CYTOKINE LEVELS AND SYSTEMIC TOXICITY IN PATIENTS UNDERGOING ISOLATED LIMB PERFUSION WITH HIGH-DOSE TUMOR-NECROSIS-FACTOR, INTERFERON-GAMMA, AND MELPHALAN

Purpose: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma. We have evaluated the relationship of systemic TNF exposure to induction of several secondary mediators and incidence of systemic toxicity. Patients and Methods: Nineteen patients with extremity melanoma (n = 16) or sarcoma (n = 3), underwent 90-minute ILP with TNF-alpha, interferon gamma (0.2 mg), and M (10 to 13 mg/L of limb volume) (TNF/IFN/M) (n = 12), or M alone (n = 7). Continuous intraoperative monitoring (CIM) for systemic leak from the perfusion circuit was performed using radioactive iodine-131 albumin. Cytokine levels in the perfusate and systemic circulation during and after ILP were measured by enzyme linked immunosorbent assay. Results: Systemic leaks greater than or equal to 1% from the perfusion circuit occurred in six patients who received TNF/IFN/M and in four who received M alone. Hypotension that required vasopressor support occurred in six of six patients with evidence of a leak(greater than or equal to 1%) and zero of six patients without a leak (< 1%). These six patients had significantly higher peak systemic TNF levels during and after perfusion than patients without a leak (2.8 and 8.2 ng/ mg v 0.7 and 2.0 ng/mL, respectively; P < .05). All patients who received TNF/IFN/M had significantly greater increases in systemic interleukin-6 (IL-6) levels than in patients with M alone (12,395 +/- 10,374 pg/mL v 79.4 +/- 7.2 pg/mL, respectively; P < .001), Intracellular adhesion molecule (ICAM), IL-8, and TNF-R levels were also increased after ILP with TNF/IFN/M. Conclusion: ILP with TNF/IFN/M can be safely performed, as I-131 albumin provides a sensitive measure of systemic leakage from the perfusion circuit. Patients with a measured leak of greater than or equal to 1% develop mild and transient postoperative hypotension with significantly higher systemic TNF levels and lower perfusate TNF levels than in patients without leaks, (C) 1995 by American Society of Clinical Oncology,