Palliative surgery is effective in patients with EGFR-mutant lung adenocarcinoma with pleural metastasis

Introduction

According to Global Cancer Statistics, there were an estimated 2.48 million new cases of lung cancer and 1.82 million lung cancer-related deaths worldwide in 2022, making it the leading cause of cancer-related mortality worldwide (1). Lung cancer is also the most common malignant tumor in China, with the highest incidence and mortality rates (2). More than half of lung cancer patients are diagnosed with stage III or IV disease (3). Non-small cell lung cancer (NSCLC) is the predominant pathological type of lung cancer, and accounts for approximately 85% of all lung cancer cases (4). In Asia, epidermal growth factor receptor (EGFR) is the most common driver gene in NSCLC (5,6). And EGFR mutations include the common Exon 19 Deletion (19DEL) and Exon 21 Leucine 858 to Arginine Mutation (L858R) and the less common Exon 18 Glycine 719 Substitution (G719X) and Exon 20 Serine 768 to Isoleucine Mutation (S768I) mutations and so on (7).

Patients with EGFR mutations treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly better survival than those treated with traditional chemotherapy alone (8). EGFR-TKIs have been recommended as the first-line therapeutic regimen for advanced EGFR-mutant NSCLC (EGFR-NSCLCm). EGFR-TKIs have also been recommend as the adjuvant treatment for locally advanced EGFR-NSCLCm postoperatively (9,10). However, resistance to EGFR-TKIs in EGFR-NSCLCm patients is inevitable (11-13); thus, the effective duration of targeted therapy needs to be extended.

With advancements in surgical techniques and improvements in drug efficacy, the range of patients who can achieve survival benefits from surgical treatment has significantly expanded. Previous studies have shown that surgical treatment can prolong the prognosis of NSCLC patients with oligometastasis who received EGFR-TKI therapy (14-16). However, controversy continues as to the efficacy of EGFR-TKIs combined with surgical treatment for advanced EGFR-NSCLCm patients (17,18). Therefore, research needs to be conducted to examine whether pleural metastatic EGFR-NSCLCm patients can benefit from EGFR-TKIs combined with surgical treatment.

In this study, we sought to compare the survival outcomes of patients with stage IVA EGFR-mutant LUAD (LUADm) with pleural metastasis who received EGFR-TKIs combined with palliative surgery to those who received targeted therapy alone. Our retrospective findings may be useful in clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037//tlcr-2025-140/rc).

Methods

Study population

EGFR-LUADm patients with pleural metastasis treated at Shanghai Pulmonary Hospital from November 2014 to November 2023 were enrolled in this study. The pathological and EGFR-mutant diagnoses were confirmed by percutaneous lung biopsy and polymerase chain reaction, respectively. The clinical staging was confirmed by positron emission tomography/computed tomography (PET-CT), chest CT, and brain magnetic resonance imaging (MRI). Pleural dissemination was defined as the presence of multiple pleural nodules with contrast enhancement on CT or increased flourodeoxyglucose (FDG) uptake [maximum standardized uptake value (SUVmax) ≥2.5] on PET-CT. To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) EGFR-LUADm clinical stage IVA (based on the eighth version of the American Joint Committee on Cancer lung cancer staging system) with exclusive pleural metastasis; and (II) a complete response radiologically with pleural metastasis tumor after targeted therapy. The patients were divided into surgical and non-surgical groups. The surgical decision-making process was rigorously conducted by our institutional multidisciplinary tumor board (MDT), comprising thoracic surgeons, medical oncologists, radiologists, and pathologists. Surgical candidacy required fulfillment of all three core criteria: (I) complete response radiologically with pleural metastasis tumor after targeted therapy; (II) exclusion of new metastatic lesions via post-TKI; and (III) functional capacity meeting surgical risk thresholds. Final decisions required unanimous consensus from surgical and medical oncology teams. Patients in the surgical group underwent a pulmonary function test and brain MRI to ensure the feasibility of surgery. Patients were excluded from the study if they met any of the following exclusion criteria: (I) underwent a pneumonectomy; and/or (II) received other antineoplastic therapies in addition to the targeted therapy. The surgical approach was not restricted and included video-assisted thoracic surgery, open thoracic surgery, and robotic-assisted thoracic surgery. The follow-up of these patients continued until July 2024.

Clinical information collection

The clinical information of the eligible patients was retrospectively collected from the clinical database of Shanghai Pulmonary Hospital. The patients’ characteristics were recorded, including diagnostic age, gender, smoking status, performance status based on the Eastern Cooperative Oncology Group Performance Status (ECOG PS), Programmed cell death ligand 1 (PD-L1) tumor expression, Tumor node metastasis classification (TNM) staging, EGFR-mutant status, targeted therapy details, surgical treatment, disease progression, and survival status.

