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Original Article Factors Associated with Postoperative Recurrence in Stage I to IIIA Non–Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data
Kyu Yean Kim1orcid, Ho Cheol Kim2, Tae Jung Kim3, Hong Kwan Kim4, Mi Hyung Moon5, Kyongmin Sarah Beck6, Yang Gun Suh7, Chang Hoon Song8, Jin Seok Ahn9, Jeong Eun Lee10, Jae Hyun Jeon11, Chi Young Jung12, Jeong Su Cho13, Yoo Duk Choi14, Seung Sik Hwang15, Chang Min Choi2, Seung Hun Jang16, Jeong Uk Lim17,orcid, Korean Association for Lung Cancer, Korea Central Cancer Registry

DOI: https://doi.org/10.4143/crt.2024.073
Published online: July 10, 2024

1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea

2Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

3Department of Hospital Pathology, Yeouido St. Mary’s hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

4Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

5Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

6Department of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

7Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang, Korea

8Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

9Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

10Division of Pulmonology, Chungnam National University College of Medicine, Daejeon, Korea

11Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

12Department of Pulmonary, Daegu Catholic University Medical Center, Daegu Catholic University School of Medicine, Daegu, Korea

13Department of Thoracic and Cardiovascular Surgery, Pusan National University Hospital, Busan, Korea

14Department of Pathology, Chonnam National University Medical School, Gwangju, Korea

15Department of Public Health Science, Graduate School of Public Healthy, Seoul National University, Seoul, Korea

16Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea

17Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence: Jeong Uk Lim, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 63 ro-10, Yeongdeungpo-gu, Seoul 07345, Korea
Tel: 82-2-3779-1035 Fax: 82-2-780-3132 E-mail: cracovian@catholic.ac.kr
• Received: January 19, 2024   • Accepted: July 8, 2024

