Cisplatin in combination with irinotecan in the treatment of patients withmalignant pleural mesothelioma - A pilot phase II clinical trial and pharmacokinetic profile

BACKGROUND. The purpose of this study was to assess the efficacy and toxici ty of a combination of cisplatin and irinotecan (CPT-11) in the treatment o f patients (SN-38). METHODS, Fifteen previously untreated patients with malignant pleural mesot helioma were treated with cisplatin (60 mg/m(2) on Day 1) and CPT-11 (60 mg /m(2) on Days 1, 8, and 15) administered intravenously and followed by a 1- week rest period. The course of treatment was repeated every 28 days. After intravenous administration, the levels of CPT-11 and SN-38 in the plasma a nd pleural fluid were determined for each histologic subtype of mesotheliom a. RESULTS, All patients were evaluable for response and toxicity. Four partia l responses (response rate of 26.7%) with a median response duration of 25. 9 weeks and 2 regressions of evaluable disease (overall response rate of 40 %) were observed. The median survival time after chemotherapy was 28.3 week s, and the median time to treatment failure was 22.1 weeks. The 1-year surv ival rate for all patients was 38.5%. Toxicity was well tolerated, and ther e were no treatment-related deaths. World Health Organization Grade 3 leuko penia occurred in 3 patients (20%), and Grade 1 or 2 diarrhea occurred in 3 patients (20%). There was no excess toxicity in patients with large pleura l effusions compared with those with no pleural effusions. CPT-11 and SN-38 were detected in the pleural fluid 1 hour after intravenous administration . The maximum concentrations of CPT-11 and SN-38 in the pleural fluid were 36.5% and 75.8%, respectively, of the corresponding plasma values. CONCLUSIONS, The combination of cisplatin and CPT-11 had definite activity against malignant pleural mesothelioma and was well tolerated. The intraven ous administration of CPT-11 produced adequate distribution of CPT-11 and i ts active metabolite SN-38 into the pleural fluid and allowed a higher conc entration of the more active SN-38 to make contact with mesothelioma cells in the thoracic cavity. These results warrant further clinical evaluation o f this combination chemotherapy for the treatment of malignant pleural meso thelioma in a confirmatory Phase II trial.