Perioperative EGFR-Targeted Therapy in Resectable EGFR-Mutated NSCLC: A Narrative Review from Drug Design to Pain-Informed MRD-Guided Care

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. Plain Language Summary: Many people with early-stage non–small cell lung cancer (NSCLC) can have surgery to remove the tumour. Even after a “complete” resection, however, the cancer often comes back. For patients whose tumours have changes in a gene called EGFR, tablets known as EGFR tyrosine kinase inhibitors (EGFR-TKIs) are now used before or after surgery to lower the risk of the cancer returning. These targeted drugs can keep the disease under control for longer, but they are taken for many months or years and can cause ongoing side effects such as skin problems, diarrhoea, nail changes, and muscle or nerve pain. Lung surgery itself may also lead to long-lasting pain in the chest and shoulder. In this review, we explain how EGFR-TKIs are designed, how they are used around the time of surgery, and how they affect pain, daily activities, and patients’ ability or willingness to keep taking treatment. We also describe blood tests that can detect tiny amounts of cancer DNA—called minimal residual disease—and electronic tools that let patients report symptoms from home. Based on these data, we suggest a practical approach in which doctors and nurses monitor pain and other symptoms regularly, combine this information with blood test results, and adjust the dose and duration of EGFR-TKIs when needed. The goal is to give patients the best chance of being cured while protecting their comfort, function, and overall quality of life.