Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer
Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer
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DOI：
10.1200/jco.2005.05.2084
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发表时间：
2006-09-01
影响因子：
45.3
通讯作者：
Schwarting, Roland
中科院分区：
文献类型：
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作者：
Meropol, Neal J.;Gold, Philip J.;Schwarting, Roland
目的评价卡培他滨联合伊立替康一线治疗转移性结直肠癌（mCRC）的临床活性和毒性，并描述胸苷磷酸化酶（TP）、胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）表达与抗肿瘤活性的关系。和卡培他滨，在21天周期中第2 - 15天口服。剂量为伊立替康125 mg/m2+卡培他滨1,000 mg/m2 bid（n = 15;队列1），或伊立替康100 mg/m2+卡培他滨900 mg/m2 bid（n = 52;队列2）。从原发和转移部位的组织进行了评估TP，TS，和DPD基因和蛋白质expression. ResultsA不可接受的水平的GI毒性在第一个15例患者导致在起始剂量的方案修改。反应率为45%（67例患者中的30例）。在原发肿瘤（P = 0.045）和转移瘤（P = 0.001）中，总生存率与TP表达相关。肿瘤的客观缓解与原发性肿瘤中TP的表达相关（比值比，4.77; 95%CI，1.25 - 18.18），转移性肿瘤中的趋势相似（比值比，8.67; 95%CI，0.95 - 79.1）。TP基因表达在原发肿瘤也与responsibility.ConclusionThese数据表明，卡培他滨加伊立替康是一个积极的方案对mCRC。生物标志物分析（包括转移组织）在多中心环境中是可行的，并提供了TP表达可能是反应的预测标志物的初步证据。
PurposeTo evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.Patients and MethodsPatients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m(2) and capecitabine 1,000 mg/m(2) bid (n = 15; cohort 1), or irinotecan 100 mg/m(2) and capecitabine 900 mg/m(2) bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.ResultsAn unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.ConclusionThese data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.