Radiotherapy in Glioblastoma Multiforme: Evolution, Limitations, and Molecularly Guided Future

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend OS to 31.6 months in selected cases. However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radiorresistencia driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab, PARP inhibitors) and immunotherapies (e.g., pembrolizumab, oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Future strategies, including reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT) and boron neutron capture therapy (BNCT), aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life.