Chemotherapy for the treatment of patients with metastatic colorectal cancer: an overview.

Approximately 50% of patients with colorectal cancer develop locally recurrent or distant metastatic disease during the course of their illness and eventually die. Since the 1950s the mainstay of treatment for patients in need of palliative therapy has been and continues to be the fluoropyrimidines. When 5-fluorouracil (5-FU) was first introduced into the clinic it was used as a single agent given by rapid intravenous injection. Results with this drug have been disappointing, with response rates consistently low, usually of brief duration, and with little or no impact on survival. During the 1970s and 1980s, multidrug regimens were evaluated with little or no improvement in outcome. More recently, our understanding of the metabolism, pharmacology, and the mechanisms of action as well as the potential mechanisms of resistance to 5-FU has led to its more rational use. This knowledge has resulted in the design of treatment programs with improved therapeutic effects by changing its route of administration, combining it with biochemical modulators and using it in conjunction with other chemotherapeutic agents. These strategies have created new optimism for improved results with less toxicity. More potent inhibitors of thymidylate synthase (TS) such as tomudex and trimetrexate have been developed and are currently being evaluated in the clinic either alone or in combination with 5-FU. Semisynthetic topoisomerase inhibitors such as irinotecan have shown encouraging results as first-line therapy, in combination with 5-FU or as salvage therapy.