Abstract
Oral mucositis is one of the most frequent and impairing acute adverse effects of radiotherapy for head and neck malignancies, occurring in almost 100% of patients. Although proton therapy provides a superior sparing of the oral cavity compared to photon therapy, up to 70% of patients still experience oral mucositis. Currently, the only countermeasure for mitigating this sequela is to set dose limits in the oral cavity, whose values have been derived from photon therapy data using the Relative Biological Effectiveness (RBE) as a scaling factor. In this work, we provide a comprehensive analysis of oral mucositis in H&N patients. Our objectives are to identify dose and radiation quality constraints on the oral cavity and build a Normal Tissue Complication Probability (NTCP) model of oral mucositis specific for proton therapy.
Our study involved 62 patients treated with Intensity-Modulated Proton Therapy (IMPT), and 124 treated with Volumetric Modulated Arc Therapy (VMAT) at one institution. Toxicity grades were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) scale v5.0. To compare the dosimetric differences between IMPT and VMAT plans, we calculate the equivalent uniform dose received by the oral cavity per fraction and cumulatively up to the fraction where oral mucositis was observed. Using the Monte Carlo software TOPAS MC, we calculated the radiation quality inside the oral cavity using the Linear Energy Transfer (LET) for all IMPT patients.
Salivary gland tumor patients showed significant benefits with IMPT, as none developed severe (grade >1) mucositis, compared to 34% of VMAT patients. Oropharyngeal tumors are the worst scenario, with 74% severe cases for IMPT versus 90% for VMAT. Severe mucositis induced by IMPT occurred at lower doses than VMAT, both per treatment fraction (1.0 vs. 1.5 Gy/fx, p<0.05) and cumulatively (22 vs. 30 Gy, p<0.05). Our findings for IMPT confirm that absorbed dose plays a central role in developing mucositis, with the more severe cases occurring at higher doses. Data also suggest a relation between grade, LET, and organ volume irradiated. Mild mucositis occurred with 10% of the organ volume receiving 1 Gy/fx and LET of 4 keV/micron, whereas the same dose and LET led to severe mucositis when 30% of the oral cavity received it. At a cumulative dose of 25 Gy, severe cases exhibited higher radiation quality than mild cases, independently of the oral cavity volume considered.
Clinical RBE underestimates the biological effectiveness of protons to induce oral mucositis. This outcome is a consequence of the complex interplay between dose, radiation quality, and organ volume effects. Our NTCP model incorporating dose-, LET- and organ volume-based constraints can be used for advanced treatment plan optimization to mitigate toxicity.