CHRONOMODULATED VERSUS FIXED-INFUSION-RATE DELIVERY OF AMBULATORY CHEMOTHERAPY WITH OXALIPLATIN, FLUOROURACIL, AND FOLINIC ACID (LEUCOVORIN) IN PATIENTS WITH COLORECTAL-CANCER METASTASES - A RANDOMIZED MULTIINSTITUTIONAL TRIAL
CHRONOMODULATED VERSUS FIXED-INFUSION-RATE DELIVERY OF AMBULATORY CHEMOTHERAPY WITH OXALIPLATIN, FLUOROURACIL, AND FOLINIC ACID (LEUCOVORIN) IN PATIENTS WITH COLORECTAL-CANCER METASTASES - A RANDOMIZED MULTIINSTITUTIONAL TRIAL
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DOI：
10.1093/jnci/86.21.1608
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发表时间：
1994-11-02
影响因子：
10.3
通讯作者：
MISSET, JL
中科院分区：
文献类型：
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作者：
LEVI, FA;ZIDANI, R;MISSET, JL
背景资料：在先前的II期试验中，氟尿嘧啶（5-FU）、亚叶酸（FA;甲酰四氢叶酸）和奥沙利铂（1-OHP;一种新的铂复合物，无肾脏和轻微血液学毒性作用）的昼夜节律（时间调节）给药在93例转移性结直肠癌患者中产生了58%的客观缓解率。目的：为了确定时间调节的药物递送是否影响治疗活性，我们在另一项试验中再次测试了这种方案，该试验在先前未经治疗的转移性结直肠癌患者中进行，这次比较了时间调节与恒定药物递送。方法：7个欧洲中心参与了本试验。入组了92例转移性结直肠癌患者，并通过中心随机化分配至治疗方案。治疗疗程包括每日给予5-FU（600 mg/m2/天）、FA（300 mg/m2/天）和1-OHP（20 mg/m2/天），持续5天，每21天重复一次（16天间歇），在门诊患者中使用可编程的及时泵。在方案A中，药物递送在5天内保持恒定（47例患者）。在方案B中进行时间调节（5-FU和FA输注的最大输送时间为04：00，1-OHP的最大输送时间为16：00; 45例患者）。将1-OHP暴露于导管中5-FU溶液的碱性pH值2小时导致其部分化学灭活的风险记录在计划表A中。结果如下：严重口腔炎（3级或4级，世界卫生组织[WHO]分级系统），5-FU的剂量限制性毒性作用，在A方案患者中的发生率是方案B的5倍（89%对18%;卡方2 = 46; P
Background: In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and oxaliplatin (1-OHP; a new platinum complex with no renal and minor hematologic toxic effects) produced an objective response rate of 58% in 93 patients with metastatic colorectal cancer. Purpose: To determine whether chronomodulated drug delivery affects therapeutic activity, we again tested this regimen in another trial in patients with previously untreated metastatic colorectal cancer, this time comparing chronomodulated with constantrate drug delivery. Methods: Seven European centers participated in this trial. Ninety-two patients with metastatic colorectal cancer were enrolled and assigned to a treatment schedule by central randomization. Treatment courses consisted of the daily administration of 5-FU (600 mg/m(2) per day), FA (300 mg/m(2) per day), and 1-OHP (20 mg/m(2) per day) for 5 days and were repeated every 21 days (16-day intermission) in ambulatory patients with the use of a programmable in-time pump. Drug delivery was kept constant over a 5-day period in schedule A (47 patients). It was chronomodulated in schedule B (maximum delivery of 5-FU and FA infusions at 0400 hours and maximum delivery of 1-OHP at 1600 hours; 45 patients). A risk of partial chemical inactivation of 1-OHP by its 2-hour exposure to the basic pH of the 5-FU solution in the catheter was documented in schedule A. Results: Severe stomatitis (grade 3 or 4, World Health Organization [WHO] grading system), the dose-limiting toxic effect of 5-FU, occurred in five times as many patients on schedule A than on schedule B (89% versus 18%; chi(2) = 46; P