Thoracoscopic lobectomy after neoadjuvant chemoimmunotherapy for lung cancer: a systematic review and meta-analysis

Introduction

Background

Lung cancer has the highest cancer incidence and mortality globally (1). Non-small cell lung cancer (NSCLC), which comprises the vast majority of lung cancer diagnoses, is associated with a 5-year survival of only 27% (2). Surgery remains the cornerstone of curative-intent treatment and is frequently integrated into a multimodal approach (3). However, even after a complete surgical resection, 5-year overall survival (OS) is as low as 50% for stage pIIIA, which is only a small gain over the 44% 5-year OS among all cIIIA, highlighting the need for more effective therapies (4).

The U.S. Food and Drug Administration (FDA) approved the first preoperative chemoimmunotherapy (chemoIO) regimen for NSCLC in March 2022 based on the results of the landmark CheckMate 816 trial, which demonstrated superior improvement in pathologic complete response (pCR), event-free survival (EFS), and OS with neoadjuvant chemoIO compared to chemotherapy alone (5,6). This marked a paradigm shift in the treatment of NSCLC. At the same time, emerging data have suggested that neoadjuvant chemoIO may increase operative complexity due to intense treatment effect (7,8). Thus, while thoracoscopic surgery has well-established advantages in a standard setting, with multiple studies validating it as the standard of care for NSCLC resection (9,10), its safety and feasibility following neoadjuvant chemoIO remain unclear.

Rationale and knowledge gap

Given the increased use of neoadjuvant chemoIO and its potential to complicate surgical resection, surgeons will need to understand the impact of chemoIO on the safety and outcomes of thoracoscopic approaches, both video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS). We focused our review on thoracoscopic lobectomy to improve homogeneity and comparability. We did not consider sublobar resections because patients receiving neoadjuvant chemoIO should, by virtue of their stage eligibility for neoadjuvant treatment, necessarily be ineligible for sublobar resection within the standard-of-care. We also excluded pneumonectomy because of its relative rarity, unique complication profile, and very different overall outcomes (11). The literature regarding thoracoscopic lobectomy following neoadjuvant chemoIO is immature, and most studies lack approach-stratified reporting. Focusing on lobectomy therefore allows for a more precise evaluation of the technical challenges in the setting of chemoIO.

Objective

This systematic review and meta-analysis aims to evaluate the current evidence on the perioperative, pathologic, and oncologic outcomes of thoracoscopic lobectomy following neoadjuvant chemoIO in patients with NSCLC. We present this article in accordance with the PRISMA reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-25-33/rc).

Methods

Search strategy and data sources

In consultation with a librarian (D.W.), we developed a search strategy to identify studies published between January 1, 2010 and May 10, 2025, using the following Medical Subject Headings (MeSH) terms and key search terms: lung neoplasms, NSCLC, thoracoscopy, minimally invasive surgery, lobectomy, preoperative, neoadjuvant, and chemoIO. This search strategy was initially developed for PubMed (Appendix 1) and translated using the Polyglot search translator tool (https://sr-accelerator.com/#/polyglot) for use in the Web of Science, Cochrane Library, and Scopus databases.

Eligibility and selection

Eligibility criteria (Appendix 2) included study populations greater than 18 years of age with NSCLC who received thoracoscopic lobectomy after at least 1 cycle of concurrent chemoIO. Eligible study types were cohorts, case series, clinical trials, cross-sectional studies, systematic reviews, meta-analyses, and case reports. We excluded studies that utilized preoperative radiotherapy or targeted therapy, reported only combined thoracoscopic and thoracotomy outcomes, included populations with ≥10% non-lobectomy resections (e.g., pneumonectomy), or described protocols without reported results. The 10% threshold was established to ensure that lobectomy remained the dominant procedure while still allowing inclusion of studies that provided meaningful data but contained a small minority of other resections.

The review was conducted in Covidence (https://www.covidence.org/), a systematic review tool developed by Veritas Health Innovation, Melbourne, Australia. For both the abstract and full-text screening, two authors (D.G. and J.B.) reviewed each study independently, and conflicts were resolved by a third reviewer (C.S.). The third reviewer, blinded to the decisions of the first two reviewers, adjudicated the conflicts and made the final decision based on the predetermined eligibility criteria. To ensure the integrity of the screening process, the principal investigator (S.E.) randomly audited a sample of included and excluded articles to verify alignment with the eligibility criteria.

