Chemotherapy for metastatic colorectal cancer

The systemic management of patients with colorectal cancer continues to focus 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 whether such parenteral 5-FU is administered in a "loading," weekly, or continuous infusion manner. The addition of other cytotoxic agents such as semustine, mitomycin C, or cisplatin to 5-FU does not appear to increase the response rate or prolong survival. The results of five randomized trials assessing the value of intraarterial hepatic infusions of 5-FU or floxuridine show that such regional chemotherapy increases the likelihood of hepatic response compared with systemic treatment but has little effect on survival and is associated with significant toxicity. Recent efforts in the management of patients with advanced disease have been directed at optimizing the activity of 5-FU by (1) enhancing the inhibition of DNA synthesis through the concomitant administration of folinic acid; (2) increasing drug incorporation into RNA through pretreatment with methotrexate or phosphonacetyl-L-aspartate; and (3) improving the drug's activity through the synergistic action of alpha-2a-interferon. Although the results of some of these investigations have been promising, only the 5-FU and folinic acid combination consistently has appeared to be superior to single-agent 5-FU. These different approaches to biochemical modulation are being compared in ongoing cooperative group trials.