Difficult Decisions in the Multidisciplinary Treatment of Resectable Non-small Cell Lung Cancer

The management of resectable non-small cell lung cancer (NSCLC) has evolved dramatically over the past three decades. Once limited to surgery, treatment strategies now include chemotherapy, immunotherapy, radiation, and targeted therapies. Despite advances in clinical trials and updated guidelines, several gray areas persist in practice. This review highlights two commonly encountered dilemmas, framed by recent trial data. The first dilemma is centered on the question: for a patient with a 4.1 cm node-negative tumor, is the optimal approach neoadjuvant, adjuvant, or perioperative chemoimmunotherapy? CheckMate 816 demonstrated improved pathological complete response and event-free survival with neoadjuvant chemoimmunotherapy. Perioperative approaches, combining neoadjuvant and adjuvant immunotherapy, showed promising outcomes in KEYNOTE-671, AEGEAN, and CheckMate 77T, whereas IMpower010 and KEYNOTE-091 demonstrated benefit with adjuvant therapy. Moreover, for patients with EGFR or ALK mutations, targeted therapies have shifted the treatment paradigm, as shown in the ADAURA and ALINA trials. However, no head-to-head comparisons among these strategies exist, limiting decision-making. The second dilemma involves a hypothetical scenario of a patient a with biopsy-proven T1cN2 disease: should treatment involve neoadjuvant chemoimmunotherapy followed by surgery, or chemoradiation followed by consolidation immunotherapy (durvalumab) or targeted agents (such as osimertinib)? The PACIFIC and LAURA trials support the latter approach for unresectable disease, while CheckMate 816 supports surgery for resectable N2 cases. Yet defining resectability remains subjective, especially with multistation or bulky N2 disease. While the upcoming AJCC 9th edition proposes a subdivision of N2 into N2a (single-station) and N2b (multi-station), offering a potential step forward, this refinement has yet to translate into clear clinical guidance. These scenarios highlight the need for prospective, stage stratified trials, designed to address these pertinent questions so that improved guidelines may help clinical decision making in borderline cases.