Comparative study of perioperative and short-to-medium-term outcomes between thoracotomy and thoracoscopy after neoadjuvant therapy for stage IIB and IIIA non-small cell lung cancer

Introduction

Background

According to global cancer epidemiological data, lung cancer, one of the most malignant of all tumor types, ranks second in terms of incidence among malignant tumors, while its mortality rate continues to top all types of cancers (1). The latest statistics from the National Cancer Center indicate that lung cancer has simultaneously become the leading cause of both incidence and mortality among malignant tumors in China, representing the dual first-place status in both cancer incidence and mortality nationwide (2). Non-small cell lung cancer (NSCLC) constitutes approximately 80–85% of the pathological subtypes of lung cancer (3). Based on the evidence from multicenter clinical research, radical resection of lung cancer, as the first-choice radical treatment for early-stage NSCLC, demonstrates significantly superior efficacy compared to other treatment modalities. The 5-year survival rate of patients with early-stage NSCLC after anatomical lung resection is higher. However, according to epidemiological surveys, about 30% of newly diagnosed patients have progressed to locally advanced stage (stage III) at initial diagnosis, and the prognosis is poor, with a 5-year survival rate of about 15–38% (4,5). Because the clinical stage of such patients is usually beyond the indications for radical surgery, their overall prognosis is poor.

Rationale and knowledge gap

Preoperative evaluation revealed that for some patients with stage IIB, factors such as extensive local tumor infiltration, specific anatomical locations, and concurrent N1 regional lymph node metastasis significantly increase the difficulty of performing radical resection. As a result, such cases do not currently meet the criteria for radical surgery. Over the past decade, the treatment paradigm for advanced NSCLC has undergone significant transformation. Patients suitable for individualized treatment regimens such as targeted therapy, immune checkpoint inhibitors (ICIs) combined with chemotherapy, and other approaches can be precisely identified among patient populations through biomarker testing. It is noteworthy that, based on data from large phase III clinical trials, neoadjuvant therapy has been proven to significantly enhance the resection rate of locally advanced NSCLC patients through downstaging treatment, and improve key prognostic indicators such as overall survival (OS) and recurrence-free survival (RFS) (6-8).

As the core strategy of comprehensive treatment for locally advanced lung cancer, the neoadjuvant therapy model is based on precise molecular biological characterization of tumors. Through multimodal interventions, including the cytotoxic effects of chemotherapy drugs, pathway inhibition by targeted drugs, and modulation of the tumor immune microenvironment via ICIs, it achieves reduction in primary tumor volume, clinical downstaging, and clearance of micro-metastatic foci, thereby enhancing the possibility of radical resection (R0) and improving long-term prognosis (9). With the widespread application of neoadjuvant therapy in clinical practice, the research controversy surrounding its surgical pathway has continued to escalate. Relevant studies have shown that neoadjuvant therapy may lead to tissue fibrosis, increased vascular fragility, local tissue edema, or pleural adhesions, which increase the difficulty of surgery after treatment (10-13).

Objective

At present, there are few studies on neoadjuvant therapy after surgery. This study retrospectively collected the clinical data of patients with middle to advanced stages (IIB and IIIA) of NSCLC who had received neoadjuvant therapy before surgery, and preliminarily analyzed the perioperative results and early and intermediate-term efficacy of NSCLC patients after receiving neoadjuvant therapy, thereby providing a reference for the postoperative efficacy of neoadjuvant therapy in patients with stage IIB and IIIA NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-820/rc).

Methods

Inclusion and exclusion criteria

This study retrospectively collected clinical data on patients who underwent video-assisted thoracoscopic surgery (VATS) and thoracotomy after neoadjuvant therapy at The Affiliated Hospital of Qingdao University from October 2018 to June 2021. Inclusion criteria were as follows: patients with stage IIB and stage IIIA NSCLC who underwent neoadjuvant therapy (single drug or combination therapy) including chemotherapy, immunotherapy, and targeted therapy after preoperative pathological diagnosis. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Affiliated Hospital of Qingdao University (No. QYFYWZLL29737), and informed consent was obtained from all individual participants.

Exclusion criteria: (I) incomplete clinical or radiological information; (II) loss of follow-up via phone after surgery; (III) previous history of lung surgery; (IV) recurrent NSCLC; (V) N3 or distant metastasis; (VI) preoperative radiotherapy; (VII) readmission within 30 days after surgery.

