Skip to main content
Download PDF

A real-world study comparing perioperative chemotherapy and EGFR-tyrosine kinase inhibitors for treatment of resected stage III EGFR-mutant adenocarcinoma

BMC Cancer volume 23, Article number: 847 (2023) Cite this article

Abstract

Background

The patient population with stage III non-small-cell lung cancer (NSCLC) is heterogeneous, with varying staging characteristics and diverse treatment options. Despite the potential practice-changing implications of randomized controlled trials evaluating the efficacy of perioperative epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), concerns have been raised due to conflicting overall survival (OS) results. Few real-world studies have examined the survival outcomes of patients with resected EGFR-mutant stage III adenocarcinoma receiving perioperative chemotherapy and EGFR–TKIs.

Methods

In this retrospective observational study, we enrolled patients with resected stage III adenocarcinoma with EGFR mutations between January 2011 and December 2021. Patients were classified into two groups: perioperative chemotherapy and perioperative EGFR–TKIs. Outcomes and prognostic factors were analyzed using Cox proportional hazards regression analysis.

Results

Eighty-four patients were enrolled in the analysis. Perioperative EGFR-TKIs led to longer progression-free survival (PFS) than chemotherapy (38.6 versus 14.2 months; p = 0.019). However, only pathological risk factors predicted poor PFS in multivariate analysis. Patients receiving perioperative chemotherapy had longer OS than those receiving EGFR-TKIs (111.3 versus 50.2 months; p = 0.052). Multivariate analysis identified perioperative treatment with EGFR-TKIs as an independent predictor of poor OS (HR: 3.76; 95% CI: 1.22–11.54).

Conclusion

Our study demonstrates that chemotherapy should be considered in the perioperative setting for high-risk patients, when taking pathological risk factors into consideration, and that optimized sequencing of EGFR–TKIs might be the most critical determinant of OS.

Peer Review reports

Background

The patient population with stage III non-small-cell lung cancer (NSCLC) is heterogeneous, with varying staging characteristics and diverse treatment options, including surgery, systemic therapy, and concurrent systemic and radiation therapy. Although surgery offers the best chances of long-term survival to patients with primary NSCLC [1], only 30% of stage III NSCLC tumors are resectable [2]. Neoadjuvant therapy is a widely accepted approach for treating patients with stage III lung cancer, as it effectively downstages NSCLC and increases the probability of successful curative surgery. Studies have shown that neoadjuvant chemotherapy can offer an overall survival (OS) advantage of up to 4% compared to surgery alone [3]. Additionally, cisplatin-based adjuvant chemotherapy is considered the standard of care for resected stage III NSCLC due to its proven OS benefit [4]. A meta-analysis indirectly compared the effects of adjuvant and neoadjuvant chemotherapy on survival and found them to be similar [5].

Adenocarcinoma accounts for approximately 50–60% of all stage III NSCLC in Asian populations [6, 7]. In these populations, the epidermal growth factor receptor (EGFR) mutation has been identified in 50–60% of patients [6]. The EGFR mutation is associated with a higher risk of metastatic recurrence in locally advanced stage III adenocarcinoma [8]. Accumulating data show the efficacy of adjuvant EGFR–tyrosine kinase inhibitors (EGFR–TKIs) for treating patients with resected EGFR-mutant NSCLC [9,10,11].

The ADJUVANT study demonstrated that adjuvant gefitinib resulted in a significantly longer disease-free survival (DFS) than cisplatin plus vinorelbine in patients with completely resected stage II–IIIA EGFR-mutant NSCLC [10]. However, this DFS advantage did not translate to a significant difference in OS [12]. A meta-analysis concluded that adjuvant EGFR–TKI therapy for resected EGFR-mutant NSCLC significantly improves DFS but not OS [13]. In the ADAURA study, patients with completely resected stage IB–IIIA EGFR-mutant NSCLC receiving the adjuvant osimertinib showed significantly longer DFS than those receiving a placebo, and the hazard ratio (HR)(0.12; 95% CI: 0.07–0.2) of patients with stage IIIA disease remained significantly lower [11]. Despite these promising results, the ADAURA trial was not designed to compare the efficacy of adjuvant chemotherapy and adjuvant EGFR-TKIs. Evidence supporting the feasibility of neoadjuvant EGFR-TKIs in the perioperative setting has also been provided by the EMERGING-CTONG1103 and NeoADAURA trials [14, 15].

