Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer.

PURPOSE: To evaluate the combination of intravenous (IV) paclitaxel, oral estramustine, and oral etoposide in patients with advanced hormone-refractory prostate cancer. PATIENTS AND METHODS: Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled onto this phase II trial. Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days, with paclitaxel 135 mg/m(2) IV over 1 hour on day 2 of each 21-day treatment cycle. Patients received a maximum of six cycles of therapy. RESULTS: Thirty-seven patients were assessable for response. Twenty-two had measurable disease at baseline; response was not assessable in six of these patients. Overall response was 45% (10 of 22 patients; 95% confidence interval [CI], 24% to 68%), and response was 63% (10 of 16) in assessable patients. Twenty-six patients had a > or = 50% decrease from their baseline prostate-specific antigen levels during therapy, for a response rate of 65% (95% CI, 48% to 79%) by this criterion. Median duration of response was 3.2 months, with an estimated median survival of 12.8 months. Major toxicities of therapy were leukopenia (eight patients had > or = grade 4 leukopenia) and anemia. Hematologic toxicity seemed to be associated with liver metastases. Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) showed no significant change in quality of life (QOL) as a result of therapy. CONCLUSION: The combination of IV paclitaxel, oral estramustine, and oral etoposide is active in patients with advanced prostate cancer. The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients.     

Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer

Background We aimed to determine the safety and efficacy of monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer (HRPC). Methods Patients with prostate cancer that was progressing despite androgen ablation therapy were treated with i.v. paclitaxel, 175 mg/m², over 3 h, followed by carboplatin (area under the curve, 5) on day 1, with oral estramustine phosphate, 280 mg twice daily, for a 28-day treatment cycle. Estramustine phosphate was precluded in those patients who had experienced adverse effects during prior chemotherapies. Patients were evaluated for response every cycle, and the treatment was continued until the cancer progressed. Results Twenty-one patients with progressive hormone-refractory disease were treated for a median of 4 cycles (range, 1 to 11 cycles). Estramustine phosphate was precluded in seven patients. Post-therapy decreases in serum prostate-specific antigen levels of 50% and 75%, respectively, were seen in 43% and 19% of the patients (95% confidence intervals, 22% to 64% and 2% to 36%). Of the nine patients with measurable disease, 1 (11%) had a complete response and 2 (22%) had a partial response. The overall median time to progression was 4 months, and the median survival time for all patients was 11 months. Major grade 3 or 4 adverse effects were anemia (29%), neutropenia (48%), and thrombocytopenia (24%). Mild peripheral neuropathy and myalgia/arthralgia were observed in 11 (52%) and 9 (43%) patients, respectively. Conclusion Monthly paclitaxel and carboplatin with oral estramustine phosphate has significant antitumor activity and is well tolerated in patients with progressive HRPC.     

Phase II trial of paclitaxel,estramustine, etoposide,and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma

BACKGROUND: Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone-refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three-drug combination of paclitaxel, estramustine, and etoposide (TEE). METHODS: Twenty patients with carcinoma of the prostate that was progressing despite hormone therapy were enrolled on this Phase II trial. Patients were treated with oral estramustine, 280 mg three times daily, and oral etoposide, 50 mg/m2, once daily on Days 1-7, with i.v. paclitaxel, 135 mg/m2, over 1 hour followed by carboplatin (area under the curve, 5) on Day 2 of each 21-day treatment cycle. Patients were evaluated for response after three cycles, and three additional cycles were given to responding or stable patients. RESULTS: Nineteen patients were evaluable for response, and 12 patients had measurable disease at baseline. The measurable response rate was 58% (7 of 12 patients; 95% confidence interval [95% CI], 28-85%), and all of those were partial responses. Eleven patients had decreases >50% from their baseline prostate specific antigen levels during therapy, for a response rate of 58% (95% CI, 34-80%) by this criterion. The median time to disease progression was 5.5 months, with a median survival of 14.2 months. Major toxicities included Grade (according to version 2 of the National Cancer Institute Common Toxicity Criteria) 4 neutropenia in 4 patients, Grade 4 thrombocytopenia in 4 patients, and anemia > or = Grade 3 in 4 patients. One patient had a deep vein thrombosis. CONCLUSIONS: The combination of TEEC was active in patients with hormone-refractory prostate carcinoma. The regimen was tolerable, with primarily hematologic toxicity. The addition of carboplatin to TEE did not appear to add to the efficacy of the three-drug combination of antimicrotubule agents.     

Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15-17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a > oe = 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/ estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/ estramustine are recommended.     

Phase II evaluation of oral estramustine, oral etoposide, and intravenous paclitaxel in patients with hormone-sensitive prostate adenocarcinoma

Purpose

The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy.

Patients and Methods

Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a ≤ 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m² orally on days 1-14, and paclitaxel 135 mg/m² intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF).

Results

Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively.

Conclusion

The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.     

Results from a pilot Phase I trial of gefitinib combined with docetaxel and estramustine in patients with hormone-refractory prostate cancer

BACKGROUND: Gefitinib, which is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated activity against hormone-refractory prostate cancer (HRPC) in preclinical studies. In this pilot Phase I trial, the authors evaluated the tolerability, efficacy, and pharmacokinetics of gefitinib combined with estramustine and docetaxel in patients with HRPC. METHODS: Patients received gefitinib (at a dose of 250 mg/day or 500 mg/day) on each day of a 21-day treatment cycle. Docetaxel (at a dose of 60 mg/m(2)) was administered on Day 1, and estramustine (at a dose of 280 mg) was administered 3 times daily on Days 1 through 5. RESULTS: Fifteen patients were recruited at each gefitinib dose level. The most common adverse events observed were consistent with the known profiles of gefitinib, docetaxel, and estramustine. No dose-limiting toxicity was observed. Adverse events considered to be gefitinib related included diarrhea (n = 23 patients), rash (n = 8 patients), nausea (n = 7 patients), dry skin (n = 6 patients), and emesis (n = 6 patients). Overall, 9 of 22 evaluable patients (40.9%) experienced a pain response. and 9 of 30 patients (30%) had a prostate-specific antigen response. A partial objective tumor response was demonstrated in 1 of 13 evaluable patients (7.7%) in each dose group; the median time to progression for both doses combined was 185 days (range, 28-233 days). Data comparisons within individual patients suggested that docetaxel and estramustine had no effect on gefitinib steady-state levels. Gefitinib had no effect on docetaxel exposure at the 250-mg dose but decreased exposure at the 500-mg dose. However, gefitinib may increase exposure to estramustine, particularly at the 500 mg/day dose. CONCLUSIONS: The results of the current study demonstrated that gefitinib combined with estramustine and docetaxel had acceptable and predictable tolerability. However, it is unclear whether gefitinib provides an additional clinical benefit over docetaxel and estramustine alone.     

Phase II trial of oral uracil/tegafur plus leucovorin in patients with hormone-refractory prostate carcinoma

BACKGROUND: The current study evaluated the efficacy of oral uracil/tegafur (UFT) and leucovorin (LV) in patients with hormone-refractory metastatic prostate carcinoma. METHODS: Twenty-eight patients with hormone-refractory metastatic carcinoma of the prostate who had undergone antiandrogen withdrawal and no more than 1 prior chemotherapy treatment were enrolled on a single-institution Phase II trial. Patients were treated with oral UFT at a dose of 300 mg/m2/d and oral LV at a dose of 90 mg/day for 28 days followed by 7 days off therapy on a 35-day cycle regimen. RESULTS: Twenty-six patients were evaluable for response and toxicity. There was no response by objective criteria in 9 patients with measurable disease. Four responses by prostate-specific antigen (PSA) criteria (i.e., PSA decrease by > 50%) were noted (15%) lasting a mean of 20.5 weeks. Therapy was generally well tolerated, with 2 patients developing Grade 4 toxicity (1 patient each with diarrhea and hand-foot syndrome) and 4 patients having significant Grade 3 toxicity (anemia, hyperbilirubinemia, and vomiting) (Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria). Six patients had stable disease by clinical, laboratory, and radiologic criteria for an average of 5 cycles of treatment (25 wks). CONCLUSIONS: Although UFT and LV are generally well tolerated in the setting of hormone-refractory metastatic prostate carcinoma, the combination has a low level of activity. Its toxicity and activity is similar to that observed when intravenous 5-fluorouracil or capecitabine are given alone. It may be an option for further investigations in combination regimens.     