Propensity score matching (PSM)

The patients were matched using PSM based on conventional prognostic factors affecting lung cancer (including ECOG score, smoke, age, N stage, and sex). The matching ratio was 1:2 (caliper: 0.05), such that two non-surgical patients were matched to each surgical patient.

Statistical analysis

The statistical analyses were conducted on the matched data. Fisher’s exact test and the independent sample t-test were used to compare the categorical and continuous variables between the two subgroups, respectively. The median follow-up time was calculated using the reverse Kaplan-Meier method. Progression-free survival (PFS) was defined as the time from the initiation of EGFR-TKI therapy to disease progression, which was calculated using the Kaplan-Meier method, and the PFS difference between the two subgroups was compared using the log-rank test. The prognostic factors were identified by Cox proportional hazards regression analysis. All the statistical analyses were conducted using R (version 4.3.2) with a two-sided significance level.

Ethics statement

This study was approved by the Ethics Committee of Shanghai Pulmonary Hospital (No. K24-495, 2024/8/9), and the study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all the patients or their family members.

Results

Patient characteristics

In total, 134 EGFR-LUADm patients with pleural metastasis in stage IVA were retrospectively included in this study. All patients received EGFR-TKI monotherapy as their first-line treatment after diagnosis. The surgical group comprised 13 patients, and the non-surgical group comprised 121 patients who received EGFR-TKI monotherapy only. Among 121 patients who did not undergo surgery, 99 (81.8%) experienced disease progression. The progression patterns were categorized as follows: primary lesion progression in 56 cases (56.6%), increased pleural metastasis or development of other distant metastases in 21 cases (21.2%), lymph node progression in 4 cases (4.0%), and new-onset pleural effusion in 18 cases (18.2%). There were 65 19DEL and 56 non ex19 deletion mutant (N-19DEL) patients (including two patients with L858R + S768I mutation and one patient with G719X + S768I). Among 13 patients undergoing surgical resection following preoperative EGFR-TKI therapy (median duration 4 months), 10 (76.9%) received lobectomy and 3 (23.1%) underwent wedge resection. The objective response rate (ORR) to targeted therapy in the surgical cohort was 69.2%. All surgical resections were targeted at primary lesions, with concurrent systematic lymph node dissection performed in accordance with standard oncological principles. In surgery cohort, adjuvant therapy commenced within 30 days post-surgery. Patients in the surgery group were maintained on same TKI therapy and underwent surveillance chest CT at 3-month intervals for disease monitoring. After PSM at a 1:2 ratio, the surgical group comprised 13 patients, while the non-surgical group comprised 26 patients. The clinical and pathological characteristics of the patients before and after PSM are set out in Table 1. After PSM, in terms of targeted therapy, four surgical patients and two non-surgical patients received a third-generation EGFR-TKI. The majority of patients had an ECOG PS of 0 (76.9%). After PSM, no differences in the baseline characteristic variables were observed between the surgical and non-surgical subgroups; all the patients were never smokers. All patients had either the 19DEL or L858R mutation after PSM.

Prognostic factors

Before PSM, the univariate analysis revealed that surgical treatment significantly extended PFS for stage IVA EGFR-LUADm patients with pleural metastasis [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.056–0.36, P<0.001] (Figure 1). Additionally, patients with a diagnostic age ≥65 years had superior PFS than those with a younger diagnostic age (HR: 0.47, 95% CI: 0.282–0.79, P=0.004). Compared to the patients with T1 stage, those with T2 stage had significantly worse PFS (HR: 1.98, 95% CI: 1.019–3.84, P=0.044). Similarly, patients with Exon 19 Deletion (Ex19-Del) had significantly superior PFS than those without Ex19-Del (HR: 1.66, 95% CI: 1.082–2.55, P=0.02).

Figure 1 Univariate Cox regression analysis before PSM. Significance codes: ***, P<0.001; **, P<0.01; *, P<0.05. AIC, Akaike information criterion; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; N-19DEL, non ex19 deletion mutant; PD-L1, programmed cell death ligand 1; PSM, propensity score matching; TKI, tyrosine kinase inhibitor.

