Variable Relative Biological Effectiveness of Proton Therapy Increases PET-Visible Mucosal Injury in Head and Neck Cancer Patients

Abstract

Despite dosimetric advantages of proton therapy in head and neck cancers, there is concern for increased end of range relative biologic effectiveness (RBE) and subsequent dose enhancement and mucosal toxicity with proton therapy. Herein, we evaluated differences in mucosal PET avidity on post-treatment scans as a surrogate for mucosal injury between proton and photon therapy patients. We further assessed the relationship between PET changes and RBE. The cohort comprised 9 proton and 10 photon patients who received ≥50 Gy adjuvant radiotherapy to oropharyngeal mucosa who remained loco-regional disease free ≥6 months post-treatment. All patients underwent follow-up fluorodeoxyglucose (FDG) PET-CT scans 3 months post-radiotherapy. PET-CTs were fused to planning CTs using deformable registration. High- and low-uptake regions were auto-contoured using a ≥150% mean liver standard uptake value (SUV) threshold and intersected with mucosal targets with/without a 5mm margin. SUV maximum (SUVMAX) values, linear energy transfer (LET) statistics, and RBE statistics based on McNamara, Jones, and linear LET models were extracted and compared. The mucosal target SUVMAX values on post-treatment PET-CTs for proton patients averaged 6.78 compared to 4.83 for photon patients (p=0.0267). Near maximum (LETd1%) LET for mucosal targets with a 5mm margin averaged 5.232 keV/µm. RBE in high-uptake regions exceeded that of low-uptake regions (p=0.0039), with mean biologic dose exceeding clinical dose by 11.05%, 18.67%, and 15.65%, respectively, using different RBE models. Post-radiotherapy PET avidity was more commonly observed in proton patients. Within proton patient mucosal targets, the location of increased PET avidity corresponded to areas with higher RBE. This is the first report of differential PET findings based on RBE. These results suggest that elevated RBE was associated with PET avidity and mucosal injury.