Progress in colorectal cancer chemotherapy - How far have we come, how farto go?

Fluorouracil has been the mainstay of treatment for colorectal cancer (CRC) for almost 40 years. Various schedules and biochemical modulators have bee n investigated in an attempt to improve the therapeutic efficacy of fluorou racil. To date, fluorouracil plus folinic acid represents the standard ther apy in CRC for the adjuvant treatment of patients at high risk for relapse and for the first-line treatment of metastatic disease. Combination chemotherapy regimens have not been developed due to the lack o f other active agents. However, the availability of several novel agents no w allows investigation of combination regimens in this disease. One group o f such agents, the oral fluoropyrimidines (tegafur/uracil plus oral folinic acid, capecitabine, eniluracil plus oral fluorouracil, and tegafur/gimerac il/potassium oxonate), are convenient oral alternatives to intravenous fluo rouracil. A particular advantage of these oral agents is the reduction in t he incidence of febrile neutropenia and mucositis compared with fluorouraci l given in an intravenous bolus schedule. To gain clinical acceptance, howe ver, oral fluoropyrimidines must confer at least the same survival advantag es associated with the optimal intravenous fluorouracil regimens. Irinotecan and oxaliplatin are 2 other novel agents that have mechanisms of action that are uniquely different from those of fluorouracil, with demons trated activity in patients with fluorouracil-refractory disease. Recent ra ndomised trials comparing fluorouracil plus folinic acid with combinations of either irinotecan or oxaliplatin and fluorouracil plus folinic acid have shown that response rates are improved and time to progression is increase d in patients receiving the combination regimens. These regimens are being rapidly introduced in the adjuvant setting, and the role and acceptance of these combination regimens as first-line therapy needs to be defined. Other novel agents bring evaluated in the treatment of patients with advanc ed CRC include oral edrecolomab (monoclonal antibody 17-1A) and tumour vacc ines. Future research is focused on enabling clinicians to individualise treatmen t strategies in patients with CRC, so as to improve clinical outcomes and r educe drug toxicity.