de Vries M R, Borel Rinkes I H, van de Velde C J, Wiggers T, Tollenaar R A, Kuppen P J, Vahrmeijer A L, Eggermont A M
Department of Surgical Oncology, Dr. Daniël den Hoed Cancer Center, University of Hospital Rotterdam, The Netherlands.
Recent Results Cancer Res. 1998;147:107-19. doi: 10.1007/978-3-642-80460-1_11.
We report our experience with isolated hepatic perfusion (IHP) with tumor necrosis factor (TNF) and melphalan in an experimental pig study and of a phase I study in humans. IHP was performed with inflow catheters in the hepatic artery and portal vein and an outflow catheter in eh caval vein. An extracorporeal venovenous bypass was used. IHP consisted of a 60-min perfusion with hyperthermia (> 41 degrees C). For the pig protocol rhTNF alpha 50 micrograms/kg alone (n = 5) or rhTNF alpha 50 micrograms/kg plus melphalan 1 mg/kg (n = 3) were added. In two control pigs no drugs were added. In the phase I study, patients received melphalan 1 mg/kg with 0.4 mg rhTNF alpha (n = 8) or 0.8 mg rhTNF alpha (n = 1). After the perfusion the liver was washed with Macrodex before vascular continuity was restored. All pigs but one survived the procedure. Systemic leakage was less than 0.02%. Transient, mild liver toxicity was seen in all pigs, including controls, as demonstrated by liver enzyme assays and histology. There was no significant hemodynamic, cardiopulmonary hematological, or renal toxicity. In the phase I clinical study there was leakage in one patient (cumulative leakage 20%). There were three perioperative deaths (one possibly drug-related). All patients demonstrated significant hepatotoxicity. Survival ranged from 6 to 26 months (median 10.3 months). All patients demonstrated a tumor response (partial response 5/6, 1/6 stable disease) with a median duration of 18 weeks. In contrast to our pig program, many problems were encountered in the phase I study. By using both the hepatic artery and portal vein for IHP we encountered more toxicity than expected based on data from the pig program, resulting in fatal coagulative disturbances in one patient who received the second rhTNF alpha dose. Furthermore, local control after one IHP with TNF alpha and melphalan is only temporary.
我们报告了在一项实验性猪研究以及一项人类I期研究中，使用肿瘤坏死因子（TNF）和马法兰进行孤立肝灌注（IHP）的经验。IHP通过肝动脉和门静脉中的流入导管以及腔静脉中的流出导管进行。使用了体外静脉-静脉旁路。IHP包括60分钟的高温（>41摄氏度）灌注。在猪实验方案中，单独给予重组人TNFα50微克/千克（n = 5）或重组人TNFα50微克/千克加马法兰1毫克/千克（n = 3）。两只对照猪未添加任何药物。在I期研究中，患者接受1毫克/千克马法兰加0.4毫克重组人TNFα（n = 8）或0.8毫克重组人TNFα（n = 1）。灌注后，在恢复血管连续性之前，用右旋糖酐冲洗肝脏。除一头猪外，所有猪均在手术后存活。全身渗漏率低于0.02%。如通过肝酶测定和组织学所示，所有猪，包括对照猪，均出现短暂、轻度的肝毒性。未出现明显的血流动力学、心肺血液学或肾毒性。在I期临床研究中，一名患者出现渗漏（累积渗漏率20%）。有3例围手术期死亡（1例可能与药物相关）。所有患者均表现出明显的肝毒性。生存期为6至26个月（中位数10.3个月）。所有患者均表现出肿瘤反应（部分缓解5/6，疾病稳定1/6），中位持续时间为18周。与我们的猪实验方案不同，I期研究中遇到了许多问题。通过使用肝动脉和门静脉进行IHP，我们遇到的毒性比基于猪实验方案数据预期的更多，导致一名接受第二剂重组人TNFα的患者出现致命的凝血障碍。此外，使用TNFα和马法兰进行一次IHP后的局部控制只是暂时的。
