Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy

Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy Yu-Wei Liu, Wei-An Lai, Jen-Yu Hung, Yen-Lung Lee, Hung-Hsing Chiang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5098964/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Feb, 2025 Read the published version in World Journal of Surgical Oncology → Version 1 posted 11 You are reading this latest preprint version Abstract Objective: Salvage resection for residual lung cancer harboring epidermal growth factor receptor (EGFR) mutations following EGFR-tyrosine kinase inhibitor (TKI) treatment is gaining traction for its survival benefits. However, the impact of pathological factors on survival remains unclear. Methods: Between 2013 and 2023, we retrospectively reviewed 34 patients with advanced lung adenocarcinoma who received EGFR-TKI therapy. After a median TKI treatment duration of 9.1 months, all patients demonstrated either partial response (n=27) or stable disease (n=7) before salvage surgery. Demographic, pathological outcomes, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Among the 34 patients, six (17.6%) achieved a pathological complete response (pCR) and nine (26.5%) had a major pathological response (MPR). Additionally, 11 patients (32.4%) exhibited spread through air spaces (STAS), and lymphovascular invasion (LVI) was observed in nine patients (26.5%). The 3-year PFS and OS rates were 55.5% and 73.2%, respectively. No significant differences in PFS or OS were observed regarding TKI generation, mutation type, pCR, MPR, or LVI. However, Kaplan-Meier analysis revealed that STAS was associated with shorter PFS compared to non-STAS cases ( p =0.011). In multivariate analysis, STAS was identified as an independent prognostic factor for PFS (hazard ratio: 1.63, 95% CI: 1.17–30.78, p =0.034). No significant prognosticators were found for OS in univariate or multivariate analyses. Conclusion: While salvage surgery following TKI treatment is feasible and prolongs survival by removing residual primary tumor with potential TKI resistance, STAS may contribute to a higher risk of early progression. This finding warrants further investigation and tailored treatment strategies. lung adenocarcinoma epidermal growth factor receptor tyrosine kinase inhibitor salvage surgery Spread through air spaces Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Previous studies have demonstrated that lung adenocarcinoma patients with actionable driver mutations, treated with matched tyrosine kinase inhibitors (TKIs), experience longer overall survival [ 1 ]. In Asia, approximately 50–60% of these patients have epidermal growth factor receptor (EGFR) mutations, with the most common being exon 19 deletions and exon 21 L858R mutations [ 2 , 3 ]. Currently, EGFR-TKIs remain the standard first-line therapy for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC) [ 4 , 5 ]. With the increasing adoption of multimodal treatment strategies in lung cancer, evidence supporting the efficacy of local consolidative therapy (LCT) has emerged in oligometastatic or oligo-progressive NSCLC patients treated with TKIs [ 6 , 7 ]. Our previous study assessed the impact of LCT in EGFR-mutant patients receiving afatinib as first-line therapy [ 8 ], revealing that patients who underwent LCT had significantly longer progression-free survival (PFS) than those who did not (median PFS: 32.8 vs. 14.5 months, p = 0.0008). Additionally, LCT was associated with improved overall survival (OS) (median OS: 67.1 vs. 34.5 months, p = 0.0011). Salvage surgery is a common LCT intervention, but prognostic factors for successful outcomes remain unclear. Recent studies have suggested expanding surgical resection for certain advanced NSCLC patients, particularly those with oligometastatic disease [ 9 – 12 ]. Several retrospective studies have demonstrated survival benefits from salvage surgery after TKI treatment in selected stage III and IV NSCLC patients [ 13 – 21 ]. Although surgery for regrown or residual tumors seems to provide good local control of the tumor burden and potentially prolong survival, some patients inevitably experience disease progression after primary tumor resection. Thus far, only one study has examined the pathological impact of treatment-resistant patterns on outcomes in advanced lung adenocarcinoma treated with TKIs and salvage resection [ 21 ], leaving the influence of other pathological factors on recurrence and survival undetermined. With this in mind, this retrospective cohort study primarily aims to evaluate surgico-pathological outcomes in patients with advanced EGFR-mutant lung adenocarcinoma who underwent salvage surgery following EGFR-TKI treatment. The secondary objective is to analyze prognostic factors and survival outcomes. Material and Methods Study design This retrospective cohort study analyzed cases from January 2013 to July 2023 at a tertiary center in southern Taiwan. The study received approval from the Institutional Review Board of Kaohsiung Medical University Hospital, and the requirement for written informed consent was waived (KMUHIRB-E(I)-20240126). A total of 59 patients with stage IIIB-IV primary lung adenocarcinoma who received TKI treatment followed by primary tumor resection were evaluated. We excluded patients who met the following criteria: ALK-TKI treatment (n=1), non-first-line EGFR-TKI treatment with or without chemotherapy prior to surgery (n=5), resection for re-examination of EGFR mutation due to clinical progressive disease (n=16), or incomplete data for analysis (n=3). This left 34 EGFR-mutant lung adenocarcinoma patients who received first-line TKI treatment and achieved a clinical partial response or stable disease for final analysis ( Figure 1 ). Clinical staging was determined based on the American Joint Cancer Committee (AJCC) eighth edition guidelines for lung cancer staging. All patients had a pre-treatment histopathological diagnosis confirmed either by flexible bronchoscopy or CT-guided biopsy. Bone scans, brain magnetic resonance imaging (MRI), and optional positron emission tomography and CT (PET-CT) scans were conducted to exclude distant metastases. Additionally, patients were confirmed to have common EGFR mutations (such as exon 19 deletion or exon 21 point mutation L858R) using real-time PCR cobas® EGFR mutation test before initiating EGFR-TKI treatment. The treatment modality, including salvage surgery, was assessed preoperatively by multidisciplinary tumor boards to reach a consensus on the surgical treatment. Indications of salvage surger y The strategy for salvage surgery was mainly concerned with the following criteria: (1) residual main tumor on CT scan showing partial response or stable disease by RECIST criteria, (2) all distant metastases were resolved on imaging studies after EGFR-TKI treatment and/or received appropriate local control, (3) adequate patient performance status, and (4) tolerable cardiopulmonary reserve. For residual primary lesions that were large or centrally located, anatomical resections typically began with ligation of the lobar vein, followed by either the bronchus or the artery, allowing for safe execution of a non-stapled lobectomy. In patients who had undergone TKI treatment followed by salvage resection, dense hilar fibrosis and adhesions were occasionally present. These fibrotic changes complicated the separation of the pulmonary artery from the bronchus and made systematic mediastinal lymph node dissection more challenging. Given the difficulty in isolating individual hilar structures, direct division of the pulmonary artery was considered dangerous and could result in massive bleeding. To address this, we sometimes opted for simultaneous stapling of the remaining pulmonary artery and lobar bronchus using a black reload, ensuring a safer procedure (simultaneously stapled lobectomy) at the surgeon's discretion (see Supplemental Video 1) ( Figures 2A-2D ). For peripherally located lesions with significant tumor shrinkage, sublobar resections were preferred. Due to the fibrotic and adhesive changes in the mediastinum, systematic mediastinal lymph node dissection was often difficult to perform. In such cases, lymph node sampling was typically carried out instead of systematic dissection. Histological assessment Among the 34 patients included, all resected tumors were microscopically reviewed and evaluated by two pathologists including one specializing in pulmonary pathology. Histologic subtypes were classified into five categories (lepidic predominant, acinar predominant, papillary predominant, micropapillary predominant, and solid predominant) as per 2015 World Health Organization classification of thoracic tumor [22]. Notably, spread through air spaces (STAS), defined as tumor cells present within alveolar spaces in the lung parenchyma beyond the edge of the main tumor, has been introduced as a novel mechanism of invasion from the pathologist's perspective [23] ( Figures 2G-2H ). Over the past decade, its importance as a significant prognostic factor for NSCLC has gained considerable attention, regardless of the tumor stage [24, 25]. In addition, lymphovascular invasion (LVI), another common factor, was also investigated. Evaluation of the treatment response was based on the recommendation of the International Association for the Study of Lung Cancer criteria proposed by Travis et al. [26], major pathologic response (MPR) is defined as 10% or less residual viable tumor following preoperative treatment, while pathologic complete response (pCR) is defined as the absence of residual viable tumor in all specimens, including the resected lung and lymph nodes ( Figures 2K-2L ). Postoperative treatment and Follow-up TKI treatment was continued throughout the perioperative period without interruption, and all patients remained on the same EGFR-TKI therapy until disease progression. In cases of progression, treatment was switched to Osimertinib if a T790M mutation was confirmed in the surgical specimen. Otherwise, patients received adjuvant chemotherapy, radiotherapy, or a combination of both, when applicable. Follow-up evaluations were conducted every 3 months using CT scans of the chest and upper abdomen. Contrast-enhanced magnetic resonance imaging (MRI) of the brain and nuclear bone scans were performed every 3 to 6 months, with additional PET-CT scans if necessary. Survival after surgery was assessed, along with the sites of disease progression. Progression-free survival (PFS) was defined as the time from the initiation of TKI therapy to confirmed disease progression, death, or the last follow-up. Overall survival (OS) was defined as the time from the start of TKI therapy to death or the last follow-up. As of March 2024, a follow-up investigation was carried out to record either the date of death or the last follow-up for surviving patients. Statistical Analysis Descriptive analysis was employed according to data normality, which was assessed using the Shapiro–Wilk test. Continuous variables were expressed as median (range) according to data normality. Categorical variables were expressed as frequency (percentage [%]). The one-way ANOVA test was used to compare perioperative continuous variables. The Chi-square test and Fisher exact test were used to compare categorical variables. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the effects of clinical factors on the prognosis of lung cancer patients who received TKI treatment. The adjusted multivariate model was employed to identify factors predicting survivals. A P-value of less than 0.05 was considered significant. All statistical operations were conducted using SPSS Statistical Software (version 29.0; IBM Corp., Armonk, NY). Results Clinical and pathological characteristics The demographic and clinical characteristics of the 34 enrolled patients are summarized in Table 1. The median age was 63 years (range: 40–81), with the majority of patients being female (64.7%) and nonsmokers (76.5%). Clinical staging at the start of TKI treatment was as follows: stage IIIB-IIIC in 5 patients (14.7%) and stage IV in 29 patients (85.3%). All patients had either an exon 21 (L858R) point mutation, an exon 19 deletion, or a combination of both. The EGFR-TKI agents used were gefitinib (17.6%), erlotinib (20.6%), afatinib (41.2%), and osimertinib (20.6%), with 6 patients (17.6%) receiving additional VEGF inhibitor therapy. Most patients (79.4%) achieved a partial response after a median TKI treatment duration of 9.1 months (range: 3.1–33.8 months). Regarding salvage surgery, the majority of patients underwent lobectomy (70.6%) via a VATS approach (91.2%). Positive surgical margins were noted in 2 patients (5.9%). The remaining perioperative outcomes and pathological findings are summarized in Table 1. In terms of pathological response, 9 patients (26.5%) achieved a major pathological response (MPR), while 6 patients (17.6%) achieved a pathological complete response (pCR). Tumor subtypes were identified in 28 patients, with the majority (58.8%) having an acinar subtype. Other subtypes included micropapillary (2.9%), papillary (5.9%), and solid (14.7%). Additionally, 11 patients (32.4%) exhibited spread through air spaces (STAS), and lymphovascular invasion (LVI) was observed in 9 patients (26.5%). Table 1. Demographic, clinical, and perioperative characteristics of the included patients Variables Patients (n =34) Age , y, median (range) 63 (40 – 81) Gender, N (%) Male 12 (35.3) Female 22 (64.7) Smoking, N (%) 8 (23.5) Family history, N (%) 8 (23.5) ECOG, N (%) 0 17 (50.0) 1 17 (50.0) AJCC stage (8 th edition), N (%) IIIB-IIIC 5 (14.7) IV 29 (85.3) Clinical T, N (%) T1 2 (5.8) T2 4 (11.6) T3 10 (29.4) T4 18 (52.9) Clinical N, N (%) N0 5 (14.7) N1 4 (11.8) N2 8 (23.5) N3 17 (50.0) Clinical M1, N (%) 29 (85.3) Metastatic site, N (%) Bone 10 (29.4) Contralateral lung 11 (32.4) Pleural 10 (29.4) Brain 8 (23.5) Others 6 (17.6) yp T stage, N (%) T0 6 (17.6) T1 12 (35.3) T2 9 (26.5) T3 5 (14.7) T4 2 (5.9) yp N stage, N (%) Nx 2 (5.9) N0 21 (61.8) N1 7 (20.6) N2 3 (8.8) N3 1 (2.9) Preoperative CEA serum level ≧5 ng/mL 7 (20.6) <5 ng/mL 27 (79.4) Tumor diameter pre-TKI , cm, median (range) 4.2 (1.3 – 10.3) Tumor diameter post-TKI , cm, median (range) 2.3 (0.5 – 6.8) EGFR mutation, N (%) Exon 21 (L858R) 16 (47.1) Exon 19 deletion 17 (50.0) Exon 21 (L858R) + Exon 19 deletion 1 (2.9) EGFR-TKI, N (%) Gefitinib 6 (17.6) Erlotinib 7 (20.6) Afatinib 14 (41.2) Osimertinib 7 (20.6) EGFR-TKI plus VEGF-i, N (%) 6 (17.6) Duration from TKI to Surgery , months, median (range) 9.1 (3.1 – 33.8) ASA grade, N (%) II 16 (47.1) III 18 (52.9) Type of resection, N (%) Lobectomy 24 (70.6) Segmentectomy 5 (14.7) Wedge resection 5 (14.7) Operative approach , N (%) Open thoracotomy 3 (8.8) VATS 28 (82.4) Robotic VATS 3 (8.8) Positive surgical margin (R1 resection), N (%) 2 (5.9) Operative time , minutes, median (range) 180 (30 – 340) Hospital stay , days, median (range) 4.5 (2 – 9) Blood loss , mL, median (range) 20 (5 – 500) Postoperative complication, N (%) 5 (14.6) Grade II 4 (11.6) Prolonged air leakage 2 (5.8) Hoarseness 1 (2.9) Postoperative atrial fibrillation 1 (2.9) Grade IIIa 1 (2.9) Cerebral ischemic stroke 1 (2.9) 30-day mortality, N (%) 0 N1 number , median (range) 2 (0 – 13) N2 number , median (range) 4 (0 – 25) Dissected LNs , median (range) 8.5 (0 – 30) Pathological response, N (%) Major pathological response (MPR) 9 (26.5) Non-MPR 19 (55.9) Pathological complete response (pCR) 6 (17.6) Spread through air space (STAS), N (%) 11 (32.4) Lymphovascular invasion (LVI), N (%) 9 (26.5) Subtype, N (%) (n =28) Acinar 20 (58.8) Micropapillary 1 (2.9) Papillary 2 (5.9) Solid 5 (14.7) Disease progression after surgery, N (%) 11 (32.4) Site of progression, N (%) (n =11) Bone 2 (18.2) Ipsilateral lung 1 (9.1) Contralateral lung 2 (18.2) N2 node 1 (9.1) Thyroid 1 (9.1) Pleural effusion 2 (18.2) Pleural and pericardial nodules 1 (9.1) Brain 1 (9.1) Death, N (%) 9 (26.5) Follow-up , month, median (range) 33.5 (7.1 – 135.3) ECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee on Cancer; CEA, carcinoembryonic antigen; EGFR, Epidermal Growth Factor Receptor; TKI, Tyrosine Kinase Inhibitor; VEGF-I, Vascular endothelial growth factor inhibitor; LNs, Lymph Nodes; ASA, American Society of Anesthesiologists; VATS, video-assisted thoracoscopic surgery; MPR, Major Pathological Response; pCR, Pathological Complete Response; STAS, Spread through air space, and LVI, Lymphovascular Invasion As shown in Supplemental Table 1, a comparison among different generations of TKI treatment revealed no significant differences in clinical characteristics. However, third-generation TKIs showed numerically higher pCR and MPR rates (5/7, 71.4%) compared to the earlier generations, though the difference was not statistically significant. Prognostic factors and outcomes after salvage surgery The median progression-free survival (PFS) from the initiation of TKI therapy was not reached (95% CI: not estimable, NE), while the median overall survival (OS) was 111.3 months (95% CI: 40.3–NE) ( Figure 3 ). Both the 3-year and 5-year PFS rates after TKI initiation were 55.5% ( Figure 3A ). The 3-year and 5-year OS rates were 73.2% and 59.3%, respectively ( Figure 3B ). No significant differences in PFS or OS were observed based on EGFR mutation type or TKI generation ( Supplemental Figure 1 ). Additionally, PFS and OS probabilities, calculated using the Kaplan-Meier method, for the STAS-negative, STAS-positive, and pCR groups are shown in Figure 4 . The STAS-positive group had significantly worse PFS compared to the STAS-negative group (HR: 7.5, 95% CI: 1.6–35.5, p =0.011) although subgroup analyses were limited by small sample sizes ( Figure 4A ). However, there were no significant differences in OS between the groups ( Figure 4B ). Other pathological factors, such as the presence of LVI, MPR, and pCR, had no significant effect on PFS or OS ( Supplemental Figure 2 ). Table 2 presents the prognostic factors for PFS and OS based on univariate and multivariate analyses. In the univariate analysis, both a worse ECOG performance status and the presence of STAS were significant predictors of PFS ( p =0.036 and p =0.002, respectively). After adjusting for relevant clinicopathological variables in the multivariate analysis, the presence of STAS remained an independent predictor of PFS ( p =0.034, HR: 1.63, 95% CI: 1.17–30.78). No significant prognostic factors were identified for OS. Table 2 . Uni and multivariate Cox regression analysis of predictors for PFS and OS Variables PFS OS Univariate Multivariate Univariate Multivariate HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Age ≧ 65 y (Ref <65 y) 0.42 (0.12 - 1.48) 0.279 - - 0.41 (0.1 – 1.64) 0.207 - - Female patients (Ref =Male) 0.68 (0.19 - 2.57) 0.57 - - 0.63 (0.10 - 3.83) 0.598 - - ECOG PS 1 (Ref = PS 0) 4.22 (1.10 - 16.19) 0.036 9.41 (0.25 – 43.3) 0.805 10.3 (1.28 – 83.1) 0.092 - - Smoking (Ref =No smoking) 0.32 (0.04 - 2.53) 0.321 - - 0.96 (0.19 – 4.7) 0.96 - - Family history (Ref =No family history) 1.78 (0.51 - 6.01) 0.369 - - 2.3 (0.61 – 8.62) 0.218 - - Preoperative serum CEA level≧5 ng/mL (Ref <5 ng/mL) 1.13 (0.82 -5.73) 0.244 - - 2.57 (1.24 - 9.87) 0.513 - - Stage IVA or IVB (Ref = III) 2.1 (0.27 – 16.58) 0.48 - - 27.9 (0.012 – 6224) 0.398 - - 19 deletion (Ref = 21 L858R) 4.17 (0.90 - 19.29) 0.068 - - 3.03 (0.62 – 14.9) 0.17 - - 2 nd & 3 rd Generation TKI (Ref = 1 st generation) 0.95 (0.26 – 3.57) 0.954 - - 1.75 (0.24 - 12.78) 0.58 - - Duration of pre-op TKI ≥9 months (Ref <9 months) 0.71 (0.22 - 2.36) 0.58 - - 1.1 (0.29 - 4.17) 0.892 - - STAS (Ref = no STAS) 8.04 (2.90 – 15.87) 0.002 1.63 (1.17 – 30.78) 0.034 3.74 (0.88 – 15.8) 0.073 - - LVI (Ref = no LVI) 1.89 (0.53 - 6.69) 0.328 - - 1.12 (0.22 – 5.71) 0.886 - - Footnote: PFS, progression-free survival; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen; TKI, Tyrosine Kinase Inhibitor; STAS, Spread through air space, and LVI, Lymphovascular Invasion During the median follow-up period of 33.5 months (range: 7.1–135.3), disease progression occurred in 11 patients (32.4%). Progression sites included bone, ipsilateral lung, contralateral lung, N2 nodes, thyroid, pleura, and brain. Nine patients (26.5%) died during the study period. A Swimmer’s plot was generated to visually represent each patient’s postoperative treatments and outcomes following salvage surgery ( Supplemental Figure 3 ). Discussion Over the past decade, several retrospective studies have demonstrated the feasibility and safety of salvage surgery following TKI treatment in patients with advanced NSCLC [ 13 – 18 ]. However, the small sample sizes, variations in disease stage and mutation types, non-first-line treatments, and differing surgical indications for regrown or residual tumors in these studies likely introduced potential bias in the reported outcomes. Recently, two