Data extraction

Data extraction was performed by any two authors, and all authors reached a final consensus on the extracted data. Extracted variables included authors, year of publication, location, study design, number of sites, target sample size, clinical stage, histology, neoadjuvant therapy, surgical intervention and approach, intraoperative outcomes [conversion time, operative time, and estimated blood loss (EBL)], post-operative outcomes [length of stay (LOS), 30-/90-day mortality, 30-day readmission, and conversion rate], pathologic outcomes [pCR, major pathologic response (MPR), nodal downstaging, and R0 resection], oncologic outcomes [follow-up duration, disease-free survival (DFS), recurrence-free survival (RFS), EFS, and OS], and other information deemed relevant. We summarized the publications descriptively and organized them into a table for visual comparison of the data, with select outcomes represented in forest plots or a bar graph. For case reports that did not explicitly state patient survival status but provided a follow-up duration, the patients were assumed to be alive and without recurrence at the time of last follow-up. For case reports that did not explicitly state positive or negative margins, R0 resection was considered to be achieved. The most common complications are listed for all studies reporting a complication rate. All stated pulmonary infections were presumed to be pneumonia (PNA).

Critical appraisal

The quality of the included cohort and case studies was assessed using Newcastle-Ottawa Scale (12). The assessment was performed independently by two reviewers (C.S. and D.G.), and a 3rd reviewer (J.B.) resolved any discrepancies. Each study was evaluated based on study setting, full-text availability, cohort size, clarity of outcome reporting, comparability of study groups, attrition rate, and reporting of adverse events.

Statistical analysis

Descriptive statistics were used to summarize outcomes across the included studies, excluding case reports. Complications were pooled across studies to illustrate the overall distribution. We performed a meta-analysis using a binary random-effects model for proportions on consistently reported and clinically relevant outcomes from cohort studies and case series. The model was chosen to account for heterogeneity in study design and sample size across studies. This model combines the proportions from individual studies while allowing the true effect to differ across studies to account for differences in study characteristics. Missing data were handled using a complete-case analysis, whereby outcomes not reported in individual studies were treated as missing and excluded from pooled estimates without imputation. The effect size for all pooled outcomes was the event rate, expressed as the proportion of patients experiencing the outcome. Results were summarized as pooled proportions with corresponding 95% confidence intervals (CIs) and presented in forest plots. Between-study heterogeneity was assessed using τ², the Cochran Q test, and the I² statistic. These analyses were conducted in OpenMeta[Analyst].

Supplementary review of randomized controlled trials (RCTs)

None of the five major international, multi-site RCTs on perioperative chemoIO in NSCLC met our inclusion criteria due to a lack of segregation of outcomes by surgical approach. However, because of the importance of these seminal trials and their utility as a benchmark, we have included a separate summary and discussion of their results.

Results

Literature search

The literature search yielded 380 abstracts after the removal of 313 duplicates. Full text review of 153 studies yielded 39 eligible studies (Figure 1).

Figure 1 PRISMA diagram of screening process.

Study characteristics

A total of one prospective cohort study, 16 retrospective cohort studies, four case series, and 18 case reports were included, comprising 1,176 patients. Study characteristics and outcomes for cohort studies and case series are shown in Table 1 (13-33), while case reports are shown separately in Table 2 (34-51). Although we searched back to 2010, the first study to meet the inclusion criteria was published in 2020, with the majority of studies published between 2022 and 2024. Most studies originated from China (35/39; 89.7%), with 2 case reports from Japan and one cohort and one case report from the United States.

Among cohort studies and case series, 15 of 21 (71%) studies reported squamous cell carcinoma (SCC) as the predominant histology, with proportions ranging from 51.6% to 100%, with the next most common being adenocarcinoma. Similarly, among the case reports, 11 of 18 (61.1%) were SCC, and 5 of 18 (27.8%) were adenocarcinoma.

All studies, except one cohort, employed some variant of platinum-based doublet chemotherapy (Tables S1,S2). Among cohort studies and case series, carboplatin (7/21; 33.3%) and cisplatin (5/21; 23.8%) were the most common platinum agents. The most used immunotherapy drugs were pembrolizumab (8/21; 38.1%), sintilimab (9/21; 42.9%), and nivolumab (8/21; 38.1%). Similarly, among the case reports, carboplatin (9/18; 50%) and cisplatin (6/18; 33.3%) were the most common platinum agents, while pembrolizumab (7/18; 38.9%), sintilimab (4/18; 22.2%), and nivolumab (3/18; 16.7%) were the most frequently used immunotherapies. Typically, 2 to 3 cycles of chemoIO were given in all studies.

