Haller Daniel G, Cassidy Jim, Clarke Stephen J, Cunningham David, Van Cutsem Eric, Hoff Paulo M, Rothenberg Mace L, Saltz Leonard B, Schmoll Hans-Joachim, Allegra Carmen, Bertino Joseph R, Douillard Jean-Yves, Gustavsson Bengt G, Milano Gerard, O'Connell Michael, Rustum Youcef, Tabernero Josep, Gilberg Frank, Sirzén Florin, Twelves Chris
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA.
J Clin Oncol. 2008 May 1;26(13):2118-23. doi: 10.1200/JCO.2007.15.2090.
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.
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).
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.
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.
我们对随机单药氟嘧啶类药物临床试验（推注氟尿嘧啶/亚叶酸钙[FU/LV]和卡培他滨）的安全性数据进行了回顾性分析，以检验氟嘧啶类药物耐受性存在地区差异这一假设。
通过多变量分析对三项III期临床研究中与治疗相关的安全性数据进行分析：两项在转移性结直肠癌（MCRC）中比较卡培他滨与推注FU/LV，一项在结肠癌辅助治疗中比较卡培他滨联合奥沙利铂（XELOX）与推注FU/LV。将美国与非美国国家（所有三项研究）以及世界其他地区和东亚（辅助治疗研究）进行比较。
在MCRC研究（n = 1,189）中，与非美国患者相比，美国患者报告的3/4级不良事件（AE）更多（相对风险[RR]，1.77）、剂量减少更多（RR，1.72）以及停药更多（RR，1.83）。同样，在结肠癌辅助治疗研究（n = 1,864）中，与非美国患者相比，美国患者报告的3/4级AE更多（RR，1.47）以及停药更多（RR，2.09）。在将非美国患者进一步分为东亚患者和世界其他地区患者后，再次观察到相关3/4级AE、4级AE和严重AE的差异RR，东亚患者的RR最低，美国患者的RR最高。
氟嘧啶类药物的耐受性存在地区差异。在一线MCRC和结肠癌辅助治疗中，与世界其他地区相比，美国报告的与治疗相关的毒性更多。在辅助治疗中，观察到一系列氟嘧啶类药物耐受性情况，东亚患者的RR最低，美国患者的RR最高。
