Surgical experience after perioperative chemoimmunotherapy for non-small cell lung cancer: technical considerations and operative complexity

Introduction

Recent results from the CheckMate 816 (1), KEYNOTE-671 (2), and AEGEAN (3) trials have demonstrated the effectiveness of perioperative systemic therapy incorporating immune checkpoint inhibitors, underscoring its expanded surgical role in locally advanced non-small cell lung cancers (NSCLCs). Robotic-assisted thoracic surgery (RATS) has been increasingly applied in lung cancer surgery because of its enhanced visualization and instrument dexterity. Several recent studies (4,5) with larger cohorts have reported the feasibility of RATS following neoadjuvant therapy. However, detailed descriptions of the technical challenges encountered after perioperative chemoimmunotherapy, particularly those related to treatment-induced fibrosis, hilar dissection, and intraoperative decision-making, remain limited.

The present study therefore aimed to describe our institutional surgical experience following perioperative chemoimmunotherapy, with particular attention to operative complexity and technical considerations across different surgical approaches.

Methods

This retrospective study included patients with locally advanced (stage II–III) NSCLC who underwent neoadjuvant therapy incorporating immune checkpoint inhibitors at the Respiratory Disease Center, SHOWA Medical University Northern Yokohama Hospital, between January 2024 and October 2025. Clinical records and operative data were reviewed. Driver gene alterations were assessed using the Oncomine Dx Target Test, the Amoy Dx Multi-PCR Panel or Lung Cancer Compact Panel. The treatment decisions were made through multidisciplinary team (MDT) discussions involving thoracic surgeons, medical oncologists, and radiologists. Patients with resectable or potentially resectable N1/N2 disease were considered for perioperative chemoimmunotherapy followed by surgery, whereas patients deemed unresectable or medically inoperable were preferentially treated with definitive chemoradiotherapy. The specific neoadjuvant chemoimmunotherapy regimen was selected through MDT discussion based on tumor histology (squamous vs. non-squamous), programmed death ligand 1 (PD-L1) expression status, clinical stage, and patient condition. In general, platinum-based doublet chemotherapy combined with immune checkpoint inhibitors was administered in accordance with contemporary clinical trial evidence.

The choice of surgical approach [thoracotomy, video-assisted thoracoscopic surgery (VATS), or RATS] was determined based on preoperative assessment of tumor location, anticipated hilar complexity, the presence of fibrosis or incomplete fissures on imaging, and surgeon experience.

RATS was selectively applied to cases considered suitable for minimally invasive surgery (MIS), whereas thoracotomy was preferred for patients with centrally located tumors, anticipated need for bronchovascular reconstruction, or higher technical complexity. Patient preference was also taken into account when appropriate.

The number of robotic arms (three-arm or four-arm approach) was primarily determined during preoperative planning based on tumor location, anticipated technical complexity, and the need for additional retraction or exposure. A three-arm approach was generally selected for relatively straightforward cases with limited hilar involvement, whereas a four-arm approach was preferred in cases with expected dense adhesions, incomplete fissures, or complex hilar dissection requiring enhanced retraction.

Intraoperative adjustments were made when necessary depending on the surgical findings.

Definitions

Pathological complete response (pCR) was defined as the absence of residual viable tumor cells in both the resected primary tumor and sampled lymph nodes on pathological examination.

Hilar and mediastinal lymph node dissection was considered technically uncomplicated when it could be performed without dense adhesions, significant bleeding requiring hemostatic intervention, or the need for conversion to thoracotomy.

Patients who did not proceed to curative-intent resection or who selected non-surgical treatment following neoadjuvant therapy were excluded from the analysis.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Review Board of SHOWA Medical University (approval number 2025-0429) and individual consent for this retrospective analysis was waived.

Statistical analysis

Given the small sample size and descriptive nature of this study, no formal statistical comparisons were performed. Continuous variables are presented as medians with ranges, and categorical variables are summarized as counts and percentages.

