Sublobar resection combined with furmonertinib in peripheral solid EGFR-mutated stage IA3 lung adenocarcinoma patients with pulmonary dysfunction: a retrospective multi-institutional study.

Introduction
Lobectomy has long been the standard procedure for peripheral, solid, pathologically confirmed stage IA3 lung adenocarcinoma (LUAD); however, in patients with pulmonary dysfunction, defined as a forced expiratory volume in 1 second (FEV1) less than 60% of the predicted value, sublobar resection (SR) is often preferred. Current guidelines strongly recommend stereotactic body radiation therapy (SBRT) as an alternative to surgery (1). However, the high cost of the equipment, long treatment duration, and risk of radiation pneumonitis pose challenges for both clinicians and patients. Some expert consensus statements also recommend percutaneous airway radiofrequency ablation (RFA) for these patients with pulmonary dysfunction (2); however, it has not yet been widely adopted due to a lack of large randomized controlled studies. Notably, the selection of SR, SBRT, or RFA may be influenced by other factors such as patient status, institutional experience, and tumor location or size. Thus, the choice of the optimal modality is complex; however, in general, a surgical approach is favored when it is considered safe (3). SBRT, RFA, or target therapy may represent the next best options.
Epidermal growth factor receptor (EGFR), the expression product of the proto-oncogene C-erbB-1, is a transmembrane protein located on the short arm of chromosome 7 with 28 exons. Mutations in the EGFR tyrosine kinase region of LUAD mainly occur in exons 18 to 21, and typical mutations include exon 19 deletion and the exon 21 L858R point mutation. Research has shown that compared with chemotherapy, adjuvant targeted therapy provides a significant advantage for stage IB–IIIA non-small cell lung cancer (NSCLC) patients with the typical EGFR mutation (4,5). However, clinical evidence on the use of adjuvant therapy for stage IA3 NSCLC with high-risk factors is limited. While SR preserves more lung function, it may pose a high risk of local recurrence or metastasis in patients with solid peripheral stage IA3 LUAD if the surgical margin or lymph node sampling or dissection is insufficient (6).
From January 2018 to July 2020, the clinicopathologic and prognostic data of peripheral, solid stage IA3 LUAD patients from three thoracic tumor centers were collected and screened. The main treatments included lobectomy, SR combined with EGFR-TKIs, and SR alone in patients with an American Society of Anesthesiologists (ASA) score ≤3. This retrospective cohort study was conducted to determine which treatment approach was the most advantageous. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0227/rc).

Methods

Inclusion and exclusion criteria
The data were sourced from the clinical pathology databases of the Affiliated Hospital of Nantong University, Nantong First People's Hospital and Nantong Tumor Hospital from January 2018 to December 2019.
The inclusion criteria of SR were as follows: (I) age >18 years; (II) SR, including segmental resection and wedge resection; (III) chest computed tomography (CT) showing a solid, peripheral nodule with a maximal diameter of 2–3 cm; (IV) a pathological diagnosis of primary LUAD, staged as IA3 according to the 8th edition of the tumor-node-metastasis (TNM) classification system; (V) pulmonary dysfunction [defined as FEV1 <60% of the predicted value based on the American Association for Thoracic Surgery (AATS) criteria] (7); (VI) no preoperative chemotherapy, radiotherapy, or targeted therapy, and no history of other malignant tumors; and (VII) tumor tissue available for groups B and C for next-generation sequencing (NGS).
The exclusion criteria were as follows: (I) CT imaging showing nodules with ground-glass opacity components or centrally located lesions; (II) non-surgical treatments, such as ablation or stereotactic radiotherapy; (III) a pathological diagnosis of metastatic adenocarcinoma or primary non-LUAD; (IV) incomplete follow-up 5 years after surgery; and/or death or loss to follow-up not related to lung cancer (V) receipt of other treatments such as chemotherapy or radiotherapy postoperatively, or participation in clinical trials related to other tumors within three months.
According to the inclusion and exclusion criteria, the patients of SR were divided in group B and C which were regrouped based on the strategies of adjuvant therapy. Patients with concurrent pathological stage IA3 LUAD who underwent standard lobectomy and lymph node dissection were selected as the standard survival control and included in group A.

