Special considerations for video-assisted thoracic surgery resection for patients receiving preoperative neoadjuvant chemoradiotherapy and/or immunotherapy: a narrative review

Introduction

Background

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide, with an annual estimate of 2.2 million new cases and about 1.8 million deaths (1). The treatment for NSCLC has undergone significant transformation driven by advances in systemic therapies and surgical techniques. Chemoradiotherapy (CRT) and immunotherapy have emerged as crucial treatment strategies for patients with locally advanced but resectable tumors. They aim to improve survival outcomes by reducing tumor size and addressing micro-metastases. Neoadjuvant therapies showed an increased likelihood of complete resection, decreased recurrence rates, and improved overall survival (OS) when compared to adjuvant therapies only (2).

Neoadjuvant CRT, by its nature, induces inflammation, fibrosis, and tissue damage. Furthermore, the radiation-induced scarring may create dense adhesions that obscure vital structures, significantly altering the lung and surrounding anatomical structures and complicating surgical resection. This increases the risk of complications such as bleeding, injury to critical structures (e.g., blood vessels and airways), and incomplete resections (3). Similarly, while immunotherapy has revolutionized the treatment of advanced NSCLC by reactivating the immune system to target cancer cells, its application as a neoadjuvant therapy has raised concerns about delayed tumor response, immune-related adverse events, and the timing of surgery. The tumor shrinkage can be slower and less predictable than that observed with traditional CRT (4). In addition, immune-related adverse events, including pneumonitis, can complicate surgical planning by impairing lung function and raising concerns about surgical risk (5).

Rationale and knowledge gap

Video-assisted thoracic surgery (VATS) emerged as a standard technique for resecting lung cancer, offering significant advantages over traditional open thoracotomy (6). It has revolutionized thoracic surgery by reducing postoperative pain, shortening recovery times, and offering better cosmetic outcomes. It became a mainstay of modern-day thoracic oncology practice and the technique of choice for resectioning early-stage lung cancers. The feasibility of using VATS for lung cancer resection has long been well established. However, performing VATS resection in patients undergoing neoadjuvant CRT or immunotherapy presents unique technical and clinical challenges. The outcomes of VATS resection post neoadjuvant CRT and/or immunotherapy for NSCLC compared to conventional open thoracotomy are yet to be established.

Objective

This narrative review explores the unique challenges faced in performing VATS resection in patients who received CRT and immunotherapy. It discusses the effects of these treatments on tumor biology, tissue integrity, immune responses, and overall surgical challenges and outcomes post-VATS resection. The review also provides recommendations for optimal management strategies, surgical timing, and postoperative care to enhance the safety and efficacy of VATS resection. We present this article in accordance with the Narrative Review reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-2/rc).

Methods

Electronic database search was done in PubMed and Google Scholar on 29 October 2024. Combinations of research Medical Subject Headings and search terms were keyed in. The search terms were ‘Neoadjuvant chemoradiotherapy AND NSCLC’, ‘Immunotherapy’, ‘Video assisted thoracoscopy’, ‘VATS’ and ‘Minimally invasive surgery AND NSCLC’. The review was limited to studies written in English with no date restrictions. Studies were included for evaluation based on the title and abstract and subsequently reviewed in detail by the authors. Additional studies regarding neoadjuvant therapy and surgical techniques were queried and reviewed as necessary. A total of 48 original manuscripts were used in writing this narrative review. See Table 1 for further information.

Discussion

Locally advanced disease and candidates for neoadjuvant CRT and/or immunotherapy in lung cancer

Locally advanced NSCLC refers to stage II–III disease which is characterized by the spread of cancer beyond the primary tumor to involve ipsilateral hilar/mediastinal lymph nodes or adjacent structures such as chest wall, diaphragm or mediastinum, without evidence of distant metastasis. Selected cases require neoadjuvant therapy before surgical resection based on the burden of lymph node involvement and response to neoadjuvant treatment (7). Patients with this stage of disease typically have tumors that are considered potentially or marginally resectable at presentation due to anatomical or nodal factors.

Neoadjuvant CRT and immunotherapy

Neoadjuvant CRT is a well-established treatment modality for selected patients with locally advanced NSCLC. CRT aims to downstage the disease, increase the probability of complete surgical resection (R0), and address micro-metastases to improve survival (8). R0 resection is defined as no identifiable tumor remaining, negative surgical margins, adequate node assessment and highest node station assessed is negative (9). Chemotherapy, often involving platinum-based agents such as cisplatin and carboplatin, causes DNA damage in rapidly dividing tumor cells. Radiation therapy induces DNA double-strand breaks and generates reactive oxygen species which lead to cell death. Combining these therapies can sensitize the tumor to further improve the overall efficacy (10). In prospective studies, neoadjuvant CRT has been associated with a pathologic complete response (pCR) rate of approximately 15–20%, with higher rates observed in patients achieving major radiologic regression. Additionally, it has shown a 5-year survival improvement in certain populations, with survival rates ranging from 35–40% (11) for patients who undergo complete resection following CRT.

