Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile.
BACKGROUND
The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma and to characterize the pharmacokinetic profiles of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38).


METHODS
Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 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 and pleural fluid were determined for each histologic subtype of mesothelioma.


RESULTS
All patients were evaluable for response and toxicity. Four partial 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 weeks, and the median time to treatment failure was 22.1 weeks. The 1-year survival rate for all patients was 38.5%. Toxicity was well tolerated, and there were no treatment-related deaths. World Health Organization Grade 3 leukopenia 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 pleural 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 intravenous administration of CPT-11 produced adequate distribution of CPT-11 and its active metabolite SN-38 into the pleural fluid and allowed a higher concentration of the more active SN-38 to make contact with mesothelioma cells in the thoracic cavity. These results warrant further clinical evaluation of this combination chemotherapy for the treatment of malignant pleural mesothelioma in a confirmatory Phase II trial.
Nakano
T
T
Third Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
Chahinian
A P
AP
Shinjo
M
M
Togawa
N
N
Tonomura
A
A
Miyake
M
M
Ninomiya
K
K
Yamamoto
T
T
Higashino
K
K
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010865:Pilot Projects; D010995:Pleural Diseases / Q000188:drug therapy* / Q000378:metabolism
D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin