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

1. Introduction

Glioblastoma multiforme (GBM), the most common malignant primary brain tumor in adults, has an incidence of 3–5 cases per-100,000 people annually, with a male predominance (1.6:1) and peak incidence at 50–60 years [1,2,3,4]. According to the 2021 World Health Organization (WHO) classification, GBM is defined as an isocitrate dehydrogenase (IDH)-Wild-Type (IDH-wt), grade 4 astrocytoma, diagnosed by histological features (necrosis, microvascular proliferation) or molecular markers, including telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor receptor (EGFR) amplification, or +7/−10 chromosomal alterations [5]. Most GBMs arise de novo, though a small percentage develop from lower-grade gliomas; risk factors include prior cranial radiotherapy (RT) or hereditary syndromes such as Cowden, Turcot, Lynch, Li-Fraumeni, or neurofibromatosis type I [2]. Characterized by rapid progression and treatment resistance, GBM has a poor prognosis, with a median overall survival (mOS) of 12–15 months and a 5-year survival rate below 10%, varying by prognostic factors such as age, functional status, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, tumor location, and involvement of deep structures or functional areas [6,7,8,9]. Multidisciplinary treatment combines maximal safe resection, RT, and chemotherapy (CTx), with no defined second-line therapy, necessitating personalized approaches. Despite recent advances, limited progress in improving outcomes underscores the urgent need for innovative strategies to improve oncologic outcomes and quality of life. This review explores the evolution, limitations, and molecularly guided advances in RT for GBM management.

2. Evolution of Radiotherapy in GBM: Foundations, Standards, and International Guidelines

The first-line treatment for GBM involves maximal safe resection, followed by adjuvant RT and CTx to target residual microscopic disease due to the tumor’s infiltrative nature [10,11]. Preoperative neuronavigation magnetic resonance imaging (MRI) and early postoperative contrast-enhanced MRI (within 48–72 hours) are recommended, with intraoperative biopsy for diagnosis confirmation if resection is not feasible [2,10]. RT should begin 3–6 weeks post-surgery to minimize recurrence risk [10,11].The standard protocol, established by the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981 trial, combines normofractionated RT (60 Gy in 30 fractions) with concomitant temozolomide (TMZ, 75 mg/m²/day), followed by 6 cycles of adjuvant TMZ (150–200 mg/m²/day, 5/28 days), improving overall survival (OS) from 12.1 to 14.6 months, particularly in patients with MGMT promoter methylation (Table 1) [12]. This regimen is recommended for patients ≤70 years with good functional status (Karnofsky Performance Status [KPS] ≥60) [13,14]. Extending TMZ beyond 6 cycles lacks evidence [15]. Tumor Treating Fields (TTFields), which disrupt cell division with alternating electric fields, further improve OS to 31.6 months in MGMT-methylated tumors (EF-14 trial) with minimal toxicity (mainly skin irritation) and are endorsed by National Comprehensive Cancer Network (NCCN) and American Society for Radiation Oncology (ASTRO) 2025 guidelines for supratentorial GBM (Table 1) [12,16,17]. Other therapeutic innovations and systemic treatment options are discussed in the therapeutic innovations section.

Hypofractionated RT (40.05 Gy/15 fractions with TMZ, 34 Gy/10 fractions, or 25 Gy/5 fractions without TMZ) is effective and better tolerated in elderly (≥70 years) or frail patients (KPS 50–70), offering comparable OS with reduced toxicity, as supported by clinical trials and meta-analyses (Table 2) [18,19,20,21,22,23,24]. ASTRO 2025 and European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) 2023 guidelines conditionally recommend these regimens for elderly or frail patients, while those with poor KPS (≤40) or extreme frailty may receive hypofractionated RT alone, TMZ alone (if MGMT-methylated), or palliative care to prioritize quality of life [10,11,13,14,25].

