Dose-effect relationship of bolus 5-fluorouracil in the treatment of advanced colorectal cancer.

The effect of different dose intensities of 5-fluorouracil (5-FU) in advanced colorectal cancer was investigated. A total of 312 patients were randomized to receive 400 mg/m2 (group A), 500 mg/m2 (group B) or 600 mg/m2 (group C) of 5-FU with leucovorin 60 mg/m2 on two consecutive days every second week. Treatment continued to progression. Pharmacokinetic analyses with calculation of the area under the concentration (AUC) were performed in 91 patients. The primary endpoint was survival, and secondary endpoints were time to disease progression, toxicity and, if the disease was measurable, tumour response. The study was well balanced in the three groups with respect to a number of patient characteristics. Crude survival as estimated by Kaplan-Meier plots was not statistically significantly different (p = 0.07) but tended to show the best results in the intermediate dose group (median survival 10, 12.5 and 10 months, respectively). Analyses of time to progression or death showed significant differences among the three groups (p = 0.02) with the longest progression-free interval in the intermediate group receiving 500 mg/m2. The objective response rates were 23%, 39% and 28%, respectively (p = 0.02). The actual/projected dose intensity (mg/m2/week) was 92%, 92% and 84%, respectively. AUC did not correlate with response or survival. The frequency of severe side effects in group C was significantly higher than that of groups A and B. The study indicated that an increase from 800 to 1000 mg/m2 of bolus 5-FU fortnightly improved the treatment results but a further increase only worsened the toxicity.