Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan

Abstract

Background. Utilization of alpha‐tumor necrosis factor (α‐TNF) in clinical practice is limited by severe general side effects. Very promising results with low toxicity were reported with administration of α‐TNF by isolation perfusion in extracorporeal circulation. Methods. From December 1991 to November 1992, 14 patients underwent perfusion with α‐TNF (2–4 mg, total dose), gamma‐interferon (1.5 × 106 IU), and melphalan (10 mg/1/perfused limb). Twelve patients presented intransit metastases of the limbs, one patient, a clear cell sarcoma of the hand, and one patient, a wide spindle cell carcinoma of the thigh. Perfusion lasted 90 minutes and was conducted in mild hyperthermia (38–40.5°C, muscle temperature). Results. Nine complete regressions and four stable diseases were recorded. In one case, a reliable evaluation of response was not possible for diffused tissue necrosis. Five patients relapsed or progressed locally from 3 to 4 months after surgery, five presented distant localizations from 2 to 7 months after surgery, and one died of disease 6 months after perfusion. Twelve patients are alive, seven without evidence of disease. A septic‐like shock syndrome was observed in all patients and required administration of dopamine, dobutamine, or noradrenaline. One patient died 30 days after perfusion from a multiorgan‐failure syndrome, likely due to α‐TNF. The follow‐up time ranges from 4 to 15 months (median, 6). Conclusions. The preliminary, impressive results reported in other series were not completely confirmed in this study adopting the same treatment scheme. Further clinical experience and biologic data are needed to state the real efficacy of the approach and to reduce the severe general toxicity consistently associated with this type of treatment.

Absence of Severe Systemic Toxicity After Leakage-Controlled Isolated Limb Perfusion With Tumor Necrosis Factor-α and Melphalan

“…5,25,26 These changes were mainly characterized by acute circulatory failure mimicking septic shock (best called Systemic Inflammatory Response Syndrome 27 ), which was associated with disturbances of gas exchanges, decreases in blood cell counts, and abnormal liver function test results. 5,25,26,28 This condition required aggressive supportive therapy, including fluid resuscitation, administration of vasopressors and inotropic agents immediately after TNF-␣ administration, and respiratory assistance. 25,28,29 Major preventive measures needed to be taken in those series to diminish severe complications.…”

“…25,28,29 Major preventive measures needed to be taken in those series to diminish severe complications. 25,26,30 A pulmonary (Swan-Ganz) catheter was installed before the procedure, and dopamine infusion (3 mg/kg/minute) was started just before the administration of TNF-␣. 25,26 The pulmonary side effects consisted of alterations in the delivery and uptake of oxygen, with reduced oxygen extraction, for 24 to 48 hours.…”

“…25,26,30 A pulmonary (Swan-Ganz) catheter was installed before the procedure, and dopamine infusion (3 mg/kg/minute) was started just before the administration of TNF-␣. 25,26 The pulmonary side effects consisted of alterations in the delivery and uptake of oxygen, with reduced oxygen extraction, for 24 to 48 hours. 28,29 Lung infiltrates were frequently seen in x-rays, but adult respiratory distress syndrome was usually not detected.…”

“…8,9,25 However, some perfusion centers were forced to lower the dose of TNF-␣ considerably to diminish severe systemic side effects, 33 probably because of uncontrollable leakage resulting in systemic peak TNF-␣ levels of up to 560 ng/ml. 26 With respect to the method of detecting leakage, continuous isotope monitoring is strongly advocated, in preference to interval systemic blood sample control; the former allows flow rates to be directly adjusted according to systemic leakage. 14,34 Obviously, complete surgical isolation should be pursued by ligating all collateral vessels and applying a tourniquet around the base of the limb.…”

Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

“…The efficacy of the application of TNF in combination with cytostatic agents in ILP for the treatment of patients with in-transit melanoma metastases or locally advanced soft tissue sarcomas has now been well established. [1][2][3] This treatment can be used as a limb-sparing neoadjuvant therapy when it is followed by local excision of residual tumor. TNF became a registered cancer drug in Europe on the basis of results obtained in multicenter studies in which clinical response rates of 75% and limb salvage rates of 71% were observed in 196 patients who had been classified as having unresectable tumors that could have been managed only by amputation.…”