Isolated Perfusion of TNF-alpha Can Save Limbs

April 1, 1996

PARIS--Perfusion of an isolated limb with tumor necrosis factor (TNF)- alpha and melphalan (Alkeran) can avoid amputation in more than 80% of patients with nonresectable soft tissue sarcomas of the extremities, Alexander Eggermont, MD, PhD, reported at the Sixth International Congress on Anti-Cancer Treatment (ICACT).

PARIS--Perfusion of an isolated limb with tumor necrosis factor(TNF)- alpha and melphalan (Alkeran) can avoid amputation in morethan 80% of patients with nonresectable soft tissue sarcomas ofthe extremities, Alexander Eggermont, MD, PhD, reported at theSixth International Congress on Anti-Cancer Treatment (ICACT).

TNF-alpha may work by stimulating the immune system, but its maintarget is the endothelial cells of tumor vessels. "TNF-alphahas been used in patients with sarcoma and melanoma, but any tumorwith a decent vascular bed should respond," said Dr. Eggermont,of the Daniel den Hoed Cancer Clinic, Rotterdam.

Extremely High Doses

He explained that, by connecting the main vein and artery of thelimb to a heart-lung machine and applying a tourniquet, the limbcan be exposed to extremely high doses of the two agents--dosesthat would be toxic if given systemically.

"With this type of delivery system, you can deliver to thetumor drug concentrations that are 20- to 50-fold the concentrationsreached when the two drugs are administered intravenously,"Dr. Egger-mont said. "This is true dose intensification,"he added.

Dr. Eggermont stressed that, realistically speaking, the goalof the procedure is to preserve the limb rather than prolong survival,since most of these patients have grade III sarcomas, a quarterhave multiple tumors, and more than a quarter have systemic metastasesat the time of limb perfusion.

The 125 patients in this multicenter European trial received TNF-alpha,3 mg (for lesions in the arm) or 4 mg (for lesions in the leg),for 90 minutes at a temperature of 38° to 39°C, with10 to 13 mg/L of mel-phalan added for the last 60 minutes of theinfusion.

Although the first 55 patients had been primed with subcutaneousinterferon-gamma, the investigators have since dispensed withthis pretreatment regimen.

Isolated limb perfusion yielded a histopathologically confirmedcomplete response rate of nearly 30% and a partial response rateof 50%, resulting in an overall limb salvage rate of 81%, Dr.Eggermont reported.

"No matter how many previous treatments patients may havereceived, they are still likely to respond very well to the TNF-alpha/melphalancombination," he said.

Local recurrences were documented in only 6% of patients withone tumor who were able to undergo resection after isolated limbperfusion, in 18% of patients with one tumor who did not undergosubsequent resection, and in 46% of patients with multiple tumors.

Severe regional toxicity occurred in 7% of patients, and grade3 to 4 systemic toxicity was likewise rare, he said.

Dr. Eggermont believes that systemic toxicity was overestimatedin early studies of isolated limb perfusion with TNF-alpha becauseleakage had not been adequately monitored and controlled.

He pointed out that by putting radiolabeled erythrocytes or albumininto the circuit and continuously monitoring gamma counts abovethe heart, more than 80% of procedures can be carried out withoutleakage.

TNF-alpha has a selective destructive effect on the vasculatureof the tumor, Dr. Eggermont said. Often, he added, large softtissue sarcomas in the extremities are hypervascular. The tumor-associatedvessels are destroyed by an isolated limb perfusion with the combinationof TNF-alpha and melphalan (see figures ).

Dr. Eggermont underscored the need to use TNF-alpha and melphalanin combination. He cited animal studies showing no inhibitionof tumor growth after isolated limb perfusion with TNF-alpha alone,and only a short period of stable disease after isolated limbperfusion with melphalan alone. The combination regimen, however,resulted in complete remissions in 75% of the rats.