Association Between Linear Energy Transfer Distribution and Local Recurrence in Recurrent Nasopharyngeal Carcinoma Reirradiated With Intensity-Modulated Carbon Ion Therapy

Why clinicians should know about it

• Picked for Radiology, Radiation Oncology, Nuclear Medicine, Medical Physics and Imaging (paper of the day, 24 August 2026): Retrospective study linking LETd to local recurrence
• Picked for Medical Physics (top studies of the week, 23 August 2026).

Abstract

PURPOSE: Local recurrence (LR) after reirradiation with intensity-modulated carbon ion therapy (IMCT) in recurrent nasopharyngeal carcinoma (rNPC) may relate to insufficient dose-averaged linear energy transfer (LETd) within the tumor. This study evaluated the prognostic value of LETd metrics for local control (LC) in rNPC. METHODS AND MATERIALS: This retrospective study enrolled 76 patients with rNPC who underwent salvage IMCT reirradiation at Shanghai Proton and Heavy Ion Center (SPHIC) from 2015 to 2019. Clinically, dosimetric and LETd variables were evaluated for association with LC using Cox models with Fine-Gray competing risk analysis accounting for competing risks of death as a sensitivity analysis. Threshold effects were evaluated using restricted cubic spline modeling and time-dependent receiver operating characteristic (time ROC) analysis, with validated by Kaplan-Meier and cumulative incidence function analyses. RESULTS: With a median follow-up of 38.3 months (range, 19.3-72.2), 26 patients developed LR. In long-term survivors, LC patients had significantly higher LETdmean, LETd50, and LETd99. The volume receiving LETd ≥50 keV/μm in gross tumor volume (GTV VL50keV/μm) was nearly 2-fold higher in the LC group than the LR group (57.50% vs 31.75%; P = .013). Multivariate analysis identified GTV LETd99 as a robust independent protective factor for LR.Restricted cubic spline analysis revealed a nonlinear "λ"-shaped association between LETd99 and LR, with a risk inflection point at 39.4 keV/μm. LETd99 showed strongest predictive value at 24 months (area under the curve = 0.77), and LETd99 ≥39.4 keV/μm correlated with improved 2-year LC (94.4% vs 65.3%; P = .003). Interval between the first radiation therapy course and reirradiation emerged as a significant protective factor in the Cox and Fine-Gray model (hazard ratio, subdistribution hazard ratio <1; P < .05). Correlation analysis revealed that tumor volume was the dominant determinant of LETd distribution (r= -0.16 to -0.67), whereas beam angular span primarily affected moderate high-LETd (50-70 keV/μm) volume coverage without influencing LETdmax or LETdmin. CONCLUSIONS: LR in patients with rNPC who underwent reirradiation treated with IMCT is influenced by multiple factors. In addition to biological equivalent dose and tumor volume, a longer interval between radiation therapy courses and higher GTV LETdmin were associated with improved LC. This study provides reference LETd levels and beam arrangement strategies for LET-guided optimization, emphasizing sufficient minimum LETd (>39.4 keV/μm) and broad high-LETd coverage (50-60 keV/μm).

Abstract as published, via PubMed.