A DNA damage multi-scale model for NTCP in proton and hadron therapy

Abstract: {\bf Purpose}: To develop a first principle and multi-scale model for normal tissue complication probability (NTCP) as a function of dose and LET for proton and in general for particle therapy with a goal of incorporating nano-scale radio-chemical to macro-scale cell biological pathways, spanning from initial DNA damage to tissue late effects. {\bf Methods}: The method is combination of analytical and multi-scale computational steps including (1) derivation of functional dependencies of NTCP on DNA driven cell lethality in nanometer and mapping to dose and LET in millimeter, and (2) 3D-surface fitting to Monte Carlo data set generated based on post radiation image change and gathered for a cohort of 14 pediatric patients treated by scanning beam of protons for ependymoma. We categorize voxel-based dose and LET associated with development of necrosis in NTCP. {\bf Result}: Our model fits well the clinical data, generated for post radiation tissue toxicity and necrosis. The fitting procedure results in extraction of in-{\it vivo} radio-biological $\alpha$-$\beta$ indices and their numerical values. {\bf Discussion and conclusion}: The NTCP model, explored in this work, allows to correlate the tissue toxicities to DNA initial damage, cell lethality and the properties and qualities of radiation, dose and LET.