Weekly paclitaxel, estramustine phosphate, and oral etoposide in the treatment of hormone-refractory prostate carcinoma: results of a Minnie Pearl Cancer Research Network phase II trial

BACKGROUND: The objective of the current study was to evaluate the efficacy and toxicity of weekly paclitaxel, oral etoposide, and estramustine phosphate in the treatment of patients with advanced, hormone-refractory prostate carcinoma. METHODS: Patients with hormone-refractory prostate carcinoma who had received no more than one previous chemotherapy regimen were eligible for this trial. Forty-two patients were treated between February 1998 and March 2000. Toxicity was excessive in the first 3 patients treated (Grade 3-4 leukopenia, 3 patients; death due to sepsis, 1 patient); the remaining 39 patients received lower doses of etoposide and estramustine phosphate (paclitaxel 50 mg/m(2) as a 1-hour, intravenous infusion on Days 1, 8, 15; etoposide 50 mg orally twice daily on Days 1-10; and estramustine phosphate 280 mg orally 3 times daily on Days 1-10). Courses were repeated every 28 days. Patients were evaluated for objective and/or serologic response after two courses of treatment; responding patients continued treatment for six courses. RESULTS: Fourteen of 40 evaluable patients (35%) had either an objective response or a serologic response to treatment. The median survival for the entire group was 9.5 months, with 1-year, 2-year, and 3-year survival rates of 38%, 12%, and 10%, respectively. Neutropenia was the most common Grade 3-4 toxicity and occurred in 38% of patients (11% of courses). Thirteen patients (33%) had severe fatigue, and 2 patients had treatment-related deaths due to sepsis. CONCLUSIONS: Although the three-drug combination had activity in patients with hormone-refractory prostate carcinoma, the results did not appear any better than the results achieved with less toxic taxane/estramustine phosphate combinations. Further development of this three-drug regimen is not recommended.     

Phase II trial of docetaxel/capecitabine in hormone-refractory prostate cancer

Background

Docetaxel is the most active single agent in the treatment of hormone-refractory prostate cancer (HRPC). Because of the preclinical and clinical evidence of synergy of capecitabine and docetaxel, it was hypothesized that this combination would be active and tolerable in HRPC.

Patient and Methods

Patients received docetaxel 60 mg/m² intravenously over 60 minutes on day 1 of each 21-day cycle and capecitabine 1000 mg/m² administered orally twice daily on days 1-14 of each cycle for a maximum of 8 cycles or until disease progression or intolerable toxicity. Seventy-seven patients were enrolled at 43 US Oncology sites. The median age was 69.3 years (range, 48-86 years); 86% were white, and the Eastern Cooperative Oncology Group performance status scores of 0 and 1 were 49% and 51%, respectively. Sixty-nine (90%) patients were evaluable for prostate-specific antigen response.

Results

Overall, 41% of patients had a decreased prostate-specific antigen level ≥ 50%. There were 4 complete responses (6%), 24 partial responses (35%), 29 incidences of stable disease (43%), and 11 incidences of progressive disease (16%). Nine patients had stable disease ≥ 6 months, and the clinical benefit rate was 54%. The median time to response was 1.5 months (range, 1-6 months), and the median duration of response was 5.2 months (range, 1-16.9 months). The estimated survival at 12 and 24 months was 65% and 22%, respectively, with a median survival of 17 months (range, < 1-27 months). There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (50%), leukopenia (22%), hand-foot syndrome (17%), fatigue (11%), and nausea (11%).

Conclusion

Docetaxel/capecitabine is an active and tolerable combination in HRPC. Toxicity was acceptable and anticipated. Response rate and survival are comparable with other docetaxel combinations.     

A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer

Background

Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.

Patients and Methods

A phase I trial of docetaxel/estramustine/imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m² to 60 mg/m² to 70 mg/m². Thirteen patients were treated.

Results

On dose level 3 (docetaxel 70 mg/m² and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m² and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.

Conclusion

The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.     

