Combined anti-microtubule therapy: a phase II study of weekly docetaxel plus estramustine in patients with metastatic breast cancer.

BACKGROUND: Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles. RESULTS: Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen. CONCLUSIONS: Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.     

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m(-2) of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1-3, 8-10, 15-17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1-9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44-72) and median duration of PSA response was 8.0 months (95% CI: 6.9-9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.     

A phase II study of single-agent docetaxel in patients with metastatic esophageal cancer.

BACKGROUND: To evaluate the activity and toxicity of docetaxel in patients with metastatic esophageal cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed carcinoma of the esophagus with measurable metastatic sites according to Response Evaluation Criteria in Solid Tumors (RECIST). Patients were either chemotherapy-na?ve or previously treated with one regimen of chemotherapy. Docetaxel 70 mg/m(2) was administered intravenously over 1-2 h, every 21 days. RESULTS: Of 52 patients enrolled in this study, three were excluded because they did not receive docetaxel due to worsening condition after enrollment. Thirty-six patients had received prior platinum-based chemotherapy. The majority of patients (94%) had squamous cell carcinoma. Ten of 49 evaluable patients [20%; 95% confidence interval (CI) 10-34%] showed a partial response. Of the 10 partial responses, six patients had received prior platinum-based chemotherapy. Grade 3 or 4 neutropenia was noted in 43 of 49 patients (88%), and nine of 49 patients (18%) developed febrile neutropenia. Twenty-eight of 49 patients (57%) required lenograstim. Grade 3 anorexia and fatigue occurred in nine (18%) and six (12%) patients, respectively. Median survival time was 8.1 months (95% CI 6.6-11.3) and the 1-year survival rate was 35% (95% CI 21-48%). CONCLUSIONS: Docetaxel as a single agent is effective in esophageal cancer, but careful management of neutropenia is needed.     

Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma

Background: To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials.Patients and methods: Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static; docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m2. Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks.Results: Five patients were entered at a docetaxel dose of 40 mg/m2, three at 60 mg/m2, six at 70 mg/m2, and three at 80 mg/m2. Only one patient had received prior chemotherapy. Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m2. The phase II dose was defined at 70 mg/m2 with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m2): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA 4 ng/ml). One patient had a partial response with measurable lung and liver lesions.Conclusion: EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are 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.     

Experience with docetaxel in hormone-refractory prostate cancer (HRPC) at three Australian cancer centers: A retrospective study

Background: Hormone‐refractory prostate cancer (HRPC) is associated with a poor prognosis and has historically been considered relatively chemoresistant. Emerging data demonstrate clinical benefit with the use of docetaxel in HRPC, culminating in two recent published phase III studies demonstrating survival benefit. Currently, docetaxel is registered but not reimbursed for HRPC in Australia. Aim: To retrospectively review prostate‐specific antigen (PSA) response rate, and survival following the use of docetaxel for metastatic HRPC. Methods: Retrospective audit of the use of docetaxel for HRPC from 1 January 2001 to 1 April 2004 in three medical oncology practices. Demographic data, baseline PSA, ECOG (Eastern Cooperative Oncology Group) Performance Status, sites of disease, number of cycles received and PSA response rates were collected. Results: Thirty five patients (median age, 71 years; range, 50–88) had an ECOG status of 0 (eight), 1 (20) and 2 (seven). The mean duration from initial prostate cancer diagnosis to start of docetaxel was 5.4 years (range, 0.2–13.5 years). The mean baseline PSA doubling time, available for 29/35 patients, was 1.9 months (range, 0.4–4.9). The median number of metastatic sites was 1 (range, 1–4): bone (34 patients), lymph nodes (10), liver (seven) and lung (seven). Twelve patients were chemotherapy naive; 23 had received prior chemotherapy (21/23 received mitoxantrone). Twenty patients received docetaxel three times weekly; 15 were on weekly schedules. Their mean dose density was 23 mg/m²/week. Patients received an average of 3.2 months of treatment (range, 0.2–11.8). There were 170 recorded toxicities, 13 of which were grade 3–4, and two likely treatment‐related deaths (sepsis). Twelve patients (34%) had >50% PSA response (four were chemotherapy naive); of these 12 responders, seven patients had a >75% PSA response (four chemotherapy naive). Median survival from start of docetaxel was 8 months with 37% alive at 12 months and 23% alive at 24 months. Conclusion: Docetaxel is active in HRPC (in both chemotherapy naive and exposed patients) with a predictable toxicity profile. More research is warranted to identify predictors of response and toxicity.     

