Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

Hyperthermia and mafosfamide in a human-derived malignant pleural mesothelioma cell line.

PURPOSE: Diffuse malignant pleural mesothelioma is the most common primary pleural malignancy. At the beginning of the last century, this tumor was of minor incidence. Meanwhile, the use of asbestos has led to and is still leading to a rise in pleural mesothelioma incidence. There is no standard therapy for this highly aggressive disease and the development of new therapeutic strategies is imperative. METHODS: We, therefore, investigated the morphological and pharmakokinetic effects of a combined thermochemotherapy consisting of the administration of different dosages of mafosfamide with and without the application of a 1-h hyperthermia at 41.7 degrees C on the human biphasic malignant pleural mesothelioma cell line MSTO-211H. After therapy, cells were prepared for light and electron microscopy. BrdU-incorporation for the S-phase fraction, TUNEL-labeling for detection of apoptosis, and quantitative assessments using the MTT assay were performed. RESULTS: Our results demonstrate that the combination of mafosfamide with hyperthermia leads to qualitatively and quantitatively enhanced cellular damage compared to monotherapy. During combined thermochemotherapy, cell damage and death is already induced at lower mafosfamide concentrations than without hyperthermia which suggests an additive effect from hyperthermia to the action of the alkylating drug mafosfamide. Cell death thereby mostly occurs as necrotic cell death rather than as apoptosis, although in a combined thermochemotherapy apoptosis is induced temperature-dependently, when comparing temperatures from 37 degrees C to 43 degrees C. CONCLUSIONS: We suggest that the effect of substances such as ifosfamide and cyclophosfamide which are in clinical use, might be enhanced by the combination of local or regional hyperthermia in order to improve the therapeutical index of these substances in the treatment of pleural mesothelioma.