The prospective study LOCATION MATTERS aims to investigate the radiation-induced damage to the heart and the cardiovascular system in patients treated with thoracic radiotherapy. Patients enrolled in the study will complete a set of extensive measures at the baseline, end of RT, and 9 months after treatment. Ultrasound exams, CT scans, pulmonary tests and wearable devices will assess functional and morphological parameters and the association with their variation and the dose delivered to the heart substructures and to the normal lung.

A cohort of locally advanced lung cancer patients treated with RT will be enrolled at Fondazione IRCCS Istituto dei Tumori. Comorbidities and cardiovascular risk factors will be recorded for all the patients. Heart substructures will be automatically contoured on each patient to provide details on the dose distribution.

The investigators will plan an extensive set of cardiac tests before, at the end of RT and 8 months after treatment (to assess cardiac remodelling and pt recovery). It will include an electrocardiogram, echo cardio, spirometry, blood circulating biomarkers (Troponin and Natriuretic peptide tests) and cardiac calcium score from CT. In addition, the researchers will include a set of measures by the use of a vascular ultrasound machine. This machine will allow the investigation of subclinical vascular organ damage indicators, including carotid distention and intima-media thickness (descriptor of the carotid inflammatory state), through a simultaneous and automatic procedure from raw imaging data. This guarantees the extraction of highly reproducible and operator-independent features. Finally, the project will provide smartwatch devices to the patients aiming to get longitudinal information on heart rate, breathe per minute, stress level, Pulse Ox and recovery time after customised exercises.

The study's aim is to associate the most "radiosensitive" functional parameters or biomarkers (i.e. the more prone to vary after RT) with the dose delivered to the HSs. First, researchers will analyze the variations of the parameters in patients with doses above and below the identified constraints from the literature. Second, investigators will test whether a dose relationship model can continuously describe the changes for the parameters with statistically significant differences. The primary focus will be the comprehension of the dose response for morphological and functional parameters that are altered chronically, i.e. with more compromised values at the 1-year measurement.

For this study, the investigators estimate to enrol 150 lung cancer patients in 3 years.

Information on the OS and MACEs will be registered during the clinical standard FU.

Researchers expect to fulfil an FU rate of 90% two years after RT completion. Registering MACEs during the FU time will allow to perform a first direct comparison of the competing part of Task 1.3.

Inclusion Criteria:

• Patients with NSCLC
• Patients with locally advanced disease (Stage 3)
• Patients treated with RT at Fondazione IRCCS Istituto Nazionale dei Tumori

Exclusion Criteria:

• Previous thoracic radiotherapy
• Previous heart surgery

The study population will include consecutive NSCLC patients with locally advanced disease treated with RT at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano