Margriet Kwint

General discussion and future perspectives 149 8 The incidence of regional failures (lymph node metastases) after radiotherapy for LA-NSCLC is generally lower than local failures (primary tumor), around 10% versus 30% after 2 years (9-11). Tumor volume is a significant factor for predicting these regional and local failures (9). Since involved mediastinal lymph nodes have a smaller volume, compared to the primary tumor in the majority of patients, we hypothesized that the dose needed to control lymph node metastases might be lower than the dose needed to control the primary tumor. A consequence of a lower dose to the mediastinum might also induce an efficient reduction of the pulmonary, esophageal and cardiac toxicity rates. In Chapter 2 , an observational study of 308 locally advanced non-small cell lung cancer patients, compared 2 sequential cohorts, treated with a different radiation dose to involved mediastinal lymph nodes with or without concurrent or sequential chemotherapy. This study demonstrated that a differentiated dose prescription to the primary tumor (24x2.75 Gy) and the involved mediastinal lymph nodes (24x2.42 Gy), as well as a margin reduction of the primary tumor and lymph nodes, led to decreased radiotherapy induced pulmonary and esophageal toxicities and improved OS compared to the reference cohort (24x2.75 Gy to the primary tumor and lymph nodes). This study demonstrated that hypofractionated radiotherapy with a differentiated dose is a safe strategy with low toxicity risk and good OS (12). Recently, it was reported that the risk of heart disease in breast cancer patients, increased significantly within 5 years after treatment (13). Since the results of the RTOG 0617 (4), more awareness has arisen that heart dose is associated with a reduced OS in lung cancer patients. Lately, in a systematic review of Zhang et al. (14) it was concluded that 20 different cardiac dose-volume parameters were significantly associated with OS in NSCLC patients. However, no consistency in these heart dose volume parameters was found. We demonstrated that dose de-escalation to the mediastinal lymph nodes and PTV-margin reduction resulted in lower heart, esophageal and lung dose, reduced toxicities, and improved OS. To further enhance treatment outcomes, improvements of radiation dose distributions and/or escalation to the primary tumor are crucial. A potential approach which facilitates dose escalation to the primary tumor, while not exceeding the dose constraints of the organs at risk (OAR), is isotoxic treatment planning. This is a personalized treatment planning method in which the maximum achievable biologically effective dose (BED) to the tumor is given, until predefined dose constraints on the OAR are reached.