Results

During the study period, eight patients received neoadjuvant chemoimmunotherapy for locally advanced NSCLC. Two patients did not proceed to surgery and were excluded from the present analysis. One patient developed painless thyroiditis as an immune-related adverse event and opted to receive radiotherapy instead of surgery. Another patient discontinued treatment because of febrile neutropenia and declined surgery after achieving partial tumor response. Therefore, six patients who underwent surgical resection were included in this study (Figure 1).

Figure 1 Flowchart of patient selection. NSCLC, non-small cell lung cancer.

The median age of the surgical patients was 75 years (range, 57–77 years). Four patients were male and two were female. Histologically, three patients had squamous cell carcinoma and three had adenocarcinoma. Clinical stages before treatment included stage IIA (n=1), IIB (n=2), and IIIA (n=3). Driver gene mutations were identified in two patients (KRAS G12C and BRAF K601E), while the remaining four patients had no detectable mutations.

The selection of neoadjuvant regimens was based on MDT discussion considering histology, PD-L1 expression, and patient condition. The neoadjuvant regimens consisted of carboplatin (CBDCA) + paclitaxel (PTX) + nivolumab (n=3), CBDCA + pemetrexed (PEM)+ nivolumab (n=1), cisplatin (CDDP) + gemcitabine (GEM) + pembrolizumab (n=1), and CDDP + PEM + pembrolizumab (n=1). Four patients completed the planned treatment cycles, whereas two patients discontinued therapy because of adverse events. Four patients achieved ≥50% tumor reduction on preoperative imaging.

Among the six surgical patients, three underwent thoracotomy, one underwent VATS, and two underwent RATS.

RATS was performed in two patients who were considered suitable for MIS based on preoperative assessment of tumor location and anticipated technical complexity. The remaining four patients underwent thoracotomy or VATS because of factors such as central tumor location, need for bronchovascular reconstruction, or higher anticipated operative difficulty.

Operative times ranged from 163 to 437 minutes, and intraoperative blood loss ranged from 0 to 481 mL. pCR was achieved in three patients.

Among the four patients who underwent non-robotic procedures, three underwent thoracotomy and one underwent VATS lobectomy. These patients generally had more complex anatomical or oncological features, including centrally located tumors or the need for bronchovascular reconstruction. One patient required bronchovascular sleeve lobectomy and had the longest operative time (412 minutes) and the highest intraoperative blood loss (481 mL) in the cohort.

Operative times in the non-RATS group ranged from 209 to 412 minutes, and blood loss ranged from <10 to 481 mL. Two of the four patients achieved pCR, while the remaining patients demonstrated partial pathological response. Postoperative recovery was uneventful in most cases, although operative complexity tended to be higher compared with minimally invasive procedures (Table 1).

The two patients selected for robotic surgery underwent RATS lobectomy with mediastinal lymph node dissection using the da Vinci Xi system. Detailed clinical courses of these two cases are described below.

Case 1

A 57-year-old man presented after a chest radiography performed during a health checkup showed an abnormal shadow. He had sleep apnea syndrome managed with continuous positive airway pressure and had smoked 20 cigarettes per day for 39 years.

Computed tomography (CT) revealed a 1.8-cm lobulated nodule in the left lower lobe (Figure 2), and fluorodeoxyglucose-position emission tomography (FDG-PET) showed an uptake in the lesion and the subcarinal (#7) and left hilar (#10) lymph nodes (Figure 3). Bronchoscopic biopsy from the subcarinal lymph node confirmed the presence of an adenocarcinoma. No driver mutation was detected, and the PD-L1 expression was low with a tumor proportion score (TPS) <1%. The clinical stage was cT1bN2aM0, stage IIB.

Figure 2 Chest computed tomography images of Case 1 before initiation of treatment. Arrows indicate the primary tumor and mediastinal lymph node.

Figure 3 Fluorodeoxyglucose positron emission tomography findings of Case 1 before initiation of treatment. Arrows indicate the primary tumor and mediastinal lymph node.

Neoadjuvant chemotherapy (NAC) with the KEYNOTE-671 regimen (CDDP + PEM + pembrolizumab) was initiated. Grade 3 neutropenia prior to cycle 3 and grade 3 hepatotoxicity—suspected to be an irAE—led to treatment discontinuation. Preoperative CT showed 10% tumor shrinkage (Figure 4), and the stage was reassessed as ycT1bN0M0 (stage IA2).

