Multiple Options, One Objective: Clearer Decisions in Resectable Non-Small Cell Lung Cancer

Background: Early-stage non-small cell lung cancer (NSCLC) accounts for nearly 50% of cases. Surgery remains the cornerstone of curative treatment, but five-year survival is suboptimal, necessitating adjuvant, neoadjuvant, and perioperative strategies including chemotherapy, targeted therapy, and immunotherapy. Methods: We reviewed randomized trials and conference abstracts from the last decade up to August 2025 on adjuvant, neoadjuvant, and perioperative systemic therapies in resectable NSCLC, focusing on major pathological response, pathological complete response, event-free survival (EFS), and overall survival (OS), and also highlighting several ongoing trials in this setting. Results: The review generated a simplified treatment algorithm to assist clinicians in navigating the multiple therapeutic options for resectable NSCLC. Cisplatin-based adjuvant chemotherapy remains standard for stage II–IIIA disease, while targeted therapy (osimertinib, alectinib) improves DFS in EGFR- and ALK-positive tumors. Adjuvant immunotherapy (atezolizumab, pembrolizumab) shows benefit primarily in PD-L1-positive patients, though regulatory approvals differ depending on PD-L1 expression thresholds. Neoadjuvant nivolumab plus chemotherapy significantly improved EFS and OS, particularly in stage IIIA (CheckMate 816). Perioperative regimens with nivolumab, durvalumab, or pembrolizumab show consistent EFS gains, most pronounced in stage III N2 patients. Emerging biomarkers such as residual viable tumor and circulating tumor DNA after surgery may further personalize therapy. Conclusions: Treatment of resectable NSCLC should be individualized based on stage, nodal status, PD-L1 expression, molecular alterations and pCR. Upfront surgery with adjuvant therapy is appropriate for lower-stage disease (IB–IIA), while perioperative chemoimmunotherapy offers maximal benefit in stage II–III, especially N2-positive patients. Biomarker-driven strategies will continue to refine patient selection to stop or continue postoperative treatment.