Kaoru Kubota1, Toyoaki Hida2, Satoshi Ishikura3, Junki Mizusawa4, Makoto Nishio5, Masaaki Kawahara6, Akira Yokoyama7, Fumio Imamura8, Koji Takeda9, Shunichi Negoro10, Masao Harada11, Hiroaki Okamoto12, Nobuyuki Yamamoto13, Tetsu Shinkai14, Hiroshi Sakai15, Kaoru Matsui16, Kazuhiko Nakagawa17, Taro Shibata4, Nagahiro Saijo18, Tomohide Tamura19. 1. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. Electronic address: kkubota@nms.ac.jp. 2. Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 3. Department of Radiation Oncology, Juntendo University Faculty of Medicine, Tokyo, Japan. 4. JCOG Data Center, National Cancer Center, Tokyo, Japan. 5. Department of Thoracic Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. 6. Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan. 7. Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. 8. Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. 9. Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan. 10. Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan. 11. Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan. 12. Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan. 13. Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi, Japan. 14. Department of Medicine and Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. 15. Department of Thoracic Oncology, Saitama Cancer Center, Ina, Japan. 16. Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan. 17. Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan. 18. Japanese Society of Medical Oncology, Toyko, Japan. 19. Division of Thoracic Oncology, National Cancer Center, Tokyo, Japan.
Abstract
BACKGROUND: 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/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on 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 [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial 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/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on 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 with ClinicalTrials.gov, number NCT00144989, 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 group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [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.
RCT Entities:
BACKGROUND: 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/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on 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 [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial 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/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on 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 with ClinicalTrials.gov, number NCT00144989, 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 group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [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.
Authors: D De Ruysscher; B Lueza; C Le Péchoux; D H Johnson; M O'Brien; N Murray; S Spiro; X Wang; M Takada; B Lebeau; W Blackstock; D Skarlos; P Baas; H Choy; A Price; L Seymour; R Arriagada; J-P Pignon Journal: Ann Oncol Date: 2016-07-19 Impact factor: 32.976