Pingpank James F, Libutti Steven K, Chang Richard, Wood Bradford J, Neeman Ziv, Kam Anthony W, Figg William D, Zhai Souping, Beresneva Tatiana, Seidel Geoffrey D, Alexander H Richard
Surgical Metabolism Section, Surgery Branch, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892-1502, USA.
J Clin Oncol. 2005 May 20;23(15):3465-74. doi: 10.1200/JCO.2005.00.927.
We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan.
The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response.
A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses.
Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.
我们进行了一项I期研究，通过经皮放置的导管对美法仑进行30分钟的肝动脉灌注，并使用置于肝后下腔静脉的双球囊导管进行肝静脉血液滤过，使肝静脉流出物通过活性炭滤器后再进入体循环。该研究的目的是在初始队列中证明其可行性，并随后确定美法仑的最大耐受剂量和剂量限制性毒性。
初始队列（n = 12）接受2.0 mg/kg的美法仑治疗，之后剂量递增至3.5 mg/kg（n = 16）。测定了肝脏的总药物输送量、全身药物水平和滤器效率百分比。对患者进行肝毒性和全身毒性以及反应的评估。
共对28例患者进行了74次治疗。12例原发性和转移性肝肿瘤患者接受了初始剂量为2.0 mg/kg的美法仑治疗30次（平均每位患者2.5次）。在3.5 mg/kg剂量时，6例患者中有2例出现剂量限制性毒性（中性粒细胞减少和/或血小板减少）。分别在19%和66%的治疗后观察到短暂的3/4级肝毒性和全身毒性。在接受治疗的患者中观察到总体影像学缓解率为30%。在10例眼黑色素瘤患者中，观察到总体缓解率为50%，包括2例完全缓解。
通过该系统给予美法仑是可行的，毒性有限且可控，并有大量抗肿瘤活性的证据；3 mg/kg是通过该技术给予美法仑的最大安全耐受剂量。