Neoadjuvant therapy and evaluation

All patients underwent preoperative pathological examinations, including bronchoscopic biopsy or computed tomography (CT)-guided lung biopsy. Routine preoperative evaluations included chest CT scans, brain CT scans or magnetic resonance imaging, B-mode ultrasound scans of the liver, gallbladder, pancreas, spleen, and adrenal glands, as well as lung function tests. If the longest diameter of the patient’s lymph node exceeded 10 mm, selective procedures such as bronchial ultrasound-guided transbronchial fine-needle aspiration or mediastinoscopy were performed for preoperative N staging. All diagnosed patients underwent 2–6 cycles of neoadjuvant therapy, with chemotherapy drugs using PP regimen (pemetrexed + platinum), TP regimen (taxanes + platinum), or GP regimen (gemcitabine + platinum). The immunotherapy drug is an ICI, including tremelimumab (200 mg, ivgtt, d1) and cediranib (200 mg, ivgtt, d1), which are primarily used in combination with chemotherapy. Targeted drugs are selected based on the patient’s driver gene. After the patient completes 2–6 cycles of neoadjuvant therapy, the surgical team assesses the patient’s surgical indications through multidisciplinary consultations. After excluding surgical contraindications, surgical treatment is implemented.

The postoperative care by professionals from the Department of Pathology at The Affiliated Hospital of Qingdao University. The major pathological response (MPR) is defined as residual tumor cells accounting for ≤10% of the total in the pathological assessment of tumor regression induced by neoadjuvant therapy. The pathological complete response (pCR) is defined as no evidence of tumor cell survival in the resected tumor or lymph node (14). After neoadjuvant therapy for NSCLC, the pathological staging is based on the American Cancer Society’s 8th edition tumor-nodes-metastasis (TNM) staging system. In the T staging, the tumor size is adjusted to the size of the residual tumor. The N staging needs to be classified according to the presence or absence of tumor cells in the lymph nodes.

Surgical treatment

After neoadjuvant therapy, patients were deemed eligible for surgery after discussion by a multidisciplinary team including surgeons. Based on the surgical approach, patients were divided into two groups: the VATS group, which received thoracoscopic surgery, and the thoracotomy group, which underwent traditional thoracotomy. The surgical resection method was tailored according to each patient’s condition. All patients underwent radical surgery, which involved removing the tumor and negative surgical margins (bronchial, arterial, venous, peribronchial, and adjacent tumor tissues), as well as clearing the mediastinal lymph nodes. R0 refers to negative microscopic margins, R1 refers to positive microscopic margins, and R2 indicates macroscopic residual tumor. All specimens were sent to the pathology department after resection for pathological examination, and the pathological response was evaluated based on the pathological results, followed by postoperative staging.

Interpretation of results

Due to the focus of this study on postoperative clinical outcomes, the OS of patients was calculated from the date of surgery to the date of death from any cause or the date of last contact. During hospitalization, variables related to perioperative outcomes were assessed (see Tables 1-4 for details). Follow-up data originated from outpatient medical records or telephone interviews.

Statistical analysis

Continuous variables following a normal distribution were described using the mean ± standard deviation, and comparisons between means were conducted using an independent two-sample t-test. Data following a skewed distribution were described using the median (with the upper and lower quartiles), and inter-group comparisons were conducted using the Mann-Whitney U test. Categorical variables were described using frequency and percentage (%), and inter-group comparisons were conducted using the Chi-squared test or Fisher’s exact test. The Kaplan-Meier method is employed to compare survival data between two groups. The Cox regression model is used to calculate the relative risk and 95% confidence interval for each prognostic factor. Statistical analysis of this analysis is conducted using R language; all reported probabilities (P values) were two-sided, and P≤0.05 was considered as significant. Propensity score matching is performed using the “matchit” function in R language, with the matching method set to “nearest” and a matching ratio of 1:1.

