Minimally invasive lung resection after neoadjuvant therapy for locally advanced non-small cell lung cancer: a narrative review of safety and evolution

Introduction

Lung cancer remains the leading cause of cancer-related deaths worldwide, with approximately 2.48 million new cases and 1.82 million deaths reported in 2022. Rising incidence has been observed among women and in low- and middle-income countries (1,2). Non-small cell lung cancer (NSCLC) accounts for almost 85% of these cases (3,4). Improvements in screening have increased early-stage detection and advances in systemic therapy have expanded the use of multimodality treatment for locoregional disease (5-7).

Since the 1990’s, surgery has been extensively documented as the gold standard of treatment for early-stage NSCLC (8). Enhancements in surgical techniques have gone hand in hand with recent developments in systemic medical therapy, most notably immunotherapy. In patients with locally extensive disease, neoadjuvant therapy has been theorized to target micro-metastases early. The efficacy of neoadjuvant chemotherapy in the same patients, has been extensively reported (9). Early data from clinical trials on neoadjuvant immunotherapy have documented improved outcomes in major and complete pathologic response rates, R0 resections, and reduced recurrence and disease-free survival rates (10-13). Thus, surgical treatment after neoadjuvant systemic therapy has gained traction among experts and high-volume centers for IB-IIIB stage NSCLC surgically fit patients.

Minimally invasive surgery (MIS) techniques such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) are associated with improved perioperative outcomes compared to thoracotomy in early-stage patients, becoming the standard of care in high volume centers (14,15). However, their use in patients receiving neoadjuvant systemic therapy for locally extended disease remains controversial, as determinants of success are less well-defined (7). These therapies may induce dense fibrosis, altered hilar anatomy, and immune-related tissue changes that can increase surgical technical difficulty and risk of bleeding, leading to strenuous lymph node dissection using MIS, and occasionally prompting conversion to thoracotomy (16). Many high-volume centers have attempted to identify the safety and efficacy of MIS for patients receiving neoadjuvant systemic treatment with excellent reported outcomes (14,15). Previous reviews have primarily described perioperative outcomes after neoadjuvant chemotherapy or chemoimmunotherapy in isolation, with limited emphasis on how evolving systemic regimens influence surgical decision-making and technical feasibility. By systematically integrating data across neoadjuvant chemotherapy, immunotherapy, and chemoradiotherapy, this review seeks not only to summarize outcomes but to explore emerging patterns that may refine patient selection, optimize surgical planning, and identify areas requiring further investigation.

The goal of this narrative review is therefore to provide a comprehensive overview of minimally invasive surgery following neoadjuvant systemic therapy, focusing on perioperative safety, conversion rates, R0 resection, long-term outcomes and patient overall survival (OS). We present this article in accordance with the Narrative Review reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-42/rc).

Methods

We conducted database searches on 5–20 July 2025 and 2–6 November 2025. We included randomized trials and observational studies regarding patients that underwent MIS after neo-adjuvant therapy published between June 2016 and October 2025. We used the PubMed and Google Scholar, under the following search terms: [(non-small cell lung cancer) OR (NSCLC)] AND [(neoadjuvant) OR (preoperative) OR (induction)] AND [(thoracoscopic) OR (minimally invasive) OR (MIS) OR (VATS) OR (RATS)]. Our research yielded a total of 356 results. We included English-language observational and randomized controlled studies that presented data on patients undergoing surgery for NSCLC after induction therapy. A group of patients undergoing MIS was also necessary. Exclusion criteria: case reports, reviews, studies still ongoing and any study that did not specify the portion of patients undergoing a minimally invasive procedure. The detailed strategy is summarized in Table 1.

Discussion

Our search resulted in 30 papers. These include 26 papers comparing minimally invasive techniques with open thoracotomy, and amongst them 2 meta-analyses. We also included 4 recent papers comparing VATS and RATS alone, without including any cases of patients receiving an open thoracotomy. Every single study included a VATS group of patients. In those studies, type of therapy was documented (chemotherapy alone, immunotherapy alone, chemo-immunotherapy, chemo-radiotherapy and all three chemo-radio-immunotherapy), conversion rates and causes, R0 resections, surgical results (blood loss, duration etc.) and morbidity-mortality. Lymph node yields were documented in 15 studies. We provide a table (Table 2) with the studies included in our search and their main findings.

