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

Background: In head and neck carbon-ion radiotherapy (CIRT), high dose-averaged LET (LETd) and relative biological effectiveness weighted dose (D_RBE) often overlap the oro-pharyngeal-mucosa (mucosa of oral cavity, oro-pharynx, nasopharynx, pharynx) beyond the target, resulting in serious complications. We investigated clinical and dosimetric predictors for late severe mucosal-toxicity/ oro-antral fistula (OAF) post-CIRT. Materials and methods: CIRT plans for 51 patients with non-squamous head and neck cancers (NSHNCs) were evaluated and correlated with clinical outcome. Prescription was D_RBE of 68.8 Gy (65.6–76.8)/16 fractions optimized using Local Effect Model-I (LEM-I). After the first 21 patients a mucosa-sparing approach (MS-CIRT) was adopted, delineating healthy mucosa-to-spare within the high-dose PTV and applying D_RBE constraints (D_RBE|0.1cm3 < 70 Gy), maintaining target coverage. For the present analysis, D_RBE was recomputed also with the modified microdosimetric kinetic model (mMKM) and LETd was calculated. Several clinical and dosimetric parameters including DLV-parameters (61 Gy ≤ D_RBE ≤ 70 Gy, LETd ≥ 50 keV/µm, volume) that may be predictors of OAF were analyzed. Results: MS-CIRT reduced mucosal doses to < 70 Gy, preserving local control (preliminary results in limited number of patients). Seven patients developed late G3 OAF after median follow-up of 23 months, including 2 with MS-CIRT. Doses to oro-pharyngeal mucosa > 70 Gy were predictive of OAF development. Even moderate-high doses correlated with OAF if they coincided with high-LETd. For instance, when more than 1 cm³ of mucosa-to-spare was exposed to D_RBE|mMKM ≥ 63 Gy and LETd ≥ 75 keV/µm, 2-yr OAF-free survival probability was 38 % versus 100 % in cases where these thresholds were not exceeded (p < 0.001). Sino-nasal primary and HD–CTV ≥ 100 cm³ also influenced OAF development. Conclusion: Besides MS-CIRT strategy, optimizing DLV-parameters for oro-pharyngeal-mucosa may be a promising strategy in preventing late G3 OAF post-CIRT.