large case-control studies compared data between patients who underwent residual tumor resection and those who did not, using propensity score matching [ 19 , 20 ]. These studies consistently showed that combining EGFR-TKI treatment with primary tumor resection provides better PFS and OS than EGFR-TKI therapy alone. However, few studies have examined the impact of pathological factors or mutation profiles on patient outcomes [ 16 , 20 , 21 ]. In our 10-year study, we evaluated the clinicopathological characteristics and survival outcomes of 34 patients with stage IIIB-IV lung adenocarcinoma who underwent salvage surgery after first-line EGFR-TKI treatment. All patients were confirmed to have common EGFR exon 19 deletions or exon 21 point mutations (L858R) and had achieved either a clinical partial response (n = 27) or stable disease (n = 7) before undergoing salvage surgery. Our study yielded several key findings. First, among the 34 patients, six (17.6%) achieved a pathological complete response (pCR), and nine (26.5%) achieved a major pathological response (MPR). Second, univariate and multivariate analyses identified the presence of STAS as the only adverse prognostic factor for PFS, while other variables such as age, mutation type, TKI generation, duration of preoperative TKI treatment, and preoperative serum CEA levels had no significant impact on PFS or OS. Third, the median PFS for the entire cohort was not reached, and the median OS was 111.3 months. The 3-year PFS and OS rates were 55.5% and 73.2%, respectively. The rates of pCR and MPR in our study were higher than those reported in previous studies, where pCR rates ranged from 0–11.4% and MPR rates from 17–44% in patients undergoing salvage surgery [ 13 – 15 , 20 ]. Additionally, the median duration of preoperative TKI therapy in our study was slightly longer, at 9.1 months. While some studies suggest that six months of treatment may be optimal for minimizing coexisting genomic alterations and improving PFS [ 19 ], there is no consensus on the ideal duration of preoperative TKI therapy. Reported treatment durations in the literature range from 5 to 14 months [ 16 – 21 ]. Regarding prognostic factors, previous studies have shown that disease progression during TKI therapy, preoperative CEA levels (≥ 5 ng/mL), and pleural seeding at pre-treatment stage are associated with worse OS [ 12 , 14 , 17 ]. Other studies have identified older age at treatment initiation (≥ 70 years), more advanced pathological T stage (T2-T4 vs. T0-T1), pleural seeding, and more advanced preoperative stage (stage III vs. I-II) as predictors of inferior PFS [ 14 , 17 , 18 ]. In our retrospective study, which included carefully selected patients, we did not find significant prognostic factors for OS or the aforementioned factors. However, we identified the presence of STAS as an independent predictor of worse PFS (HR: 1.63; 95% CI: 1.17–30.78, p = 0.034). To our knowledge, this is the first study to demonstrate the important role of STAS in patients with advanced lung adenocarcinoma treated with salvage surgery following EGFR-TKI therapy. There is compelling evidence in the literature associating STAS with lower survival rates and identifying it as an independent prognostic factor, regardless of lung cancer stage [ 24 ]. Large cohort studies and meta-analyses have shown that STAS is a significant prognosticator for surgical patients with stage I-IV NSCLC [ 25 , 27 ]. Furthermore, a recent study by Lin et al. [ 21 ] highlighted the presence of morphologically treatment-resistant tumor regions with acquired T790M mutations and histologic transformations, indicating the existence of resistant subclones in TKI-treated tumors prior to disease progression. These findings underscore the value of timely resection of residual primary tumors in selected patients, potentially improving survival by removing TKI-resistant subclones before progression. In the present study, the 3- and 5-year PFS rates after initial TKI treatment were both 55.5%, while the 3- and 5-year OS rates were 73.2% and 59.3%, respectively. These data are comparable to previously reported rates in the literature, with 3-year PFS and OS rates ranging from 22–34.5% and 76%, respectively [ 17 , 21 ]. While it is challenging to directly compare our results with earlier studies, our findings indicate an encouraging prognosis, with perioperative morbidity remaining comparable. No mortality occurred within 30 days of surgery, and the overall incidence of postoperative complications was 14.6% (5/34), with prolonged air leakage being the most common. As noted in previous literature, tissue fibrosis and adhesions related to the post-TKI treatment response often complicate surgery technically [ 16 ]. However, these challenges did not substantially affect postoperative outcomes when managed by experienced surgeons using appropriate techniques [ 16 , 21 ]. In our opinion, salvage surgeries following TKI treatment were not associated with increased morbidity. In fact, they facilitate more accurate pathological and genomic analyses without significantly increasing complications in carefully selected cases. Although non-surgical local consolidative therapies remain essential for treating oligometastatic NSCLC in patients on TKIs, as shown in our prior experience [ 8 ], surgery offers a major advantage over radiation therapy by providing entire tissue samples for pathological and genetic analysis. Assessing TKI efficacy by determining the fraction of remnant viable tumor, MPR, pCR, and other pathological prognostic factors (e.g., STAS) allows for more accurate prognoses and the development of further treatment strategies. This study has several limitations. First, as a retrospective study with a relatively small sample size, despite being one of the larger studies evaluating clinicopathological factors in patients undergoing TKI therapy followed by salvage resection, it remains subject to bias. Second, the optimal timing between the initiation of TKI therapy and surgery remains uncertain, especially given the varying treatment efficacy across first- to third-generation TKIs. Third, we did not include data from patients with similar oncological profiles who did not undergo surgical intervention. Lastly, long-term outcomes and extended follow-up data are still lacking, even though certain survival outcomes showed differences when stratified by pathological factors. Whether the aforementioned factors have a decisive impact on survival requires confirmation through longer follow-up periods. In conclusion, salvage surgery for treating EGFR-mutant advanced NSCLC is proven to be both safe and effective, providing benefits such as local tumor control and prolonged survival outcomes. Our study specifically highlights that STAS is a significant adverse prognostic factor for PFS in patients treated with TKI therapy followed by salvage surgery. Identifying patients with STAS may help guide postoperative multimodality treatment strategies and reduce the risk of early progression. Further large-scale, prospective studies are warranted to confirm the prognostic significance of STAS in these patients. Declarations Acknowledgements: None Authors’ contributions: The authors confirm contribution to the paper as follows: study conception and design: YL, CY; data collection: all authors; analysis and interpretation of results: YL, WL, JH, CY; draft manuscript preparation: YL, WL, CY. All authors reviewed the results and approved the final version of the manuscript. Funding: This research was funded by grants from the National Science and Technology Council in Taiwan (NSTC-113-2314-B-037-104-MY3) Availability of data and materials : Research data supporting this publication is available upon editor’s request. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Kaohsiung Medical University Hospital (approval no. KMUHIRB-E(I)-20240126). Consent for publication: The need for informed consent for publication was waived according to the policy of our IRB. Competing interests: All authors declare that they have no competing interests. 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Primary Tumor Resection Is Associated with a Better Outcome among Advanced EGFR-Mutant Lung Adenocarcinoma Patients Receiving EGFR-TKI Treatment. Oncology. 2021;99(1):32-40. Chen YY, Yen YT, Lai WW, Huang WL, Chang CC, Tseng YL. Outcomes of salvage lung resections in advanced EGFR-mutant lung adenocarcinomas under EGFR TKIs. Thorac Cancer. 2021 Oct;12(20):2655-2665. Li K, Cao X, Ai B, Xiao H, Huang Q, Zhang Z, et al. Salvage surgery following downstaging of advanced non-small cell lung cancer by targeted therapy. Thorac Cancer. 2021 Aug;12(15):2161-2169. Park BJ, Shim HS, Lee CY, Lee JG, Kim HR, Lee SH, et al. Genetic Analysis and Operative Outcomes in Patients with Oncogene-Driven Advanced NSCLC Treated with Cytoreductive Surgery as a Component of Local Consolidative Therapy. Cancers (Basel). 2021 May 22;13(11):2549. Ohtaki Y, Shimizu K, Suzuki H, Suzuki K, Tsuboi M, Mitsudomi T, et al. Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment. Lung Cancer. 2021 Mar;153:108-116. Diong NC, Liu CC, Shih CS, Wu MC, Huang CJ, Hung CF. Is there a role for lung surgery in initially unresectable non-small cell lung cancer after tyrosine kinase inhibitor treatment? World J Surg Oncol. 2022 Nov 26;20(1):370. Kuo SW, Chen PH, Lu TP, Chen KC, Liao HC, Tsou KC, et al. Primary Tumor Resection for Stage IV Non-small-cell Lung Cancer Without Progression After First-Line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Treatment: A Retrospective Case-Control Study. Ann Surg Oncol. 2022 Aug;29(8):4873-4884. Chen YY, Su PL, Huang WL, Chang CC, Yen YT, Lin CC, et al. The surgical resection of the primary tumor increases survival in patients with EGFR-mutant advanced non-small cell lung cancer: a tertiary center cohort study. Sci Rep. 2022 Dec 29;12(1):22560. Lin MW, Yu SL, Hsu YC, Chen YM, Lee YH, Hsiao YJ, et al. Salvage Surgery for Advanced Lung Adenocarcinoma After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment. Ann Thorac Surg. 2023 Jul;116(1):111-119. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015 Sep;10(9):1243-1260. Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol. 2015 May;10(5):806-814. Shih AR, Mino-Kenudson M. Updates on spread through air spaces (STAS) in lung cancer. Histopathology. 2020 Aug;77(2):173-180. Warth A, Muley T, Kossakowski CA, Goeppert B, Schirmacher P, Dienemann H, et al. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. Am J Surg Pathol. 2015 Jun;39(6):793-801. Travis WD, Dacic S, Wistuba I, Sholl L, Adusumilli P, Bubendorf L, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. J Thorac Oncol. 2020 May;15(5):709-740. Chen D, Mao Y, Wen J, She Y, Zhu E, Zhu F, et al. Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Ann Thorac Surg. 2019 Sep;108(3):945-954. Additional Declarations No competing interests reported. Supplementary Files Supplementalvideo168MB.mp4 SupplementalFguresTables.docx Cite Share Download PDF Status: Published Journal Publication published 26 Feb, 2025 Read the published version in World Journal of Surgical Oncology → Version 1 posted Editorial decision: Revision requested 24 Nov, 2024 Reviewers agreed at journal 23 Nov, 2024 Reviews received at journal 22 Nov, 2024 Reviewers agreed at journal 20 Nov, 2024 Reviews received at journal 19 Nov, 2024 Reviewers agreed at journal 12 Nov, 2024 Reviewers agreed at journal 09 Nov, 2024 Reviewers invited by journal 27 Sep, 2024 Editor assigned by journal 21 Sep, 2024 Submission checks completed at journal 17 Sep, 2024 First submitted to journal 16 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5098964","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381935712,"identity":"cd1a3e3c-ea66-4bac-afa0-a87bc6672a01","order_by":0,"name":"Yu-Wei Liu","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu-Wei","middleName":"","lastName":"Liu","suffix":""},{"id":381935714,"identity":"86607e9a-a5c4-4c57-8b6b-a6b8c32b4747","order_by":1,"name":"Wei-An Lai","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wei-An","middleName":"","lastName":"Lai","suffix":""},{"id":381935715,"identity":"12e4b7fe-da90-423e-938d-5a5db9d3014f","order_by":2,"name":"Jen-Yu Hung","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jen-Yu","middleName":"","lastName":"Hung","suffix":""},{"id":381935716,"identity":"2601946b-a4f8-436e-b3e6-22dec840ae7b","order_by":3,"name":"Yen-Lung Lee","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yen-Lung","middleName":"","lastName":"Lee","suffix":""},{"id":381935717,"identity":"2996b49f-5b7f-4275-ba17-3b5e44642eec","order_by":4,"name":"Hung-Hsing Chiang","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hung-Hsing","middleName":"","lastName":"Chiang","suffix":""},{"id":381935718,"identity":"1b6d1314-7c1d-4b4c-97d1-ae3c078feb2d","order_by":5,"name":"Jui-Ying Lee","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jui-Ying","middleName":"","lastName":"Lee","suffix":""},{"id":381935719,"identity":"709d99e3-a602-4c34-8b0e-c7ff7ae5300a","order_by":6,"name":"Hsien-Pin Li","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hsien-Pin","middleName":"","lastName":"Li","suffix":""},{"id":381935720,"identity":"60a7279d-2727-4bda-a5cc-3cd9da9b71a8","order_by":7,"name":"Shah-Hwa Chou","email":"","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shah-Hwa","middleName":"","lastName":"Chou","suffix":""},{"id":381935721,"identity":"2ee72f2c-f2ef-4390-9948-05d0d1e28cc6","order_by":8,"name":"Chih-Jen Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYDACCYYEIGljAObwkKAlDa5FghgtIHCYBC38sxsePuapOW+sOyOB8cHbNoY6gwOELLlzINmY59htM7MbCcyGc9sYJAhqMZBISJPmYbttA9TCJs0L1GJGhJb03zz/zoG0sP8mVksaM2/bAZDD2JiJ0iJxIyFZcm5fsrHZmYfNknPOSUjuJ6SFf0ZO4oc33+wMtx1PPvjhTZkNv2QDAS3AuEhggkQ6I0gtETHJwMB+gPEHMepGwSgYBaNg5AIASEw+k4rqaocAAAAASUVORK5CYII=","orcid":"","institution":"Kaohsiung Medical University Hospital, Kaohsiung Medical University","correspondingAuthor":true,"prefix":"","firstName":"Chih-Jen","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-09-16 17:36:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5098964/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5098964/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12957-025-03707-3","type":"published","date":"2025-02-26T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70908409,"identity":"dccfb7ee-413b-40f7-9742-fe1af36240f2","added_by":"auto","created_at":"2024-12-09 06:57:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":173741,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patient recruitment.\u003c/p\u003e\n\u003cp\u003eTKI, \u003cem\u003etyrosine kinase inhibitor\u003c/em\u003e; ALK, \u003cem\u003eanaplastic lymphoma kinase\u003c/em\u003e; EGFR, \u003cem\u003eEpidermal Growth Factor Receptor\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/e4c0f6c366f785c24e539d4d.png"},{"id":70908951,"identity":"09917f5c-6bc8-4a2a-95c3-d59201796b9b","added_by":"auto","created_at":"2024-12-09 07:05:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1027977,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative patients with (A-D) apparent radiological shrinkage of the main tumor (patient #19), (E-H) presence of spread through air spaces (patient #24), and (I-L) presence of pathological complete response(patient #16).\u003c/p\u003e\n\u003cp\u003e(A-D) Computed tomographic (CT) scan revealed a marked decrease of tumor size (\u003cem\u003eyellow squares\u003c/em\u003e) and apparent shrinkage of mediastinal lymph nodes (\u003cem\u003ered squares\u003c/em\u003e) after Erlotinib plus Bevacizumab treatment. Evident left pulmonary hilum invasion by tumor was also shown (\u003cem\u003ered arrow\u003c/em\u003e) (see Supplemental Video 1). (E-H) CT scan revealed marked reduction of tumor size after Afatinib treatment. Pathologic examination showed spread through air spaces, with tumor cells in air spaces beyond the edge of the main tumor. (I-L) CT scan revealed marked decrease of tumor size after Osimertinib treatment. Pathologic examination showed extensive fibrosis and inflammation without viable tumor cells in the tumor bed area, indicating the pathological complete response. (Hematoxylin and eosin stain; G and L: original magnification x40; H: original magnification x200.)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/30af0e3fdf1c5c3a52b35553.png"},{"id":70910411,"identity":"5c535947-8650-42b6-8d94-f16355f23590","added_by":"auto","created_at":"2024-12-09 07:13:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122073,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves of patients after initiation of TKI treatment.\u003c/p\u003e\n\u003cp\u003eTKI, \u003cem\u003etyrosine kinase inhibitor\u003c/em\u003e; PFS, \u003cem\u003eprogression-free survival\u003c/em\u003e; OS, \u003cem\u003eoverall survival\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/32cdc103436c13530e682a9d.png"},{"id":70908410,"identity":"4ca343ec-dac9-499c-81a2-081d4ed844cf","added_by":"auto","created_at":"2024-12-09 06:57:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":157814,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves of patients after initiation of TKI treatment stratified by STAS.\u003c/p\u003e\n\u003cp\u003eTKI, \u003cem\u003etyrosine kinase inhibitor\u003c/em\u003e; PCR, \u003cem\u003epathological complete response\u003c/em\u003e; STAS, \u003cem\u003espread through air spaces\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/bfb16e4a9d22252e59fc2568.png"},{"id":77622475,"identity":"7a9cc38a-db3a-4a13-8064-129c558ef9c1","added_by":"auto","created_at":"2025-03-03 16:07:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2767554,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/e21e4cac-f16b-41c2-b05a-d6d1e8756c63.pdf"},{"id":70908415,"identity":"ba624978-5c48-4d91-8ee0-8953c0b1d78d","added_by":"auto","created_at":"2024-12-09 06:57:43","extension":"mp4","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":71804848,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalvideo168MB.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/093c79f595849cc666a98aa0.mp4"},{"id":70908411,"identity":"796cd36f-1d55-4ff7-885a-49430c7f68cb","added_by":"auto","created_at":"2024-12-09 06:57:42","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":738133,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFguresTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5098964/v1/3539631e831bc1cc00803c9c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrevious studies have demonstrated that lung adenocarcinoma patients with actionable driver mutations, treated with matched tyrosine kinase inhibitors (TKIs), experience longer overall survival [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Asia, approximately 50\u0026ndash;60% of these patients have epidermal growth factor receptor (EGFR) mutations, with the most common being exon 19 deletions and exon 21 L858R mutations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Currently, EGFR-TKIs remain the standard first-line therapy for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith the increasing adoption of multimodal treatment strategies in lung cancer, evidence supporting the efficacy of local consolidative therapy (LCT) has emerged in oligometastatic or oligo-progressive NSCLC patients treated with TKIs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our previous study assessed the impact of LCT in EGFR-mutant patients receiving afatinib as first-line therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], revealing that patients who underwent LCT had significantly longer progression-free survival (PFS) than those who did not (median PFS: 32.8 vs. 14.5 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0008). Additionally, LCT was associated with improved overall survival (OS) (median OS: 67.1 vs. 34.5 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0011). Salvage surgery is a common LCT intervention, but prognostic factors for successful outcomes remain unclear.\u003c/p\u003e \u003cp\u003eRecent studies have suggested expanding surgical resection for certain advanced NSCLC patients, particularly those with oligometastatic disease [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Several retrospective studies have demonstrated survival benefits from salvage surgery after TKI treatment in selected stage III and IV NSCLC patients [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although surgery for regrown or residual tumors seems to provide good local control of the tumor burden and potentially prolong survival, some patients inevitably experience disease progression after primary tumor resection. Thus far, only one study has examined the pathological impact of treatment-resistant patterns on outcomes in advanced lung adenocarcinoma treated with TKIs and salvage resection [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], leaving the influence of other pathological factors on recurrence and survival undetermined.