Lung resection after neoadjuvant chemoimmunotherapy: a narrative review

Introduction

Background

The modern treatment of non-small cell lung cancer (NSCLC) requires a multi-modality approach. While surgery remains a mainstay of curative intent treatment in early-stage and some locally advanced disease, the success of immunotherapy for resectable NSCLC has been transformative, broadening the range of patients eligible for curative surgery (1,2).

While surgical technology has seen major innovations enabling lung resections to be performed minimally invasively, options for systemic therapy have expanded beyond chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment (2). After demonstrating its effectiveness in advanced-stage disease, several large phase 3 randomized trials have confirmed its role in the neoadjuvant setting when combined with platinum-based chemotherapy for resectable stage II–III NSCLC (3-6). The rationale for neoadjuvant systemic therapy includes downstaging the primary tumor and nodal disease, reducing the extent of resection required, improving surgical margins, and eliminating early micro-metastatic disease.

In 2022, the phase III Checkmate 816 clinical trial found that neoadjuvant chemotherapy plus nivolumab followed by surgery resulted in higher rates of pathologic complete response (pCR) and event-free survival (EFS) compared with neoadjuvant chemotherapy alone followed by surgery in patients with resectable stage IB to IIIA NSCLC [American Joint Committee on Cancer (AJCC) 7^th edition] (3). Several subsequent phase III trials confirmed the benefits of ICI-based therapy for resectable disease by also demonstrating favorable oncologic outcomes. Specifically, the use of neoadjuvant ICI-based therapies increased the chances of achieving pCR and major pathologic response (MPR), thereby improving long-term prognosis and overall survival (OS). These trials include Keynote 671 (pembrolizumab), AEGEAN (durvalumab), and Neotorch (toripalimab) (4-6).

Given the impressive oncologic results compared to chemotherapy alone, ICI-based neoadjuvant therapy followed by surgery is now a recommended treatment for resectable stage II–III NSCLC without driver mutations, especially in tumors expressing programmed death ligand 1 (PD-L1), as supported by guidelines from numerous societies (Society of Thoracic Surgeons, the American Association for Thoracic Surgery, and the National Comprehensive Cancer Network) (7-9).

Rationale

Given the strong evidence for efficacy based on oncologic endpoints, overall safety, and the feasibility of surgery in the setting of ICI-based neoadjuvant treatment, thoracic surgeons can expect to confront an expanding number of lung cancer patients, including those who, before the era of immunotherapy, may not have been candidates for surgery. This shifting paradigm presents new complexities and unique challenges in the surgical approach to these patients with regards to what disease to operate on, who to operate on, when to operate, and how best to execute the operation. While current guidelines provide some direction, it is crucial to understand why some of the answers to these questions remain amorphous and under debate.

Objective

In this narrative review, we aim to discuss four areas of clinical-decision challenges that the surgeon can expect to confront in the care of patients being treated within the neoadjuvant chemoimmunotherapy paradigm:

❖The changing definition of resectability;

❖Assessing response to treatment and timing of surgery;

❖Potential technical challenges posed by immunotherapy;

❖Use of minimally invasive techniques.

The discussion weaves in findings from the seminal phase III ICI-based neoadjuvant trials introduced above, incorporates current guidelines, and lends practical guidance. We present this article in accordance with the Narrative Review reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-39/rc).

Methods

An electronic database search was conducted in PubMed and Google Scholar from 24 June 2025 to 15 July 2025, with additional selected articles added later up to 10 November 2025. Search terms included “surgery” OR “lung resection”, “neoadjuvant therapy”, “chemoimmunotherapy”, “non-small cell lung cancer”, and “minimally invasive surgery”. The search was restricted to English-language publications involving human studies. Single case reports, abstracts, and basic science literature were excluded. Publications from January 2000 to November 2025 were included, though earlier studies were incorporated when necessary for background and context. The authors selected studies based on relevance and current importance to this review’s objectives. Literature involving neoadjuvant radiation therapy was excluded. Additionally, referenced publications cited within relevant articles (outside the search terms and date range), along with society and practice guidelines deemed pertinent and significant, were included (Table 1).