RT techniques have evolved from whole-brain RT (WBRT) in the 1970s to three-dimensional conformal RT (3D-CRT) in the 1990s, and now to intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), which optimize dose delivery and spare healthy tissues. Treatment planning integrates thin-slice CT and MRI (T1 with gadolinium, T2/FLAIR) performed ≤14 days before RT for precise tumor and organ-at-risk delineation. ASTRO 2025 and ESTRO-EANO 2023 guidelines prioritize IMRT/VMAT over 3D-CRT to reduce neurological toxicity. ESTRO-EANO 2023 recommends a single-phase approach (gross tumor volume [GTV]: surgical cavity + T1 enhancement, clinical target volume [CTV]: GTV + 15 mm, edema optional only for non-hyperintense T1 tumors), while ASTRO 2025 allows a single phase (edema optional) or two phases (initial phase with T2/FLAIR, boost without edema), with CTV of 10–20 mm and planning target volume (PTV) of 2–5 mm with image-guided RT (IGRT) (Table 3) [11,12,14,25,26,27,28,29]. A randomized trial with 245 patients with grade 3–4 gliomas compared the RTOG/NRG approach (including edema with a boost) and the EORTC approach (including edema in the initial phase), finding no significant differences in grade 3–4 toxicity (36.1% vs. 32.3%) or recurrence patterns (predominantly central), though neurocognitive outcomes were not assessed [30,31]. The MD Anderson Cancer Center (MDACC) protocol, excluding edema, improved OS (17 vs. 12 months) and quality of life without increasing toxicity, suggesting smaller volumes may be beneficial (Table 3) [27].

Post-treatment follow-up includes MRI at 4 weeks, then every 2–4 months, per Response Assessment in Neuro-Oncology (RANO) criteria. Pseudoprogression, challenging to distinguish from true progression, may require advanced imaging (diffusion MRI, spectroscopy MRI, or amino acid positron emission tomography (PET)/CT), correlating findings with conventional MRI. In case of progression, a personalized approach is recommended, considering tumor characteristics (size, location, molecular profile), initial treatment response, age, KPS, symptoms, needs, and patient preferences, with multidisciplinary evaluation of options (reoperation, reirradiation, or systemic therapy) [11,25]. These advances underscore the need for tailored RT strategies to optimize GBM treatment outcomes.

3. Limitations of Radiotherapy in GBM

RT combined with TMZ is a cornerstone of GBM treatment but faces technical, biological, and clinical limitations that reduce efficacy and lead to high recurrence and resistance rates. These barriers, summarized in Table 4, underscore the need for innovative strategies discussed later.

Technically, 90% of GBMs recur within 2 cm of the irradiated field due to diffuse infiltration [32], despite advanced techniques like IMRT, VMAT, or proton therapy (PT). High doses cause fatigue, radiation necrosis, and cognitive deficits, linked to irradiated brain volumes receiving 20 Gy (V20Gy) and 40 Gy (V40Gy) , though IMRT, VMAT, and PT reduce neurotoxicity [25]. Dosimetric constraints (<54 Gy to brainstem and optic chiasm) limit dose escalation [25]. Delays >6 weeks from surgery to RT worsen OS and PFS, though moderate delays (~6 weeks) may benefit patients with residual disease [33,34]. TTFields extend PFS by 2.7 months (6.7 vs. 4.0 months) but are limited by cost and adherence (≥18 hours/day) [35]. Biologically, GBM radioresistance is driven by genetic heterogeneity, including EGFR amplification (40–60%), phosphatase and tensin homolog (PTEN) mutations, or or cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, and tumor stem cells [36,37]. Poly (ADP-ribose) polymerase (PARP) inhibitors such as veliparib and other radiosensitizers show promise in early-phase trials by inhibiting DNA repair, awaiting phase III confirmation [36,37]. EGFR amplification activates the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, conferring RT resistance, with limited benefits from inhibitors like erlotinib [38]. Tumor hypoxia, mediated by hypoxia-inducible factor 1-alpha (HIF-1α), promotes resistance [37]. The subventricular zone (SVZ), a reservoir of tumor stem cells with genetic alterations, drives recurrence; irradiating the SVZ with doses ≥56 Gy (ipsilateral) or ≥50 Gy (contralateral) does not significantly improve PFS or OS [39,40]. RT-induced lymphopenia (14% with PT vs. 39% with photons) limits immunotherapy efficacy [41]. Clinically, pseudoprogression (30–40% with methylated MGMT) complicates assessment up to 12 weeks [42,43]. Multimodal imaging, including multiparametric MRI and amino acid PET enables RT personalization, achieving a median overall survival (mOS) of 23 months in a phase I trial without significant toxicity [44]. Biomarkers (EGFR, PTEN, TERT, MGMT) enable stratification; only MGMT methylation improves OS in phase III trials [45]. A recent meta-analysis showed that combined targeted therapies improve PFS in newly diagnosed GBM (nGBM) but not OS in nGBM or recurrent GBM (rGBM), reflecting tumor heterogeneity and molecular resistance [46].

