Pneumonectomy after neoadjuvant immunotherapy combined with chemotherapy is a safe and effective option for central non-small-cell lung cancer patients, a single-center experience

Introduction

Lung cancer continues to be one of the most prevalent malignant tumors worldwide. For resectable locally advanced non-small cell lung cancer (NSCLC), multimodality therapy is now the primary treatment option for oncologists. The rapid advancement of multimodality treatment has led to significant changes in surgical approaches to lung cancer. Considerable advanced NSCLC patients have been downstaged and could be radically resected with lobectomy and sleeve resection of the lung. However, in cases where the bronchial tumor is located in the main bronchus or the proximal middle bronchus, or across the large interlobular fissure of the lung and adjacent to the bronchial opening of the upper lobe of the right lung, pneumonectomy is preferred over less extensive resections such as lobectomy (1). Despite the development of surgical techniques, higher morbidity and mortality following pneumonectomy present significant challenges for surgeons. Along with a marked reduction in patient survival after the surgery, complications such as bleeding, bronchopleural fistula, and postoperative empyema are among the more prevalent and life-threatening occurrences (2,3). In a recent study investigating the safety profile of neoadjuvant immunotherapy combined with chemotherapy in NSCLC, the incidence of bronchopleural fistula was observed to be higher than previously reported. The investigators hypothesized that prolonged inflammatory cell infiltration and more severe necrosis induced by immunotherapy may contribute to bronchopleural fistula pathogenesis, underscoring the clinical importance of evaluating the optimal interval between surgical intervention and immunotherapy administration (4).

Nevertheless, the safety and practicality of surgery following neoadjuvant therapy remain a concern. Existing research confirms that neoadjuvant immunotherapy does not result in a higher risk during conventional lobectomy (5,6). However, no current study has been conducted to comprehensively assess the safety and practicality of pneumonectomy following neoadjuvant therapy. Therefore, this study aims to evaluate the efficacy of neoadjuvant treatment in patients who required pneumonectomy, with a special focus on the impact of neoadjuvant immunotherapy on patient prognosis. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1923/rc).

Methods

Patients

We conducted a retrospective analysis of NSCLC patients who underwent surgical treatment at Zhongshan Hospital of Fudan University from 2014 to 2022, and identified those who underwent pneumonectomy. As a retrospective analysis, we identified patients who underwent pneumonectomy for stage IB–IIIB NSCLC. The neoadjuvant treatment group received immunotherapy, which could be combined with chemotherapy, while the non-induction treatment group underwent pneumonectomy alone. Patients with other significant comorbidities or a history of other malignancies were excluded. Ultimately, we identified 149 eligible patients, 32 of whom received neoadjuvant therapy, including immunotherapy and chemotherapy. Twenty patients received chemotherapy and 11 patients received immunotherapy with chemotherapy, and 1 patient’s therapy was unknown (Figure 1).

Figure 1 Flowchart of the study design.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University (No. B2021-128 on 2023-01-09). Written informed consent was obtained from the patients for the use of surgical samples and clinical information for medical research.

Statistical analysis

In this investigation, we aimed to evaluate the impact of neoadjuvant therapy on the prognosis of patients undergoing pneumonectomy. Patients were categorized based on whether they received neoadjuvant therapy or not, and the disparity in prognosis between the two groups was assessed with Kaplan-Meier (K-M) survival analysis tested by log-rank. To eliminate the influence of confounding variables on the variation in prognosis between groups, we employed propensity score matching (PSM) to match a subset of the overall sample with no statistically significant distinction in confounding factors between groups. We utilized the “MatchIt” package (7) in the R language to conduct PSM using nearest neighbor matching and logit distance calculation. This process resulted in the creation of pairs of the most similar individuals between the treatment and control groups based on the proximity of the propensity scores, thus mitigating the impact of confounders.

