Potential regional differences for the tolerability profiles of fluoropyrimidines

Purpose We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials ( bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. Methods Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States ( US) was compared with non-US countries ( all three studies) and with the rest of the world and East Asia ( adjuvant study). Results In the MCRC studies ( n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions ( RR, 1.72), and discontinuations ( RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study ( n = 1,864), more grade 3/4 AEs ( RR, 1.47) and discontinuations ( RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. Conclusion Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.