多西他赛联合泼尼松或米托蒽醌联合泼尼松治疗激素抵抗性前列腺癌

背景与目的：以多西他赛为核心的化疗方案已经成为激素抵抗性前列腺癌治疗的一线方案：本文初步比较多西他赛联合泼尼松或米托蒽醌联合泼尼松在雄激素抵抗性前列腺癌中的疗效差异，进一步探讨这两种方案的毒副反应。方法：入选雄激素抵抗性前列腺癌患者共83例，其中44例给予多西他赛75mg／m^2 d1静脉滴注联合泼尼松，5mg，每天2次，d1～21口服方案治疗（简称多西他赛组），39例给予米托蒽醌12mg／m^2 d1静脉滴注联合泼尼松，5mg，每天2次，d1～21口服方案治疗（简称米托蒽醌组）。两方案均以21天为1周期，平均治疗5周期：结果：多西他赛组中13．6％（6／44）完全缓解（治疗后PSA下降至4．0ng／ml以下），29．5％（13／44）部分缓解，29．5％（13／44）稳定，27．3％（12／44）进展。缓解和稳定患者的PSA进展中位时间是37．8周（12～101周）。进展的12例患者接受了后续的米托蒽醌组挽救治疗，结果部分缓解16．7％（2／12），稳定25．0％（3／12），2例患者死于疾病进展。米托蒽醌组中7．7％（3／39）完全缓解，25．6％（10／39）部分缓解，25．6％（10／39）稳定，41．0％（16／39）进展：缓解和稳定患者的PSA进展中位时间是25．3周（8～61周）。进展的14例患者接受了后续的多西他赛组方案的挽救治疗，结果完全缓解7．1％（1／14），部分缓解35．7％（5／14），稳定21．4％（3／14）．4例患者死于疾病进展：毒性评估：接受多西他赛组治疗者44例，Ⅲ～Ⅳ度骨髓抑制9例（2例因不能耐受化疗退出），Ⅱ度骨髓抑制14例；接受米托蒽醌组治疗者39例，Ⅲ～Ⅳ度骨髓抑制4例，Ⅱ度骨髓抑制12例。结论：多西他赛组或米托蒽醌组均是治疗雄激素抵抗性前列腺癌的有效化疗方案。两种方案对中国的前列腺癌患者的治疗效果比较接近，但米托蒽醌联合泼尼松的治疗方案的副作用略轻。两种方案交替使用仍可产生部分的反应率，两种方案可以互为挽救方案．且多西他赛联合泼尼松作为挽救方案疗效好于米托蒽醌联合泼尼松。     

A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel

BACKGROUND: Prostate cancer is the second leading cause of cancer mortality among men in the U.S. To the authors' knowledge, there is no proven, effective, second-line therapy for docetaxel-refractory disease. Recent data suggest that platinum salts may be effective when combined with taxanes in metastatic hormone-refractory prostate cancer (HRPC). The authors conducted a phase 2 trial of docetaxel plus carboplatin chemotherapy in this disease setting. METHODS: Eligible men had metastatic HRPC that had progressed during or within 45 days after the completion of docetaxel-based chemotherapy. Patients were treated with intravenous docetaxel at a dose of 60 mg/m(2) plus carboplatin at an area under the curve of 4 once every 21 days until they had either disease progression or unacceptable toxicity. RESULTS: Thirty-four patients were enrolled. Therapy was tolerated reasonably well; Grade 3 leukopenia (graded according to the Common Toxicity Criteria grading system) was the most common adverse event (experienced by 56% of patients), but there was only 1 episode of febrile neutropenia reported. Prostate-specific antigen (PSA) declines > or =50% were noted in 18% of patients, and measurable responses were observed in 14%. The median duration of PSA response was 5.7 months. The median progression-free survival was 3 months, and the median overall survival was 12.4 months. Patients were more likely to respond to the combination if they previously had responded to docetaxel. CONCLUSIONS: In men with HRPC who developed progressive disease during or shortly after treatment with docetaxel, the addition of carboplatin resulted in modest additional activity. Taxane-refractory HRPC is an area of unmet need, and the current trial has provided evidence that platinum chemotherapy may be an important therapeutic option.     

A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of >/=12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA-response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.     

A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone.     

A phase II study of vinorelbine and estramustine in patients with hormone-resistant prostate cancer

Introduction

This phase II study was designed to evaluate the efficacy of vinorelbine in combination with estramustine in patients with chemotherapy-naïve hormone-refractory prostate cancer.

