Association Between Linear Energy Transfer Distribution and Local Recurrence in Recurrent Nasopharyngeal Carcinoma Reirradiated With Intensity-Modulated Carbon Ion Therapy.
retrospective_cohort · Level III
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- Record sourced from PubMed, PMID 42610991.
- Also identified by DOI 10.1016/j.ijrobp.2026.07.033.
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Abstract
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 (LET<sub>d</sub>) within the tumor. This study evaluated the prognostic value of LET<sub>d</sub> metrics for local control (LC) in rNPC. 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 LET<sub>d</sub> 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. 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 LET<sub>d</sub>mean, LET<sub>d</sub>50, and LET<sub>d</sub>99. The volume receiving LET<sub>d</sub> ≥50 keV/μm in gross tumor volume (GTV VL<sub>50keV/μm</sub>) was nearly 2-fold higher in the LC group than the LR group (57.50% vs 31.75%; P = .013). Multivariate analysis identified GTV LET<sub>d</sub>99 as a robust independent protective factor for LR.Restricted cubic spline analysis revealed a nonlinear "λ"-shaped association between LET<sub>d</sub>99 and LR, with a risk inflection point at 39.4 keV/μm. LET<sub>d</sub>99 showed strongest predictive value at 24 months (area under the curve = 0.77), and LET<sub>d</sub>99 ≥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 LET<sub>d</sub> distribution (r= -0.16 to -0.67), whereas beam angular span primarily affected moderate high-LET<sub>d</sub> (50-70 keV/μm) volume coverage without influencing LET<sub>d</sub>max or LET<sub>d</sub>min. 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 LET<sub>d</sub>min were associated with improved LC. This study provides reference LET<sub>d</sub> levels and beam arrangement strategies for LET-guided optimization, emphasizing sufficient minimum LET<sub>d</sub> (>39.4 keV/μm) and broad high-LET<sub>d</sub> coverage (50-60 keV/μm).