Purpose: To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8°C whole-body hyperthermia (WBH) for 60 minutes. Patients and Methods: Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1; thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n=6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY). Results: Comparisons of mean WBC count and platelet nadirs far L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no in stances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail. Conclusion: We conclude that L-PAM with 41.8°C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.
ASJC Scopus subject areas
- Cancer Research