Results

Patients

After screening NSCLC patients who underwent surgical treatment at Zhongshan Hospital from 2014 to 2022, 149 patients who had undergone pneumonectomy were identified. These patients were then classified into two groups based on whether they received neoadjuvant therapy: the no-induction therapy group (Group 1, N=117) and the induction therapy group (Group 2, N=32). Twenty patients received chemotherapy and 11 patients received immunotherapy with chemotherapy, 1 for unknown therapy. The flow chart of the study is shown in Figure 1. The characteristics of the patients are summarized in Table 1. Notably, the majority of patients were male (N=135, 90.6%) and squamous cell carcinoma (N=112, 75.2%).

There was a substantial variation in the distribution of these patients in terms of clinical stage, with Group 1 having a higher number of patients at stages I–II, whereas Group 2 had a greater number of patients at stages III–IV (P<0.05). To reduce the impact of data bias and confounding factors, we used PSM to match the induced treatment and non-induced treatment patients. A total of 22 pairs of NSCLC patients were obtained, and no significant statistical differences were found between the two groups (Table 2). We conduct hypothesis tests to determine whether the mean differences between the treatment and control groups are significantly reduced after matching, thereby evaluating the effectiveness of the matching. The standardized mean difference (SMD) is 0.073.

Neoadjuvant therapy efficiency

The mean overall survival (OS) for all patients enrolled in the research was 38 months, and the 1-, 3-, and 5-year OS were 91.2%, 71.3%, and 65%, respectively (Figure 2A). There was no statistically significant difference in OS between the two groups (P=0.32, P=0.16, and P=0.19, respectively). After PSM, the mean OS was 27 months, with a 1-, 3-, and 4-year OS of 81.8%, 55.6%, and 44.3%, respectively. Although there still was no significant difference in survival between the two groups after PSM (P=0.11, P=0.23, and P=0.37, respectively, Figure 2B), we did observe a better survival curve in patients who underwent neoadjuvant therapy compared to those who did not. According to previous studies and past clinical experience, pneumonectomy is a surgical procedure that requires high patient physical condition and is associated with significant trauma. With the progress of treatment modalities, pneumonectomy has gradually decreased in recent years. Therefore, only a small number of cases were obtained in our center, leading to the failure to achieve statistically significant study results.

Figure 2 Survival of the patients. (A) The mean OS for all patients enrolled in the research. (B) The OS for patients after PSM. CI, confidence interval; IT, induction therapy; OS, overall survival; PSM, propensity score matching.

Furthermore, in induction group, the postoperative pathology findings indicated significant pathological downstaging compared with initial clinical stage (Figure 3A,3B). Upon further subgroup analysis, patients who received a combination of neoadjuvant immunotherapy and chemotherapy showed improved prognosis (Figure 3C). Meanwhile, a higher rate of reduction in pathological stage was observed in chemo-immunotherapy group (Figure 3D), compared to neoadjuvant chemotherapy only.

Figure 3 Efficacy evaluation of neoadjuvant therapy. (A) Comparative analysis of pre- versus post-treatment tumor staging. (B) Treatment response assessment. (C) Survival outcomes between chemotherapy and chemoimmunotherapy regimens. (D) Therapeutic efficacy comparison of chemotherapy versus chemoimmunotherapy. CI, confidence interval; HR, hazard ratio.

Surgery safety

To evaluate the impact of neoadjuvant therapy on surgical safety, we conducted a comparative analysis of postoperative morbidity and mortality between the two groups. The overall morbidity, mortality, and 90-day mortality rates were 16.1%, 0%, and 0% respectively (Table 3). In group 1, the morbidity rate was 17.1%, predominantly due to atrial fibrillation, while in group 2, the rate was 12.5%, with one instance of each type of morbidity observed. Surgical trauma and perioperative inflammatory responses are significant triggers for the development of postoperative atrial fibrillation (POAF). Direct manipulation of the atria and pericardium during surgery can cause localized inflammation, which in turn leads to changes in atrial electrical excitability. Neoadjuvant immunotherapy may reduce the incidence of POAF by modulating the immune system and thereby attenuating the inflammatory response. Additionally, patients in the non-induction group, who may have a higher tumor burden, are at increased risk of POAF due to structural changes in the atria (such as atrial dilation) and functional impairment. Surgical stress can activate the autonomic nervous system, leading to increased catecholamine secretion, which may induce arrhythmias. Neoadjuvant treatment may reduce the incidence of POAF by alleviating surgical stress and thereby reducing the overactivation of the autonomic nervous system. No statistically significant difference in incidence was observed between the two groups (P>0.05). These findings indicate that pneumonectomy after neoadjuvant therapy is safe and feasible with no significant increase in surgical morbidity and mortality.

