Denda Tadamichi, Kanda Mitsuro, Morita Yoshitaka, Kim Ho Min, Kashiwada Tomomi, Matsuda Chu, Fujieda Shinji, Nakata Ken, Murotani Kenta, Oba Koji, Sakamoto Junichi, Mishima Hideyuki
Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Cancer Chemother Pharmacol. 2016 Dec;78(6):1253-1261. doi: 10.1007/s00280-016-3184-6. Epub 2016 Nov 2.
Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC.
This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m on day 1, infused leucovorin 200 mg/m, followed by a 2400 mg/m infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate.
The median initial area under the concentration-time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34-62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively.
Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.
与基于体表面积给药相比，在转移性结直肠癌（mCRC）患者中，基于药代动力学监测调整5-氟尿嘧啶（FU）剂量已显示可降低毒性并提高疗效。我们评估了在日本初治mCRC患者中，在改良FOLFOX7（mFOLFOX7）加贝伐单抗方案中进行FU药代动力学剂量调整的疗效和安全性。
这项单臂、多中心II期试验纳入了48例mCRC患者。治疗包括静脉注射5mg/kg贝伐单抗，随后进行mFOLFOX7（第1天奥沙利铂85mg/m²，静脉滴注亚叶酸钙200mg/m²，然后从第1天开始静脉滴注2400mg/m²的FU，持续46小时），每2周重复一次。在持续FU输注开始后18至36小时通过免疫测定法测量FU浓度，随后在后续周期中根据需要调整FU剂量。主要终点是缓解率。
FU浓度-时间曲线下的初始中位面积为23mg·h/L。29例患者（60%）在第一个周期达到目标浓度，所有48例患者在第四个周期内均达到目标浓度。3/4级不良反应的总体发生率为38%，需要和不需要剂量调整的患者之间无显著差异。总体缓解率为48%（95%置信区间=34-62%）。中位无进展生存期和总生存期分别为11.3个月和24.1个月。
在mFOLFOX7加贝伐单抗方案中对FU进行药代动力学剂量调整可迅速优化FU浓度，对日本mCRC患者是安全的。
