Margriet Kwint

Chapter 8 160 studies present a positive view of the potential for radiomics signatures to deliver personalizedmedicine. However, there are some limitations. The radiomics signatures associated with treatment outcome vary substantially between the different studies reported. There is not one specific radiomic signature identified to evaluate in larger multicenter studies. Besides, radiomics studies suffer from several technical and methodological limitation such as lack of biological and technical validation (67). This is illustrated by the external validation (68-70) of the radiomics signature of Aerts et al. (71). The subsequently performed study of Welch et al.(72) demonstrated that this radiomics signature was highly correlated with tumor volume rather than reflecting tumor heterogeneity. In recent years several studies on the limitation of radiomics studies were performed (67), and the awareness increases that standardization and transparency of technical and methodological aspects of radiomics studies are necessary to establish true progress in this research field. Finally, it is important that radiomics signatures are tested for clinical relevance at a multi institutional level. Incorporating radiomics signatures into clinical models, should improve the accuracy of these existing models for patients risk stratification. Radiotherapy and the immune system How can we further optimize treatment outcome? The immune system has an important role in tumor response and treatment outcome. It is well established that radiotherapy can activate the immune system by different mechanisms like immunogenic cell death, leading to host immune responses as well as local inflammatory responses. This is illustrated by the abscopal effect of radiotherapy (73). Besides its immune activating effect, radiotherapy can also suppress the immune system (74). This is, amongst other mechanisms, explained by destruction of mature circulating lymphocytes in the blood-flow or lymphocytes in the tumor-draining lymph nodes. This cell type exhibits DNA fragmentation already at low doses of radiation (<1 Gy) (75). The heart and many large blood vessels are situated within the thoracic region, subsequently leading to irradiation of the blood flow (and thus with mature lymphocytes) during lung cancer irradiation. Several studies identified that lymphocyte count is associated with treatment outcome in different solid cancers including NSCLC (76-81). The study of Contreras (78) found a worse OS in patients with a neutrophil to lymphocyte ratio (NLR) >10.5, four months post radiotherapy. An expected association between heart dose and NLR >10.5 was found in multivariate analysis. This substantiates that larger radiation fields expose more circulating