Investigation of the combined role of dose and dose-averaged LET in the occurrence of brain necrosis after intensity modulated proton therapy for meningioma and solitary fibrous tumours

This study investigates the combined influence of physical dose and dose-averaged linear energy transfer (LETd) on the risk of radiation-induced brain necrosis following intensity-modulated proton therapy (IMPT) in patients with meningioma and solitary fibrous tumors. While proton therapy offers superior dose conformity compared with photon-based radiotherapy, uncertainties remain regarding the biological effects of elevated LET at the distal edge of proton beams, where the relative biological effectiveness (RBE) may exceed the conventional constant value of 1.1.

The authors performed a retrospective analysis of treated patients, correlating spatial dose and LETd distributions with the occurrence of brain necrosis identified on follow-up imaging. Voxel-wise and region-based analyses were conducted to determine whether high-LET regions overlapping with moderate-to-high dose areas were associated with increased toxicity. Statistical modeling evaluated the predictive value of dose alone versus combined dose–LET metrics.

Results indicate that brain necrosis is not solely correlated with high physical dose but is significantly associated with regions where elevated LET coincides with intermediate-to-high dose levels. Areas receiving moderate doses with high LETd showed increased risk compared to regions characterized by dose alone. Models incorporating both dose and LET parameters demonstrated improved predictive performance over dose-only models, suggesting that biological dose heterogeneity plays a clinically relevant role in toxicity.

In conclusion, the study provides evidence that incorporating LETd into treatment evaluation improves risk assessment for brain necrosis after IMPT. These findings support the need for biologically informed treatment planning strategies that consider variable RBE effects. Future prospective studies and refinement of LET-guided optimization may enhance treatment safety while preserving the therapeutic advantages of proton therapy.

Published by Radiotherapy and Oncology 214 (2026)
DOI: 10.1016/j.radonc.2025.111290