Renormalization of radiobiological response functions by energy loss fluctuations and complexities in chromosome aberration induction: deactivation theory for proton therapy from cells to tumor control.

We employ a multi-scale mechanistic approach built upon our recent phenomenological/computational methodologies [R. Abolfath et al., Sci. Rep. , 8340 (2017)] to investigate radiation induced cell toxicities and deactivation mechanisms as a function of linear energy transfer in hadron therapy. Our theoretical model consists of a system of Markov chains in microscopic and macroscopic spatio-temporal landscapes, i.e., stochastic birth-death processes of cells in millimeter-scale colonies that incorporates a coarse-grained driving force to account for microscopic radiation induced damage. The coupling, hence the driving force in this process, stems from a nano-meter scale radiation induced DNA damage that incorporates the enzymatic end-joining repair and mis-repair mechanisms. We use this model for global fitting of the high-throughput and high accuracy clonogenic cell-survival data acquired under exposure of the therapeutic scanned proton beams, the experimental design that considers -H2AX as the biological endpoint and exhibits maximum observed achievable dose and LET, beyond which the majority of the cells undergo collective biological deactivation processes. An estimate to optimal dose and LET calculated from tumor control probability by extension to ~10 cells per mm-size voxels is presented. We attribute the increase in degree of complexity in chromosome aberration to variabilities in the observed biological responses as the beam linear energy transfer (LET) increases, and verify consistency of the predicted cell death probability with the in vitro cell survival assay of approximately 100 non-small cell lung cancer (NSCLC) cells. The present model provides an interesting interpretation to variabilities in and indices via perturbative expansion of the cell survival fraction (SF) in terms of specific and lineal energies, and , corresponding to continuous transitions in pair-wise to ternary, quaternary and more complex recombination of broken chromosomes from the entrance to the end of the range of proton beam.