Influence of neoadjuvant immunotherapy on surgical approaches in non-small cell lung cancer: insights from a Chinese Expert Questionnaire Survey on Contemporary Practices

Introduction

Immunotherapy has shattered the therapeutic ceiling once imposed by systemic chemotherapy in the management of metastatic non-small cell lung cancer (NSCLC) (1-3). Surgical resection remains the bedrock of treatment for operable NSCLC. The CheckMate 816 trial heralded significant success with neoadjuvant immunotherapy, paving the way for its anticipated integration as the standard of care for locally advanced resectable NSCLC devoid of driver mutations (4). Consequently, the United States Food and Drug Administration (FDA) has approved the employment of neoadjuvant nivolumab in synergy with chemotherapy.

The depiction of intraoperative outcomes within the CheckMate-816 trial is succinct—indicating reduced surgical duration, a higher incidence of minimally invasive procedures, and no discernible increase in complications—suggesting that neoadjuvant immunotherapy does not adversely influence the technical demands of surgery. However, the patient demographic encompassed by clinical trials does not invariably mirror the heterogeneous nature of the real-world setting. In routine clinical practice, there tends to be a lower representation of early-stage patients and a higher prevalence of stage III cases. The potential for increased surgical complexity remains an open question, one that is best addressed by the subjective experiences of the surgeons themselves. To this end, we devised a questionnaire to investigate the impact of neoadjuvant immunotherapy on surgical complexity and to elucidate the concerns paramount to thoracic surgeons. This survey was conducted through a specialized thoracic surgery group on WeChat, China’s ubiquitous social networking platform. We present this article in accordance with the SURGE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1376/rc).

Methods

Study design and participants

This investigation entailed a national electronic survey executed in May 2022. The instrument was disseminated to a dedicated group of 300 thoracic surgery professionals via WeChat, a prevalent Chinese social networking application. Experts were identified based on the thoracic surgery expert committee rosters from each province and municipality. To ensure balanced representation, the country was stratified into eastern, central, and western regions. Within each region, further stratification was performed according to secondary and tertiary hospitals. Invitations were then extended to the selected experts via WeChat. Data collection was facilitated through an internet-based survey interface hosted on www.wjx.cn, a prominent online crowdsourcing service in mainland China.

Participants were apprised that the survey would necessitate approximately 10 to 15 minutes for completion. No incentives were proffered for participation. Prior to engaging with the survey content, respondents were required to affirm their experience in performing surgical procedures on lung cancer patients’ post-neoadjuvant immunotherapy.

Survey creation and content

For the execution of this study, a bespoke survey questionnaire was devised, drawing upon previously established expert consensus regarding neoadjuvant immunotherapy for NSCLC (5,6). The questionnaire was appended as supplementary material (Appendix 1). The initial draft of the survey was developed collaboratively with contributions from several co-authors. It underwent a validation process with a select group of thoracic surgeons, during which the narrative, content, and sequence were meticulously optimized through successive iterations over a fortnight. Surgeons involved in the survey’s development and refinement were precluded from partaking in the definitive study.

The dataset encompassed demographic details, management predilections, preoperative assessments, intraoperative protocols, and postoperative occurrences to evaluate surgical inclinations and the perceived complexity of surgery following neoadjuvant immunotherapy. The survey was structured into five distinct segments. The initial segment solicited information on practice characteristics, encompassing details of the institution and duration of professional practice. The subsequent segment delved into clinical caseloads and treatment proclivities for the preliminary assessment of NSCLC patients undergoing neoadjuvant immunotherapy. The third segment was dedicated to preferences in surgical management, while the fourth segment probed into perceptions of the intraoperative milieu. The concluding segment concentrated on experiences with postoperative events.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Institutional Review Board of Shanghai Chest Hospital (No. KS24010), which served as the leading institution. For multicenter questionnaire-based studies, only the principal institution is required to obtain IRB approval under national regulations, and all participating centers followed the approved protocol. Written informed consent was waived because the anonymous survey did not involve patients, personal health information, or sensitive identifiers. Participation was voluntary, and completion of the questionnaire was regarded as implied consent.

Statistical analysis

Descriptive statistics were reported as counts and percentages for categorical variables, and as appropriate measures for nonparametric data. We also employed a multivariate logistic regression model to analyze the correlation between surgical complexity, perioperative adverse events and the surgeon’s experience and facility characteristics. Analytical procedures were conducted utilizing Excel version 16.55 and SPSS version 26.0.

