ESTRO 2024 - Abstract Book

S89 ESTRO 2024 being the result of cell kill only. This narrow approach has certainly had its merits and resulted in the widely used LQ based predictions. More recently, insights in germline DNA repair differences between individuals and especially in inflammatory pathways have resulted in a more comprehensive insight in RT-induced toxicity that can have consequences for prevention and treatment. Radiation induces DNA damage that may lead to malignant transformation and second cancer. Senescence and/ or cell death by e.g. apoptosis and mitotic catastrophe may lead to loss of epithelial integrity and breakdown of mucosal barriers. An acute sterile inflammation that may induce antitumor as well as anti-self inflammatory responses may be induced. As a next step, chronic inflammation, fibrosis, late vascular damage and atrophy with chronic organ and tissue dysfunction may be the end-stage result. The sterile inflammation is fueled by the production ROS (reactive oxygen species) and RNS (reactive nitrogen species). T H 1 and T H 17 cells play together with dentritic cells, M1 macrophages that make tumor-necrosis factor (TNF), inflammatory monocytes, IFN-γ producing cytotoxic lymphocytes (CTL) and neutrophils a central role in this process. In the chronic phase, T H 2 cells, M2 macrophages and regulatory T cells, with release of T H 2 cytokines and TGF-β. The latter may result in a recurrent chronic inflammation. Endothelial and epithelial damage occurs within minutes to hours after radiation, with also here a central role for ROS and RNS. This leads to a disturbed endothelial or epithelial signaling and to immune infiltration. Cytokine and chemokine release, DAMPs, adhesion molecule overexpression, and again, release of TGF-β occurs. After some months, the endothelium is partially repaired and pericytes and myeloid suppressor cells are increasing. After a longer time, a damaged endothelium with a changed glycocalyx remains. A similar process occurs after epithelial damage, in which fibroblast activation results in excessive collagen deposits, which, together with infiltration of myofibroblasts, will lead to chronic fibrosis. Examples of activation of these inflammatory pathways are radiation-induced lung damage and intestinal side-effects. Especially in the gut, microbial invasion plays a major role in RT-induced damage, although the details of this process are largely unknown. Similar to the immunological cross-talk between organs like the intestine, the lungs and the brain in physiological conditions, connections between the gut and the lungs have been observed in radiation damage as well. When the lung is irradiated, lung-homing signals such as VCAM1 and CCL17 are expressed on T-cells and CCL28 on B-cells. Lung homing receptors such as CCR4 on T-cells and integrin α4β1 and CCR10 are expressed on B-cells. Immune cells from the whole body are therefore attracted to the lung. Irradiation of the gut leads to expression of gut-homing signals such as MADCAM1 and CCL25 and to expression of gut-homing receptors such as integrin α4β7 and CCR9 on T-cells and B-cells. Interestingly, other types of inflammatory injury lead to similar upregulation of homing signals and receptors. Radiation-induced and non-radiation induced inflammation will therefore influence and mostly increase each other via trafficking of immune cells through different parts of the body. The differential diagnosis of the cause of inflammation in irradiated organs may therefore be complex, especially in patients receiving checkpoint-inhibition immune therapy. Deep-learning based algorithms may be helpful in this regard. Invited Speaker

Mitigation of radiation-induced inflammation such as reducing the total body dose by e.g. proton therapy is an interesting method that is explored extensively.

Insight in the mechanisms of radiation-induced toxicities will lead to rational mitigation strategies and treatments. Importantly, as many if not most cancer patients receiving radiotherapy are also treated with systemic agents, insights