A Phase I Study of 5-Fluorouracil/Leucovorin and Arsenic Trioxide for Patients with Refractory/Relapsed Colorectal Carcinoma
A Phase I Study of 5-Fluorouracil/Leucovorin and Arsenic Trioxide for Patients with Refractory/Relapsed Colorectal Carcinoma
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DOI：
10.1158/1078-0432.ccr-09-2590
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发表时间：
2010-06-01
影响因子：
11.5
通讯作者：
Ganjei-Azar, Parvin
中科院分区：
文献类型：
--
作者：
Ardalan, Bach;Subbarayan, Pochi R.;Ganjei-Azar, Parvin
目的：这项I期研究旨在确定5-氟尿嘧啶（5-FU）和三氧化二砷（ATO）治疗5-FU耐药复发/难治性结直肠癌患者的安全联合剂量。我们研究了ATO在下调胸苷酸合成酶（TS）在外周血单核细胞和肿瘤biopsies.Experimental Design的影响：ATO连续5天，在第一周和两次在第2至3周和第4周一次。在第8、15和22天给予5-FU/亚叶酸（LV）。采用改进的加速滴定设计。5-FU的剂量逐步增加，其次是一个计划的剂量增加ATO.Results：没有剂量限制性毒性被认为是在7例患者谁收到0.15 mg/kg的ATO; 3级毒性如下：中性粒细胞减少症1，腹泻1，肠梗阻1。在接受0.20 mg/kg ATO的患者中，3级毒性为QTc延长1例、疲乏4例、碱性磷酸酶升高2例、腹泻2例和外周水肿1例。所有患者外周血单个核细胞TS基因表达均降低。八个肿瘤活检，四个显示TS下调，三个显示上调，一个没有变化。估计的中位无进展生存期和总生存期分别为3.1和13.9个月。在TS增加或无变化与TS减少的患者中，估计的中位无进展生存期为2.6个月与7.9个月（P = 0.188），总生存期分别为8.6个月和11.7个月结论：因此，我们确定0.20 mg/kg ATO、2，600 mg/m2 5-FU和500 mg/m2甲酰四氢叶酸（LV）为推荐的II期剂量。临床癌症研究; 16（11）; 3019-27。(C)2010年AACR。
Purpose: This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU-resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies.Experimental Design: ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO.Results: No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively.Conclusions: Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m(2) 5-FU, and 500 mg/m(2) leucovorin (LV) to be the recommended phase II dose. Clin Cancer Res; 16(11); 3019-27. (C) 2010 AACR.