Clinicopathologic data collection
The following clinical data were collected: age, gender, smoking history, cardiac function index (ejection fraction value), lung function status (FEV1%), concomitant diseases (e.g., hypertension, diabetes, and cerebral infarction), tumor location and size. The following pathological data were collected: tumor grade, vascular invasion, spread through air space (STAS) (Table 1). The incidence of adverse events (AEs), such as cardiovascular events, rashes, and diarrhea, within 90 days was also recorded.

Treatment procedure
Preoperatively, no metastasis was found through cranial magnetic resonance imaging (MRI), whole-body bone scanning, thoracic and abdominal enhanced CT examination or positron emission tomography-CT. The choice of surgical treatment was mainly based on lung function following multidisciplinary discussion. Whether the patients underwent lobectomy or SR, the lymph node resection included at least ≥3 hilar and mediastinal lymph node stations. In the SR group, the surgeons ensured that the surgical margins were greater than the tumor diameter whenever possible, and targeted therapies, such as furmonertinib, were selected based on EGFR mutation status. Furmonertinib was performed 1 week after surgery, and the time period was at least 3 years, or until recurrence and discontinuation of treatment. Postoperative related adverse drug reactions were recorded. Relevant treatment measures are fully communicated with patients. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by ethics committee of Affiliated Hospital of Nantong University (No. 2024-K185-01). Nantong First People's Hospital and Nantong Tumor Hospital were informed and agreed with this study. Individual consent for this retrospective analysis was waived.

Recurrence risk analysis
A Cox regression analysis was performed on each variable in the enrolled cohort. The univariate Cox regression model was constructed as follows: (I) the 3-year recurrence-free survival (RFS) status of the study population was defined as the dependent variable; (II) each potential prognostic factor was entered into the model as an independent variable individually; and (III) the hazard ratio (HR) and its 95% confidence interval (CI) were calculated for each independent variable and tested for significance, with P values <0.05 considered statistically significant. The multivariate Cox regression model was then constructed as follows: (I) all variables with P values <0.05 in the univariate analysis were included in the multivariate Cox regression model to identify independent prognostic factors; (II) the multivariate Cox regression model was constructed using the all-variable entry method; and (III) the HR for each of the independent variables was calculated, along with the 95% CI, to assess the independent effect of each factor on survival time. All variables with P values <0.05 in the multivariate analysis were considered independent risk factors for recurrence.

Follow-up
Perioperative mortality was defined as mortality occurring within 30 days of surgery. Oncologic follow-up included chest and upper abdomen CT scans, serial peripheral blood carcinoembryonic antigen measurements, complete blood counts, and liver and renal function assessments, which were repeated every 3–6 months for the first 2 years, and every 6 months for the next 3 years. Cranial MRI and bone scans were performed annually. Marginal and regional recurrences were diagnosed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria; some patients were also diagnosed pathologically by fiberoptic bronchoscopy or percutaneous puncture techniques. The primary study endpoint was 3-year RFS, and the secondary study endpoints were 5-year OS and the incidence of AEs within 90 days.

Statistical analysis
For the clinical and pathologic data, the continuous variables are expressed as the mean ± standard deviation, and were compared using the unpaired t-test. The categorical variables are expressed as the number and percentage, and were compared using the Chi-squared test. Comparisons of the incidence of AEs within 90 days were performed using the Chi-squared test or Fisher’s exact test. Univariate and multivariate Cox regression analyses were conducted to analyze the independent variables associated with recurrence or metastasis. Potential prognostic factors with P values <0.05 in the univariate analysis were included in the final multivariate analysis. All P values were based on two-tailed statistical analysis, with P values <0.05 considered statistically significant. All survival analyses were performed using the Kaplan-Meier method to generate RFS and OS curves, which were compared using the log-rank test. Kaplan-Meier curves were produced using R version 4.3.3 (The R Foundation for Statistical Computing, 2024) software, and the remaining statistical analyses were performed using SPSS 27.0 software (IBM, Armonk, NY, USA).