Results

The survey was completed by 267 participants, resulting in an estimated response rate of 89.0% out of the 300 targeted respondents. However, 12 surgeons were residents and 5 surgeons indicated a lack of surgical experience with NSCLC post-neoadjuvant immunotherapy, culminating in 250 valid responses for analysis.

Demographics of respondents

The cohort of respondents spanned 25 distinct provinces out of the total 34 provincial-level administrative divisions in China. The majority of the respondents (208, 83.2%) were fully qualified, independently practicing thoracic surgeons, having completed their specialist training. The remainder were fellows serving in an assistant capacity during post-neoadjuvant immunotherapy procedures. Table 1 provides a detailed breakdown of the respondents’ thoracic surgical experience and their respective case volumes. The preponderance of surgeons within this study would be classified as “high-volume” practitioners (82.0% reported annual case volumes exceeding 100, with 24.0% handling more than 500 cases per year), operating within institutions that are similarly regarded as “high-volume” centers for thoracic surgery (71.6% reported institutional annual case volumes surpassing 1,000).

Surgical perspective of neoadjuvant immunotherapy

A substantial majority (86.4%) of the respondents commenced conducting surgeries for NSCLC subsequent to neoadjuvant immunotherapy post-2019. Among them, 16.8% reported performing over 50 cases, 36.0% had conducted between 11 to 50 cases, and 47.2% had completed fewer than 10 cases. Notably, 52.8% of the surgeons had experience with more than 10 cases. Table 2 indicated that approximately half (46.4%) of the survey respondents favored administering neoadjuvant immunotherapy to patients with stage IIIA/IIIB NSCLC, while 23.2% and 26.4% respectively opted for patients at stage IIIA or stages II–IIIA. A minority of 4% selected patients at stage IB–IIIA. The respondents identified the potential for achieving an R0 resection (89.6%), the presence of lymph node metastasis (86.0 %), and tumor size (64.4%) as primary factors in the decision to employ neoadjuvant immunotherapy prior to surgery. Additionally, nearly half (44.4%) of the respondents considered patient acceptance as a significant factor.

The preponderance of respondents indicated a preference for utilizing neoadjuvant immunotherapy in patients presenting with hilar or mediastinal lymph node metastasis. Close to half (46.4%) would opt for neoadjuvant immunotherapy specifically in cases involving N2 lymph node metastasis. A significant majority (91.6%) reported the routine incorporation of positron emission tomography-computed tomography (PET-CT) in the preoperative assessment of mediastinal lymph nodes, while 42.4% employed endobronchial ultrasound (EBUS) or mediastinoscopy for evaluating mediastinal lymph nodes, either as a complement to or in the absence of PET-CT imaging.

Over three-quarters (75.6%) of the respondents were inclined to choose patients with centrally located tumors for neoadjuvant immunotherapy. Nearly half (45.2%) reported encountering severe immune-related adverse events (irAEs) during the neoadjuvant immunotherapy period, which necessitated postponement or cancellation of the planned surgical intervention. Among patients with negative driver gene mutations who are candidates for neoadjuvant therapy, a majority (59.2%) of the respondents favored neoadjuvant immunotherapy, while 34.0% advocated for a deliberation through a Multi-Disciplinary Team (MDT) approach.

Surgical strategy

Table 3 provides that the predominant share of respondents (81.2%) elected to conduct surgery within a 4–6-week window following neoadjuvant immunotherapy. A smaller fraction opted for a shorter interval of less than 4 weeks (10.8%) or an extended period beyond 6 weeks (8.0%). The consensus (66.0%) among participants was that surgical strategy post-neoadjuvant immunotherapy should be tailored to the individual patient’s condition. Herein lies the dilemma of neoadjuvant immunotherapy. Most surgeons would say that there is a wide range of effects on the tissues, leading to a wide range of technical challenge. Some cases are fairly routine while some cases are very challenging.

An overwhelming majority of respondents (86.0%) indicated that lobectomy constitutes the most frequent surgical intervention subsequent to neoadjuvant immunotherapy, while 13.2% reported a higher prevalence of sleeve lobectomy within their respective institutions.

