Guthoff Irene, Lotspeich Erkki, Fester Claudia, Wallin Inger, Schatz Miriam, Ehrsson Hans, Kornmann Marko
Department of Visceral and Transplantation Surgery, University of Ulm, Steinhövelstrasse 9, 89075 Ulm, Germany.
Anticancer Res. 2003 Nov-Dec;23(6D):5203-8.
Several studies have demonstrated the efficacy of systemic oxaliplatin (Oxa) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of colorectal liver metastases (CRLM). However, nothing is presently known about the pharmacokinetics of Oxa administered via the hepatic artery and only very little about the feasibility and toxicity of Oxa used for hepatic artery infusion (HAI).
We designed a phase II trial using Oxa in combination with 5-FU/FA and mitomycin C (MMC) for HAI treatment of patients with isolated non-resectable CRLM. Oxa (130 mg/m2) was delivered on day (d) 1 as a 120-min infusion followed by FA (140 mg/m2) for 10 min and 5-FU (480 mg/m2) for 120 min from d1 to d5 and MMC (7 mg/m2) for 30 min on d5 every 35 days. For Oxa pharmacokinetics, peripheral venous blood was collected before, during and after arterial infusion. Oxaliplatin was determined by liquid chromatography with post-column derivatization in blood ultra filtrate.
A total of 33 HAI cycles were administered to 5 patients with tolerable toxicity, which mainly consisted of grade I and II nausea, vomiting, leucopenia, thrombopenia and abdominal pain. During 4 cycles nausea/vomiting III degree occurred, during 3 cycles diarrhoea and abdominal pain III degree. No neurotoxicity > or = II degree and no catheter occlusion was observed. Staging showed 4 PR and 1 PD. Pharmacokinetic analysis revealed an AUC value of 85.3 micrograms x min/ml after HAI. Recalculating these values with the previously reported AUC value for systemic administration (161 micrograms x min/ml) revealed a liver extraction ratio of 0.47 for Oxa.
We conclude from our results that Oxa in combination with 5-FU/FA and MMC may be a feasible protocol for HAI treatment without major toxicity, especially avoiding higher grade neurotoxicity. This is probably attributable to the low systemic bioavailability of Oxa.
多项研究已证明，全身应用奥沙利铂（Oxa）联合5-氟尿嘧啶（5-FU）和亚叶酸（FA）治疗结直肠癌肝转移（CRLM）具有疗效。然而，目前对于经肝动脉给药的奥沙利铂的药代动力学情况尚无了解，对于用于肝动脉灌注（HAI）的奥沙利铂的可行性和毒性也知之甚少。
我们设计了一项II期试验，使用奥沙利铂联合5-FU/FA和丝裂霉素C（MMC）通过肝动脉灌注治疗孤立性不可切除的CRLM患者。奥沙利铂（130mg/m²）在第1天静脉滴注120分钟，随后在第1天至第5天依次给予FA（140mg/m²）静脉滴注10分钟、5-FU（480mg/m²）静脉滴注120分钟，第5天给予MMC（7mg/m²）静脉滴注30分钟，每35天重复一次。为研究奥沙利铂的药代动力学，在动脉灌注前、灌注期间和灌注后采集外周静脉血。采用柱后衍生化液相色谱法测定血液超滤液中的奥沙利铂含量。
共对5例患者进行了33个肝动脉灌注周期，毒性可耐受，主要包括I级和II级恶心、呕吐、白细胞减少、血小板减少和腹痛。4个周期出现III级恶心/呕吐，3个周期出现III级腹泻和腹痛。未观察到≥II级神经毒性，也未出现导管堵塞情况。分期显示4例部分缓解（PR），1例疾病进展（PD）。药代动力学分析显示肝动脉灌注后奥沙利铂的曲线下面积（AUC）值为85.3μg·min/ml。根据先前报道的全身给药的AUC值（161μg·min/ml）重新计算这些值，得出奥沙利铂的肝脏提取率为0.47。
我们从研究结果得出结论，奥沙利铂联合5-FU/FA和MMC可能是一种可行的肝动脉灌注治疗方案，且无严重毒性，尤其可避免较高等级的神经毒性。这可能归因于奥沙利铂较低的全身生物利用度。
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