Deenen Maarten J, Meulendijks Didier, Boot Henk, Legdeur Marie-Cecile J C, Beijnen Jos H, Schellens Jan H M, Cats Annemieke
Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2015 Dec;76(6):1285-95. doi: 10.1007/s00280-015-2872-y. Epub 2015 Oct 23.
The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses.
Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome.
A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m(2), oxaliplatin 100 mg/m(2) plus capecitabine 850 mg/m(2) b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade ≥ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival.
Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.
胃食管癌预后较差，当前治疗方案疗效有限。本研究旨在探讨多西他赛、奥沙利铂联合卡培他滨治疗晚期胃癌或胃食管交界（GEJ）癌的安全性和初步疗效。次要目标包括药代动力学和药物遗传学分析。
患者接受多西他赛和奥沙利铂（均在第1天）剂量递增治疗，联合卡培他滨每日两次，于第1 - 14天给药，每3周重复一次，以确定剂量限制性毒性和最大耐受剂量（MTD）。一个扩大队列接受MTD治疗。对药代动力学和药效学候选基因中的总共10个多态性进行分析，并测试其与治疗结果的相关性。
共纳入34例可评估患者。MTD为多西他赛50 mg/m²、奥沙利铂100 mg/m²联合卡培他滨850 mg/m²每日两次。治疗周期中位数为6（范围2 - 8）。≥3级毒性包括中性粒细胞减少（24%）、白细胞减少（15%）、发热性中性粒细胞减少（12%）、疲劳（9%）和腹泻（6%）。总缓解率为45%；2例患者达到完全缓解。无进展生存期和总生存期的中位数分别为6.5个月（95%CI 5.4 - 7.6）和11.0个月（95%CI 7.9 - 14.1）。ERCC1 354C>T、TYMS 1053C>T和ENOSF1中的rs2612091多态性与严重毒性相关；ERCC1 354C>T和ERCC2 2251A>C与无进展生存期较差相关。
多西他赛、奥沙利铂联合卡培他滨是晚期胃癌或GEJ癌患者耐受性良好、安全有效的治疗方案。药代动力学和药效学候选基因中的药物遗传学标志物可能对治疗结果具有预测性。
