Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: Magnetic resonance imaging evidence for altered tumor blood flow
Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: Magnetic resonance imaging evidence for altered tumor blood flow
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DOI：
10.1200/jco.2003.12.986
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发表时间：
2003-12-01
影响因子：
45.3
通讯作者：
O'Dwyer, PJ
中科院分区：
文献类型：
--
作者：
Stevenson, JP;Rosen, M;O'Dwyer, PJ
目的：Combretastatin A4 (CA4) phosphate （CA4P）抑制微管聚合，对体外增殖的内皮细胞具有毒性。它在体内引起已建立肿瘤的可逆血管关闭，与抗血管作用机制一致。本研究调查了晚期癌症患者静脉注射CA4P的递增剂量。患者与方法：对于身体健康状况良好的实体恶性肿瘤患者，给予CA4P静脉滴注，每日10分钟，连续5天，每3周重复一次。在第1周期进行药代动力学取样。接受大于或等于52 mg/m(2)/d的患者进行一系列动态对比增强磁共振成像（DCE-MRI）研究，以测量CA4P治疗后肿瘤灌注的变化。结果：37例患者共接受133个治疗周期。CA4P的剂量水平为每日6mg /m(2)至75mg /m(2)。已知肿瘤部位剧烈疼痛的剂量限制为75 mg/m2。剂量限制的心肺毒性（晕厥、呼吸困难或缺氧）也在两名接受75 mg/m剂量治疗的患者中被注意到。其他毒性包括低血压、共济失调、呼吸困难、恶心或呕吐、头痛和一过性感觉神经病变。血浆CA4P和CA4在浓度-时间曲线下的面积和最大浓化值随剂量呈线性增加。在DCE-MRI研究中，通过钆血浆到组织转移的一级速率常数测量的肿瘤灌注，发现10例患者中有8例减少。灌注变化与药代动力学指标之间也存在相关性。在一例转移性软组织肉瘤患者中观察到部分缓解，14例患者表现出至少两个周期的疾病稳定性。结论：CA4P每日5次给药52 ~ 65mg /m2具有较好的耐受性。基于CA4P的累积I期经验，推荐52 mg/m2剂量用于进一步研究。观察抗肿瘤效果，DCE-MRI的使用为CA4P治疗的血管效应提供了有价值的无创测量。(C) 2003年由美国临床肿瘤学会出版。
Purpose: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer.Patients and Methods: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving greater than or equal to 52 mg/m(2)/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment.Results: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m(2) to 75 mg/m(2) daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m(2). Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles.Conclusion: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment. (C) 2003 by American Society of Clinical Oncology.