Implementation of a 4D dose calculation workflow to assess uncertainties in spatially fractionated proton minibeam radiation therapy.

Proton minibeam radiation therapy (pMBRT) is a highly promising new approach in radiotherapy which uses strong spatial dose fractionation to create alternating regions of high and low doses. Numerous studies have demonstrated the sparing effect of this modality on healthy tissues for intracranial or thorax tumour irradiation in preclinical models. Computing accurate dose distributions in this specific configuration is therefore a crucial step in bringing this technique towards clinical applications. Organ motion (induced by breathing, small motion, positioning uncertainties etc). during radiation therapy associated with increased beam-on time of pMBRT and geometrical uncertainties of scanned protons can lead to a possible overlap of peaks and valleys. Therefore, it is essential to assess the impact of such effects on the beneficial sparing effect of healthy tissues. We have developed a workflow based on time-resolved Monte Carlo simulations to quantify the dose distribution for realistic pMBRT clinical treatments. 4D CT datasets, deformable image registration, a realistic machine model and physical dose calculation using the TOPAS/Geant4 toolkit were combined to obtain 4D dose distributions. Dose measurements with a rigid respiratory motion phantom were performed to validate this theoretical workflow for a conventional pencil-beam scanning plan. 4D dose distributions in representative clinical cases were then computed to assess the impact of intrafractional motion during intracranial or thorax treatments. Regarding 4D dose calculation in pMBRT patients, dose profile, dose volume histogram and peak-to-valley dose ratios were estimated to evaluate the impact of breathing/positioning movements and increased beam-on time on the spatial fractionation of the dose and particularly at the beam entrance. This 4D dose calculation framework based on an accurate description of the temporal parameters was used to assess the dose rates and robustness requirements of pMBRT irradiation.