Beyond 5-Fluorouracil

Fluorouracil (5-FU) is one of the most extensively investigated chemotherapy agents in medical oncology. Generations of medical oncologists have equated this agent with the optimal treatment of colorectal cancer, both in the advanced and adjuvant setting.

5-FU has been examined in multiple schedules and also with agents to modulate its activity biochemically. 5-FU has well-described schedule-dependent toxicities. Many of these toxic effects can be reduced with protracted intravenous schedules. Although protracted 5-FU infusion reduces the toxicities of neutropenia, mucositis, and diarrhea, there is a clinical “trade-off” with its use because hand-foot syndrome emerges as a novel toxicity. Also, patients are inconvenienced with portable infusion pumps and experience complications associated with indwelling central venous catheters, such as line slippage, infection, and thrombosis.

The biochemical modulation of 5-FU has focused on calcium leucovorin. Regimens of 5-FU plus leucovorin improve response rates and may exert a small effect on overall survival when compared to bolus 5-FU schedules. Results of large, randomized clinical trials examining 5-FU plus leucovorin regimens remind oncologists that only a minority of patients receive benefit from our therapy as assessed by response rates. Unfortunately, the median survival of patients with metastatic colorectal cancer hovers around 12 months. Toxic effects of our “best” schedules of intravenous 5-FU and leucovorin are not trivial, with over one-fourth of patients experiencing either grade 3 or 4 neutropenia, stomatitis, or diarrhea.

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