Intraoperative impact

In addressing the question of whether neoadjuvant immunotherapy extends the duration of surgery relative to identical procedures without such therapy, respondents were divided: 36.0% perceived an increased operative time, 31.2% reported no significant difference, and 31.6% remained neutral on the matter in Table 4.

Concerning the comparison of intraoperative bleeding in surgeries following neoadjuvant immunotherapy to those without, a majority of the respondents (61.2%) considered the bleeding to be comparable. Approximately one-sixth (14.8%) believed that neoadjuvant immunotherapy resulted in increased bleeding, while over one-fifth (20.4%) felt that bleeding variability was contingent upon patient-specific conditions.

When queried about the relative difficulty of surgeries post-neoadjuvant immunotherapy compared to similar procedures without such therapy, close to one-third (30.0%) of the respondents considered them more challenging. An equivalent proportion (33.2%) found the difficulty level to be on par with non-immunotherapy surgeries, while nearly one-third (28.8%) opined that complex cases become more demanding, whereas simpler cases remain unaffected.

Among the respondents who perceived increased difficulty in surgeries following neoadjuvant immunotherapy, 72% (54/75) reported “difficulty with hilar and mediastinal lymph node dissection”. Some respondents also noted that “extensive tumor regression can result in ambiguous surgical landmarks, particularly with fibrosis of metastatic hilar lymph nodes being more problematic”, or that “there is considerable variability among individuals; increased difficulty may be due to pronounced tissue collagen and less discernible interstitial planes”, or that “anatomical spaces are comparatively constricted”, or “there is an overgrowth of fibrous scar tissue”.

Over half (56.0%) of the respondents were of the opinion that surgery following neoadjuvant immunotherapy did not heighten the incidence of potentially lethal intraoperative severe complications. Multivariate logistic regression, which incorporating multiple factors such as practice type, institutional or individual surgical volume, years in practice, cases performed after neoadjuvant immunotherapy, revealed that there was no correlation between surgical complexity and the surgeon’s experience or medical infrastructure characteristics (Table S1).

Postoperative events

A majority (59.2%) of the respondents concurred that surgery subsequent to neoadjuvant immunotherapy did not escalate the frequency of severe postoperative irAEs. Additionally, multivariate logistic regression revealed that surgeons with greater experience reported a higher incidence of serious irAEs that resulted in delayed or cancelled surgery, and severe postoperative irAEs following neoadjuvant immunotherapy (Table S1). Notably, nearly half of the surgeons who had managed more than 50 cases reported an increase in serious postoperative irAEs.

Over half (53.6%) of the survey participants maintained that surgeries performed after neoadjuvant immunotherapy did not result in a heightened incidence of postoperative complications classified as grade 2 or above. A smaller contingent, constituting 16.8% of respondents, held the opinion that neoadjuvant immunotherapy contributed to an increased rate of serious postoperative complications of grade 2 or higher.

Discussion

Neoadjuvant immunotherapy for resectable NSCLC has been the focus of numerous clinical trials, such as CheckMate-816 (7), KEYNOTE-671 (8), AEGEAN (9), CheckMate-77T (10), RATIONALE-315 (11), Neotorch (12), and among others. The updated results of the CheckMate-816 trial (7), which was the first phase 3 randomized study investigating a neoadjuvant immunotherapy-based regimen in resectable NSCLC, demonstrated that neoadjuvant nivolumab combined with platinum-based chemotherapy resulted in a higher pathological complete response (pCR) and an extension of 5-year overall survival rate (65.4% versus 55%). Compared to chemotherapy alone, the combination of nivolumab with chemotherapy was associated with a higher incidence of minimally invasive surgical procedures and a reduced frequency of pneumonectomy, with negligible differences in treatment-related adverse events. These results lend credence to the proposition that in the context of resectable NSCLC, neoadjuvant immunotherapy significantly outperforms chemotherapy when administered as a solitary modality.

In this survey, an online questionnaire was disseminated to professional surgeons within a WeChat thoracic surgery group, ensuring prompt responses that reflect the professionalism and immediacy of the survey. The majority of respondents hailed from high-volume thoracic surgery centers and possessed relevant experience, underscoring the representativeness of the survey findings.

The respondents advocated for the utilization of PET-CT imaging in conjunction with EBUS or mediastinoscopic biopsy as a more judicious strategy for the precise staging of mediastinal lymph nodes prior to commencing neoadjuvant chemoradiotherapy. It was recommended that a MDT approach be employed for all patients slated for neoadjuvant therapy across stages I to III. Moreover, the surgical team should be responsible for making informed decisions regarding neoadjuvant therapy, particularly with the objective of achieving an R0 resection.

