Chemotherapy of colorectal cancer

Advanced colorectal cancer belongs to the most chemotherapy-resistant human malignancies. The cytotoxic agent with the most consistent antitumor activity has been 5-fluorouracil (5-FU). With this drug, response rates vary between 15% (with conventional weekly or 5-day bolus injection) and 30% (with continuous infusions of 24 h to 12 weeks); survival advantages of the latter approach have not been demonstrated. Combinations of 5-FU with other cytotoxic agents with some activity have been found unsuccessful. Because of its complex metabolism the efficacy-toxicity ratio of 5-FU can be positively influenced by biochemical modulation with agents leading to decreased availability of competing substrates, increased availability of co-substrates or more efficient interactions with target substances. Superior response rates (20-40%) have been observed upon the addition of leucovorin, methotrexate and N-(phosphonacetyl)-L-aspartic acid; survival was modestly prolonged (2-3 months) in two leucovorin and one methotrexate study. Interferon-alpha, inactive as a single agent, appears to synergize with 5-FU at the cost of considerable toxicity; results from randomized trials of this combination are awaited. 5-FU has also been the mainstay of adjuvant treatments; in poor-prognosis rectal cancer it appears to improve survival if added to radiotherapy, whereas in combination with levamisole the survival of node-positive colonic carcinoma patients can be prolonged.