After PSM, the results of the survival analysis confirmed that the patients who received EGFR-TKI combined with surgical treatment had significantly better PFS than those who received EGFR-TKI monotherapy alone (HR: 0.15, 95% CI: 0.04–0.54, P=0.004) (Figure 2). Compared to the N0 patients, the N1 patients had a higher risk of recurrence (HR: 5.39, 95% CI: 1.053–27.65, P=0.043). Notably, this trend was not observed in the N2 patients (HR: 0.92, 95% CI: 0.314–2.71, P=0.88).

Figure 2 Univariate Cox regression analysis after PSM. Significance codes: **, P<0.01; *, P<0.05. AIC, Akaike information criterion; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; N-19DEL, non ex19 deletion mutant; PD-L1, programmed cell death ligand 1; PSM, propensity score matching; TKI, tyrosine kinase inhibitor.

After PSM, the surgical and non-surgical groups comprised 13 and 26 patients. In the surgical group, there were five patients without recurrence; however, in the non-surgical group, there were only two patients without disease progression. As Figure 3 shows, the PFS of the patients in the surgical group was significantly better than that of those in the non-surgical group [median PFS: 43 (95% CI: 30–not available) vs. 11 (95% CI: 10–26) months, P<0.001].

Figure 3 After PSM, PFS comparison between the surgical and non-surgical groups. NA, not available; PFS, progression-free survival; PSM, propensity score matching.

Discussion

Lung cancer is highly prevalent, and is frequently diagnosed as advanced stage disease that is not suitable for surgical treatment (3). In such cases, the therapeutic regimens aim to prolong the PFS of patients. This situation is particularly relevant to NSCLC patients harboring EGFR mutations, which is the most prevalent mutation in Aisa (5,6). Treatment adjustments are considered in multidisciplinary team discussions when resistance develops. As resistance to targeted therapy is inevitable (11-13), it is crucial to extend the resistance-free period, thereby prolonging PFS.

Tseng et al. reported that primary tumor resection in patients with advanced EGFR-LUADm undergoing EGFR-TKI therapy can result in a better prognosis (14). Ohtaki et al. found that salvage surgery in NSCLC patients receiving EGFR-TKI or Anaplastic Lymphoma Kinase-TKI (ALK-TKI) therapy is safe and feasible, and may extend overall survival by reducing the local tumor burden (15). Conversely, Hu et al. found that tumor resection did not improve the overall survival of patients receiving targeted therapy (HR: 0.649, P=0.38) (19).

In our study, both pre- and post-PSM, the results show that univariate analyses can detect a significant impact of surgery on patients’ PFS (pre-PSM HR: 0.14, 95% CI: 0.056–0.36, P<0.001; post-PSM HR: 0.15, 95% CI: 0.04–0.54, P=0.004). This indicates that palliative surgery of the primary tumor lesion may provide some therapeutic benefits for patients with pleural metastatic LUAD.

The univariate analysis after PSM revealed that the presence of lymph node metastasis was more likely to lead to the development of resistance to targeted therapy. Meanwhile, patients with N1 staging were more prone to disease progression than patients with other N stages; however, the reasons for its rapid progression are not yet known. There may be two possible reasons for this outcome. First, it may be related to the small sample size of the study. Second, it may be that the malignancy level differs due to varying metastasis patterns. Research of other cancers has shown that patients with hematogenous metastasis are at higher risk than those with lymphatic metastasis (20). Thus, LUAD with predominantly hematogenous metastasis may have a higher malignancy level. We speculate that in patients with N1 lymph node metastasis and concurrent pleural metastasis, the primary metastatic routes are likely hematogenous metastasis.

After PSM, all smoking patients were excluded from the study. Of the total 13 smoking patients, none underwent surgery [which suggests that the effect of EGFR-TKI may be worse in smokers (21)]; 10 experienced disease progression (median PFS: 15.1 months), and three did not experience disease progression. These patients had follow-up times of 16, 17, and 21 months, respectively. The overall PFS of the smoking patients was better than that of non-smoking patients (median PFS: smokers, 15.1 months; non-smokers, 11 months), but this is likely due to the small sample size of this study.

Among the eight patients who experienced postoperative recurrence (seven of whom had N2/3 stage), four showed pleural carcinoma recurrence, while the other four showed pulmonary carcinoma recurrence. However, the underlying causes of this phenomenon remain unclear; thus, further research needs to be conducted to explore the reasons behind it.

In the non-surgical group, disease progression was observed in 99 patients, with primary lesion progression accounting for 56.6% of cases (56/99). These findings suggest a potential therapeutic advantage of palliative resection. Therefore, in surgical candidates with preserved functional status, proactive resection of primary lesions through palliative surgery should be considered to optimize oncological outcomes.