Based on these studies, perioperative (neoadjuvant and/or adjuvant) chemotherapy and EGFR-TKIs provided a survival benefit in early-stage NSCLC. Despite many studies evaluating the role of perioperative EGFR–TKIs, the patient pool with stages IB–IIIA represents a very wide variety of cancers with inconstant prognosis [16], which may limit the application of these results to resected stage III EGFR-mutant adenocarcinoma. Currently, there are few real-world studies examining the survival outcomes of patients receiving perioperative chemotherapy and EGFR–TKIs for resected EGFR-mutant stage III adenocarcinoma [17]. The prognostic effect of pathological factors has never been emphasized in previous randomized controlled trials (RCTs). This retrospective study aimed to compare the treatment outcomes, with a focus on OS, between patients with resected EGFR-mutant stage III adenocarcinoma who received either perioperative chemotherapy or EGFR-TKIs.

Materials and methods

Study design and patients

This retrospective study investigated patients with resected stage III (according to American Joint Committee on Cancer, 8th edition) [18] EGFR–mutant adenocarcinoma at a tertiary referral center in Taiwan between January 2011 and December 2021. The study adhered to the Declaration of Helsinki and followed the STROBE guidelines for reporting observational studies. The Institutional Review Board of China Medical University Hospital (IRB number: CMUH110-REC1-244) waived the need for informed consent from study subjects due to the retrospective design.

The study collected and recorded data on the baseline characteristics of each patient, which included sex, age, smoking status, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), tumor-node-metastasis (TNM) stage, EGFR mutation subtype, perioperative antineoplastic therapy, and subsequent antineoplastic therapy after disease progression.

Treatment exposure

As routine clinical practice, the treatment for each patient was discussed by the multidisciplinary team. Patients who received surgery and either neoadjuvant or adjuvant antineoplastic therapy were included in our study. The surgical procedures were decided by individual surgeons according to the size and location of the tumors. Based on the perioperative treatment regimen, the patients were classified into two groups: the perioperative chemotherapy group and the perioperative EGFR–TKI group. During the study period, the use of neoadjuvant EGFR-TKIs was an off-label treatment, and patients were given the choice to receive the treatment after a thorough explanation from their physician. Decisions about whether patients would receive radiotherapy were made by the physician.

Pathological examination

Tissue slides stained with the hematoxylin–eosin stain, immunohistochemistry stain, or elastic stain were reviewed by experienced pathologists. The presence of tumor cells in the lymphatic or vascular lumen, the space around nerves, or the visceral pleura was defined as lymphovascular invasion [19], perineural invasion [20, 21], or visceral pleural invasion [22], respectively. Margin involvement was defined as microscopic residual disease at the resection margin. The extension of malignant cells through the nodal capsule was considered an extranodal extension. The above-mentioned characteristics from the pathological examination were defined as “pathological risk factors.”

Clinical assessments and efficacy evaluations

At baseline, patients underwent imaging studies including chest computed tomography (CT), brain magnetic resonance imaging, and positron emission tomography to determine the stage of the disease and evaluate any metastasis. In selected patients, endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) was performed for N staging based on the multidisciplinary team’s suggestion.

All patients received chest CT evaluations every 12 weeks to evaluate tumor response after initiation of antineoplastic therapy. Other images were obtained when suspicious new symptoms developed. Progression-free survival (PFS) was the time elapsed between the date of initiation of stage III NSCLC treatment and radiological progression (according to the Response Evaluation Criteria in Solid Tumors v1.1), clinical progression, or death. OS was the time elapsed between the date of diagnosis and death. In cases where disease progression or death were not recorded, patients were censored either at the end of the observation period, which was 30 June 2022, or at the time of their last available medical record entry.

