Impact of dose and dose-averaged linear energy transfer on oro-pharyngeal-mucosal toxicity in patients with non-squamous head and neck cancers treated with carbon-ion radiotherapy

The article analyzes the relationship between physical dose, dose-averaged linear energy transfer (LETd), and acute mucosal toxicity in patients undergoing carbon-ion radiotherapy (CIRT). While carbon-ion therapy offers superior dose conformity and higher relative biological effectiveness (RBE) compared with conventional photon therapy, its elevated LET may increase the risk of normal tissue toxicity, particularly in sensitive mucosal structures.

In this clinical study, patients with non-squamous head and neck malignancies were evaluated for the development of oro-pharyngeal mucositis during and after treatment. The authors correlated treatment planning parameters—including total dose and LETd distributions—with the incidence and severity of mucosal toxicity. The analysis demonstrated that both higher physical doses and increased LETd values were significantly associated with more severe acute mucositis. Importantly, regions receiving elevated LETd appeared to have a disproportionately higher risk of toxicity, suggesting that LET distribution within the target and adjacent normal tissues plays a critical role in biological response.

The findings indicate that mucosal toxicity cannot be predicted solely by physical dose; instead, the combined influence of dose and LETd must be considered in treatment planning. The study concludes that incorporating LET-based optimization strategies may help reduce severe oro-pharyngeal mucositis without compromising tumor control. Overall, the results underscore the need for biologically informed planning approaches in carbon-ion radiotherapy to better balance therapeutic efficacy and normal tissue protection, particularly in anatomically complex and functionally critical head and neck regions.

Published by Radiotherapy and Oncology 214 (2026) 111314
DOI: 10.1016/j.radonc.2025.111314