Figure 4 Chest computed tomography images of Case 1 after completion of two cycles of cisplatin, pemetrexed, and pembrolizumab. Arrows indicate the primary tumor and mediastinal lymph node.

A robot-assisted left lower lobectomy with ND2a-2 lymph node dissection was performed using the da Vinci Xi system with three arms, as the tumor location and limited hilar involvement allowed a simplified approach. The operation lasted for 163 minutes, with a console time of 109 minutes, and blood loss was minimal (<10 mL). Hilar and #7 and #10 lymph node dissection was performed without dense adhesions or significant bleeding The patient’s postoperative course was uneventful, and he was discharged on postoperative day 4.

Pathology confirmed the presence of an invasive adenocarcinoma, pT1bN0M0 (stage IA2) with 90% residual viable tumor (RVT) (Ef.1a). The patient remained recurrence-free at the 6-month follow-up.

Case 2

A 75-year-old man presented with dyspnea. CT revealed a 4.3-cm right upper-lobe mass contiguous with hilar lymph nodes, accompanied by severe emphysematous changes and a fissureless configuration between the upper–middle and upper–lower lobes (Figure 5). FDG-PET showed intense uptake in the primary lesion and mild uptake in the #11s lymph node (Figure 6).

Figure 5 Chest computed tomography images of Case 2 before initiation of treatment. Arrows indicate the primary tumor.

Figure 6 Fluorodeoxyglucose positron emission tomography findings of Case 2 before initiation of treatment. The arrow indicates the primary tumor.

CT-guided biopsy confirmed the presence of a squamous cell carcinoma. No actionable driver mutations were found, and PD-L1 TPS was ≥50% (90–100%). The patient’s clinical stage was cT2aN1M0 (stage IIB).

Four cycles of CDDP + GEM + pembrolizumab were completed. CT demonstrated a 55% reduction in tumor size (Figure 7), and the disease was restaged as ycT1bN0M0 (stage IA2).

Figure 7 Chest computed tomography images of Case 2 after completion of two cycles of cisplatin, gemcitabine, and pembrolizumab. Arrows indicate the primary tumor.

Robotic-assisted lobectomy with ND2a-2 dissection was performed using the da Vinci Xi system with four arms, given the anticipated technical complexity related to dense fibrosis, emphysema, and incomplete fissures. The operative and console times were 437 and 352 minutes, respectively, with blood loss of 10 mL. Dense fibrosis, emphysema, and incomplete fissures prolonged the operation. Air leaks from the remaining middle and lower lobes were sutured and reinforced with a PGA sheet and fibrin glue. The procedure was completed without conversion to thoracotomy.

The postoperative air leak persisted until postoperative day 14. Because the amount of air leak gradually decreased, we opted for continued drainage and close observation. After complete cessation of the air leak was confirmed, the chest drain was removed. The patient was discharged on postoperative day 16. Pathological examination revealed no residual tumor (%RVT 0%, Ef.3), confirming pCR. Treatment with adjuvant pembrolizumab was continued, and no recurrence was observed at 4-month follow-up.

Discussion

Although systemic therapy for NSCLC has advanced considerably, surgery remains essential for achieving curative treatment. When determining the surgical indications, the following two key concepts must be evaluated: resectability and operability. Resectability refers to the feasibility of achieving a complete resection with adequate margins, whereas operability concerns the patient’s physiological ability to tolerate major lung resection (6).

Importantly, surgical and oncological resectability do not always align, particularly in locally advanced diseases. The differences in judgment between surgeons and oncologists have been reported (5), emphasizing the importance of MDT discussions (7,8). The Society of Thoracic Surgeons also stresses that resectability should encompass not only technical feasibility but also surgical risk, tumor biology, and the effectiveness of alternative nonsurgical treatments—not merely whether a tumor can be removed but whether it should be removed (9).

The PACIFIC trial (10) has established the benefit of durvalumab following chemoradiotherapy in patients with locally advanced NSCLCs. As a result, the PACIFIC regimen became widely used, particularly for patients with N2-positive disease deemed unresectable. More recently, however, perioperative systemic therapy incorporating immune checkpoint inhibitors has demonstrated considerable efficacy (1-3), leading to an expansion of surgical indications for locally advanced NSCLCs. According to the EORTC Lung Cancer Group (11,12), single-station N2 disease—except when accompanied by T4 invasion—is considered resectable, whereas multistation N2 disease that is non-bulky and non-invasive, as well as single-station N2 disease with T4 invasion are classified as potentially resectable because it did not reach a consensus of 75% or greater within the MDT.

With expanding evidence supporting perioperative immunotherapy, the surgical indications for stage II–III NSCLCs have broadened. At our institution, the number of patients with locally advanced NSCLC (clinical stages II–III) undergoing surgery after perioperative systemic therapy combined with immune checkpoint inhibitors has been increasing.

In the present analysis, we evaluated six such surgical cases. Four of these six patients completed all planned neoadjuvant treatment cycles, each achieving tumor reduction of >50% on preoperative CT imaging; pCR was observed in three of these patients.

The choice of surgical approach was not randomized and was influenced by tumor location, anticipated technical complexity, and the potential need for bronchovascular reconstruction. Therefore, the application of RATS in this study reflects a selected subgroup of patients, and the generalizability of these findings is limited.

Patients eligible for perioperative immunochemotherapy often have tumors located in the hilar region, possibly requiring bronchoplastic or angioplastic procedures. In our series, one patient required a bronchovascular sleeve lobectomy, whereas two patients successfully underwent robotic-assisted lobectomy. However, it should be noted that Case 1 involved early discontinuation of chemo-immunotherapy due to irAEs and therefore did not undergo surgery following a standard course of perioperative systemic therapy.

Robotic-assisted surgery has rapidly gained acceptance as its indications have broadened and is now widely performed in clinical practice. Gallina et al. (13) reported that the enhanced 3D visualization, tremor filtration, and multi-articulated instruments characteristic of RATS enable highly precise mediastinal lymph node dissection, rendering robot-assisted lobectomy with systematic lymphadenectomy both safe and oncologically sound. In a previous randomized controlled trial involving 320 patients with resectable NSCLC, Fabbri et al. (14) demonstrated that robot-assisted surgery was non-inferior to VATS in terms of overall survival, the study’s primary endpoint. Similarly, Niu et al. (15), in their analysis of 619 patients who underwent either RATS or VATS lobectomy, found no significant difference in overall survival between the two approaches; however, RATS was associated with significantly improved disease-free survival and lower recurrence rates.

Regarding surgery after NAC, Zheng et al. (16) demonstrated in a systematic review that NAC improves the oncologic outcomes without increasing the incidence of severe AEs or surgical complications as compared with chemotherapy alone, indicating comparable safety. Nonetheless, treatment-induced fibrosis and adhesions are well recognized to increase operative difficulty (17,18), and several reports have suggested a higher likelihood of conversion from MIS (VATS/RATS) to thoracotomy in this such cases (19). Gatteschi et al. (20) have suggested particular caution in cases of central bulky tumors or invasive disease, as the transition from the inflammatory to the fibrotic phase following treatment response may further complicate the surgery. Conversely, Gao et al. (5) have reported that RATS after neoadjuvant chemoimmunotherapy can still offer stable visualization and instrument control, even in the presence of fibrosis and adhesions, and the conversion rates remain low. Sedighim et al. (21) have emphasized that, although MIS remains safe and feasible following NAC, surgeons must remain vigilant due to reduced visibility from inflammatory changes, hardened and adherent lymph nodes, and an elevated risk of bleeding during vascular dissection. They underscored the importance of promptly converting to thoracotomy when necessary and prioritizing complete oncologic resection over maintaining an MIS approach.

