Normal tissue response of combined temporal and spatial fractionation in proton minibeam radiotherapy.

Abstract Purpose Proton minibeam radiotherapy, a spatial fractionation concept, widens the therapeutic window. By reducing normal tissue toxicities, it allows a temporally fractionated regime with high daily doses. However, an array shift between daily fractions can affect the tissue-sparing effect by decreasing the total peak-to-valley dose ratio. Therefore, combining temporal fractions with spatial fractionation raises questions of the impact of daily applied dose modulations, re-irradiation accuracies, and total dose modulations. Methods and material Healthy mouse ear pinnae were irradiated with four daily fractions of 30Gy mean dose, respectively, applying proton pencil minibeams (pMB) of Gaussian σ=222μm in three different schemes: A 16pMB array with a center-to-center distance (ctc) of 1.8mm was delivered to the same position in all sessions (FS1) or was shifted by 0.9mm to never hit the previously irradiated tissue in each session (FS2). A 64pMB array with a ctc of 0.9 mm was irradiated to the same position in all sessions (FS3) resulting in the same total dose distribution of FS2. Re-irradiation positioning and its accuracy were obtained from image-guidance using the unique vessel structure of ears. Acute toxicities (swelling, erythema and desquamation) were evaluated for 153 days after the first fraction. Late toxicities (fibrous tissue, inflammation) were analysed on day 153. Results Re-irradiation of highly dose modulated arrays at a positioning accuracy of 110±52μm induced the lowest severity of acute and late toxicities. A shift of the same array in FS2 led to significantly inducted acute toxicities, a higher otitis score, and a slight increase of fibrous tissue. FS3 led to the strongest increase of acute and late toxicities. Conclusion The highest normal tissue-sparing is achieved after accurate re-irradiation of a highly dose modulated pMB array, although high positioning accuracies are challenging in a clinical environment. Nevertheless, the same integral dose applied in highly dose modulated fractions is superior to lowly daily dose modulated fractions.