Challenges around neoadjuvant therapy

Neoadjuvant multimodality treatment has become standard care for locoregional IB–IIIB NSCLC, improving compliance with systemic therapy (19), downstaging tumors, eliminating micrometastatic disease, increasing the likelihood of R0 resection, and potentially enhancing survival (20), while also allowing in vivo assessment of tumor response. Trials including NADIM I and II, AEGEAN, NEOSTAR, and CHECKMATE 816 have shown that incorporating immunotherapy preoperatively enhances pathologic responses and outcomes. However, these benefits pose surgical challenges: dense fibrosis, adhesions, and distorted anatomical planes, particularly around the hilum and mediastinum, along with therapy-induced lymph node inflammation, complicate dissection and increase risk of injury (16).

Immune checkpoint inhibitors such as nivolumab, atezolizumab, and pembrolizumab can induce robust anti-tumor responses, resulting in major or even complete pathological responses in a substantial proportion of patients (47-49). However, these therapies can also lead to nodal fibrosis, increased tissue inflammation, and immune-related adverse events (irAEs) that may complicate surgery (21). For instance, checkpoint inhibitor pneumonitis (CIP), although relatively uncommon, can significantly reduce pulmonary reserve and has been associated with higher postoperative morbidity (50). The programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis plays a critical role in downregulating immune responses, and its blockade may result in excessive T-cell activation and subsequent lung injury (51,52).

CIP is particularly concerning in the surgical context because it may lead to pulmonary fibrosis, reducing lung compliance and functional reserve (53). These fibrotic changes can obscure tissue planes, increase dissection difficulty, and heighten the risk of complications such as bleeding or prolonged air leak (53,54). Moreover, immunotherapy may induce changes in vascular integrity or provoke peritumoral fibrosis that increases dissection complexity (54). Additionally, CIP has been associated with a higher incidence of postoperative pneumonia and impaired recovery (55).

A large pooled meta-analysis evaluating over 6,000 patients treated with anti-PD-1 therapies across several tumor types, found that the overall incidence of pneumonitis was approximately 2.92% for all grades and 1.53% for high-grade cases (56). Importantly, NSCLC patients showed a higher susceptibility than other cancers, with pneumonitis rates of 4.27% (all-grade) and 2.04% (high-grade), highlighting the need for increased vigilance in this population.

Despite the recognized risks, preoperative identification of patients at high risk for CIP remains challenging. Emerging research suggests that radiomics-based models using CT imaging may help predict susceptibility to immunotherapy-related lung toxicity, offering a promising, albeit preliminary, tool for pre-surgical risk stratification (57).

Studies investigating the impact of immunotherapy on perioperative outcomes have generally shown that it is well tolerated, with most patients proceeding to surgery without delay (22,58,59). However, a subset of patients—particularly those with preexisting pulmonary disease or low pre-treatment DLCO—may be at increased risk of complications (22). Recent analyses have suggested that reduced DLCO may serve as a predictor of adverse outcomes in post-immunotherapy resections, prompting calls for more rigorous preoperative pulmonary assessment in this population. In addition, radiologic tools such as computed tomography (CT) texture analysis and positron emission tomography (PET)-CT may help identify patients with high inflammatory burdens who may benefit from adjusted timing of surgery or even extended rehabilitation (22,59).

Taken together, these observations emphasize the importance of thorough preoperative evaluation in patients receiving neoadjuvant immunotherapy. Pulmonary function testing, including diffusing capacity of the lungs for carbon monoxide (DLCO) measurement, should be considered essential, and advanced imaging techniques may further aid in surgical planning. Responses to immunotherapy remain variable with many tumors exhibiting resistance for reasons that are not yet thoroughly understood (60). Consequently, there is increasing need to discover reliable biomarkers of response and immunotoxicity in order to optimize patient selection, minimizing complications, and improving surgical outcomes.

Conversion rates, intraoperative challenges and complications

Conversion from MIS to thoracotomy becomes a necessary and sometimes unavoidable decision. Conversion rates reported in the literature range from as low as 0% to over 50%, depending on the study population, disease burden, surgeon experience, and neoadjuvant treatment type (61,62). In general, a higher conversion rate is documented for patients operated after neoadjuvant therapy, in comparison to patients that did not receive neoadjuvant treatment before surgery. A large retrospective analysis of the National Cancer database in the US found a median conversion rate of 18.3% for neoadjuvant cases, while a meta-analysis of early-stage NSCLC found a conversion rate of 8.1% (61).

The most common intraoperative challenges leading to conversion from MIS to thoracotomy, include vascular involvement, uncontrolled bleeding, bulky or calcified lymph nodes, and lack of sufficient visualization due to scarring and dense adhesions (23-26,63). A correlation between higher stage-lymph node involvement and conversion rate has also been reported (64). Importantly, conversion should not be viewed as a failure of MIS but rather as a judicious and often life-saving surgical decision to preserve patient safety and ensure oncologic adequacy.

