Abstract
The role of post-operative radiotherapy (PORT) in radically resected non-small-cell lung cancer (NSCLC) remains a topic of debate, particularly in pN2 disease. While phase III trials like PORT-C and LungART have demonstrated a significant reduction in mediastinal recurrence, they have failed to show improvements in disease-free survival (DFS) or overall survival (OS), raising concerns about increased cardiopulmonary toxicity. The rapid integration of chemo-immunotherapy and targeted therapies into peri-operative treatment has reshaped the NSCLC landscape, lowering the risk of distant failure and overall mortality while leaving local recurrence rates largely unchanged. Striking results from trials on immune checkpoint inhibitors and tyrosine kinase inhibitors in early-stage NSCLC highlight the potential for improved outcomes, yet the role of PORT in this evolving framework remains uncertain. Preclinical evidence suggests that PORT could enhance loco-regional control when combined with systemic treatments, but the lack of prospective trials exploring this synergy along with unanswered questions about additive toxicity hinders its clinical implementation. There is a critical need for tailored clinical trials that integrate advanced radiation techniques and systemic therapies to further optimize patients' outcome, both in terms of survival and quality of life. Such studies should focus on balancing the risks of mediastinal relapse, systemic progression and treatment-related toxicities, particularly for PORT-related grade 3 and 4 cardiac or pulmonary events. As treatment strategies continue to evolve, a multidisciplinary and personalized approach will be key to refining the management of resected NSCLC.