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)

Lancet Oncol. 2010 Sep;11(9):853-60. doi: 10.1016/S1470-2045(10)70181-9. Epub 2010 Aug 12.


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, number NCT00284258.

Findings: 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.

Interpretation: 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.

Funding: Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / mortality
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Disease-Free Survival
  • Drug Combinations
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / analogs & derivatives
  • Humans
  • Irinotecan
  • Kaplan-Meier Estimate
  • Leucovorin / administration & dosage
  • Leucovorin / adverse effects
  • Male
  • Middle Aged
  • Organoplatinum Compounds / administration & dosage
  • Oxaliplatin
  • Oxonic Acid / administration & dosage
  • Oxonic Acid / adverse effects
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Tegafur / administration & dosage
  • Tegafur / adverse effects


  • Drug Combinations
  • Organoplatinum Compounds
  • Prodrugs
  • Oxaliplatin
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Irinotecan
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Supplementary concepts

  • IFL protocol

Associated data