Di Paolo Antonello, Lencioni Monica, Amatori Federica, Di Donato Samantha, Bocci Guido, Orlandini Cinzia, Lastella Marianna, Federici Francesca, Iannopollo Mauro, Falcone Alfredo, Ricci Sergio, Del Tacca Mario, Danesi Romano
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy.
Clin Cancer Res. 2008 May 1;14(9):2749-55. doi: 10.1158/1078-0432.CCR-07-1529.
To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study.
One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS.
The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06).
Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.
在一项非随机、回顾性药代动力学研究中，评估接受基于5-氟尿嘧啶（5-FU）辅助化疗的结直肠癌患者的5-氟尿嘧啶（5-FU）和5-氟-5,6-二氢尿嘧啶（5-FDHU）药代动力学及无病生存期（DFS）。
115例患者，包括72名男性（中位年龄63岁；范围36 - 79岁）和43名女性（中位年龄60岁；范围36 - 73岁），接受6个周期的亚叶酸钙100 mg/m²/天和5-氟尿嘧啶370 mg/m²/天静脉推注（每4周5天）。在第一个周期的第1天，采用经过验证的高效液相色谱法测定5-FU和5-FDHU的个体血浆浓度，并确定主要药代动力学变量。所有患者的随访在辅助化疗结束后延长至5年，并记录DFS。进行单因素和多因素分析，以评估5-FU药代动力学、临床和病理变量与DFS之间的任何相关性。
58例复发患者的5-氟尿嘧啶时间/浓度曲线下面积（AUC）（7.5±2.9 h·mg/L）显著低于其他患者（9.3±4.1 h·mg/L）。此外，在单因素分析中，低于8.4 h·mg/L的AUC值以及淋巴结受累和治疗中断或剂量减少被确定为危险因素。多因素分析中，在不改变剂量的情况下完成6个周期的辅助治疗是唯一的独立危险因素，尽管观察到5-FU AUC值有显著趋势（临界值，8.4 h·mg/L）（P = 0.06）。
5-氟尿嘧啶的药代动力学应被视为预测结直肠癌疾病复发的重要因素。