Material and methods

Patients received vinorelbine (i.v. 25 mg/m²) on days 1 and 8 every 3 weeks and estramustine (oral, 600 mg/m²) daily. Eligible patients were required to have progressive metastatic disease following the first hormonal manipulation.

Results

Of the 51 patients enrolled (median age=69 years), 84% presented bone involvement and 75% had at least two organs involved at the time of study entry and 47 were evaluable for treatment efficacy. Prostate specific antigen (PSA) response (≥50% decrease) which was the primary efficacy criterion was reported in 21 patients (41.2%) in the intent-to-treat (ITT) population and in 20 patients (48.8%) in the perprotocol (PP) population. Of the 7 patients with measurable disease, 2 achieved partial response. Median progression-free survival and overall survival were 4.7 months (range: 1.9–8.6) and 14.3 months (range: 4.2–21.2), respectively. grade 3–4 neutropenia was reported in 6.1% of patients and in 1% of cycles. The incidence of complicated neutropenia (febrile neutropenia reported in 1 patient and septic shock with severe neutropenia reported in 2 patients) was 5.8%. The most frequent grade 3–4 non-haematological events (% of patients ≥5%) included anorexia (10%), thrombosis/embolism (8%), vomiting and hypotension (6% each). There were 3 toxic deaths (5.9%) resulting from pulmonary embolism, angina pectoris, and septic shock. The impact of combined chemotherapy on the quality-of-life (QL) of the patients was assessed between baseline and the first evaluation scheduled at 6 weeks indicated a marked reduction in pain while the rest of the symptoms remained stable. Overall, health status improved slightly over the treatment period.

Conclusions

This study confirmed that the combination of vinorelbine and estramustine is an active regimen in patients with hormone-resistant prostate cancer who had not been treated previously with chemotherapy. Main toxicities included complicated neutropenia even though the incidence of severe neutropenia was low. We observed a higher incidence of toxic deaths which could have been related to the regimen of estramustine used in the study.     

Phase II study of sequential chemotherapy with docetaxel-estramustine followed by mitoxantrone-prednisone in patients with advanced hormone-refractory prostate cancer

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m(-2) intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m(-2) i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3-4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63-82%) obtained a >/=50% PSA decline with 15 patients (37.5%; 95% CI 20-50%) that demonstrated a >/=90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8-8.2 months) and 19.2 months (95% CI 13.9-24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.     

Phase II study of weekly docetaxel in patients with metastatic breast cancer.

BACKGROUND: This study was conducted to investigate the efficacy and toxicity of weekly docetaxel administration in patients with metastatic breast cancer. PATIENTS AND METHODS: Thirty-seven women were treated with 1 h infusions of docetaxel at 40 mg/m2/week after pre-medication with 8 mg dexamethazone. Each cycle consisted of three consecutive weekly treatments followed by a 1 week rest. All patients were assessed for toxicity; five patients were not assessable for clinical response, time to progression (TTP) and overall survival (OS) because of early treatment failure, but they were included in intention-to-treat analysis. RESULTS: Patients received a median of four cycles (range, 1-9), with a median dose intensity of 28 mg/m2/week (range 22-30) and a median relative dose intensity of 0.95 (range 0.73-1.0). No patients showed complete response, whereas 14 had partial response, which accounted for 38% of objective response rate [95% confidence interval (CI) 22% to 53%]. In addition, three patients (8%, 95% CI 0% to 17%) had stable disease over 6 months. Clinical responses were achieved at a median of three cycles (range 1-4 cycles). The median TTP and OS were 5 and 12 months, respectively. The weekly docetaxel regimen was generally well tolerated. About half of the patients experienced grade > or = 1 neutropenia; only 19% had grade 3/4 neutropenia, including one case of grade 4. No febrile neutropenia was observed and fluid retention syndrome was uncommon. Non-hematologic toxicity, however, such as asthenia/fatigue, nail damage, tearing or hearing disorders, was seen with successive treatment cycles. CONCLUSIONS: Weekly docetaxel at 40 mg/m2/week is an active and feasible regimen for patients with metastatic breast cancer.     

Sequential mitoxantrone/prednisone followed by docetaxel/estramustine in patients with hormone refractory metastatic prostate cancer: results of a phase II study.