Statistical analyses

Statistical analyses were conducted with MedCalc for Windows version 18.10 (MedCalc Software, Ostend, Belgium). For normally distributed variables, the mean ± standard deviation was used, while the median and interquartile range were used for non-normally distributed variables. t-tests were used to analyze continuous data with normal distributions, while categorical variables were presented as percentages and numbers, and analyzed with either the chi-square or Fisher’s exact test. The Kaplan-Meier method was used to evaluate PFS and OS, while Cox proportional hazards regression analysis was used to analyze prognostic factors. The HR of disease progression and mortality was calculated using univariate analysis, and the multivariate regression model included significant variables from univariate analysis and clinically important variables to adjust potential confounders. The strength of the association was presented as the HR and its 95% confidence interval (CI). A p-value of < 0.05 was considered statistically significant.

Results

Eighty-four patients with resected stage III EGFR-mutant adenocarcinoma were enrolled in this study. Sixty-three patients received perioperative chemotherapy and 21 received perioperative EGFR–TKIs (Fig. 1). Of the patients receiving perioperative EGFR–TKIs, nine were treated with erlotinib, five with gefitinib, five with afatinib, and two with osimertinib.

Fig. 1
figure 1

Flowchart showing patient selection. ALK: anaplastic lymphoma kinase; CT: chemotherapy; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor

Full size image

Patients receiving perioperative EGFR–TKIs were older than those receiving chemotherapy (61.9% of patients in the EGFR–TKI group were ≥ 65 years old versus 30.2% in the chemotherapy group, p = 0.009). No significant differences in gender, ECOG–PS, smoking status, and the EGFR mutation were observed between groups (Table 1). More patients in the EGFR–TKI group received neoadjuvant treatment (38.1% versus 9.5%, p = 0.002).

Table 1 Clinical characteristics of the patients with resected EGFR–mutant stage III adenocarcinoma in this study
Full size table

After a median follow-up of 53.2 months (range 45.5–61.0 months), 85.7% of patients in the perioperative chemotherapy group and 47.6% in the perioperative EGFR–TKI group experienced disease progression. The median PFS of patients receiving perioperative EGFR–TKIs was significantly longer than that of patients receiving perioperative chemotherapy (38.6 versus 14.2 months; p = 0.019; Fig. 2).

Fig. 2
figure 2

PFS of patients with EGFR-mutant NSCLC treated with perioperative chemotherapy and EGFR–TKIs. EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor

Full size image

Multivariate Cox proportional hazards regression analysis was used to identify prognostic factors of poor PFS. The difference in HR between perioperative EGFR–TKIs and perioperative chemotherapy was not statistically significant. The presence of pathological risk factors was an independent prognosticator of poor PFS (HR: 2.36; 95% CI: 1.14–4.91) (Table 2).

Table 2 Cox proportional hazards regression analysis of the PFS of patients with resected EGFR–mutant stage III adenocarcinoma
Full size table

In the case of patients experiencing disease progression, 96.3% (52/54) in the perioperative chemotherapy group and 90% (9/10) in the perioperative EGFR–TKI group received subsequent EGFR–TKI treatment (Fig. 3). Of these patients, 32% (16/50) in the chemotherapy group and 33.3% (3/9) in the EGFR–TKI group received osimertinib as the later-line treatment. Of the 10 patients with disease progression in the perioperative EGFR–TKI group, only four received chemotherapy as their subsequent treatment (Fig. 3).

Fig. 3
figure 3

Subsequent treatment regimens of patients treated with perioperative chemotherapy or EGFR–TKIs. EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. *Nine of the ten patients with disease progression in the perioperative EGFR-TKI group received EGFR-TKI treatment, while only four received chemotherapy

Full size image

Twenty-eight (33.3%) deaths were recorded; 30.2% (19/63) of patients in the chemotherapy group and 42.9% (9/21) in the EGFR–TKI group died. The median OS of patients receiving perioperative chemotherapy was longer than that of patients receiving perioperative EGFR–TKIs (111.3 versus 50.2 months; p = 0.052; Fig. 4). Cox proportional hazards regression analysis to identify prognostic factors of poor OS revealed that treatment with perioperative EGFR–TKIs (HR: 3.76; 95% CI: 1.22–11.54) was an independent prognosticator of poor OS (Table 3). Although not statistically significant, a trend toward poor OS was observed in patients with a history of smoking (HR: 2.53; 95% CI: 1.00–6.48, p = 0.051).

Fig. 4
figure 4

OS of patients with EGFR-mutant NSCLC treated with perioperative chemotherapy and EGFR–TKI. EGFR, epidermal growth factor receptor; OS, overall survival; TKI, tyrosine kinase inhibitor

Full size image
Table 3 Cox proportional hazards regression analysis of the OS of patients with resected EGFR–mutant stage III adenocarcinoma
Full size table

Discussion

The heterogeneity of stage III NSCLC presents greater clinical complexity than patients enrolled in clinical trials. Neoadjuvant and/or adjuvant (perioperative) therapy is a frequently used treatment modality in clinical practice. Our study is the first real-world investigation to compare the impact of perioperative chemotherapy and EGFR-TKIs on the OS of patients with EGFR-mutant stage III NSCLC after incorporating pathological factors.

In this study, the median PFS of the perioperative chemotherapy group was 14.2 months and that of the perioperative EGFR–TKI group was 38.6 months. The PFS benefit of EGFR–TKIs in this patient population was similar to that of patients with advanced EGFR-mutant NSCLC [23,24,25]. However, the HR between perioperative EGFR–TKIs and chemotherapy was not statistically significant in the multivariate analysis. We found that the presence of pathological risk factors was an independent prognosticator of poor PFS (Table 2). The predictive effect of lymphovascular invasion on local–regional failure [19] and distant recurrence [26, 27] has been demonstrated before. Visceral pleural invasion [19, 22] and perineural invasion [20, 21] are also considered prognostic factors of poor PFS. Our results suggest that pathological features are critical and recognizing patients with higher risk of recurrence might facilitate the selection of adjuvant systemic treatments.

Despite the lower PFS associated with perioperative chemotherapy, OS was better due to this treatment. While more than 90% of patients in the chemotherapy group received EGFR–TKIs after disease progression, only 44.4% of patients in the EGFR–TKI group received chemotherapy as their subsequent treatment. This low crossover rate may be a factor contributing to the poorer OS seen in the EGFR group. Fewer patients in the EGFR–TKI group experienced disease progression (47.6% versus 85.7% in the chemotherapy group), but 90% (9/10) of them died. Although patients receiving perioperative EGFR–TKIs were older, the prognostic effect of age was adjusted in the multivariate analysis. The pathological examination showed that the EGFR–TKI group had fewer pathological risk factors than the chemotherapy group. However, adjuvant chemotherapy overcame the disadvantage to PFS and the poor pathological risk factors and contributed to better OS.

Accumulating evidence indicates the potential efficacy of neoadjuvant EGFR-TKIs in patients with resectable NSCLC, which has led to the design of RCTs, notably the phase II EMERGING-CTONG1103 and phase III NeoADAURA trials. Although the NeoADAURA trial was designed to evaluate the efficacy of neoadjuvant osimertinib with or without chemotherapy, adjuvant systemic treatment with either osimertinib or chemotherapy was allowed based on investigator choice for optimal care. In the EMERGING-CTONG 1103 trial, patients were divided into neoadjuvant/adjuvant erlotinib and chemotherapy groups. Both studies did not clearly distinguish between neoadjuvant and adjuvant treatments, leading to a more generalized “perioperative” treatment proposition [15, 28] as in the current study. The analysis of OS in the EMERGING-CTONG 1103 trial showed that, although there was a survival benefit in PFS, it did not translate into a difference in OS [28]. Moreover, this study was limited by the fact that only 69.7% of patients in the chemotherapy group received subsequent EGFR-TKI treatment after disease progression, which may confound the OS result.

