Proton-specific dose and radiation quality constraints to reduce acute oral mucositis in head and neck cancer patients.

Abstract

Radiation-induced oral mucositis (RIOM) is one of the most frequent and impairing toxicities in head and neck cancer patients. The current clinical mitigation strategy for RIOM relies on photon-derived dosimetric constraints normalized by the proton generic relative biological effectiveness (RBE) of 1.1, and applied to the mean dose at the oral cavity. The approach neglects any dependence of toxicity on organ volume effects and radiation quality. In the present study, we provide a comprehensive characterization of RIOM in proton therapy patients, and develop proton-specific constraints to reduce RIOM which do not rely on RBE. We evaluated RIOM in 79 patients treated with Intensity Modulated Proton Therapy (IMPT) and 94 patients with Volumetric Modulated Arc Therapy (VMAT) photon therapy at the University of Miami. For each patient, we collected the physical dose and radiation quality received by the oral cavity, as well as patient-specific information. We used microdosimetry to describe radiation quality. VMAT is associated to a significantly higher grade of RIOM, with 84% of cases (68% G2 + G3), compared to 56% for IMPT (33% G2 + G3). Dose and volume are the primary drivers of mucositis, with radiation quality influencing severity. The new IMPT dose-volume tolerances are consistently lower than VMAT, and decrease with increasing radiation quality for y¯_D > 5 keV/μm. The constraints demonstrated good discrimination of G2 + G3 toxicity (AUC = 0.81), and model-based simulations projected a reduction of RIOM from 33% to 20% under full compliance. Integrating dose, organ volume, and radiation quality into proton-specific constraints without relying on a constant clinical RBE or photon-derived tolerances improves toxicity discrimination and provides a clinically attainable framework for reducing G2 + G3 RIOM in IMPT.