Role of chemotherapy for advanced colorectal cancer: new opportunities

Since the late 1950s, 5-fluorouracil (5-FU) has remained the most effective chemotherapeutic agent in the treatment of advanced colorectal cancer, although response rates to 5-FU monotherapy are typically no more than 15%. However, efforts at improving the response to this agent have involved its administration with biochemical-modulating agents and in protracted infusion schedules. The combination of 5-FU with folinic acid has evinced the most promising results, with an approximate twofold increase in response rate compared with monotherapy (23% versus 11%). Preliminary evidence also suggests further benefits when this regimen is administered by continuous infusion. These results support the current clinical practice of using 5-FU plus folinic acid as first-line therapy in advanced colorectal cancer. However, for those patients refractory to a 5-FU-based chemotherapy, there is no established effective treatment option. Current approaches to enhance second-line therapy involve biochemical modulation of 5-FU and prolongation of its administration schedule or the use of new antitumor agents such as CPT-11 (irinotecan) and oxaliplatin. Among the new agents in development, CPT-11 has demonstrated promising antitumor activity in phase II studies of patients with advanced colorectal cancer, achieving response rates of 15% to 32% and 17% to 25% in chemotherapy-naive and pretreated patients, respectively. Prior disease progression on 5-FU does not affect the response to CPT-11, indicating no cross-resistance between the two agents. This suggests that CPT-11 is a promising new second-line agent for this difficult-to-treat disease. Additional studies will address the benefit of CPT-11 alone in second-line treatment and determine the role of CPT-11 in combination with thymidylate synthase inhibitors in first-line treatment.