Studies comparing converted cases with completed MIS procedures show that conversion is associated with longer operative time, higher blood loss, and increased length of stay (61,62,64). However, when compared to planned open resections, outcomes in converted cases are often comparable, particularly when conversion occurs early and preemptively rather than as a last resort (64). These findings support a flexible operative strategy in post-neoadjuvant cases, where the initial intention to perform MIS should be accompanied by a low threshold for conversion when technically indicated.

Multiple studies compared complications based on surgical approach (15,20,23,27-34). Most found no significant differences in complication rate, but some found reduced operative times (24,28,37) and reduced estimated blood loss (19,30,37,65) when MIS techniques were utilized. When one or more deaths were reported, no significant difference was noted based on surgical approach (29,32,35). Pneumonia, atrial fibrillation and prolonged air leak are the main complications documented, in both MIS and open cases (29,32,35). The vast majority of researchers found no significant difference of morbidity and mortality between the two categories, while some reported a reduced incidence of major complications (35), cardiac complications (66) and medical complications (29). A shorter duration of medical stay was a common advantage documented for patients operated by MIS (29,36) as well as a reduced chest drainage output (27,29).

RO resection and effects on OS

Multiple studies report that complete (R0) resection rates after minimally invasive approaches (VATS or RATS) are comparable to open thoracotomy (24,25,29,38,39,42,67). These studies consistently found no significant difference in R0 rates between MIS and open approaches across multiple cohorts, including propensity-matched multicenter analyses and meta-analyses, supporting the oncologic adequacy of MIS when performed by experienced teams. Factors influencing R0 success include tumor response to neoadjuvant therapy, extent of fibrosis, and surgical expertise; conversion to open operation is sometimes required but generally does not compromise final R0 status.

MIS has been shown to achieve comparable OS to open thoracotomy in patients with resectable NSCLC following neoadjuvant therapy. Large retrospective and multicenter studies (29,38,39) found no significant difference in long-term OS between MIS and open approaches, despite MIS offering shorter hospital stays and fewer postoperative complications. Propensity-matched analyses (19,35,36) confirmed that VATS does not compromise oncologic outcomes after induction therapy, even in locally advanced or N2 disease. Furthermore, recent evidence incorporating neoadjuvant immuno- or chemo-immunotherapy (24,68) suggests that MIS remains feasible and safe, maintaining equivalent OS while reducing perioperative morbidity. Meta-analytic data (42) support that MIS provides comparable long-term survival and lymph node dissection adequacy, when compared with open surgery, reinforcing its role as an oncologically sound and less morbid alternative for appropriately selected patients.

Lymph node yields

Another critical concern in this setting is the ability of MIS to achieve adequate lymphadenectomy. Complete and accurate lymph node staging is a cornerstone of lung cancer surgery, not only for prognosis but also for guiding postoperative management, including adjuvant therapy decisions (69).

Some researchers have even corelated complete node dissection with survival benefits as well as a higher likelihood of finding occult N2 disease (70-72). Several early studies raised concerns about inferior nodal harvests with MIS compared to thoracotomy (19,24,27,29). However, these same studies demonstrated comparable survival results. These concerns have largely been mitigated by more recent data. Numerous studies now report no significant differences in the number of lymph nodes or stations dissected between MIS and open approaches, especially when procedures are performed by experienced thoracic surgeons adhering to established nodal dissection protocols (30,32,33,35). In fact, some evidence suggests that MIS may enable superior access to certain nodal stations due to enhanced visualization and maneuverability, resulting in higher N1 node yields and even increased rates of nodal upstaging in some cohorts (31,38,68,73).

Nonetheless, neoadjuvant therapy can itself confound the assessment of nodal yield. Treatment-related fibrosis and nodal shrinkage or necrosis can reduce the number of histologically identifiable lymph nodes, potentially giving the impression of incomplete dissection when, in fact, a thorough lymphadenectomy was performed. Pathological examination post-treatment can be complicated by treatment-induced changes, underscoring the importance of close collaboration between surgeons and pathologists. Efforts are underway to establish alternative metrics that may more accurately reflect lymph node evaluation quality in the post-treatment setting (74).

The role of radiation therapy within neoadjuvant protocols adds another layer of complexity. Radiation, particularly when delivered at curative doses (e.g., >50 Gy), induces significant tissue fibrosis, oedema, and adhesions, especially in mediastinal structures (35,39,40). These changes increase surgical difficulty and are strongly associated with higher conversion rates and longer operative times (34,40,66). Some studies suggest that surgeons may prefer planned thoracotomy in patients known to have received high-dose radiation, especially when central tumors or extensive nodal disease is present (34,39). However, MIS after radiation is not uniformly contraindicated. Several centers have reported successful VATS and RATS resections in post-radiation cases, albeit with meticulous preoperative planning and a readiness to convert if needed (35,40,62). Advanced imaging modalities, including high-resolution CT and PET-CT, are crucial in surgical planning to delineate fibrotic changes and differentiate viable tumor from post-treatment effects.

