospective phase 2 trial investigated the potential for improvement in disease control by using autologous peripheral blood stem cell transplant to permit administration of high activities of a bone seeking radionuclide, Rhenium-186 HEDP in patients with progressive hormone refractory prostate cancer. Methods: Eligible patients had histologically confirmed prostate cancer metastatic to the skeleton, rising PSA despite castrate testosterone levels, WHO PS 0–1, and minimal soft-tissue disease. Patients received between 4500 and 5000MBq of Rhenium-186 HEDP i.v. (approximately 4 times the dose normally used for palliation), followed 14 days later by the return of pre-harvested PBSCs. Response was assessed using PSA, survival, pain scores, and quality of life measurement. Results: Thirty-eight patients with a median age of 67 years (range 50–77), and a median PSA of 57 ng/ml (range 4–3628) received a median activity of 4978 MBq Rhenium-186 HEDP (range 4400–5097). At a median follow up of 12 months (range 3–32), the most serious toxicity was short-lived (<7 days) grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 31 months with a Kaplan-Meier estimated 1 and 2-year survivals of 81% and 50% respectively. Twenty six patients (60%, 95% CI, 45–74%) had stable or reduced PSA levels 3 months post therapy, 10 of whom had PSA reductions of > 50% lasting > 4 weeks. Quality of life measures were stable or improved in 29 (76%) at 3 months. Conclusions: We believe the survival data and PSA response rates in this group of heavily pre-treated patients are encouraging and merit further investigation in a randomised trial. No significant financial relationships to disclose.

High activity rhenium-186 hydroxyethylidene diphosphonate (HEDP) with autologous peripheral blood stem cell (PBSC) transplant: A novel treatment strategy in hormone refractory prostate cancer metastatic to bone

4562 Background: Bone marrow is the dose-limiting organ for bone seeking radionuclide therapy of bone metastases from prostate cancer. This prospective phase 2 trial investigated the potential for improvement in disease control by using autologous peripheral blood stem cell transplant to permit administration of high activities of a bone seeking radionuclide, Rhenium-186 HEDP in patients with progressive hormone refractory prostate cancer. Methods: Eligible patients had histologically confirmed prostate cancer metastatic to the skeleton, rising PSA despite castrate testosterone levels, WHO PS 0–1, and minimal soft-tissue disease. Patients received between 4500 and 5000MBq of Rhenium-186 HEDP i.v. (approximately 4 times the dose normally used for palliation), followed 14 days later by the return of pre-harvested PBSCs. Response was assessed using PSA, survival, pain scores, and quality of life measurement. Results: Thirty-eight patients with a median age of 67 years (range 50–77), and a median PSA of 57 ng...

Low dose docetaxel, estramustine and thalidomide followed by maintenance thalidomide for the treatment of hormone refractory prostate cancer (HRPC): A phase II community based trial

4681 Background: Elderly men in the community often have co-morbidities that limit their ability to tolerate standard doses of chemotherapy. This trial was designed to minimize exposure to chemotherapy by exploiting its potential synergy with anti-angiogenesis agents and to evaluate the role of maintenance anti-angiogenic therapy. Methods: Eligible patients had progressive HRPC after hormone therapy and antiandrogen withdrawal, adequate performance status (0–2) and no prior treatment with chemotherapy or angiogenesis inhibitors. All patients received the TET regimen: Docetaxel (Taxotere) 25 mg/m2 weekly for 3 weeks per month, Estramustine 140 mg po tid x 3 days per week beginning the day before Taxotere, and daily Thalidomide (Thal) 100 or 200 mg as tolerated. TET was given for six months followed by six months of Thal alone as maintenance therapy. Coumadin 2 mg per day was given for prophylaxis. Results: 12 patients have been enrolled thus far. The median age is 76 (55–85), median PS 1 (0–2), and median ...

A phase I study of estramustine, weekly docetaxel and carboplatin (EDC) chemotherapy in patients with hormone refractory prostate cancer (HRPC)

