Perioperative EGFR-Targeted Therapy in Resectable EGFR-Mutated NSCLC: A Narrative Review from Drug Design to...

Perioperative EGFR-targeted therapy has transformed the management of resectable EGFR-mutated NSCLC. However, prolonged exposure introduces chronic toxicity and pain that may erode long-term benefit. This narrative review synthesizes evidence from pivotal perioperative EGFR-TKI trials, emerging fourth-generation EGFR-TKIs, and studies on pain, toxicity, adherence, and patient-reported outcomes, with a focus on minimal residual disease (MRD)-guided treatment adaptation. Current data show that adjuvant and neoadjuvant EGFR-TKIs substantially reduce recurrence and may improve survival, yet pain and related functional impairment remain under-recognized, under-measured, and inconsistently managed. Procedure-related and treatment-emergent pain, neuropathy, and musculoskeletal symptoms interact with psychological, comorbid, and social factors to undermine adherence, particularly during prolonged adjuvant therapy. Fourth-generation EGFR-TKIs and MRD-guided strategies create opportunities to optimize exposure and duration but demand structured monitoring of pain, standardized electronic patient-reported outcomes, and integrated oncology-anesthesiology-palliative care pathways. We propose an efficacy-safety-pain-adherence loop in which pain is treated as a core determinant of therapeutic success, aiming to maximise cure potential while preserving quality of life.