Copyright © 2024 by the Korean Cancer Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Purpose
    Recent development in perioperative treatment of resectable non–small cell lung cancer (NSCLC) have changed the landscape of early lung cancer management. The ADAURA trial has demonstrated the efficacy of adjuvant osimertinib treatment in resectable NSCLC patients; however, studies are required to show which subgroup of patients are at a high risk of relapse and require adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment. This study evaluated risk factors for postoperative relapse among patients who underwent complete resection.
  • Materials and Methods
    Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee.
  • Results
    A total of 3,176 patients who underwent curative resection was evaluated. The mean observation time was approximately 35.4 months. Among stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients, and 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Within the EGFR-mutant subgroup, 44 (5.1%) and 121 (14.0%) patients showed early and late recurrence, respectively. Multivariate analysis on association with postoperative relapse among the EGFR-mutant subgroup showed that age, pathologic N and TNM stages, pleural invasion status, and surgery type were independent significant factors.
  • Conclusion
    Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.
The treatment of choice in stage I to IIIA lung cancer is surgery. Despite curative resection, the 5 years postoperative recurrence-free survival (RFS) rates were 87.8% for patients with stage I, 54.7% for those with stage II, and 33.4% for those with stage III in non–small cell lung cancer (NSCLC) [1]. After curative resection in patients with stage II to IIIA NSCLC, adjuvant cisplatin-based chemotherapy is recommended [2]. Also, among patients with stage IB NSCLC, adjuvant systemic therapy is recommended in high-risk groups. According to the recent study in stage IB (American Joint Commission on Cancer [AJCC] 8th) NSCLC patients, adjuvant chemotherapy is beneficial in patients with high-risk factors, reducing recurrence rate and risk of mortality (hazards ratio, 0.408 and 0.176, respectively) [3]. According to the National Comprehensive Cancer Network (NCCN) guidelines, high-risk groups include patients with poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status.
Recent advances in perioperative treatment of resectable NSCLC have changed the landscape of early lung cancer management [4]. The ADAURA trial has shown significant efficacy of adjuvant osimertinib treatment in resectable NSCLC patients [5]. Among patients with resected, epidermal growth factor receptor (EGFR)–mutant, stage II to IIIA NSCLC, the 5-year overall survival (OS) was 85% in the osimertinib group, while only 73% in the placebo group [5]. It is undeniable that adjuvant treatment is effective in decreasing the chance of postoperative relapse and improving postoperative survival in EGFR-mutant patients who underwent complete resection for stage I to IIIA NSCLC.
However, osimertinib treatment for adjuvant purposes is not often covered by insurance or reimbursed in many countries, and financial burden is significant for most patients considering that there is no consensus regarding when to discontinue the adjuvant treatment [6]. Furthermore, both the prevalence and clinical characteristics of EGFR-mutant NSCLC patients vary according to region and race [7-9]. More clinical data are required to show which EGFR-mutant patient subgroups are at high risk of postoperative relapse and would benefit from adjuvant EGFR tyrosine kinase inhibitor (TKI) treatment.
This study evaluated risk factors for postoperative recurrence among patients who underwent complete resection using national Korean cancer data, with a focus among EGFR-mutant patients.
1. Patient selection
Data were obtained from the Korean Association for Lung Cancer Registry, a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee [10]. During the 2014-2017 period, the KCCR registered patients newly diagnosed with NSCLC. Among a total of 9,860 NSCLC patients, 3,364 underwent curative resection. Among them, 188 patients who were diagnosed as clinical stage IV or unknown stage were excluded. Finally, a total of 3,176 patients was enrolled in this study (Fig. 1). All patients were confirmed as having undergone operation for curative resection. Patients were staged according to the AJCC 7th edition TNM classification. Registered patients were followed for approximately 5 years after operation. All data in this study were obtained from the registered database with no additional review of individual data.
2. Definition of pleural invasion
According to a modified Hammar classification for pathologic assessment of visceral pleural invasion, PL0 is defined as no pleural invasion [11]. PL1 is defined as invasion beyond the elastic layer of the visceral pleura. PL2 is defined as invasion to the surface of the visceral pleura, and PL3 is defined as invasion to the parietal pleura.
3. Definition of early recurrence
Patients who showed postoperative relapse within one year of resection were classified as early recurrence patients.
4. Statistical analysis
Continuous variables are shown as mean±standard deviation, and categorical variables are shown as percentages. Risk factors for mortality were analyzed using Cox proportional hazards model. All statistical analyses were performed using SPSS ver. 20.0 (IBM Corp., Armonk, NY).
1. Clinical characteristics of enrolled patients
A total of 3,176 patients who underwent curative resection was evaluated (S1 Table). The proportion of patients with smoking history was 56.0%. Approximately 81.5% of enrolled patients had good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1). According to pathologic stage, 67.2%, 17.0%, and 12.9% of the patients were classified as stage I, stage II, and stage III, respectively. Regarding pathologic type, 70.7% were adenocarcinoma. Among the stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients.
Among the overall 3,176 patients, postoperative recurrence after curative resection occurred in 545 patients (17.1%). Median RFS was 31.73 months. Among 2,133 patients with EGFR results, the duration of OS was significantly shorter for EGFR-wild type patients than EGFR-mutant patients (S2A Fig.). However, the RFS showed no significant difference between EGFR-wild type and mutant patients (S2B Fig.).
2. Clinical characteristics of EGFR-mutant patients
The 867 patients with EGFR-mutant NSCLC who underwent curative surgery were analyzed (Table 1). Female sex and never-smokers were more prevalent than male sex and ever-smokers, respectively. Of these patients, 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Among them, 94.3% were adenocarcinoma, accounting for the largest proportion. Among the EGFR-mutant subgroup, 44 (5.1%) patients showed early recurrence and 121 (14.0%) patients showed late recurrence. The median RFS was 33.02 months.
3. Comparison between early, late, and no recurrence groups among EGFR-mutant patients
There was no significant difference in age, sex, ECOG performance status, or pulmonary function among the early recurrence group (ERG), late recurrence group (LRG), or no recurrence group (NRG) (Table 2). In the ERG, the proportion of patients with smoking history was higher than in the LRG and NRG (p=0.015). Also, the proportion of patients with higher T, N, and TNM stage cancer was higher in the ERG than the other groups (p < 0.001). Regarding pleural invasion, 15.9% of patients in the ERG were PL2 or PL3, which is significantly higher than the invasion seen in the LRG or NRG. The proportion of patients with perioperative chemotherapy and radiotherapy (RT) was higher in the ERG compared to the LRG and NRG.
4. Clinicopathologic risk factors associated with postoperative recurrence in NSCLC patients after curative surgery
S3 Table shows univariate and multivariate analyses of clinicopathologic risk factors for postoperative recurrence. In multivariate analysis, sex, body mass index (BMI), smoking, diffusing capacity of the lungs for carbon monoxide (DLco), pathologic N and TNM stages, and pleural invasion significantly associated with RFS.
Female sex (female vs. male: hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.57 to 0.88; p=0.001), patients with higher BMI (HR, 0.97; 95% CI, 0.94 to 1.00; p=0.027), and higher DLco (HR, 0.99; 95% CI, 0.99 to 1.0; p=0.001) had lower risk of recurrence. Ever smokers (ever vs. never-smokers: HR, 1.47; 95% CI, 1.20 to 1.80; p < 0.001), patients with higher N (pN1 vs. pN0: HR, 2.15; 95% CI, 1.63 to 2.83; p < 0.001; pN2 vs. pN0: HR, 2.07; 95% CI, 1.57 to 2.73; p < 0.001) and TNM stages (stage II vs. stage I: HR, 2.11; 95% CI, 1.68 to 2.64; p < 0.001; stage III vs. stage I: HR, 2.83; 95% CI, 2.24 to 3.57; p < 0.001), and patients with pleural invasion (visceral pleural invasion [VPI] vs. no pleural invasion: HR, 1.54; 95% CI, 1.19 to 2.01; p=0.001) had higher risk of recurrence.
