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Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a.

PURPOSE
To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM).


PATIENTS AND METHODS
Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression.


RESULTS
Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively).


CONCLUSION
The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.