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。     

Ixabepilone,mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

BACKGROUND:

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second‐line chemotherapy in patients with docetaxel‐refractory castration‐resistant prostate cancer. Clinical noncross‐ resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose‐limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.

METHODS:

Patients with metastatic progressive castration‐resistant prostate cancer during or after 3 or more cycles of taxane‐based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m² and mitoxantrone 12 mg/m² administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.

RESULTS:

Results are reported for the 56 evaluable patients. Twenty‐five (45%; 95% confidence interval [CI], 31%‐59%) experienced confirmed ≥50% prostate‐specific antigen (PSA) declines, 33 (59%; 95% CI, 45%‐72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%‐39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5‐5.6), and median progression‐free survival was also 4.4 months (95% CI, 3.0‐6.0). Median overall survival was 12.5 months (95% CI, 10.2‐15.9). Thirty‐two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment‐related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.

CONCLUSIONS:

These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration‐resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.     

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.     

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.     

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 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer

BACKGROUND.

Atrasentan is a potent, oral, selective endothelin‐A (ET_A) receptor antagonist that has clinical activity in patients with hormone‐refractory prostate cancer (HRPC). In this article, the authors report the results from a phase 3, randomized, double‐blind, placebo‐controlled trial of atrasentan in patients with nonmetastatic HRPC.

METHODS.

Of 941 patients who had adequate androgen suppression and no radiographic evidence of metastases but rising prostate‐specific antigen (PSA) levels, 467 patients were randomized to receive atrasentan at a dose of 10 mg, and 474 patients were randomized to receive placebo daily. The primary endpoint was the time to disease progression (TTP), which was defined as the onset of metastases. Secondary endpoints were the time to PSA progression, change in bone alkaline phosphatase (BALP) levels, PSA doubling time, and overall survival.

RESULTS.

There was a 93‐day delay in the median TTP with atrasentan, but the difference from placebo in TTP was not statistically significant (P = .288). Large geographic differences in the median TTP were noted: in the US: The difference was 81 days longer with placebo; whereas, in non‐US sites, the difference was 180 days longer with atrasentan. Atrasentan lengthened the PSA doubling time (P = .031) and slowed the increase in BALP (P < .001). The median survival was 1477 days with atrasentan and 1403 days with placebo. The most common adverse events associated with atrasentan were peripheral edema, nasal congestion, and headache, consistent with the vasodilatory properties of ET_A receptor antagonists.

CONCLUSIONS.

Although the primary endpoint was not achieved, large regional differences in TTP were noted, suggesting that trial conduct may have influenced the results. The biologic activity was consistent with findings from other clinical trials of atrasentan in HRPC. Cancer 2008. © 2008 American Cancer Society.     

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.     

激素抗拒性前列腺癌的化疗和新药物治疗

对于雄激素撤除治疗后进展的前列腺癌尚无有效的治疗方法,二线内分泌治疗效果亦不明显。两个大型随机临床试验表明:以多西紫杉醇为基础的化疗能够延长患者的生存期,延缓疾病进展,这为多西紫杉醇联合一些新的生物制剂,巩固长期疗效提供了动力。随着肿瘤疫苗、单克隆抗体、骨靶向药物、反义寡核苷酸、抗血管生成药物和小分子酪氨酸激酶受体抑制剂等的出现,前列腺癌的治疗前景令人振奋。     

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 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.     

Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone-refractory prostate cancer

New therapeutic strategies are needed to improve treatment outcomes in men with hormone-refractory prostate cancer. A better understanding of the molecular mechanisms of cell death in response to therapeutic strategies will help avoid ineffective treatment regimens and provide a molecular basis for new therapeutic modalities targeting apoptosis-resistant forms of prostate cancer. In this review, the authors focused on the established aberrations of apoptosis in hormone-refractory prostate cancer, and they have described novel treatment strategies to overcome apoptosis resistance.     

Higher prostate-specific antigen levels predict improved survival in patients with hormone-refractory prostate cancer who have skeletal metastases and normal serum alkaline phosphatase

BACKGROUND: Higher prostate-specific antigen (PSA) and alkaline phosphatase (ALK-P) levels predicted worse survival in men with metastatic hormone-refractory prostate cancer (HRPC). In the current study, the authors evaluated the combined effects of PSA and ALK-P on survival. METHODS: Two hundred twenty-four men who had HRPC with bone metastases and who were receiving chemotherapy were identified, and 143 of those men had data available on both ALK-P and PSA levels at chemotherapy initiation. The primary endpoint of the study was overall survival (OS) after chemotherapy. The men were dichotomized into normal and abnormal ALK-P groups according to levels based on institutional normal ranges. The effect of PSA was evaluated as both a categorical value and a continuous value using Cox regression. RESULTS: Eighty-nine of 143 patients (62%) had elevated ALK-P levels. The median PSA was 147 ng/mL (93 ng/mL in patients with normal ALK-P, 171 ng/mL in patients with elevated ALK-P). At a median follow-up of 30 months after chemotherapy initiation, 93 patients had died. The median OS after chemotherapy was 15.8 months (95% confidence interval, 12.8-18.4 months) and was significantly longer if ALK-P was in the normal range (21.3 months vs 14 months; P = .005). For the group with normal ALK-P levels, the median OS was 12.5 months, 24.5 months, and 36.9 months for patients with low, medium, and high PSA levels, respectively. In contrast, the effect of PSA on survival was not as evident in the group with elevated ALK-P levels (16.5 months vs 11.9 months vs 12.1 months, respectively; P = .14 for interaction). Age-adjusted multivariate analysis demonstrated statistically significant interactions of PSA and ALK-P with OS (P = .02). CONCLUSIONS: ALK-P significantly predicted OS in men with HRPC who had bone metastases. In patients with normal ALK-P levels, higher PSA levels were associated with improved survival.     