Results

Baseline characteristics of patients

This study included a total of 107 patients with NSCLC in preoperative assessment stages IIB and IIIA. Among them, 77 (71.9%) were male and 30 (29.1%) were female. The average age of all patients was 60.50±6.23 years. Sixty-four patients (59.8% of the total) had a history of smoking. The pathological types were adenocarcinoma (72.0%) and squamous cell carcinoma (28.0%). The American Society of Anesthesiologists (ASA) scores were either 1 (18.7%) or 2 (81.3%). According to the Eastern Cooperative Oncology Group (ECOG) functional status score, 70 cases (65.4%) were scored as 0, and 37 cases (34.6%) were scored as 1. The average length of the tumor before surgery was 3.80 centimeters. The distribution of tumor locations was as follows: left upper (24.3%), left lower (19.6%), right upper (25.2%, slightly higher proportion), right middle (10.3%), and right lower (20.6%). Preoperative staging revealed 24 cases (22.4%) at stage IIB and 83 cases (77.6%) at stage IIIA. Based on individual patient conditions, three surgical approaches were implemented: lobectomy in 82 cases (76.6%), sleeve lobectomy in 16 cases (15.0%), and pneumonectomy in 9 cases (8.4%). Neoadjuvant therapies included chemotherapy alone in 8 cases (7.5%), immunotherapy alone in 1 case (0.9%), chemotherapy plus immunotherapy in 45 cases (42.1%), targeted therapy alone in 28 cases (26.2%), and chemotherapy plus targeted therapy in 25 cases (23.4%). Forty-six patients (43.0%) achieved major pathologic response (MPR), 52 patients (48.6%) did not achieve MPR, and 9 patients achieved pCR (8.4%). All patients underwent radical resection, with R0 margins. Based on the surgical approach, patients were divided into the thoracotomy group (41 cases) and the VATS group (66 cases), with 4 patients requiring conversion to thoracotomy intraoperatively. Due to statistical differences in forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) and tumor diameter between the two groups, propensity matching was performed to eliminate the influence of confounding factors. After matching, there were 41 patients in the thoracotomy group and 1 in the VATS group. The differences in baseline data between the two matched groups were not statistically significant, as detailed in Tables 1,2.

Intraoperative and pathological results of patients

In terms of intraoperative process, the VATS group had less blood loss (P<0.001) and a shorter operation time (P<0.001). There were no statistically significant differences between the two groups in terms of the number of lymph node dissections conducted during the surgery, the classification of positive lymph nodes post-surgery, and the pathological T, N, and TNM staging after surgery (P>0.05) (Table 3).

Postoperative data and complications

There were statistically significant differences in postoperative drainage volume between the open group and the VATS group on postoperative days 1–3 (P<0.05), with the VATS group exhibiting a lower postoperative drainage volume. Additionally, the VATS group had shorter postoperative drainage duration (P=0.003) and postoperative hospital stay (P<0.001). Furthermore, between the thoracotomy group VATS group, there were no statistically significant differences in postoperative complications, including pulmonary infection, bronchopleural fistula, arrhythmia, persistent air leakage (≥7 days), empyema, chylothorax, pulmonary embolism, respiratory failure, and heart failure (P>0.05) (Table 4).

Follow-up and survival analysis

The 1-year survival rate for patients in both groups (n=82) was 100%, and the 3-year survival rate of 64.63%. For patients in the VATS group (n=41), the 1-year survival rate was 100% and the 3-year survival rate was 68.29%. For patients in the open group (n=41), the 1-year survival rate was 100% and the 3-year survival rate was 60.98%. There was no significant difference in survival rate between two groups (χ²=0.667, P=0.41) (Figure 1).

Figure 1 Comparison of survival curves between the two groups of patients. VATS, video-assisted thoracoscopic surgery.

The 1-year survival rate for patients in both groups (n=82) was 100% and the 3-year survival rate was 64.63%. For patients in group IIB (n=17), the 1-year survival rate was 100%, and the 3-year survival rate was 66.15%. For patients in group IIIA (n=65), the 1-year survival rate was 100%, and the 3-year survival rate was 58.82%. No significant difference was observed in survival rate between two groups (χ²=0.506, P=0.48) (Figure 2).

Figure 2 Comparison of survival curves between the two groups of patients with TNM staging. TNM, tumor-nodes-metastasis.

Age, gender, FEV₁/FVC, smoking history, preoperative TNM stage, pulmonary resection method, and tumor diameter were gradually incorporated into the Cox regression model, with α in set at 0.05 and α out set at 0.10, for multifactor analysis. The results indicated that age, gender, FEV₁/FVC, smoking history, and tumor diameter were independent prognostic factors affecting NSCLC (Table 5).

