Systemic therapy for colorectal cancer: an overview

The systemic management of patients with colorectal cancer continues to center on the use of 5-fluorouracil (5-FU). In the setting of metastatic disease, parenteral 5-FU has been shown to be superior to oral 5-FU; however, survival duration seems similar regardless of whether parenteral 5-FU is administered in a "loading schedule," weekly, or in a continuous-infusion regimen. The addition of other cytotoxic agents, such as semustine (methyl-CCNU) and/or mitomycin C, to 5-FU does not appear to be beneficial. Recent efforts have been directed toward enhancing the activity of 5-FU by (1) increasing its incorporation into RNA through pretreatment with methotrexate or phosphonoacetyl-L-aspartate (PALA), (2) enhancing DNA synthesis inhibition via the concomitant administration of folinic acid, and (3) an undetermined modulatory action by the addition of alpha-interferon. These pharmacologic approaches are being compared in ongoing cooperative group trials. The results of five randomized trials assessing the value of intra-arterial, hepatic infusions of 5-FU or 5-fluorodeoxyuridine have demonstrated that regional chemotherapy increases the likelihood of a hepatic response when compared with systemic treatment, but has little effect on survival and is associated with significant toxicity. Recent adjuvant chemotherapy trials have indicated both a decrease in recurrence and a prolongation in survival when chemotherapy (5-FU + levamisole) is administered to patients with stage C colon cancer; and combined radiation therapy and chemotherapy is given to patients with stages B2 and C rectal cancer.