Feasibility and safety of minimally invasive lung resection after neoadjuvant immunotherapy: a narrative review

Introduction

In 2020, lung cancer was responsible for an estimated 2.2 million new cases and 1.8 million deaths globally, representing about 18% of all cancer-related mortality worldwide (1). For early and locally advanced stage non-small cell lung cancer (NSCLC), surgical resection is the treatment of choice (2), and minimally invasive surgery (MIS) has become the standard approach for early stage lung cancer (3). Nevertheless, even after complete resection, a substantial number of patients develop eventual recurrence (4,5).

Neoadjuvant therapy has gained expanded indications in recent years, offering promise as a potential means of improving long-term impacts on recurrence, survival, often correlated with pathologic response. Historically, neoadjuvant chemotherapy alone has shown limited benefit (6). In the last decade, neoadjuvant immune checkpoint inhibitors (ICIs), specifically programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, changed the treatment paradigm for advanced as well as resectable NSCLC, demonstrating significant improvements in survival outcomes (7). The PD-1/PD-L1 interaction allows tumor cells to evade immune surveillance by inhibiting cytotoxic T-cell activity. Blocking this pathway with ICIs has become a treatment strategy for NSCLC. Currently, PD-1 inhibitors nivolumab and pembrolizumab, and PD-L1 inhibitors atezolizumab and durvalumab are approved by the Food and Drug Administration (FDA) in the treatment of NSCLC (8).

In NSCLC clinical trials, major pathologic response (MPR), defined as ≤10% viable tumor cells, and pathologic complete response (pCR), defined as 0% viable tumor cells, are being progressively adopted as surrogate endpoints to evaluate treatment efficacy (9). Studies have shown superior outcomes with neoadjuvant chemoimmunotherapy compared to chemotherapy alone, including higher pCR and MPR rates (44.8% vs. 2.6% and 66.4% vs. 20.7%, respectively) and longer disease-free and overall survival (10,11).

MIS techniques have transformed the management of early-stage NSCLC, offering proven safety, lower complication rates, faster recovery, and comparable oncologic outcomes to thoracotomy. Consequently, MIS has become the standard approach for early-stage disease, with expanding application to more advanced cases. Multiple studies have demonstrated superior perioperative outcomes with video-assisted thoracoscopic surgery (VATS) compared to thoracotomy, including fewer respiratory, cardiac, and surgical complications, lower mortality, shorter length of stay, and better long-term survival (12-15). VATS has also been associated with reduced postoperative pain and improved quality of life (16). Robotic-assisted thoracoscopic surgery (RATS) has emerged as another MIS option, showing comparable outcomes to VATS but with longer operative times (17-19). Overall, both VATS and RATS offer substantial perioperative and long-term benefits in NSCLC surgery, with ongoing research aimed at defining their roles in more complex and post-immunotherapy cases.

From an oncologic standpoint, ICIs have been a groundbreaking advancement. Yet, from a surgical perspective, it remains unclear whether immunotherapy increases surgical complexity, leading to operation delays, more open surgeries, conversions, and complications. Few reviews have specifically addressed the feasibility, safety, and technical considerations of MIS after immunotherapy. This narrative review aims to fill this knowledge gap by synthesizing current evidence on MIS following neoadjuvant immunotherapy, highlighting conversion rates, intraoperative challenges, predictors of surgical difficulty, and differences between trial and real-world outcomes. We present this article in accordance with the Narrative Review reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-24/rc).

Methods

A search of the MEDLINE (PubMed) database was conducted on May 31, 2025, using the terms “minimally invasive thoracic surgery”, “neoadjuvant”, and “immunotherapy”. No start date restriction was applied, and only studies published in English were considered (Table 1). The study selection process was conducted by D.P., who independently screened all retrieved records based on predefined inclusion and exclusion criteria. Any cases in which uncertainty arose were resolved through discussion, and consensus was reached via joint review.

Surgical challenges and feasibility of MIS following immunotherapy

While lung cancer surgery is inherently complex, the introduction of neoadjuvant immunotherapy presents unique intraoperative challenges that can further complicate surgical management. Hilar fibrosis is one of the common findings after neoadjuvant immunotherapy (20). Moreover, fibrosis of lymph nodes can result in the distortion of anatomical planes and cause tissues to become adherent, thereby increasing the technical difficulty of dissection (21). As a result, surgical consideration, especially with MIS, after neoadjuvant immunotherapy, remains a topic of debate.