Discussion

Pneumonectomy remains an unavoidable procedure for specific cases. However, high postoperative complications, ranging from 5% to 10% for 30-day postoperative complication rates (8), also require special focus. Despite the significant decrease in complication rates over the past 30 years, there has not been a substantial decline in mortality following pneumonectomy. A US National Database study reported a 30-day mortality rate of 5.6% in 2007 and 5.9% in 2014 (9). In our research, we found that neoadjuvant therapy led to a better prognosis and a significant reduction in disease stage, indicating the effectiveness of this approach. Furthermore, the subsequent surgery did not result in increased mortality or morbidity.

Tumor treatment has transitioned into the era of immunotherapy, with neoadjuvant therapy, particularly neoadjuvant immunotherapy, significantly decreasing the risk of disease recurrence, progression, and mortality. The CheckMate-816 study further cements the standard status of the combined neoadjuvant treatment approach in the domain of comprehensive surgical treatment for NSCLC. The research was conducted to assess the effectiveness and safety of nivolumab combined with chemotherapy as neoadjuvant treatment for stage IIIA NSCLC with a pathological complete response (pCR) of 24% and major pathological response (MPR) of 36.9% (5). The pooled rate of MPR was up to 53.8% in a systematic review and meta-analysis included 53 trials (10).

According to our study findings, patients in the induction therapy group (those who received neoadjuvant immunotherapy or chemotherapy) were observed to have relatively more advanced disease stages compared to those in the non-induction therapy group (patients who did not receive neoadjuvant treatment). Typically, patients with more advanced stages are associated with poorer prognosis, which may lead to anticipated inferior therapeutic efficacy and increased surgical risks, as well as a higher incidence of complications. Therefore, to balance these differences, we employed PSM to avoid potential biases. We acknowledged that pre-PSM imbalances (e.g., more advanced stages in the no-induction group) could reflect real-world treatment patterns, but PSM mitigated confounding.

Although neoadjuvant therapy improves the prognosis and shows a significant downstage for patients with NSCLC, the postoperative complication risk of pneumonectomy after neoadjuvant therapy remains controversial. Samancilar et al. considered neoadjuvant chemotherapy as a risk factor for bronchopleural fistula after pneumonectomy (11). Under the European Society of Thoracic Surgeons (ESTS) database, Brunelli et al. found that incidence of cardiopulmonary complications was higher in the neoadjuvant group, chemotherapy alone or chemoradiotherapy after neither lobectomy (P<0.001) nor pneumonectomy (P=0.03). However, no correlation between neoadjuvant therapy and perioperative mortality was detected between the two groups (12).

Theoretically, effective neoadjuvant therapy has the potential to reduce the size of the primary tumor, tumor stage, and lymph node involvement. As a result, researchers speculate that neoadjuvant therapy could minimize the extent of surgical resection, lessen the surgical complexity, and enhance the probability and safety of surgical resection. In fact, the surgical resection rate following neoadjuvant immune monotherapy or combination chemotherapy ranges between 75–95% (5,13,14), which is comparable to the 70–90% range for neoadjuvant chemotherapy (15,16). Additionally, the incidence of surgical complications is estimated to be around 10–30% (14-18), lower than the 40–50% probability of surgical complications after neoadjuvant chemotherapy (19,20).

