Natural History and Clinical/Dosimetric Determinants of Osteoradionecrosis in a Large Cohort of Head and Neck Cancer Following Curative Radiotherapy: Debunking the Myth of Decreased Rates of Osteoradionecrosis in the Modern Radiotherapy Era

Abstract

Osteoradionecrosis (ORN) of the mandible is the most devastating toxicity following head and neck cancer (HNC) radiotherapy (RT). The rate of ORN occurrence has been debatable in the modern era of advanced RT. We aim to determine the natural history and time to ORN development in a large cohort of HNC. After IRB approval, we identified HNC patients treated with curative-intent RT between 2005 and 2020 at MD Anderson Cancer Center. Dental oncology notes were reviewed and all dental procedures were recorded. Available dose volume histograms (DVHs) for the segmented mandibular volumes were extracted. Based on our previously published ORN normal tissue complication probability (NTCP) model, any dental procedure pre-RT is a clinical high-risk factor and, therefore, data were coded as (high vs. low clinical risk) accordingly. We also coded the dosimetric risk factors to (high vs. low dosimetric risk) according to our published DVH thresholds (high dosimetric risk if any applies: V45≥40%, V55≥25%, and/or D30 ≥40 Gy). Finally, patients were classified to four groups according to combined clinical and dosimetric risk factors (No, clinical, dosimetric, and both). We used the Kaplan-Meier method to calculate time to ORN development and ORN-free survival. For time to ORN development, any grade ORN occurrence was coded as event and all others were censored. For ORN-free survival, death and ORN were coded as events and all others were censored. Log-rank test was used to compared curves of different risk groups. One thousand eight hundred sixty-six patients were included. Median follow-up was 38 months (range 4-162). ORN was reported in 252 patients (13.5%). The median time to ORN development was 18.5 months (range 4-145). 95 patients (37.7%) developed ORN after 2-years post-RT. The 1-, 3-, and 5-year ORN rates were 4.7%, 12.7%, and 17.8%, respectively. The 1-, 3-, and 5-year ORN-free survival were 94.3%, 85.5%, and 80.3%, respectively. There were statistically significant differences (P < 0.0001) between ORN-free survival in different clinical/dosimetric risk factors. The patients with no, clinical-only, dosimetric-only, and both clinical and dosimetric risk factors were 35%, 19%, 22%, and 24%, respectively. The 5-year ORN-free survival was 94.3%, 89.8%, 76.3%, and 69.6% for patients with no, clinical-only, dosimetric-only, and both clinical and dosimetric risk factors, respectively. The hazard-ratio (HR) of ORN development in clinical-only, dosimetric-only, and both clinical and dosimetric risk groups was 2.1, 5.4, and 7.5 compared to the no risk group (P<0.05 for all). Our findings indicate that ORN remains a remarkable toxicity hazard for HNC survivors. A prolonged surveillance time is required for the majority of HNC survivor since more than one-third of the ORN events occurred after 2-year follow-up. Patients with combined clinical and dosimetric risk factors have a staggering ORN risk profile and are proper candidates for future prophylactic pharmacotherapy clinical studies.