\u003c/p\u003e \u003cp\u003eWith this in mind, this retrospective cohort study primarily aims to evaluate surgico-pathological outcomes in patients with advanced EGFR-mutant lung adenocarcinoma who underwent salvage surgery following EGFR-TKI treatment. The secondary objective is to analyze prognostic factors and survival outcomes.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study analyzed cases from January 2013 to July 2023 at a tertiary center in southern Taiwan. The study received approval from the Institutional Review Board of Kaohsiung Medical University Hospital, and the requirement for written informed consent was waived (KMUHIRB-E(I)-20240126).\u003c/p\u003e\n\u003cp\u003eA total of 59 patients with stage IIIB-IV primary lung adenocarcinoma who received TKI treatment followed by primary tumor resection were evaluated. We excluded patients who met the following criteria: ALK-TKI treatment (n=1), non-first-line EGFR-TKI treatment with or without chemotherapy prior to surgery (n=5), resection for re-examination of EGFR mutation due to clinical progressive disease (n=16), or incomplete data for analysis (n=3). This left 34 EGFR-mutant lung adenocarcinoma patients who received first-line TKI treatment and achieved a clinical partial response or stable disease for final analysis (\u003cem\u003eFigure 1\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eClinical staging was determined based on the American Joint Cancer Committee (AJCC) eighth edition guidelines for lung cancer staging. All patients had a pre-treatment histopathological diagnosis confirmed either by flexible bronchoscopy or CT-guided biopsy. Bone scans, brain magnetic resonance imaging (MRI), and optional positron emission tomography and CT (PET-CT) scans were conducted to exclude distant metastases. Additionally, patients were confirmed to have common EGFR mutations (such as exon 19 deletion or exon 21 point mutation L858R) using real-time PCR cobas\u0026reg; EGFR mutation test before initiating EGFR-TKI treatment. The treatment modality, including salvage surgery, was assessed preoperatively by multidisciplinary tumor boards to reach a consensus on the surgical treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIndications of salvage surger\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003ey\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe strategy for salvage surgery was mainly concerned with the following criteria: (1) residual main tumor on CT scan showing partial response or stable disease by RECIST criteria, (2) all distant metastases were resolved on imaging studies after EGFR-TKI treatment and/or received appropriate local control, (3) adequate patient performance status, and (4) tolerable cardiopulmonary reserve. For residual primary lesions that were large or centrally located, anatomical resections typically began with ligation of the lobar vein, followed by either the bronchus or the artery, allowing for safe execution of a non-stapled lobectomy. In patients who had undergone TKI treatment followed by salvage resection, dense hilar fibrosis and adhesions were occasionally present. These fibrotic changes complicated the separation of the pulmonary artery from the bronchus and made systematic mediastinal lymph node dissection more challenging. Given the difficulty in isolating individual hilar structures, direct division of the pulmonary artery was considered dangerous and could result in massive bleeding. To address this, we sometimes opted for simultaneous stapling of the remaining pulmonary artery and lobar bronchus using a black reload, ensuring a safer procedure (simultaneously stapled lobectomy) at the surgeon\u0026apos;s discretion (see Supplemental Video 1) (\u003cem\u003eFigures 2A-2D\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eFor peripherally located lesions with significant tumor shrinkage, sublobar resections were preferred. Due to the fibrotic and adhesive changes in the mediastinum, systematic mediastinal lymph node dissection was often difficult to perform. In such cases, lymph node sampling was typically carried out instead of systematic dissection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHistological assessment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 34 patients included, all resected tumors were microscopically reviewed and evaluated by two pathologists including one specializing in pulmonary pathology. Histologic subtypes were classified into five categories (lepidic predominant, acinar predominant, papillary predominant, micropapillary predominant, and solid predominant) as per 2015 World Health Organization classification of thoracic tumor [22]. Notably, spread through air spaces (STAS), defined as tumor cells present within alveolar spaces in the lung parenchyma beyond the edge of the main tumor, has been introduced as a novel mechanism of invasion from the pathologist\u0026apos;s perspective [23] (\u003cem\u003eFigures 2G-2H\u003c/em\u003e). Over the past decade, its importance as a significant prognostic factor for NSCLC has gained considerable attention, regardless of the tumor stage [24, 25]. In addition, lymphovascular invasion (LVI), another common factor, was also investigated. Evaluation of the treatment response was based on the recommendation of the International Association for the Study of Lung Cancer criteria proposed by Travis et al. [26], major pathologic response (MPR) is defined as 10% or less residual viable tumor following preoperative treatment, while pathologic complete response (pCR) is defined as the absence of residual viable tumor in all specimens, including the resected lung and lymph nodes (\u003cem\u003eFigures 2K-2L\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePostoperative treatment and Follow-up\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTKI treatment was continued throughout the perioperative period without interruption, and all patients remained on the same EGFR-TKI therapy until disease progression. In cases of progression, treatment was switched to Osimertinib if a T790M mutation was confirmed in the surgical specimen. Otherwise, patients received adjuvant chemotherapy, radiotherapy, or a combination of both, when applicable. Follow-up evaluations were conducted every 3 months using CT scans of the chest and upper abdomen. Contrast-enhanced magnetic resonance imaging (MRI) of the brain and nuclear bone scans were performed every 3 to 6 months, with additional PET-CT scans if necessary. Survival after surgery was assessed, along with the sites of disease progression.\u003c/p\u003e\n\u003cp\u003eProgression-free survival (PFS) was defined as the time from the initiation of TKI therapy to confirmed disease progression, death, or the last follow-up. Overall survival (OS) was defined as the time from the start of TKI therapy to death or the last follow-up. As of March 2024, a follow-up investigation was carried out to record either the date of death or the last follow-up for surviving patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive analysis was employed according to data normality, which was assessed using the Shapiro\u0026ndash;Wilk test. Continuous variables were expressed as median (range) according to data normality. Categorical variables were expressed as frequency (percentage [%]). The one-way ANOVA test was used to compare perioperative continuous variables. The Chi-square test and Fisher exact test were used to compare categorical variables. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the effects of clinical factors on the prognosis of lung cancer patients who received TKI treatment. The adjusted multivariate model was employed to identify factors predicting survivals. A P-value of less than 0.05 was considered significant. All statistical operations were conducted using SPSS Statistical Software (version 29.0; IBM Corp., Armonk, NY).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical and pathological characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of the 34 enrolled patients are summarized in Table 1. The median age was 63 years (range: 40\u0026ndash;81), with the majority of patients being female (64.7%) and nonsmokers (76.5%). Clinical staging at the start of TKI treatment was as follows: stage IIIB-IIIC in 5 patients (14.7%) and stage IV in 29 patients (85.3%). All patients had either an exon 21 (L858R) point mutation, an exon 19 deletion, or a combination of both. The EGFR-TKI agents used were gefitinib (17.6%), erlotinib (20.6%), afatinib (41.2%), and osimertinib (20.6%), with 6 patients (17.6%) receiving additional VEGF inhibitor therapy. Most patients (79.4%) achieved a partial response after a median TKI treatment duration of 9.1 months (range: 3.1\u0026ndash;33.8 months). Regarding salvage surgery, the majority of patients underwent lobectomy (70.6%) via a VATS approach (91.2%). Positive surgical margins were noted in 2 patients (5.9%). The remaining perioperative outcomes and pathological findings are summarized in\u003cem\u003e\u0026nbsp;\u003c/em\u003eTable 1.\u003c/p\u003e\n\u003cp\u003eIn terms of pathological response, 9 patients (26.5%) achieved a major pathological response (MPR), while 6 patients (17.6%) achieved a pathological complete response (pCR). Tumor subtypes were identified in 28 patients, with the majority (58.8%) having an acinar subtype. Other subtypes included micropapillary (2.9%), papillary (5.9%), and solid (14.7%). Additionally, 11 patients (32.4%) exhibited spread through air spaces (STAS), and lymphovascular invasion (LVI) was observed in 9 patients (26.5%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Demographic, clinical, and perioperative characteristics of the included patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n =34)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e, y, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e63 (40 \u0026ndash; 81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Male\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e22 (64.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily history,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAJCC stage (8\u003csup\u003eth\u0026nbsp;\u003c/sup\u003eedition),\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;IIIB-IIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29 (85.