4. Molecular Determinants in Glioblastoma Multiforme

Most GBMs, classified as IDH-wt, exhibit aggressive biology and radioresistance due to genetic and epigenetic alterations that enhance DNA repair and cell survival [45]. MGMT methylation (~45%) increases sensitivity to chemoradiation (CRT), while EGFR, PTEN, and TERT contribute to resistance [12,45]. Patients with MGMT methylation show significantly higher OS (21.7 vs. 15.3 months) and better response to reirradiation in relapse compared to unmethylated cases [12,47,48] (Table 5).

A key radioresistance mechanism in IDH-wt GBMs is activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, driven by EGFR amplification and PTEN loss, which promotes proliferation, inhibits apoptosis, and enhances DNA repair post-RT [49]. Inhibitors like erlotinib yield modest results (ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) IIIA) [50]. Other alterations, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and cyclin-dependent kinases 4 and 6 (CDK4/6) amplification, enhance cell cycle progression, while CDKN2A/B homozygous deletion, causing loss of cyclin-dependent kinase inhibitor 2A (p16^INK4a^) and alternate reading frame protein p14 (p14^ARF^), is linked to poor prognosis [45,51]. These biomarkers lack effective targeted therapies due to signaling redundancy and pharmacokinetic limitations in the central nervous system [52]. In contrast, IDH1/2 mutations (~10%) confer greater radiosensitivity and better prognosis (ESCAT I) [53]. TERT promoter mutations, present in >80% of IDH-wt GBMs, activate telomerase and may promote immune evasion, though their role as predictive markers or therapeutic targets remains unclear [3,54]. Ongoing clinical trials are exploring TERT as a potential immunotherapeutic target, particularly in combination with immune checkpoint inhibitors, to enhance RT efficacy in immunosuppressive tumor microenvironments [3]. Given the limited clinical impact of standard RT in unfavorable molecular subgroups, radiosensitization strategies are being explored to enhance its therapeutic effect [55]. Among the most promising are poly (ADP-ribose) polymerase (PARP) inhibitors, which interfere with single-strand DNA break repair, exacerbating radiation-induced damage [56]. These inhibitors are particularly relevant for MGMT-unmethylated tumors, where TMZ resistance limits therapeutic options [12]. Although preclinical evidence shows synergy between PARP inhibitors and RT, their clinical efficacy is still under evaluation [45]. A recent phase II trial demonstrated that the PARP inhibitor veliparib, combined with TMZ and RT, improved PFS in MGMT-unmethylated patients, pending phase III confirmation (see Section 4 for details) [36]. RT-induced lymphopenia restricts synergy with immunotherapy, but MGMT methylation identifies patients with favorable immune microenvironments, and PT may reduce lymphopenia to enhance combined therapies [41]. Genomic profiling is a promising approach to personalize RT and its combination with targeted therapies or immunotherapy, with EANO 2025 guidelines recommending systematic profiling to optimize diagnosis and identify candidates for personalized trials [55,57].

5. Advances in the Treatment of Glioblastoma Multiforme

GBM is an aggressive brain tumor with a high recurrence rate. In non-elderly patients with good functional status (KPS ≥70), the Stupp protocol has been the standard of care for nearly two decades [12]. However, tumor resistance has limited progress over the past decade [37]. Novel approaches, including advanced radiotherapies, immunotherapies, targeted therapies, advanced imaging, and nuclear medicine, aim to improve tumor control and quality of life while reducing toxicity.

