近年高级别胶质瘤治疗的研究进展

Research Progress in the Treatment of High-Grade Glioma in Recent Years

摘要: 高级别胶质瘤(HGG)是中枢神经系统最具侵袭性的恶性肿瘤之一，其治疗因肿瘤异质性高、血脑屏障(BBB)限制及免疫抑制微环境而面临巨大挑战。传统治疗以手术切除联合放化疗为主，但疗效有限。近年来，分子分型与精准医学的引入显著改变了HGG的诊疗范式。WHO CNS5分类整合分子标志物(如IDH突变、1p/19q共缺失)为预后评估和治疗分层提供了依据，而术中荧光导航、清醒开颅及多模态影像技术提升了手术全切率与安全性。放疗领域通过剂量优化(如大分割立体定向放疗)和新技术(质子治疗、图像引导放疗)改善局部控制，但剂量提升因正常组织耐受性受限。化疗药物替莫唑胺(TMZ)仍是基石，但其疗效受限于MGMT启动子甲基化状态，PARP抑制剂与HDAC抑制剂等新型增敏策略正在探索中。靶向治疗基于分子特征实现个体化用药，如伯瑞替尼通过抑制PTPRZ1-MET融合基因显著延长IDH突变型患者生存期(中位OS达29.3个月)，贝伐珠单抗虽未改善总生存，但可缓解血管源性水肿。免疫治疗成为近年热点，CAR-T细胞疗法在早期试验中展现持久抗肿瘤活性，双联给药模式(瘤内 + 脑室内)使中位OS延长至10.2个月；溶瘤病毒(如Ad-TD-nsIL12)通过重塑肿瘤微环境激活免疫应答，部分患者生存期超3年；树突状细胞疫苗(DCVax-L)联合标准治疗使新诊断患者中位OS提升至19.3个月。然而，免疫检查点抑制剂(如PD-1/PD-L1单抗)在HGG中疗效有限，可能与中枢免疫抑制特性及异质性相关。新兴疗法如近红外光基诊疗(PDT/PTT协同)和低频磁场(LF-MFs)通过非侵入方式克服耐药，初步临床数据显示肿瘤体积缩小及生存获益。本文综述近五年HGG治疗领域的重要进展，以期为临床实践与研究提供参考。

Abstract: High grade glioma (HGG) is one of the most aggressive malignant tumors of the central nervous system. Its treatment faces great challenges due to high tumor heterogeneity, blood-brain barrier (BBB) limitations and immunosuppressive microenvironment. The traditional treatment is mainly surgical resection combined with chemoradiotherapy, but the curative effect is limited. In recent years, the introduction of molecular typing and precision medicine has significantly changed the diagnosis and treatment paradigm of HGG. The WHO CNS5 classification integrates molecular markers (such as IDH mutation and 1p/19q co deletion) to provide a basis for prognosis assessment and treatment stratification, while intraoperative fluorescence navigation, awake craniotomy and multimodal imaging technology improve the total resection rate and safety. In the field of radiotherapy, local control is improved through dose optimization (such as hypofractionated stereotactic radiotherapy) and new technologies (proton therapy, image-guided radiotherapy), but dose escalation is limited due to normal tissue tolerance. The chemotherapy drug temozolomide (TMZ) is still the cornerstone, but its efficacy is limited by the methylation status of MGMT promoter. New sensitization strategies such as PARP inhibitors and HDAC inhibitors are being explored. Targeted therapy realizes individualized drug use based on molecular characteristics. For example, beretinib significantly prolongs the survival of IDH mutant patients (median OS 29.3 months) by inhibiting the ptprz1-met fusion gene. Although bevacizumab does not improve the overall survival, it can alleviate angiogenic edema. Immunotherapy has become a hot spot in recent years. CAR-T cell therapy showed long-lasting anti-tumor activity in early trials. The dual administration mode (intratumoral + intraventricular) extended the median OS to 10.2 months; Oncolytic viruses (such as Ad-TD-nsIL12) activate immune responses by remodeling the tumor microenvironment, and some patients survive for more than 3 years; Dendritic cell vaccine (DCVax-L) combined with standard treatment improved the median OS of newly diagnosed patients to 19.3 months. However, immune checkpoint inhibitors (such as PD-1/PD-L1 mAb) have limited efficacy in HGG, which may be related to the central immunosuppressive properties and heterogeneity. Emerging therapies such as near-infrared light-based diagnosis and treatment and low-frequency magnetic fields (LF-MFS) overcome drug resistance through non-invasive methods. Preliminary clinical data showed that tumor volume reduced and survival benefit. This article reviews the important progress in the field of HGG treatment in the past five years, in order to provide reference for clinical practice and research.