A pilot study of melphalan, tumor necrosis factor-α and 41.8 °C whole- body hyperthermia

H. I. Robins, D. M. Katschinski, W. Longo, E. Grosen, G. Wilding, W. Gillis, C. Kraemer, C. L. Tiggelaar, D. Rushing, J. A. Stewart, D. Spriggs, R. Love, R. Z. Arzoomanian, C. Feierabend, D. Alberti, K. Morgan, K. Simon, F. D'Oleire

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12 Scopus citations

Abstract

Purpose: To evaluate the feasibility of sequencing (based on preclinical modeling) tumor necrosis factor-α (TNF) at two dose levels with melphalan (L-PAM) and 41.8 °C whole-body hyperthermia (WBH) for 60 min. Patients and methods: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 μg/m2) and six patients were treated at TNF dose level II (100 μg/m2). 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/m2 based on a previous phase I WBH/L-PAM trial. WBH was administered 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 were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with ≤25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). Conclusion: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

Original languageEnglish (US)
Pages (from-to)409-414
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume43
Issue number5
DOIs
StatePublished - Mar 18 1999

Keywords

  • Melanoma
  • Melphalan
  • Tumor necrosis factor
  • Whole body hyperthermia

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Robins, H. I., Katschinski, D. M., Longo, W., Grosen, E., Wilding, G., Gillis, W., Kraemer, C., Tiggelaar, C. L., Rushing, D., Stewart, J. A., Spriggs, D., Love, R., Arzoomanian, R. Z., Feierabend, C., Alberti, D., Morgan, K., Simon, K., & D'Oleire, F. (1999). A pilot study of melphalan, tumor necrosis factor-α and 41.8 °C whole- body hyperthermia. Cancer Chemotherapy and Pharmacology, 43(5), 409-414. https://doi.org/10.1007/s002800050915