SummaryRadiotherapy-despite being a local therapy that meanwhile is characterized by an impressively high degree of spatial accuracy-can stimulate systemic phenomena which occasionally lead to regression and rejection of non-irradiated, distant tumor lesions. These abscopal effects of local irradiation have been observed in sporadic clinical case reports since the beginning of the 20th century, and extensive preclinical work has contributed to identify systemic anti-tumor immune responses as the underlying driving forces. Although abscopal tumor regression still remains a rare event in the radiotherapeutic routine, increasing numbers of cases are being reported, particularly since the clinical implementation of immune checkpoint inhibiting agents. Accordingly, interests to systematically exploit the therapeutic potential of radiotherapy-stimulated systemic responses are constantly growing. The present review briefly delineates the history of radiotherapy-induced abscopal effects and the activation of systemic anti-tumor immune responses by local irradiation. We discuss preclinical and clinical reports with specific focus on the corresponding controversies, and we propose issues that should be addressed in the future in order to narrow the gap between preclinical knowledge and clinical experiences. K E Y W O R D Sabscopal effect, anti-tumor immunity, immunogenic cell death, radiotherapy | INTRODUCTIONTogether with surgery and chemotherapy, radiotherapy (RT) plays a central role in oncological treatment regimens. More than 60% of all cancer patients receive RT at one point during their medical attendance. 1 Traditionally, the efficacy of RT has been exclusively credited to its ability to induce cancer cell death and the notion that tumors are more prone to damage induced by ionizing radiation (IR) than non-malignant, normal tissues. According to the concept of the four R's of radiotherapy, repair (of IR-induced damage), reoxygenation, redistribution (to other cell cycle phases), and regeneration are the major determinants of a tissue's response toward IR.2 Importantly, tumors and non-malignant tissues are considered to differ in these characteristics, thus forming the rationale for the use of fractionated irradiation regimens with daily fractions over a period of 3-6 weeks in the clinical routine.It needs to be stressed that in the majority of all cases RT is applied in local settings with a high degree of spatial precision and the cardinal aim to achieve locoregional tumor control. However, there is accumulating evidence that-although applied locally-RT can induce systemic anti-tumor responses leading to regression and rejection of non-irradiated, distant tumor lesions. Collectively, these observations have been summarized under the term 'abscopal effects of RT', and meanwhile it is well accepted that immune mechanisms are the underlying driving forces. For distinct chemotherapeutics, the induction of such systemic, immune-mediated effects has been extensively analyzed by the groups of G. Kroemer and L. ZitvogeI....

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We present a rare manifestation of chronic lymphatic leukemia with progressive bilateral visual loss and the typical fundoscopic picture of anterior ischemic optic nerve neuropathy (AION). Clinical symptoms were due to meningeal metastases and tumor cell infiltration of the optic nerve. The diagnostic clue was provided by lumbar puncture with pressure measurement, which made it possible to differentiate AION from papillitis and papilledema. In this case the patient was able to regain his initial visual activity after intrathecal and systemic polychemotherapy.

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