Reframing Biological Potency In SBRT: A Damage–Commitment Index Framework Incorporating Sublethal Damage Repair Saturation and Immune Effects.
Abstract
Purpose
Ablative hypofractionated radiotherapy(AHRT), including stereotactic body radiotherapy(SBRT) and stereotactic radiosurgery(SRS), achieves tumor control that is not reliably predicted by Linear–Quadratic (LQ) model. Clinical observations of failure of BED equivalence, linear high-dose survival tails, delayed tumor regression, and strong fraction-size dependence, indicate a fundamental shift at high dose per fraction. This work develops a unified mechanistic framework to explain this transition and provide a biologically interpretable alternative to extrapolative LQ model.
Methods
A damage–commitment index(DCI) model is formulated in which radiation dose induces a reparable sublethal damage(SLD) reservoir followed by delayed lethal commitment. Damage induction during delivery is described by dR/dD=ηN(D) (1) where η and N(D) are damage induction efficiency (Gy−1) and number of viable clonogenic cells at dose D(Gy), respectively. Eq.(1) produces quadratic-leading behavior at low dose. Post-irradiation dynamics follow dR/dt=–[µ+λc(D)]R (2) and λc(D)=(λ0D)/(Ds+D) (3) Where µ is intrinsic repair constant, Ds is SLD repair saturation dose, λ0 and are saturating lethal commitment rates at maximum and dose D, respectively. Survival is given by S=exp[–∫ο∞ λc(D)R(t)dt] (4) For SBRT, biological potency is summarized by DCI as DCI=∑i=1n [Di/(Ds+Di)][1+ΥDi/(Di+DI)] (5) where Di is the dose/fraction of ith fraction and DI is the dose/fraction at which immune amplification reaches 50% of its maximum. This formulation incorporates SLD repair saturation and immune amplification. The model is embedded in a hierarchical time-to-event survival framework to analyze heterogeneous SBRT datasets.
Results
The model reproduces classical LQ-like behavior at lower doses(≤5Gy) and exhibits linearity above 10–12Gy. For lung SBRT regimens of 3×18Gy versus 5×10Gy(≅BED), DCI differed by 35–40%, consistent with reported 10–15% differences in local control. Immune-mediated clearance shortened predicted tumor regression times by 25%.
Conclusion
AHRT operates in a commitment-dominated regime beyond classical fractionation theory. The framework explains LQ model failure and provides a radiobiological-grounded tool for SBRT/SRS optimization.