In our series, hilar dissection was straightforward in Case 1 but proved challenging in Case 2 due to the presence of dense fibrosis and incomplete fissures. In Case 1, chemoimmunotherapy had been discontinued after two cycles because of an irAE, resulting in only minimal tumor shrinkage (10%). Although enlargement and FDG uptake were noted in the hilar and mediastinal lymph nodes, they were not bulky, thus, the treatment effect on the hilar structures appeared limited. Contrarily, Case 2 exhibited marked tumor regression after treatment, with the size of the primary tumor—originally contiguous with the hilar lymph nodes—markedly reduced. Severe fibrosis was observed in this case and was associated with increased technical difficulty during dissection. At our institution, RATS is performed with CO₂ insufflation, which typically provides excellent visualization and facilitates identification of tissue planes; however, in areas with dense fibrosis, persistent oozing and unclear planes made dissection difficult, contributing to prolonged operative time and a delayed resolution of postoperative air leakage. Patients undergoing NAC frequently present with hilar tumors or bulky nodal disease, and several of our cases involved a considerable hilar pathology. In this small case series, cases with marked tumor regression tended to require longer operative times, possibly reflecting increased technical complexity related to treatment-induced anatomical changes. In our limited experience, the precision of RATS facilitated hilar dissection in selected cases. However, the small sample size precludes definitive conclusions regarding the safety or superiority of RATS. Okazaki et al. (22) reported that the fissureless technique—where the pulmonary artery, pulmonary vein, and bronchus are dissected first—can be effectively performed using RATS. Such an approach may contribute to shortening operative time, reducing postoperative air leakage, and lowering the rate of conversion to thoracotomy. Reports of robotic vascular and bronchial reconstructions continue to increase (23-25), and as institutional experience and emergency management capabilities improve, the application of RATS for NAC-treated cases is expected to further expand.

When considering all six cases in this series, perioperative outcomes varied according to the surgical approach and case complexity. The two patients who underwent RATS had operative times of 163 and 437 minutes, with minimal blood loss (<10 mL in both cases). In contrast, patients undergoing non-robotic procedures demonstrated a wider range of operative times (209–412 minutes) and blood loss (<10–481 mL). The highest operative time and blood loss were observed in the patient who required bronchovascular sleeve lobectomy via thoracotomy.

From an oncological perspective, pCR was achieved in three patients overall, including one patient in the RATS group and two patients in the non-RATS group. The remaining patients showed partial pathological response with residual viable tumor. Postoperative recovery was generally acceptable across all approaches, although prolonged air leakage was observed in one RATS case with severe emphysema and dense fibrosis.

These findings suggest that perioperative outcomes were influenced more by tumor characteristics and anatomical complexity than by the surgical approach itself. Therefore, comparisons between RATS, VATS, and thoracotomy in this small series should be interpreted descriptively, and no definitive conclusions regarding superiority can be drawn.

To fully realize the benefits of NAC, carefully assessing both operability and resectability is essential, ensuring that surgical and oncological resectability are aligned. Although RATS allows highly precise surgical manipulation and can be extremely effective, surgeons must also account for treatment-related inflammation, fibrosis, the patient’s physiological status, and the potential consequences of prolonged operative time. Rather than adhering rigidly to MIS, it is important to evaluate the intraoperative field and consider the potential impact of an extended operative duration on patient outcomes. Maintaining a willingness to convert to thoracotomy when warranted is crucial to performing RATS safely and effectively.

Conclusions

Perioperative systemic therapy incorporating immune checkpoint inhibitors offers substantial benefits for patients with locally advanced NSCLCs, yet treatment-induced inflammation, fibrosis, and tumor location can increase surgical complexity. In this small institutional series, surgery following perioperative chemoimmunotherapy was feasible across different surgical approaches. Operative complexity varied depending on anatomical and treatment-related factors rather than surgical modality alone. Careful patient selection and intraoperative judgment remain essential. Further studies with larger cohorts are required to clarify its role after neoadjuvant chemoimmunotherapy.

Acknowledgments

None.

Footnote

Data Sharing Statement: Available at https://vats.amegroups.com/article/view/10.21037/vats-2025-1-60/dss

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-2025-1-60/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-2025-1-60/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Review Board of SHOWA Medical University (approval number 2025-0429) and individual consent for this retrospective analysis was waived.

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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