Journal of Clinical Oncology, Vol 10, 52-60, Copyright © 1992 by American Society of Clinical Oncology
High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma
D Lienard, P Ewalenko, JJ Delmotte, N Renard and FJ Lejeune
Department of Surgery, Jules Bordet Institute, Universite Libre de Bruxelles, Belgium.
PURPOSE: To determine the toxicity and the therapeutic efficacy of the
combination of the recombinant tumor necrosis factor alpha (rTNF alpha),
recombinant interferon gamma (rIFN-gamma), and melphalan, we designed a
protocol using isolation limb perfusion (ILP) with hyperthermia for
in-transit metastases of melanoma and recurrent sarcoma. The triple
combination was chosen because of the reported synergistic antitumor effect
of rTNF alpha with IFN-gamma and of rTNF alpha with alkylating agents.
PATIENTS AND METHODS: Twenty-three patients received a total of 25 ILPs
with the triple combination. There were 19 females and four males with
either multiple progressive in- transit melanoma metastases of the
extremities (stage IIIa or IIIab; 19 patients) or recurrent soft tissue
sarcoma (five). The rTNF alpha was injected as a bolus in the arterial
line, and total dose ranged between 2 and 4 mg, under hyperthermic
conditions (40 degrees C to 40.5 degrees C) for 90 minutes. The rIFN-gamma
was given subcutaneously (SC) on days -2 and -1 and in the perfusate, with
rTNF alpha at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome
Co, London, England) was administered in the perfusate at 40 micrograms/mL.
RESULTS: Toxicity observed during three ILPs in a pilot study with rTNF
alpha included only two severe toxicities: one severe hypotension with
tachycardia and transient oliguria and one moderate hypotension for 4 hours
followed by severe kidney failure with complete recovery on day 29. In all
18 ILPs performed in the triple combination protocol, the patients received
continuous infusion dopamine at 3 micrograms/kg/min from the start of ILP
and for 72 hours and showed only mild hypotension and transient chills and
temperature. Regional toxicity attributable to rTNF alpha was minimal.
There have been 11 cases with hematologic toxicity consisting of
neutropenia (one grade 4 and one grade 3) and neutropenia with
thrombocytopenia (one grade 4 and three grade 2). Twelve patients had been
previously treated with melphalan in ILP (11) or with cisplatin (one). The
23 patients are assessable: there have been 21 complete responses (CRs;
range, 4 to 29 months; 89%), two partial responses (PRs; range, 2 to 3
months), and no failures. Overall disease- free survival and survival have
been 70% and 76%, respectively, at 12 months. In all cases, softening of
the nodules was obvious within 3 days after ILP and time to definite
response ranged between day 5 and 30. CONCLUSION: This preliminary analysis
of a phase II study suggests that high-dose rTNF alpha can be administered
with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor
responses can be evidenced in melanoma and sarcoma. Furthermore,
combination of rTNF alpha, rIFN-gamma, and melphalan seems to achieve high
efficacy with minimal toxicity, even after failure of prior therapy with
melphalan alone.
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