Among previous RCTs evaluating the efficacy of adjuvant EGFR–TKIs, the EVAN phase II trial was the first to show a significantly higher OS benefit from erlotinib than from chemotherapy (vinorelbine plus cisplatin) in patients with resected stage IIIA EGFR-mutant NSCLC [29]. However, the sample size was relatively small (n = 51 in each group) and only 37.3% of the patients in the chemotherapy group received EGFR–TKIs after disease progression [30]. In our study, more than 90% of the patients in the perioperative chemotherapy group with disease progression received EGFR–TKIs. The negative OS outcomes reported in both the CTONG1104 and IMPACT trials have raised concerns about the potential for adjuvant targeted therapy to only delay disease recurrence rather than providing a cure [31, 32]. In the ADAURA trial, adjuvant osimertinib provided a significant OS benefit among patients with completely resected EGFR-mutant NSCLC [33]. However, only 43% of patients in the control arm received osimertinib as subsequent treatment after disease progression [33], which may bias the OS result. Based on the available evidence and the results of the current study, chemotherapy remains an essential component in perioperative settings for resected EGFR-mutant NSCLC patients [34].

Patients with a history of smoking tended to have worse OS outcomes in our study (HR 2.54; 95% CI 1.00–6.48; p = 0.051). For advanced NSCLC patients with EGFR mutations, smoking was associated with shorter PFS during EGFR–TKI treatment [35] and reduced OS [36, 37]. Smokers’ tumors are hypothesized to have a higher burden of alternative driver oncogene mutations and the likelihood of an escape mechanism [38]. In the subgroup analysis of the ADJUVANT study, the DFS benefit of gefitinib was non-significant for smokers (HR 0.56; 95% CI: 0.27–1.19). We regard smoking as a risk factor of reduced response to EGFR–TKIs; therefore, standard chemotherapy should be considered in the adjuvant setting for this patient group.

The NEJ009 study reported that patients with EGFR-mutant NSCLC could gain an OS benefit from combined treatment with chemotherapy and EGFR–TKIs compared to EGFR–TKIs alone [39]. In the ADAURA trial, subgroup analysis stratifying the benefit of adjuvant chemotherapy showed that the two-year DFS of patients who received adjuvant chemotherapy was better than that of the patients who did not receive this treatment (HR of 0.16 vs. 0.23) [40]. The present study also showed that perioperative chemotherapy with sequential EGFR–TKIs resulted in better OS. Subsequent therapy after disease progression also plays an important role in contributing OS.

Our study has several limitations. First, it was a retrospective, single-institution study, and the number of patients in our cohort was small. As a result, we were unable to divide patients who received perioperative systemic treatment into neoadjuvant or adjuvant treatment separately. However, currently available evidence suggests no difference in the survival of neoadjuvant or adjuvant chemotherapy [5]. Second, different types of EGFR-TKIs were analyzed together, and the effectiveness of a specific drug could not be evaluated. Third, there were imbalanced baseline characteristics between the two groups, and neoadjuvant treatment inevitably affected the pathology findings. However, due to the limited number of patients, we were unable to perform propensity score matching. To account for the influence of age, pathologic risk factors, T and N staging, and smoking history on OS, we utilized multivariate Cox proportional hazards regression analysis. Fourth, due to the retrospective nature of this study, the entry time varied across the patient population. Furthermore, only 9 cases with OS events were observed in the EGFR-TKI group, potentially leading to insufficient observation time for other patients and unavoidable bias. Fifth, excluding inoperable patients with neoadjuvant treatment may introduce selection bias. PFS was defined as the time from the initiation of antineoplastic treatment until disease progression in this study. For those undergoing neoadjuvant treatment followed by surgery, the combined treatment and surgical duration in PFS could lead to longer observed PFS times and potential immortal time bias. However, the patient’s neoadjuvant EGFR-TKI within three months before surgery ensures the immortal time bias is not significant, similar to neoadjuvant chemotherapy. Sixth, the result from this study should be interpreted cautiously in patients with uncommon mutations. All 5 patients with uncommon mutations received perioperative chemotherapy in our study. This bias was explained by the less active treatment effect of EGFR-TKIs in treating uncommon mutations, as compared with common mutations such as the del 19 mutation [41]. Finally, the percentage of patients using osimertinib after disease progression was relatively small (32% in the chemotherapy group and 33.3% in the EGFR–TKI group).

