ESTRO 2025 Congress report
By the ESTRO CNS focus group
ESTRO 2025 showcased significant advances across physics, therapy, biology, and oncology. This report summarises the key highlights of the central nervous system (CNS) journey and provides an overview of the most impactful developments presented at the conference.
Imaging Biomarkers and Radiotherapy Adaptation
Adaptive radiotherapy was prominently featured. In glioblastoma management, the use of low-dose gadolinium contrast MRI enabled surveillance during MRI-linac-guided therapy, although full-dose scans remain essential for adaptation. Histological validation of time-dependent diffusion MRI further reinforced its correlation with tumour-cell density and outperformed conventional apparent diffusion coefficient (ADC). In other, similar reports, MR-guided online adaptive radiotherapy was shown to significantly improve coverage in glioblastoma patients through accommodation of daily anatomical changes, particularly in patients with methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase (IDH) wild-type tumours. Other imaging studies demonstrated that voxel-wise analysis of CT with angiography and oxygen extraction fraction perfusion biomarkers showed improved predictive power for glioma recurrence, potentially refining target delineation strategies.
Simulation-Free Radiotherapy: The Next Frontier
A major theme was the simulation-free paradigm, or direct-to-unit radiotherapy. In a pitch session and associated physics discussions, presenters described workflows that omitted dedicated simulation CTs and relied instead on diagnostic or onboard imaging. Case series and technical evaluations confirmed that CT-equivalent image quality and dosimetric accuracy could be achieved through the use of cone-beam CT and MR-based planning, even in emergent hippocampal avoidance settings. The implications for palliative and even curative indications are promising, pending further standardisation.
Particle Therapy and LET Optimisation
Several presenters tackled emerging frontiers in particle therapy. A novel approach for supine ocular proton therapy that used a general-purpose vertical beam-line was shown to achieve comparable dosimetric precision to dedicated eye rooms. The world’s first clinical helium ion trial—conducted at Heidelberg—showed favourable early outcomes in CNS and skull-base tumours, with no toxicity above grade 3. This underscores the potential use of helium to combine precision with biological safety.
A series of reports advanced the paradigm of planning in proton- and carbon-ion therapy that is guided by linear energy transfer (LET). Authors of one study reported on sacral chordoma patients who had been treated with LET-optimised carbon-ion plans and for whom significantly increased LETd-min values were achieved with comparable robustness and no additional toxicity. These results demonstrated the feasibility of biologically informed optimisation. Similarly, a study on low-grade glioma patients showed that the use of LET-optimised proton-arc therapy could significantly reduce the dose to visual organs at risk and the cerebrum, while preserving target coverage. A study on paediatric craniopharyngioma found strong spatial correlations between high-LET regions and post-treatment imaging abnormalities, underscoring the importance of field-specific LET analysis. Importantly, these approaches suggest that LET-guided strategies can serve as surrogates for biologically variable optimisation of relative biological effectiveness (RBE).
Dose-Response Relationship and Toxicities
A series of presenters addressed dose-response relationships. A large prospective study confirmed an increase in local control, dependent on the biologically effective dose with an alpha/beta ratio of 10, for brain metastases that were treated via stereotactic radiosurgery (SRS), regardless of tumour size. In the same brain metastasis setting, the use of neoadjuvant SRS demonstrated low toxicity and high local control in pooled international data, while intraoperative radiotherapy showed encouraging results when 20Gy doses were used. Finally, SRS dose modelling studies led to refined dose-volume constraints for small metastases; the recommendations were V15Gy < 5cm3 and V18Gy < 4cm3 to minimise radionecrosis. A complementary meta-analysis identified cumulative biologically effective dose as a key predictor of myelopathy in re-irradiation settings. Also, new data highlighted a dose-dependent impact of radiotherapy on functional brain hubs. Structural-functional disconnectivity in left-sided hubs was linked to cognitive impairment, suggesting a rationale for functional avoidance planning. Similarly, contrast-enhanced perfusion imaging was explored as a tool that could be used to distinguish tumour progression from radiation-induced changes.
Advances in Adult Diffuse Gliomas
Since the World Health Organisation classified IDH mutation testing in 2021, it has become essential for diagnosis and treatment planning. The IDH inhibitor vorasidenib is approved for the treatment of IDH-mutant grade 2 gliomas, with ongoing trials such as VIGOR evaluating its role after surgery and radiotherapy. Radiotherapy for IDH-mutant gliomas now benefits from improved imaging and tumour classification, enabling reductions in clinical target volume (CTV) margins (1.0cm for grade 2, 1.5cm for grades 3 and 4) and standard fractionation schedules (50.4 Gy in 28 fractions, 59.4 Gy in 33, and 60 Gy in 30 for grades 2, 3, and 4, respectively). While the use of IDH inhibitors may allow deferral of radiotherapy, the biological changes at progression remain unclear and need further investigation.