Typically, conventional neoadjuvant chemotherapy is succeeded by surgery after an interlude of 3 to 4 weeks, while the zenith of irAEs commonly manifests around 6 weeks post-immunotherapy. A majority of respondents in our study preferred a surgical window of 4–6 weeks subsequent to neoadjuvant treatment. Theoretically, earlier surgical interventions may elevate the risk of serious complications, while postponements may augment the likelihood of tumor progression (13). The results of neoadjuvant immunotherapy in early-stage NSCLC from finished or onging clinical trials have retained their relevance as a point of reference. The CheckMate 159 (14), LCMC3 (15), and TOP1501 (16) studies employed two cycles of neoadjuvant monotherapy with surgery scheduled between 28 to 56 days after initiation, or 1–5 weeks post-therapy completion. Neoadjuvant immunotherapy spanned three to four cycles when combined with chemotherapy or dual immunotherapies (17,18), with surgical procedures being conducted 3 to 7 weeks after the neoadjuvant immunotherapy’s conclusion. Presently, the recommended timing for surgery is 4 to 6 weeks following the last dose of neoadjuvant immunotherapy.

The survey findings suggest that surgeons with greater experience have encountered a higher incidence of irAEs. Consequently, heightened vigilance for irAEs following neoadjuvant immunotherapy is warranted. The consensus regarding the incidence of serious postoperative complications of grade 2 or higher following neoadjuvant immunotherapy remains elusive, with ongoing discourse surrounding the morbidity and safety of subsequent surgical interventions. Although surgery post-neoadjuvant radiotherapy (NRT) or chemotherapy (NCT) is deemed safe and feasible, concerns have been raised about the potential for neoadjuvant immunotherapy to induce tissue adhesion and complicate surgical procedures. Generally, neoadjuvant immunotherapy is considered safe for patients with resectable NSCLC. In the AEGEAN study (9), the incidence of postoperative complications (59.1% vs. 60.1%) and grade 3–4 adverse events (8.4% vs. 9.3%) were similar, with no increased surgical-related risk. In the CheckMate 816 study (7), the incidence of grade 3–4 adverse events within 90 days post-surgery (11% vs. 15%) was comparable to the chemotherapy group, with no new fatal complications. The RATIONALE-315 study (11) showed a controllable incidence of grade 3–4 complications (11.1% vs. 15.6%) and no significant difference in postoperative 90-day mortality (1.3% vs. 1.8%). In the KEYNOTE-671 study (8), the incidence of postoperative complications (38% vs. 42%) and grade 3–4 events (15.6% vs. 19.3%) were similar. The CheckMate 77T study (10) showed a slightly lower incidence of postoperative adverse events (38% vs. 42%) and a controllable rate of grade 3–4 complications (15% vs. 19%). In the Neotorch study (12), the incidence of postoperative complications (9.4% vs. 7.4%) and grade 3–4 events (3.0% vs. 2.0%) were comparable to the chemotherapy group. These phase III clinical trials demonstrate that the incidence of postoperative complications with the neoadjuvant immunotherapy plus chemotherapy regimen is similar to that of the chemotherapy-only group, and perioperative immunotherapy exhibits controllable safety in resectable NSCLC. During the perioperative administration of immunotherapy, stringent monitoring of organ function is imperative, encompassing a suite of evaluations such as laboratory assays, radiographic imaging, pulmonary function tests, electrocardiography, thyroid function tests, and other foundational assessments. Early detection of immune-related cardiotoxicity and severe pneumonia is of paramount importance (19).

The formulation of a surgical strategy should be predicated on oncological indications as well as a comprehensive assessment of the patient’s overall health status, including factors such as age, pulmonary function, and comorbid conditions. Post-neoadjuvant therapy surgical planning must incorporate an evaluation of the tumor and nodal status. Nonetheless, the paramount goal of curative lung cancer surgery is the achievement of an R0 resection. It is imperative that all cases of advanced lung cancer undergo systematic lymph node dissection to accurately stage the disease and to ensure the complete excision of potential nodal metastases.