Discussion

Resectability

Following diagnosis and staging, a key treatment decision involves tumor resectability intending to achieve complete (R0) resection. The International Association for the Study of Lung Cancer defines rigorous standards for a complete resection, including (I) en bloc removal of the tumor with microscopically clear margins; (II) systematic lymph node dissection; (III) no extracapsular nodal extension of the tumor; (IV) the highest mediastinal lymph node being negative for tumor; and (V) negative pleural and pericardial cytology. The resection is not regarded as complete if these criteria are not met (10,11). In standard practice, the goal of lung cancer surgery is a complete oncologic (R0) resection with adequate lymph node assessment, including three mediastinal stations and at least one hilar station, as defined by the American College of Surgeons Commission on Cancer (12). Surgeons determine whether R0 resection is feasible by careful image review to assess tumor size, extent of local invasion, and extent of lymph node involvement.

Despite being a critical decision point, the definition of resectability, especially for stage III NSCLC patients, has long been debated and lacks a universally accepted consensus. Currently, criteria vary across different societies’ guidelines and are mainly focused on the size or bulk of lymph nodes and the number of stations involved (single versus multi-station) (13). While the T stage informs the technical feasibility of removing the primary tumor, significant technical challenges can also arise in patients with bulky, multi-station, or invasive mediastinal lymph node metastases. Post-publication of the phase III trials, the European Organization for Research and Treatment of Cancer Lung Cancer Troup conducted a survey with the goal of forming a “consensual definition” of resectable stage III NSCLC that could be applied for future clinical trials (Figure 1). Of note, the practitioners surveyed included thoracic surgeons (38%), radiation oncologists (27%), medical oncologists (17%), pulmonologists (14%), and others (4%). There was agreement that bulky, invasive N2 lymph nodes are generally unresectable across all T stages, as is multi-station N2 disease with T4 disease. There was also agreement that a smaller T stage with a single N2 station and a larger T stage with N1 is usually feasible. There were two areas of no agreement: (I) multi-station N2 with less than T4 and (II) T4 with lesser nodal involvement (14). As the results of this survey suggest, establishing a reproducible definition may be very challenging as the concept of resectability can be relatively subjective based on practitioner and institutional experience.

Figure 1 Summary of survey results on resectability assessment of TNM-subsets in stage III non-small cell lung cancer (per AJCC 8th edition) (14). a, 83% of respondents answered “yes”. In potentially resectable and no agreement groups, the percentage compromises “yes” + “maybe” answers. In unresectable cases, the percentage compromises “no” answers. b, considered as potentially resectable by thoracic surgeons versus no agreement among others. c, no agreement among thoracic surgeons versus unresectable by others. Reproduced from Houda I, Bahce I, Dickhoff C, et al. An international and multidisciplinary EORTC survey on resectability of stage III non-small cell lung cancer. Lung Cancer 2025;199:108061. Distributed under the terms of the Creative Commons Attribution (CC BY) license. N, node; N/A, not applicable; T, tumor.

For stage III patients deemed unresectable or inoperable, the alternative definitive treatment is concurrent chemoradiation followed by consolidation durvalumab per the PACIFIC protocol. The PACIFIC trial demonstrated that adding durvalumab after chemoradiation significantly lengthened progression-free survival (PFS) and OS in patients with “unresectable” NSCLC. As a major caveat of this study, no standardized criteria for defining resectability were used before enrolling patients, nor was a surgical opinion required (15).

The definition of resectability has remained unaddressed in the neoadjuvant ICI-based trials, even as the trials focused on resectable IIA–IIIB disease. These trials established no strict resectability criteria, and assessments were based on surgical consultation and investigator judgment. In Checkmate 816, patients with cT1-4, N0-2 disease considered resectable were eligible for the study. However, details about the extent of T4, the number of N2 nodes, and nodal bulkiness were not recorded in the data collection (3). Keynote 671 included patients with stage II–IIIB (N2) disease. Again, there was no information on whether N2 multi-station or bulky N2 disease was included among these patients (4). Finally, in the AEGEAN trial, resectability was to be assessed by a board-certified thoracic surgeon who regularly performed lung cancer surgeries. Notably, patients requiring pneumonectomy were excluded from AEGEAN (5).