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical T,\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;T1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;T2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;T3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical N,\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical M1,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29 (85.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic site,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Contralateral lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pleural\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eyp T stage,\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; T0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; T1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; T2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; T3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eyp N stage,\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Nx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21 (61.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (8.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative CEA serum level\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e≧5 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;5 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27 (79.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor diameter pre-TKI\u003c/strong\u003e, cm, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.2 (1.3 \u0026ndash; 10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor diameter post-TKI\u003c/strong\u003e, cm, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.3 (0.5 \u0026ndash; 6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEGFR mutation,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Exon 21 (L858R)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Exon 19 deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Exon 21 (L858R) + Exon 19 deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEGFR-TKI,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Gefitinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Erlotinib\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Afatinib\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Osimertinib\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEGFR-TKI plus VEGF-i,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from TKI to Surgery\u003c/strong\u003e, months, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.1 (3.1 \u0026ndash; 33.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eASA grade,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (47.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of resection,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lobectomy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Segmentectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Wedge resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOperative approach\u003c/strong\u003e, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Open thoracotomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;VATS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28 (82.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Robotic VATS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive surgical margin (R1 resection),\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOperative time\u003c/strong\u003e, minutes, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e180 (30 \u0026ndash; 340)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHospital stay\u003c/strong\u003e, days, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.5 (2 \u0026ndash; 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlood loss\u003c/strong\u003e, mL, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (5 \u0026ndash; 500)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostoperative complication,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProlonged air leakage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHoarseness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePostoperative atrial fibrillation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade IIIa\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCerebral ischemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e30-day mortality,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN1 number\u003c/strong\u003e, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (0 \u0026ndash; 13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN2 number\u003c/strong\u003e, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (0 \u0026ndash; 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDissected LNs\u003c/strong\u003e, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.5 (0 \u0026ndash; 30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological response,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMajor pathological response (MPR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon-MPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19 (55.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePathological complete response (pCR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpread through air space (STAS),\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphovascular invasion (LVI),\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubtype,\u0026nbsp;\u003c/strong\u003eN (%)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(n =28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Acinar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMicropapillary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Papillary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Solid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease progression after surgery,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSite of progression,\u0026nbsp;\u003c/strong\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(n =11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Ipsilateral lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Contralateral lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;N2 node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Thyroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pleural effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Pleural and pericardial nodules\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath,\u003c/strong\u003e N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e, month, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.5 (7.1 \u0026ndash; 135.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee on Cancer; CEA, carcinoembryonic antigen; EGFR, Epidermal Growth Factor Receptor; TKI, Tyrosine Kinase Inhibitor; VEGF-I, Vascular endothelial growth factor inhibitor; LNs, Lymph Nodes; ASA, American Society of Anesthesiologists; VATS, video-assisted thoracoscopic surgery; MPR, Major Pathological Response; pCR, Pathological Complete Response; STAS, Spread through air space, and LVI, Lymphovascular Invasion\u003c/p\u003e\n\u003cp\u003eAs shown in Supplemental Table 1, a comparison among different generations of TKI treatment revealed no significant differences in clinical characteristics. However, third-generation TKIs showed numerically higher pCR and MPR rates (5/7, 71.4%) compared to the earlier generations, though the difference was not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrognostic factors and outcomes after salvage surgery\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median progression-free survival (PFS) from the initiation of TKI therapy was not reached (95% CI: not estimable, NE), while the median overall survival (OS) was 111.3 months (95% CI: 40.3\u0026ndash;NE) (\u003cem\u003eFigure 3\u003c/em\u003e). Both the 3-year and 5-year PFS rates after TKI initiation were 55.5% (\u003cem\u003eFigure 3A\u003c/em\u003e). The 3-year and 5-year OS rates were 73.2% and 59.3%, respectively (\u003cem\u003eFigure 3B\u003c/em\u003e). No significant differences in PFS or OS were observed based on EGFR mutation type or TKI generation (\u003cem\u003eSupplemental Figure 1\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eAdditionally, PFS and OS probabilities, calculated using the Kaplan-Meier method, for the STAS-negative, STAS-positive, and pCR groups are shown in \u003cem\u003eFigure 4\u003c/em\u003e. The STAS-positive group had significantly worse PFS compared to the STAS-negative group (HR: 7.5, 95% CI: 1.6\u0026ndash;35.5, \u003cem\u003ep\u003c/em\u003e=0.011) although subgroup analyses were limited by small sample sizes (\u003cem\u003eFigure 4A\u003c/em\u003e). However, there were no significant differences in OS between the groups (\u003cem\u003eFigure 4B\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eOther pathological factors, such as the presence of LVI, MPR, and pCR, had no significant effect on PFS or OS (\u003cem\u003eSupplemental Figure 2\u003c/em\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 presents the prognostic factors for PFS and OS based on univariate and multivariate analyses. In the univariate analysis, both a worse ECOG performance status and the presence of STAS were significant predictors of PFS (\u003cem\u003ep\u003c/em\u003e=0.036 and \u003cem\u003ep\u003c/em\u003e=0.002, respectively). After adjusting for relevant clinicopathological variables in the multivariate analysis, the presence of STAS remained an independent predictor of PFS (\u003cem\u003ep\u003c/em\u003e=0.034, HR: 1.63, 95% CI: 1.17\u0026ndash;30.78). No significant prognostic factors were identified for OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Uni and multivariate Cox regression analysis of predictors for PFS and OS\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"926\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 369px;\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 331px;\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;≧\u0026nbsp;65 y (Ref \u0026lt;65 y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.42 (0.12 - 1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.41 (0.1 \u0026ndash; 1.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eFemale patients (Ref =Male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.68 (0.19 - 2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.63 (0.10 - 3.