Mandibular dose-volume predicts time-to-osteoradionecrosis in an actuarial normal-tissue complication probability (NTCP) model: External validation of right-censored clinico-dosimetric and competing risk application across international multi-institutional observational cohorts and online graphical user interface clinical support tool assessment

BackgroundExisting studies on osteoradionecrosis of the jaw (ORNJ) have primarily used cross-sectional data, assessing risk factors at a single time point. Determining the time-to-event profile of ORNJ has important implications to monitor oral health in head and neck cancer (HNC) long-term survivors. MethodsDemographic, clinical and dosimetric data were retrospectively obtained for a clinical observational cohort of 1129 patients with HNC treated with radiotherapy (RT) at The University of Texas MD Anderson Cancer Center. ORNJ was diagnosed in 198 patients (18%). A multivariable logistic regression analysis with forward stepwise variable selection identified significant predictors for ORNJ. These predictors were then used to train a Weibull Accelerated Failure Time (AFT) model, which was externally validated using an independent cohort of 265 patients (92 ORNJ cases and 173 controls) treated at Guys and St. Thomas Hospitals. FindingsOur model identified that each unit increase in D25% is significantly associated with a 12% shorter time to ORNJ (Adjusted Time Ratio [ATR] 0{middle dot}88, p<0{middle dot}005); pre-RT dental extractions was associated to a 27% faster (ATR 0{middle dot}73, p=0{middle dot}13) onset of ORNJ; male patients experienced a 38% shorter time to ORNJ (ATR 0{middle dot}62, p = 0{middle dot}11). The model demonstrated strong internal calibration (integrated Brier score of 0{middle dot}133, D-calibration p-value 0.998) and optimal discrimination at 72 months (Harrells C-index of 0{middle dot}72). The model also showed good generalization to the independent cohort, despite a slight drop in performance. InterpretationThis study is the first to demonstrate a direct relationship between radiation dose and the time to ORNJ onset, providing a novel characterization of the impact of delivered dose not only on the probability of a late effect (ORNJ), but the conditional risk during survivorship. FundingThis work was supported by various funding sources including NIH, NIDCR, NCI, NAPT, NASA, BCM, Affirmed Pharma, CRUK, KWF Dutch Cancer Society, NWO ZonMw, and the Apache Corporation.