Phase II Study of Weekly Oxaliplatin and High-dose Infusional 5-Fluorouracil plus Leucovorin in Pretreated Patients with Metastatic Colorectal Cancer

Background: Chemotherapy with oxaliplatin, fluorouracil (5-FU) and leucovorin (LV) has proven efficacy in patients with advanced colorectal carcinoma (CRC), although the optimal dosage and administration schedule are still unclear. This phase II trial investigated the tolerability and activity of weekly oxaliplatin, high-dose infusional 5-FU and LV in pretreated patients with metastatic CRC. Materials and Methods: Patients received weekly courses of i.v. oxaliplatin 50 mg/m 2 (1-h infusion), LV 100 mg/m 2 (1-h infusion) and 5-FU 2100 mg/m 2 (24-h infusion) until disease progression or unacceptable toxicity. NCI-CTC criteria were used for assessment of side-effects (at each cycle) and WHO criteria for assessment of tumour response (every 8 cycles). For descriptive purposes, time to progression, overall survival and duration of objective response were also calculated. Results: Forty-four patients were enrolled and received a total of 606 cycles (median 13/patient, range 4-33), and 70% of courses (421/606) were delivered at 100% of the planned dose. The most frequent side-effects were gastrointestinal and neurological and incidence rates were: diarrhoea 66% (grade III: 29%), nausea/vomiting 54%, neurotoxicity 34% (grade III: 2%), fatigue 27%, mucositis 22%, leucopenia 14%. No grade IV toxicity was observed. Objective response rates were: partial response 23% (10 patients), stable disease 59% (26) and progressive disease 11% (5). Median time to progression was 7 months, overall survival 13 months and the duration of partial response and stable disease were 9 and 6 months, respectively. Conclusion: The study demonstrated that this regimen has a favourable tolerability profile and is an active combination in the pretreated metastatic CRC patient, deserving further evaluation in phase III trials. For the last five decades, fluorouracil (5-FU) has been the mainstay of chemotherapy for colorectal carcinoma (CRC), both in the treatment of metastatic disease and in the adjuvant setting. However, when administered as a single agent for first-line treatment of advanced disease, 5-FU has produced only modest response rates, with no major impact on survival (1). The addition of leucovorin (LV) was found to improve the response rate (by up to 2-fold) but not overall survival (2). More recently, a meta-analysis of 6 studies comparing different methods of 5-FU administration has demonstrated improved response rates with continuous infusion compared with bolus injection (22 vs. 14%), as well as decreased toxicity. Survival rates, however, remained poor (12.1 vs. 11.3 months, respectively) (3). Different types of administration also appear to affect the pattern of toxicity of 5-FU, with haematological side-effects being more frequent with bolus administration and hand-foot syndrome with continuous infusion (4,5). In our experience too, LV modulation of weekly short-term continuous infusion of high-dose 5-FU has proved to be a well tolerated and highly active regimen in both untreated and 5-FU-resistant patients with advanced CRC (6). With the recent introduction of novel agents with activity against 5-FU-refractory tumours, such as oxaliplatin, there has been considerable progress in the therapy of advanced CRC. Oxaliplatin, a third-generation platinum derivative with a thymidylate synthase-independent mechanism of action, has