Nevertheless, it is essential to recognize that, although the seminal phase III trials did not clarify whether clinical N2 was single-station versus multi-station or discrete versus bulky, they did include patients with clinical N2 disease. Keynote 671 and Neotorch also included clinical Stage IIIB (cT3/4N2). NADIM II (perioperative nivolumab in stage IIIB) provided further clarification. Within the 72% of patients with N2 disease in NADIM II, 39% had multi-station N2, and another 23% had cT3N2. With ICI-based neoadjuvant therapy, pCR occurred in 37% (versus 7%), 24-month PFS was seen in 67.2% (versus 40.9%) and OS was 85% (versus 63.8%) (16). These findings support durability of the oncologic outcomes with neoadjuvant chemoimmunotherapy and surgery despite initial nodal burden.

Adding further complexity, the high rates of clinical and pathologic downstaging observed in the ICI-based neoadjuvant therapy trials may redefine resectability. Results from these phase III trials demonstrate an unprecedented rate of pCR—17.2% to 24.8% with ICI-based regimens compared to 1% to 4.3% with chemotherapy alone (3-6) (Table 2). For patients initially deemed unresectable based on disease burden but who have demonstrated remarkable tumor downstaging, is it reasonable then to reconsider resection? Wang et al. retrospectively compared outcomes [3-year disease-free survival (DFS) and OS] between cohorts of initially unresectable stage III and resectable IB–IIIA patients who underwent induction chemoimmunotherapy followed by surgery. Of the 469 patients initially deemed unresectable, 278 (59.3%) ultimately underwent resection. Compared to their initially resectable counterparts, this cohort demonstrated comparable 3-year DFS and OS. R0 rates, 30-day mortality, and 90-mortality were also not significantly different (17). The ongoing MDT-BRIDGE is a phase II non-randomized trial in which patients with resectable or borderline resectable stage IIB–IIIB tumors are given two cycles of neoadjuvant chemoimmunotherapy, then restaged and re-assessed for resectability. Patients deemed resectable are offered 1–2 more cycles of chemoimmunotherapy then proceed with surgery (those deemed unresectable are directed to definitive chemoradiation) (18).

While resectability may be clear in cases of small, isolated tumors and single-station non-bulky disease, borderline situations involving complex T4 disease, central tumors, and/or extensive nodal involvement can be more difficult. This can be a challenging decision point for surgeons, especially if the patient is otherwise operable (acceptable performance status, intact cardiopulmonary reserve, no prohibitive co-morbidities). In our practice, this decision is made in a multidisciplinary setting with input from oncologists and radiation oncologists, weighing the risks and benefits of all available treatment pathways while considering tumor biology, the patient’s baseline disposition, and the patient’s wishes and social support. We consider large tumors to be resectable if R0 margins can be achieved with acceptable morbidity. The number of stations involved is not an exclusion for the neoadjuvant chemoimmunotherapy approach, but only if the nodes can be removed completely.

Response to treatment and timing of surgery

Following neoadjuvant chemoimmunotherapy, it is essential to restage the patient and assess disease response and re-evaluate patient fitness before proceeding with surgery. The phase III chemoimmunotherapy trials reported that 16–23% of patients did not reach surgery (3-7) (Table 2). Reasons cited include morbidity and mortality from chemoimmunotherapy, severe adverse events, becoming unfit for surgery during treatment, disease progression, cancer deemed unresectable, patient refusal, physician decision, or withdrawal of consent (3-7).

Evidence of disease progression after completing neoadjuvant chemoimmunotherapy is generally a contraindication to proceeding with resection. A phenomenon called “pseudoprogression” has been described in the setting of immunotherapy, where radiographic progression or stability is observed despite pathologic response (3,19). Immunotherapy can cause peritumoral inflammation leading to apparent enlargement of the mass on imaging or what the NEOSTAR investigators called “nodal immune flare”, where lymph nodes display diffuse granulomatous inflammation that can mimic progression and result in new or residual hypermetabolic activity in the mediastinum (20). In such cases, multidisciplinary review with radiology input and consideration of invasive mediastinal staging should be pursued.

