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Abstract
Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC.
Methods
We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m2on days 1-3; intravenous cisplatin 80 mg/m2on day 1) plus AHTRT (1·5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0vs1], response to induction chemoradiotherapy [complete response plus near complete responsevspartial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m2on days 1, 8, 15; intravenous cisplatin 60 mg/m2on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered withClinicalTrials.gov, numberNCT00144989, and the UMIN Clinical Trials Registry, number C000000095.
Findings
281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3·2 years (95% CI 2·4-4·1). In the irinotecan and cisplatin group, median overall survival was 2·8 years (95% CI 2·4-3·6); overall survival did not differ between the two groups (hazard ratio 1·09 [95% CI 0·80-1·46], one-sided stratified log-rank p=0·70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin groupvs101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%]vs50 [39%]), thrombocytopenia (26 [21%]vssix [5%]), febrile neutropenia (21 [17%]vs18 [14%]), and diarrhoea (two [2%]vs13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group).
Interpretation
Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.
Funding
National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.