5.1. Technological Advances in Therapies

Technological advancements have enhanced the precision of treatment, minimizing damage to healthy tissues [58]. PT is increasingly relevant, particularly in reirradiation and selected cases [58]. It leverages the Bragg peak, depositing maximum energy at the end of its range with a sharp fall-off, to target the tumor, with a relative biological effectiveness (RBE) of 1.1 [58]. A phase II trial (NCT01854554) demonstrated that PT (60 Gy/30 fractions) significantly reduced grade ≥3 lymphopenia (14% vs. 39%), minimized irradiated brain volumes (V5–V40), and preserved immune function, potentially enhancing immunotherapy efficacy [6,41]. Although it did not delay cognitive decline compared to IMRT, it reduced fatigue and grade ≥2 toxicity, lowering doses to critical structures, suggesting potential for cognitive preservation in low-grade gliomas [6,59]. The NRG-BN001 trial is evaluating PT dose escalation versus photons, with results pending [60,61]. Carbon ion radiotherapy (CIRT) achieves a median mOS of 18 months in nGBM, surpassing 14 months with photons plus TMZ [62]. Boron neutron capture therapy (BNCT) reports an mOS of 25.7 months in nGBM with TMZ and 18.9 months in rGBM [63,64]. Magnetic resonance-guided radiotherapy (MRgRT) achieves an mOS of 18.5 months and a PFS of 11.6 months in nGBM (UNITED, non-randomized phase II), with UNITED2 ongoing [65,66]. TTFields, a standard in NCCN (category 1) and American Society of Clinical Oncology (ASCO) guidelines but not endorsed by the National Institute for Health and Care Excellence (NICE) due to cost-effectiveness, low adherence, and biases in EF-14 (unblinded, selected patients), achieve an mOS of 20.9 months (PFS 6.7 months) in nGBM (phase III EF-14) and an mOS of 10.3 months in rGBM (EF-11). These biases include lack of blinding and selection of healthier patients, potentially inflating efficacy estimates. Trials include phase II 2-THE-TOP (NCT03405792), reporting an mOS of 24.8 months and PFS of 12.0 months with pembrolizumab plus TMZ in nGBM [14], and ongoing phase III trials (TRIDENT with RT/TMZ, EF-41 with TMZ plus pembrolizumab in nGBM) [67,68,69]. Modulated electrohyperthermia (mEHT), laser interstitial thermal therapy (LITT), and magnetic hyperthermia (MHT) have limited evidence in rGBM, supported by non-randomized phase I/II trials [70,71,72,73]. These techniques, detailed in Table 6, face challenges related to cost and accessibility.

5.2. Modified Fractionation Schedules

Modified fractionation schedules optimize RT by counteracting tumor repopulation and reducing treatment duration [37,74]. Hypofractionation, standard in elderly patients with poor functional status (40 Gy/15 fractions), shows promise in younger patients (50–60 Gy/20 fractions with TMZ). The randomized phase II HART-GBM trial achieved an mOS of 26.5 months compared to 22.4 months with standard fractionation [74]. An institutional study reported an mOS of 19.8 months [75], and a meta-analysis showed a 12-month OS of 71.3% across various ages [76]. Hyperfractionation shows no clear benefit, with similar survival outcomes and moderate toxicity compared to standard fractionation [37,77]. Dose escalation (75 Gy/30 fractions) improves PFS but not mOS (NRG-BN001, randomized phase II, mOS 18.7 months, PT arm ongoing) [60]. Dose escalation with a CIRT boost (16.8–24.8 GyE) achieves an mOS of 18 months [62]. Toxicities include radionecrosis (6.7–14.2%) and cognitive decline [75,78,79]. Tumor heterogeneity and hypoxia necessitate phase III trials, as detailed in Table 7.