4656 Background: The purpose of this study was to define the maximal tolerated dose (MTD) of weekly docetaxel combined with carboplatin and estramustine in the treatment of patients with HRPC. Methods: Patients with progressive HRPC were eligible. Prior chemotherapy was allowed, except taxanes and platinum drugs. 25 patients were treated with escalating doses (20, 25, 30, 36, 43 mg/m2) of weekly docetaxel on days 2, 9, 16 of a 28-day cycle. Doses of estramustine [140 mg po TID days 1–5, 8–12, 15–19] and carboplatin [AUC (5) on day 2] were fixed. Results: Patient characteristics: median age 64 yrs, PS 0 (33%), 1 (66%), median PSA 117 ng/ml. Prior ketoconazole (53%), mitoxantrone (10%). A total of 3, 3, 3, 4 and 12 patients were treated at each of 5 dose levels of docetaxel. No DLTs were noted. Though MTD was not reached, dose escalation was stopped at the docetaxel dose (43 mg/m2) because of significant activity; 9 additional patients were accrued. No grade 3/4 myelosuppression was seen until this dose level, when 1 patient each developed grade 3 anemia, neutropenia and thrombocytopenia. One patient developed grade 4 thrombocytopenia and two patients grade 4 neutropenia. Of 12 patients treated at this dose level, 7 and 4 patients had maximum grade 3 and 4 toxicities, respectively. Among all treated patients, PSA declines ≥50% occurred in 60%. At the recommended phase II dose, PSA declines ≥50% were seen in 75% (95% C.I., 43–95%). 3 of 14 (21%) total patients with measurable disease had a partial response. Median survival was 14.6 months. Conclusions: EDC is a well-tolerated and active regimen in HRPC. Grade 3/4 toxicity was primarily myelosuppression. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines ≥50% were seen in 75% of patients at the recommended phase II dose, though responses were seen at every dose level. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

A phase I study of estramustine, weekly docetaxel and carboplatin (EDC) chemotherapy in patients with hormone refractory prostate cancer (HRPC)

4656 Background: The purpose of this study was to define the maximal tolerated dose (MTD) of weekly docetaxel combined with carboplatin and estramustine in the treatment of patients with HRPC. Methods: Patients with progressive HRPC were eligible. Prior chemotherapy was allowed, except taxanes and platinum drugs. 25 patients were treated with escalating doses (20, 25, 30, 36, 43 mg/m2) of weekly docetaxel on days 2, 9, 16 of a 28-day cycle. Doses of estramustine [140 mg po TID days 1–5, 8–12, 15–19] and carboplatin [AUC (5) on day 2] were fixed. Results: Patient characteristics: median age 64 yrs, PS 0 (33%), 1 (66%), median PSA 117 ng/ml. Prior ketoconazole (53%), mitoxantrone (10%). A total of 3, 3, 3, 4 and 12 patients were treated at each of 5 dose levels of docetaxel. No DLTs were noted. Though MTD was not reached, dose escalation was stopped at the docetaxel dose (43 mg/m2) because of significant activity; 9 additional patients were accrued. No grade 3/4 myelosuppression was seen until this dose level, when 1 patient each developed grade 3 anemia, neutropenia and thrombocytopenia. One patient developed grade 4 thrombocytopenia and two patients grade 4 neutropenia. Of 12 patients treated at this dose level, 7 and 4 patients had maximum grade 3 and 4 toxicities, respectively. Among all treated patients, PSA declines ≥50% occurred in 60%. At the recommended phase II dose, PSA declines ≥50% were seen in 75% (95% C.I., 43–95%). 3 of 14 (21%) total patients with measurable disease had a partial response. Median survival was 14.6 months. Conclusions: EDC is a well-tolerated and active regimen in HRPC. Grade 3/4 toxicity was primarily myelosuppression. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines ≥50% were seen in 75% of patients at the recommended phase II dose, though responses were seen at every dose level. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

566 Poster Encouraging early results of a phase 1/2 trial of high activity rhenium-186 HEDP with autologous peripheral blood stem cell support in progressive hormone refractory prostate cancer metastatic to bone

566 Poster Encouraging early results of a phase 1/2 trial of high activity rhenium-186 HEDP with autologous peripheral blood stem cell support in progressive hormone refractory prostate cancer metastatic to bone

Chemotherapy for androgen-independent prostate cancer

While men with metastatic prostate cancer frequently show a good initial response to androgen ablation, few options have been available for progressive hormone-refractory prostate cancer, and survival following chemotherapy has not exceeded 9 to 12 months. The combination of prednisone and mitoxantrone has significant palliative effects on bone pain but does not extend survival. The combination of estramustine phosphate (EMP) with the taxanes paclitaxel or docetaxel produces greater than additive cytotoxicity in vivo, and phase I and II studies of taxane-based therapy demonstrate improved survival in hormone-refractory prostate cancer compared to historical controls. Docetaxel appears to have relatively high activity as a single agent and in combination with EMP. Further studies are needed to clarify the optimum dose of EMP, taking into account potential cardiovascular toxicity. Phase III studies of its combination with docetaxel are in progress.