Discussion

With the deepening of the concept of minimally invasive surgical procedures and the innovation of thoracoscopic technology, the application of VATS in lung cancer surgery has gradually become mainstream. In recent years, with the incorporation of the neoadjuvant therapy concept and the continuous refinement of treatment modalities, surgical treatment has also ushered in new opportunities (15,16). Neoadjuvant therapy serves to decrease tumor burden and enhance the R0 resection rate. Additionally, serving as an early systemic treatment, it can control micrometastatic lesions promptly. This presents more favorable conditions for surgical treatment and is expected to further improve the medium- and long-term survival rates of patients (17,18). As neoadjuvant therapy is increasingly used in patients with NSCLC, there is controversy over the selection of the optimal surgical approach after neoadjuvant therapy.

VATS and traditional thoracotomy each have their advantages and disadvantages. VATS boasts advantages such as minimal trauma, rapid recovery, mild postoperative pain, and little impact on respiratory function, which can reduce the incidence of postoperative complications, especially beneficial for patients with poor pulmonary function. However, VATS may have certain limitations when dealing with complex anatomical structures and large tumors, and it demands higher technical skills from the surgeon. Traditional thoracotomy has advantages when dealing with complex lesions, performing extensive lymph node dissection, and managing large blood vessels and vital organs. However, it involves greater trauma, heavier postoperative pain, longer recovery time, and a significant impact on patients' respiratory function and quality of life (19). Yang et al. reported that the postoperative drainage volume and hospital stay in the VATS group were significantly better than those in the open group after neoadjuvant therapy (11). Although neoadjuvant therapy increases the risk of pleural adhesions, edema, and fibrosis, which may increase the complexity of surgery and the likelihood of conversion to thoracotomy, especially for patients who have already shown significant therapeutic response. However, when handled meticulously, VATS can still achieve good surgical outcomes (20,21). The data from this study show that the VATS group was significantly superior to the Open group in terms of intraoperative blood loss, operation duration, postoperative hospital stay, postoperative drainage volume, and drainage duration (P<0.05). This may be closely related to the mechanisms of VATS, which include reducing chest wall trauma, decreasing inflammatory responses, and shortening pleural cavity exposure time. Open is often applied in more complex preoperative evaluations after neoadjuvant therapy due to the increased difficulty and complexity of lung and lymph node resection, resulting in a longer operation duration compared to VATS (P<0.05). There was no statistical difference in the incidence of postoperative complications between the two groups (P>0.05). This indicates that both surgical procedures can effectively control risks under standardized perioperative management.

In addition, research by Bott et al. indicates that neoadjuvant therapy can reduce the volume of the primary tumor, lower the tumor stage, decrease the invasion of surrounding blood vessels and bronchi, and decrease the complexity of surgery, thereby improving the resection rate (R0 resection rate) (10). Regarding the control of micrometastatic foci, preoperative treatment can eliminate circulating tumor cells or occult metastatic lesions, thereby reducing the risk of postoperative recurrence. All patients included in this study’s samples achieved R0 resection, indicating that the implementation of neoadjuvant therapy offers hope for radical cure for patients with advanced-stage disease. However, neoadjuvant therapy also potentially increases intraoperative risks for patients. Research by Cottrell et al. and Song et al. has shown that neoadjuvant chemotherapy can cause inflammation and fibrosis in the tissues surrounding the tumor, and fibrosis or calcification in lymph nodes, which obscures tissue layers and increases the difficulty of dissection (22,23). Another study has indicated that after neoadjuvant immunotherapy, more than half of patients who underwent minimally invasive surgery converted to thoracotomy (7/13, 54%), due to inflammation and fibrosis in the hilum (10). Furthermore, tumor regression after treatment may result in deformation or displacement of the original anatomical structures within the chest, thereby increasing the surgical difficulty. However, VATS can still be effectively utilized to complete the surgery (21). Sepesi et al. found that neoadjuvant chemotherapy combined with immunotherapy may lead to thinner and more brittle vascular walls around the tumor (12), especially when separating the hilar or mediastinal regions, thereby increasing the risk of major intraoperative bleeding. In this study, four patients underwent conversion to thoracotomy, two due to anatomical difficulties due to intraoperative changes in tissue structure, and two due to excessive intraoperative bleeding due to unclear pleural adhesion layers. The conversion rate was 5.6%, which is similar to a previous study (20). Romero found that the neoadjuvant treatment model combining chemotherapy and immunotherapy is safe for surgical resection of locally advanced stage IIIA NSCLC (24). The VATS method was used to treat 21 patients (51.2%), and the thoracotomy method was used to treat 20 patients (48.8%). Four patients (19%) in the VATS group underwent conversion to thoracotomy, and the postoperative prognosis was good. No neoadjuvant treatment was found to increase the rate of conversion to thoracotomy. This study cannot confirm a correlation between neoadjuvant treatment and an increased conversion rate. However, in terms of surgery duration, intraoperative blood loss, postoperative drainage volume, drainage duration, and hospital stay, the advantages and safety of VATS surgery after neoadjuvant treatment are demonstrated.