5.3. Reirradiation

Reirradiation is a viable option for rGBM in patients with recurrence more than 6 months after initial RT, following multidisciplinary discussion. The 2025 ESTRO/EANO guidelines (KPS >60, tumor volume <35 cm³) and ASTRO 2025 guidelines (KPS ≥70, tumor volume ≤6 cm³) endorse its selective use [11,80]. Post-contrast T1 MRI delineates the GTV, complemented by [18F]-FET or [18F]-FDOPA PET to detect recurrence [80,81]. Regimens such as hypofractionated RT (35 Gy/10 fractions) with bevacizumab (BEV) achieve an mOS of 10.1 months and PFS of 3–6 months, with approximately 5% radionecrosis [80]. NRG Oncology/RTOG 1205 demonstrated improved PFS with hypofractionated RT plus BEV [80]. The LEGATO trial evaluates lomustine with or without reirradiation [82]. Hypofractionated stereotactic RT (25 Gy/5 fractions) showed outcomes similar to 35 Gy/5 fractions, with lower toxicity but higher radionecrosis in larger volumes [83]. CIRT (45 Gy RBE/15 fractions) improves mOS (8.0 months) compared to photons [62]. PT achieves an mOS of 7.8–19.4 months in reirradiation [61]. While not detailed here, brachytherapy, pulsed low-dose-rate radiotherapy (pLDR), and flash radiotherapy are promising for recurrent GBM [11,37] See Table 8.

5.4. Neoadjuvant Therapy

Neoadjuvant therapy (NAT) reduces tumor volume to facilitate resection or enhance CRT, though it faces challenges such as the need for invasive stereotactic biopsy to confirm diagnosis [84]. In preoperative NAT, BEV in patients with low KPS improves resection (>95%), with an mOS of 15.7 months [85]. POBIG (phase I) evaluates stereotactic RT (6–14 Gy/1 fraction) [86], and PARADIGMA (phase II, NCT03480867) explores RT plus TMZ [84]. In postoperative NAT for unresectable GBM, TMZ plus BEV, the most promising regimen, achieves an mOS of 12.5 months and PFS of 7.4–8.6 months, but BEV increases intracranial hemorrhages [84,87,88]. In resectable GBM, MAGMA (phase III) evaluates neoadjuvant TMZ (75 mg/m² daily) and extended adjuvant TMZ (150–200 mg/m² until progression) before CRT (60 Gy/20 fractions), achieving an mOS of 23 months in MGMT-methylated cases [89]. Neoadjuvant immunotherapies, such as pembrolizumab in resectable rGBM and triple immunotherapy (nivolumab plus ipilimumab plus relatlimab) in nGBM, show potential in selected subgroups [90,91]. Preliminary data from a single nGBM case in the GIANT trial (NCT06816927) suggest no recurrence at 17 months, pending further validation [91]. Future trials should combine immune checkpoint inhibitors (ICIs) with intratumoral oncolytic viruses to enhance immune responses, with strict patient selection due to variable toxicity [84]. ICI immunotherapy combined with oncolytic viruses may benefit selected subgroups [84] (Table 9)

5.5. Immunotherapy, Targeted Therapies, and Chemotherapy

Chemotherapies, targeted therapies, and immunotherapies are evaluated for nGBM and rGBM (Table 10).

