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Purpose  To develop a first principle and multiscale 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 nanoscale radio‐chemical to macroscale cell biological pathways, spanning from initial DNA damage to tissue late effects.    Methods  The method is a combination of analytical and multiscale computational steps including (a) derivation of functional dependencies of NTCP on DNA‐driven cell lethality in nanometer and mapping to dose and LET in millimeter, and (b) three‐dimensional‐surface fitting to Monte Carlo data set generated based on postradiation 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.    Result  Our model fits well the clinical data, generated for postradiation tissue toxicity and necrosis. The fitting procedure results in extraction of  in vivo  radio‐biological  α ‐ β  indices and their numerical values.    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.

A DNA damage multiscale model for NTCP in proton and hadron therapy