Second-line therapy for castrate-resistant prostate cancer: a literature review

Despite a survival benefit in the first-line treatment of castrate-resistant prostate cancer (CRPC) with docetaxel, the prognosis remains limited. There are increasing options available for patients with CRPC in the second-line setting, but there is currently little consensus regarding the optimal treatment. There have been numerous phase II and retrospective studies examining second-line options in CRPC, including retreatment with docetaxel, mitoxantrone, cyclophosphamide and carboplatin, which can be associated with meaningful responses in a significant minority of patients. In 2010 three randomized trials were published or presented which demonstrated a survival benefit in the second-line setting. These included cabazitaxel compared with mitoxantrone, sipuleucel-T (immunotherapy) and abiraterone acetate versus placebo. Ongoing research in the second-line setting of CRPC to optimize treatment options, with the objectives of survival prolongation, improvement in quality of life and pain management, is still needed.     

Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer

BACKGROUND: This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). METHODS: Dose levels ranged from 100 x 10(6) cells q28d x 6 to 500 x 10(6) cells prime/300 x 10(6) cells boost q14d x 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics. RESULTS: Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test). CONCLUSIONS: This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway.     

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid

BACKGROUND: Bisphosphonates have been used to treat bone metastases in hormone-refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005. METHODS: A comprehensive medical records review was performed in a major tertiary oncology center (n = 122 patients). The primary outcome of renal impairment was defined as an increase >or=0.5 mg/dL or >or=1.0 mg/dL over baseline creatinine value if the baseline value was <1.4 mg/dL or >or=1.4 mg/dL, respectively. A risk factor analysis was conducted using the Andersen-Gill extension to the Cox proportional hazards model. RESULTS: Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy (<6 months, 11.1%; >or=24 months, 26.3%) and previous pamidronate treatment (45.5% vs 19.0% for patients with no prior pamidronate). A significantly greater risk of renal impairment was associated with increasing age at zoledronic acid initiation, prior pamidronate use, and a history of renal disease, hypertension, or smoking (P 相似文献   

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.     

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.     

A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate‐resistant prostate cancer

BACKGROUND:

The objective of this study was to identify subgroups of patients with castrate‐resistant prostate cancer (CRPC) who had a prolonged response to combined dexamethasone and diethylstilbestrol (DS) therapy by constructing a prognostic index.

METHODS:

Multivariate and cutoff point analyses with bootstrapping were performed 1 month after commencing DS therapy, and data were validated using an independent external dataset.

RESULTS:

The median overall survival for 145 patients was 18.3 months (95% confidence interval [CI], 15.4‐23.3 months). Only 2 factors were significant on multivariate analysis: a prostate‐specific antigen (PSA) level below the median at the start of DS therapy and a decline >50% in the PSA level after 1 month on DS therapy. Subsequent cutoff point analyses revealed that a PSA level <88 ng/mL at the start of DS therapy and a reduction >53.1% in PSA after the first month of treatment were the most significant factors. These 2 factors were used to construct a prognostic index, which was validated successfully by the external dataset (median overall survival, 18.3 months [95% CI, 16.4‐28.0 months]; concordance, 72% [95% CI, 68%‐76%]). The prognostic index identified 3 prognostic groups: The 2‐year overall survival rate for these 3 groups was 68% (95% CI, 57%‐98%) for the good prognostic group, 40% (95% CI, 31%‐52%) for the intermediate prognostic group, and 12% (95% CI, 5%‐25%) for the poor prognostic group.

CONCLUSIONS:

The easy‐to‐use prognostic index that the authors developed was able to identify a subgroup of patients with CRPC who had prolonged survival only 1 month after starting DS therapy. Cancer 2010. © 2010 American Cancer Society.     

Diethylstilbestrol and docetaxel: a Phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer

BACKGROUND: The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS: Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m(2) intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS: The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS: The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.     

Management of patients with hormone refractory prostate cancer

Prostate cancer is the second most common cancer in men in the UK, and the incidence of prostate cancer has increased dramatically over the past two decades. Although most men are diagnosed at early stage, more than 50% develop locally advanced or metastatic disease. Androgen ablation with luteinising hormone-releasing hormone (LHRH) agonists alone, or in combination with anti-androgens, is the standard treatment for men with metastatic prostate cancer. Unfortunately, almost all men develop progressive disease after a variable time period, despite the maximal androgen blockade. The management of hormone refractory prostate cancer (HRPC) is challenging, as there is no uniformly accepted strategy. Various treatment options, including second-line hormone therapy, are discussed. Chemotherapy is being increasingly used and, importantly, docetaxel and estramustine may play an important role in the near future. The role of radiotherapy, strontium-89, bisphosphonates, novel agents and future therapies are also outlined.