Adverse events from neoadjuvant chemoimmunotherapy may worsen a patient’s clinical condition and interfere with treatment completion, including the ability to proceed to surgery. The phase III trials report rates of grade 3–4 adverse events ranging from 22% to 45% (3-7) (Table 2). While gastrointestinal side effects are most common, other immune-related adverse events, such as pneumonitis, endocrinopathies (hypothyroidism, adrenal insufficiency, hyperglycemia), hepatitis, and autoimmune skin disorders, may also occur (21). Careful risk assessment, early recognition with vigilant monitoring, and timely intervention are essential (22), not only to prevent mortality but also to consider pivoting the treatment strategy. Corticosteroid therapy, symptom management, and dose re-adjustment is used to mitigate many of these side effects so that a patient can complete the full neoadjuvant regimen (21). However, in our experience, severe immune-related side effects may also indicate a significant tumor response, such that proceeding without completing the full neoadjuvant course could be considered. Again, such decisions are made by a multi-disciplinary team.

Operability requires re-assessment as some patients may see a functional decline followed neoadjuvant therapy, often related to side effects. Pulmonary function tests should be repeated, especially if patients experienced immune-related pneumonitis. Most trials have no reported pulmonary function test results but modest reductions (~10) in forced expiratory volume in 1 second (FEV₁) and diffusing capacity of lungs for carbon monoxide (DLCO) have been observed (23).

Based on the treatment protocols of the phase III clinical trials, the National Comprehensive Cancer Network (NCCN) guidelines recommend surgery within 3–6 weeks after the final neoadjuvant chemoimmunotherapy cycle (9), contingent on recovery and confirmation of operability. Delays beyond this 6-week window were observed in the phase III trials, with reasons including drug toxicity, adverse events, and logistical issues (3-7). However, the ideal timing for surgery remains unclear, especially as it relates to tumor behavior and biology. There are yet no prospective trials examining the question of optimal surgical timing. A retrospective study by Chen et al. of 171 patients who received neoadjuvant chemoimmunotherapy compared outcomes between surgery at ≤28, within 29–42, and ≥43 days. They found no significant differences in intraoperative or post-operative between the cohorts, nor was there a difference in pCR (24). On the other hand, a retrospective study by Lin et al. of 82 patients who received neoadjuvant chemoimmunotherapy compared outcomes between those who underwent surgery at ≤4 weeks versus surgery at ≥4–6 weeks, finding that the ≤4 weeks cohort had better pathologic outcomes (pCR or MPR), but there was no statistical difference in DFS between the two groups. They did not examine post-operative clinical outcomes (25).

While guidelines do not recommend excluding patients with low or negative PD-L1 expression from consideration for neoadjuvant immunotherapy, tumor PD-L1 expression is an important predictor of response to ICI therapy in NSCLC. Across phase III trials, higher PD-L1 expression (≥1%, especially ≥50%) is associated with a significantly higher odds of achieving pCR and MPR (3-7). Other biomarkers currently under investigation include tumor mutation burden (TMB), KRAS mutation status and DNA damage response (DDR) mutations (26-28).

Still, many lung cancers do not respond to ICIs even when combined with chemotherapy. A reliable predictor of treatment response remains elusive. Additionally, developing comprehensive predictive models for immune-related adverse events (irAEs) may be difficult, given the inherent heterogeneity of NSCLC and patient’s immunologic disposition. Lack of response to chemoimmunotherapy leads to disease progression and severe drug toxicities, destabilizing a patient’s fitness during neoadjuvant treatment, which can remove surgery as a treatment option. These are two important “risk factors” to consider with the neoadjuvant chemoimmunotherapy approach, especially for earlier-stage (stage II) patients. A thorough clinical assessment of operability, including review of laboratory data, after completion of neoadjuvant chemoimmunotherapy is crucial. While targeting surgery within a 3–6-week window is recommended, delays beyond this point to ensure operative fitness is prudent.

Technical challenges and surgical outcomes

Neoadjuvant therapy can increase surgical complexity from a technical perspective. Treatment-related effects, especially with ICI therapy, include perihilar inflammation and fibrosis, which can obscure tissue planes and make dissection around vascular structures particularly difficult. Additionally, intrathoracic adhesions and tissue changes can complicate distinguishing between fibrosis and residual tumor (Figure 2). Since their focus was mainly on oncologic outcomes, none of the phase III clinical trials detailed the technical challenges encountered during resection after neoadjuvant treatment. Instead, the intraoperative challenges of lung resections following neoadjuvant ICI therapy are better documented in case series and phase 1 and phase 2 studies.

Figure 2 Flowchart illustrating decision-making points in surgical patients treated with neoadjuvant chemoimmunotherapy. ICI, immune-checkpoint inhibitor; MIS, minimally invasive surgery; OR, operating room; PFTs, pulmonary function tests.

