Department of Hematology and Oncology, University Medical Center Freiburg, Hugstetterstrasse 5, 79106 Freiburg, Germany.
Ann Hematol. 2012 Aug;91(8):1257-64. doi: 10.1007/s00277-012-1441-2. Epub 2012 Mar 29.
Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female N=30, male N=19, median age 73 years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [C (max), μmol/L g] and dose normalized area under the curve [AUC(dn), μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), P<0.001; 373.2 (f) vs. 271.9 (m), P=0.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126 h μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95 % CI 1.74-11.94; HR 2.87, 95 % CI 1.18-7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.
关于大剂量甲氨蝶呤化疗（HD-MTX）在老年原发性中枢神经系统淋巴瘤（PCNSL）患者中的药代动力学和药效学研究较为少见。最近提出 MTX 暴露时间是 PCNSL 的一个决定预后的因素。我们调查了 49 例免疫功能正常的 PCNSL 患者（女性 N=30，男性 N=19，中位年龄 73 岁），他们根据基于 HD-MTX 的方案进行治疗。采用两室药代动力学模型来描述 MTX 清除率。通过 MRI 评估治疗反应。我们使用多变量模型来研究 MTX 暴露与肿瘤反应和生存之间的关联。与男性相比，女性的剂量标准化 MTX 峰血清水平[C(max)，μmol/L g]和剂量标准化曲线下面积[AUC(dn)，μmol h/L g]更高[59.4(f) vs. 48.1(m)，P<0.001；373.2(f) vs. 271.9(m)，P=0.008]。AUC 的增加与肿瘤反应呈负相关。AUC 值超过 2,126 hμmol/L 与总生存和无进展生存时间缩短独立相关[风险比（HR），4.56，95 % CI 1.74-11.94；HR 2.87，95 % CI 1.18-7.00]。极高的 MTX AUC 水平可能对老年 PCNSL 患者的无进展生存和总生存产生负面影响。
