Introduction
EGFR-mutated NSCLC tumors invading the heart, great vessels, trachea, or esophagus represent a heterogeneous subgroup of locally advanced non-small cell lung cancer (NSCLC). According to current guidelines, stage IIIB (T4N2) disease is generally considered unresectable[
1,
2]. Nevertheless, some carefully selected patients may benefit from a multimodal approach, including surgery combined with modern systemic therapy. We present a case of successful management of stage IIIB EGFR-mutated NSCLC treated with curative-intent surgery followed by targeted therapy.
Case presentation
A 60-year-old female patient, with a history of breast cancer treated a decade prior with breast-conserving surgery, chemotherapy, and radiotherapy, presented in October 2021 with a persistent dry cough of 4 months’ duration. A chest radiograph revealed a lesion in the right lung.
Contrast-enhanced computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT) demonstrated a 70 mm × 56 mm × 65 mm mass in the right upper lobe with intense FDG avidity (maximum standardized uptake value [SUVmax] = 16.5; Figure 1A). The tumor invaded the right main, upper lobe bronchi, the distal trachea, and infiltrated the superior vena cava (SVC) over an area of approximately 2 cm2. Enlarged, FDG-avid lymph nodes were identified at multiple stations: bronchopulmonary (32 mm, SUVmax 10.5), subcarinal (26 mm, SUVmax 15.1), and right lower paratracheal (9 mm, SUVmax 6.2). Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the subcarinal node confirmed metastatic lung adenocarcinoma. Molecular testing was not performed at the time of initial diagnosis. The clinical stage was assigned as IIIB (T4N2M0).
The patient was evaluated by our institutional multidisciplinary tumor board. Our center has a longstanding protocol for managing select patients with cT4N2 disease (typically involving no more than two mediastinal nodal stations), which involves administering of two cycles of neoadjuvant chemotherapy (NACT) and proceeding to radical surgery in the absence of disease progression. This approach has historically yielded a five-year overall survival rate of 19.2% in this patient population[
3]. After discussion, the patient, who had excellent performance status, opted for this aggressive surgical approach.
She received two cycles of neoadjuvant chemotherapy (cisplatin 150 mg on day 1 + vinorelbine 50 mg on days 1 and 8, every 21 days) from October to November 2021. A restaging PET/CT scan demonstrated significant radiographic regression of the primary tumor and lymph nodes. A detailed 3D reconstruction based on the pre-treatment CT scan was created to facilitate surgical planning (Figure 1B). The planned procedure was a right upper double-sleeve bilobectomy with sleeve resection of the tracheal bifurcation, complex airway reconstruction, and SVC replacement with a xenopericardial conduit.
The 3D model provided in Figure 2 was instrumental in confirming the technical feasibility of the resection and precisely determining the required resection margins, which were planned to be at least 15 mm from the tumor. The model also helped anticipate tension on the planned airway anastomoses, leading to preoperative planning of tension-reducing maneuvers, including a wide, circumferential pericardial release around the pulmonary hilum and complete intrapericardial release. We routinely use xenopericardium to create SVC and aortic conduits, as well as for patches on the left atrium, pulmonary trunk, and pericardium. We prefer this material in cases where prolonged air leakage into the pleural cavity is expected, given the theoretical risk of prosthesis infection.
The surgery was successfully performed in December 2021 without perioperative complications. After systematic lymph node dissection and systemic heparinization (5000 units IV), the SVC was clamped, circumferentially resected, and replaced with a xenopericardial conduit. Following ligation of the upper and middle lobe vessels, the right pulmonary artery and inferior pulmonary vein were isolated. A wide pericardiotomy was performed around the hilum, and an intrapericardial release was completed by dividing the longitudinal connection between the right atrium, the inferior vena cava, and the pericardium. After clamping the pulmonary artery and vein, the retrocaval arterial segment and the artery to the lower lobe were transected. The distal third of the trachea, the left main stem bronchus and the bronchus intermedius were divided, and the specimen was removed. Cross-field ventilation was established. A circumferential tracheobronchial anastomosis was created. A window was then created in the medial wall of the left main bronchus, and high-frequency jet ventilation of the left lung was initiated. An anastomosis was created between the left main bronchus and the right lower lobe bronchus, followed by the pulmonary artery anastomosis. The ischemia time for the right lower lobe was 60 min.
