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)

• Published in: The lancet oncology 2010-09, Vol.11 (9), p.853-860
• Main Authors: Muro, Kei, Dr, Boku, Narikazu, MD, Shimada, Yasuhiro, MD, Tsuji, Akihito, MD, Sameshima, Shinichi, MD, Baba, Hideo, Prof, Satoh, Taroh, MD, Denda, Tadamichi, MD, Ina, Kenji, MD, Nishina, Tomohiro, MD, Yamaguchi, Kensei, MD, Takiuchi, Hiroya, Prof, Esaki, Taito, MD, Tokunaga, Shinya, MD, Kuwano, Hiroyuki, Prof, Komatsu, Yoshito, MD, Watanabe, Masahiko, Prof, Hyodo, Ichinosuke, Prof, Morita, Satoshi, Prof, Sugihara, Kenichi, Prof
• Format: Article
• Language: English
• Subjects: 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; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Leucovorin - administration & dosage; Leucovorin - adverse effects; Male; Middle Aged; Organoplatinum Compounds - administration & dosage; Oxonic Acid - administration & dosage; Oxonic Acid - adverse effects; Prodrugs - administration & dosage; Prodrugs - adverse effects; Tegafur - administration & dosage; Tegafur - adverse effects
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(10)70181-9

Summary 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/m2 ) and irinotecan (150 mg/m2 ) and then a bolus injection of fluorouracil (400 mg/m2 ) on day 1 and a continuous infusion of fluorouracil (2400 mg/m2 ) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m2 ) 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. 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