Neoadjuvant immunotherapy, specifically immune checkpoint inhibitors (ICIs) [e.g., programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) inhibitors], has recently emerged as an effective neoadjuvant treatment. This approach stimulates the immune system to recognize and destroy tumor cells, potentially enhancing the therapeutic benefit when combined with chemotherapy. Immunotherapy, such as pembrolizumab, nivolumab, and atezolizumab, has revolutionized the treatment of advanced NSCLC. These agents block immune checkpoint proteins [(PD-1, PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)], enhancing the immune system’s ability to target cancer cells (12). On the other hand, recent trials have highlighted the transformative role of immunotherapy as a neoadjuvant treatment for resectable NSCLC. The KEYNOTE-091 trial (13) investigated pembrolizumab, either as monotherapy or combined with chemotherapy, in patients with stage II–III NSCLC before surgery. Results showed a significant improvement in event-free survival (EFS) and a higher pCR rate in the pembrolizumab-treated group, with the greatest benefits observed in patients whose tumors exhibited high PD-L1 expression. Surgical outcomes from AEGEAN (14) and KEYNOTE-671 (15) trials further support the feasibility of neoadjuvant chemoimmunotherapy treatment (nCIT), reporting low rates of disease progression leading to failure to undergo surgery—5% for stage IB–II and 8% for stage III disease in the nCIT arm compared to 2% and 14% in chemotherapy alone. The CheckMate-816 trial (16) evaluated nivolumab combined with chemotherapy for stage IIB–IIIA NSCLC. It demonstrated a dramatic improvement in pCR rates (24% vs. 2.2% with chemotherapy alone), emphasizing the potential of neoadjuvant immunotherapy to enhance outcomes and improve long-term survival. It also significantly improved median EFS to 31.6 months compared with 20.8 months with chemotherapy alone. The 2-year EFS rate was 63.8% in the nCIT group vs. 45.3% in the chemotherapy-only group, and the pCR rate was markedly higher at 24% vs. 2.2%, respectively (16). Meanwhile, the IMpower010 trial assessed the addition of atezolizumab, a PD-L1 inhibitor, following chemotherapy in patients with stage II–IIIA NSCLC (15). It found significant improvements in disease-free survival, particularly in patients with high PD-L1 expression, further cementing the role of immunotherapy in early-stage NSCLC. Together, these trials suggest that neoadjuvant immunotherapy, particularly in patients with high PD-L1 levels, could redefine the standard of care for resectable NSCLC.

Additionally, the rate of pCR, which is associated with improved long-term survival, was significantly higher in the immunotherapy groups. This suggests that immunotherapy may not only enhance tumor resectability but also improve long-term outcomes by eradicating micro-metastases. The NADIM trial [2020] showed that neoadjuvant nivolumab combined with chemotherapy achieved a pCR rate of 63% and a 2-year OS rate of 85.3%, significantly higher than historical results with chemotherapy alone (17).

Moreover, concerns about increased surgical complexity due to tissue inflammation or fibrosis post-nCIT are minimal, as evidenced by the NADIM trial (18), where 89.1% of patients proceeded to surgery with complete (R0) resection rates, a 19% conversion from VATS to open surgery, and only a single major complication reported.

In the metastatic NSCLC setting, DeLasos highlight the benefits of triplet therapy—tremelimumab, durvalumab, and chemotherapy—in patients with aggressive molecular subtypes characterized by KRAS, STK11, and KEAP1 mutations (19). The POSEIDON trial’s updated 5-year OS analysis revealed a 24% reduction in the risk of death with triplet therapy compared to chemotherapy alone [hazard ratio (HR) =0.76], with a favorable but not statistically significant trend for the durvalumab-plus-chemotherapy arm (HR =0.84) (18).

Candidate selection

Candidates for neoadjuvant CRT or immunotherapy are carefully selected based on clinical and biological factors (20), including:

• Tumor stage: stage IIIA or IIIB disease with resectable or borderline-resectable tumors.
• Biomarkers: PD-L1 expression ≥1% or presence of other markers of immunotherapy sensitivity, such as high tumor mutation burden.
• Comorbidities: absence of contraindications such as autoimmune diseases or prior history of severe immune-related adverse events.
• Performance status: Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 is preferred.

Determining the extent of lung cancer resection post-neoadjuvant CRT

The extent of lung cancer resection following CRT is determined by the tumor response, patient anatomy and the feasibility of achieving R0 resection while preserving adequate lung function. The primary goal of surgical resection is to remove all residual tumor and lymph nodes while minimizing perioperative morbidity and mortality.