This study had several limitations. First, some biases were inevitable because of the retrospective and single-center nature of this study. The decision to perform surgery was solely determined by the multidisciplinary team at our hospital. Additionally, the sample size was not large, which might be due to the strict inclusion criteria, which limited the number of eligible patients. And the 134 patients included thus far have had a mortality rate of less than 5%. It remains unclear whether surgical intervention would impact survival, which will be the focus of our subsequent research.

Conclusions

We found that palliative surgery of the primary tumor lesion provided some therapeutic benefits for pleural metastatic LUAD patients, and may delay the EGFR-TKI therapy resistance.

Acknowledgments

We gratefully acknowledge the participation of the study participants. We would also like to thank Shanghai Pulmonary Hospital for providing data support.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037//tlcr-2025-140/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037//tlcr-2025-140/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037//tlcr-2025-140/prf

Funding: This study was funded by the Clinical Research Plan of SHDC (No. SHDC2022CRS047, to J.L.), the Clinical Research Foundation of Shanghai Pulmonary Hospital (No. SKPY2021002, to Y.Z.), the Clinical Research Plan of SMHC (No. 20184y0051, to J.L.), and the Shanghai Pulmonary Hospital “Elite Sail” Talent Program (No. 2024 fkjy2403, to D.B.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037//tlcr-2025-140/coif). J.L. reports funding from Clinical Research Plan of SHDC (No. SHDC2022CRS047), and Clinical Research Plan of SMHC (No. 20184y0051). K.H. reports receiving personal fees from AstraZeneca, MSD, Kyorin Pharmaceutical, Chugai Pharmaceutical, and Daiichi-Sankyo, outside the submitted work. Yuming Zhu reports funding from Clinical Research Foundation of Shanghai Pulmonary Hospital (No. SKPY2021002). D.B. reports funding from Shanghai Pulmonary Hospital “Elite Sail” Talent Program (No. 2024 fkjy2403). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of Shanghai Pulmonary Hospital (No. K24-495, 2024/8/9), and the study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from all the patients or their family members.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [PubMed]
2. Zheng RS, Chen R, Han BF, et al. Cancer incidence and mortality in China, 2022. Zhonghua Zhong Liu Za Zhi 2024;46:221-31. [PubMed]
3. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [PubMed]
4. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [PubMed]
5. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62. [PubMed]
6. Dearden S, Stevens J, Wu YL, et al. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013;24:2371-6. [PubMed]
7. Trinh JQ, Abughanimeh O. Current management of uncommon EGFR mutations in non-small cell lung cancer. Curr Probl Cancer. 2024;49:101064. [PubMed]
8. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-9. [PubMed]
9. Bian D, Sun L, Hu J, et al. Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study. Nat Commun 2023;14:4655. [Crossref] [PubMed]
10. Riely GJ, Wood DE, Ettinger DS, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024;22:249-74. [Crossref] [PubMed]
11. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357-60. [Crossref] [PubMed]
12. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 2019;121:725-37. [PubMed]
13. Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging Treatment Paradigms for EGFR-Mutant Lung Cancers Progressing on Osimertinib: A Review. J Clin Oncol 2020; [PubMed]
14. Tseng JS, Hsu KH, Zheng ZR, et al. Primary Tumor Resection Is Associated with a Better Outcome among Advanced EGFR-Mutant Lung Adenocarcinoma Patients Receiving EGFR-TKI Treatment. Oncology 2021;99:32-40. [Crossref] [PubMed]
15. Ohtaki Y, Shimizu K, Suzuki H, et al. Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment. Lung Cancer 2021;153:108-16. [PubMed]
16. Lin MW, Yu SL, Hsu YC, et al. Salvage Surgery for Advanced Lung Adenocarcinoma After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment. Ann Thorac Surg 2023;116:111-9. [Crossref] [PubMed]
17. Casiraghi M, Bertolaccini L, Sedda G, et al. Lung cancer surgery in oligometastatic patients: outcome and survival. Eur J Cardiothorac Surg 2020;57:1173-80. [Crossref] [PubMed]
18. He J, Li Y, An J, et al. Surgical treatment in non-small cell lung cancer with pulmonary oligometastasis. World J Surg Oncol 2017;15:36. [Crossref] [PubMed]
19. Hu J, Chen Y, Zhu X, et al. Surgical choice of non-small cell lung cancer with unexpected pleural dissemination intraoperatively. BMC Cancer 2021;21:445. [Crossref] [PubMed]
20. Li H, Wu X, Cheng X. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol 2016;27:e43. [Crossref] [PubMed]
21. Middleton G, Fletcher P, Popat S, et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature 2020;583:807-12. [Crossref] [PubMed]