Conclusion

Our study demonstrates that standard chemotherapy still should be considered in the perioperative setting for high-risk patients, when taking pathological risk factors into consideration, and that optimized sequencing of EGFR–TKIs might be the most critical determinant of OS in patients with stage III EGFR-mutant NSCLC.

Data availability

The datasets used and analyzed during the present study are available from the corresponding author on reasonable request.

Abbreviations

CI:

Confidence interval

DFS:

Disease free survival

EGFR:

Epidermal growth factor receptor

EGFR-TKI:

Epidermal growth factor receptor tyrosine kinase inhibitor

HR:

Hazard ratio

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

TKI:

Tyrosine kinase inhibitor

References

  1. Subotic D, Van Schil P, Grigoriu B. Optimising treatment for post-operative lung cancer recurrence. Eur Respir J. 2016;47(2):374–8.

    Article  PubMed  CAS  Google Scholar 

  2. Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl4):iv1–iv21.

    Article  PubMed  CAS  Google Scholar 

  3. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383(9928):1561–71.

    Article  Google Scholar 

  4. Kris MG, Gaspar LE, Chaft JE, Kennedy EB, Azzoli CG, Ellis PM, 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(25):2960–74.

    Article  PubMed  Google Scholar 

  5. Lim E, Harris G, Patel A, Adachi I, Edmonds L, Song F. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol. 2009;4(11):1380–8.

    Article  PubMed  Google Scholar 

  6. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Jazieh AR, Onal HC, Tan DSW, Soo RA, Prabhash K, Kumar A, et al. Real-world treatment patterns and clinical outcomes in patients with stage III NSCLC: results of KINDLE, a Multicountry Observational Study. J Thorac Oncol. 2021;16(10):1733–44.

    Article  PubMed  CAS  Google Scholar 

  8. Galvez C, Jacob S, Finkelman BS, Zhao J, Tegtmeyer K, Chae YK, et al. The role of EGFR mutations in predicting recurrence in early and locally advanced lung adenocarcinoma following definitive therapy. Oncotarget. 2020;11(21):1953–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kelly K, Altorki NK, Eberhardt WE, O’Brien ME, Spigel DR, Crino L, et al. Adjuvant Erlotinib Versus Placebo in patients with Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): a Randomized, Double-Blind, phase III trial. J Clin Oncol. 2015;33(34):4007–14.

    Article  PubMed  CAS  Google Scholar 

  10. Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(1):139–48.

    Article  PubMed  CAS  Google Scholar 

  11. Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, et al. Osimertinib in Resected EGFR-Mutated non-small-cell Lung Cancer. N Engl J Med. 2020;383(18):1711–23.

    Article  PubMed  CAS  Google Scholar 

  12. Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Wei YC, et al. Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: final overall survival analysis of CTONG1104 phase III trial. J Clin Oncol. 2021;39(7):713–22.

    Article  PubMed  CAS  Google Scholar 

  13. Li M, Hou X, Lin S, Zheng L, Liang J, Chen J, et al. Efficacy of adjuvant EGFR inhibitors and impact of clinical factors in resected EGFR-mutated non-small-cell lung cancer: a meta-analysis. Future Oncol. 2022;18(9):1159–69.

    Article  PubMed  CAS  Google Scholar 

  14. Zhong WZ, Chen KN, Chen C, Gu CD, Wang J, Yang XN, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant non-small-cell Lung Cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235–45.

    Article  PubMed  CAS  Google Scholar 

  15. Tsuboi M, Weder W, Escriu C, Blakely C, He J, Dacic S, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol. 2021;17(31):4045–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cansouline X, Lipan B, Sizaret D, Tallet A, Vandier C, Carmier D et al. EGFR-Mutant Non-Small-Cell Lung Cancer at Surgical Stages: what is the place for tyrosine kinase inhibitors? Cancers (Basel). 2022;14(9).