5. Clinicopathologic risk factors associated with mortality in NSCLC patients after curative surgery
S4 Table shows univariate and multivariate analyses of clinicopathologic risk factors for mortality. In multivariate analysis, sex, age, BMI, DLco (%), EGFR mutation, pathologic TNM stage, and pleural invasion were significantly associated with OS.
Female sex, patients with higher BMI, patients with higher DLco, and patients with EGFR mutation had a lower risk of mortality. Patients with older age, higher pathologic stage, and VPI had a higher risk of mortality.
6. Clinicopathologic risk factors associated with postoperative recurrence in EGFR-mutant NSCLC patients after curative surgery
Table 3 shows univariate and multivariate analyses of clinicopathologic risk factors for recurrence. In multivariate analysis, age, pathologic N and TNM stages, pleural invasion, and surgery type were significantly associated with RFS. The HR of recurrence in patients with pathologic N2 category was 2.53 compared to patients with pathologic N0 (p=0.019). Also, the HR of recurrence in patients with pathologic stage II was 1.93 compared to patients with pathologic stage I (p=0.021). Patients with VPI had a 1.89-fold higher risk of recurrence compared to patients without pleural invasion (p < 0.001). Also, the HR of recurrence in patients with pneumonectomy was 0.45 compared to patients with wedge resection (p=0.006).
7. Clinicopathologic risk factors associated with mortality in EGFR-mutant NSCLC patients after curative surgery
Table 4 shows univariate and multivariate analyses of clinicopathologic risk factors for mortality. In multivariate analysis, sex, age, BMI, ECOG performance status, DLco, pathologic TNM stage, and pleural invasion were significantly associated with OS.
Female sex or patients with higher BMI or DLco had a lower risk of mortality in EGFR-mutant NSCLC patients after curative surgery. Patients with older age, higher ECOG performance status, higher pathologic stage, and PL3 had a higher risk of mortality.
8. RFS of patients with EGFR mutation according to pleural invasion
The duration of RFS was significantly shorter for patients with parietal pleural invasion than in patients with VPI and patients without pleural invasion (p < 0.001, log-rank test) (S5 Fig.). The mean time to recurrence after curative surgery was 36.77 months for patients with parietal pleural invasion, 45.02 months for patients with VPI, and 53.42 months for patients without pleural invasion. At 24 months, 85.7% of patients with parietal pleural invasion were recurrence-free compared to 91.5% in patients with VPI and 96.2% in patients without pleural invasion.
9. RFS of patients with EGFR mutation according to pathologic N category
The RFS was significantly shorter according to pathologic N category (p < 0.001, log-rank test) (S6 Fig.). The mean time of RFS was 22.28 months for pathologic N3, 39.41 months for pathologic N2, 40.08 months for pathologic N1, and 53.75 months for pathologic N0. At 24 months, 88.2% of patients with pathologic N2 category were recurrence-free compared to 90.8% in patients with pathologic N1 category and 96.6% in patients with pathologic N0 category.
10. RFS of patients with EGFR mutation according to pathologic stage
The duration of RFS was significantly shorter according to pathologic stage (p < 0.001, log-rank test) (S7 Fig.). The mean time of RFS was 40.41 months for stage III, 42.90 months for stage II, and 53.80 months for stage I. At 24 months, 97.7% of the patients with pathologic stage I were recurrence-free compared to 86.6% in patients with pathologic stage II and 87.3% in patients with pathologic stage III.
11. Comparison between early, late, and no recurrence groups among EGFR-mutant stage IA patients
Subgroup analysis was done among 390 patients with EGFR-mutant stage IA (AJCC 7th edition) without neoadjuvant treatment. There was no significant difference in age, BMI, sex, smoking status, ECOG performance status, or pulmonary function, surgery type, histologic type, presence of mediastinal lymph node (LN) resection or anaplastic lymphoma kinase (ALK) among the ERG, LRG, or NRG (S8 Table). The proportion of patients with adjuvant chemotherapy and RT was higher in the ERG compared to the LRG and NRG.
12. Clinicopathologic risk factors associated with postoperative recurrence in EGFR-mutant stage IA NSCLC patients after curative surgery
S9 Table shows univariate and multivariate analyses of clinicopathologic risk factors for recurrence in EGFR-mutant stage IA NSCLC patients after curative surgery. In multivariate analysis, sex and surgery type were significantly associated with recurrence. The HR of recurrence in female patients was 0.46 compared to male patients (95% CI, 0.22 to 0.97; p=0.043). The HR of recurrence in patients who took lobectomy was 0.35 compared to patients who took wedge resection (95% CI, 0.14 to 0.90; p=0.029).
13. Comparison between early, late, and no recurrence groups among EGFR-mutant stage IB patients
Subgroup analysis was done among 203 patients with EGFR-mutant stage IB (AJCC 7th edition) without neoadjuvant treatment. There was no significant difference in age, BMI, sex, smoking status, ECOG performance status, or pulmonary function, surgery type, histologic type, presence of mediastinal LN resection or ALK among the ERG, LRG, or NRG (S10 Table). As pleural invasion, there were higher proportion of patients with pleural invasion in the ERG and LRG compared to NRG. The proportion of patients with adjuvant chemotherapy and RT was higher in the ERG compared to the LRG and NRG.
14. Clinicopathologic risk factors associated with postoperative recurrence in EGFR-mutant stage IB NSCLC patients after curative surgery
S11 Table shows univariate and multivariate analyses of clinicopathologic risk factors for recurrence in EGFR-mutant stage IB NSCLC patients after curative surgery. In multivariate analysis, pleural invasion was significantly associated with recurrence. Increased DLco showed a trend toward decreased risk for recurrence, but statistical significance was not present (p=0.078). The HR of recurrence in patients with VPI was 2.75 compared to patients without pleural invasion (95% CI, 1.31 to 5.75; p=0.007).
15. Clinicopathologic risk factors associated with early recurrence in EGFR-mutant stage NSCLC patients after curative surgery
S12 Table shows univariate and multivariate logistic regression analyses of risk factors for early recurrence in EGFR-mutant NSCLC patients after curative surgery. In multivariate analysis, ever-smokers showed 2.24 fold higher risk of early postoperative recurrence compared to never-smokers (95% CI, 1.18 to 4.23; p=0.013). Patients with pathologic T3 category were 5.11 times higher risk of early recurrence after curative resection, compared to patients with pathologic T1 category (95% CI, 1.75 to 14.93; p=0.003). Also, patients with pathologic N2 category were 3.11 times higher risk of early recurrence after curative resection, compared to patients with pathologic N0 category (95% CI, 1,44 to 6.68; p=0.004).
The present study evaluated a nationwide lung cancer database to assess patients who are at risk of postoperative relapse, specifically for EGFR-mutant populations. We showed that, among various clinical parameters, patients with older age, higher N and pathologic stages, and those with presence of VPI are more likely to experience postoperative relapse and are in need of adjuvant EGFR TKI treatment. In regard to OS in EGFR-mutant NSCLC patients after curative surgery, male sex, older age, low BMI, high ECOG performance status, low DLco, high pathologic stage, and pleural invasion were significant prognostic markers.
There are some notable studies regarding the assessment of risk factors associated with postoperative relapse specifically for EGFR-mutant NSCLC patients who underwent resection. In a retrospective analysis of 531 patients, N category along with lympho-vascular invasion and cytokeratin 5/6 positivity were independent predictors of locoregional recurrence [12]. In another retrospective study, smoking history, vessel invasion, and lymph node metastasis were associated with RFS in EGFR-mutant patients [13]. In addition, Yu et al. [14] indicated that smoking history, large tumor size, elevated lymph node ratio, and platelet to lymphocyte ratio in stage pIIIA-N2 NSCLC patients after complete resection are associated with early recurrence. In the present study, among curatively resected EGFR-mutant NSCLC patients, the 1-year RFS was 94.9%, the 2-year RFS was 85.8%, and the 3-year RFS was 81.7%. At 24 months, 85.7% of patients with parietal pleural invasion were recurrence-free compared to 91.5% in patients with VPI and 96.2% in patients without pleural invasion. VPI is an important prognostic factor regardless of tumor size or N category [15]. In a previous study, exfoliated tumor cells were found to drain through the pleural lymphatics, which supports the association between VPI and extensive N2 involvement [16]. The visceral pleura is rich in lymphatics and can easily involve the hilar lymph nodes. As a consequence, VPI is associated with locoregional recurrence and distant metastasis [17].