Factors influencing the extent of resection

Tumor response to CRT: neoadjuvant CRT aims to downstage lymph node involvement, improving the chances of resectability. pCR, defined as no residual viable tumor cells in the surgical specimen, occurs in 15–25% (11,21) of patients after CRT. Patients achieving pCR have significantly improved long-term survival, with 5-year OS rates of up to 35–40% (11,12). Lobectomy is the standard surgical approach for most resectable NSCLC cases. It provides sufficient oncologic resection while preserving pulmonary function. Studies report that up to 70–80% of patients undergoing surgery post-CRT can successfully receive lobectomy (13). Among patients undergoing resection after neoadjuvant CRT, 80% achieved R0 resection, with lobectomy performed in 75% and pneumonectomy in 25% of cases. Patients with R0 resection had a median survival of 33 months, compared to 15 months for those with incomplete resections (16). Pneumonectomy may be necessary in cases where the tumor extensively involves adjacent lobes or central structures. It is associated with higher perioperative mortality (5–10%) and long-term morbidity compared to lobectomy (15). Careful patient selection is necessary in these cases. In a retrospective study, patients undergoing lobectomy had a perioperative mortality rate of 2%, significantly lower than the 6–8% observed in pneumonectomy cases, emphasizing the importance of pursuing lobectomy when anatomically feasible (17,22). Sub-lobar resections such as segmentectomy or wedge resection are rarely performed in the post-CRT setting due to their reduced oncologic efficacy. The ability to achieve an R0 resection, including complete mediastinal lymph node dissection, is crucial in these cases. Persistent nodal involvement (ypN1-2) after CRT and or immunotherapy is associated with worse outcomes, with 5-year survival rates declining to 20–30% (23). Postoperative complications, such as respiratory failure, are more common in patients with limited lung reserve after surgery. The extent of surgical resection is heavily influenced by preoperative pulmonary function tests (PFTs) and overall cardiopulmonary reserve, emphasizing the importance of individualized patient assessments (24). Up to 19% of patients will not be candidates for surgical resection post-neoadjuvant chemoimmunotherapy. Failure to proceed with surgical resection following neoadjuvant chemoimmunotherapy was defined by an inability to resect or to achieve complete resection secondary to disease progression, toxicity or poor ECOG performance post-neoadjuvant treatment (14). Analysis of phase 3 trials [CheckMate 816 (16), Keynote-671 (13), AEGEAN (25), Neotorch (26)] reveals that a significant proportion of patients (16% to 22%) do not undergo planned surgical resection after neoadjuvant chemoimmunotherapy. Reasons for cancellation include disease progression, adverse events rendering patients unfit for surgery, and other factors. The authors highlight the cancellation rate in CheckMate 816, where 15.6% of patients in the intervention arm, and this cancellation occurred even in patients with earlier stages (12% in stage IB–II) (16). This level of cancellation, especially in early-stage resectable disease, raises concerns. While patients desire rapid surgical removal, neoadjuvant chemoimmunotherapy can lead to delays in getting to the operating room due to neoadjuvant toxicity, logistics, and advanced events (AEs).

Tumor and tissue changes post neoadjuvant CRT and immunotherapy in lung cancer

One of the major effects of neoadjuvant CRT is the induction of fibrosis. It results from tissue damage that is followed by an inflammatory response, ultimately leading to the deposition of collagen and the formation of scar tissue. It can make the surrounding tissues more rigid and less compliant, affecting the surgeon’s ability to perform smooth dissection. Additionally, vascular changes such as endothelial injury, vascular occlusion, and thrombosis may occur, further complicating surgical procedures and increasing the risk of bleeding.

Another complication of neoadjuvant CRT is the formation of adhesions. Radiation causes injury to the pleura, diaphragm, and surrounding structures, which can lead to the development of dense adhesions. This can make the procedure technically challenging and elevates the risk of bleeding, injury to the pleura, and difficulty in achieving clear surgical margins and complete resection, leading to potential local recurrence (27). It also can make the dissection of lung tissue more difficult and increase operative time. Furthermore, radiation-induced changes in nearby structures, such as the heart, esophagus, and major blood vessels, heighten the risk of intraoperative injury (28).