RATS vs. VATS

While RATS has received increasing attention for its technical innovations, emerging data suggest that VATS remains a highly effective and practical approach—especially in the context of neoadjuvant chemoimmunotherapy for NSCLC. VATS offers many of the same perioperative benefits as RATS, often without the added complexity, resource demands, or cost burden.

In a recent study both RATS and VATS achieved comparable short-term outcomes after neoadjuvant immunochemotherapy. Although RATS demonstrated marginal advantages in operative bleeding and drainage duration, these did not translate into substantial differences in overall complication rates or resection quality (43). Notably, operative times were longer in the RATS group, reflecting the increased setup and docking requirements. Another study reported similar findings, with both surgical techniques demonstrating low morbidity and high R0 resection rates. While RATS showed slightly reduced pneumonia rates and shorter hospital stays, the clinical significance of these differences remains modest, particularly when balanced against the greater costs and learning curve associated with robotic surgery (44).

Moreover, in a propensity score-matched study, although RATS showed improved lymph node yields, there was no demonstrated survival advantage, and VATS still provided excellent nodal dissection when performed by experienced surgeons (45). This suggests that VATS is not inherently inferior but rather highly dependent on surgical expertise—an important consideration in community or resource-limited settings.

Both RATS and VATS are safe and feasible following neoadjuvant chemoimmunotherapy, with no significant differences in major complications or conversion rates (46). Importantly, this reinforces the idea that the additional technological investment in RATS does not necessarily result in proportionately better outcomes, especially in the immediate postoperative period.

Economic analyses comparing VATS to RATS, indicate that VATS is generally more cost-efficient. In a single-institution study, overall hospital costs were significantly higher for RATS than for VATS (3,4). A separate cohort study in Italy reported similar findings, with RATS associated with higher procedural costs compared to VATS (75). Moreover, a UK-based analysis showed that although theatre costs for RATS approached those of VATS after the learning curve, overall costs remained higher due to postoperative factors (76). Collectively, these studies support that VATS currently represents the more cost-effective minimally invasive approach in most settings, with RATS approaching parity only in high-volume, optimized programs (77).

Challenges, limitations, and future directions in MIS post-neoadjuvant therapy

It is also worth highlighting the role of institutional and surgeon experience in influencing outcomes. Multiple studies have demonstrated that high-volume centers and surgeons with extensive MIS experience achieve better perioperative and oncologic results, even in challenging post-neoadjuvant cases (78). These findings suggest that centralization of care and adherence to multidisciplinary tumor board recommendations are essential for optimizing outcomes. Enhanced recovery after surgery (ERAS) protocols, when integrated into perioperative pathways, further reduce complications, shorten hospital stays, and improve patient satisfaction (79).

Despite the growing body of evidence supporting MIS post-neoadjuvant therapy, limitations persist in the literature. Most available data are derived from retrospective, observational studies, which are inherently subject to selection bias. Patients chosen for MIS often have more favorable anatomy, less extensive disease, or better pulmonary function, limiting generalizability. In addition, variability in definitions, surgical techniques, lymph node dissection protocols, and neoadjuvant regimens complicate comparisons across studies. There is an urgent need for prospective, randomized controlled trials that specifically evaluate the role of minimally invasive approaches, including VATS and emerging robotic techniques, in the post-neoadjuvant setting using standardized outcome measures and long-term follow-up.

Conclusions

In conclusion, accumulating evidence supports the use of minimally invasive techniques, in patients with NSCLC undergoing resection after neoadjuvant therapy. Although such cases present unique technical challenges due to treatment-induced fibrosis, nodal changes, and altered tissue planes, MIS remains feasible, safe, and oncologically effective in experienced hands. Conversion to open surgery should be regarded as a strategic and patient-centered decision, not a failure. Furthermore, outcomes appear closely linked to institutional experience and surgical volume, emphasizing the importance of centralizing care. However, current evidence remains largely retrospective, underscoring the need for prospective, randomized studies with standardized definitions and long-term oncologic follow-up. With the continued evolution of systemic therapies and surgical technology, MIS is poised to become an increasingly dominant modality in the multidisciplinary treatment of locally advanced lung cancer.

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-25-42/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-25-42/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-25-42/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.

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