High serum levels of TNF-alpha after its administration for isolation perfusion of the limb.
In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by isolation perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) (4 mg). Bioactive TNF-alpha and interleukin 6 (IL-6) serum levels were measured serially. In the limb, TNF-alpha rapidly reached a plateau at 2 mu/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-alpha rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-alpha infusion in ILP results in extremely high levels of bioactive TNF-alpha in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.
Gérain
J
J
Service de Médecine Interne et Laboratoire d'Investigation, Institut Jules Bordet, Université Libre de Bruxelles, Belgium.
Liénard
D
D
Ewalenko
P
P
Lejeune
F J
FJ
D010478:Chemotherapy, Cancer, Regional Perfusion; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D007866:Leg; D008545:Melanoma / Q000097:blood / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*
D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha