A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees Cwhole-body hyperthermia

Purpose: To evaluate the feasibility of sequencing (based on preclinical mo deling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L- PAM) and 41.8 degrees C whole-body hyperthermia (WBH) for 60 min. Patients and methods: Nine patients with refractorv cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatme nt courses. Three patients were treated at TNF dose level I (50 mu g/m(2)) and six patients were treated at TNF dose level II (100 mu g/m(2)). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH: L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m(2); based on a previous phase I WBH/L-PAM trial. WBH was adm inistered with an Aquatherm radiant heat device. Results: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments w ere associated with grade 3 toxicity, and 45% with grade 4 toxicity, and re garding white blood cell count, 50% of treatments were associated with grad e 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed w as equivalent to that seen in our earlier phase I study of WBH and L-PAM (w ithout TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diar rhea, fevers, and headache. There were no instances of hypotension. There w as no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments. these incl uded nausea, vomiting. and herpes simplex I. Responses included two complet e remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF do se level I). Conclusion: We conclude that the combination of TNF, L-PAM, an d WBH is well tolerated at the dose levels studied. The clinical results ju stify further clinical investigation for this trimodality treatment approac h.