Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan

Abstract

Summary Isolated limb perfusion with tumour necrosis factor alpha (TNF-a) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-a with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 ,ug kg-' TNF-ca (n = 5), (2) 50 9g kg-' TNF-a plus 1 mg kg-' melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-a levels of 5.1 ± 0.78 x 106 pg ml-(± s.e.m). Systemic leakage of TNF-a from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-a levels was observed in groups 1 and 2 with a median peak level of 23 ± 3 x 103 pg ml-' at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-a with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.Keywords: isolation; liver; perfusion; metastases; tumour necrosis factor The liver is the commonest site of dissemination in patients with colorectal cancer (Bengmark, 1969;Wagner, 1984;Strangl, 1994). Five-year survival rates of up to 35% have been reported for patients amenable for partial hepatic resection (Hughes, 1986;Scheele, 1990; Van Ooyen, 1992;Sugihara, 1993;Que, 1994). Unfortunately, the vast majority of colorectal metastases confined to the liver are considered to be unresectable (Greenway, 1988;Cady, 1991;Genari, 1992). In addition, systemic chemotherapy has so far failed to provide satisfactory results in these cases (Kemeny, 1983(Kemeny, , 1987. Therefore, it is mandatory to develop novel strategies to obtain tumour control in the liver.The concept of locoregional administration of chemotherapy is aimed at achieving high local concentrations while minimizing systemic drug levels in an attempt to reduce dose-limiting sideeffects. This might enhance anti-tumour efficacy as steep dose-response curves have been described for most chemotherapeutic agents (Frei, 1980;Canellos, 1987). Several techniques have been developed for regional therapy of hepatic malignancies, of which hepatic artery infusion (HAI) has become most widely used (Sullivan, 1964;Pentecost, 1993;De Takats, 1994 (Kemeny, ...

Isolated Hyperthermic Liver Perfusion with High Dose Tumor Necrosis Factor Alpha in Pigs: An Experimental Study in Preparation of Clinical Use

“…All changes in serum enzyme levels had returned to normal at the end of the first postoperative week. Similar results are reported by Borel Rinkes et al [21]. Furthermore, in our control group enzyme levels revealed transient increases of transaminases and also a decrease of synthetic liver function (Quick test).…”

“…Thus, in our series a significant reduction of systemic human TNF· and pTNF· levels after reperfusion as well as of severe cardiopulmonary side effects could be achieved. Similarly, Borel Rinkes et al [21] did also not observe lethal complications of serum rhTNF· levels of 17 ! 10 3 pg/ml (17 ng/ml) after isolated liver perfusion in pigs with 50 Ìg rhTNF·/ kg BW.…”

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

“…These findings might be of clinical relevance in more than one way. First, it suggests that the very high doses used presently in the clinical setting may well be reduced while retaining efficacy, but even more importantly this observation increases the chances that TNF may become applicable in other settings such as isolated hepatic perfusions (Fraker et al, 1994;Borel Rinkes et al, 1997;Alexander et al, 1998;De Vries et al, 1998). These settings are clearly less ideal, due to local toxicity, than the setting of the 'inert' limb perfusion.…”

In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

“…Different models have been developed to evaluate the efficacy of TNF-α in organ perfusion, such as in lung (Weksler et al, 1993(Weksler et al, , 1994Pogrebniak et al, 1994), and in liver (Fraker et al, 1994;Borel Rinkes et al, 1997). TNF-α in isolated lung perfusion has been shown to be safe, and in a phase I study tumour responses have been observed in patients with lung metastases (Pass et al, 1996).…”

“…Isolated singlelung perfusion with TNF-α proved to be safe (Pogrebniak et al, 1994;Weksler et al, 1994;Pass et al, 1996). Reports on the use of TNF-α in isolated liver perfusion at the National Cancer Institute in the USA (Fraker et al, 1994) as well as by our group (Borel Rinkes et al, 1997) have appeared very recently.…”