Twenty-six (87%) patients in the NADIM study underwent R0 surgical resection, and no surgical complications related to neoadjuvant therapy were observed (21). The research conducted by Zhu et al. demonstrated that neoadjuvant immunotherapy led to enhanced MPR and pCR rates. In this research, 29 patients (96.67%) underwent lobectomy and 1 patient (3.33%) underwent pneumonectomy, and no more postoperative complications were observed during immunotherapy (22).

The Checkmate 816 trial compared neoadjuvant nivolumab combination with neoadjuvant chemotherapy. The pCR rate was 24.0% [95% confidence interval (CI): 18.0–31.0] in the combination therapy group and 2.2% (95% CI: 0.6–5.6) in the chemotherapy-alone group, [odds ratio (OR) =13.94; 95% CI: 3.49–55.75; P<0.001]. Overall, the surgical outcomes of nivolumab combination chemotherapy were superior to those of the chemotherapy-alone group. As evidenced by the CheckMate 816 trial, neoadjuvant nivolumab combined with chemotherapy demonstrates a statistically significant improvement in event-free survival (EFS) and a higher proportion of pCR compared to chemotherapy alone in patients with resectable NSCLC. Importantly, the addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or compromise surgical feasibility. However, this study did not evaluate the efficacy or safety outcomes specific to pneumonectomy following neoadjuvant immunotherapy, leaving a critical gap in understanding postoperative outcomes in this high-risk surgical subset. Even though 59 patients underwent total pneumonectomy in this trial, no comprehensive analysis was conducted on this topic (5). Our study uniquely evaluates pneumonectomy—a higher-risk procedure—after neoadjuvant immunotherapy.

Previous studies have not addressed the assessment of surgical safety of total pneumonectomy after neoadjuvant immunotherapy. In our investigation, we focus on the safety and efficacy of pneumonectomy. We conducted a retrospective analysis of 149 patients with NSCLC who underwent pneumonectomy following evaluation by thoracic surgeons. Among these patients, 32 underwent preoperative neoadjuvant therapy, among which 20 patients received chemotherapy and 11 patients received immunotherapy with chemotherapy, and 1 for unknown therapy. When the survival of these patients who underwent neoadjuvant therapy was assessed, it was observed that those who had neoadjuvant therapy experienced improved survival. In subgroup analyses, patients who received neoadjuvant immunotherapy along with chemotherapy showed better survival compared to those who received only neoadjuvant chemotherapy. Although statistical significance was not achieved, there was a tendency towards improved survival, likely due to the limited amount of data and the shorter follow-up duration. These results trend in line with the Checkmate 816 results (23).

Upon evaluating the safety of the procedure, we found no evidence that neoadjuvant immunotherapy resulted in an increase in surgical morbidity or mortality. Beattie et al.’s research involved 37 NSCLC patients, with 49% at stage IIIB and IV, 46% receiving immunotherapy alone, and 54% receiving combined immunotherapy with chemotherapy and/or radiotherapy. From a surgical perspective, 11 patients underwent pneumonectomy, with a 90-day mortality of 0%, which was consistent with our result. This retrospective study illustrated the possibility and safety of extensive surgery following immunotherapy for NSCLC, despite the majority of patients having advanced-stage disease necessitating complex resection (24).

There are certain constraints in our research. Firstly, being a retrospective study, it limits and influences the ability to analyze all variables. Predominantly, preoperative staging was conducted using imaging. Furthermore, the study was confined to advancements in surgical techniques with a small sample size and a brief follow-up period. In the future, we aim to conduct prospective studies to minimize the aforementioned biases and delve deeper into the subject.

Conclusions

In our research, we found that neoadjuvant therapy led to a better prognosis and a significant reduction in disease stage, indicating the effectiveness of this approach. Furthermore, the subsequent surgery did not result in increased mortality or morbidity, indicating that pneumonectomy after neoadjuvant therapy for NSCLC is a safe and effective option for patients with locally advanced disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1923/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1923/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1923/prf

Funding: This work was supported by the Natural Science Foundation of Shanghai (Nos. 20ZR1410800 and 22ZR1410700).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1923/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. This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University (No. B2021-128 on 2023-01-09). Written informed consent was obtained from the patients.

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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