Studies evaluating intraoperative characteristics after neoadjuvant immunotherapy have yielded mixed findings. A study by Zhang et al. showed that there was no difference in the proportion of intrathoracic adhesions between the neoadjuvant immunotherapy (sintilimab) and upfront surgery groups or between the neoadjuvant immunotherapy and neoadjuvant chemotherapy group (22). The same study found a higher proportion of patients with easy/normal grade lymph node dissection in the neoadjuvant immunotherapy group than in the upfront surgery group, and no statistically significant difference between the neoadjuvant immunotherapy and neoadjuvant chemotherapy groups. Moreover, Feldman et al. reported that 13 patients out of 22 (59.1%) in the nivolumab plus chemotherapy group were described as more difficult than a standard lobectomy due to adhesions, scarring, or fibrosis of the hilar structures and large and central tumors (23). In this study, cases were assigned a numerical difficulty score by the performing surgeon when available, or, for cases without a numeric score, operative reports were reviewed, and complexity was confirmed by a second provider based on detailed descriptions of surgical conduct.

In the literature, it has been reported that MIS following neoadjuvant immunotherapy depends on various factors, including visualization limitations, dense hilar lymphadenopathy, pleural adhesions, and the surgeon’s technical expertise (24). Despite these potential challenges, growing evidence supports the safety and efficacy of MIS in the post-immunotherapy setting. For instance, Chu et al. demonstrated that MIS after neoadjuvant treatment is both feasible and effective, reporting low conversion rates (conversion rate =16%), high rates of complete (R0) resection (R0 resection rate =96%), and low postoperative morbidity [major complication (Clavien-Dindo grade 3 or greater) rate =6%] (3). Notably, this study also found that the type of neoadjuvant treatment was not a determinant of success. Importantly, the type of neoadjuvant therapy was not identified as a determinant of successful MIS. Similarly, Forde et al. found that the minimally invasive approach was more frequently used in patients who received nivolumab combined with chemotherapy compared to those treated with chemotherapy alone (25).

Conversion rates from minimally invasive to open surgery after neoadjuvant therapy vary considerably across published studies (Table 2). In a systematic review, Takada et al. reported conversion rates ranging from 0% to 53.8% among seven clinical trials, reflecting heterogeneity in patient selection and surgical expertise (35). Romero Román et al. observed a conversion rate of 19% (26), while Gao et al. reported a much lower rate of 4.5% in patients undergoing robotic-assisted thoracic surgery following neoadjuvant immunochemotherapy (27). Moreover, a study by El Husseini et al. showed no statistically significant difference in conversion rates between neoadjuvant immunotherapy and control groups (28).

When comparing neoadjuvant immunotherapy to chemotherapy, evidence indicates that MIS outcomes are largely similar between the two modalities. Research conducted by Mathey-Andrews et al. demonstrated that there was no difference in the rate of MIS lobectomy between patients who received neoadjuvant immunotherapy and neoadjuvant chemotherapy (29). Furthermore, conversion rates were comparable between groups. Together, these findings highlight that MIS remains an appropriate surgical strategy regardless of the neoadjuvant treatment regimen used.

These findings highlight the need for continued evaluation of surgical outcomes following immunotherapy, as well as the refinement of techniques to safely manage fibrosis and altered tissue planes, particularly in the context of MIS. Surgical outcomes should be assessed across multiple dimensions, including intraoperative metrics such as conversion to open surgery and operative time, postoperative complications, oncologic completeness, including R0 resection and lymph node yield, and functional recovery, to provide a comprehensive understanding of procedural safety and effectiveness. However, it is also important to acknowledge that the current evidence remains limited, and the safety and feasibility of MIS after immunotherapy cannot yet be generalized. Most available studies are retrospective, involve small patient cohorts, and are conducted at high-volume centers with significant expertise in complex thoracic procedures. Consequently, outcomes may not be reproducible in lower-volume or less experienced institutions. Furthermore, the presence of dense fibrosis and distorted tissue planes can increase operative complexity, potentially offsetting the advantages typically associated with MIS. Therefore, careful patient selection and institutional readiness are essential when considering minimally invasive approaches in this setting.

