## 3 Synchrotron-Generated Novel RT Modalities
### MRT Delivered in a FLASH Mode  
Micrometer collimation allows for the application of heto-Gy doses and is the basis for the FLASH-mode MRT [22] (Figure 2). A highly heterogeneous pattern of high and low radiation doses is delivered simultaneously in just a few milliseconds thanks to the ultra-high dose rates of the synchrotron facilities (up to 16 kGy/s). Compared to conventional RT, this MRT dose delivery pattern has been proven to (i) spare various normal tissues from radiation-related toxicity [6], and (ii) efficiently eradicate local tumors [23] (Figures 3 and 4). Studies of synchrotron MRT in animal models indicated that tumors can be ablated by MRT at radiation levels that spare normal tissues [8, 24, 25, 26]. Thus, the therapeutic index for MRT is greater than conventional RT, and it is quite conceivable that MRT may become a major mode of cancer RT in the future. Recently, the first dog patient treatment of spontaneous glioma was successfully treated at the ESRF (report pending), and issues surrounding the clinical implementation of MRT have been discussed in several publications [20, 22, 27, 28]. The reason for the beneficial difference in response to MRT in tumors and normal tissues are being actively investigated, with inter-cellular effects between maximally and minimally irradiated cells in the peak and valley regions implicated [9, 24, 29]. An integrated knowledge of the effect of MRT on tumor and normal tissues can be summarized as follows:* MRT has been proven to be an efficient treatment strategy for several tumor types in animal models, including glioma, glioblastoma, mammary carcinoma, melanoma, squamous cell carcinoma and lung cancer [23]. * A fractionated MRT schedule controls the primary tumor better than a single MRT treatment [26; 30; 31]. * MRT has been proven to efficiently spare normal tissues of the central nervous system (CNS, including immature CNS), skin, liver, lung, liver, vasculature and testis from detrimental effects of radiation [6; 12]. * The higher the dose rate, the better the normal tissue sparing effect [16; 32]. * MRT valley doses correlate best with lower acute normal tissue toxicity [21; 23]. * MRT selectively destroys tumor neovascular leading to tumor hypoxia and necrosis, while vasculature in normal tissues is more tolerant and, if damaged, can repair itself. This contributes to differences in survival between tumor and normal tissues [33; 34; 35]. * Ultra-high doses of MRT beams are likely to induce high DNA damage-generated 'immunogenic cell death', as has been suggested for FLASH irradiation [36]. * Similar to the activation of the immune system after heterogenous dose delivery with conventional-source SFRT [37], immune cells in the valleys are spared following MRT and can activate an anti-tumor immune response (manuscript under review). In addition, short-pulse FLASH mode is capable of protecting the majority of local and circulating immune cells [36], thus further contributing to the active recruitment of immune cells to the microbeam paths. * MRT promotes an anti-tumor immune response that contributes to exceptional killing of the primary tumor [38]. We recently showed that fractionated MRT-induced immunomododulation is associated with a pronounced decrease in metastasis (manuscript under review). The ability of local MRT to trigger immune-mediated, systemic, non-targeted radiation effects can contribute significantly to the future clinical utility of this irradiation modality. Figure 2: Synchrotron X-ray radiation properties are essential for both MRT and FLASH RT. Synchrotron MRT in FLASH mode is the combinatorial result of MRT and FLASH RT, whose properties dictate its therapeutic potential. Figure 4: Non-targeted effects in animals that can be generated at synchrotron facilities. RIAE within the same organism in tumor (**a**) and non-tumor settings (**b**) display different systemic effects mediated by the immune system. RIAE can be both beneficial (**a**) or genotoxic (**b**).