ESTRO 2025 - Abstract Book

S156

Invited Speaker

ESTRO 2025

4931

Speaker Abstracts Radiobiological rationale and clinical evidence Slavisa Tubin Radiation Oncology, University Clinic Krems, Krems and der Donau, Austria

Abstract: Spatially fractionated radiotherapy (SFRT) represents a group of emerging, innovative and unconventional techniques for the treatment of complex, unresectable bulky tumors that either failed standard of care therapy or are not suitable for treatment with conventional radiotherapy. There are three SFRT techniques currently used in clinic: GRID, LATTICE and Partial Tumor Irradiation (PATHY). Minibeam- and Microbeam Radiotherapy are still under preclinical investigation. Although the full mechanisms of action of these techniques are currently not totally understood, what can be concluded from the available data is that their therapeutic effect follows the radiobiological mechanisms that are different from those generated by conventional radiotherapy. Therefore, the linear quadratic model cannot predict response to SFRT as we are used to with conventional radiotherapy. The mechanisms of anti-tumor effect by SFRT include cell signaling effects, inflammation and immunomodulatory effects, free radical production and diffusion and high-dose vascular damage. Tumor-cell killing determined by SFRT seems to be given by the combination of therapeutic anti-tumor effects in high-dose "peaks" region by direct radiation-induced DNA damage and vascular damage, and low-dose in "valley" region by immune-mediated and cytokine-mediated damage. SFRT are characterized by a potentially improved therapeutic ratio, which is determined by a major anti-tumor effect and local control on the one hand, and lower toxicity on the other. The typical „signature“ of this type of radiotherapy is a much more effective OAR-sparing. However, that normal tissue sparing of SFRT cannot be predicted by the classical volume effect due to the highly unconformal, heterogeneous dose distribution which characterizes these radiation techniques. Currently available clinical data concerning SFRT consist of mainly retrospective data analyses as well as early prospective data in terms of phase 1-2 studies. The randomized phase 3 study data are still lacking. From the available clinical data so far, it can be realized that the evidence is heterogeneous in terms of the tumors treated, or the way in which these techniques were prescribed, planned and delivered, as well as the doses that were used. Keeping that in mind, those evidence suggest significant efficiency of SFRT and its safety and tollerability with very limited toxicity. Finally, what can be emphasized is their high neoadjuvant and immunomodulatory potential which could play a critical role as a game changer by the very complex tumors currently deprived of the possibility of being cured. Since the radiobiological mechanisms behind SFRT are unique and different from those accompanying conventional radiotherapy, SFRT needs additional specific radiobiological models that would have to be integrated into mathematical models of the immune response such as immune-weighted RBE . In addition, it is necessary to take into account the dose that the immune system receives by these treatments at the loco-regional level, which is currently not the case with most of SFRT techniques. The new concept of "immune dose of radiation", or radiation dose to the immune organs and tissues, needs to be integrated as well in the treatment planning process. Currently, a general consensus has not yet been reached regarding the planning and delivery of SFRT techniques, as well as the optimal dose of radiation that would need to be prescribed and delivered to the peaks and valleys during these treatments. In summary, currently there are still no treatment recommendations and guidelines for the use of SFRT, which compromises its further use and development. Two large scientific groups of experts are currently working on all these issues in order to unify and facilitate the further development and use of SFRT: ESTRO SFRT Focus Group and American Working Group for SFRT. This lecture will touch all the most important aspects and issues concerning the clinical use and further development of SFRT.