Combined radiation- and immune checkpoint-inhibitor-induced pneumonitis - The challenge to predict and detect overlapping immune-related adverse effects from evolving laboratory biomarkers and clinical imaging.

The risk of overlapping pulmonary toxicity induced by thoracic radio(chemo)therapy and immune checkpoint inhibitor therapy in the treatment of patients suffering from non-small cell lung cancer (NSCLC) is one important challenge in successful radioimmunotherapy. In the present opinion we highlight factors that we find important to be considered before treatment initiation, during the treatment sequence, and after treatment completion combined or sequential application of radio(chemo)therapy and immune checkpoint inhibitor therapy. A major aim is to optimize the therapeutic index and to avoid immune related adverse effects. The goals in the future will be focused not only on identifying patients already in the pretreatment phase who could benefit from this complex treatment, but also in identifying patients, who are most likely to have higher grade toxicity. In this respect, proper assessment of clinical performance status, monitoring for the presence of certain comorbidities, evaluation of laboratory parameters such as TGF-α and IL-6 levels, human leukocyte antigens (HLA), and consideration of other potential biomarkers which will evolve in near future are essential. Likewise, the critical parameters must be monitored during the treatment phase and follow-up care to detect potential side effects in time. With the help of high-end imaging which is already used on a daily basis in image guided radiotherapy (IGRT) for intensity modulated radiotherapy (IMRT), its advanced form volumetric modulated arc therapy (VMAT), and adaptive radiation therapy (ART), clinically relevant changes in lung tissue can be detected at an early stage of disease. Concurrent radiotherapy and immunotherapy requires a special focus on adverse events, particularly of the lung, but, when properly approached and applied, it may offer new perspectives for patients with locally advanced NSCLC to be seriously considered as a curative option.