An initial report demonstrating the safety and feasibility of pulmonary resection during immunotherapy was published by Bott et al. in 2018 (29). They conducted a retrospective review of 19 patients who underwent lung resection within 6 months of ICI therapy for previously metastatic or unresectable biopsy-confirmed NSCLC or metastatic cancer from another site. The report highlighted technical challenges due to dense hilar and chest wall adhesions in this context. Anatomic resections (lobectomy or greater) were performed in half of the patients. Four cases were attempted minimally invasively, with one requiring conversion to thoracotomy. Complications were observed in 32% of patients (29). Similarly, Baek et al., in a case series of minimally invasive surgery (MIS) lobectomy for residual primary tumors of advanced NSCLC after ICI treatment, described fibrotic changes and adhesions in the fissure and interlobar lymph nodes (30).

Subsequently, Bott et al. (19) and Tong et al. (31) reported surgical outcomes in a phase I trial with neoadjuvant nivolumab and a phase II trial with neoadjuvant pembrolizumab, respectively, for patients with resectable NSCLC. Most patients in both studies underwent lobectomy. Both studies showed that lung resection following neoadjuvant immunotherapy did not lead to excessive perioperative morbidity or mortality. There was no death in either study. The most common post-operative complication was atrial fibrillation. The median length of hospital stay was 4 days. Both studies noted increased surgical complexity in these post-induction cases, as reflected in longer operating times and higher rates of conversion to open thoracotomy, often due to hilar inflammation and fibrosis at the hilar and mediastinal lymph node stations. MPR was observed in 45% of patients treated with nivolumab and 28% when treated with pembrolizumab.

More detailed surgical outcomes have been reported from the phase II Neostar (23) and phase II LCMC3 trials (32). Notably, in addition to outlining the standard surgical endpoints—such as timing of resection, extent of resection, completeness of resection, and post-operative morbidity and mortality—Neostar also included a report on technical difficulty, requiring the operating surgeon to rate the difficulty of tissue dissection compared to a “normal” anatomic lobectomy with mediastinal lymph node dissection for stage I lung cancer. Overall, 40% of the cases were graded 3–4, indicating greater complexity than a typical lobectomy for stage I disease. The complexity score correlated with longer operative times and higher blood loss. In this cohort, 73% of resections were performed via thoracotomy, with the remaining done by MIS. The conversion rate was 17%. Zhang et al. (33) compared the difficulty of surgery in patients with resectable NSCLC treated with different neoadjuvant modalities in a small propensity-matched retrospective cohort study. Surgical difficulty was assessed using a scoring system based on the extent of intrathoracic adhesions, the difficulty of lymph node dissection, and tumor invasion. The three treatment groups were neoadjuvant immunotherapy alone (with sintilimab), neoadjuvant chemotherapy, or upfront surgery. The authors highlight that the neoadjuvant immunotherapy group had a higher complication rate of 37.8% compared to the neoadjuvant chemotherapy (16.2%) and upfront surgery (10.8%) groups. While the percentage of cases graded hard or extremely hard was similar across the three groups (40–50%), a significantly higher percentage of cases in the neoadjuvant immunotherapy group were graded hard or extremely hard compared to the upfront surgery group (40.5% vs. 13.5%) for lymph node dissection. This may explain why the median number of lymph nodes harvested in the immunotherapy group was half that harvested in the chemotherapy and upfront surgery groups.

As Rusch et al. highlight in the report on surgical outcomes of the phase II LCMC3 trial, perihilar fibrosis is an unpredictable and variable phenomenon that has not been quantified by frequency or severity (32). One obstacle to doing so is the lack of a validated and accepted scoring system (32). Several groups have proposed scoring methods. Sepesi et al. base their 4-point scoring system on the difficulty of dissection compared to the “normal” anatomic dissection of stage 1 lung cancer (23). Lee et al. proposed a scoring system for surgical complexity based on (I) size of lymphadenopathy; (II) degree of peripheral fibrosis; (III) tumor location (central versus peripheral); and (IV) degree of perihilar/mediastinal fibrosis (34). Zhang et al. described intraoperative difficulty using a scoring system that considers (I) the extent of intrathoracic adhesions; (II) challenges in nodal dissection; (III) tumor involvement with the pulmonary artery/bronchus; and (IV) overall procedural difficulty (33). Rusch et al. introduced a simple 4-point system based on hilar and mediastinal fibrosis, calling for such a surgical data point to be included in future prospective trials (32) (Table 3).

