Margriet Kwint

Chapter 8 162 PD-1 blockade in patients with metastatic NSCLC by analyzing tumor response in non-irradiated lung cancer lesions. In this phase II study, metastatic NSCLC patients (unselected for PD-L1 status) with progression after chemotherapy, were randomized to receive treatment with Pembrolizumab, either after SBRT (3 x 8 Gy) to a single tumor site or without SBRT. Improvement of overall response was seen (18% vs 36%, p <0.10) in the experimental arm. However, the results did not meet the study predefined endpoints for meaningful clinical benefit. Other trials (87, 88) reported that the response rate of Pembrolizumab is dependent on the PD-L1 expression levels of the tumor. Therefore, the PD-L1 negative subgroup is expected to have influenced the results of the Pembro-trial (86). A currently ongoing multicenter study examining the activity of immunotherapy (L19-IL2) and SBRT in metastatic NSCLC is the phase II ImmunoSABR study (89). The expected activity is a systemic immune response preventing disease progression and resulting in an improvement of PFS. The ability that SBRT in combination with immunotherapy might provoke a systemic immune response to improve PFS is auspicious. These studies illustrate that radiotherapy and immunotherapy are a very promising combination with the potential to further improve treatment outcome for lung cancer patients. Proton therapy and NTCP-modelling Predicting the risk of AET enables us to take appropriate precautions, such as individualized patient information, hydration, tube feeding or dietary guidance and supplements. Accurate NTCP-models will help to select the ideal patients who might benefit from novel radiotherapy techniques such as proton therapy (90, 91). A phase III study (92) randomizing between IMRT and passive scattering proton therapy (PSPT), reported a significantly lower mean heart dose in the PSPT-arm. However, no significant differences in the mean lung dose and mean esophagus dose were achieved. In spite of the similar mean lung dose, PSPT reduced the low-dose bath (lung V 5-10 ), but exposed significantly larger volumes to higher doses (lung V 20-80 ). The primary end points of this study were radiation pneumonitis grade 3 and local failure. No significant differences in grade 3 radiation pneumonitis (IMRT 6.5%; PSPT 10.5%, p=0.537) and in local failure was reported (IMRT 10.9%; PSPT 10.5%, p=1.0). Intensity Modulated Proton Therapy (IMPT) is a new and more advanced technique compared to PSPT. IMPT has the ability to deliver a more conformal dose to the tumor and spare the nearby organs at risk even more compared to PSPT. But this can make IMPT more sensitive for patient and tumor movements and anatomical changes. The