###### Abstract  
Background:The standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is represented by concomitant chemo- Radiotherapy followed by consolidation with durvalumab that ensures a 5-year survival of 46%. However, the risk of radiotherapy-induced pneumonia (RIP) is almost 10-15%. Complete cardiological examination is also usually performed during the cardiopulmonary pre-treatment evaluation and pulmonary function testing is one of the most used tool to predict the risk of RIP development. **Aim:** The aim of this study is to investigate the impact of Tc-99 macroaggregated albumin (MAA) lung perfusion scan with single photon emission-computed tomography/computed tomography (SPECT/CT) in the preliminary assessment of lung functions and its potential role for the optimization of the radiotherapy treatment planning. **Methods:** Descriptive and statistical analysis were performed on eight patients affected by unresectable stage III LA-NSCLC treated with chemo-radiotherapy. Before starting radiotherapy, patients underwent lung perfusion SPECT/CT. The SPECT/CT images were firstly co-registered with the simulation CT scan ones, then a specific region of interest (ROI) of lung volumes was created to represent the areas with a perfusion of at least 20% 40%, 60% and 80% of maximum perfusion, respectively. Finally, optimization of the standard treatment plan was performed with the aim of preserving the better perfused lung volumes. The dosimetric correlations of both plans were made comparing pulmonary V20 and V5, mean pulmonary, esophagus and heart dose. **Results:** From the DVH comparative analysis of the two treatment plans (standard one versus SPECT optimized one) obtained for each patient, the data confirmed an equal coverage of the target volume while respecting all lungs, heart and esophagus dose constraints. At the same time, SPECT-optimized plans allowed to reduce the average dose to the better perfused lung volumes. **Conclusions:** Lung perfusion scintigraphy could be considered a preliminary assessment tool to explore lung functions and stratify the risk of RIP development. SPECT/TC may also be proposed as a dose painting tool to optimize radiotherapy treatment plans. Only prospective analysis will be enable us to confirm the real reduction of RIP risk in lung areas with an optimal perfusion. Keywords:lung perfusion SPECT/TC; lung radiotherapy; stage III LA-NSCLC; radiotherapy-induced pneumonia; immunotherapy; pulmonary toxicity; SPECT-guided radiotherapy; dose painting imrt +
Footnote †: journal: Medical Physics Unit, University ASST Spedali Civil di Brescia, 25123 Brescia, Italy
cancer (LA-NSCLC) due to the findings showed in the Pacific trial [1] and in other \"real world\" studies [2]. Regarding toxicities, old data showed a radiation induced pneumonia (RIP) rate of 15-20% [3; 4; 5], while in the Pacific trial, the risk of RIP was 13.1% and 7.7% in the durvalumab and placebo arm, respectively. These findings confirmed that RIP still remains a critical issue when radical radiotherapy (RT) is performed. RIP may arise approximately 4-12 weeks after the end of RT, and it is clinically characterized by dyspnea, cough, pain and low-grade fever [6]. Radiologically, it presents distinctive changes on computed tomography (CT) scan, such as ground glass opacity, areas of pulmonary consolidation and consolidations with air bronchogram. Lung perfusion evaluation with Tc-99 MAA SPECT/CT is a quantitative differential analysis of the lung functions able to provide additional information. Lung perfusion scintigraphy is often used by thoracic surgeons to test the residual respiratory function and to estimate the hemodynamic tolerance of the residual lung parenchyma after surgical resection [7]. Similarly, the lung perfusion scan with SPECT/CT could be used to estimate the risk of RIP in patients who are candidates for CRT with radical intent, without precluding the indication for treatment even in patients with comorbidities or respiratory symptoms [8].