Treatment-related fibrosis presents a significant challenge for surgeons in the post-induction setting. It influences the surgical approach, the risk of intraoperative complications (such as major hemorrhage from vascular injury), resectability at the time of surgery, and the quality of lymphadenectomy. While certain factors—such as central tumor location, large tumor size, re-operative procedures, and involvement of nearby structures—are known to contribute to the technical difficulty of any anatomic lung resection, there are few reliable pre-operative indicators of treatment-related fibrosis and the resulting technical challenges in the post-induction setting. The extent and occurrence of treatment-related fibrosis remain largely unpredictable and are not necessarily identifiable on pre-operative imaging alone.

Feldman et al. (35) proposed a link between nodal response to preoperative therapy and intraoperative complexity. In a retrospective review at a single of 124 patients with node-positive disease who received any induction treatment, they found that N1 disease was associated with a greater need for complex surgical maneuvers than N2 disease. Surgical complexity was assessed based on a set of defined criteria and determined through review of operative notes. They also observed that a greater treatment response—that is radiographic node size reduction—was associated with greater technical complexity. Most of these cases (86.3%) began with a thoracotomy. Among the smaller group that attempted minimally invasive methods [both video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS)], there was a 12.8% conversion rate.

Altogether, these studies demonstrate that lung resection after induction chemoimmunotherapy is safe with acceptable morbidity and mortality. Surgeons should prepare for the possibility of a more difficult dissection imposed by treatment-related changes such as increased perihilar and mediastinal fibrosis, vascular fragility, and peritumoral fibrosis. In our experience, though treatment-related fibrosis is often encountered, it is not always present nor is always predictable. Currently, there are no objective measures or correlations to predict the presence and degree of fibrosis. We recommend consistently documenting this variable using a simple scoring system, such as that proposed by Rusch et al., and including it as a surgical data point in future prospective trials (32).

Use of minimally invasive techniques

Surgical techniques for treating lung cancer have greatly advanced over the past 20 years. MIS methods for lung resection, including VATS and RATS, are now standard treatments for early-stage lung cancer. Compared with traditional thoracotomy, MIS offers better postoperative outcomes with similar oncologic outcomes. Benefits of VATS or RATS include less early post-operative pain, lower complication rates, shorter hospital stays, and faster overall recovery (36). RATS also provides high-resolution 3D visualization, improved instrument dexterity with wristed tools, and more comfortable ergonomics for the surgeon. Comparable long-term survival has been observed between open versus MIS lobectomy and VATS versus RATS lobectomy for NSCLC (37).

The Video-Assisted Thoracoscopic versus Open Lobectomy in Patients with Early-Stage Lung Cancer (VIOLET), a large-randomized trial from the United Kingdom, provided high-quality evidence demonstrating the superiority of VATS over open lobectomy for postoperative pain, complications, functional recovery, and economic outcomes. Additionally, there were no differences in short- or long-term oncologic results (38). As a result, MIS for early-stage lung cancer has become widely adopted over the past 20 years as surgeons gradually gained the necessary technical skills and as evidence supporting its effectiveness from both surgical and oncologic perspectives grew. An analysis of the 2020 National Cancer Database found that approximately 72% of lung cancer resections for stage I NSCLC were performed using minimally invasive approaches (39). This rate exceeds 80% for lobectomies performed at high-volume centers, with robotic-assisted procedures making up more than half of these cases (40,41). The VIOLET trial included stage I to II cancers but did not include patients who had undergone induction therapy (38).

Given the inherent challenges of large tumor size, nodal involvement, tumor invasion of surrounding structures, and treatment-related tissue changes, surgeons may prefer an upfront thoracotomy approach for post-induction lung resections over MIS. In Zhang et al.’s retrospective comparison of surgical difficulty for lung resections performed after neoadjuvant immunotherapy, neoadjuvant chemotherapy, or upfront surgery, the open approach was strongly favored in the neoadjuvant therapy groups. The open and VATS approaches were equally common in the upfront surgery group (33). However, VATS and RATS techniques have also been used for resecting locally advanced tumors, including those treated with induction therapy.

