Prospective Phase II Trial of Second-line FOLFIRI in Patients with Advanced Colorectal Cancer Including Analysis of UGT1A1 Polymorphisms: FLIGHT 2 Study

Aim: This is a multicenter phase II study to assess the efficacy and toxicity of FOLFIRI treatment agents in full and the influence of UGT1A1*28 polymorphism in Japanese patients with advanced/metastatic colorectal cancer (mCRC). Patients and Methods: Fifty patients with mCRC participated in this study. Treatment consisted of FOLFIRI (irinotecan; 150 mg/m 2 ) as second-line chemotherapy; 34 patients consented to the evaluation of UGT1A1 genotype. Results: The overall response rate was 12% for all 50 evaluable patients; 31 patients (62.0%) had stable disease, and only in 12 (24.0%) did disease progress. The median progression-free survival was 5.8 months. The tolerance treatment was acceptable, with only 15 out of 50 patients (30%) experiencing grade 3/4 neutropenia, and grade 4 thrombocytopenia was observed in only one case. Grade 3 non-hematological adverse reactions included stomatitis in three, diarrhea in one, and a clinically insignificant increase in serum alkaline phosphatases in one patient, respectively. There was no definite relation between the UGT1A1*28 polymorphism and toxicity. Conclusion: Standard FOLFIRI regimen can be administered to Japanese patients. The results showed good tolerability and efficacy for second-line FOLFIRI, provided that evaluation of UGT1A1 polymorphism is properly implemented before the start of the chemotherapy. The management of advanced colorectal cancer has achieved outstanding improvements during the past two decades. New active drugs include the cytotoxic agents, oxaliplatin and irinotecan, and the molecular-targeting agents, bevacizumab, cetuximab, and panitumumab. Although at the beginning of the 1990s, the median survival time for patients with advanced colorectal cancer was 5-6 months, chemotherapies with 5-fluorouracil and folinic acid or capecitabine combined with those cytotoxic and molecular-targeting agents as first- line treatment have increased median survival to 20-24 months (1-4). In contrast to first-line treatment, optimum second-line chemotherapy options have not been fully-defined. The combination of oxaliplatin, 5-fluorouracil with leucovorin (5- FU/LV) in the FOLFOX regimen is superior to oxaliplatin alone in second-line treatment in terms of response rate and survival, albeit with certain increase in toxicity (5). Second- line irinotecan and the combination of irinotecan and 5- FU/LV in the FOLFIRI regimen improved survival over best supportive care or infusional 5-FU alone (6-8). However, it is not clear whether FOLFIRI is preferable to single-agent