Normal Tissue Complication Probability (NTCP) Prediction Model for Osteoradionecrosis of the Mandible in Patients With Head and Neck Cancer After Radiation Therapy: Large-Scale Observational Cohort

Abstract

Purpose: Osteoradionecrosis (ORN) of the mandible represents a severe, debilitating complication of radiation therapy (RT) for head and neck cancer (HNC). At present, no normal tissue complication probability (NTCP) models for risk of ORN exist. The aim of this study was to develop a multivariable clinical/dose-based NTCP model for the prediction of ORN any grade (ORN_I-IV) and grade IV (ORN_IV) after RT (±chemotherapy) in patients with HNC.

Methods and materials: Included patients with HNC were treated with (chemo-)RT between 2005 and 2015. Mandible bone radiation dose-volume parameters and clinical variables (ie, age, sex, tumor site, pre-RT dental extractions, chemotherapy history, postoperative RT, and smoking status) were considered as potential predictors. The patient cohort was randomly divided into a training (70%) and independent test (30%) cohort. Bootstrapped forward variable selection was performed in the training cohort to select the predictors for the NTCP models. Final NTCP model(s) were validated on the holdback test subset.

Results: Of 1259 included patients with HNC, 13.7% (n = 173 patients) developed any grade ORN (ORN_I-IV primary endpoint) and 5% (n = 65) ORN_IV (secondary endpoint). All dose and volume parameters of the mandible bone were significantly associated with the development of ORN in univariable models. Multivariable analyses identified D_30% and pre-RT dental extraction as independent predictors for both ORN_I-IV and ORN_IV best-performing NTCP models with an area under the curve (AUC) of 0.78 (AUC_validation = 0.75 [0.69-0.82]) and 0.81 (AUC_validation = 0.82 [0.74-0.89]), respectively.

Conclusions: This study presented NTCP models based on mandible bone D_30% and pre-RT dental extraction that predict ORN_I-IV and ORN_IV (ie, needing invasive surgical intervention) after HNC RT. Our results suggest that less than 30% of the mandible should receive a dose of 35 Gy or more for an ORN_I-IV risk lower than 5%. These NTCP models can improve ORN prevention and management by identifying patients at risk of ORN.

Fig. 1.

Average dose-volume histogram (DVH) for patients who develop osteoradionecrosis (ORN) (red) versus those who do not (green) for volume (V_xGy) (left) and dose (D_x%) parameters (right). Error bars represent 95% confidence interval. Color shading indicates the univariable significance of parameters, indicating that D_2% to D_98% and V_15Gy to V_70Gy were significant with a P < .0001. Notably, the curves are inversions of each other, but show the univariable separation ability between the groups and significance per V_xGy and D_x% variable.

Fig. 2.

Final osteoradionecrosis (ORN) normal tissue complication probability (NTCP) models. NTCP curves are plotted against D_30% split into patients with pretreatment dental extraction (orange lines) and those without (green lines) for NTCP models for ORN any grade (left plot) and grade IV (right). The dotted line indicates the most outer 95% confidence interval (CI) limits of the NTCP curves. Point with 95% CI error bars of the actual observed ORN rates by binning all patients sorted by dose in X percentiles; points are positioned at the average dose per bin.