Modulation of Fluorouracil by Leucovorin in Patients With Advanced Colorectal Cancer: An Updated Meta-Analysis

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Abstract
Purpose The modulation of fluorouracil (FU) by folinic acid (leucovorin [LV]) has been shown to be effective in terms of tumor response rate in patients with advanced colorectal cancer, but a meta-analysis of nine trials previously published by our group failed to demonstrate a statistically significant survival difference between FU and FU-LV. We present an update of the meta-analysis, with a longer follow-up and the inclusion of 10 newer trials. Patients and Methods Analyses are based on individual data from 3,300 patients randomized in 19 trials on an intent-to-treat basis. Two trials had multiple comparisons, leading to a total of 21 pair-wise comparisons. FU doses were similar in both arms in 10 pair-wise comparisons, 15% to 33% higher in the FU-alone arm in six comparisons, and more than 66% higher in five comparisons. Results Overall analysis showed a two-fold increase in tumor response rates (11% for FU-LV v 21% for FU alone; odds ratio, 0.53; 95% CI, 0.44 to 0.63; P < .0001) and a small but statistically significant overall survival benefit for FU-LV over FU alone (median survival, 11.7 v 10.5 months, respectively; hazards ratio, 0.90; 95% CI, 0.87 to 0.94; P = .004), which were primarily seen in the first year. We observed a significant interaction between treatment benefit and dose of FU, with tumor response and overall survival advantages of FU-LV over FU-alone being restricted to trials in which a similar dose of FU was prescribed in both arms. Conclusion This updated analysis demonstrates, on a large data set, that FU-LV improves both response rate and overall survival compared with FU alone and that this benefit is consistent across various prognostic factors.

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