Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.

Dr. Ruggiero is a consultant for Amgen Pharmaceuticals. Dr. Fuller receives salary, grant and infrastructure support from MD Anderson Cancer Center via the NIH/NCI Cancer Center Support Grant (CCSG) (P30CA016672). Dr. Fuller has received direct industry grant/in-kind support, honoraria, and travel funding from Elekta AB. Dr. Fuller has served as a consulting capacity for Varian/Siemens Healthineers. Philips Medical Systems, and Oncospace, Inc. Dr. Moreno received/receives unrelated funding and salary support from: NIH National Institute of Dental and Craniofacial Research (NIDCR) Exploratory/Developmental Research Grant Program (R21DE031082-01) and Mentored Career Development Award to Promote Diversity (K01DE030524-01A1). Dr. Moreno is the Delphi study lead of the ORAL Consortium currently reviewing ORN grading and staging data elements for clinical and dental consensus recommendations. Drs. Moreno and Fuller receives infrastructure support from MD Anderson Cancer Center via philanthropic support from the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program.

Dr. Huang acknowledges support by the Bartley-Smith/Wharton, the Gordon Tozer, the Wharton Head and Neck Translational, Dr. Mariano Elia, the Joe's Team, and the Petersen Funds at the Princess Margaret Foundation of author's (SHH) academic activity. Dr. Fuller received/receives related funding and salary support from: NIH National Institute of Dental and Craniofacial Research (NIDCR) Establishing Outcome Measures for Clinical Studies of Oral and Craniofacial Diseases and Conditions award (R01DE025248), Exploratory/Developmental Research Grant Program (R21DE031082), and NIDCR Prospective Observational or Biomarker Validation Study Cooperative Agreement Award (U01DE032168); and a National Cancer Institute Parent Research Project Grant (R01CA258827).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee board of Princess Margaret Cancer Centre gave ethical approval for this work prior to initiation of the study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the corresponding author.