Although neoadjuvant immunotherapy holds significant promise, it is not without challenges. Unlike chemotherapy or radiation, which exert immediate cytotoxic effects on tumor cells, immunotherapy works by stimulating the immune system, a process that can take weeks to months to reach its full therapeutic effect. This delayed response can complicate the timing of surgery and make it difficult to assess the full extent of tumor regression before the operation (29). In some patients, tumors may initially appear stable or even increase in size before eventually shrinking as the immune response matures. This phenomenon, known as “pseudoprogression”, can pose a challenge for clinicians in establishing operative time. This phenomenon has been observed in up to 10–20% of patients treated with ICIs (30). Recognizing pseudoprogression is critical for avoiding unnecessary delays in surgery. Surgeons must be mindful of these unique tumor dynamics when determining the timing of surgery. In clinical practice, surgery is generally delayed by 4–6 weeks following the completion of immunotherapy to ensure the full effects of the immune response are realized and to allow for the resolution of immune-related side effects (31). However, longer delays may increase the risk of tumor recurrence or progression, particularly in high-risk patients. Thus, the decision must be individualized, considering both the tumor response and the patient’s overall health. Emerging data from clinical trials, including the IMpower010 study demonstrated that atezolizumab improved disease-free survival in patients with resectable stage II–III NSCLC, but the timing of surgery was again not fixed, with patients undergoing surgery after varying durations (15). This trial, along with CheckMate-816, suggests that surgery can be safely delayed until the full effects of immunotherapy are apparent, but careful patient selection and close monitoring are necessary (16). Radiation therapy and ICIs can also cause granulomatous inflammation, which may present as nodules or masses on imaging. Granulomatous changes can affect lymph nodes, complicating the assessment of lymph node involvement during surgery. Consequently, surgeons may need to rely on advanced imaging techniques or intraoperative frozen section to guide the resection (32).

Pulmonary function and anesthesia considerations

Given the potential for pulmonary damage caused by neoadjuvant treatment, preoperative pulmonary function testing is essential. This provides valuable information regarding lung function and help assess the patient’s ability to tolerate surgery (33). High-resolution computed tomography (HRCT) scans can also reveal signs of radiation-induced fibrosis, such as ground-glass opacities or consolidation, as well as any signs of immunotherapy-induced pneumonitis. Anesthesia management in patients with compromised lung function must be carefully planned to minimize the risk of complications such as ventilator-associated lung injury. Protective ventilation strategies such as low tidal volume ventilation and positive end-expiratory pressure are employed to minimize lung injury during surgery (34). Additionally, regional anesthesia techniques, such as epidural or paravertebral blocks, can be used to manage pain while reducing the need for systemic opioids, which can further depress pulmonary function leading to post-operative hypoxia and atelectasis (35).

Special considerations for VATS resection after neoadjuvant CRT and or immunotherapy

Technical challenges for VATS post neoadjuvant therapy

One of the most significant challenges in performing VATS on patients who have undergone neoadjuvant therapy is the presence of dense adhesions due to radiation-induced pleural thickening. These adhesions complicate the surgical process, requiring surgeons to use blunt dissection techniques and specialized instruments such as ultrasonic scalpels or electrocautery to safely separate tissues without damaging adjacent structures. Tumor identification and achieving clear resection margins are also challenging, as necrosis and fibrosis caused by radiation and chemotherapy can obscure the tumor’s boundaries. Surgeons often depend heavily on preoperative imaging and intraoperative frozen sections to guide resection (36). Another critical issue is the increased risk of intraoperative bleeding, as radiation and chemotherapy can damage the vasculature, rendering the vascular supply to the tumor and surrounding tissues fragile. This necessitates meticulous handling to prevent vascular injury. Surgeons are advised to secure proximal and distal vascular control preemptively and employ advanced hemostatic techniques such as laser coagulation, ultrasonic coagulators, and electrocautery to manage bleeding effectively (3). The complexity of VATS, combined with the challenges posed by altered anatomy after neoadjuvant chemotherapy or CRT, often leads to longer surgical times compared to open thoracotomy. This contradicts previous studies indicating that VATS may require shorter operative time, with a quicker recovery time and reduced postoperative complications (36).

The conversion rate from VATS to open surgery in patients treated with neoadjuvant therapy for lung cancer varies widely, ranging from 0% to 53.8%, depending on the patient population and intraoperative challenges (37). This higher conversion rate is primarily due to complications such as tissue changes and difficulty in tumor resection. Despite these challenges, VATS generally leads to shorter hospital stays compared to open surgery. Patients undergoing VATS experience less postoperative pain, faster mobilization, and a quicker return to normal activities, with hospital stays averaging 2–4 days shorter than those undergoing open surgery (38).

