Hyperthermic isolated limb perfusion with tumor necrosis factor alone for melanoma.

PURPOSE: Recent reports indicate that hyperthermic isolated limb perfusion using tumor necrosis factor, interferon gamma and melphalan is associated with response rates of greater than 90% in patients with in-transit metastatic melanoma. We evaluated the toxicity and efficacy of tumor necrosis factor alone administered during hyperthermic isolated limb perfusion. PATIENTS AND METHODS: Six patients were perfused at 39.7 degrees to 40 degrees C for 60 to 90 minutes with tumor necrosis factor: three patients at a total dose of 1 mg, 2 mg, and 3 mg, respectively, and three patients at a total dose of 4 mg. Systemic leak was monitored using iodine 131-labelled albumin injected into the perfusate. Tumor necrosis factor levels were measured by enzyme-linked immunoabsorbent assay in plasma samples obtained from the hyperthermic isolated limb perfusion circuit and systemic circulation. RESULTS: Peak perfusate tumor necrosis factor levels, available in five of six patients, ranged between 2000 and 8500 ng/mL (mean, 4200 +/- 2104 ng/mL). Peak systemic tumor necrosis factor levels in three patients without evidence of systemic leak ranged between 0.02 and 0.7 ng/mL (mean, 0.22 +/- 0.24 ng/mL). The first two patients with mean systemic tumor necrosis factor levels of 35.6 +/- 14.5 ng/mL exhibited moderate to severe hypotension with transient renal insufficiency. Only fever and chills were noted in patients where systemic leakwas negligible. Partial response of less than 1 month's duration was seen in two patients and no response was noted in three. One patient had a complete response of 7 months' duration and then progressed. Three patients have been reperfused with triple drug hyperthermic isolated limb perfusion (two complete responses and one partial response). CONCLUSIONS: In light of the impressive results of triple drug hyperthermic isolated limb perfusion, it appears that hyperthermic isolated limb perfusion with tumor necrosis factor alone has inadequate activity to warrant further investigation. The relative contribution of tumor necrosis factor and interferon gamma to melphalan requires further study.

Treatment of hepatic-metastatic colorectal cancer with a chemotherapeutic emulsion: interim results of a phase I trial.

BACKGROUND: Hepatic arterial infusion of 5-fluoro-2-deoxyuridine (FUdR) is associated with a 60% response rate among previously untreated patients who have hepatic-metastatic colorectal cancer. One obstacle to further dose escalation has been concomitant hepatic toxicity. We are evaluating a FUdR-containing chemotherapeutic emulsion to further dose intensify therapy without associated toxicity. METHODS: The in vitro pharmacokinetics of the emulsion were determined using high-pressure liquid chromatography (HPLC). The rate at which FUdR is released from emulsion into an overlying aqueous phase was determined in static and dynamic assays. Fifteen patients with hepatic-metastatic colorectal cancer were treated with intrahepatic arterial infusions of emulsion on a phase I dose-escalating clinical protocol. Serum collection determined systemic drug levels using HPLC. RESULTS: In vitro studies demonstrate that FUdR is slowly released from emulsion into overlying aqueous medium. The emulsion serves as a depot for FUdR. Therapy was well tolerated. Emulsion was sequestered in the liver after infusion in all treated patients. CONCLUSIONS: This Ethiodol-based, oil-in-water emulsion serves as a sustained-release preparation of FUdR. An Ethiodol-based oil-in-water emulsion is a clinically effective vehicle for delivering FUdR to hepatic-metastatic colorectal tumors.