Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques - A pharmacokineticstudy in pigs

Objective To validate the methodology of isolated hypoxic hepatic perfusion (IHHP) us ing balloon catheter techniques and to gain insight into the distribution o f tumor necrosis factor-alpha (TNF), melphalan, and mitomycin C (MMC) throu gh the regional and systemic blood compartments when applying these techniq ues. Summary Background Data There is no standard treatment for unresectable liver tumors. Clinical resu lts of isolated limb perfusion with high-dose TNF and melphalan for the tre atment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting. T he magnitude and toxicity of the surgical procedure, however, have limited clinical applicability. Methods Rigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intraveno usly. After a 20-minute per fusion, a washout procedure was performed for 1 0 minutes, after which isolation was terminated. Throughout the procedure a nd afterward, blood samples were obtained from the hepatic and systemic blo od compartments and concentrations of perfused agents were determined. Results During perfusion, locoregional plasma drug concentrations were 20- to 40-fo ld higher than systemic concentrations. Compared with systemic concentratio ns after intravenous administration, regional concentrations during IHHP we re up to 10-fold higher. Regional MMC and melphalan levels steadily decline d during perfusion, indicating rapid uptake by the liver tissue; minimal sy stemic concentrations indicated virtually no leakage to the systemic blood compartment. During isolation, concentrations of TNF in the perfusate decli ned only slightly, indicating limited uptake by the liver tissue; no leakag e of TNF to the systemic circulation was observed. After termination of iso lation, systemic TNF levels showed only a minor transient elevation, indica ting that the washout procedure at the end of the perfusions was fully effe ctive. Conclusions Complete isolation of the hepatic vascular bed can be accomplished when per forming IHHP using this balloon catheter technique. Thus, as in extremities , an ideal leakage-free perfusion of the liver can now be performed, and re peated, without major surgery. The effective washout allows the addition of TNF in this setting.