Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC. PATIENTS AND METHODS: Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE). RESULTS: Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups. CONCLUSION: Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.     

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。     

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.     

Vinorelbine and prednisone in older cancer patients with hormone-refractory metastatic prostate cancer. A phase II study

AIMS AND BACKGROUND: Prostate cancer is a common disease in older men. Since it is hormone resistant, no treatment may improve survival. In patients with hormone-refractory prostate cancer, clinical benefit is an important treatment end point. STUDY DESIGN: This study evaluated the efficacy and toxicity of a vinorelbine and prednisone combination in hormone-refractory prostate cancer patients. Vinorelbine was administered at the dose of 25 mg/m2 on days 1 and 8, every three weeks; prednisone was administered orally at the dose of 12 mg/day. Thirty consecutive patients, 65 years or older, with progressive (PSA increase or increase in bidimensionally measurable lesion) metastatic prostate adenocarcinoma were enrolled. Four patients (13%) had a partial response and 14 (46%) stable disease. Time to progression for the entire group was 4.5 months (range, 2-13) and 7.5 months for the group of responders (range, 3-13). A PSA decrease >50% was registered in 36% of the patients. Pain reduction was recorded in 44.4% of the patients and stability in 14.8%. RESULTS: The treatment was well tolerated and grade 3 toxicity was found in 2 cases of anemia and 2 cases of leukopenia without fever. CONCLUSIONS: The schedule is able to control the evolution of hormone-refractory prostate cancer and to give a clinical benefit. These results provide information for further clinical trials in a large series of elderly cancer patients.     

A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.

PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.     

Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer

Purpose

Cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel.

Materials and Methods

Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m² intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m² I.V. (400 mg/m² day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP).

Results

A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01).

Conclusions

The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy.     

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.     

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.     

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.     

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.     

Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain.

PURPOSE: To compare the incidence of palliative response in patients with hormone-resistant prostate cancer (HRPC) treated with mitoxantrone and prednisone (MP) plus clodronate with that of patients treated with MP plus placebo. MATERIALS AND METHODS: Men with HRPC, bone metastases, and bone pain were randomly assigned to receive clodronate 1,500 mg administered intravenously (IV) or placebo every 3 weeks, in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid. Patients completed the present pain intensity (PPI) index and Prostate Cancer-Specific Quality-of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis. The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50% in analgesic intake, without increase in either. RESULTS: The study accrued 209 eligible patients over 44 months. One hundred sixty patients (77%) had mild PPI scores (1 or 2), and 49 (24%) had moderate PPI scores (3 or 4). The primary end point of palliative response was achieved in 46 (46%) of 104 patients on the clodronate arm and in 41 (39%) of 105 patients on the placebo arm (P =.54). The median duration of response, symptomatic disease progression-free survival, overall survival, and overall quality of life were similar between the arms. Subgroup analysis suggested possible benefit in patients with more severe pain. CONCLUSION: MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.     

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 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.     

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone

BACKGROUND: This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC). METHODS: Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed. RESULTS: Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients). CONCLUSIONS: Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months.     

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.     

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?     

Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer

BackgroundThis multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC).Patients and methodsTwo schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m² for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m² (Cohort B1, n = 5) and 1.2 mg/m² (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP).ResultsTrabectedin resulted in PSA declines ≥50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1–8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m² (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m² q3wk and 0.58 mg/m² weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase.ConclusionsTwo different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.     

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.