Hyperthermic isolated limb perfusion with tumor necrosis factor alone for melanoma

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.

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.

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).

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.