BACKGROUND: Mitoxantrone/prednisone ameliorates symptoms in hormone refractory prostate cancer (HRPC) but has no effect on survival. Docetaxel (Taxotere)/estramustine improves response but with significant toxicity. We reasoned that a sequential administration of the two regimens could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity. PATIENTS AND METHODS: Thirty HRPC patients were treated with mitoxantrone 10 mg/m(2), day 1, every 3 weeks, plus prednisone 5 mg twice daily, for three cycles, followed by estramustine phosphate, 280 mg three times daily, days 1 to 5, plus docetaxel 75 mg/m(2), day 2, every 3 weeks for a maximum of 10 cycles. RESULTS: All patients were assessable for response and toxicity. After mitoxantrone/prednisone treatment, the prostate-specific antigen (PSA) response rate was 23%, which increased to 63% after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine treatment (12 partial and 7 complete responses). With a median follow-up of 18 months, median survival for all patients was 18 months, and median progression-free survival was 10 months. The mitoxantrone/prednisone regimen was well tolerated, and the only grade 3-4 toxicity was grade 3 neutropenia in four (13%) patients. Twenty-nine patients received a total of 173 cycles of docetaxel/estramustine (median, 6 cycles/patient). Six (20%) patients had grade 3-4 neutropenia and two (6%) patients had febrile neutropenia episodes. The most frequent non-hematological toxic effects were asthenia, nausea and vomiting, edemas and onycholysis. Two (6%) patients had deep venous thrombosis. CONCLUSIONS: Mitoxantrone/prednisone followed by docetaxel/estramustine is a well-tolerated and active regimen in HRPC. Sequential therapy is feasible and can be used to integrate novel, more active regimens.     

Long-term outcome of a phase II study of weekly docetaxel with a short course of estramustine and enoxaparine in hormone-resistant prostate cancer patients

Objective The objective was to define the toxicity and activity of weekly docetaxel administered with a short course of estramustine and enoxaparine in patients with hormone-resistant prostate cancer (HRPC). Patients and methods Twenty-four patients were treated with the next regimen: weekly docetaxel 36 mg/m² iv for three consecutive weeks every 28 days, and estramustine 280 mg three times a day for three consecutive days beginning the day before docetaxel (days 1–3, 8–10 and 15–17). In order to prevent thromboembolic events, 40 mg of subcutaneous enoxaparine was administered daily sc on the same days as estramustine. Primary endpoints were: toxicity, especially the presence of thromboembolic events, PSA response rate and response in measurable disease. Secondary endpoints were: time to PSA progression and overall survival. Results Nineteen of 24 patients (79.1%, 95% CI 71–87%) had a PSA response ≥50%. Four of the eleven patients with measurable disease had a partial response. The median time to PSA progression was 7 months (CI 95%: 6.5–9) and the median survival was 19 months (IC 95%: 11–24). Toxicity was manageable with no treatment-related mortality. Only two patients had grade 4 neutropenia. Two patients had thrombotic events, one deep venous thrombosis and one stroke. The main grade 3 non-haematologic toxicity was diarrhoea and asthenia, both in 25% of patients. Conclusions Weekly docetaxel with a short course of estramustine and enoxaparine is active and tolerable in HRPC patients. The observed incidence of thrombosis was lower than previously reported but the association of enoxaparine was not enough to completely prevent the thromboembolic events.     

Dose-finding study of weekly docetaxel plus estramustine in patients with hormone-refractory metastatic prostate cancer

OBJECTIVE: The aim of this phase I study was to find the maximum tolerated dose of weekly docetaxel in association with estramustine in hormone-refractory prostate cancer. METHODS: Eleven patients with hormone-refractory prostate cancer were treated with escalating weekly doses of docetaxel (level I, 3 patients, 30 mg/m2; level II, 3 patients, 35 mg/m2, level III, 3 patients, 40 mg/mz; level IV, 2 patients, 45 mg/m2) associated with fixed dosage of estramustine (840 mg/day). RESULTS: In level I, there was only one episode of grade 3 neutropenia; grade 1 nausea and vomiting were registered in 1 patient; in 1 patient mild edema of the lower limbs was noted. In level II, grade 2 stomatitis and grade 1 sensory symptoms occurred in 1 patient, and grade 1 edema in 1 case. In level Ill, grade 2 edema was noted in 2 patients, damage to nails in 1 patient, asthenia in 1 patient, grade 1 neuropathy in 2 patients, and grade 1 nausea in 1 patient. In level IV, grade 2 edema was present in 1 patient, grade 3 edema in 1 patient, changes with fall of nails and grade 2 erythema of face in 2 patients, asthenia in 2 patients, grade 1 neuropathy in both patients. Nine patients had a more than a 50% decrease in PSA after 2 cycles of therapy. CONCLUSIONS: The results of the study suggest a good tolerability of weekly 35 Mg/m2 docetaxel in hormone-refractory prostate cancer in association with estramustine.     