Before immunotherapy, the feasibility and oncologic efficacy of MIS after induction therapy (chemotherapy with or without radiation) were supported by several early retrospective studies (42-44). With the introduction of immunotherapy to neoadjuvant regimens for resectable lung cancer, a significant portion of cases in initial phase I and II trials were performed using MIS: 13 out of 20 with a 54% conversion rate and 23 out of 25 with a 21.7% conversion rate, respectively (19,31). MIS approaches were also employed in the multi-institutional prospective trials. In Checkmate 816, 29.5% of patients in the neoadjuvant chemotherapy with ICI group and 21.5% in the neoadjuvant chemotherapy alone group underwent MIS, with conversion rates of 11.4% and 15.6%, respectively (3). In AEGEAN, 39.6% of cases in the durvalumab arm and 38% in the placebo arm were performed with VATS; however, conversion rates were not specified (5). Keynote 671 and Neotorch did not specify surgical approaches (4,6) (Table 4).

In a retrospective analysis of the National Cancer Database, Mathey-Andrews et al. examined the surgical outcomes of lung resections after neoadjuvant chemotherapy versus neoadjuvant ICI-based therapy, demonstrating the safety and feasibility of MIS resections (including VATS and RATS) after immunotherapy (45). Out of 4,229 patients in the cohort analyzed between 2010 and 2018, 5% received ICI-based neoadjuvant therapy. The rest had received neoadjuvant chemotherapy alone. Following chemotherapy, 63.6% of lobectomies were performed via thoracotomy, while 37.4% were done using MIS. Lobectomies after neoadjuvant ICI-based therapy showed the opposite distribution: 39.4% open and 60.5% via MIS. However, in their propensity-matched analysis, there was no difference in the rate of MIS lobectomy between patients who received ICI-based therapy and those who received chemotherapy alone (60.8% vs. 51.6%, P=0.11). There were also no differences in the rate of conversion from MIS to open surgery (14% vs. 15%, P=0.83), or in nodal positivity, margin positivity, 30-day readmission, or 30- and 90-day mortality. Among patients treated with immunotherapy, there were no differences in pathologic or preoperative outcomes between the open and MIS approaches. Therefore, compared with neoadjuvant chemotherapy, neoadjuvant immunotherapy was not associated with an increased likelihood of thoracotomy or conversion, or with inferior preoperative outcomes in the propensity-matched analysis.

To clarify which factors may predict successful post-induction lung resection by MIS and assist in operative planning, Chu et al. conducted a retrospective review of their institutional experience at Memorial Sloan Kettering Cancer Center (46). In this study, 57% of post-induction lung resections were performed open, while 43% used MIS approaches (VATS or RATS). A successful MIS approach was defined by no conversion to open surgery, R0 resection, and no major complications. Using these criteria, 77% of post-induction cases successfully used MIS. Among the “unsuccessful” cases, conversion to open surgery (rate of 23%) was the main reason, rather than R0 resection or major morbidity. They found that pretreatment clinical N stage, especially the presence of N1 disease, and surgeon experience (measured by the total number of MIS lung resections performed annually) significantly affected the success of minimally invasive lung resections after induction therapy.

The collection of these studies supports MIS as a safe and feasible approach for post-induction lung resections. Minimally invasive techniques are practical and should be attempted for post-neoadjuvant resections, even though conversion to thoracotomy might be necessary to ensure an excellent oncologic outcome and safe procedure. The extent of intrathoracic adhesions and peri-hilar fibrosis caused by treatment effects remains hard to predict before surgery, but should be expected. Pre-treatment nodal disease and the degree of treatment response can help forecast a difficult hilar dissection, increased technical difficulty, and a higher chance of conversion. Nevertheless, the technical complexity of these post-induction cases and the best surgical approach still need prospective study. This requires a universally accepted, quantitative scale for grading post-treatment fibrosis severity, consistent documentation of this parameter, and thorough collection of radiographic data. Several authors have proposed grading scales for fibrosis severity and scoring systems for intra-operative complexity (32-34).

