Beylerli Ozal, Gareev Ilgiz, Kaprin Andrey, Ahmad Aamir, Chekhonin Vladimir, Yang Shanshan, Yang Guang
Central Research Laboratory, Bashkir State Medical University, Ufa, Russia.
National Medical Research Radiological Centre (NMRRC) of the Ministry of Health of the Russian Federation, Moscow, Russia.
Cancer Gene Ther. 2025 May 21. doi: 10.1038/s41417-025-00914-8.
Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤之一，其特征是广泛的新生血管形成和高度浸润性表型。抗血管内皮生长因子（VEGF）疗法，如贝伐单抗，已成为复发性和高级别GBM的重要辅助治疗手段，通过靶向异常肿瘤血管来发挥作用。尽管在减缓肿瘤进展和减轻瘤周水肿方面已显示出益处，但这些药物与显著的血管并发症相关，包括出血性和缺血性事件。出血性并发症范围从轻微的颅内微出血到危及生命的颅内出血（ICH）。从机制上讲，VEGF抑制会破坏内皮功能并降低血管完整性，使本就脆弱的肿瘤血管易于破裂。胶质瘤相关的血管异常，包括紊乱的血管网络和受损的血脑屏障，会进一步加剧出血风险。同时使用抗凝剂、高血压以及遗传易感性也会显著提高出血风险。除了出血并发症外，接受抗VEGF治疗的患者中缺血性事件也越来越受到关注。血管内皮细胞（ECs）存活减少和微血管密度降低可导致局部灌注不足，并可能引发脑血管缺血。血管反应性受损和血管阻力增加，通常伴有内皮功能障碍和微血管稀疏，会增加中风和动脉血栓形成风险。本综述综合了关于GBM抗VEGF治疗引起的出血性和缺血性并发症的现有证据。我们讨论了潜在的病理生理机制、危险因素和临床相关生物标志物，以及预防策略，如严格控制血压（BP）和密切监测凝血参数。我们进一步强调了精准医学中的新兴途径，包括药物基因组学分析和保护血管完整性的靶向辅助药物，旨在减轻不良血管事件的同时保持治疗效果。目标是通过平衡抗VEGF治疗的益处与其固有的血管风险的警惕管理，优化GBM患者的治疗结果。此外，本研究使用clinicaltrials.gov网站的数据，分析了使用抗VEGF药物治疗胶质瘤的现有临床试验。
