基于MGMT甲基化状态的复发/进展性胶质母细胞瘤个体化同步放化疗方案:一项前瞻性研究

doi:10.19854/j.cnki.1008-2425.2025.03.0007

摘要/Abstract

摘要： 目的通过前瞻性随机对照试验(RCT),评估基于MGMT启动子甲基化状态的剂量强化同步放化疗对复发/进展性胶质母细胞瘤(rGBM)患者总生存期(OS)、无进展生存期(PFS)及安全性的影响,为rGBM精准治疗提供高级别循证依据,验证分子标志物指导的个体化治疗策略的临床价值。方法采用多中心、开放标签、分层随机设计,纳入2019年1月至2023年12月经组织病理学确诊的IDH野生型rGBM患者(n=120)。按MGMT甲基化状态分层(甲基化组vs非甲基化组),每组以2:1比例随机分配至实验组(n=80)或对照组(n=40)。实验组接受调强放疗(IMRT,35 Gy/10次)联合剂量强化替莫唑胺(TMZ 同步期100 mg/m²/d,辅助期150 mg/m²d1~7/14d);对照组采用标准同步放化疗(放疗方案同实验组,TMZ同步期75 mg/m²/d,辅助期150~200 mg/m²d1~5/28d)。主要终点为OS,次要终点包括PFS、3~4级不良事件及生活质量。通过每8周脑MRI、每4周实验室检测及定期随访完成数据采集。结果两组人口学及肿瘤特征等基线资料具有均衡性(均P＞0.05)。中位随访16个月,实验组MGMT甲基化患者OS显著优于对照组(11.4个月[95%CI:10.0~13.5]vs8.1个月[7.1~9.4],HR=0.52,95%CI:0.34~0.79,P=0.003),PFS亦显著延长(6.5个月[5.8~7.3]vs3.9个月[3.2~4.8],HR=0.61,95% CI:0.41~0.90,P=0.013)。非甲基化组OS与PFS均无统计学差异(均P＞0.05)。实验组3级淋巴细胞减少发生率高于对照组(27.5%vs15%,P=0.041),但两组放射性坏死及3~4级非血液学毒性差异无统计学意义(均P＞0.05)。生活质量评估显示,两组EORTCQLQ~C30整体健康评分无显著差异(68.3±12.5 vs65.7±14.2,P=0.152)。结论在MGMT甲基化的rGBM患者中,剂量强化TMZ联合IMRT可显著延长OS与PFS,且未显著增加严重毒性。基于MGMT分层的个体化同步放化疗可显著为复发/进展性rGBM带来生存获益。

关键词: 胶质母细胞瘤, O6-甲基鸟嘌呤-DNA甲基转移酶, 同步放化疗方案, 预后

Abstract: Objective Through prospective randomized controlled trials (RCTs),evaluate the effects of dose enhanced synchronous chemoradiotherapy based on MGMT promoter methylation status on overall survival (OS),progression free survival (PFS),and safety in patients with recurrent/advanced glioblastoma (rGBM),providing high-level evidence-based support for precision treatment of rGBM and validating the clinical value of individualized treatment strategies guided by molecular markers.Methods Adopting a multicenter,open label,stratified randomized design,we included 120 IDH wild-type rGBM patients diagnosed by histopathology between January 2019 and December 2023.Stratified according to the methylation status of MGMT (methylation group vs non methylation group),each group was randomly assigned to the experimental group (n=80) or the control group (n=40) in a 2:1 ratio.The experimental group received intensity-modulated radiation therapy (IMRT,35Gy/10 times) combined with dose enhanced temozolomide (TMZ synchronous phase 100mg/m²/d,adjuvant phase 150mg/m 2 d1-7/14 days);The control group received standard synchronous radiotherapy and chemotherapy (with the same radiotherapy regimen as the experimental group,TMZ synchronous period of 75mg/m²/d,adjuvant period of 150-200mg/m² d1-5/28d).The primary endpoint is overall survival (OS),while secondary endpoints include progression free survival (PFS),grade 3-4 adverse events,and quality of life.Data collection is completed through brain MRI every 8 weeks,laboratory testing every 4 weeks,and regular follow-up.Results The baseline data of demographic and tumor characteristics between the two groups were balanced (both P＞0.05).At a median follow-up of 16 months,the OS of MGMT methylated patients in the experimental group was significantly better than that in the control group (11.4 months [95% CI:10.0~13.5] vs 8.1 months [7.1~9.4],HR=0.52,95% CI:0.34~0.79,P=0.003),and PFS was also significantly prolonged (6.5 months [5.8~7.3] vs 3.9 months [3.2~4.8],HR=0.61,95% CI:0.41~0.90,P=0.013).There was no statistically significant difference in OS and PFS between the non methylated group (both P＞0.05).The incidence of grade 3 lymphocyte reduction in the experimental group was higher than that in the control group (27.5% vs 15%,P=0.041),but there was no statistically significant difference in radiation necrosis and grade 3-4 non hematological toxicity between the two groups (all P＞0.05).The quality of life assessment showed no significant difference in overall health scores between the two groups of EORTCQLQ~C30 (68.3±12.5 vs 65.7±14.2,P=0.152)。Conclusion In rGBM patients with MGMT methylation,dose enhanced TMZ combined with IMRT significantly prolonged OS and PFS without significantly increasing severe toxicity.Individualized synchronous chemoradiotherapy based on MGMT stratification can significantly bring survival benefits to recurrent/progressive rGBM.

Key words: Glioblastoma, 06 methylguanine DNA methyltransferase, Synchronous chemoradiotherapy regimen, Prognosis

中图分类号:

R739.4

王雅迪, 彭粉花, 岳鹏. 基于MGMT甲基化状态的复发/进展性胶质母细胞瘤个体化同步放化疗方案:一项前瞻性研究[J]. 立体定向和功能性神经外科杂志, 2025, 38(3): 170-177.

Wang Yadi , Peng Fenhua, Yue Peng. Individualized synchronous chemoradiotherapy regimen for recurrent/progressive glioblastoma based on MGMT methylation status:a prospective study[J]. Chinese Journal of Stereotactic and Functional Neurosurgery, 2025, 38(3): 170-177.

参考文献

[1] Fariselli L,Pinzi V,Milanesi I,et al.Short-course radiotherapy in elderly patients with glioblastoma:feasibility and efficacy of results from a single centre [J].Strahlenther Onkol,2013,189(6):456~461.
[2] 张伟,王政.中国抗癌协会脑胶质瘤整合诊治指南(精简版)[J].中国肿瘤临床,2022,49(16):811~818.
[3] Matos B,Bostjancic E,Matjasic A,et al.Dynamic expression of 11 miRNAs in 83 consecutive primary and corresponding recurrent glioblastoma:correlation to treatment,time to recurrence,overall survival and MGMT methylation status[J].Radiol Oncol,2018,52(4):422~432.
[4] 黄国浩,曹勇勇,杨林,等.成人胶质母细胞瘤预后因素分析:单中心176例临床回顾[J].陆军军医大学学报,2024,46(17):2002~2008.
[5] Wang YN,Li JL,Cao YN,et al.Characteristic analysis and identification of novel molecular biomarkers in elderly glioblastoma patients using the 2021 WHO Classification of Central Nervous System Tumors[J].Front Neurosci,2023,17(9):1165823.
[6] Sarkaria JN,Ballman KV,Kizilbash SH,et al.Efficacy of adding veliparib to temozolomide for patients with MGMT-methylated glioblastoma:a randomized clinical trial[J].JAMA Oncol,2024,10(12):1637~1644.
[7] Chen CJ,Xu H,Song K,et al.Tumor treating fields combine with temozolomide for newly diagnosed glioblastoma:a retrospective analysis of Chinese patients in a single center[J].J Clin Med ,2022,11(19):5855~5855.
[8] 彭超,陈宇澄,张之娟,等.脑胶质瘤患者SEL1L基因多态性与总生存率和替莫唑胺敏感性的关系[J].立体定向和功能性神经外科杂志,2024,37(4):205~209+216.
[9] Ellingson BM,Cloughesy TF,Pope WB,et al.Anatomic localization of O6-methylguanine DNA methyltransferase(MGMT) promoter methylated and unmethylated tumors:a radiographic study in 358 de novo human glioblastomas[J].Neuroimage,2012,59(2):908~916.
[10] Pointer KB,Gatson NTN.MGMT methylation status in grades2 and 3Gliomas is important,but Is It prognostic[J].JAMA oncology,2023,9(7):928~929.
[11] John P,David JC,Keiko K,et al.Treatment practices and survival outcomes for IDH-wildtype glioblastoma patients according to MGMT promoter methylation status:insights from the U.S.National Cancer Database[J].J Neurooncology,2025,172(3):655~665.
[12] Gupta T,Selvarajan JMP,Kannan S,et al.Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma[J].Neurooncol adv,2023,5(1):vdad086.
[13] 张静,刘彦伟.MGMT启动子甲基化对不同分子亚型弥漫性胶质瘤的预后影响与预测价值[J].中国微侵袭神经外科杂志,2025,30(1):24~30.
[14] Salihoglu AK,Booth TC.Editorial for “apparent diffusion coefficient as imaging biomarker for IDH mutation,1p19q codeletion,and MGMT promoter methylation status in patients with glioma”[J].J Magn Reson imaging,2023,58(3):739~740.
[15] Trevino CR,Weathers SS,Alfaro MK,et al.Retrospective review for outcomes of IDH mutant,1p/19q co-deleted gliomas based on initial treatment[J].J Clin Oncol,2019,37(15):2063~2063.
[16] Yang JT,Wen P.Y.Imber BS.Safety and preliminary efficacy of AZD1390 +radiation therapy for glioblastoma[J].Int J Radiat Oncol,2024,120(2):S119~S120.
[17] Miller R,Song A,Ali A,et al.Scalp-sparing radiation with concurrent temozolomide and tumor treating fields (SPARE) for patients with newly diagnosed glioblastoma[J].Front Oncol,2022,12:896246.
[18] Tosoni A,Franceschi E,Blatt V,et al Recurrence pattern after concomitant radio-chemotherapy in newly diagnosed glioblastoma patients:Correlation with MGMT promoter methylation status[J].J Clin Oncol,2008,26(15):2027.
[19] 杜云,王卫中,刘梦,等.异柠檬酸脱氢酶1R132H与同源框C10在脑胶质瘤组织的表达及其临床意义[J].立体定向和功能性神经外科杂志,2023,36(3):135~140.
[20] Petermann E,Keil C,Oei SL,et al.Roles of DNA ligase III and XRCC1 in regulating the switch between short patch and long patch BER[J].DNA Repair,2005,5(5):544~555.
[21] Castello A,Albano D,Muoio B.et al.Diagnostic accuracy of PET with 18F-fluciclovine(FACBC)in detecting high-grade gliomas:a systematic review and meta-analysis[J].Diagnostics,2023,13(24):3610.
[22] Marwah R,Xing D,Squire T,et al.Reirradiation versus systemic therapy versus combination therapy for recurrent high-grade glioma:a systematic review and meta-analysis of survival and toxicity[J].J Neurooncol,2023,164(3):505~524.
[23] Fleischmann DF,Gajdi L,Corradini S,et al.Re-irradiation treatment regimens for patients with recurrent glioma-Evaluation of the optimal dose and best concurrent therapy[J].Radiother Oncol,2024,199:110437.
[24] 何振强,钟升,杜晓京,等.脑胶质瘤治疗研究进展[J].中国微侵袭神经外科杂志,2024,28(5):303~316.
[25] Gonzalez-quarante LH,Fernandez Carballal C,Agarwal V,et al.Angiocentric glioma in an elderly patient:case report and review of the literature[J].World Neurosurg,2016,97:755.e5~755.e10.
[26] 倪春霞,汪洋,盛晓芳,等.应用DWI和DTI技术评估胶质母细胞瘤术后替莫唑胺标准放化疗后早期进展的初步研究[J].立体定向和功能性神经外科杂志,2015,28(2):97~101.
[27] Wu HB,Guo CC,Wang CY,et al Single-cell RNA sequencing reveals tumor heterogeneity,microenvironment,and drug-resistance mechanisms of recurrent glioblastoma[J].Cancer sci,2023,114(6):2609~2621.
[28] Yang YC,Cui HH,Li DH,et al.S100A8 promotes tumor progression by inducing phenotypic polarization of microglia through the TLR4/IL-10 signaling pathway in glioma[J].J Natl Cancer Center Cent,2024,4(4):369~381.
[29] 姜琳,刘绮颖,贾利晴,等.胶质瘤中MGMT甲基化状态及其临床意义的回顾性研究[J].中国癌症杂志,2023,33(8):740~750.
[30] Long SW,Huang GX,Ouyang M,et al.Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression[J].Cell Death Dis,2023,14(6):365.
[31] Wei YF,Li GZ,Feng J,et al.Stalled oligodendrocyte differentiation in IDH-mutant gliomas[J].Genome Med,2023,15(1):24.
[32] Eudocia QL,Brian MA,Carlos GR,et al.Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma.[J].Clinical cancer research:an official journal of the American Association for Cancer Research.Volume,Issue .2025,17 879~892.
[33] Xu KR,Ramesh K,Huang V,et al.Final report on clinical outcomes and tumor recurrence patterns of a pilot study assessing efficacy of belinostat(PXD-101) with chemoradiation for newly diagnosed glioblastoma[J].Tomography,2022,8(2):688~700.