Isolated hepatic perfusion for lapine liver metastases: Impact of hyperthermia on permeability of tumor neovasculature

Background. Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHF: the contribution of perfusion hyperthermia is unknown. Purpose. A large animal model of unresectable liver metastases and a techni cal standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. Methods. Sixty-five New Zealand White rabbits were used in a series of expe riments. Disseminated liver tumors were established by direct injection of 1 x 10(6) VX-2 cells into the portal vein by laparotomy, in anesthetized an imals. Several surgical perfusion techniques were explored to determine a r eliable and reproducible IHP model. Vascular permeability in tumor versus l iver was then assessed with Evan's Blue labeled bovine albumin under normot hermic (tissue temperature 36.5 degrees C +/- 0.5 degrees C), moderate hype rthermic (39 degrees C +/- 0.5 degrees C), or severe hyperthermic (41 degre es C +/- 0.5 degrees C) conditions. Results. Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segmen t of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular pe rmeability tons higher in tumor than in normal tissues (P = .03) at all tim e points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in. permeability of neovasculature; when severe hyperthermia was u sed, tumor vascular permeability was increased even more than normal liver permeability (P = .01). Conclusions, The VX-2/New Zealand White rabbit system can be used as a repr oducible large-animal model for IHP of unresectable liver metastases. It ca n be used to characterize the contribution and mechanism of action of diffe rent treatment parameters used in IHP. Hyperthermia preferentially increase s vascular permeability in tumors compared with liver tissue in a dose-depe ndent fashion, thus providing a mechanism for its presumed benefit during i solated organ perfusion.