Margriet Kwint

Chapter 2 40 The patients treated in the reduction-cohort revealed a better median OS than the reference-cohort. It is unclear whether there is an independent association between dose-reduction and OS. MLD was found to influence the association between dose- reduction and OS. However, the reduced dose to the mediastinum could potentially have the greatest impact, which might also explain the negative outcome of the RTOG-0617. The great advantage of a differential dose-prescription to the primary tumour and involved lymph nodes is the balance between maximizing the local control (high dose to the primary tumour) while the toxicity rates decrease because of a less intense dose to the mediastinum. Due to this favourable profile many patients, including the elderly and the patients with considerable co-morbidity, can benefit from this intensive treatment with curative intent. We acknowledge that the observational nature of this study has its limitations. First, this is a retrospective analysis. Second, since heart toxicity is insufficiently recognized during FU, we were not able to report on the acute and late heart toxicity in detail. Third, the median FU differed between the 2 cohorts. Nevertheless, with a median FU of 27 months in the reduction-cohort, we are confident that the majority of the local and regional failures have developed already. Also, to compare the two cohorts with a similar FU, we censored the reference-cohort after 27 months. No different outcomes were observed (supplementary material, Fig.S2a-c ). Fourth, 17 patients who received 70 Gy (EQD2 10 ) to the mediastinum due to a protocol violation and were excluded. The median OS between these 17 patients and the reduction-cohort was comparable; therefore we believe that excluding these patients did not influence outcome. Last, we simultaneously implemented 2 treatment adaptations resulting in a lower dose to the OARs followed by a decrease in the acute toxicity rates. To distinguish the contribution of each adaptation is challenging. We have calculated within a subset of the patients the effect of the reduced margins as well as the dose reduction to the lymph nodes on the MLD and other dose parameters (supplementary material, Table S3A-C ). In conclusion, this observational study compared dose-reduction to the lymph nodes as well as a margin reduction in 2 consecutive LA-NSCLC cohorts +/- concurrent or sequential chemotherapy. With 60 Gy (EQD2 10 ) instead of 70 Gy (EQD2 10 ) to the involved mediastinal lymph nodes of LA-NSCLC patients, the acute toxicity rates decreased significantly while the RF rates were comparable. Furthermore, OS improved significantly. A differentiated dose to primary tumour and lymph nodes