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. SUMMARY BACKGROUND DATA: 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