Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs.
OBJECTIVE
To validate the methodology of isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques and to gain insight into the distribution of tumor necrosis factor-alpha (TNF), melphalan, and mitomycin C (MMC) through the regional and systemic blood compartments when applying these techniques.


BACKGROUND
There is no standard treatment for unresectable liver tumors. Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting. The magnitude and toxicity of the surgical procedure, however, have limited clinical applicability.


METHODS
Pigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously. After a 20-minute perfusion, a washout procedure was performed for 10 minutes, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the hepatic and systemic blood compartments and concentrations of perfused agents were determined.


RESULTS
During perfusion, locoregional plasma drug concentrations were 20- to 40-fold higher than systemic concentrations. Compared with systemic concentrations after intravenous administration, regional concentrations during IHHP were up to 10-fold higher. Regional MMC and melphalan levels steadily declined during perfusion, indicating rapid uptake by the liver tissue; minimal systemic concentrations indicated virtually no leakage to the systemic blood compartment. During isolation, concentrations of TNF in the perfusate declined only slightly, indicating limited uptake by the liver tissue; no leakage of TNF to the systemic circulation was observed. After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective.


CONCLUSIONS
Complete isolation of the hepatic vascular bed can be accomplished when performing IHHP using this balloon catheter technique. Thus, as in extremities, an ideal leakage-free perfusion of the liver can now be performed, and repeated, without major surgery. The effective washout allows the addition of TNF in this setting.
van Ijken
M G
MG
Department of Surgical Oncology, University Hospital Rotterdam-Daniël den Hoed Cancer Center, Rotterdam, The Netherlands.
de Bruijn
E A
EA
de Boeck
G
G
ten Hagen
T L
TL
van der Sijp
J R
JR
Eggermont
A M
AM
D000818:Animals; D002404:Catheterization / Q000379:methods*; D015687:Cell Hypoxia; D010478:Chemotherapy, Cancer, Regional Perfusion; D005240:Feasibility Studies; D008099:Liver / Q000378:metabolism*; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013552:Swine; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics*
D014409:Tumor Necrosis Factor-alpha; D016685:Mitomycin; D008558:Melphalan