There is a heterogenous response and the technical difficulty after neoadjuvant immunotherapy is varied. Theoretically, the duration of surgery correlates with the surgeon’s expertise and technical proficiency, with those more adept and experienced being less impeded by the effects of neoadjuvant immunotherapy. Our findings indicated that there is no significant correlation between the perception of surgical complexity after neoadjuvant immunotherapy and the physician’s experience. Additionally, most surgeons concurred that neoadjuvant immunotherapy does not exacerbate surgical hemorrhage nor does it elevate the risk of intraoperative complications with potential lethality. Among the surgeons who perceived an increased difficulty in post-neoadjuvant immunotherapy surgeries, the primary concern was the dissection of hilar and mediastinal lymph nodes. Across the CheckMate-816 (7), KEYNOTE-671 (8), AEGEAN (9), CheckMate-77T (10), RATIONALE-315 (11), and Neotorch (12) trials, the proportion of patients who discontinued surgery due to disease progression or adverse events was consistently lower in the neoadjuvant chemo-immunotherapy group compared with the neoadjuvant chemotherapy group. Furthermore, the combination group achieved higher R0 resection rates, lower rates of pneumonectomy and thoracotomy, higher rates of minimally invasive resection, and fewer conversions to thoracotomy. Consistent with these findings, our previous study demonstrated that neoadjuvant immunotherapy combined with chemotherapy did not increase the risk of postoperative complications within 30 days, and that sleeve lobectomy following neoadjuvant therapy is both safe and feasible (20,21).

This study, while providing valuable insights, is subject to several limitations that should be acknowledged. These limitations may have an impact on the generalizability and applicability of the findings. First limitation is the recall bias. In assessing the surgical management after immunotherapy, our study may be subject to recall bias. It is possible that some individuals may not accurately remember the clinical practice or may selectively recall events. This potential discrepancy between actual past behaviors and their recollection could lead to an overestimation or underestimation of the association between immunotherapy and surgical practice, thereby skewing the results of the study. Second limitation is that the design of the questionnaire might not be perfect, failing to include many issues of concern to surgeons. Third limitation is due to constraints, this study was not conducted in association with professional associations of thoracic surgery, resulting in a limited number of questionnaire responses that may not fully represent the opinions of the entire thoracic surgical community in China. If the survey were initiated by professional associations, the audience might be more extensive, leading to a significantly higher number of responses and more authoritative analytical results. The fourth limitation is the temporal drift. The survey for was conducted in May 2022, representing the early phase of implementation. By 2025, there have been certain changes in perioperative immunotherapy protocols, multidisciplinary treatment approaches, and the application of new surgical techniques. Therefore, the conclusions of this study are applicable only to the early phase of implementation, and current clinical practice may have evolved. The last is the selection bias, our findings are not generalizable to low-volume or newly adopting centers and may underestimate conversion/complexity.

Conclusions

In conclusion, the extant data do not provide definitive proof that neoadjuvant immunotherapy compromises the conduct or safety of surgical interventions in field of thoracic surgery. While the efficacy of neoadjuvant immunotherapy has been increasingly recognized, it should also be acknowledged that irAEs remain an unavoidable clinical reality. These events warrant close monitoring and careful management, as emphasized by previous studies, to ensure patient safety and optimize therapeutic outcomes.

Acknowledgments

We extend our gratitude to all the thoracic surgeons from mainland China who participated in this survey research. Parts of the manuscript were presented as an electronic poster at the 2023 WCLC conference. It only included a brief abstract that reported preliminary results, without comprehensive data or detailed discussion. The current submission is a completely new manuscript and has not been formally published elsewhere. In addition, we have communicated with Elsevier and secured the copyright authorization for the reuse of the conference abstracts in a journal or magazine.

Footnote

Reporting Checklist: The authors have completed the SURGE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1376/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1376/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1376/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82272679), the Shanghai Oriental Talent Youth Project, the Shanghai Talent Development Fund (No. 2019073), and the Talent Project of Shanghai Chest Hospital (No. 2022YNJCQ02).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1376/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Institutional Review Board of Shanghai Chest Hospital (No. KS24010), which served as the leading institution. For multicenter questionnaire-based studies, only the principal institution is required to obtain IRB approval under national regulations, and all participating centers followed the approved protocol. Written informed consent was waived because the anonymous survey did not involve patients, personal health information, or sensitive identifiers. Participation was voluntary, and completion of the questionnaire was regarded as implied consent.

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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