Margriet Kwint

Chapter 1 10 General aspects of Lung Cancer Lung cancer is one of the most commonly occurring cancers in the world, with approximately 2 million new patients in 2018 (1). The global epidemic of lung cancer is primarily caused by tobacco smoking (2, 3), accounting for 80-90% of lung cancer cases (2). Lung cancer has a high mortality rate in the Netherlands; only 19% of the patients are alive 5 years after diagnosis (based on the period 2011-2015) (4). In 2018, 13.800 people were newly diagnosed with lung cancer in the Netherlands (4). Lung cancer is generally divided into 2 major subtypes; Non-Small Cell Lung Cancer (NSCLC, 80%) and Small Cell Lung Cancer (SCLC, 15%). SCLC-patients have the worst prognosis with a 5 year overall survival (OS) of 8% compared to 20% for NSCLC (4). Lung cancer is staged based on the TNM principle: extension of the primary tumor (T-stage), involved lymph nodes (N-stage) and presence of distant metastasis (M-stage) (5). When there is a large primary tumor and/or involvement of mediastinal lymph nodes, but without distant metastasis, it is defined as Locally-Advanced Non- Small Cell Lung Cancer (LA-NSCLC), also known as stage III. About 25% of all NSCLC patients present with LA-NSCLC at diagnosis. This stage is often inoperable due to local or regional tumor extension. Therefore, these patients are often treated with a combination of systemic treatment and radical radiotherapy. This thesis focused on studies to optimize radiotherapy for patients with LA-NSCLC. Treatment of locally advanced NSCLC Since the mid-1990s, the standard treatment for LA-NSCLC has been thoracic radiotherapy. After the meta-analysis of the Non-Small Cell Lung Cancer Collaborative Group in 1995 (6), the value of additional chemotherapy was established. An absolute OS benefit of 10%, 4% and 5% for 1, 2 and 5 years respectively, was reported in this meta-analysis in favor of radiotherapy combined with chemotherapy compared to radiotherapy alone. In 2010, a meta-analysis (7) showed an absolute OS benefit of 5.7% and 4.5% at 3 and 5 years for concurrent chemoradiation (CCRT) compared to sequential chemoradiation (SCRT). Currently, for patients with LA-NSCLC, the treatment of choice is CCRT (7, 8). Nonetheless, with 2-year OS rates ranging between 44 and 59%, there is certainly room for improvement (9-11). Recently, a phase III trial investigating the potential benefits from adjuvant immunotherapy after CCRT in LA-NSCLC patients, reported significant improvements of progression free survival (PFS) (median PFS 5.6 months versus 17.2 months) and OS ( 2-year OS 55.6% versus