  17. Li Q, Ma L, Qiu B, Wen Y, Liang W, Hu W, et al. Benefit from adjuvant TKIs Versus TKIs Plus Chemotherapy in EGFR-Mutant Stage III-pN2 Lung Adenocarcinoma. Curr Oncol. 2021;28(2):1424–36.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: what does it mean on main street? J Thorac Cardiovasc Surg. 2018;155(1):356–9.

    Article  PubMed  Google Scholar 

  19. Saynak M, Veeramachaneni NK, Hubbs JL, Nam J, Qaqish BF, Bailey JE, et al. Local failure after complete resection of N0-1 non-small cell lung cancer. Lung Cancer. 2011;71(2):156–65.

    Article  PubMed  Google Scholar 

  20. Sayar A, Turna A, Solak O, Kilicgun A, Urer N, Gurses A. Nonanatomic prognostic factors in resected nonsmall cell lung carcinoma: the importance of perineural invasion as a new prognostic marker. Ann Thorac Surg. 2004;77(2):421–5.

    Article  PubMed  Google Scholar 

  21. Demir A, Gunluoglu MZ, Kara HV, Buyukpinarbasili N, Dincer SI. Prognostic factors in resected T3 non-small cell lung carcinoma: perineural invasion as a new prognostic factor. Thorac Cardiovasc Surg. 2008;56(2):93–8.

    Article  PubMed  CAS  Google Scholar 

  22. Yilmaz A, Duyar SS, Cakir E, Aydin E, Demirag F, Karakaya J, et al. Clinical impact of visceral pleural, lymphovascular and perineural invasion in completely resected non-small cell lung cancer. Eur J Cardiothorac Surg. 2011;40(3):664–70.

    PubMed  Google Scholar 

  23. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.

    Article  PubMed  CAS  Google Scholar 

  24. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for european patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.

    Article  PubMed  CAS  Google Scholar 

  25. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141–51.

    Article  PubMed  CAS  Google Scholar 

  26. Brandt WS, Bouabdallah I, Tan KS, Park BJ, Adusumilli PS, Molena D, et al. Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma. J Thorac Cardiovasc Surg. 2018;155(3):1212–24e3.

    Article  PubMed  Google Scholar 

  27. Park C, Lee IJ, Jang SH, Lee JW. Factors affecting tumor recurrence after curative surgery for NSCLC: impacts of lymphovascular invasion on early tumor recurrence. J Thorac Dis. 2014;6(10):1420–8.

    PubMed  PubMed Central  Google Scholar 

  28. Zhong WZ, Yan HH, Chen KN, Chen C, Gu CD, Wang J, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial. Signal Transduct Target Ther. 2023;8(1):76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Yue D, Xu S, Wang Q, Li X, Shen Y, Zhao H, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med. 2018;6(11):863–73.

    Article  PubMed  CAS  Google Scholar 

  30. Yue D, Xu S, Wang Q, Li X, Shen Y, Zhao H et al. Updated overall survival and exploratory analysis from Randomized, Phase II EVAN Study of Erlotinib Versus Vinorelbine Plus Cisplatin adjuvant therapy in stage IIIA epidermal growth factor receptor + non-small-cell Lung Cancer. J Clin Oncol. 2022:JCO2200428.

  31. Kulkarni AA, Naqash AR, Puri S, Dienstmann R. Is it Time to implement adjuvant targeted therapy in EGFR-Mutant Non-Small-Cell Lung Cancer? JCO Precis Oncol. 2021;5.

  32. Liu SY, Zhang JT, Zeng KH, Wu YL. Perioperative targeted therapy for oncogene-driven NSCLC. Lung Cancer. 2022;172:160–9.

    Article  PubMed  CAS  Google Scholar 

  33. Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohe C, et al. Overall survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023;389(2):137–47.

    Article  PubMed  CAS  Google Scholar 

  34. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552–9.

    Article  PubMed  Google Scholar 

  35. Zhang Y, Kang S, Fang W, Hong S, Liang W, Yan Y, et al. Impact of smoking status on EGFR-TKI efficacy for advanced non-small-cell lung cancer in EGFR mutants: a meta-analysis. Clin Lung Cancer. 2015;16(2):144–51. e1.