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.598\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eECOG PS 1 (Ref = PS 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e4.22 (1.10 - 16.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.036\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e9.41 (0.25 \u0026ndash; 43.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e10.3 (1.28 \u0026ndash; 83.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eSmoking (Ref =No smoking)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.32 (0.04 - 2.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.96 (0.19 \u0026ndash; 4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eFamily history (Ref =No family history)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.78 (0.51 - 6.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2.3 (0.61 \u0026ndash; 8.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.218\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003ePreoperative serum CEA level≧5 ng/mL\u0026nbsp;(Ref \u0026lt;5 ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.13 (0.82 -5.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2.57 (1.24 - 9.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eStage IVA or IVB (Ref = III)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2.1 (0.27 \u0026ndash; 16.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e27.9 (0.012 \u0026ndash; 6224)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.398\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e19 deletion (Ref = 21 L858R)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e4.17 (0.90 - 19.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3.03 (0.62 \u0026ndash; 14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e \u0026amp; 3\u003csup\u003erd\u003c/sup\u003e Generation TKI\u003c/p\u003e\n \u003cp\u003e(Ref = 1\u003csup\u003est\u003c/sup\u003e generation)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.95 (0.26 \u0026ndash; 3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.75 (0.24 - 12.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eDuration of pre-op TKI \u0026ge;9 months\u003c/p\u003e\n \u003cp\u003e(Ref \u0026lt;9 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.71 (0.22 - 2.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.1 (0.29 - 4.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eSTAS (Ref = no STAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e8.04 (2.90 \u0026ndash; 15.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.002\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.63 (1.17 \u0026ndash; 30.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.034\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3.74 (0.88 \u0026ndash; 15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eLVI (Ref = no LVI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.89 (0.53 - 6.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.328\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.12 (0.22 \u0026ndash; 5.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.886\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFootnote: PFS, progression-free survival; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen; TKI, Tyrosine Kinase Inhibitor; STAS, Spread through air space, and LVI, Lymphovascular Invasion\u003c/p\u003e\n\u003cp\u003eDuring the median follow-up period of 33.5 months (range: 7.1\u0026ndash;135.3), disease progression occurred in 11 patients (32.4%). Progression sites included bone, ipsilateral lung, contralateral lung, N2 nodes, thyroid, pleura, and brain. Nine patients (26.5%) died during the study period.\u0026nbsp;A Swimmer\u0026rsquo;s plot was generated to visually represent each patient\u0026rsquo;s postoperative treatments and outcomes following salvage surgery (\u003cem\u003eSupplemental Figure 3\u003c/em\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOver the past decade, several retrospective studies have demonstrated the feasibility and safety of salvage surgery following TKI treatment in patients with advanced NSCLC [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, the small sample sizes, variations in disease stage and mutation types, non-first-line treatments, and differing surgical indications for regrown or residual tumors in these studies likely introduced potential bias in the reported outcomes. Recently, two large case-control studies compared data between patients who underwent residual tumor resection and those who did not, using propensity score matching [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These studies consistently showed that combining EGFR-TKI treatment with primary tumor resection provides better PFS and OS than EGFR-TKI therapy alone. However, few studies have examined the impact of pathological factors or mutation profiles on patient outcomes [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our 10-year study, we evaluated the clinicopathological characteristics and survival outcomes of 34 patients with stage IIIB-IV lung adenocarcinoma who underwent salvage surgery after first-line EGFR-TKI treatment. All patients were confirmed to have common EGFR exon 19 deletions or exon 21 point mutations (L858R) and had achieved either a clinical partial response (n\u0026thinsp;=\u0026thinsp;27) or stable disease (n\u0026thinsp;=\u0026thinsp;7) before undergoing salvage surgery.\u003c/p\u003e \u003cp\u003eOur study yielded several key findings. First, among the 34 patients, six (17.6%) achieved a pathological complete response (pCR), and nine (26.5%) achieved a major pathological response (MPR). Second, univariate and multivariate analyses identified the presence of STAS as the only adverse prognostic factor for PFS, while other variables such as age, mutation type, TKI generation, duration of preoperative TKI treatment, and preoperative serum CEA levels had no significant impact on PFS or OS. Third, the median PFS for the entire cohort was not reached, and the median OS was 111.3 months. The 3-year PFS and OS rates were 55.5% and 73.2%, respectively.\u003c/p\u003e \u003cp\u003eThe rates of pCR and MPR in our study were higher than those reported in previous studies, where pCR rates ranged from 0\u0026ndash;11.4% and MPR rates from 17\u0026ndash;44% in patients undergoing salvage surgery [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, the median duration of preoperative TKI therapy in our study was slightly longer, at 9.1 months. While some studies suggest that six months of treatment may be optimal for minimizing coexisting genomic alterations and improving PFS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], there is no consensus on the ideal duration of preoperative TKI therapy. Reported treatment durations in the literature range from 5 to 14 months [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding prognostic factors, previous studies have shown that disease progression during TKI therapy, preoperative CEA levels (\u0026ge;\u0026thinsp;5 ng/mL), and pleural seeding at pre-treatment stage are associated with worse OS [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Other studies have identified older age at treatment initiation (\u0026ge;\u0026thinsp;70 years), more advanced pathological T stage (T2-T4 vs. T0-T1), pleural seeding, and more advanced preoperative stage (stage III vs. I-II) as predictors of inferior PFS [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our retrospective study, which included carefully selected patients, we did not find significant prognostic factors for OS or the aforementioned factors. However, we identified the presence of STAS as an independent predictor of worse PFS (HR: 1.63; 95% CI: 1.17\u0026ndash;30.78, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034). To our knowledge, this is the first study to demonstrate the important role of STAS in patients with advanced lung adenocarcinoma treated with salvage surgery following EGFR-TKI therapy.\u003c/p\u003e \u003cp\u003eThere is compelling evidence in the literature associating STAS with lower survival rates and identifying it as an independent prognostic factor, regardless of lung cancer stage [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Large cohort studies and meta-analyses have shown that STAS is a significant prognosticator for surgical patients with stage I-IV NSCLC [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Furthermore, a recent study by Lin et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] highlighted the presence of morphologically treatment-resistant tumor regions with acquired T790M mutations and histologic transformations, indicating the existence of resistant subclones in TKI-treated tumors prior to disease progression. These findings underscore the value of timely resection of residual primary tumors in selected patients, potentially improving survival by removing TKI-resistant subclones before progression.\u003c/p\u003e \u003cp\u003eIn the present study, the 3- and 5-year PFS rates after initial TKI treatment were both 55.5%, while the 3- and 5-year OS rates were 73.2% and 59.3%, respectively. These data are comparable to previously reported rates in the literature, with 3-year PFS and OS rates ranging from 22\u0026ndash;34.5% and 76%, respectively [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. While it is challenging to directly compare our results with earlier studies, our findings indicate an encouraging prognosis, with perioperative morbidity remaining comparable. No mortality occurred within 30 days of surgery, and the overall incidence of postoperative complications was 14.6% (5/34), with prolonged air leakage being the most common. As noted in previous literature, tissue fibrosis and adhesions related to the post-TKI treatment response often complicate surgery technically [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, these challenges did not substantially affect postoperative outcomes when managed by experienced surgeons using appropriate techniques [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our opinion, salvage surgeries following TKI treatment were not associated with increased morbidity. In fact, they facilitate more accurate pathological and genomic analyses without significantly increasing complications in carefully selected cases. Although non-surgical local consolidative therapies remain essential for treating oligometastatic NSCLC in patients on TKIs, as shown in our prior experience [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], surgery offers a major advantage over radiation therapy by providing entire tissue samples for pathological and genetic analysis. Assessing TKI efficacy by determining the fraction of remnant viable tumor, MPR, pCR, and other pathological prognostic factors (e.g., STAS) allows for more accurate prognoses and the development of further treatment strategies.