104 • Clinical Colorectal Cancer August 2002 Contribution Original Introduction For nearly 4 decades, 5-fluorouracil (5-FU) has been the most effective chemotherapeutic agent in the treatment of pa- tients with advanced colorectal cancer (ACC) although re- sponse rates to 5-FU monotherapy are typically not higher than 15%. 1 Efforts at improving the response to this agent have involved its administration with biochemical-modulat- ing agents and in protracted infusion schedules. 2-8 A combi- nation of 5-FU with the reduced folate leucovorin produced more promising results, with an approximately two-fold in- crease in the response rate compared to that seen with monotherapy (23% vs. 11%). 3 Preliminary evidence has sug- gested further benefits when this regimen is administered via continuous infusion, which has produced response rates in the range of 30%, 9,10 and/or with higher doses of 5-FU/leucov- orin using short-term continuous infusions. These infusional schedules might replace the bolus regimens without sacrific- ing overall clinical efficacy. 11 Current approaches to enhancing therapy involve the use of new antitumor agents such as irinotecan, a topoisomerase I inhibitor, and oxaliplatin, a third-generation platinum com- pound. 12 Over the past decade, these agents have been evalu- ated extensively in patients with metastatic colorectal cancer in a wide variety of settings: phase I-III trials in first-line and second-line advanced disease, as monotherapy, and in combi- Irinotecan, Oxaliplatin, and 5-Fluorouracil/ Leucovorin Combination Chemotherapy in Advanced Colorectal Carcinoma: A Phase II Study Abstract The purpose of this study was to evaluate the efficacy and tolerance of a combination of irinotecan, oxaliplatin, and 5-fluorouracil (5-FU)/leucovorin in advanced colorectal cancer (ACC).Twenty-six consecutive patients with ACC and an Eastern Cooperative Oncology Group performance status of 0-2 were treated with a combination of oxaliplatin (120 mg/m 2 intravenously [I.V.] for 2 hours) on day 1,irinotecan (250 mg/m 2 I.V. for 90 minutes) on day 1, and 5-FU (2600 mg/m 2 plus leucovorin 500 mg/m 2 I.V. in a 24-hour infusion) on days 1 and 15, every 4 weeks. Five of the pa- tients (19.2%) had shown previous chemoresistance. One hundred sixty-two cycles were administered (median, 6; range, 3-13 cycles).All patients were evaluated for toxicity; 23 were evaluable for response. According to intention- to-treat, the overall response rate was 69.2% (18 patients; 95% CI: 48.2%-85.7%), including 3 complete remissions (11.5%). Four additional patients (15.3%) had stable disease, and only 1 (3.8%) progressed. Major toxicities were neu- tropenia and diarrhea. Grade 3 neutropenia occurred in 9 patients (34.6%), and grade 4 occurred in 1 patient (3.8%). Grade 3 diarrhea occurred in 8 patients (30.7%) and grade 4 in 1 patient (3.8%). Other toxicities were mild.After a median follow-up of 15.5 months, the median progression-free survival was 14 months. Seventeen patients (65.4%) are still alive, and the median overall survival has not been reached yet.This combination of irinotecan, oxaliplatin, and 5-FU/leucovorin is fairly well tolerated and shows promising activity in ACC.This treatment merits further com- parison with other combination regimens. Clinical Colorectal Cancer, Vol. 2, No. 2, 104-110, 2002 Key words: Colorectal cancer, Irinotecan, Oxaliplatin, 5-Fluorouracil, Diarrhea Submitted: Mar 8, 2002; Revised: Apr 25, 2002; May 15, 2002; Accepted: Jun 19, 2002 Address for correspondence: Emiliano Calvo, MD, Oncology, Hospital San Jaime, Ptda. de La Loma, s/n, 03180 Torrevieja, Alicante, Spain Fax: 34-96-692-5733; e-mail: calvo@hsanjaime.com 1 Oncology, Hospital San Jaime, Alicante, Spain 2 Department of Oncology, Division of Medical Oncology, Clinica Universitaria de Navarra, Pamplona, Spain 3 Department of Oncology, Clínica San Miguel, Navarra, Spain 4 Department of Oncology, Division of Radiotherapy, Clínica Universitaria de Navarra, Pamplona, Spain 5 Department of Epidemiology and Public Health, School of Medicine, University of Navarra, Pamplona, Spain Emiliano Calvo, 1 Javier Cortés, 2 Javier Rodríguez, 2 Óscar Fernández-Hidalgo, 2 Joseba Rebollo, 3 Salvador Martín-Algarra, 2 Jesús García-Foncillas, 2 Rafael Martínez-Monge, 4 Jokin de Irala, 5 Antonio Brugarolas 1