A multicenter retrospective study by Chu et al. (28) compared open thoracotomy and VATS for lung cancer resections after neoadjuvant immunochemotherapy. Among 627 resections analyzed, 360 (57%) were performed via thoracotomy, and 267 (43%) via minimal invasive surgery (MIS). The study found that MIS patients had better pulmonary function, evidenced by a higher median forced expiratory volume in one second (94.0% vs. 88.0%) and diffusing capacity of the lungs for carbon monoxide (76.0% vs. 73%). Additionally, MIS was associated with improved postoperative outcomes, including fewer overall complications (31% vs. 41%) and major complications (6% vs. 13%), shorter hospital stays (median 4 vs. 5 days), and lower 30-day (0 vs. 6) and 90-day mortality (0 vs. 14). MIS success rates were 77%, with 96% achieving R0 resection, but complications were more frequent in the “not successful” MIS group (53% vs. 25%). Surgeon experience emerged as a key factor, with those performing more than 50 MIS cases annually achieving higher success rates.

Prolonged air leak, defined as an air leak lasting more than 5 days, is a common complication after VATS lobectomy. Studies report its incidence ranges from 10% to 30% in standard cases, increasing to 25–30% in patients who have undergone neoadjuvant therapy (39). This underscores the importance of careful patient selection and meticulous intraoperative techniques in optimizing outcomes for this high-risk population.

Post neoadjuvant chemoimmunotherapy comparing VATS to open approach

Eight studies were selected based on the search tool mentioned in Table 2, comparing VATS vs. open approach post neoadjuvant chemoimmunotherapy. These studies reported that VATS and open thoracotomy yield similar long-term survival outcomes but differ in several short-term surgical metrics. Zhang et al., 2022 (40) reported VATS had a shorter operative time but Cao et al., 2024 (41) reported no difference. Three studies consistently observed lower intraoperative blood loss with VATS (40-42). Conversion rates for VATS ranged from 8.6% to 42%. In terms of complications and recovery, complication rates of 9.7% compared with 30.4% (P=0.036) reported, with Clavien-Dindo severity classifications offering comparable outcomes (43). Hospital stay was shorter with VATS in six of eight studies (for instance, a median stay of 6 vs. 8 days in one report), whereas time to full recovery was not consistently reported. Overall, the papers indicate that VATS and open thoracotomy provide comparable long-term overall and disease-free survival, with VATS showing modest advantages in select perioperative and recovery measures.

Robotic-assisted resection [robotic-assisted thoracic surgery (RATS)]

The evolution of VATS has been significantly enhanced by the introduction of robotic-assisted surgery. In complex cases, RATS may offer distinct advantages, including enhanced visualization and precision. It minimizes tissue dissection and improved accuracy in the resection, which is particularly important in fragile lung parenchyma post neoadjuvant treatment changes. Robotic platforms allow for even greater precision in thoracic surgery by improving the ergonomics of the surgeon’s movements and providing enhanced 3D visualization. It offers greater dexterity and fine motor control compared to conventional VATS, making it especially useful in challenging cases, when the tumor location, tumor size or position complicates access.

A study involving patients with stage III NSCLC receiving neoadjuvant chemoimmunotherapy found that RATS resulted in significantly lower conversion rates to thoracotomy (6.67% vs. 9.68%) compared with conventional VATS (47).

Postoperative care and complications

The risk of pneumonia and respiratory failure is elevated in patients who have received neoadjuvant CRT or immunotherapy, due to the immunosuppressive effects of these therapies. A study by Whitson et al. (38) in 2008 found that pulmonary complications occurred in 18–20% of patients following VATS, with a significant portion of these cases involving postoperative pneumonia. In addition, radiation-induced fibrosis can impair lung function and hinder postoperative recovery. Studies have shown that patients who underwent neoadjuvant CRT prior to surgery were more likely to require long-term mechanical ventilation and had prolonged hospital stays compared to those who underwent surgery alone (48-50). Minimally invasive surgical techniques such as VATS have been shown to reduce some of these complications by minimizing the trauma to lung tissue and allowing for quicker recovery. Pneumonitis occurs in 3–5% of patients receiving ICIs for NSCLC, with more severe cases leading to hospitalization and even death in some instances (51). The onset of pneumonitis can range from a few weeks to several months after initiating immunotherapy. The presence of pneumonitis can complicate VATS in several ways. The underlying lung tissue may be more fragile, leading to an increased risk of air leaks, bleeding, and incomplete resections. Additionally, if the patient is still symptomatic with pneumonitis at the time of surgery, the risk of hypoxemia and pulmonary edema may be significantly elevated (52).

Outcomes and prognosis of VATS after neoadjuvant therapy

The survival outcomes for patients undergoing VATS following neoadjuvant CRT or immunotherapy have shown promising results in several studies, though these patients often face an increased risk of postoperative complications due to the effects of treatment. Notably, the response to CRT—in particular, the degree of tumor regression—has been identified as a critical prognostic factor. Tumors that show a pCR, where there is no residual viable cancer after treatment, are associated with significantly better outcomes, including higher survival rates and lower recurrence rates (51,53).

