Absence of severe systemic toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-alpha and melphalan.
BACKGROUND
Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF-alpha) and melphalan, with or without interferon-gamma, have been reported in several series. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation.


METHODS
Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF-alpha (3-4 mg) and melphalan, with or without interferon-gamma, were studied. Leakage rates and TNF-alpha levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes.


RESULTS
Only two patients experienced leaks (2% and 13%) during ILP. For 18 patients without leakage, the mean peak systemic TNF-alpha level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF-alpha levels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consisted mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first day after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolving spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited significantly higher TNF-alpha levels after ILP, compared with other patients.


CONCLUSIONS
Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.
Vrouenraets
B C
BC
Department of Surgery, The Netherlands Cancer Institute (Antoni van Leeuwenhoek ziekenhuis), Amsterdam.
Kroon
B B
BB
Ogilvie
A C
AC
van Geel
A N
AN
Nieweg
O E
OE
Swaak
A J
AJ
Eggermont
A M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000633:toxicity; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D005121:Extremities / Q000098:blood supply*; D005260:Female; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007371:Interferon-gamma / Q000008:administration & dosage; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage* / Q000633:toxicity; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D013610:Tachycardia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000633:toxicity
D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan