A combined dose and microdosimetric modeling framework incorporating volume effects correlates with tissue sparing in proton minibeam radiotherapy

Proton minibeam (pMB) radiotherapy, delivers highly heterogeneous dose distributions alternating high-dose peaks and low-dose valleys. This aims to widen the therapeutic window by improving normal tissue sparing while maintaining the same or even better tumour control. The performance of pMB strongly depends on the collimator design and physical parameters. To better understand the physical and radiobiological drivers of this enhanced therapeutic window, we perform a detailed microdosimetric characterization of proton minibeams and assess their impact. We characterize radiation quality with microdosimetry through Monte Carlo simulations. Then we extend the Generalized Stochastic Microdosimetric Model to predict the normal tissue complication probability (NTCP) at different depths in water, 1cm, 2cm, and 4cm, for 100MeV proton minibeams realized with varying configurations of collimator. Results are compared with conventional homogeneous field (HF) irradiation after dose normalization to the tumor. The developed model is applied by considering tissues as divided into several functional subunits, connected by a seriality parameter. Microdosimetric characterization of proton minibeam irradiation shows differences between peak and valley regions in shaping lineal energy spectra, especially at low depth, while radiation quality uniforms progressively getting closer to the tumor. NTCP calculations results suggest an increased sparing effect for pMB over conventional HF. A strong dependence is found on the peak-to-valley dose ratio (PVDR), and on the seriality parameter. Predictions indicate substantial sparing from pMB, especially for PVDR > 15, including relatively serial organs with seriality around 0.7. This integrated dose-microdosimetric-biological framework elucidates how spatial fractionation, radiation quality, and organ architecture collectively shape tissue sparing in pMB.