Margriet Kwint

General discussion and future perspectives 161 8 lymphocytes and neutrophils to a radiation dose and that this plausibly leads to more immune suppression leading consecutive to a worse treatment outcome. In addition, larger radiation fields include more often lymph nodes, leading to an increased radiation dose to lymphocytes as well. The effect of larger thoracic radiation fields is illustrated for example by the study of Tang (82). Tang et al. reported that larger GTV’s were correlated with lower lymphocytes nadirs in NSCLC patients who were treated with definitive radiotherapy, regardless whether concurrent chemotherapy was administered. Moreover, a lower lymphocyte nadir and larger GTV volume were associated with worse OS in this study. These blood biomarkers (total lymphocyte count and neutrophil to lymphocyte ratio) have the advantage of being cheap and easily repeatable during treatment since they can be calculated using routine blood analysis. Since the first results are promising, ongoing research is needed to unravel the exact mechanism of immunosuppression during radiotherapy and to validate the value of lymphocyte count as predictive biomarker in LA-NSCLC. Hopefully in the future these blood biomarkers can refine current treatment outcome prediction models. Optimizing radiotherapy by adding immunotherapy As described in the previous paragraph, radiotherapy could, besides suppress, also stimulate the immune system (73). This immune stimulating effect nourished the theory that the combination of radiotherapy and immunotherapy might improve treatment outcome. Pre-clinical evidence showed that radiotherapy up-regulates death ligand 1 (PD-L1) expression in tumor cells (83). Durvalumab is a selective, high affinity, human immunoglobulin-G1 (IgG1) monoclonal antibody that blocks programmed PD-L1 binding to programmed death 1 (PD-1) and CD80, allowing T-cells to recognize and kill tumor cells (84). In the phase III Pacific study, randomization occurred between placebo and Durvalumab as consolidation therapy after CCRT in NSCLC patients (2, 3). Because of the improved OS and PFS in the Durvalumab-arm, Durvalumab is now standard of care after CCRT in responding patients. The results of the Pacific study generated new research questions and trials. One of these trials was the phase 1 study that addressed whether immunotherapy (Pembrolizumab) could be given concurrently with chemoradiation (85). The trial concluded that it was tolerable (no dose limiting toxic-effects) with a promising PFS of 69.7% at 1 year. Pembrolizumab is another monoclonal antibody that blocks PD-1. The Pembro-trial (86) investigated the effect of stereotactic radiotherapy (SBRT) on the response to