Standard TMZ chemotherapy, established by the EORTC/NCIC CE.3 trial, is the reference treatment in nGBM, improving survival compared to RT alone [12], though intensive TMZ offers no benefit (RTOG 0525) [92]. In rGBM, metronomic TMZ shows limited activity, particularly after BEV (RESCUE), and lomustine offers modest results (EORTC 26101) [93-95]. Lomustine plus TMZ achieves an mOS of 48.1 months in nGBM with MGMT methylation (CeTeG/NOA-09) [96]. Chemotherapy- and RT-induced lymphopenia, as discussed in Section 4, may limit subsequent immunotherapy efficacy. Targeted therapies, such as BEV, do not extend OS in nGBM (AVAglio, RTOG 0825; mOS 16.8 months, mPFS 10.6 months) but improve disease control in rGBM (BRAIN, EORTC 26101, BELOB; mOS 9.2 months, mPFS 4.2 months) [94,95,97,98] (see Table 9 for its neoadjuvant role). PARP inhibitors, such as veliparib, tested in the VERTU trial, are a promising targeted therapy in nGBM with unmethylated MGMT by enhancing radiation-induced damage, one of the few strategies with clinical evidence in specific subgroups [36].Cilengitide is ineffective in nGBM (CENTRIC, CORE) [95,99], as are erlotinib and everolimus, both inhibitors of tumor signaling pathways [38,95]. Regorafenib has limited efficacy in rGBM (REGOMA), outperforming erlotinib or everolimus but with modest benefits [95]. BRAF/MEK inhibitors show promising responses in BRAF V600E-mutated cases [95]. IDH inhibitors, such as vorasidenib, are under investigation for IDH-mutant gliomas, with no data in GBM [95]. In immunotherapy, nivolumab does not outperform BEV in rGBM (CheckMate 143) or TMZ with RT in nGBM with unmethylated (CheckMate 498) or methylated MGMT (CheckMate 548), where treatment-induced lymphopenia may reduce efficacy [3,90,100]. Adoptive cellular therapies and oncolytic viruses, such as G47Δ (modified herpes simplex virus) or DNX-2401 (adenovirus), are promising in rGBM. DNX-2401, in monotherapy (20% 3-year survival) or combined with pembrolizumab in the CAPTIVE trial (mOS 12.5 months, ongoing), shows preliminary efficacy, though immunosuppression from dexamethasone and RT may limit its effectiveness [90,101]. Neoadjuvant pembrolizumab before surgery in rGBM improves survival with an mOS of 13.8 months in specific subgroups [90,102] (see Table 9 for neoadjuvant use). The DCVax-L vaccine benefits nGBM (mOS 19.3 months) and rGBM (mOS 13.2 months) but is not standard; rindopepimut does not improve survival in EGFRvIII-positive nGBM (ACT IV) [90,103]. Other vaccines are in development for GBM [90]. Cytokines like interferon-alpha (IFN-α) enhance TMZ in nGBM (mOS 26.7 months, phase III), though not standard, and neoadjuvant triple immunotherapy before surgery prevents recurrences in isolated nGBM cases (GIANT, ongoing) [3,91]. The blood–brain barrier (BBB) and treatment-induced immunosuppression limit the combination of immunotherapy with RT [90] (Table 10).

5.6. Advanced Imaging and Theranostics

Multiparametric MRI, including T1/T2-FLAIR, dynamic susceptibility contrast perfusion (DSC), diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS), detects gliomas with high sensitivity, evaluates recurrence per RANO 2.0 criteria, including non-enhancing disease in IDH-mutant gliomas, and distinguishes pseudoprogression from true progression using DSC, DWI, and MRS (Table 11) [43,104,105]. Challenges include high costs and the need for specialized expertise in interpreting multiparametric MRI [104,105]. PET with amino acid tracers ([18F]-FET, [11C]-MET, [18F]-FDOPA, [18F]-FACBC) and [68Ga]-PSMA-11 differentiates recurrence from pseudoprogression with high specificity [106,107,108,109]. These techniques optimize RT planning by improving tumor delineation and enabling dose escalation in high-risk regions. A phase I trial using multiparametric MRI and [18F]-FDOPA PET achieved an mOS of 23 months without significant toxicity, though phase III trials have not confirmed OS benefits [44].Theranostics with [131I]-IPA achieves an mOS of 16 months in rGBM, limited by BBB penetration [107] (Table 11). Ongoing trials are evaluating novel theranostic agents [107,109].

6. Conclusions and Future Directions

Despite significant advancements in GBM management, RT continues to face inherent limitations, primarily due to diffuse tumor infiltration and intrinsic radioresistance, often driven by specific molecular alterations. While advanced RT techniques, including IMRT, adaptive RT, PT, and TTFields, have refined dose precision, their direct translation into substantial clinical benefits remains limited.

However, promising strategies are emerging. Neoadjuvant approaches, modified fractionation (such as hypofractionated RT), and reirradiation for recurrent GBM show therapeutic potential. The integration of various systemic therapies, including immunotherapies, chemotherapies, and targeted agents, is crucial for enhancing tumor control. Furthermore, radiotheranostics are expanding treatment possibilities.

The future of GBM RT lies in leveraging molecular biomarkers (e.g., MGMT methylation, IDH mutations) and advanced imaging to enable truly tailored treatment planning. The paramount challenge will be to effectively integrate complex tumor biology, cutting-edge technological tools, and comprehensive clinical data, ideally through AI-driven predictive models, to achieve precise and adaptive RT planning. Only through this integrated and individualized approach can we anticipate significant improvements in oncological outcomes for GBM patients.