Liposomal Doxorubicin for the Treatment of Hormone-Refractory Prostate Cancer

There is a pressing need for new agents to treat hormone-refractory prostate cancer (HRPC). Doxorubicin has shown modest activity in this setting, but its use is limited by its toxicities. Liposomal encapsulation of doxorubicin appears to promote enhanced tumor accumulation in some tumor types, and toxicity appears to be reduced. A phase II trial of liposomal doxorubicin was therefore conducted in patients with HRPC. Fourteen patients with progressive HRPC were treated. For the first dose only, patients were randomized to receive either doxorubicin 50 mg/m2 or liposomal doxorubicin 50 mg/m2 in order to evaluate exploratory pharmacokinetics. For all subsequent cycles, all patients received liposomal doxorubicin 50 mg/m2. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. All 14 patients were evaluable for response and toxicity. Two patients (14%) had declines in serum PSA of ≥ 50%. The first patient had a baseline PSA of 34.7 ng/mL and a nadir of 17.0 ng/mL. The second patient had a baseline PSA of 5580.0 ng/mL and a nadir of 200.7 ng/mL. The latter of these 2 patients had an unambiguous improvement in bone scan and a reduction in pain. Treatment was well tolerated overall. One patient was removed from treatment after the development of a grade 3 infusion reaction with the first cycle of liposomal doxorubicin. Neutropenia was the most common toxicity; in only 1 case was it grade 3, and no cases of grade 4 were seen. Doxorubicin plasma concentrations were best fit by a linear, two-compartment model. Liposomal doxorubicin plasma concentrations were best fit by a linear, one-compartment model. Treatment with liposomal doxorubicin was well tolerated overall. While monotherapy with liposomal doxorubicin has only modest activity in the treatment of HRPC, it may be of interest to study this agent as part of combination chemotherapy.

A phase II study of temozolomide in hormone-refractory prostate cancer

Hormone-refractory disseminated prostate cancer is a major oncological problem. Preclinical studies with temozolomide, an oral alkylating agent, in prostate cancer have shown encouraging results. In phase I studies the safety of temozolomide in non-prostate cancer patients has been demonstrated. Based on these results, a phase II study of temozolomide in patients with metastatic disease who had developed progressive symptomatic disease while on antiandrogen therapy, was initiated. A group of 18 patients started a 5-day temozolomide regimen, with a 28-day treatment cycle. Response parameters (prostate-specific antigen, bone scan, quality of life questionnaire) and toxicity (common toxicity criteria for international studies) were recorded at regular intervals. Of the 18 patients, 16 were evaluable by completing two or three cycles. All patients developed progressive disease within two cycles, except one who had progressive disease at the end of cycle 3. Of the 16 evaluable patients, 11 developed new bone metastases (bone scan), 1 developed lung metastases, 4 had progressive disease as reflected by a 25% increase in serum PSA together with subjective progression, and 7 and 5 had progressive disease as reflected by decreased quality of life and increased pain score, respectively. Toxicity was limited to nausea and vomiting, which was effectively treated with antiemetic medication, and anemia and thrombocytopenia, which returned to normal values within 1 week. Treatment with temozolomide was generally well tolerated, with occasionally moderate toxicity. As all patients developed progressive disease the results are rather discouraging. Temozolomide is ineffective for the treatment of patients with symptomatic progressive hormone-refractory prostate cancer.

Palliative radiotherapy for local progression of hormone refractory stage D2 prostate cancer

From 1970 to 1992, 10 patients with hormone refractory stage D2 adenocarcinoma of the prostate presenting themselves with urinary retention and/or gross hematuria were treated by palliative irradiation for local progression at Cancer Institute Hospital. External beam irradiation was delivered to the primary lesion at dose of 38 Gy to one patient and 30 approximately 27 Gy to seven patients. Five of these patients in whom an urethral catheter had been indwelling were able to void without difficulty following the treatment. Of four patients with severe hematuria resulting vesical tamponade, none had hematuria after the treatment. These effect lasted until patients' death or more than 11 months follow-up. In other 2 patients, irradiation had to be discontinued at dose less than 20 Gy because of deteriorated general conditions and no significant effect. Complications of the treatment were minimal. These results indicate that the optimal dose of local palliative irradiation is around 30 Gy. Irradiation is a good choice for palliation of locally progressive hormone refractory prostate cancer in view of its certain and long-lasting effect, low invasiveness and minimal complications. When to institute palliative irradiation is one of the most important question in order to secure a good quality of life for patients. From our experiences, it is our belief that if local progression is symptomatic, palliative irradiation should be initiated as soon as possible.

Estramustine and Vinblastine: Use of Prostate Specific Antigen as a Clinical Trial End Point for Hormone Refractory Prostatic Cancer

The combination of estramustine phosphate and vinblastine sulfate, 2 agents with separate and unique antimicrotubular effects, has demonstrated additive cytotoxicity against the DU145 human prostate derived cell line in vitro. We evaluated this combination in 25 patients with progressive hormone refractory prostate cancer. Of 24 patients with an elevated prostate specific antigen (PSA) level at the start of treatment 13 (54%, 95% confidence limits 34 to 74%) had a greater than 50% decrease in PSA levels on at least 3 consecutive biweekly determinations. The median decrease in PSA in responding patients was 64% (mean 71.7%) and the median duration of response was 7 months. In 5 patients with bidimensionally measurable disease 2 partial responses were observed. Treatment was well tolerated, with mild and manageable toxicity. This is a well tolerated outpatient treatment regimen for patients with hormone-refractory prostatic cancer which deserves further investigation.