As the literature shows that the minimally invasive approach is feasible and safe, our experience suggests it is reasonable to consider all post-induction patients for a minimally invasive approach based on the individual surgeon’s comfort level and experience, with anticipation of a likelihood of conversion to an open approach. Treatment-related tissue changes observed after neoadjuvant immunotherapy are a correlation, not a guarantee. The state of the tumor, more so than the type of neoadjuvant therapy, informs our operative strategy. The reviewed literature suggests that pre-treatment N1 (and degree of treatment response) predicts a more challenging resection, as these nodes often abut major bronchovascular structures (especially the pulmonary artery). A large, bulky tumor likely necessitates a thoracotomy to extract regardless. Situations in which MIS should not be considered upfront generally relate to high T stage: chest wall invasion requiring reconstruction, anticipated bleeding or need for arterioplasty to complete the resection, planned pneumonectomy, and proximal bronchovascular involvement that would require direct tactile feedback to evaluate or control. Of note, we have found that an uninvolved hilum can be more easily visualized and dissected in the setting of a bulky peripheral tumor. Adhesiolysis may also be easier with a minimally invasive approach if the adhesions are not dense. Fundamentally, persisting through a minimally invasive approach should not come at the expense of safe and high-quality cancer surgery without preparedness for catastrophic events, such as bleeding.

Strengths and limitations

The effectiveness of ICI-based neoadjuvant therapy for NSCLC treatment is consistently demonstrated across several multi-institutional phase III trials, which form the basis of this narrative review. In addition to summarizing key findings, we aim to highlight evolving issues raised by these practice-changing findings regarding surgical decision-making and oncologic care. A limitation of this review is that it is only an introduction, as each topic or issue deserves its own detailed review. The literature chosen supports the central themes. The reality is that lung cancer care and research are becoming more multidimensional and multidisciplinary as we continue to push the boundaries of what was previously considered incurable or even surgically treatable. Given the heterogeneity of the disease, affecting an increasingly diverse population, and the highly technical nature of treatments like surgery—which depend on experience—there are inherent biases and challenges that make rigid standardization difficult. We offer our perspective, acknowledging these complexities in the context of the evidence and real-world experience.

Conclusions

The oncologic outcomes of immunotherapy combined with chemotherapy have been impressive compared to previous options. It has raised many open questions about who would benefit from which treatment modalities and in what sequence. Surgery will continue to play a key role, but with new challenges and opportunities as its role interacts with emerging therapeutics. We have highlighted some key considerations pertinent to the surgeon arising from the practice-changing studies that have established the oncologic effectiveness of neoadjuvant chemoimmunotherapy and share our clinical experience and insight (as summarized in Figures 2,3).

Figure 3 Case example illustrating decision-making process and intraoperative challenges. AJCC, American Joint Committee on Cancer; EBUS, endobronchial ultrasound; M, metastasis; N, node; PD-L1, programmed death-ligand 1; PET/CT, positron emission tomography/computed tomography; PFTs, pulmonary function tests; T, tumor.

One can say that emerging systemic therapies are expanding surgical indications rather than limiting their role. Surgeons are confronting more complex disease than ever before. The effects of immunotherapy (and other emerging drug strategies) on the primary tumor are redefining what is resectable, and the collateral tissue changes require careful surgical decision-making, planning, and execution. The enthusiasm and demand for minimally invasive techniques, which have evolved in parallel, add another layer of complexity to surgical decision-making. Therefore, it is crucial for surgeons to actively participate in the ongoing evolution of lung cancer treatment and care.

Future topics for investigation are abundant. In addition to the questions already raised in this review, areas of innovation include development of imaging adjuvants to predict treatment-related tissue changes pre-operatively or real-time intraoperative tools to distinguish residual tumor from tissue fibrosis. Development of reliable serum biomarkers can facilitate patient selection and guide surgical timing. Long-term consequences of immunotherapy, patient quality of life, and cost-effectiveness will certainly be areas of inquiry. Moreover, how can artificial intelligence be implemented to guide patient selection, build prediction models, and assess treatment response?

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-25-39/rc

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-25-39/coif). B.C.G. was a K12 scholar from Jan. 22 to Dec. 24 with a focus on learning how to develop clinical trials in thoracic malignancies and received a 2-year mentored training grant on the Paul Calabresi Clinical Oncology Training Program (NIH-K12CA157688). There is no overlap in his particular research focus while a K12 scholar. The other author has no conflicts of interest to declare.

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