IDH-wildtype gliomas, particularly glioblastomas, exhibit aggressive biology. Updated radiotherapy guidelines refine target volumes to improve control while sparing healthy tissue; CTV margins have been reduced to 1.5cm, and oedema has been excluded by using fluid-attenuated inversion recovery imaging and FET-PET. The PRIDE study utilises the imaging advancements to apply dose-escalation precisely to the high-risk areas while mitigating toxicity with bevacizumab. Re-irradiation may improve survival in recurrent glioblastoma, particularly when combined with chemotherapy and bevacizumab, although prospective confirmation is pending. Treatment planning should use advanced imaging for target delineation and adhere strictly to cumulative dose constraints (e.g., equivalent dose in 2Gy fractions < 100Gy to healthy brain tissue).
Furthermore, the new ESTRO and European Association of Neuro-Oncology guideline on glioblastoma re-irradiation was introduced through the use of classical and non-classical case examples. Key challenges included the individualisation of fractionation based on tumour size, optimisation of treatment timing, and integration of bevacizumab into re-irradiation regimens.
Novel CNS-Targeted Therapies and Radiotherapy Integration
Several CNS-active agents – including HER2 tyrosine kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates such as trastuzumab deruxtecan – show efficacy in HER2+ brain metastases in breast cancer. Preclinical models that closely mimic intracranial disease more accurately predict CNS activity than earlier models, and even agents with limited penetration of the blood-brain barrier may achieve clinical effectiveness.
SRS is preferred over whole-brain radiotherapy for patients with up to (or more than) ten brain metastases. In patients with targetable mutations or immunotherapy-sensitive tumours, SRS can be safely delayed with close MRI monitoring, although it should be applied upfront if local control is expected to improve outcomes. Combining SRS with systemic therapies may produce synergistic effects and carry an acceptable risk of brain necrosis, but more clinical data are needed. Ongoing research is focused on the optimisation of treatment sequencing and minimisation of toxicity.
Paediatric Tumour Insights
Several studies highlighted advances in paediatric CNS tumour care. Children with craniopharyngioma that was treated with stereotactic conformal radiotherapy experienced better long-term cognitive and endocrine outcomes without compromise of tumour control or survival rates (10-year overall survival rate 86%, local control 93%) compared to conventional radiotherapy. In ependymoma, factors such as severity of tumour grade, incomplete resection, lateral tumour location, delayed radiotherapy and total doses below 54Gy were linked to poorer prognosis and higher relapse rates. These results emphasised the need for timely, precise treatment. In recurrent, diffuse, intrinsic pontine glioma and diffuse midline glioma, re-irradiation showed significant survival benefits, especially with longer intervals (>1 year) after initial therapy. Identification of further predictive factors is warranted.
In children who underwent cranial radiotherapy, neurocognitive and emotional regulation issues were found to correlate with radiation dose to brain regions such as the temporal lobes and cerebellum (but not the amygdala as initially hypothesised). These findings highlighted the need for broader dose-sparing strategies. Growth hormone deficiency remains a concern following proton therapy, particularly in cases in which the hypothalamus and pituitary receive doses that exceed 20Gy RBE and 30Gy RBE, respectively. Proton therapy for paediatric low-grade gliomas and intracranial germ-cell tumours showed excellent tumour control, minimal late toxicity, favourable cognitive and visual outcomes, and good reintegration, all of which support its early integration into treatment strategies.
Conclusion
The CNS journey at ESTRO 2025 highlighted progress toward biologically personalised, image-adaptive, and workflow-efficient radiotherapy. Advances from simulation-free planning to LET-guided dose sculpting and perfusion biomarkers are shaping the next generation of precision care. Importantly, the integration of radiotherapy with novel systemic treatments for IDH-mutant gliomas and brain metastases is enhancing multidisciplinary management, treatment sequencing, and patient outcomes, paving the way for more effective and tailored CNS cancer therapy.
Authors:
Andrada Turcas, MD, PhD
The Oncology Institute, Cluj-Napoca, Romania;
Babes-Bolyai University, Cluj-Napoca, Romania
andrada.turcas@iocn.ro
Raphael Bodensohn, MD
Department of Radiation Oncology, University Hospital Tübingen, Germany
Raphael.Bodensohn@med.uni-tuebingen.de