Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer.
Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer.
复制标题
静脉注射雌莫司汀磷酸盐联合紫杉醇和卡铂治疗晚期前列腺癌的剂量递增研究。
DOI：
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发表时间：
2003
影响因子：
11.5
通讯作者：
M. Rocchetti
中科院分区：
文献类型：
--
作者：
W. Kelly;A. Zhu;H. Scher;T. Curley;M. Fallon;S. Slovin;L. Schwartz;S. Larson;W. Tong;B. Hartley‐åsp;C. Pellizzoni;M. Rocchetti
目的
目的是确定每周安全的静脉注射剂量。EMP联合每周紫杉醇和每月卡铂治疗晚期前列腺癌。
实验设计
晚期前列腺癌患者(去势和非去势)接受每周1-h静脉滴注的递增剂量。EMP(500-1000-1500 mg/m(2))联合紫杉醇(100 mg/m(2)，每周1小时静脉滴注)。卡铂(曲线下面积6 mg/ml·min，每4周一次)。四周的治疗被视为一个周期。在前三个队列中，静脉注射EMP。紫杉醇前3h。队列4和5颠倒了给药顺序：紫杉醇输注结束后立即给予EMP(剂量1000-1500 mg/m(2))。分别于0、120min、20h、21h和168h监测血浆EMP及其代谢物雌孕激素和雌孕激素水平。在紫杉醇开始输注后的基础(0)、30、60、90、120min和18h测定紫杉醇的血药浓度，并绘制浓度-时间曲线。在治疗的第1周和第2周期进行药代动力学评估。
结果
19名患者进入了最初的三个剂量水平(队列1-3)。队列3出现剂量限制性的一过性肝毒性(EMP=1500 mg/m(2))。另有13例患者先用紫杉醇(100 mg/m(2))，然后静脉滴注。EMP为1000 mg/m(2)(队列4)和1500 mg/m(2)(队列5)。没有发现剂量限制毒性，第5组队列被确定为安全的II期研究。9%的患者发生血栓栓子事件(未使用预防性香豆素)。EMP及其代谢物的血浆浓度随剂量的增加而成比例增加。在所有的队列中，在周期1和周期2之间，EMP和雌激素的血浆浓度略有下降。虽然不显著，但在周期2观察到比周期1更高的雌激素水平。紫杉醇清除减少导致在第一周期的紫杉醇血浆浓度高于预期。在第二周期中，紫杉醇的血浆浓度较低。在17名雄激素非依赖性疾病患者中，59%的患者治疗后PSA下降50%，22%的患者病情明显消退。
结论
每周一次的静脉注射方案。EMP联合紫杉醇和卡铂可以安全地给药，肝毒性是短暂的和可逆的。药代动力学结果表明，EMP在第一次给药后竞争性抑制紫杉醇的生物转化。在反复给药后，这种效应被电磁脉冲可能引起的代谢系统的诱导所抵消。第二阶段测试正在进行中，以评估这种组合的疗效。
PURPOSE
The purpose is to determine a safe weekly dose of i.v. estramustine phosphate (EMP) to combine with weekly paclitaxel and monthly carboplatin in patients with advanced prostate cancer.
EXPERIMENTAL DESIGN
Patients with advanced prostate cancer (castrate and noncastrate) were administered escalating doses of weekly 1-h infusion of i.v. EMP (500-1000-1500 mg/m(2)) in combination with weekly paclitaxel (100 mg/m(2) over 1 h) and i.v. carboplatin (area under the curve 6 mg/ml-min every 4 weeks). Four weeks of therapy were considered one cycle. In the first three cohorts, EMP was given i.v. 3 h before paclitaxel. Cohorts 4 and 5 reversed the administration order: EMP (doses 1000-1500 mg/m(2)) was given immediately after the end of paclitaxel infusion. Plasma levels of EMP and its metabolites, estramustine and estromustine, were monitored at time 0, at 120 min, and approximately at 20, 21, and 168 h from the start of EMP infusion. Paclitaxel concentrations were determined at basal (0), 30, 60, 90, and 120 min and 18 h after the start of paclitaxel infusion, and a concentration-time curve was estimated. Pharmacokinetic evaluation was performed in cycles 1 and 2 during the first week of therapy.
RESULTS
Nineteen patients were entered on the initial three dose levels (cohorts 1-3). Dose-limiting transient hepatic toxicity was encountered in cohort 3 (EMP = 1500 mg/m(2)). An additional 13 patients were treated with paclitaxel (100 mg/m(2)) first, followed by i.v. EMP at 1000 mg/m(2) (cohort 4), and 1500 mg/m(2) (cohort 5). No dose-limiting toxicities were seen, and cohort 5 was determined safe for Phase II studies. Thromboembolic events were observed in 9% of patients (no prophylactic coumadin was used). Plasma concentrations of EMP and metabolites increased proportionally with dose. In all cohorts, there was a slight decrease in EMP and estramustine plasma concentrations between cycles 1 and 2. Although not significant, higher levels of estromustine at cycle 2 were observed in comparison to cycle 1. Decreased clearance of paclitaxel leading to higher than expected paclitaxel plasma concentrations was observed during the first cycle of therapy. Paclitaxel plasma concentrations were lower during cycle 2. In 17 patients with androgen-independent disease, 59% had >/=50% posttherapy decline in PSA and 22% showed measurable disease regression.
CONCLUSIONS
The regimen of weekly i.v. EMP in combination with paclitaxel and carboplatin can be safely administered with hepatic toxicity being transient and reversible. Pharmacokinetic results suggest that EMP competitively inhibits the biotransformation of paclitaxel after the first administration. This effect is counterbalanced, after repeated administrations, by a possible induction of the metabolic system caused by EMP. Phase II testing is ongoing to evaluate the efficacy of this combination.
影响因子：
11.2
作者：
L. Speicher;L. Barone;K. Tew
通讯作者：
L. Speicher;L. Barone;K. Tew
影响因子：
4.1
作者：
Yamazaki, H;Shaw, PM;Shimada, T
通讯作者：
Shimada, T
复发性前列腺癌的临床试验：确定目标。
DOI：
10.1093/jnci/88.22.1623
发表时间：
1996
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Scher,HI;Mazumdar,M;Kelly,WK
通讯作者：
Kelly,WK