Safety outcomes

Postoperative outcomes following neoadjuvant immunotherapy have been the focus of several recent studies, with overall findings supporting its safety profile (Table 2). In the CheckMate 816 trial, neoadjuvant nivolumab plus chemotherapy achieved a 5-year overall survival of 65.4%, compared to 55.0% in the chemotherapy-alone group [hazard ratio (HR) =0.72; 95% confidence interval (CI): 0.523–0.998]. Importantly, no new safety signals were observed with longer follow-up (36). Beyond assessing postoperative outcomes alone, it is equally important to investigate conversion rates, as intraoperative conversion from MIS to open thoracotomy not only reflects potential surgical challenges but has also been associated with increased perioperative morbidity and mortality, thereby serving as an additional indicator of the overall safety and feasibility of the surgical approach (37).

Aforementioned study by Mathey-Andrews et al. comparing patients who received neoadjuvant immunotherapy and neoadjuvant chemotherapy found that there was no significant difference in 30-day readmission, and 30- and 90-day mortality rates among the two groups (29). Deng et al. reported that while there were no mortality among patients who received neoadjuvant immunotherapy, there was a complication rate of 16.1% without any grade 3 complications (30).

A systematic review by Takada et al. reported that the mortality rate ranged from 0% to 5.4% (35). Similarly, another study by Bott et al. showed 0% of mortality of patients who received nivolumab as neoadjuvant therapy and underwent surgical resection. Nevertheless, the same study reported 50% of morbidity (31). Moreover, research conducted by Hu et al. demonstrated 0% mortality in patients who received neoadjuvant chemoimmunotherapy and underwent MIS (32).

Another study by Zhang et al. showed that VATS demonstrated comparable outcomes to open thoracotomy in terms of definitive resection rates, postoperative recovery, complication rates, and recurrence-free survival (RFS), and it offered additional benefits, including shorter operative time, reduced intraoperative blood loss, and a lower rate of postoperative ICU admissions (33).

Collectively, these findings suggest that neoadjuvant immunotherapy does not significantly increase the risk of postoperative morbidity or mortality and that MIS remains a viable and safe surgical option in appropriately selected patients following such treatment.

Discussion

As the role of neoadjuvant immunotherapy in resectable NSCLC continues to expand, future research efforts are focusing on optimizing patient selection, treatment sequencing, and surgical planning. Ongoing clinical trials are investigating not only the efficacy of novel immunotherapeutic agents but also their combination with chemotherapy, targeted therapies, or radiation (38). Trials have already demonstrated the survival benefit of neoadjuvant immunotherapy, and additional studies aim to validate surrogate endpoints such as pCR and MPR as predictors of long-term outcomes (39).

Moreover, new investigations are examining the impact of immunotherapy on surgical complexity and perioperative morbidity, with the goal of developing evidence-based guidelines for surgical planning after neoadjuvant treatment (40). Prospective multicenter trials are also needed to compare MIS and open approaches in the setting of immunotherapy, particularly with respect to conversion rates, intraoperative challenges, and long-term oncologic outcomes.

The predictors of unsuccessful MIS remain an area of ongoing investigation. Bao et al. reported that patients with a favorable response to neoadjuvant therapy tend to undergo less invasive procedures and have a higher likelihood of successful MIS, whereas those with a less favorable response more often require extended resections using an open approach (34). In addition to treatment response, other factors such as tumor burden, nodal involvement, and specific imaging characteristics may also influence the likelihood of conversion or operative difficulty. While these associations are still being explored, understanding these predictors is essential for surgical planning and optimizing patient selection for minimally invasive approaches.

The wide variation in reported conversion rates (0–53.8%) likely reflects differences in patient selection, disease stage, tumor location, degree of fibrosis, type and duration of neoadjuvant immunotherapy, and surgeon or institutional experience. Further analyses focusing on these factors are warranted to better understand their relative contributions to conversion risk and to identify strategies that may optimize patient selection and surgical planning.