EGFR TKI treatment has provided better clinical outcomes in EGFR-mutant NSCLC patients [18,19]. Osimertinib treatment has shown longer progression-free survival compared to earlier-generation EGFR TKIs [18]. According to a recent study, a significant OS benefit was shown in EGFR-mutant NSCLC patients with adjuvant osimertinib treatment after complete resection [5]. Therefore, an updated version of the NCCN guidelines suggests adjuvant osimertinib treatment in EGFR-mutant patients in stage IIB-IIIA and stage IB-IIA with high-risk factors.
However, in clinical practice, we have encountered medical insurance problems. In many countries including Korea, the nationwide medical reimbursement system does not cover the cost of adjuvant osimertinib treatment in EGFR-mutant NSCLC patients, and the recommended 3 years of prescription often entail significant financial burden for the patients. A previous study showed that certain features associated with postoperative relapse do not translate directly to need for adjuvant EGFR TKI treatment. Patients enrolled in the ADAURA study were stage IB to IIIA (classified according to the AJCC 7th edition) EGFR-mutant (Ex19del or L858R) NSCLC [20]. Specifically for the EGFR-mutant subgroup, certain enrollment criteria between ADAURA and present study do not match. In our study, there were 4.0% squamous lung cancer patients included in the EGFR-mutant subgroup, and it is likely that EGFR mutations other than Ex19del and L858R could have been included. However, it was interesting to see that enrollment criteria of the ADUARA study mostly overlapped with factors associated with postoperative relapse in our study, suggesting a possibility that patients with stage N1-2 or pleural invasion could have benefited from adjuvant EGFR TKI treatment. Clearly, more studies to better predict postoperative relapse are necessary to enable selection of patients for adjuvant EGFR TKI treatment.
When EGFR-mutant patients were stratified according to timing of postoperative relapse (early, late, or no recurrence), several features were distinguished. TNM stage, pleural invasion level, and smoking history showed significant difference between the groups. Early recurrence patients show a higher proportion of PL2 and PL3 compared to late recurrence patients. Furthermore, VPI was an independent factor associated with RFS. However, according to logistic regression analysis for early recurrence in EGFR-mutant NSCLC patients in the present study, only pathologic T, N stage and smoking history were significantly associated with early postoperative recurrence. While these risk factors need to be validated in larger population study, patients with regarding risk factors should undergo close surveillance for early postoperative recurrence.
In a previous retrospective analysis of NSCLC patients who underwent complete resection, association between VPI and EGFR mutation was shown, with a higher frequency of EGFR mutation patients among the subgroup [21]. In our study, risk of postoperative relapse was stratified by level of VPI. Considering that the presence of sole pleural invasion (PL1) is staged as T2, we should concurrently approach T stage and presence of VPI [22], and it is likely that clinicians should consider the presence and level of pleural invasion as an important factor when initiating and maintaining adjuvant EGFR TKI treatment.
In our analysis of stage IA lung cancer patients without pleural invasion, we observed that epidemiological factors, such as sex and age, might correlate with recurrence risk. ERG group showed significantly higher proportion of old-age patients, and male sex was associated with higher risk of recurrence in the multivariate analysis. In a retrospective study of NSCLC patients who underwent surgery for stage I and II cancer, females demonstrated significantly higher 5-year OS rates (76.2%) compared to males (57.3%), with gender identified as a favorable prognostic factor in multivariate analysis [23]. Among EGFR-mutant stage IA NSCLC patients, patients with lobectomy had lower risk of recurrence, compared to patients with wedge resection. This finding is consistent with the previous study, which compared locoregional RFS between wedge resection versus lobectomy for early-stage NSCLC. In the study, overall locoregional RFS was worse in wedge resection patients vs. lobectomy patients, 82.0% vs 93.4% [24]. In addition, one meta-analysis of comparison between wedge resection and lobectomy for early-stage NSCLC showed that patients with lobectomy had higher OS than patients with wedge resection [25]. So, even in early-stage NSCLC, lobectomy should be actively considered in patients without contraindication such as low lung function or poor general condition.
In our study, a subgroup analysis of EGFR-mutant stage IB (AJCC 7th edition) patients revealed that the hazard ratio for recurrence in patients with VPI was 2.75 times higher compared to those without pleural invasion. Despite differences in TNM editions, this finding aligns with a recent article by Choi et al. [3], which also identified VPI as a high-risk factor for postoperative recurrence in the stage IB patients. Another notable finding is that the ERG had a higher percentage of adjuvant chemotherapy and RT compared to late-recurrence or no-recurrence groups. It is more reasonable to consider that patients with more risk factors underwent postoperative treatment at the time of adjuvant therapy, rather than attributing recurrence risk to the adjuvant treatment itself. Therefore, we believe that efficacy of adjuvant treatment is difficult to be analyzed due to the limitations of the retrospective design. Future studies are needed to evaluate the efficacy of adjuvant treatment in patients with EGFR mutations.
Among the factors associated with postoperative outcomes in the EGFR subgroup of our study, DLco was independently associated with postoperative survival but not with RFS. DLco, along with other pulmonary function parameters, has long been shown to affect postoperative course of patients who undergo lung resection [26], and our results reconfirm this finding [27]. Low DLco values are associated with several lung conditions including emphysema or pulmonary fibrosis [28]. Patients with relatively low DLco values may have underlying emphysema or other chronic lung diseases that could impact their survival. Additionally, a study found that a low preoperative DLco is predictive of postoperative cardiopulmonary complications, mortality, and poor long-term survival in surgical patients [29]. Clinicians should pay more attention to patients with poor lung function when managing lung cancer patients who undergo lobectomy.
In the present study, duration of OS was significantly shorter for EGFR-wild type patients than EGFR-mutant patients. However, the RFS showed no significant difference between EGFR-wild type and mutant patients. Further studies should be done about treatment after recurrence.
There are notable limitations of this study. First, a large proportion of overall study patients did not undergo EGFR mutation testing. The database includes patients diagnosed with lung cancer from years 2014 to 2017, during the early phase of which mutation testing was not routinely performed. Despite this limitation, a large number of EGFR-mutant patients added to the importance of the present study. Second, no detailed results on EGFR mutation subtype or next-generation sequencing results were available for our study, which deterred us from confirming the association between mutation subtype and postoperative outcomes. Third, TNM staging was based on the AJCC 7th edition TNM staging, and it is likely that some T2 patients would have been classified as T3 according to the 8th edition [30]. Lastly, in our study, there was no statistically significant difference in recurrence risk between stage I and stage III EGFR-mutant patients. Although other clinical outcomes appeared relatively more favorable for stage I patients compared to stage III patients, we believe this discrepancy may be due to the smaller sample size of stage III patients. A larger sample size in future studies could potentially address this discrepancy.
Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

Ethical Statement

The study protocol was reviewed and approved by the Institutional Review Board at the National Cancer Center (NCC2018-0193), which waived the requirement for informed consent due to the retrospective nature of the study.

Author Contributions

Conceived and designed the analysis: Kim KY, Lim JU.

Collected the data: Kim HC, Kim TJ, Kim HK, Moon MH, Beck KS, Suh YG, Song CH, Ahn JS, Lee JE, Jeon JH, Jung CY, Cho JS, Hwang SS, Choi CM, Jang SH, Lim JU.

Contributed data or analysis tools: Kim KY, Kim HC, Kim TJ, Kim HK, Moon MH, Beck KS, Suh YG, Song CH, Ahn JS, Lee JE, Jeon JH, Jung CY, Cho JS, Hwang SS, Choi CM, Jang SH, Lim JU.

Performed the analysis: Kim KY.

Wrote the paper: Kim KY, Lim JU.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgements
This study was supported by Korean Association for Lung Cancer, Korea Central Cancer Registry.
Fig. 1.
Study flow diagram. NSCLC, non–small cell lung cancer.
crt-2024-073f1.jpg
Table 1.
Baseline characteristics of EGFR-mutant patients (n=867)
Characteristic No. of patients (%)
Age (yr) 62.54±9.97
 ≤ 65 511 (58.9)
 > 65 356 (41.1)
Sex
 Male 338 (39.0)
 Female 529 (61.0)
Smoking status
 Never 592 (68.3)
 Ever 272 (31.4)
 Unknown 3 (0.3)
ECOG
 0-1 754 (87.0)
 ≥ 2 19 (2.2)
 Unknown 94 (10.8)
PFT
 FVC (L) 3.23±0.83
 FEV1 (L) 2.46±0.65
 DLCO (%) 93.97±19.69
Pathologic T category
 T1 494 (57.0)
 T2 331 (38.2)
 T3 36 (4.2)
 T4 4 (0.5)
 Unknown 2 (0.2)
Pathologic N category
 N0 669 (77.2)
 N1 87 (10.0)
 N2 102 (11.8)
 N3 3 (0.3)
 Unknown 6 (0.7)
Surgery type
 Wedge resection 61 (7.0)
 Segmentectomy 77 (8.9)
 Lobectomy 712 (82.1)
 Pneumonectomy 17 (2.0)
Pathologic TNM stage
 I 652 (75.2)
 II 97 (11.2)
 III 102 (11.8)
 IV 8 (0.9)
 Unknown 8 (0.9)
Histologic type
 Squamous 35 (4.0)
 Adenocarcinoma 818 (94.3)
 Large cell carcinoma 0
 NSCLC, NOS 1 (0.1)
 Adenosquamous 8 (0.9)
 Carcinoid 0
 Others 5 (0.6)
Pleural invasion
 None (PL0) 637 (73.5)
 Visceral pleural invasion (PL1) 167 (19.3)
 Invasion to the surface of the visceral pleura (PL2) 45 (5.2)
 Extend to the parietal pleura (PL3) 14 (1.6)
 Pleural invasion, NOS 0
 Unknown 4 (0.5)
Mediastinal LN resection
 No 43 (5.0)
 Sampling 51 (5.9)
 Dissection 768 (88.6)
 Unknown 5 (0.6)
ALK
 Positive 26 (3.0)
 Negative 700 (80.7)
 Unknown 141 (16.3)
Recurrence
 No recurrence 702 (81.0)
 Late recurrence 121 (14.0)
 Early recurrence (≤ 1 yr) 44 (5.1)
Death
 No 749 (86.4)
 Yes 118 (13.6)
Observation time (mo) 36.56±10.97
Recurrence-free survival time (mo) 33.02±13.52
Recurrence-free survival rate (%)
 1-Year 94.9
 2-Year 85.8
 3-Year 81.7

Values are presented as mean±SD or number (%). ALK, anaplastic lymphoma kinase; ALK positive, ALK immunohistochemistry or fluorescence in situ hybridization positive; DLco, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FEV1, forced expiratory volume exhaled in the first second; FVC, forced vital capacity; LN, lymph node; NOS, not otherwise specified; NSCLC, non–small cell lung cancer; PFT, pulmonary function test; SD, standard deviation.

Table 2.
Clinical characteristics of ERG, LRG, and NRG among EGFR-mutant patients
Characteristic ERG (n=44) LRG (n=121) NRG (n=702) p-value
Age (yr) 63.20±10.22 61.94±11.18 62.61±9.74 0.778
 ≤ 65 24 (54.5) 73 (60.3) 414 (59.0)
 > 65 20 (45.5) 48 (39.7) 288 (41.0)
Sex
 Male 20 (45.5) 50 (41.3) 268 (38.2) 0.266
 Female 24 (54.5) 71 (58.7) 434 (61.8)
Smoking status
 Never 21 (47.7) 78 (64.5) 493 (70.2) 0.015
 Ever 23 (52.3) 42 (34.7) 207 (29.5)
 Unknown 0 1 (0.8) 2 (0.3)
ECOG
 0-1 37 (84.1) 107 (88.4) 611 (87.0) 0.555
 ≥ 2 4 (9.1) 1 (0.8) 14 (2.0)
 Unknown 3 (6.8) 13 (10.7) 77 (11.0)
PFT
 FVC (L) 3.22±0.84 3.22±0.80 3.24±0.83 0.968
 FEV1 (L) 2.38±0.63 2.45±0.59 2.46±0.66 0.690
 DLCO (%) 91.23±24.77 93.06±19.50 94.21±19.36 0.524
Pathologic T category
 T1 14 (31.8) 47 (38.8) 433 (61.7) < 0.001
 T2 23 (52.3) 66 (54.5) 242 (34.5)
 T3 6 (13.6) 8 (6.6) 22 (3.1)
 T4 1 (2.3) 0 3 (0.4)
 Unknown 0 0 2 (0.3)
Pathologic N category
 N0 23 (52.3) 68 (56.2) 578 (82.3) < 0.001
 N1 8 (18.2) 24 (19.8) 55 (7.8)
 N2 12 (27.3) 28 (23.1) 62 (8.8)
 N3 0 1 (0.8) 2 (0.3)
 Unknown 1 (2.3) 0 5 (0.7)
Surgery type
 Wedge resection 3 (6.8) 7 (5.8) 51 (7.3) 0.304
 Segmentectomy 2 (4.5) 11 (9.1) 64 (9.1)
 Lobectomy 38 (86.4) 98 (81.0) 576 (82.1)
 Pneumonectomy 1 (2.3) 5 (4.1) 11 (1.6)
Pathologic TNM stage
 I 15 (34.1) 60 (49.6) 577 (82.2) < 0.001
 II 13 (29.5) 24 (19.8) 60 (8.5)
 III 13 (29.5) 35 (28.9) 54 (7.7)
 IV 2 (4.5) 1 (0.8) 5 (0.7)
 Unknown 1 (2.3) 1 (0.8) 6 (0.9)
Histologic type
 Squamous 4 (9.1) 5 (4.1) 26 (3.7) 0.986
 Adenocarcinoma 40 (90.9) 111 (91.7) 667 (95.0)
 Large cell carcinoma 0 0 0
 NSCLC, NOS 0 0 1 (0.1)
 Adenosquamous 0 4 (3.3) 4 (0.6)
 Carcinoid 0 0 0
 Others 0 1 (0.8) 4 (0.6)
Pleural invasion
 None (PL0) 24 (54.5) 63 (52.1) 550 (78.3) < 0.001
 Visceral pleural invasion (PL1) 13 (29.5) 45 (37.2) 109 (15.5)
 Invasion to the surface of the visceral pleura (PL2) 5 (11.4) 11 (9.1) 29 (4.1)
 Extend to the parietal pleura (PL3) 2 (4.5) 1 (0.8) 11 (1.6)
 Pleural invasion, NOS 0 0 0
 Unknown 0 1 (0.8) 3 (0.4)
Mediastinal LN resection
 No 3 (6.8) 5 (4.1) 35 (5.0) 0.624
 Sampling 2 (4.5) 7 (5.8) 42 (6.0)
 Dissection 39 (88.6) 107 (88.4) 622 (88.6)
 Unknown 0 2 (1.7) 3 (0.4)
ALK
 Positive 3 (6.8) 5 (4.1) 18 (2.6) 0.549
 Negative 37 (84.1) 94 (77.7) 569 (81.1)
 Unknown 4 (9.1) 22 (18.2) 115 (16.4)
Chemotherapy
 Adjuvant 31 (70.5) 82 (67.8) 155 (22.1) < 0.001
 Neoadjuvant 5 (11.4) 5 (4.1) 14 (2.0)
 None 8 (18.2) 34 (28.1) 533 (75.9)
RT
 Adjuvant 21 (47.7) 41 (33.9) 48 (6.8) < 0.001
 Neoadjuvant 3 (6.8) 4 (3.3) 7 (1.0)
 None 20 (45.5) 76 (62.8) 647 (92.2)
Observation time (mo) 32.69±11.10 37.21±7.89 36.69±11.38 0.05
Recurrence-free survival time (mo) 10.56±7.37 24.48±9.04 35.90±12.49

Values are presented as mean±SD or number (%). The significance level of p-value was set after Bonferroni correction. ALK, anaplastic lymphoma kinase; ALK positive, ALK immunohistochemistry or fluorescence in situ hybridizationpositive; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; ERG, early recurrence group; FEV1, forced expiratory volume exhaled in the first second; FVC, forced vital capacity; LN, lymph node; LRG, late recurrence group; NOS, not otherwise specified; NRG, no recurrence group; NSCLC, non–small cell lung cancer; PFT, pulmonary function test; RT, radiotherapy; SD, standard deviation.

Table 3.
Univariate and multivariate analyses of risk factors associated with recurrence (n=867) in EGFR-mutated NSCLC patients after curative surgery
Parameter Univariate
Multivariate
HR (95% CI) p-value HR (95% CI) p-value
Sex
 Female vs. male (Ref) 0.75 (0.51-1.10) 0.136 0.73 (0.53-1.00) 0.053
Age (yr)
 > 65 vs. ≤ 65 (Ref) 1.46 (1.05-2.03) 0.023 1.41 (1.02-1.94) 0.037
BMI 0.96 (0.91-1.00) 0.074
Smoking
 Ever vs. never (Ref) 1.00 (0.67-1.48) 0.994 - -
ECOG
 ≥ 2 vs. 0-1 (Ref) 0.67 (0.16-2.74) 0.573
DLCO (per) 0.99 (0.99-1.00) 0.106 0.99 (0.99-1.00) 0.080
pT
 T3-4 vs. T1-2 1.42 (0.70-2.90) 0.332 - -
pN
 N1 vs. N0 (Ref) 2.08 (1.15-3.75) 0.015 2.00 (1.12-3.56) 0.019
 N2 vs. N0 (Ref) 2.68 (1.37-5.25) 0.004 2.53 (1.31-4.91) 0.006
pStage
 Stage II vs. stage I (Ref) 1.92 (1.07-3.45) 0.028 1.93 (1.10-3.39) 0.021
 Stage III vs. stage I (Ref) 1.34 (0.65-2.75) 0.431 1.38 (0.71-2.71) 0.345
Pleural invasion
 Visceral pleural invasion vs. no pleural invasion (Ref) 1.97 (1.37-2.83) 0.000 1.89 (1.33-2.70) < 0.001
Surgery type
 Lobectomy vs. limited resection (Ref) 0.64 (0.30-1.33) 0.228 0.66 (0.32-1.37) 0.264
 Pneumonectomy vs. limited resection (Ref) 0.45 (0.25-0.79) 0.006 0.45 (0.26-0.79) 0.006

BMI, body mass index; CI, confidence interval; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small cell lung cancer.

Table 4.
Univariate and multivariate analyses of risk factors associated with overall survival (n=867) in EGFR-mutated NSCLC patients after curative surgery
Parameter Univariate
Multivariate
HR (95% CI) p-value HR (95% CI) p-value
Sex
 Female vs. male (Ref) 0.48 (0.30-0.76) 0.002 0.48 (0.32-0.71) < 0.001
Age (yr)
 > 65 vs. ≤ 65 (Ref) 2.02 (1.35-3.00) 0.001 1.99 (1.35-2.94) 0.001
BMI 0.94 (0.89-0.99) 0.014 0.93 (0.89-0.99) 0.012
Smoking
 Ever vs. never (Ref) 1.04 (0.65-1.65) 0.877 - -
ECOG
 ≥ 2 vs. 0-1 (Ref) 2.88 (1.14-7.30) 0.026 2.86 (1.14-7.19) 0.026
DLCO (per) 0.99 (0.98-1.00) 0.002 0.98 (0.98-0.99) 0.002
pT
 T3-4 vs. T1-2 0.68 (0.32-1.45) 0.318 - -
pN
 N1 vs. N0 (Ref) 1.04 (0.51-2.15) 0.911 - -
 N2 vs. N0 (Ref) 1.29 (0.55-3.00) 0.561 - -
pStage
 Stage II vs. stage I (Ref) 2.77 (1.64-4.69) 0.000 2.61 (1.58-4.31) < 0.001
 Stage III vs. stage I (Ref) 5.27 (3.10-8.97) 0.000 4.69 (2.85-7.71) < 0.001
Pleural invasion
 Visceral pleural invasion vs. no pleural invasion (Ref) 3.84 (1.27-11.61) 0.017 3.34 (1.33-8.40) 0.010
Surgery type
 Lobectomy vs. limited resection (Ref) 0.71 (0.26-1.91) 0.496 - -
 Pneumonectomy vs. limited resection (Ref) 0.73 (0.33-1.64) 0.448 - -

BMI, body mass index; CI, confidence interval; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small cell lung cancer.

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      Factors Associated with Postoperative Recurrence in Stage I to IIIA Non–Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data
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      Fig. 1. Study flow diagram. NSCLC, non–small cell lung cancer.
      Factors Associated with Postoperative Recurrence in Stage I to IIIA Non–Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data
      Characteristic No. of patients (%)
      Age (yr) 62.54±9.97
       ≤ 65 511 (58.9)
       > 65 356 (41.1)
      Sex
       Male 338 (39.0)
       Female 529 (61.0)
      Smoking status
       Never 592 (68.3)
       Ever 272 (31.4)
       Unknown 3 (0.3)
      ECOG
       0-1 754 (87.0)
       ≥ 2 19 (2.2)
       Unknown 94 (10.8)
      PFT
       FVC (L) 3.23±0.83
       FEV1 (L) 2.46±0.65
       DLCO (%) 93.97±19.69
      Pathologic T category
       T1 494 (57.0)
       T2 331 (38.2)
       T3 36 (4.2)
       T4 4 (0.5)
       Unknown 2 (0.2)
      Pathologic N category
       N0 669 (77.2)
       N1 87 (10.0)
       N2 102 (11.8)
       N3 3 (0.3)
       Unknown 6 (0.7)
      Surgery type
       Wedge resection 61 (7.0)
       Segmentectomy 77 (8.9)
       Lobectomy 712 (82.1)
       Pneumonectomy 17 (2.0)
      Pathologic TNM stage
       I 652 (75.2)
       II 97 (11.2)
       III 102 (11.8)
       IV 8 (0.9)
       Unknown 8 (0.9)
      Histologic type
       Squamous 35 (4.0)
       Adenocarcinoma 818 (94.3)
       Large cell carcinoma 0
       NSCLC, NOS 1 (0.1)
       Adenosquamous 8 (0.9)
       Carcinoid 0
       Others 5 (0.6)
      Pleural invasion
       None (PL0) 637 (73.5)
       Visceral pleural invasion (PL1) 167 (19.3)
       Invasion to the surface of the visceral pleura (PL2) 45 (5.2)
       Extend to the parietal pleura (PL3) 14 (1.6)
       Pleural invasion, NOS 0
       Unknown 4 (0.5)
      Mediastinal LN resection
       No 43 (5.0)
       Sampling 51 (5.9)
       Dissection 768 (88.6)
       Unknown 5 (0.6)
      ALK
       Positive 26 (3.0)
       Negative 700 (80.7)
       Unknown 141 (16.3)
      Recurrence
       No recurrence 702 (81.0)
       Late recurrence 121 (14.0)
       Early recurrence (≤ 1 yr) 44 (5.1)
      Death
       No 749 (86.4)
       Yes 118 (13.6)
      Observation time (mo) 36.56±10.97
      Recurrence-free survival time (mo) 33.02±13.52
      Recurrence-free survival rate (%)
       1-Year 94.9
       2-Year 85.8
       3-Year 81.7
      Characteristic ERG (n=44) LRG (n=121) NRG (n=702) p-value
      Age (yr) 63.20±10.22 61.94±11.18 62.61±9.74 0.778
       ≤ 65 24 (54.5) 73 (60.3) 414 (59.0)
       > 65 20 (45.5) 48 (39.7) 288 (41.0)
      Sex
       Male 20 (45.5) 50 (41.3) 268 (38.2) 0.266
       Female 24 (54.5) 71 (58.7) 434 (61.8)
      Smoking status
       Never 21 (47.7) 78 (64.5) 493 (70.2) 0.015
       Ever 23 (52.3) 42 (34.7) 207 (29.5)
       Unknown 0 1 (0.8) 2 (0.3)
      ECOG
       0-1 37 (84.1) 107 (88.4) 611 (87.0) 0.555
       ≥ 2 4 (9.1) 1 (0.8) 14 (2.0)
       Unknown 3 (6.8) 13 (10.7) 77 (11.0)
      PFT
       FVC (L) 3.22±0.84 3.22±0.80 3.24±0.83 0.968
       FEV1 (L) 2.38±0.63 2.45±0.59 2.46±0.66 0.690
       DLCO (%) 91.23±24.77 93.06±19.50 94.21±19.36 0.524
      Pathologic T category
       T1 14 (31.8) 47 (38.8) 433 (61.7) < 0.001
       T2 23 (52.3) 66 (54.5) 242 (34.5)
       T3 6 (13.6) 8 (6.6) 22 (3.1)
       T4 1 (2.3) 0 3 (0.4)
       Unknown 0 0 2 (0.3)
      Pathologic N category
       N0 23 (52.3) 68 (56.2) 578 (82.3) < 0.001
       N1 8 (18.2) 24 (19.8) 55 (7.8)
       N2 12 (27.3) 28 (23.1) 62 (8.8)
       N3 0 1 (0.8) 2 (0.3)
       Unknown 1 (2.3) 0 5 (0.7)
      Surgery type
       Wedge resection 3 (6.8) 7 (5.8) 51 (7.3) 0.304
       Segmentectomy 2 (4.5) 11 (9.1) 64 (9.1)
       Lobectomy 38 (86.4) 98 (81.0) 576 (82.1)
       Pneumonectomy 1 (2.3) 5 (4.1) 11 (1.6)
      Pathologic TNM stage
       I 15 (34.1) 60 (49.6) 577 (82.2) < 0.001
       II 13 (29.5) 24 (19.8) 60 (8.5)
       III 13 (29.5) 35 (28.9) 54 (7.7)
       IV 2 (4.5) 1 (0.8) 5 (0.7)
       Unknown 1 (2.3) 1 (0.8) 6 (0.9)
      Histologic type
       Squamous 4 (9.1) 5 (4.1) 26 (3.7) 0.986
       Adenocarcinoma 40 (90.9) 111 (91.7) 667 (95.0)
       Large cell carcinoma 0 0 0
       NSCLC, NOS 0 0 1 (0.1)
       Adenosquamous 0 4 (3.3) 4 (0.6)
       Carcinoid 0 0 0
       Others 0 1 (0.8) 4 (0.6)
      Pleural invasion
       None (PL0) 24 (54.5) 63 (52.1) 550 (78.3) < 0.001
       Visceral pleural invasion (PL1) 13 (29.5) 45 (37.2) 109 (15.5)
       Invasion to the surface of the visceral pleura (PL2) 5 (11.4) 11 (9.1) 29 (4.1)
       Extend to the parietal pleura (PL3) 2 (4.5) 1 (0.8) 11 (1.6)
       Pleural invasion, NOS 0 0 0
       Unknown 0 1 (0.8) 3 (0.4)
      Mediastinal LN resection
       No 3 (6.8) 5 (4.1) 35 (5.0) 0.624
       Sampling 2 (4.5) 7 (5.8) 42 (6.0)
       Dissection 39 (88.6) 107 (88.4) 622 (88.6)
       Unknown 0 2 (1.7) 3 (0.4)
      ALK
       Positive 3 (6.8) 5 (4.1) 18 (2.6) 0.549
       Negative 37 (84.1) 94 (77.7) 569 (81.1)
       Unknown 4 (9.1) 22 (18.2) 115 (16.4)
      Chemotherapy
       Adjuvant 31 (70.5) 82 (67.8) 155 (22.1) < 0.001
       Neoadjuvant 5 (11.4) 5 (4.1) 14 (2.0)
       None 8 (18.2) 34 (28.1) 533 (75.9)
      RT
       Adjuvant 21 (47.7) 41 (33.9) 48 (6.8) < 0.001
       Neoadjuvant 3 (6.8) 4 (3.3) 7 (1.0)
       None 20 (45.5) 76 (62.8) 647 (92.2)
      Observation time (mo) 32.69±11.10 37.21±7.89 36.69±11.38 0.05
      Recurrence-free survival time (mo) 10.56±7.37 24.48±9.04 35.90±12.49
      Parameter Univariate
      Multivariate
      HR (95% CI) p-value HR (95% CI) p-value
      Sex
       Female vs. male (Ref) 0.75 (0.51-1.10) 0.136 0.73 (0.53-1.00) 0.053
      Age (yr)
       > 65 vs. ≤ 65 (Ref) 1.46 (1.05-2.03) 0.023 1.41 (1.02-1.94) 0.037
      BMI 0.96 (0.91-1.00) 0.074
      Smoking
       Ever vs. never (Ref) 1.00 (0.67-1.48) 0.994 - -
      ECOG
       ≥ 2 vs. 0-1 (Ref) 0.67 (0.16-2.74) 0.573
      DLCO (per) 0.99 (0.99-1.00) 0.106 0.99 (0.99-1.00) 0.080
      pT
       T3-4 vs. T1-2 1.42 (0.70-2.90) 0.332 - -
      pN
       N1 vs. N0 (Ref) 2.08 (1.15-3.75) 0.015 2.00 (1.12-3.56) 0.019
       N2 vs. N0 (Ref) 2.68 (1.37-5.25) 0.004 2.53 (1.31-4.91) 0.006
      pStage
       Stage II vs. stage I (Ref) 1.92 (1.07-3.45) 0.028 1.93 (1.10-3.39) 0.021
       Stage III vs. stage I (Ref) 1.34 (0.65-2.75) 0.431 1.38 (0.71-2.71) 0.345
      Pleural invasion
       Visceral pleural invasion vs. no pleural invasion (Ref) 1.97 (1.37-2.83) 0.000 1.89 (1.33-2.70) < 0.001
      Surgery type
       Lobectomy vs. limited resection (Ref) 0.64 (0.30-1.33) 0.228 0.66 (0.32-1.37) 0.264
       Pneumonectomy vs. limited resection (Ref) 0.45 (0.25-0.79) 0.006 0.45 (0.26-0.79) 0.006
      Parameter Univariate
      Multivariate
      HR (95% CI) p-value HR (95% CI) p-value
      Sex
       Female vs. male (Ref) 0.48 (0.30-0.76) 0.002 0.48 (0.32-0.71) < 0.001
      Age (yr)
       > 65 vs. ≤ 65 (Ref) 2.02 (1.35-3.00) 0.001 1.99 (1.35-2.94) 0.001
      BMI 0.94 (0.89-0.99) 0.014 0.93 (0.89-0.99) 0.012
      Smoking
       Ever vs. never (Ref) 1.04 (0.65-1.65) 0.877 - -
      ECOG
       ≥ 2 vs. 0-1 (Ref) 2.88 (1.14-7.30) 0.026 2.86 (1.14-7.19) 0.026
      DLCO (per) 0.99 (0.98-1.00) 0.002 0.98 (0.98-0.99) 0.002
      pT
       T3-4 vs. T1-2 0.68 (0.32-1.45) 0.318 - -
      pN
       N1 vs. N0 (Ref) 1.04 (0.51-2.15) 0.911 - -
       N2 vs. N0 (Ref) 1.29 (0.55-3.00) 0.561 - -
      pStage
       Stage II vs. stage I (Ref) 2.77 (1.64-4.69) 0.000 2.61 (1.58-4.31) < 0.001
       Stage III vs. stage I (Ref) 5.27 (3.10-8.97) 0.000 4.69 (2.85-7.71) < 0.001
      Pleural invasion
       Visceral pleural invasion vs. no pleural invasion (Ref) 3.84 (1.27-11.61) 0.017 3.34 (1.33-8.40) 0.010
      Surgery type
       Lobectomy vs. limited resection (Ref) 0.71 (0.26-1.91) 0.496 - -
       Pneumonectomy vs. limited resection (Ref) 0.73 (0.33-1.64) 0.448 - -
      Table 1. Baseline characteristics of EGFR-mutant patients (n=867)

      Values are presented as mean±SD or number (%). ALK, anaplastic lymphoma kinase; ALK positive, ALK immunohistochemistry or fluorescence in situ hybridization positive; DLco, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FEV1, forced expiratory volume exhaled in the first second; FVC, forced vital capacity; LN, lymph node; NOS, not otherwise specified; NSCLC, non–small cell lung cancer; PFT, pulmonary function test; SD, standard deviation.

      Table 2. Clinical characteristics of ERG, LRG, and NRG among EGFR-mutant patients

      Values are presented as mean±SD or number (%). The significance level of p-value was set after Bonferroni correction. ALK, anaplastic lymphoma kinase; ALK positive, ALK immunohistochemistry or fluorescence in situ hybridizationpositive; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; ERG, early recurrence group; FEV1, forced expiratory volume exhaled in the first second; FVC, forced vital capacity; LN, lymph node; LRG, late recurrence group; NOS, not otherwise specified; NRG, no recurrence group; NSCLC, non–small cell lung cancer; PFT, pulmonary function test; RT, radiotherapy; SD, standard deviation.

      Table 3. Univariate and multivariate analyses of risk factors associated with recurrence (n=867) in EGFR-mutated NSCLC patients after curative surgery

      BMI, body mass index; CI, confidence interval; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small cell lung cancer.

      Table 4. Univariate and multivariate analyses of risk factors associated with overall survival (n=867) in EGFR-mutated NSCLC patients after curative surgery

      BMI, body mass index; CI, confidence interval; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non–small cell lung cancer.


      Cancer Res Treat : Cancer Research and Treatment
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