HPB O03 Preclinical safety and feasibility of in situ Isolated Normothermic Liver Chemoperfusion (INLiC) for enhanced drug delivery

Abstract

Abstract Background Up to 85% of patients with liver metastases have inoperable disease. Isolated liver chemoperfusion involves vascular isolation of the liver with regional delivery of chemotherapy, and aims to maximise the therapeutic response and limit extra-hepatic toxicity. Historically, the morbidity associated with drug leak from the liver circuit has limited its success. To improve the safety of this approach, we developed a surgical protocol for Isolated Normothermic Liver Chemoperfusion (INLiC) and assessed its short-term safety, and feasibility for enhancing drug delivery. Methods Laparotomy and complete, vascular isolation of the liver was performed on (n=9) 55–65 Kg pigs. The gastroduodenal artery, portal vein and inferior vena cava (IVC) were cannulated and normothermic machine perfusion of the liver established in situ. Systemic circulation was maintained with veno-venous bypass. High-dose, intra-arterial doxorubicin was delivered to the isolated liver, circulated for 1 hour and vascular reconnection performed. Biochemical and physiological parameters were assessed and doxorubicin quantified in blood, bile and tissue by high performance liquid chromatography. Results A standardised, surgical protocol was developed to enable INLiC. Physiological median liver outflows (1.1 L/min (0.9–1.1)), pH (7.35 (7.26–7.42)), lactate concentration (1.1 mM (0.33–2.3)) and an acceptable peak AST (805 U/L (308–1667)) were achieved. Population two-compartmental analysis of plasma doxorubicin decay demonstrated a distribution half-life of 1.3 minutes and a Cmax 8-times higher than tolerable by systemic delivery, due to cardiotoxicity. The resulting hepatic tissue concentration of doxorubicin was significantly higher than could be safely achieved with systemic delivery (p=0.019). Notably, there was no extra-hepatic leak of doxorubicin and it did not accumulate in cardiac or renal tissue. Conclusions INLiC is feasible, safe and enables high-dose drug delivery to the liver without extra-hepatic tissue accumulation.