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, as a retrospective study with a relatively small sample size, despite being one of the larger studies evaluating clinicopathological factors in patients undergoing TKI therapy followed by salvage resection, it remains subject to bias. Second, the optimal timing between the initiation of TKI therapy and surgery remains uncertain, especially given the varying treatment efficacy across first- to third-generation TKIs. Third, we did not include data from patients with similar oncological profiles who did not undergo surgical intervention. Lastly, long-term outcomes and extended follow-up data are still lacking, even though certain survival outcomes showed differences when stratified by pathological factors. Whether the aforementioned factors have a decisive impact on survival requires confirmation through longer follow-up periods.\u003c/p\u003e \u003cp\u003eIn conclusion, salvage surgery for treating EGFR-mutant advanced NSCLC is proven to be both safe and effective, providing benefits such as local tumor control and prolonged survival outcomes. Our study specifically highlights that STAS is a significant adverse prognostic factor for PFS in patients treated with TKI therapy followed by salvage surgery. Identifying patients with STAS may help guide postoperative multimodality treatment strategies and reduce the risk of early progression. Further large-scale, prospective studies are warranted to confirm the prognostic significance of STAS in these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm contribution to the paper as follows: study conception and design: YL, CY; data collection: all authors; analysis and interpretation of results: YL, WL, JH, CY; draft manuscript preparation: YL, WL, CY. All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was funded by grants from the National Science and Technology Council in Taiwan (NSTC-113-2314-B-037-104-MY3)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch data supporting this publication is available upon editor\u0026rsquo;s request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Kaohsiung Medical University Hospital (approval no. KMUHIRB-E(I)-20240126).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe need for informed consent for publication was waived according to the policy of our IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014 May 21;311(19):1998-2006. \u003c/li\u003e\n\u003cli\u003eHsu KH, Ho CC, Hsia TC, Tseng JS, Su KY, Wu MF, et al. Identification of five driver gene mutations in patients with treatment-na\u0026iuml;ve lung adenocarcinoma in Taiwan. 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Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Non-small-cell Lung Cancer (NSCLC). Clin Lung Cancer. 2019 Jan;20(1):43-47.\u003c/li\u003e\n\u003cli\u003eXu Q, Zhou F, Liu H, Jiang T, Li X, Xu Y, et al. Consolidative Local Ablative Therapy Improves the Survival of Patients With Synchronous Oligometastatic NSCLC Harboring EGFR Activating Mutation Treated With First-Line EGFR-TKIs. J Thorac Oncol. 2018 Sep;13(9):1383-1392.\u003c/li\u003e\n\u003cli\u003eTsai MJ, Hung JY, Ma JY, Tsai YC, Wu KL, Lee MH, et al. Local Consolidative Therapy May Have Prominent Clinical Efficacy in Patients with \u003cem\u003eEGFR\u003c/em\u003e-Mutant Advanced Lung Adenocarcinoma Treated with First-Line Afatinib. Cancers (Basel). 2023 Mar 28;15(7):2019.\u003c/li\u003e\n\u003cli\u003eDavid EA, Andersen SW, Beckett LA, Melnikow J, Clark JM, Brown LM, et al. Survival benefits associated with surgery for advanced non-small cell lung cancer. J Thorac Cardiovasc Surg. 2019 Apr;157(4):1620-1628.\u003c/li\u003e\n\u003cli\u003eRen J, Ren J, Wang K, Tan Q. The consideration of surgery on primary lesion of advanced non-small cell lung cancer. BMC Pulm Med. 2023 Apr 14;23(1):118.\u003c/li\u003e\n\u003cli\u003eCoster JN, Groth SS. Surgery for Locally Advanced and Oligometastatic Non-Small Cell Lung Cancer. Surg Oncol Clin N Am. 2020 Oct;29(4):543-554. \u003c/li\u003e\n\u003cli\u003eSuzuki S, Asakura K, Okui M, Izawa N, Sawafuji M, Sakamaki H, et al. Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study. World J Surg Oncol. 2023 Sep 15;21(1):290. \u003c/li\u003e\n\u003cli\u003eTseng JS, Hsu KH, Zheng ZR, Yang TY, Chen KC, Huang YH, et al. 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The surgical resection of the primary tumor increases survival in patients with EGFR-mutant advanced non-small cell lung cancer: a tertiary center cohort study. Sci Rep. 2022 Dec 29;12(1):22560. \u003c/li\u003e\n\u003cli\u003eLin MW, Yu SL, Hsu YC, Chen YM, Lee YH, Hsiao YJ, et al. Salvage Surgery for Advanced Lung Adenocarcinoma After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment. Ann Thorac Surg. 2023 Jul;116(1):111-119.\u003c/li\u003e\n\u003cli\u003eTravis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015 Sep;10(9):1243-1260. \u003c/li\u003e\n\u003cli\u003eKadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol. 2015 May;10(5):806-814.\u003c/li\u003e\n\u003cli\u003eShih AR, Mino-Kenudson M. Updates on spread through air spaces (STAS) in lung cancer. Histopathology. 2020 Aug;77(2):173-180.\u003c/li\u003e\n\u003cli\u003eWarth A, Muley T, Kossakowski CA, Goeppert B, Schirmacher P, Dienemann H, et al. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. Am J Surg Pathol. 2015 Jun;39(6):793-801.\u003c/li\u003e\n\u003cli\u003eTravis WD, Dacic S, Wistuba I, Sholl L, Adusumilli P, Bubendorf L, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. J Thorac Oncol. 2020 May;15(5):709-740. \u003c/li\u003e\n\u003cli\u003eChen D, Mao Y, Wen J, She Y, Zhu E, Zhu F, et al. Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Ann Thorac Surg. 2019 Sep;108(3):945-954. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"lung adenocarcinoma, epidermal growth factor receptor, tyrosine kinase inhibitor, salvage surgery, Spread through air spaces","lastPublishedDoi":"10.21203/rs.3.rs-5098964/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5098964/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003cbr\u003e\nSalvage resection for residual lung cancer harboring epidermal growth factor receptor (EGFR) mutations following EGFR-tyrosine kinase inhibitor (TKI) treatment is gaining traction for its survival benefits. However, the impact of pathological factors on survival remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nBetween 2013 and 2023, we retrospectively reviewed 34 patients with advanced lung adenocarcinoma who received EGFR-TKI therapy. After a median TKI treatment duration of 9.1 months, all patients demonstrated either partial response (n=27) or stable disease (n=7) before salvage surgery. Demographic, pathological outcomes, progression-free survival (PFS), and overall survival (OS) were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nAmong the 34 patients, six (17.6%) achieved a pathological complete response (pCR) and nine (26.5%) had a major pathological response (MPR). Additionally, 11 patients (32.4%) exhibited spread through air spaces (STAS), and lymphovascular invasion (LVI) was observed in nine patients (26.5%). The 3-year PFS and OS rates were 55.5% and 73.2%, respectively. No significant differences in PFS or OS were observed regarding TKI generation, mutation type, pCR, MPR, or LVI. However, Kaplan-Meier analysis revealed that STAS was associated with shorter PFS compared to non-STAS cases (\u003cem\u003ep\u003c/em\u003e=0.011). In multivariate analysis, STAS was identified as an independent prognostic factor for PFS (hazard ratio: 1.63, 95% CI: 1.17–30.78, \u003cem\u003ep\u003c/em\u003e=0.034). No significant prognosticators were found for OS in univariate or multivariate analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nWhile salvage surgery following TKI treatment is feasible and prolongs survival by removing residual primary tumor with potential TKI resistance, STAS may contribute to a higher risk of early progression. This finding warrants further investigation and tailored treatment strategies.\u003c/p\u003e","manuscriptTitle":"Spread through air spaces may predict early progression after salvage surgery for EGFR-mutant advanced lung adenocarcinoma treated with targeted therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 06:57:37","doi":"10.21203/rs.3.rs-5098964/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-24T15:17:14+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"95578587006858239225121736615404440163","date":"2024-11-23T15:39:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-22T10:15:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153714614026202407980825879794522208296","date":"2024-11-20T22:48:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-19T21:57:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191733617140494399022790456896042635240","date":"2024-11-12T09:14:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66435870267549196027014562771250529097","date":"2024-11-09T09:12:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-27T06:20:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-21T07:38:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-17T22:56:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2024-09-16T17:34:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b938f8ce-822d-4bac-9d3a-521ab0dd9d91","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-03T16:01:29+00:00","versionOfRecord":{"articleIdentity":"rs-5098964","link":"https://doi.org/10.1186/s12957-025-03707-3","journal":{"identity":"world-journal-of-surgical-oncology","isVorOnly":false,"title":"World Journal of Surgical Oncology"},"publishedOn":"2025-02-26 15:57:32","publishedOnDateReadable":"February 26th, 2025"},"versionCreatedAt":"2024-12-09 06:57:37","video":"","vorDoi":"10.1186/s12957-025-03707-3","vorDoiUrl":"https://doi.org/10.1186/s12957-025-03707-3","workflowStages":[]},"version":"v1","identity":"rs-5098964","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5098964","identity":"rs-5098964","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}