title: Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.
  
  
  BACKGROUND
  National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. Electronic address: kkubota@nms.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Department of Radiation Oncology, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishikura
authors.affiliation: JCOG Data Center, National Cancer Center, Tokyo, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Mizusawa
authors.affiliation: Department of Thoracic Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kawahara
authors.affiliation: Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yokoyama
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
authors.affiliation: Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Negoro
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Medicine and Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Shinkai
authors.affiliation: Department of Thoracic Oncology, Saitama Cancer Center, Ina, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: JCOG Data Center, National Cancer Center, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Japanese Society of Medical Oncology, Toyko, Japan.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.affiliation: Division of Thoracic Oncology, National Cancer Center, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D018288:Carcinoma, Small Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D019583:Dose Fractionation, Radiation; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging
chemical_list: D005047:Etoposide; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin