The prognosis and treatment consideration for non-small cell lung carcinoma patients with tumor size of >2.0–3.0 cm and visceral pleural invasion: a SEER-based study

Introduction

Background

Lung cancer is the most common cancer type and the leading cause of cancer-related death worldwide (1). Non-small cell lung carcinoma (NSCLC) accounts for 80% of lung cancer (1). The Global Cancer Statistics 2020 data indicates that the 5-year overall survival (OS) rate of lung cancer is about 10–20% in the majority of countries.

Visceral pleural invasion (VPI) is defined as cancer cells invading elastic layers of visceral pleural and has been proven to be a poor prognostic factor for early-stage NSCLC patients (2,3). According to current guideline, VPI can be classified into four levels: tumor invades subpleural lung parenchyma or superficially into the connective tissue (PL0); tumor invades beyond the elastic layer of visceral pleura (PL1); tumor invades the visceral pleural surface (PL2); tumor invades into parietal pleura or chest wall (PL3) (4).

The Surveillance, Epidemiology, and End Results (SEER) database is a national cancer epidemiology database with extensive and representative data collection of cancer patient information from across the United States. Several previous studies have also examined the prognostic impact of VPI on lung cancer utilizing the SEER database. Qi et al. [2021] conducted an analysis on the prognostic implications of VPI and recommended upgrading stage of early-stage NSCLC cases exhibiting VPI and tumor size (TS) between 3.1 and 4.0 cm, utilizing data from the SEER database (5). Fang et al. [2022] redefined the T stage of NSCLC in the SEER database based on the degree of VPI and lymph node metastasis (6).

Rationale and knowledge gap

In accordance with the 8^th edition of the American Joint Committee on Cancer (AJCC) staging manual, pN0M0 NSCLC patients with TS below 5.0 cm can be divided into stage T1 (TS ≤3.0 cm), T2a (3.0< TS ≤4.0 cm) and T2b (4.0 <TS ≤5.0 cm). Regarding patients with a T1 tumor and VPI (+), the current guideline recommends to upgrade their T stage to T2 (7). However, specific guidelines for precisely categorizing these patients into T2a or T2b stages are currently unavailable. This difference is quite significant as it determines whether these patients should receive postoperative adjuvant therapy. The determination of whether NSCLC patients with TS less than 3.0 cm and VPI should be treated as stage IB or IIA remains uncertain. Additionally, the potential benefits of adjuvant therapy for these patients have not received significant attention in the current study. Hence, the debate persists regarding the necessity of administering postoperative chemotherapy to NSCLC pN0M0 patients with TS ranging from >2.0 to 3.0 cm and VPI (+) (5,6,8,9).

Objective

The present study focused on pN0M0 NSCLC patients with TS <3 cm and VPI (+). We compared their prognosis with T2a and T2b patients to highlight the severity of the disease. Additionally, we also discussed the impact of adjuvant therapies on the outcome of these patients. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-33/rc).

Methods

Study population

This study included 10,452 patients who were diagnosed with NSCLC from 2010 to 2019 in the SEER database (www.seer.cancer.gov/seerstat). Inclusion criteria were as follows: (I) patients who had been diagnosed with NSCLC and the location code in SEER was C34.0–C34.9; (II) patients who had only one primary cancer; (III) patients with TS between >2.0–5.0 cm. Exclusion criteria were as follows: (I) age less than 20 years old; (II) with metastatic diseases; (III) unknown tumor location, grade, histology type, and size; (IV) unknown VPI status or PL3; (V) patients without surgery; (VI) patients with unknown survival information or survive less than 1 month. The flowchart of data processing is shown in Figure 1. We exported the following characteristics of each enrolled patient from the SEER database: patient ID, age, gender, race, histological type, pathological grade, location, TS, VPI status, tumor-node-metastasis (TNM) stage, surgical approach, adjunctive therapy, survival information. The T stage of these patients was reclassified in accordance with the 8^th edition of TNM classification.

Figure 1 Flowchart of patient selection. NSCLC, non-small cell lung carcinoma; SEER, Surveillance, Epidemiology, and End Results; VPI, visceral pleural invasion; PL0, tumor invades subpleural lung parenchyma or superficially into the connective tissue; PL1, tumor invades beyond the elastic layer of visceral pleura; PL2, tumor invades the visceral pleural surface; PL3, tumor invades into parietal pleura or chest wall.

The VPI status was exported from cs site-specific factor 2 (codes 00, 10, 20, 30) and visceral and parietal pleural invasion recode (PL0, PL1 or PL2, PL3) in the SEER database. We reclassified the grade into low grade (well-differentiated, moderate differentiate) and high grade (poor differentiate, undifferentiated). The surgical approach was reclassified into sub-lobular resection (codes 21–22) and lobular resection (codes 30–80). According to the ICD-O-3 coding system, the histology code of NSCLC was composed of adenocarcinoma (8140, 8144, 8200, 8250-8255, 8260, 8310, 8323, 8480, 8481, 8490, 8550), squamous cell carcinoma (8052, 8070-8075, 8083-8084) and other NSCLC (8012-8014, 8022, 8030-8032, 8050, 8082, 8123, 8230, 9240, 8249, 8430,8560, 8980) (10,11). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Grouping of patients

Patients were divided into different groups based on their TS, VPI status (+, with; −, without), and postoperative chemotherapy status (+, with; −, without). The details of the grouping are listed in Table 1. Group A: TS extends from >2.0 to 3.0 cm with VPI (+) and postoperative chemotherapy (+); Group B: TS extends from >2.0 to 3.0 cm with VPI (+) and postoperative chemotherapy (−); Group C: TS extends from >3.0 to 4.0 cm with VPI (+/−) and postoperative chemotherapy (−); Group D: TS extends from >4.0 to 5.0 cm with VPI (+/−) and postoperative chemotherapy (+); Group E: TS extends from >4.0 to 5.0 cm with VPI (+/−) and postoperative chemotherapy (−).

Statistical analysis

Demographic and clinical characteristics were described using numbers (percentage). Categorical variables were compared using Pearson’s χ² test or Fisher’s exact test. Propensity score matching (PSM) was performed with the nearest-neighbor method (matching ratio =1:1, caliper =0.02) to balance the baseline characteristics between different groups. OS was defined as the duration from the diagnosis of cancer to the date of death or last follow-up date. The survival curves were calculated by Kaplan-Meier and compared with the Log-rank test between groups. Univariate and multivariate logistic regression were used to identify independent risk factors for VPI. All statistical tests conducted were two-tailed, with a significance threshold set at P<0.05. The statistical analyses were executed using R software, version 4.2.3 (http://www.r-project.org/).

Results

Baseline characteristics of the study cohort

According to the inclusion and exclusion criteria, a total of 10,452 NSCLC patients with TS interval of >2.0–5.0 cm were included in the study (Figure 1). The baseline characteristics of patients are listed in Table 2. The number of patients with or without VPI in the general study population was 2,708 (25.9%) and 7,744 (74.1%), respectively. The proportion of patients with age over 65 years old, tumor in the upper lobe, lower pathological grade, adenocarcinoma, sub-lobar resection, and adjunctive therapy, was significantly lower in the VPI negative group compared to the VPI positive group (P<0.05).

Patients with TS between >2.0–3.0 cm and VPI (+) have a worse prognosis than T2 tumor

The overall analysis flowchart is shown in the Figure 2. Survival analysis before PSM is shown in Figure S1. Since some variables were significantly different between groups, the effect of confounders was eliminated by PSM. The variables that listed in the PSM included: age, gender, race, location, laterality, grade, histology, surgical type, and adjunctive therapy. To assess the difference in outcomes among individuals without postoperative treatment in their natural state, we examined the prognoses of patients who did not receive postoperative chemotherapy and analyzed the difference in their prognoses.

Figure 2 Risk factors of VPI in the study cohort. TS, tumor size; VPI, visceral pleural invasion.

Table 3 shows the characteristics of patients with TS intervals of >2.0–3.0 cm (Group B) and >3.0–4.0 cm (Group C) without postoperative chemotherapy before and after PSM. There were 1,174 patients in Group B and 2,566 patients in Group C. After PSM, the number of patients in each group was matched to 642. The result of OS is shown in Figure 3A. The 5-year OS of patients in Group B and Group C was 49.1% and 56.8%, respectively. The difference in prognosis between these groups were significant (P=0.03) and the prognosis of Group B was worse than that of Group C.

Figure 3 Kaplan-Meier survival curves between groups. (A) OS of patients with TS interval of >2.0–3.0 and >3.0–4.0 cm who did not received postoperative chemotherapy; (B) OS of patients with TS interval of >2.0–3.0 and >4.0–5.0 cm who did not received postoperative chemotherapy; (C) OS of patients with TS interval of >2.0–3.0 and >4.0–5.0 cm who received postoperative chemotherapy; (D) OS of patients with TS interval of >2.0–3.0 cm with and without postoperative chemotherapy. VPI, visceral pleural invasion; TS, tumor size; OS, overall survive.

Similarly, Table 4 shows the characteristics of the TS of >2.0–3.0 cm (Group B) and >4.0–5.0 cm (Group E) without postoperative chemotherapy. There were 334 patients in Group B and Group E after PSM respectively. Figure 3B shows that the 5-year OS for Group B and Group E were 45.4% and 64.2%, respectively. The difference between Group B and Group E was significant (P<0.001) and the prognosis of patients in Group B was poorer than that of Group E.

Postoperative chemotherapy can improve prognosis of patients with T1c tumor and VPI

Given the unfavorable prognosis for patients with T1c tumor and VPI, we conducted a comparative analysis of the prognosis in patients with TS of >2.0–3.0 cm who underwent postoperative therapy (Group A) and those who did not receive such treatment (Group B). The objective of this analysis was to explore the potential benefits of adjuvant therapy in improving the prognosis of these patients.

Table 5 shows the characteristics of Group A and Group B. After PSM, between-group differences for all variables were eliminated. Survival analysis demonstrated that patients in Group A had a significantly better 5-year OS than patients in Group B (55.2% vs. 34.5%, P<0.001, Figure 3C).

T1c tumor with VPI exhibits a comparable prognosis to stage IIA tumor after chemotherapy

To assess whether patients with T1c tumor and VPI have a similar prognosis to stage IIA patients, we conducted a comparison between Group A and patients with TS between >4.0 and 5.0 cm who received chemotherapy (Group D). Table 6 shows the characteristics of patients in Group A and Group D. After PSM, there were 104 patients in both Group A and Group D, respectively. The 5-year OS of patients in Group A and Group D were 48.4% and 48.5%, respectively (Figure 3D). There was no between-group difference in survival (P=0.54).

Risk factors of VPI

In this study, logistic regression analysis was employed to identify the risk factors associated with VPI in patients with a TS interval ranging from >2.0 to 5.0 cm. Figure 4 shows the result of risk factors of NSCLC patients with VPI in this study cohort. In each subgroup, we can conclude that age greater than 65 years old (OR: 1.33, 95% CI: 1.21–1.47, P<0.001), lesions not located in upper and lower lobe (OR: 1.06, 95% CI: 0.90–1.26, P<0.001), poor differentiated and undifferentiated (OR: 0.59, 95% CI: 0.50–0.69, P<0.001), sublobectomy resection (OR: 1.22, 95% CI: 1.07–1.39, P=0.002) were prognostic risk factors of VPI.

Figure 4 Flowchart of analysis of the study cohort. OR, odds ratio; CI, confidence interval; SCC, squamous cell carcinoma; NSCLC, non-small cell lung carcinoma.

Discussion

VPI has been listed as a characteristic indicator in the TNM classification of the International Union Against Cancer staging system (12). According to the 8^th edition of TNM, NSCLC patients with TS less than 3.0 cm and VPI (+) should upgrade from T1 to T2. However, whether T1cN0M0 NSCLC patients with VPI (+) should be classified alongside with stage IB or stage IIA is yet to be decided, which leads to a discussion about whether early-stage NSCLC patients with VPI should receive postoperative anti-neoplastic agents combined treatment. Our study focused on analyzing primary NSCLC patients diagnosed between 2010–2019, using data obtained from the SEER database. Specifically, we aimed to compare the prognosis of different patient groups based on their receipt of postoperative chemotherapy and the presence of VPI. The results indicated that NSCLC patients with TS extends from >2.0 to 3.0 cm and VPI (+) had a better prognosis if they received postoperative chemotherapy as stage IIA.

However, there are some conflicts about the postoperative treatment regimen of early-stage NSCLC patients with VPI (+). According to the American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline, NSCLC patients with stage IIA should receive cisplatin-based adjuvant chemotherapy as routine after complete surgical resection. However, for patients with stage IB, routine cisplatin-based adjuvant chemotherapy is not recommended (13). Whether patients with TS interval of >2.0–3.0 cm and VPI (+) should be grouped with stage IB or stage IIA is still not determined which directly impacts the selection of postoperative treatment for these patients. In previous studies, according to the study by Kim et al. [2024], their findings suggest that adjuvant chemotherapy is suitable for individuals with stage IB NSCLC with VPI, including those with smaller tumors ranging from 1.0 to 3.0 cm (14). Yoshida et al. and Lakha et al. both indicate that the T stage of all NSCLC patients with TS less than 7.0 cm with VPI should be upgraded in further TNM classification which also shares the same conclusion as our research (9,15). Xie et al. [2020] reported that postoperative chemotherapy had no effects on the VPI patients in stage IB (16). Liang et al. [2021] showed that NSCLC patients with TS of 3.0 cm and PL2 should be graded into stage IB (17). Nitadori et al. [2013] indicated that the VPI-positive patients with TS ranging from >2.0 to 3.0 cm should be graded into new stage IB (18). During our analysis of the study cohort, there was a significant difference in the prognosis between TS interval of >2.0–3.0 and >3.0–4.0 cm who did not receive postoperative chemotherapy. Additionally, a significant difference in prognosis was also observed between TS interval of >2.0–3.0 and >4.0–5.0 cm who did not undergo postoperative chemotherapy. Based on our findings, it can be concluded that VPI (+) patients with TS interval of >2.0–3.0 cm exhibit a worse prognosis compared to patients with TS interval of >3.0–5.0 cm and VPI (+/−). These results suggest that patients with TS interval of >2.0–3.0 cm and VPI (+) should not be classified as a stage below IB. Secondly, there was a similar prognosis of patients with TS interval of >2.0–3.0 and >4.0–5.0 cm who received postoperative chemotherapy which means VPI patients with TS interval of >2.0–3.0 cm should be graded as T2bN0M0 patients to receive postoperative chemotherapy. On the other hand, we conducted a comparison of the OS curve between VPI (+) patients with a TS interval of >2.0–3.0 cm who received postoperative chemotherapy and those who did not. The analysis revealed that patients who underwent postoperative chemotherapy exhibited better prognosis. It follows that postoperative chemotherapy can help to improve the prognosis of patients with TS ranging from >2.0 to 3.0 cm with VPI.

With the development of target therapy and immunotherapy, postoperative adjuvant therapy is not limited to chemotherapy and/or radiotherapy (19). As the ADAURA trial has shown that the use of osimertinib after surgical resection can improve outcomes in patients with stage IB–IIIA NSCLC with EGFR mutation (20). Although stage IB patients with TS ranging from >2.0 to 3.0 cm and VPI positive were not included in this study, previous studies have shown that there may be a close relationship between VPI and some gene mutation. Shi et al. concluded that there is a significant relationship between EGFR mutations and VPI (21). Another retrospective study involving 80 NSCLC patients showed that patients with advanced NSCLC with KRAS mutation who received chemotherapy had a better prognosis than those who did not receive first-line chemotherapy which means KRAS mutation may also be associated with VPI (22,23). In terms of adjuvant immunotherapy after lung cancer surgery, in a study of 1,280 patients treated with atezolizumab after surgery for stage II–IIIA NSCLC, Felip found that the use of atezolizumab after surgery improved disease-free survival (DFS) of patients, particularly in those with 1% or more programmed death-ligand 1 (PD-L1) expression in tumor cells (TCs) (24). In the study by O’Brien M, pembrolizumab significantly improved DFS in patients with completely resected stage IB–IIIA postoperative NSCLC without PD-L1 selection (25). Therefore, it was proposed in the guidelines of the Chinese Society of Clinical Oncology (CSCO) guideline 2023 that after radical surgery, the adjuvant treatment of atezolizumab (limited to PD-L1 TC ≥1%) was upgraded from the grade II recommendation to the grade I recommendation, and pembrolizumab adjuvant treatment was added as the grade II recommendation. It can be seen that adjuvant treatment for NSCLC after surgery has become increasingly abundant. For VPI patients with TS interval of >2.0–3.0 cm after surgery, if further detection of gene mutation or PD-L1 TC ratio can be more beneficial than chemotherapy, it will be an area worth further exploration.

Before the lack of clear data on postoperative adjuvant therapy for this group of patients in existing guidelines, we are the first study to explore the relationship between postoperative chemotherapy and prognosis in patients with >2.0–3.0 cm NSCLC complicated with VPI. Moreover, our sample size is large, including patients with primary NSCLC diagnosed from 2010 to 2019 in the SEER database. The primary distinction between the treatment approaches for stage IB and stage IIA is the administration of postoperative chemotherapy. Based on our findings, we recommend that postoperative chemotherapy should be included in the recommended regimen for VPI (+) patients with TS interval of >2.0–3.0 cm.

In this study, there are still some limitations. Since the data from this research were extracted from the SEER database, which lacked information on the patient’s smoking history, we cannot discuss this risk factor of VPI. In addition, as some data in SEER did not classify the VPI state into PL1 or PL2, the specific role in the VPI subgroup cannot be discussed. Beyond that, the patients who received postoperative chemotherapy from the SEER database were selected by clinicians, these patients may be those the clinicians perceive as having a worse prognosis. An additional confounding factor may have been introduced here.

Conclusions

Postoperative chemotherapy can improve the prognosis of patients with TS ranging from >2.0 to 3.0 cm with VPI. According to the analysis of OS based on the postoperative chemotherapy, patients with NSCLC featuring TS extend from >2.0 to 3.0 cm and VPI may be classified within stage IIA. Consequently, the consideration of postoperative chemotherapy for this patient cohort may be warranted.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-33/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-33/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-33/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

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

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Seok Y, Lee E. Visceral Pleural Invasion Is a Significant Prognostic Factor in Patients with Partly Solid Lung Adenocarcinoma Sized 30 mm or Smaller. Thorac Cardiovasc Surg 2018;66:150-5. [Crossref] [PubMed]
3. Zhao LL, Xie HK, Zhang LP, et al. Visceral pleural invasion in lung adenocarcinoma ≤3 cm with ground-glass opacity: a clinical, pathological and radiological study. J Thorac Dis 2016;8:1788-97. [Crossref] [PubMed]
4. Travis WD, Brambilla E, Rami-Porta R, et al. Visceral pleural invasion: pathologic criteria and use of elastic stains: proposal for the 7th edition of the TNM classification for lung cancer. J Thorac Oncol 2008;3:1384-90.
5. Qi M, Bian D, Zhang J, et al. The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: A retrospective analysis based on the SEER database. Lung Cancer 2021;158:47-54. [Crossref] [PubMed]
6. Fang P, Cheng J, Lu Y, et al. Rethinking the Selection of Pathological T-Classification for Non-Small-Cell Lung Cancer in Varying Degrees of Visceral Pleural Invasion: A SEER-Based Study. Front Surg 2022;9:902710. [Crossref] [PubMed]
7. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015;10:990-1003.
8. Fibla JJ, Cassivi SD, Brunelli A, et al. Re-evaluation of the prognostic value of visceral pleura invasion in Stage IB non-small cell lung cancer using the prospective multicenter ACOSOG Z0030 trial data set. Lung Cancer 2012;78:259-62. [Crossref] [PubMed]
9. Yoshida J, Nagai K, Asamura H, et al. Visceral pleura invasion impact on non-small cell lung cancer patient survival: its implications for the forthcoming TNM staging based on a large-scale nation-wide database. J Thorac Oncol 2009;4:959-63. [Crossref] [PubMed]
10. Adamo M, Dickie L, Ruhl J. SEER Program Coding and Staging Manual. Bethesda, MD: National Cancer Institute. 2015.
11. Travis WD, Brambilla E, Nicholson AG, 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;10:1243-60. [Crossref] [PubMed]
12. Zhang X, Xie J, Hu S, et al. Prognostic value of visceral pleural invasion in the stage pT1-2N2M0 non-small cell lung cancer: A study based on the SEER registry. Curr Probl Cancer 2021;45:100640. [Crossref] [PubMed]
13. Kris MG, Gaspar LE, Chaft JE, et al. Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non-Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update. J Clin Oncol 2017;35:2960-74. [Crossref] [PubMed]
14. Kim BG, Choi J, Lee SK, et al. Impact of adjuvant chemotherapy on patients with stage IB non-small cell lung cancer with visceral pleural invasion. J Thorac Dis 2024;16:875-83. [Crossref] [PubMed]
15. Lakha S, Gomez JE, Flores RM, et al. Prognostic significance of visceral pleural involvement in early-stage lung cancer. Chest 2014;146:1619-26. [Crossref] [PubMed]
16. Xie J, Zhang X, Hu S, et al. Effects of adjuvant chemotherapy on survival of patients with stage IB non-small cell lung cancer with visceral pleural invasion. J Cancer Res Clin Oncol 2020;146:2231-9. [Crossref] [PubMed]
17. Liang RB, Li P, Li BT, et al. Modification of Pathologic T Classification for Non-small Cell Lung Cancer With Visceral Pleural Invasion: Data From 1,055 Cases of Cancers ≤ 3 cm. Chest 2021;160:754-64. [Crossref] [PubMed]
18. Nitadori JI, Colovos C, Kadota K, et al. Visceral pleural invasion does not affect recurrence or overall survival among patients with lung adenocarcinoma ≤ 2 cm: a proposal to reclassify T1 lung adenocarcinoma. Chest 2013;144:1622-31. [Crossref] [PubMed]
19. Vansteenkiste J, Wauters E, Reymen B, et al. Current status of immune checkpoint inhibition in early-stage NSCLC. Ann Oncol 2019;30:1244-53. [Crossref] [PubMed]
20. Wu YL, John T, Grohe C, et al. Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC. J Thorac Oncol 2022;17:423-33. [Crossref] [PubMed]
21. Shi J, Yang Y, Zhao Y, et al. EGFR mutations are significantly associated with visceral pleural invasion development in non-small-cell lung cancer patients. Cancer Manag Res 2019;11:1945-57. [Crossref] [PubMed]
22. Raparia K, Villa C, Raj R, et al. Peripheral lung adenocarcinomas with KRAS mutations are more likely to invade visceral pleura. Arch Pathol Lab Med 2015;139:189-93. [Crossref] [PubMed]
23. Hames ML, Chen H, Iams W, et al. Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer☆. Lung Cancer 2016;92:29-34. [Crossref] [PubMed]
24. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-57. [Crossref] [PubMed]
25. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-86. [Crossref] [PubMed]