IFOSFAMIDE AND CARBOPLATIN COMBINED WITH 41.8-DEGREES-C WHOLE-BODY HYPERTHERMIA IN PATIENTS WITH REFRACTORY SARCOMA AND MALIGNANT TERATOMA

The purpose of this study was to evaluate the pharmacokinetics, biolog ical interactions, and toxicities of ifosfamide and carboplatin combin ed with 41.8 degrees C whole-body hyperthermia (WBH) for 1 h in a pilo t clinical study. Nineteen patients with refractory sarcoma or maligna nt teratoma were treated. To obtain baseline pharmacokinetic data for ifosfamide, the first chemotherapy course was given without WBH in six patients. This enabled comparison of systemic toxicity and pharmacoki netics of the drug combination with and without WBH (+/- WBH). Ah othe r patients received three thermochemotherapy treatments every 3 weeks. Ifosfamide was escalated from 5 to 10 g/m(2) with a fixed carboplatin dose of 480 mg/m(2) WBH was induced by extracorporally heated blood ( in a hemodialysis apparatus) with general anesthesia. The drugs were g iven at target temperature. A total of 49 thermochemotherapy treatment s was administered. The use of the hemodialysis device resulted in an approximate one-third reduction of blood concentrations of 4-hydroxyif osfamide, one activated intermediate metabolite of ifosfamide and carb oplatin, but in an increase of chloroacetaldehyde, the other main ifos famide metabolite. The WBC counts and the platelet nadirs (up to WBH g rade 4) were not significantly different +/- WBH. Of 19 evaluable pati ents, 7 partial remissions, 8 disease stabilizations (average duration , 3 months), and 4 patients with progressive disease were observed. Th ere was no WBH-related mortality. Toxicities observed included mild (a nasarca, diarrhea, pressure sores, and perioral herpes simplex) and se vere (reversible neuropathy, cardiopulmonary distress, and severe rena l dysfunction). No hepatic or central nervous system toxicity occurred . Nephropathy was the dose-limiting toxicity. In conclusion, ifosfamid e and carboplatin can be administered with extracorporally induced WBH with acceptable toxicity. Results obtained are consistent with contin ued evaluation of this combined modality approach.