Results

Clinical and pathological characteristics of study patients
From January 2018 to July 2020, 160 patients diagnosed with solid, peripheral, pathologic stage IA3 LUAD from three thoracic tumor centers were enrolled in the study. Of these patients, 105 were allocated to group A, 21 to group B and 34 to group C. SR included wedge resection (n=26) and segmentectomy (n=29). The patients had a mean age of 63.5 years; 69 (43.13%) were male and 91 (56.87%) were female; 107 (66.87%) had no history of smoking or were occasional smokers, and 55 (34.38%) had preoperative pulmonary function with FEV1% <60%.
The average nodule size was 2.56 cm (range, 2–3 cm). In terms of nodule location, the nodules were located in the right upper lung in 40 (25%) patients, the right lower lung in 40 (25%) patients, the left upper lung in 38 (23.75%) patients, and the left lower lung in 42 (26.25%) patients. There was no significant difference in the incidence rate of concomitant diseases such as hypertension, diabetes, and cerebral infarction among the three groups (Table 1).
The pathologic features, which were classified according to the International Association for the Study of Lung Cancer (IASLC) 2021 classification criteria (2), included 8 cases (5%) of grade I, 104 cases (65%) of grade II, and 48 cases (30%) of grade III. The microscopic pathologic features included vascular invasion in 17 cases (10.62%), nerve invasion in 29 cases (18.13%), and STAS in 73 cases (45.62%). The EGFR-mutated status including Del19 or L858R 21 were 65 (40.62%) in group A, 21(13.12%) in group B and 1 (0.62%) in group C (Table 1).

Comparison of the incidence of complications and AEs within 90 days
The Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) (8) were used to evaluate postoperative complications. In this study, perioperative mortality was 0% across all three surgical groups. In terms of the incidence of postoperative complications, 26 (24.8%) were observed in group A (n=105), 6 (28.6%) were observed in group B (n=21), and 9 (26.5%) were observed in group C (n=34). A comparative analysis of the overall complication rates revealed no statistically significant differences among the groups (χ2=0.149, P=0.92). Thus, the rates of early postoperative complications did not differ significantly between groups A, B, or C (Table 2). The AEs in the targeted therapy group were fewer, including rash in 8 of 21 patients, diarrhea in 5 of 21 patients, and abnormal liver function in 1 of 21 patients.

Survival analysis
The univariate Cox regression analysis of groups B and C revealed that gender, smoking history, IASLC grade, EGFR mutation status, vascular invasion and treatment modality were independent prognostic factors for postoperative recurrence. The multivariate Cox regression analysis further revealed that IASLC grade (HR 0.224, 95% CI: 0.134–0.376, P<0.001), treatment modality (HR 0.231, 95% CI: 0.197–0.351, P<0.001) and EGFR mutation status (HR 0.065, 95% CI: 0.055–0.833, P<0.001) were independent prognostic factors for postoperative recurrence (Table 3). Among all the enrolled patients, 73 developed recurrence, of whom 31 (42.47%) developed distant recurrence and 42 (57.53%) developed locoregional recurrence only. Kaplan-Meier survival curves demonstrated that 3-year RFS and 5-year OS did not differ significantly between groups A and B (P=0.06 and P=0.09, respectively). However, both survival outcomes were significantly better in group A than in group C (3-year RFS: HR 0.597, 95% CI: 0.356–0.999, P=0.045; 5-year OS: HR 0.568, 95% CI: 0.322–1.005, P=0.046). Similarly, group B showed significantly better 3-year RFS (HR 0.266, 95% CI: 0.100–0.707, P=0.004) and 5-year OS (HR 0.217, 95% CI: 0.064–0.739, P=0.006) compared with group C (Figures 1-3).

