Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance
Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance
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DOI：
10.1200/jco.2009.24.8252
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发表时间：
2010-01-20
影响因子：
45.3
通讯作者：
Heymach, John V.
中科院分区：
文献类型：
--
作者：
Kopetz, Scott;Hoff, Paulo M.;Heymach, John V.
目的：在一项针对转移性结直肠癌（mCRC）患者的II期临床试验中，研究氟尿嘧啶（FU）、亚叶酸钙、伊立替康和贝伐单抗（FOLFIRI + B）的疗效，以及治疗期间血浆细胞因子和血管生成因子（CAFs）的变化作为治疗反应和治疗耐药的潜在标志物。患者和方法我们进行了FOLFIRI + b的II期、两机构试验，每个14天周期包括贝伐单抗（5mg /kg）、伊立替康（180mg /m(2)）、FU （400mg /m(2)）和亚叶酸素（400mg /m(2)），随后输注FU (2400 mg/m(2)) 46小时。在基线、治疗期间和进展性疾病（PD）时，使用多重头测定法和酶联免疫吸附测定法评估37种CAFs的水平。结果共纳入43例患者。研究的主要终点——中位无进展生存期（PFS）为12.8个月。中位总生存期为31.3个月，有效率为65%。基线时白细胞介素-8升高与较短的PFS相关（11个月vs 15.1个月，P = 0.03）。在PD影像学发展之前，与基线相比，与血管生成和髓细胞募集相关的几种CAFs增加，包括碱性成纤维细胞生长因子（P = 0.046）、肝细胞生长因子（P = 0.046）、胎盘生长因子（P < 0.001）、基质衍生因子-1 （P = 0.04）和巨噬细胞化学引诱蛋白-3 （P < 0.001）。结论在这项单组研究中，FOLFIRI + B的疗效和耐受性优于历史对照组。在放射学进展之前，CAFs的平衡发生了变化，在患者亚群中，替代的促血管生成细胞因子和骨髓募集因子升高，这可能代表了耐药性的机制。
PurposeWe investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance.Patients and MethodsWe conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD).ResultsForty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001).ConclusionEfficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.