Department of Clinical and Experimental Medicine, University of Pisa, Italy.
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy.
Pharmacol Res. 2022 Jul;181:106290. doi: 10.1016/j.phrs.2022.106290. Epub 2022 Jun 6.
Glioblastoma multiforme (GBM) is an aggressive brain tumor, often occurring with seizures managed with antiepileptic drugs, such as levetiracetam (LEV). This study is aimed at associating progression-free survival (PFS) and overall survival (OS) of GBM patients with LEV plasma concentration, MGMT promoter methylation, and sex. In this retrospective, non-interventional, and explorative clinical study, GBM patients underwent surgery and/or radiotherapy and received LEV during adjuvant temozolomide (TMZ) treatment. A high-performance liquid chromatography with UV-detection was used for therapeutic drug monitoring of LEV plasma concentrations. Follow-up average drug concentration was related to patients' clinical characteristics and outcomes. Forty patients (42.5 % female; mean age=54.73 ± 11.70 years) were included, and GBM MGMT methylation status was assessed. All were treated with adjuvant TMZ, and LEV for seizure control. Patients harboring methylated MGMT promoter showed a longer median PFS (460 vs. 275 days, log-rank p < 0.001). The beneficial effect of MGMT promoter methylation was more evident for females (p < 0.001) and in patients with LEV concentration ≤ 20.6 µg/mL (562 days vs. 274.5 days, p = 0.032). Female patients also showed longer OS (1220 vs. 574 days, p = 0.03). Also, higher LEV concentration (>20.6 µg/mL) synergized with MGMT promoter methylation by extending the OS (1014 vs. 406 days of patients with no methylation and low LEV average concentration, p = 0.021). Beneficial effect of higher LEV plasma levels was more evident in males (p = 0.024). Plasma concentrations of LEV may support better outcomes for chemoradiotherapy when other positive prognostic factors are lacking and may promote overall survival by synergizing with MGMT promoter methylation and male sex.
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，常伴有癫痫发作，需用抗癫痫药物治疗，如左乙拉西坦（LEV）。本研究旨在将GBM 患者的无进展生存期（PFS）和总生存期（OS）与 LEV 血浆浓度、MGMT 启动子甲基化和性别相关联。在这项回顾性、非干预性和探索性临床研究中，GBM 患者接受了手术和/或放疗，并在辅助替莫唑胺（TMZ）治疗期间接受 LEV 治疗。采用高效液相色谱法结合紫外检测法进行 LEV 血浆浓度的治疗药物监测。随访平均药物浓度与患者的临床特征和结局相关。共纳入 40 例患者（42.5%为女性；平均年龄=54.73±11.70 岁），并评估了 GBM MGMT 甲基化状态。所有患者均接受辅助 TMZ 和 LEV 治疗以控制癫痫发作。携带甲基化 MGMT 启动子的患者中位 PFS 更长（460 天 vs. 275 天，对数秩检验 p<0.001）。MGMT 启动子甲基化的有益作用在女性中更为明显（p<0.001），在 LEV 浓度≤20.6µg/mL 的患者中更为明显（562 天 vs. 274.5 天，p=0.032）。女性患者的 OS 也更长（1220 天 vs. 574 天，p=0.03）。此外，较高的 LEV 浓度（>20.6µg/mL）与 MGMT 启动子甲基化协同作用，延长 OS（无甲基化和低 LEV 平均浓度的患者为 1014 天 vs. 406 天，p=0.021）。较高的 LEV 血浆水平的有益作用在男性中更为明显（p=0.024）。当缺乏其他阳性预后因素时，LEV 血浆浓度可能有助于改善放化疗的结果，并通过与 MGMT 启动子甲基化和男性性别协同作用来促进总生存期。