Discussion
None of the current major guidelines recommend SR for peripheral stage IA3 LUAD. However, controversy remains regarding whether sublobectomy is appropriate and which patients are the best candidates for this procedure. A small number of retrospective studies have suggested that SR may be considered for subsolid peripheral stage IA3 NSCLC. Kamigaichi et al. (9) prospectively compared the efficacy of lobectomy and anatomical sublobectomy in 297 patients with stage IA3 NSCLC mainly composed of solid components. After propensity score matching, the 3-year relapse-free survival (RFS) rates and the 5-year overall survival (OS) rates do not reach statistical significance between the two groups.
Conversely, other studies suggest that SR for solid IA3 NSCLC carries a high risk of recurrence. First, occult lymph node metastasis may occur in SR. Nobel et al. (10) reported that after lobectomy or SR for cT1-stage patients, about 4% had occult lymph node metastasis, including N2 metastasis. Although the prognosis of SR is similar to that of lobectomy, the probability of occult lymph node metastasis is significantly increased, which poses important requirements for lymph node dissection during surgery. Unfortunately, wedge resection may be limited by insufficient lymph node assessment. In our study, 16 patients underwent wedge resection, one of whom had N2 metastasis after surgery, which might have been related to insufficient lymph node assessment. Second, SR, especially wedge resection, is limited by insufficient surgical margins. Huang et al. (11) conducted a retrospective study and reported that during SR, the risk of local recurrence is only significantly reduced when the surgical margin is greater than 2 cm. In our study, the surgical margins of the patients in the SR group generally exceeded 2 cm. However, for IA3 stage patients, a surgical margin greater than 2 cm may still be insufficient. Thus, a more accurate determination of the surgical margin during surgery is particularly important. In the future, if the surgical margin is not sufficient, intraoperative frozen section examination of the surgical margin or an expansion of the resection of the adjacent lung segments could be considered. In recent years, there have also been reports (12) that the intraoperative use of indocyanine green may further enhance the precision of identifying resected margins. Finally, research (13) has shown that compared with subsolid nodules, solid nodules are more likely to be associated with a poor prognosis, which may be related to adverse pathological features such as STAS and micropapillary patterns. In patients with solid LUAD measuring 2–3 cm undergoing SR, it is necessary to rule out the presence of pleural invasion or STAS, which are the main causes of postoperative recurrence. Fick et al. (14) found that stage I NSCLC recurrence was related to a higher maximum standardized uptake value, SR, a higher IASLC grade, lymphovascular invasion, visceral pleural invasion, and tumor size. Kubota et al. (15) found that the IASLC grading system was correlated with the outcomes of EGFR-mutated LUAD. Specifically, grade 3 was found to have the tumor microenvironment most strongly associated with poor tumor progression. In our study, a higher IASLC grade and treatment strategy were also identified as important factors for postoperative recurrence. Thus, postoperative adjuvant therapy is particularly important, especially for high-risk IA3 solid peripheral EGFR-mutated LUAD, even after lobectomy. Since 2015, several studies (5,16) have reported that EGFR-TKIs as postoperative adjuvant therapy achieves significant survival advantages over chemotherapy in stage IB–III NSCLC patients. Meanwhile, there are very few adjuvant treatments for stage IA patients, even when high-risk factors are present. Using the 8th edition of the TNM classification system, in a retrospective study, Jiang et al. (17) found that with adjuvant targeted therapy, the 5-year disease-free survival (DFS) rate of high-risk patients for stage IA NSCLC increased from 84.5% to 100%, and the 5-year DFS rate of stage IB NSCLC increased from 75.3% to 100%, suggesting that the vast majority of stage I patients can be completely cured with targeted adjuvant therapy. It is gratifying that large-scale prospective clinical studies (18) are underway. In other studies on combination therapy, Sun et al. (19) found that SBRT combined with EGFR-TKIs for inoperable EGFR-mutated stage I LUADs significantly improved 3-year PFS (HR 0.420, 95% CI: 0.291–0.605, P<0.005) and 5-year OS (HR 0.420, 95% CI: 0.287–0.614, P<0.001), compared with EGFR-TKIs alone. Similarly, this study showed that SR combined with EGFR-TKIs significantly improved 3-year RFS and 5-year OS, compared with SR alone. Further, and even more promisingly, SR combined with EGFR-TKIs achieved 3-year PFS and 5-year OS outcomes comparable to those of lobectomy.

Limitations
This study had some limitations. First, it was a retrospective study, which might have led to selection bias in the enrolled patients, including clear documentation of preoperative gene testing, rigorous adjustment for treatment selection bias, standardized and justified adjuvant therapy protocols. Second, SBRT, which is recommended in many NSCLC guidelines, might have served as a more compelling comparator if it had been included as a control group. In addition, in the subgroups, propensity score matching adjusted multivariable analysis was not used to minimize these limitations due to the small number of patients enrolled and the significant individual differences between the SR groups. Finally, we did not strictly differentiate between different types of SR (e.g., segmentectomy or wedge resection). However, several studies have shown that the local recurrence rate of segmentectomy is lower to that of wedge resection.

Conclusions
SR combined with EGFR-TKI may represent a good treatment strategy for patients of peripheral, solid EGFR-mutated stage IA3 LUAD with pulmonary dysfunction, as it does not increase postoperative complications, and its long-term survival outcomes are superior to those of SR alone.

Supplementary
The article’s supplementary files as