In recent years, multiple clinical studies have confirmed the efficacy of neoadjuvant therapy in stage IIB and stage IIIA lung cancer. For instance, the NADIM study demonstrated that neoadjuvant therapy combining immunotherapy and chemotherapy resulted in a high pCR and significant benefits in event-free survival (EFS) in stage IIIA patients (25). In addition, the CheckMate 816 trial further demonstrated that neoadjuvant immunotherapy combined with chemotherapy can significantly improve disease-free survival (DFS) and OS in patients with stage IIB-IIIA lung cancer. The study offers compelling evidence for the use of neoadjuvant therapy in locally advanced lung cancer (26). Through telephone follow-up, this study found no statistically significant difference (P>0.05) in the near-to-mid-term survival rate (1–3 years) OS between patients with stage IIB and IIIA lung cancer after surgical treatment. This outcome may be attributed to the significant downstaging effect of neoadjuvant therapy on tumors. Neoadjuvant therapy systematically eliminates micro-metastatic foci and reduces the size of the primary tumor, enabling patients with late preoperative stage IIIA to achieve a tumor burden status similar to that of patients with stage IIB, thereby narrowing the gap in survival rates between the two groups (27). In addition, neoadjuvant therapy may further narrow the prognostic differences among patients with different stages by improving the biological behavior of tumors (such as reducing tumor aggressiveness and metastatic potential) (28). Through the Cox regression model, we found that age, gender, FEV₁/FVC, smoking history, and tumor diameter are independent prognostic factors affecting NSCLC. The high incidence of lung cancer in males can be primarily attributed to the cumulative effects of smoking, occupational exposure, biological factors, social life, and psychological stress. According to the sample in this study, no statistically significant difference was found between stages IIB and IIIA. This may be related to our rationally tailored neoadjuvant therapy regimen and the thorough preoperative assessment and rational surgical planning by the surgical team, which enabled patients with stage IIIA to achieve similar short- and medium-term efficacy as those with stage IIB.

It is noteworthy that in this study, patients with advanced preoperative stage IIIA who underwent neoadjuvant therapy had similar survival rates to those with stage IIB after surgical treatment. This finding is of significant importance, as it suggests that neoadjuvant therapy not only improves the resection rate but may also, through systemic therapeutic effects, enable late-stage patients to achieve similar survival benefits as intermediate-stage patients. This result aligns with recent research trends on the application of neoadjuvant therapy in locally advanced lung cancer, emphasizing the potential value of neoadjuvant therapy in improving patient prognosis. In the future, with further optimization of neoadjuvant therapy strategies, the survival rate of late-stage patients is expected to further improve, bringing hope for long-term survival to more patients.

The sample size in this study is relatively small, lacking a comparative analysis of the long-term survival rates over 3 years for the two surgical procedures. Further large-sample data support and exploration of new adjuvant therapy modalities are still needed.

Conclusions

After neoadjuvant therapy for lung cancer, the perioperative outcomes of VATS surgery are superior to those of thoracotomy, and postoperative recovery is faster. There is no difference in short- and medium-term survival rates between the two surgical methods. With appropriate neoadjuvant therapy and surgical planning, patients with stage IIIA disease may achieve postoperative treatment outcomes similar to those of patients with stage IIB disease, demonstrating considerable short- and medium-term efficacy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-820/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-820/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-820/prf

Funding: This study was funded by the Scientific research project of Weifang Municipal Health Commission (No. WFWSJK-2025-349, to K.G.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-820/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 and its subsequent amendments. The study was approved by the Ethics Committee of The Affiliated Hospital of Qingdao University (No. QYFYWZLL29737), and informed consent was obtained from all individual participants.

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/.

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