Conclusions

In conclusion, neoadjuvant CRT and immunotherapy are increasingly utilized in the management of locally advanced, potentially resectable NSCLC, particularly for patients with stage III disease. These treatments have demonstrated the ability to downstage tumors, enhance resectability, and improve survival outcomes, particularly when combined with surgery. Neoadjuvant CRT remains a well-established approach with significant benefits in terms of pCR rates and long-term survival, while immunotherapy has shown promising results in boosting pCR and EFS, especially in tumors with high PD-L1 expression.

However, both therapies introduce unique challenges. CRT may cause fibrosis and adhesions, complicating surgical resection, while immunotherapy’s delayed effects and potential for pseudoprogression require careful timing and patient selection. The evolving role of VATS, has shown great promise, although it also presents challenges in patients post-neoadjuvant therapy due to altered anatomy and increased risk of complications. Advances such as robotic-assisted VATS have the potential to overcome some of these hurdles, offering enhanced precision and reduced conversion rates. Ultimately, the integration of neoadjuvant therapies with surgical approaches offers a tailored, multi-faceted strategy for improving survival in NSCLC, but careful management of postoperative complications and long-term monitoring are essential to optimize outcomes. With ongoing research and evolving techniques, the future of lung cancer treatment looks increasingly personalized and effective, providing hope for patients with locally advanced disease. Real-world data are needed to establish the true impact of neoadjuvant chemo-immunotherapy with ICIs on thoracic surgery daily practice, to evaluate whether lymphadenectomy and rates of upstaging are affected, and to learn the scope of the surgical technical challenges faced after immunotherapy.

Strengths

This narrative review provides an extensive analysis of the unique surgical challenges encountered during VATS in patients with NSCLC who have undergone neoadjuvant CRT and/or immunotherapy. It synthesizes data from 53 original studies, covering tumor biology, immune and tissue responses, and surgical outcomes. Furthermore, it highlights practice-changing trials in a summarized form, with particular attention toward clinically significant outcomes. A key strength of the review is that it provides practical guidance on surgical timing and perioperative management.

Limitations

The included studies vary in design, population, and outcome measures, which reduces the ability to generalize findings across all clinical settings. Many data points, especially those regarding VATS conversion rates, surgical morbidity, and survival outcomes post-neoadjuvant therapy, stem from retrospective studies with heterogeneous protocols and surgeon experience. Additionally, the review does not address cost-effectiveness or resource availability for VATS or robotic techniques, which may affect broader applicability. Prospective studies and randomized controlled trials are needed to validate the review’s recommendations and determine standardized protocols for optimal surgical management in this complex patient population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Gregory Trachiotis) for the series “Preoperative Planning and Assessment for VATS Lung Cancer Resection” published in Video-Assisted Thoracic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-25-2/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-25-2/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-25-2/coif). The series “Preoperative Planning and Assessment for VATS Lung Cancer Resection” was commissioned by the editorial office without any funding or sponsorship. P.J.V. reports receiving a research grant from the Department of Surgery, University of Ottawa and accreditation-related work from the Royal College International. He has received educational grants for training from Intuitive Surgical, Inc. and Johnson & Johnson. The authors have no other 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/.

