title: Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study).
abstract: BACKGROUND
  Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer.
  
  
  METHODS
  Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258.
  
  
  RESULTS
  All randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group.
  
  
  CONCLUSIONS
  Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer.
  
  
  BACKGROUND
  Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.
authors: Department of Clinical Oncology, Aichi Cancer Centre Hospital, Chikusa-ku, Nagoya, Japan. kmuro@aichi-cc.jp
authors: Kei
authors: K
authors: Muro
authors: Narikazu
authors: N
authors: Boku
authors: Yasuhiro
authors: Y
authors: Shimada
authors: Akihito
authors: A
authors: Tsuji
authors: Shinichi
authors: S
authors: Sameshima
authors: Hideo
authors: H
authors: Baba
authors: Taroh
authors: T
authors: Satoh
authors: Tadamichi
authors: T
authors: Denda
authors: Kenji
authors: K
authors: Ina
authors: Tomohiro
authors: T
authors: Nishina
authors: Kensei
authors: K
authors: Yamaguchi
authors: Hiroya
authors: H
authors: Takiuchi
authors: Taito
authors: T
authors: Esaki
authors: Shinya
authors: S
authors: Tokunaga
authors: Hiroyuki
authors: H
authors: Kuwano
authors: Yoshito
authors: Y
authors: Komatsu
authors: Masahiko
authors: M
authors: Watanabe
authors: Ichinosuke
authors: I
authors: Hyodo
authors: Satoshi
authors: S
authors: Morita
authors: Kenichi
authors: K
authors: Sugihara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D004338:Drug Combinations; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin