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

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