Histopathology confirmed poorly differentiated adenocarcinoma with negative resection margins. The right upper and lower paratracheal, subcarinal, and paraesophageal lymph nodes (stations 2R, 4R, 7, and 9) were involved by the tumor. There was no evidence of a major pathological response to the neoadjuvant chemotherapy. Postoperative molecular testing of the resected tumor revealed an EGFR exon 19 deletion. The patient was started on adjuvant osimertinib (80 mg daily). However, she self-reduced the dose to 40 mg daily two months later without medical consultation, citing fatigue.
The patient remained under close surveillance. At 29 months post-surgery (May 2024), a routine PET/CT scan showed no evidence of recurrence and a patent SVC conduit (Figure 3A). At 35 months (November 2024), a follow-up PET/CT revealed a new 17-mm mediastinal lesion (SUVmax 6.9) located between the esophagus and the left atrium (Figure 3B), along with several small subpleural nodules (≤ 6 mm) and thrombosis of the SVC conduit. Thoracoscopy with biopsy confirmed pleural dissemination. Next-generation sequencing (NGS) of the biopsied tissue identified the original EGFR exon 19 deletion (L747_T751del) in addition to new amplifications in mesenchymal-epithelial transition factor (MET), cyclin-dependent kinase 4 (CDK4), and murine double minute 2 (MDM2), as well as homozygous loss of CDKN2A/MTAP/CDKN2B.
The patient was subsequently started on the MET inhibitor crizotinib. Within two months, a chest CT demonstrated a significant radiological response with resolution of the intrathoracic lesions. Despite this, she developed progressive weakness, weight loss, and dyspnea. At 41 months (May 2025), imaging revealed no evidence of active disease, but she remained severely cachectic. The patient died at home 42 months post-surgery (June 2025). No autopsy was performed.
Discussion
Concurrent chemoradiation followed by durvalumab remains the standard of care for unresectable stage IIIB NSCLC[
4]. However, adjuvant EGFR-targeted therapy after curative-intent surgery is increasingly used in carefully selected patients with EGFR-mutated tumors. This case illustrates that prolonged survival can be achieved with a multimodal approach including curative-intent surgery followed by targeted therapy, even in a patient with a highly unfavorable prognosis (multistation N2 disease).
The 35-month recurrence-free period following this complex, multimodality treatment is notable and supports the consideration of surgery in specialized centers for carefully chosen patients with T4N2 disease[
3]. The initial plan, guided by an institutional protocol, was to use neoadjuvant chemotherapy as a test of biology. Although a radiographic response was seen, the lack of a major pathological response in the lymph nodes underscores the aggressive nature of the disease and the critical importance of effective adjuvant therapy.
The subsequent emergence of osimertinib resistance, driven by MET and CDK4 amplifications along with CDKN2A loss, is consistent with known resistance mechanisms to third-generation EGFR-TKIs[
5]. This case vividly illustrates two key principles in the modern management of oncogene-driven lung cancer. First, even with optimal local and systemic therapy, residual micrometastatic disease can harbor or acquire resistance mutations, leading to eventual relapse. Second, obtaining a comprehensive tissue (or liquid) biopsy at the time of progression is essential for identifying these mechanisms and guiding subsequent therapy, as demonstrated by the initial, albeit short-lived, response to crizotinib.
Finally, this case highlights the invaluable role of advanced 3D modeling in the preoperative planning of complex, combined airway and vascular resections. The ability to visualize the tumor’s relationship with critical structures, simulate resections, and anticipate technical challenges such as anastomotic tension was instrumental in the safe and successful execution of this demanding procedure.
The limitations of this single report are inherent to its nature. The patient’s unsupervised dose reduction of osimertinib is a confounding variable, and the absence of a post-mortem examination limits our understanding of the exact cause of death in the context of radiographic remission and profound cachexia.
Conclusion
In conclusion, this case contributes to the growing body of evidence that select patients with stage IIIB EGFR-mutated NSCLC can achieve durable benefit from a multidisciplinary approach that includes complex surgery and adjuvant targeted therapy. It reinforces the need for individualized decision-making in specialized centers and the critical importance of molecular surveillance and rebiopsy at the time of progression.
The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.
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