多西他赛加泼尼松3周方案失败后联合雌二醇氮芥治疗激素难治性前列腺癌

目的激素难治性前列腺癌（ hormone refractory prostate cancer, HRPC）的治疗,在2004年取得了突破性进展,TAX327研究证实多西他赛联合泼尼松3wk方案可以延长病人的生存期,从而确立了其一线标准化疗方案的地位。但是,多西他赛联合泼尼松方案失败后的治疗选择仍然是一难题,为此,我们观察多西他赛联合雌二醇氮芥及泼尼松三联方案在一线标准方案失败后治疗HRPC的疗效和安全性。方法2005年11月至2007年3月,6例HRPC在多西他赛联合泼尼松3wk方案治疗过程中病情恶化（血PSA升高）时,用多西他赛联合雌二醇氮芥及泼尼松治疗。治疗方案：多西他赛75mg／m^2,d1,强的松5mg bid,d1起连续应用,雌二醇氮芥280mg,2次,d,d1起连用5d。21d为1疗程。病人平均年龄75．8a,血睾酮维持去势水平,WHO体力状态评分≤2,骨髓、心、肝、肾等重要脏器功能正常。估计生存时间〉3mo。疗效及不良反应判断标准：①血PSA下降〉50％,且维持〉3wk判断为有效。②可测量病灶按RECIST实体瘤评价标准评价。③骨痛者按主诉疼痛程度分级法（VRS）评价,评分下降1级为有效。④不良反应按WHO不良反应标准评定。结果6例共完成27个疗程。PSA有效5例,有效率为83.3％。有效病人PSA从治疗前的10．9～606．2（223．6±218．0）mg／mL下降到治疗后最低1．1～127．6（61．5±50．4）ng／mL。1例肺转移者,转移灶为稳定。1例骨痛者VRS疼痛评分从Ⅱ下降到Ⅰ。到分析日止,已死亡1例。此例从诊断激素非依赖前列腺癌到死亡共53mo。5例存活者从诊断激素非依赖前列腺癌起已存活14～36mo。主要不良反应为骨髓抑制（100％）,脱发（100％）,乏力（67％）等。结论多西他赛联合雌二醇氮芥及泼尼松三联方案对多西他赛联合泼尼松3wk方案治疗失败后的病人疗效肯定,毒副反应可以耐受,值得进一步观察?     

Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer.

BACKGROUND: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. PATIENTS AND METHODS: Patients with metastatic prostate cancer, progressive after primary hormonal therapy, were randomised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression. Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy (HT) for all their patients. Randomisation was stratified by centre. Further chemotherapy was allowed after progression. The primary end point was progression-free survival (PFS). The final analysis was performed on a total of 414 patients. Reported results were all based on intention-to-treat analyses. All progressions and responses were reviewed by an independent panel. RESULTS: PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm, according to the statistical hypothesis of the protocol (P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10%). The 6-month PFS rates were 33.2% versus 22.8%, and the median durations of PFS were 3.7 versus 2.8 months. In the multivariate Cox analysis, which included age, Karnofsky performance status (PS), haemoglobin, alkaline phosphatase at study entry and number of prior hormonal treatments, the P value was decreased to 0.005. The prostate-specific antigen (PSA) response rate (> or =50% decline sustained for at least 6 weeks) was significantly higher for VRL plus HT compared with HT (30.1% versus 19.2%; P=0.01). Clinical benefit, defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks, and at least stable assessment in the other two, was also more frequently observed in patients who received VRL plus HT versus HT alone (30.6% and 19.2%; P=0.008). There was no statistical difference in overall survival. Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression, compared with 28% of patients in the VRL-based arm. Aminoglutethimide did not seem to result in better efficacy for either arm. VRL plus HT was well tolerated, with a median administered relative dose intensity of 90%; grade 4 neutropenia occurred in 6.5% of patients and non-haematological toxicity was rare. CONCLUSIONS: The combination of VRL and hydrocortisone compared with hydrocortisone alone resulted in improved clinical benefit, PFS and PSA response rate. This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids. There was no gain in survival; however, the combination is well tolerated in this elderly group of patients, who often present cardiac co-morbidities, and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer.     

Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Background:

BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.

Methods:

This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m⁻², every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.

Results:

Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.

Conclusion:

Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m⁻² of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.     

A phase II trial of docetaxel and vinorelbine in patients with hormone-refractory prostate cancer

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m² on day 1 and vinorelbine 15 mg/m² on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2–6 and 9–13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by >50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy.This trial was supported in part by research grants from Aventis, Amgen, and P30 CA72720-01-03.