Oldhafer K J, Frerker M K, Lang H, Fauler J, Flemming P, Schmoll E, Nadalin S, Moreno L, Pichlmayr R
Department of Abdominal and Transplantation Surgery, Hannover Medical School, Germany.
J Invest Surg. 1998 Nov-Dec;11(6):393-400. doi: 10.3109/08941939809032216.
In order to reduce systemic side effects and increase intrahepatic mitomycin C (MMC) concentrations, isolated hyperthermic liver perfusion (IHLP) has been performed using MMC. This article describes the pharmacokinetics of MMC in IHLP and presents our clinical experience with its use in six patients suffering from unresectable liver metastases. Primary tumors consisted of colorectal carcinomas in three cases, breast cancer in two, and a choroidal melanoma in one. Dosages of MMC varied between 0.5 and 1.0 mg MMC/kg body weight. MMC was added as a bolus directly into the extracorporeal circuit. Intrahepatic temperature was elevated to 40.0-41.0 degrees C by hyperthermic perfusion. MMC concentrations were measured in peripheral blood (preperfusion, then at 5, 30, and 55 min during perfusion, and finally at 5 and 60 min and 6 and 24 h after perfusion) and in recirculating perfusate (5, 30, and 55 min). While markedly elevated MMC concentrations (maximum 6290 ng/mL) were found in the liver perfusate, systemic concentrations remained low (maximum 45 ng/mL), indicating no considerable leakage. MMC concentrations in the perfusate constantly decreased during perfusion. After rinsing with 1500 mL saline, a mean concentration of 52.5+/-33 ng MMC/mL was measured in the washout from 5 patients. In 1 patient with a colorectal carcinoma, MMC concentrations in the perfusion medium were 10-fold and in the plasma 2-fold higher than in the other patients. This high MMC concentration caused severe intrahepatic vascular damage and finally led to the patient's death. In conclusion, IHLP and intrahepatic perfusion with MMC resulted in a high response of hepatic tumors. Systemic exposure of MMC can be reduced effectively by isolated perfusion. However, hepatic toxicity of MMC must be considered.
为了减少全身副作用并提高肝内丝裂霉素C（MMC）浓度，已使用MMC进行了离体热灌注肝灌注（IHLP）。本文描述了MMC在IHLP中的药代动力学，并介绍了我们在6例不可切除肝转移患者中使用它的临床经验。原发性肿瘤包括3例结直肠癌、2例乳腺癌和1例脉络膜黑色素瘤。MMC的剂量在0.5至1.0mg MMC/千克体重之间变化。MMC作为大剂量直接添加到体外循环中。通过热灌注将肝内温度升高至40.0-41.0摄氏度。在灌注前、灌注期间的5、30和55分钟以及灌注后5和60分钟以及6和24小时的外周血中以及再循环灌注液（5、30和55分钟）中测量MMC浓度。虽然在肝灌注液中发现MMC浓度显著升高（最高6290ng/mL），但全身浓度仍然很低（最高45ng/mL），表明没有明显渗漏。灌注期间灌注液中的MMC浓度持续下降。用1500mL生理盐水冲洗后，在5例患者的冲洗液中测得MMC的平均浓度为52.5±33ng/mL。在1例结直肠癌患者中，灌注介质中的MMC浓度比其他患者高10倍，血浆中高2倍。这种高MMC浓度导致严重的肝内血管损伤，最终导致患者死亡。总之，IHLP和MMC肝内灌注导致肝肿瘤有较高反应。通过离体灌注可有效降低MMC的全身暴露。然而，必须考虑MMC的肝毒性。
