Relevance of Scheduling to the Efficacy of 5-Fluorouracil Alone and in Combination with Other Agents

Abstract

Until 4–5 years ago the hot topics in clinical colorectal cancer research were scheduling of 5-fluorouracil (5-FU) and its biochemical modulation. The long series of clinical failures on one side and the lack of strong evidence for something new coming up soon, generated the feeling that several years should pass before seeing appreciable progress in the clinical management of this disease. The situation has changed dramatically. Recently, in the last few years, a series of well-designed, well-conducted, randomized studies have demonstrated the value of CPT-11 as second line treatment of patients with advanced colorectal cancer (1,2) and subsequently the value of CPT-11 + 5-FU in the front line treatment of this disease (3–5). Oxaliplatin is somewhat behind CPT-11, but it elicits similar optimism among oncologists, particularly in Europe (6,7). although from a research perspective the small improvements afforded by the two new agents, particularly CPT-11, must be greeted as major breakthroughs, caution must be exercised from a broader perspective. The very small (< 3 mo) advantage in survival for CPT-11 + 5-FU combination vs 5-FU alone must be weighed against the increased toxicity and cost of the combinations. It is thus a pity that most of the research aimed at defining the best 5-FU schedule and modulation has been dropped: first, because the issue whether the new agents are most effective when given in combination or sequentially after 5-FU failure is still not solved; second, because it is likely that each of the new agents produces different effects depending on the schedule of 5-FU used when given in combination.