References

1. Li C, Lei S, Ding L, et al. Global burden and trends of lung cancer incidence and mortality. Chin Med J (Engl) 2023;136:1583-90. [Crossref] [PubMed]
2. Romero Román A, Campo-Cañaveral de la Cruz JL, Macía I, et al. Outcomes of surgical resection after neoadjuvant chemoimmunotherapy in locally advanced stage IIIA non-small-cell lung cancer. Eur J Cardiothorac Surg 2021;60:81-8. [Crossref] [PubMed]
3. Bai G, Chen X, Peng Y, et al. Surgery challenges and postoperative complications of lung cancer after neoadjuvant immunotherapy. Thorac Cancer 2024;15:1138-48. [Crossref] [PubMed]
4. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
5. Lin X, Xie M, Yao J, et al. Immune-related adverse events in non-small cell lung cancer: Occurrence, mechanisms and therapeutic strategies. Clin Transl Med 2024;14:e1613. [Crossref] [PubMed]
6. Pan H, Chen H, Kong W, et al. Video-Assisted Thoracoscopic Surgery Versus Thoracotomy Following Neoadjuvant Immunochemotherapy in Resectable Stage III Non-Small Cell Lung Cancer Among Chinese Populations: A Multi-Center Retrospective Cohort Study. Clin Lung Cancer 2024;25:395-406.e5. [Crossref] [PubMed]
7. Kim SS, Cooke DT, Kidane B, et al. The Society of Thoracic Surgeons Expert Consensus on the Multidisciplinary Management and Resectability of Locally Advanced Non-small Cell Lung Cancer. Ann Thorac Surg 2025;119:16-33. [Crossref] [PubMed]
8. Yalman D. Neoadjuvant radiotherapy/chemoradiotherapy in locally advanced non-small cell lung cancer. Balkan Med J 2015;32:1-7. [Crossref] [PubMed]
9. Detterbeck FC, Woodard GA, Bader AS, et al. The Proposed Ninth Edition TNM Classification of Lung Cancer. Chest 2024;166:882-95.
10. Chen P, Kuang P, Wang L, et al. Mechanisms of drugs-resistance in small cell lung cancer: DNA-related, RNA-related, apoptosis-related, drug accumulation and metabolism procedure. Transl Lung Cancer Res 2020;9:768-86. [Crossref] [PubMed]
11. Andolfi M, Meacci E, Salati M, et al. Uniportal Video-Assisted Thoracoscopic Anatomic Lung Resection after Neoadjuvant Chemotherapy for Lung Cancer: A Case-Matched Analysis. Cancers (Basel) 2024;16:2642. [Crossref] [PubMed]
12. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. [Crossref] [PubMed]
13. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274-86. [Crossref] [PubMed]
14. Nardini M, Lodhia J, Muthiverula A, et al. P90 Surgical outcomes after neoadjuvant nivolumab and platinum-based chemotherapy in resectable non-small cell lung cancer. Thorax 2024;79:A158-9.
15. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023;34:907-19. [Crossref] [PubMed]
16. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
17. Melloul E, Egger B, Krueger T, et al. Mortality, complications and loss of pulmonary function after pneumonectomy vs. sleeve lobectomy in patients younger and older than 70 years. Interact Cardiovasc Thorac Surg 2008;7:986-9. [Crossref] [PubMed]
18. Johnson ML, Cho BC, Luft A, et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol 2023;41:1213-27. [Crossref] [PubMed]
19. Delasos L. Optimizing Therapeutic Approaches for Aggressive Molecular Subtypes of Metastatic NSCLC. J Thorac Oncol 2025;20:23-6. [Crossref] [PubMed]
20. Godoy LA, Chen J, Ma W, et al. Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives. Biomark Res 2023;11:7. [Crossref] [PubMed]
21. Pisters KM, Vallières E, Crowley JJ, et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol 2010;28:1843-9. [Crossref] [PubMed]
22. Lee ES, Park SI, Kim YH, et al. Comparison of operative mortality and complications between bronchoplastic lobectomy and pneumonectomy in lung cancer patients. J Korean Med Sci 2007;22:43-7. [Crossref] [PubMed]
23. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21:1413-22. [Crossref] [PubMed]
24. Minervini F, Kestenholz PB, Kocher GJ, et al. Thoracic surgical challenges after neoadjuvant immunotherapy for non-small cell lung cancer: a narrative review. AME Surg J 2023;3:15. [Crossref]
25. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
26. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
27. Burrows WM. Anatomical lung resection after neoadjuvant chemoradiotherapy. Semin Thorac Cardiovasc Surg 2007;19:360-5. [Crossref] [PubMed]
28. Chu NQ, Tan KS, Dycoco J, et al. Determinants of successful minimally invasive surgery for resectable non-small cell lung cancer after neoadjuvant therapy. J Thorac Cardiovasc Surg 2025;169:753-762.e6. [Crossref] [PubMed]
29. Huynh C, Sorin M, Rayes R, et al. Pathological complete response as a surrogate endpoint after neoadjuvant therapy for lung cancer. Lancet Oncol 2021;22:1056-8. [Crossref] [PubMed]
30. Bahce I, Dickhoff C, Schneiders FL, et al. Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study. J Immunother Cancer 2024;12:e009799. [Crossref] [PubMed]
31. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
