Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer

Abstract

To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m À2 was administered on days 1, 8 and 15, and cisplatin 80 mg m À2 was administered on day 1. In the VDS-P arm, cisplatin 80 mg m À2 was administered on day 1, and vindesine 3 mg m À2 was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m À2 was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P ¼ 0.115, CPT-P vs VDS-P; P ¼ 0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65 -1.11) for CPT-P vs VDS-P and 0.83 (0.64 -1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.

A randomised phase II trial of docetaxel vs docetaxel and irinotecan in patients with stage IIIb–IV non-small-cell lung cancer who failed first-line treatment

“…Two other single agents were recently investigated in a secondline setting in NSCLC patients. Gefitinib, an orally active EGFR tyrosine kinase inhibitor, was studied in a randomised phase II trial (Fukuoka et al, 2003). Antitumour activity, with a response rate between 18 and 19%, as well as symptom relief and improvement in quality of life was reported.…”

“…Treatment with platinum-based chemotherapy improves survival and quality of life in patients with advanced non-small-cell lung cancer (NSCLC) (Souquet et al, 1993; Non-small Cell Lung Cancer Collaborative Group, 1995; Cullen et al, 1999;Anderson et al, 2000;Ranson et al, 2000;Schiller et al, 2002). Since two trials demonstrated clinically beneficial effects of docetaxel in second-line setting (Fossella et al, 2000;Shepherd et al, 2000), docetaxel 75 mg m À2 is currently considered the standard regimen to which other experimental schedules should be compared.Irinotecan, a semisynthetic water-soluble analogue of camptothecin, has shown activity in NSCLC patients as single agent and in combination with docetaxel (Fukuoka et al, 1992; Adjei et al, 2000;Masuda et al, 2000;Satouchi et al, 2001;Negoro et al, 2003). Moreover, Irinotecan demonstrated activity as single agent in pretreated patients (Sanchez et al, 2003).…”

“…Irinotecan, a semisynthetic water-soluble analogue of camptothecin, has shown activity in NSCLC patients as single agent and in combination with docetaxel (Fukuoka et al, 1992; Adjei et al, 2000;Masuda et al, 2000;Satouchi et al, 2001;Negoro et al, 2003). Moreover, Irinotecan demonstrated activity as single agent in pretreated patients (Sanchez et al, 2003).…”

Front-line paclitaxel and irinotecan combination chemotherapy in advanced non-small-cell lung cancer: a phase I–II trial

“…The choice of irinotecan for gastrointestinal cancers is more or less empirical and use within clinical trials for other malignant tumours may show equal effectiveness. Existing data combining irinotecan with other agents such as cisplatin (Cardenal et al, 2003) show an effectiveness comparable to other established treatments in NSCLC (Negoro et al, 2003). For the present study, the second agent selected for combination treatment with irinotecan was paclitaxel, which has been tested as first-line combined treatment for advanced NSCLC (Chang et al, 1996;Greco and Hainsworth, 1997;Belani et al, 1999;Bonomi et al, 2000;Stathopoulos et al, 2004).…”

“…This biweekly (every 2 weeks) chemotherapy schedule was based on recent trials with proper dosage adjustment and a successful outcome (Cardenal et al, 2003;Negoro et al, 2003). Our objectives were to determine response rate, toxicity, and median and overall survival.…”