Grootenboers Marco Jj H, Hendriks Jeroen M H, van Boven Wim J, Knibbe Catherijne A J, van Putte Bart, Stockman Bernard, De Bruijn Ernst, Vermorken Jan B, Van Schil Paul E Y, Schramel Franz Mnh
Department of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.
J Surg Oncol. 2007 Dec 1;96(7):583-9. doi: 10.1002/jso.20838.
Isolated lung perfusion (ILuP) with melphalan was performed under normo- and hyperthermic conditions combined with pulmonary metastasectomy for patients with resectable lung metastases. We present the results of pharmacokinetic analysis of a phase I and extension trial.
Twenty-one procedures of ILuP with melphalan were performed in the phase I trial according to a dose-escalation schedule under normothermic and hyperthermic conditions followed by surgical resection of pulmonary metastases. In an extension trial 8 additional procedures with 15 and 45 mg melphalan were performed under hyperthermic conditions. Samples of serum, perfusate, lung, and tumor tissue were obtained.
High perfusate concentrations of melphalan were recorded in contrast to low systemic concentrations. Marked interindividual variability was observed in melphalan concentrations in perfusate, tumor, and lung tissue. Statistically significant correlation between melphalan dose, and perfusate area under the concentration-time curve (R(2) = 0.578, P = 0.001) and lung tissue concentrations (R(2) = 0.459, P = 0.028) were noted. No significant correlation between melphalan dose and tumor tissue concentrations could be established.
Isolated lung perfusion effectively delivers high doses of melphalan to the lung and tumor tissues with minimal systemic levels. Significant correlation between perfused melphalan dose, perfusate area under the concentration-time curve and lung tissue melphalan concentrations were observed.
对可切除肺转移瘤患者在常温和高温条件下进行美法仑隔离肺灌注（ILuP）并联合肺转移瘤切除术。我们展示了一项I期及扩展试验的药代动力学分析结果。
在I期试验中，根据剂量递增方案在常温和高温条件下进行了21次美法仑隔离肺灌注操作，随后进行肺转移瘤的手术切除。在扩展试验中，在高温条件下又进行了8次分别使用15毫克和45毫克美法仑的操作。采集了血清、灌注液、肺和肿瘤组织样本。
与低全身浓度形成对比的是，记录到灌注液中美法仑浓度较高。在灌注液、肿瘤和肺组织中美法仑浓度观察到明显的个体间差异。注意到美法仑剂量与灌注液浓度-时间曲线下面积（R² = 0.578，P = 0.001）以及肺组织浓度（R² = 0.459，P = 0.028）之间存在统计学显著相关性。美法仑剂量与肿瘤组织浓度之间未建立显著相关性。
隔离肺灌注能以最低的全身水平有效地将高剂量美法仑输送至肺和肿瘤组织。观察到灌注的美法仑剂量、灌注液浓度-时间曲线下面积与肺组织美法仑浓度之间存在显著相关性。
