Causal Machine Learning Analysis of Empirical Relative Biological Effectiveness (RBE) for Mandible Osteoradionecrosis in Head and Neck Cancer Radiotherapy

Mandible Osteoradionecrosis (ORN) is one of the most severe adverse events (AEs) for head and neck (H&N) cancer radiotherapy. Previous retrospective investigations on real-world data relied on conventional statistical models that primarily elucidate correlation rather than establishing causal relationships. Through the novel causal machine learning, we aim to obtain empirical relative biological effectiveness (RBE) for ORN in H&N cancer patients treated with pencil-beam-scanning proton therapy (PBSPT). 335 patients treated by PBSPT and 931 patients treated by volumetric-modulated arc therapy (VMAT) were included. We use 1:1 case-matching to minimize the imbalance in clinical factors between PBSPT and VMAT. The bias test of standardized mean differences (SMD) was applied on the case-matched patient cohorts. The causal machine learning method, causal forest (CF), was adopted to investigate the causal effects between dosimetric factors and the incidence of ORN. The dose volume constraints (DVCs) for VMAT and PBSPT were derived based on causal effects. RBE values were further empirically derived based on tolerance curves formed from DVCs. 335 VMAT patients were case-matched to 335 PBSPT patients; however, SMD analysis revealed persistent covariate imbalances within each group, indicating residual confounding influence. Using CF modeling, we identified DVCs of mandible ORN and found that PBSPT had lower critical volumes than those of VMAT, leading to empirical RBE exceeding 1.1 in the moderate dose range (1.61 at 40 Gy[RBE=1.1], 1.30 at 50 Gy, and 1.13 at 60 Gy). This study presents a novel application of causal machine learning to evaluate mandible ORN in radiotherapy. The results indicate that proton RBE may significantly exceed 1.1 in the moderate dose range, underscoring the importance of incorporating the variable RBE into PBSPT treatment planning to mitigate the risk of ORN.