The learning curve for MIS after neoadjuvant immunotherapy is an important consideration. Several studies suggest that operative complexity and conversion rates are influenced not only by patient- and tumor-related factors but also by surgeon experience. Therefore, careful patient selection, mentorship, and gradual accumulation of experience are critical for safely performing MIS in this patient population.

An important consideration for future research is the adoption of standardized, objective measures of surgical complexity (41). Current studies often rely on surrogate indicators such as estimated blood loss (EBL) and operative time, which may not accurately reflect the true technical challenges of a procedure. Developing and implementing validated complexity scoring systems, accounting for factors such as extent of dissection, anatomical distortion, tissue quality, and intraoperative decision-making (42), will provide a more nuanced understanding of how treatments like immunotherapy impact surgical difficulty. For example, Feldman et al. defined operative complexity based on the presence or absence of specific criteria, including but not limited to lymph nodes described as matted, sticky, or hard; lymph nodes that could not be separated from the pulmonary artery; and lymph node adherence to the pulmonary artery causing vascular tears (41). Such standardized measures are essential for comparing outcomes across studies and for guiding operative planning and patient counseling.

Another consideration in thoracic surgery is the selection of patients for MIS, particularly after neoadjuvant therapy. Patient eligibility is influenced by several factors, including tumor characteristics such as size, location, and lymph node involvement, as well as the presence of fibrosis or tissue changes resulting from neoadjuvant treatment. Patient-related factors, including lung function, comorbidities, and overall functional status, also play a critical role in determining suitability for MIS. Additionally, technical considerations, such as the surgeon’s experience with thoracoscopic or robotic-assisted approaches and the potential need to convert to an open procedure, must be taken into account. Careful patient selection ensures that the benefits of MIS, including reduced complications, shorter hospital stay, and faster recovery, are achieved without compromising safety or oncologic outcomes. Further research is needed to establish evidence-based guidelines for patient selection in minimally invasive thoracic surgery.

The role of MIS in patients undergoing resection after extensive pretreatment for more advanced-stage disease also remains an area requiring further investigation. These cases are often particularly challenging, which can complicate dissection and increase the risk of intraoperative complications. As a result, the feasibility, safety, and oncologic adequacy of MIS in this context are not yet fully established (43). Future studies should aim to define clear selection criteria and assess outcomes specific to this subgroup to better understand when MIS can be appropriately and effectively employed.

As the treatment landscape evolves, integrating molecular and radiographic biomarkers into preoperative decision-making may allow for more precise prediction of treatment response and surgical difficulty. Ultimately, a multidisciplinary, personalized approach that incorporates oncologic efficacy and surgical safety will be key to advancing care for patients with resectable NSCLC.

This narrative review has several limitations. First, it is important to distinguish clinical trial data from real-world experience. Trials often include highly selected patients under standardized protocols, which may not reflect broader populations, whereas real-world data capture variability in patient characteristics, comorbidities, and institutional practices, offering complementary insights into the feasibility and safety of MIS after neoadjuvant immunotherapy. Second, the sample sizes and follow-up durations varied across studies, limiting the ability to draw definitive conclusions. Third, heterogeneity in neoadjuvant regimens, surgical techniques, and reporting of outcomes may have influenced the findings. Finally, as a narrative review, the selection and synthesis of studies were not conducted using formal systematic review methodology, which may introduce selection bias. Despite these limitations, this review provides a comprehensive overview of the current evidence on MIS following neoadjuvant immunotherapy.

Conclusions

Neoadjuvant immunotherapy has emerged as a transformative approach for resectable NSCLC, improving pathologic responses and survival while raising concerns about surgical complexity. Current evidence indicates that MIS remains both feasible and safe in appropriately selected patients, with outcomes comparable to those after chemotherapy alone. Further prospective studies using standardized measures of surgical difficulty are needed to refine patient selection and guide operative planning, but the integration of immunotherapy with MIS holds promise for advancing care in resectable NSCLC.

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-25-24/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-25-24/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-25-24/coif). M.B.A. received consulting fees from Merck, AstraZeneca (AZ), Bristol Myers Squibb (BMS), and Johnson and Johnson (J&J). The other author has 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.

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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