Chemotherapy in patients with prostate specific antigen-only disease after primary therapy for prostate carcinoma: a phase II trial of oral estramustine and oral etoposide

BACKGROUND: A Phase II study was initiated to evaluate the effectiveness of an oral regimen of etoposide and estramustine in patients with early recurrent prostate carcinoma. METHODS: Patients with early recurrent prostate carcinoma as indicated by an increasing prostate specific antigen (PSA) level and without any evidence of metastatic disease were treated with oral etoposide 50 mg/m2/day and estramustine 15 mg/kg/day in divided doses for 21 days, followed by a 7-day rest period. Patients received a maximum of four cycles. RESULTS: Eighteen patients were entered in this study. The median serum PSA was 3.1 (range, 0.3-30.3) at the time of entry into the trial. Sixteen patients were assessable for response. Serum PSA declined to undetectable levels in 13 patients with 2 additional patients meeting the criteria for partial response; the median duration of response was 8.5 months (range, 1-18 months). Most patients developed gastrointestinal, cardiac, or hematologic complications. Grade 3 toxicities included neutropenia (one patient), deep venous thrombosis (three patients), and chest pain (one patient). One patient developed acute myelogenous leukemia (French-American-British, acute myelogenous leukemia M5) 23 months after initiating the chemotherapy. CONCLUSIONS: The combination of oral etoposide and oral estramustine resulted in a high rate but only a short duration of response in patients with early recurrent prostate carcinoma. The regimen was poorly tolerated, and the toxicity was significant. This regimen should not be considered standard therapy for the treatment of early recurrent prostate carcinoma, but further exploration of treatment in this setting is warranted.     

A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer.

BACKGROUND: The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer. PATIENTS AND METHODS: Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week. RESULTS: From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50-83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0-802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75-10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%). CONCLUSIONS: Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.     

Randomized Phase II trial assessing estramustine and vinblastine combination chemotherapy vs estramustine alone in patients with progressive hormone-escaped metastatic prostate cancer

Based on the results of combined data from three North American Phase II studies, a randomised Phase II study in the same patient population was performed, using combination chemotherapy with estramustine phosphate (EMP) and vinblastine (VBL) in hormone refractory prostate cancer patients. In all, 92 patients were randomised into a Phase II study of oral EMP (10 mg kg day continuously) or oral EMP in combination with intravenous VBL (4 mg m(2) week for 6 weeks, followed by 2 weeks rest). The end points were toxicity and PSA response in both groups, with the option to continue the trial as a Phase III study with time to progression and survival as end points, if sufficient responses were observed. Toxicity was unexpectedly high in both treatment arms and led to treatment withdrawal or refusal in 49% of all patients, predominantly already during the first treatment cycle. The mean treatment duration was 10 and 14 weeks, median time to PSA progression was 27.2 and 30.8 weeks, median survival time was 44 and 50.9 weeks, and PSA response rate was only 24.6 and 28.9% in the EMP/VBL and EMP arms, respectively. There was no correlation between PSA response and survival. While the PSA response in the patients tested was less than half that recorded in the North American studies, the toxicity of EMP monotherapy or in combination with VBL was much higher than expected. Further research on more effective and less toxic treatment strategies for hormone refractory prostate cancer is mandatory.     

Intermittent docetaxel therapy with estramustine for hormone-refractory prostate cancer in Japanese patients

Background  We evaluated the efficacy and toxicity of intermittent docetaxel (DCT) with estramustine (EM) for hormone-refractory prostate cancer (HRPC). Methods  Fifteen patients were enrolled. They received injected DCT (70 mg/m² body surface) on day 1 in association with oral EM 560 mg/day (days 1–5). Treatments were repeated every 3 weeks. Serum prostate-specific antigen (PSA) levels were categorized based on the first three courses. Patients exhibiting either a response or stable disease (SD) could have a holiday from treatment (intermittent schedule). The holiday continued until elevation of the PSA level from the nadir baseline level occurred three times. All patients were evaluated for toxicity and quality of life (QOL). Survival curves were established using Kaplan-Meier graphs. Results  The median number of courses of DCT/EM therapy was five (range, 3–12 courses). The response rate of the first cycle was 53%: 3 patients with complete response (CR), 5 patients with partial response (PR), 4 patients with SD, and 3 patients with disease progression. Eight patients were able to begin the second re-entry cycle. No patients showed a CR, 2 patients exhibited PR, 4 patients had SD, and the overall response rate was 25%. The survival rates were 93% at 1 year, and 26.1% at 2 years Grade 3–4 anemia was observed in 2 patients (13.3%), neutropenia in 11 (73.3%), and thrombocytopenia in 2 (13.3%). The QOL scale showed good QOL after 6 months, with improvement in the score for nausea and vomiting. Conclusion  Intermittent DCT/EM therapy was well tolerated, and has the potential to prolong survival, with a high QOL, in patients with HRPC.     

Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer.

PURPOSE: Estramustine phosphate (EMP) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro. Their modest single-agent activities in hormone-refractory prostate cancer, nonoverlapping toxicities, and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer. PATIENTS AND METHODS: Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously (IV) once a week for 6 weeks. Courses were repeated every 8 weeks. Response assessment was based on a change in serum prostate-specific antigen (PSA) levels and was correlated with change in pain scores. RESULTS: PSA decreased from baseline by at least 50% in 22 patients (61.1%) and by > or = 75% in eight patients (22.2%). A 50% or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score, performance status, and measurable soft tissue disease (if present) was required for a partial response (PR), which occurred in 11 patients for an overall response rate of 30.5% (95% confidence interval, 15.6% to 45.6%). In seven patients with measurable nonosseous disease, there was one PR (14%) and one minor response (MR). In 28 patients with assessable pain, major pain responses occurred in 12 (42.9%). PSA response (> or = 50% decrease times three measurements) was predictive of major pain response with a 93.7% specificity, a 50% sensitivity, and a positive predictive value of 85.7%. CONCLUSION: We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer.     

Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial.

PURPOSE: To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m(2) by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m(2) PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V. RESULTS: Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P =.08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P <. 001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with >/= 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P <.0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P <.0001); however, grade 2 or worse nausea (26% v 7%, respectively; P =.0002) and extremity edema (22% v 8%, respectively; P =.005) were more frequent for EM-V. CONCLUSION: Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.     

Phase II study of low-dose docetaxel/estramustine in elderly patients or patients aged 18-74 years with hormone-refractory prostate cancer

Purpose

Chemotherapy is often poorly tolerated in elderly patients or patients with poor performance status. This trial was designed to determine whether low-dose weekly docetaxel/estramustine was efficacious with acceptable toxicity.

Patients and Methods

Dexamethasone was administered as premedication. Subjects received docetaxel 25 mg/m² intravenously on days 2, 9, and 16 and estramustine 140 mg orally twice daily on days 1-3, 8-10, and 15-17. Cycles were 28 days. Participants received ≤ 6 cycles unless progression or intolerable toxicity occurred.

Results

Fifty-eight subjects were enrolled at 31 sites in the US Oncology Network. Median age was 78 years (range, 64-92 years); performance status scores (0, 1, 2, and 3) were 36%, 38%, 24%, and 2%, respectively; 55 subjects received ≤ 1 cycle of treatment; and 4 participants were nonevaluable because they completed < 2 cycles. Among the 56 treated subjects, 38 (68%) had a decreased prostate-specific antigen level (≤ 50% compared with baseline level and maintained for ≤ 4 weeks). There were 40 subjects with measurable tumor(s). Responses, assessed using Response Evaluation Criteria in Solid Tumors, were 1 complete response (2.5%), 7 partial responses (17.5%), 26 stable diseases (65%), and 6 progressive diseases (15%). At 1 year, 17% of participants were progression free; median progression-free survival was 5.3 months (range, 1-14.5 months); estimated 1-year survival was 65%. There were no grade 4 treatment-related events. Grade 3 treatment-related events included fatigue/asthenia (11%) and arrhythmia, dehydration, cerebral ischemia, thrombocytopenia, and dyspnea (4% each). There was 1 treatment-related death (acute respiratory distress syndrome).

Conclusion

These findings suggest that elderly men with advancedstage prostate cancer tolerate this regimen, with significant responses and prolonged progression-free survival. These patients should not be excluded from chemotherapeutic interventions based on age alone.     

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma

BACKGROUND: The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS: Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS: Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS: The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents.