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This study aimed to assess the shifting patterns of the mediastinum, including the target volume and the isocenter point during the postoperative radiotherapy (PORT) process of non-small cell lung cancer (NSCLC), and to observe the occurrence of radiation injury. Additionally, we investigated the significance of mid-term assessment during the implementation of the PORT process. We established coordinate axes based on bone anatomy and measured the mediastinum's three-dimensional direction and the shift of the isocenter point's shift in the PORT process. Statistical analysis was performed using Wilcoxon, Kruskal-Wallis, and the Chi-square test. P < 0.05 was considered statistically significant. In this study, the analysis of patients revealed that the shift of anterior and posterior mediastinum (X), left and right mediastinum (Y), upper and lower mediastinum (Z), anterior and posterior isocenter point (X i), and the left and right isocenter points (Y i) in the PORT process were 0.04–0.53, 0.00–0.84, 0.00–1.27, 0.01–0.86, and 0.00–0.66 cm, respectively. The shift distance of the mediastinum was Z > Y > X, and the shift distance of the isocenter point was X i > Y i. According to the ROC curve, the cut-off values were 0.263, 0.352, 0.405, 0.238, and 0.258, respectively, which were more significant than the cut-off values in 25 cases (25%), 30 cases (30%), 30 cases (30%), 17 cases (17%), and 15 cases (15%). In addition, there was a significant difference in the shift of the mediastinum and the isocenter point (all P = 0.00). Kruskal-Wallis test showed no statistically significant difference between mediastinal shift and resection site in X, Y, and Z directions (P = 0.355, P = 0.239, P = 0.256), surgical method (P = 0.241, P = 0.110, P = 0.064). There was no significant difference in the incidence of RE and RP in PORT patients (P > 0.05). No III–IV RP occurred. However, the incidence of ≥ grade III RE in the modified plan cases after M-S was significantly lower than in the original PORT patients, 0% and 7%, respectively (P = 0.000). In conclusion, this study provides evidence that mediastinal shift is a potential complication during the PORT process for patients with N2 stage or R1–2 resection following radical resection of NSCLC. This shift affects about 20–30% of patients, manifesting as actual radiation damage to normal tissue and reducing the local control rate. Therefore, mid-term repositioning of the PORT and revision of the target volume and radiation therapy plan can aid in maintaining QA and QC during the treatment of NSCLC patients and may result in improved patient outcomes. [ABSTRACT FROM AUTHOR]