@phdthesis{,
    author = {Sammer, Matthias },
    title = {Tissue-sparing of Proton Minibeam Therapy depends on beam size, fractionation scheme and interlacing geometry},
    editor = {},
    booktitle = {},
    series = {},
    journal = {},
    address = {},
    publisher = {},
    edition = {},
    year = {2021},
    isbn = {},
    volume = {},
    number =  {},
    pages = {},
    url = {},
    doi = {},
    keywords = {Radiation Therapy, Proton, Minibeam, Interlacing, Side effects},
    abstract = {Proton Minibeam Radiotherapy (pMBRT) is a spatial fractionation method that widens the therapeutic window in the radiation therapy of cancers. Sub-millimeter planar or pencil proton beams (minibeams) are applied to the patient with a few mm center-to-center distances (ctc). Due to the small-angle scattering of protons, the submillimeter beams increase in size with depth. Adjusting the ctc distances to the tumor depth and its size yields an overlapping, up to homogeneous dose distribution in the tumor volume. Therefore, a tumor dose coverage as in conventional radiotherapy approaches can be maintained while the minibeam pattern within the entrance channel spares healthy tissues and reduces side effects due to the low dose regions in the valleys between the minibeams. The goal of this work was to improve the understanding of the sparing potential of spatial fractionation by conducting experiments at the ion microprobe SNAKE as well as further developing proton minibeams based on theoretical dose and cell survival calculations. In the first experiment, the dependence of the radiation response on the dose modulation within an in-vivo mouse ear model of healthy BALB/c mice was investigated. Proton pencil minibeam sizes from σ=95 µm to σ=883 µm (standard deviation) were applied with a 60 Gy mean dose on a 4x4 grid with 1.8 mm center-to-center distance ctc, corresponding to σ/ctc ratios between 0.05 and 0.5. The largest σ/ctc of 0.5 corresponds to a homogeneous irradiation. The results provide an insight into the sparing effect of different dose distributions of minibeam irradiations as they could be applied on the skin or as they occur in depth due to the lateral spread of the minibeams. Visible skin reactions and ear swelling were observed for 90 days post-irradiation. The results state that the closer the dose modulation is to that of a homogeneous irradiation (σ/ctc=0.5), the stronger the tissue toxicities. Transferred to patient irradiation, the tissue-sparing potential of proton minibeams decreases with depth but proton minibeams are still superior to conventional proton irradiations even at large depths. The σ/ctc ratio without any side effects in the mouse model was extrapolated to σ/ctc=0.032. In the second animal trial, the combination of temporal and spatial fractionation was studied within the BALB/c mouse ear model. Four daily fractions of 30 Gy mean dose were applied to the ears with 16 proton minibeams (σ=222 µm; ctc=1.8 mm). The minibeams were reirradiated accurately (fractionation scheme 1; FS1) or with a maximum spatial shift between the temporal fractions (FS2). The third irradiation group (FS3) accurately reirradiated the resulting 64 proton minibeam positions from FS2 (σ=222 µm; ctc=0.9 mm) with 30 Gy mean dose per fraction. Due to the halving of the ctc in FS3, the daily dose distribution changed with increased valley doses compared to FS1 and FS2. However, the integral dose distributions after the full treatment were equal to the integral dose distribution of FS2, allowing to evaluate the influence of different daily dose distributions. The achieved reirradiation accuracy of (110±52) µm led to a maximum ear swelling of only 1.6-fold for the strongly modulated dose distributions of FS1. The irradiation with maximally shifted minibeams (FS2) led to a swelling of 2.4-fold ear thickness compared to sham irradiated ears. The accurate irradiation of the weaker dose modulations of FS3 yielded even three times the ear thickness of sham irradiated ears. An increased ear thickness was found for FS2 (~1.4-fold) and FS3 (~1.7-fold) ears at the end of the observational period of 160 days. In FS2 and FS3, histological sections confirmed a significantly increased amount of fibrotic tissue at the end of the observational period. The results suggest that most tissue-sparing in temporally fractionated proton minibeam therapy is achieved for accurate reirradiation of strong daily dose modulations (FS1). The same daily dose modulations as in FS1 but maximally shifted (FS2) are also of advantage compared to accurately reirradiated but weaker dose modulations (FS3). Hence, fractionated proton minibeam therapy presumably also has an advantage over fractionated conventional radiotherapy. In theoretical proton minibeam dose calculations, further developments and potential application variations were considered. In a 5 cm thick tumor located at 10 cm depth, interlaced minibeams from two opposing or four orthogonal directions were calculated to maximize the clonogenic cell survival. Additionally, the combination of interlacing and heterogeneous tumor dose was examined to evaluate optimized tissue-sparing capabilities at the close tumor vicinity. The computed dose distributions were biologically weighted by the calculated clonogenic cell survival. Interlacing proton minibeams with homogeneous tumor irradiation was only of minor benefit in terms of mean clonogenic cell survival compared to unidirectional minibeam irradiations. Allowing a heterogeneous dose distribution within the tumor enabled larger ctc distances between the minibeams. This resulted in enhanced cell survival even for an elevated mean tumor dose, which was necessary to cover the tumor with a prescribed minimum dose. Interlaced minibeams with at least 10 Gy minimum tumor dose could still maintain a mean cell survival of up to 47% even close to the tumor margin. According to the calculations, 
the sparing-effect of proton minibeams is of most advantage for high dose fractions, which brings hypo- or even single-fractionated radiotherapy into reach. Similar benefits as for proton minibeams are expected for heavy-ion minibeams with the advantage of lower scattering and, therefore, smaller, less harmful minibeams in deeper tissues. The elaborated results within this thesis elucidate in detail the sparing potential of proton Minibeam Radiotherapy. The resolution of proton minibeam dose distributions and their effect on biological tissue paves the way for a deeper understanding of the sparing potential of spatial fractionation. A first-of-its-kind temporal fractionation of proton minibeams suggests that the sparing effect of minibeam irradiation is preserved also when fractionated compared to conventional radiotherapy. Substantial improvements to conventional radiotherapy are revealed by dose simulations. Nevertheless, the experimental results need to be validated in other and human tissues. The theoretical cell survival calculations must also be placed in the context of a complex biological system. Furthermore, the technical feasibility of a clinically applicable proton or heavy ion minibeam needs to be elucidated, in particular for potential interlaced irradiation approaches.},
    note = {},
    
    school = {Universität der Bundeswehr München},
    
}