32. Rodriguez EF, Lipson E, Suresh K, et al. Immune checkpoint blocker-related sarcoid-like granulomatous inflammation: a rare adverse event detected in lymph node aspiration cytology of patients treated for advanced malignant melanoma. Hum Pathol 2019;91:69-76. [Crossref] [PubMed]
33. Cerfolio RJ, Talati A, Bryant AS. Changes in pulmonary function tests after neoadjuvant therapy predict postoperative complications. Ann Thorac Surg 2009;88:930-5; discussion 935-6. [Crossref] [PubMed]
34. Villeneuve PJ. Interventions to avoid pulmonary complications after lung cancer resection. J Thorac Dis 2018;10:S3781-8. [Crossref] [PubMed]
35. Ding X, Jin S, Niu X, et al. A comparison of the analgesia efficacy and side effects of paravertebral compared with epidural blockade for thoracotomy: an updated meta-analysis. PLoS One 2014;9:e96233. [Crossref] [PubMed]
36. Dell'Amore A, Lomangino I, Tamburini N, et al. Video-assisted thoracoscopic lobectomy after neoadjuvant chemotherapy for non-small cell lung cancer: a multicenter propensity-matched study. Surg Endosc 2022;36:1466-75. [Crossref] [PubMed]
37. Takada K, Takamori S, Brunetti L, et al. Impact of Neoadjuvant Immune Checkpoint Inhibitors on Surgery and Perioperative Complications in Patients With Non-small-cell Lung Cancer: A Systematic Review. Clin Lung Cancer 2023;24:581-590.e5. [Crossref] [PubMed]
38. Whitson BA, Groth SS, Duval SJ, et al. Surgery for early-stage non-small cell lung cancer: a systematic review of the video-assisted thoracoscopic surgery versus thoracotomy approaches to lobectomy. Ann Thorac Surg 2008;86:2008-16; discussion 2016-8. [Crossref] [PubMed]
39. Sedighim S, Frank MI, Heutlinger O, et al. A Systematic Review of Short-Term Outcomes of Minimally Invasive Thoracoscopic Surgery for Lung Cancer after Neoadjuvant Systemic Therapy. Cancers (Basel) 2023;15:3908. [Crossref] [PubMed]
40. Zhang B, Xiao Q, Xiao H, et al. Perioperative Outcomes of Video-Assisted Thoracoscopic Surgery Versus Open Thoracotomy After Neoadjuvant Chemoimmunotherapy in Resectable NSCLC. Front Oncol 2022;12:858189. [Crossref] [PubMed]
41. Cao J, Zhang C, Zhang X, et al. The Clinical Outcomes of Thoracoscopic Versus Open Lobectomy for Non-Small-Cell Lung Cancer After Neoadjuvant Therapy: A Multi-Center Retrospective Cohort Study. Clin Lung Cancer 2024;25:e153-60. [Crossref] [PubMed]
42. Kamel MK, Nasar A, Stiles BM, et al. Video-Assisted Thoracoscopic Lobectomy Is the Preferred Approach Following Induction Chemotherapy. J Laparoendosc Adv Surg Tech A 2017;27:495-500. [Crossref] [PubMed]
43. Jeon YJ, Choi YS, Cho JH, et al. Thoracoscopic Vs Open Surgery Following Neoadjuvant Chemoradiation for Clinical N2 Lung Cancer. Semin Thorac Cardiovasc Surg 2022;34:300-8. [Crossref] [PubMed]
44. Fang L, Wang L, Wang Y, et al. Video assisted thoracic surgery vs. thoracotomy for locally advanced lung squamous cell carcinoma after neoadjuvant chemotherapy. J Cardiothorac Surg 2018;13:128. [Crossref] [PubMed]
45. Wang YF, Deng HY, Huang W, et al. Is video-assisted thoracoscopic surgery comparable with thoracotomy in perioperative and long-term survival outcomes for non-small-cell lung cancer after neoadjuvant treatment? Interact Cardiovasc Thorac Surg 2022;35:ivac271. [Crossref] [PubMed]
46. Yang CF, Meyerhoff RR, Mayne NR, et al. Long-term survival following open versus thoracoscopic lobectomy after preoperative chemotherapy for non-small cell lung cancer. Eur J Cardiothorac Surg 2016;49:1615-23. [Crossref] [PubMed]
47. Pan H, Zou N, Tian Y, et al. Short-term outcomes of robot-assisted versus video-assisted thoracoscopic surgery for non-small cell lung cancer patients with neoadjuvant immunochemotherapy: a single-center retrospective study. Front Immunol 2023;14:1228451. [Crossref] [PubMed]
48. Loscertales J, Quero Valen Zuela F, Congregado M, et al. Video-assisted thoracic surgery lobectomy: results in lung cancer. J Thorac Dis 2010;2:29-35. [PubMed]
49. Kim HE, Yu WS, Lee CY, et al. Risk factors for pulmonary complications after neoadjuvant chemoradiotherapy followed by surgery for non-small cell lung cancer. Thorac Cancer 2022;13:361-8. [Crossref] [PubMed]
50. Peer M, Azzam S, Cyjon A, et al. Major pulmonary resection after neoadjuvant chemotherapy or chemoradiation in potentially resectable stage III non-small cell lung carcinoma. Sci Rep 2021;11:20232. [Crossref] [PubMed]
51. Lin MX, Zang D, Liu CG, et al. Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management. Front Immunol 2024;15:1266850. [Crossref] [PubMed]
52. Sengupta S. Post-operative pulmonary complications after thoracotomy. Indian J Anaesth 2015;59:618-26. [Crossref] [PubMed]
53. Waser NA, Quintana M, Schweikert B, et al. Pathological response in resectable non-small cell lung cancer: a systematic literature review and meta-analysis. JNCI Cancer Spectr 2024;8:pkae021. [Crossref] [PubMed]