    Article  PubMed  CAS  Google Scholar 

  36. Kim IA, Lee JS, Kim HJ, Kim WS, Lee KY. Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs: a retrospective study. BMC Cancer. 2018;18(1):768.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tseng CH, Chiang CJ, Tseng JS, Yang TY, Hsu KH, Chen KC, et al. EGFR mutation, smoking, and gender in advanced lung adenocarcinoma. Oncotarget. 2017;8(58):98384–93.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Macari D, Ibironke O, Jinna S, Stender MJ, Jaiyesimi IA. Survival differences between smokers and nonsmokers with EGFR mutated non-small cell lung cancer. J Clin Oncol. 2020;38(15suppl):e21509–e.

    Article  Google Scholar 

  39. Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, et al. Gefitinib alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol. 2020;38(2):115–23.

    Article  PubMed  CAS  Google Scholar 

  40. Wu YL, John T, Grohe C, Majem M, Goldman JW, Kim SW, et al. Postoperative chemotherapy use and outcomes from ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC. J Thorac Oncol. 2022;17(3):423–33.

    Article  PubMed  CAS  Google Scholar 

  41. Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank each of the anonymous reviewers for taking the time to review our manuscript.

Funding

This research received no external funding.

Author information

Author notes

  1. Chieh-Lung Chen and Sing-Ting Wang contribute the article equally.

Authors and Affiliations

  1. Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 404327, Taiwan

    Chieh-Lung Chen, Wei-Chih Liao, Chia-Hung Chen, Chih-Yen Tu, Te-Chun Hsia, Wen-Chien Cheng & Hung-Jen Chen

  2. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, 404327, Taiwan

    Sing-Ting Wang

  3. School of Medicine, College of Medicine, China Medical University, Taichung, 404333, Taiwan

    Wei-Chih Liao, Chia-Hung Chen, Chih-Yen Tu, Te-Chun Hsia, Wen-Chien Cheng & Hung-Jen Chen

  4. Department of Life Science, National Chung Hsing University, Taichung, 40227, Taiwan

    Wen-Chien Cheng

  5. Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, 40227, Taiwan

    Wen-Chien Cheng

  6. Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 40227, Taiwan

    Wen-Chien Cheng

Authors
  1. Chieh-Lung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sing-Ting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei-Chih Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chia-Hung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chih-Yen Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Te-Chun Hsia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-Chien Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hung-Jen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, C.-L.C., S.-T.W., W.-C.C., and H.-J.C.; methodology, C.-L.C., W.-C.C., and H.-J.C.; software, W.-C.C.; validation, W.-C.C. and H.-J.C.; formal analysis, C.-L.C. and W.-C.C.; investigation, W.-C.C. and H.-J.C.; resources, C.-L.C., S.-T.W., W.-C.L., C.-H.C., C.-Y.T., T.-C.H, W.-C.C., and H.-J.C; data curation, C.-L.C., S.-T.W., W.-C.C.; writing—original draft preparation, C.-L.C., S.-T.W.; writing—review and editing, C.-L.C., S.-T.W., W.-C.C., and H.-J.C.; visualization, C.-L.C. and W.-C.C.; supervision, W.-C.C. and H.-J.C. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Wen-Chien Cheng or Hung-Jen Chen.

Ethics declarations

Ethics approval and consent to participate

The study adhered to the Declaration of Helsinki and followed the STROBE guidelines for reporting observational studies. The study was approved by the Investigational Review Board of the China Medical University Hospital (CMUH110-REC1-244) and the Institutional Review Board of China Medical University Hospital waived the need for informed consent from study subjects due to the retrospective design.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, CL., Wang, ST., Liao, WC. et al. A real-world study comparing perioperative chemotherapy and EGFR-tyrosine kinase inhibitors for treatment of resected stage III EGFR-mutant adenocarcinoma. BMC Cancer 23, 847 (2023). https://doi.org/10.1186/s12885-023-11342-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-023-11342-y

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us