Impact of RBE variations on risk estimates of temporal lobe necrosis in patients treated with intensity-modulated proton therapy for head and neck cancer

Background: Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC. Material and Methods: Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWD_Fix) and variable RBE-weighed doses (RWD_Var) were calculated using RBE = 1.1 and two RBE models, respectively. RWD_Fix and RWD_Var for temporal lobes were compared using Friedman’s test. Based on RWD_Fix, six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWD_Fix and RWD_Var were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWD_Fix and RWD_Var by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints. Results: RWD_Var were significantly higher than RWD_Fix (p < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWD_Fix and RWD_Var ranged between 5.3% and 20.0% points (p < 0.01), with V_60GyRBE and D_Max at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWD_Fix (4.0%–13.1%) versus RWD_Var (1.3%–5.3%). For V_65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWD_Fix and RWD_Var. Conclusion: NTCP estimates were significantly influenced by RBE variations. D_max as model predictor resulted in the largest deviations in risk estimates between RWD_Fix and RWD_Var. V_65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWD_Fix and RWD_Var..