Among the cohorts and case series, three studies mentioned thoracoscopic approach but did not specify VATS or RATS. Of 18 studies that specified, 13 of 18 (72.2%) examined only VATS, and 2 of 18 (11.1%) examined only RATS. In these studies, the surgical approach was explicitly reported for 708 patients, with 255 (36.0%) undergoing RATS and 453 (64.0%) undergoing VATS. Three studies directly compared VATS and RATS, providing stratified outcomes for each technique (16-18). There were 8 studies (8/21; 38.1%) that were not exclusively lobectomy and included less than 10% of other procedures in total, specifically pneumonectomy, wedge, or limited resection.

Among the case reports, 10/18 (55.5%) were VATS, 2/18 (11.1%) were RATS, and 6/18 (33.3%) were unspecified.

Quality and risk of bias assessment

The Newcastle-Ottawa Scale scores range from 0 to 9, with higher scores indicating lower risk of bias. Eight studies (8/21; 38.1%) scored 7–9, indicating low risk, and 13 studies (13/21; 61.9%) scored 4–6, indicating moderate risk (Table S3).

Cohort/case series intraoperative outcomes

For intraoperative outcomes, conversion rates were documented in 16 of 21 studies (76.2%), operative time in 19 of 21 studies (90.5%), and EBL in 19 of 21 studies (90.5%). The conversion rate ranged from 0 to 38.9%, with a median of 10.4% [interquartile range (IQR), 4.3–14.8%]. The pooled proportion for conversion rate was 9.2% (95% CI: 5.7–12.8%), with substantial between-study heterogeneity (I²=72.4%, P<0.001, Figure 2). Studies had operative times ranging from 90 to 268.3 minutes, and EBL ranging from 50 to 390 mL. One outlier reported a conversion rate of 38.9%, notable for being the only study that involved video-assisted thoracoscopic extended sleeve lobectomy. This study also had the longest operative time and EBL, at 330 minutes and 415 mL, respectively (16). Among the 16 studies reporting conversion rates, nine provided reasons for conversions. Adhesions were mentioned as a reason in 88.9% of studies (8/9), bleeding in 55.6% (5/9), fibrosis in 33.3% (3/9), primary tumor invasion in 22.2% (2/9), and calcified lymph nodes in 22.2% (2/9). Of note, adhesions, bleeding, and fibrosis were not only the most cited reasons but also aligned with the most common causes of conversion when frequencies were explicitly reported. One study demonstrated a statistically significantly lower conversion rate in RATS (8.2%) compared to VATS (33.7%) after inverse probability of treatment weighting (IPTW) (13). However, the other two studies that compared VATS and RATS found no statistically significant difference (14,15).

Figure 2 Pooled conversion rate after thoracoscopic lobectomy post chemoIO: random effects forest plot. chemoIO, chemoimmunotherapy; CI, confidence interval.

Cohort/case series postoperative outcomes

Regarding postoperative outcomes, median LOS generally ranged from 4 to 9 days among the Chinese studies. The only United States study documented a markedly shorter median LOS of 2 days (17). Among 16 studies that reported complications, the complications with highest pooled proportions (Figure 3) were PNA (6.9%), air leak (6.3%), arrhythmia (3.5%), chylothorax (1.5%), pneumothorax (PTX) (1.5%), and bronchopleural fistula (BPF) (1.4%). Given that most of the studies were retrospective and only reported observed complications, the studies reporting each outcome and the number of cases are reported in Table S4. Complication rates generally ranged from 0% to 38.7%, with a median of 18.3% (IQR, 10.8–28.5). The pooled complication rate was 19.1% (95% CI: 13.7–24.6%), with substantial between-study heterogeneity (I²=70.3%, P<0.001, Figure 4). Among 9 studies (9/21; 42.9%), 30-day mortality generally ranged from 0% to 1.2%, with two outliers at 3.2% and 3.0% (14,15). Among 6 studies (6/21; 28.6%), 90-day mortality was typically 0%, with one study noting 1.6% (18). Furthermore, among 4 studies (4/21; 19.0%), 30-day readmission ranged typically from 0% to 6.5%, with one outlier study noting 16% (17). The authors attributed this to the increased technical difficulty during dissection due to the loss of tissue planes and the inflammatory response in hilar lymph nodes (17). In the three cohort studies that stratified the VATS and RATS outcomes, complication rate, LOS, 30-day mortality, and readmission rate were not statistically significantly different compared to RATS (13-15).

Figure 3 Pooled postoperative complications after thoracoscopic lobectomy following neoadjuvant chemoIO. BPF, bronchopleural fistula; chemoIO, chemoimmunotherapy; DVT, deep vein thrombosis; MI, myocardial infarction; OR, operating room; PE, pulmonary embolism; PNA, pneumonia; PTX, pneumothorax; RLN injury, recurrent laryngeal nerve injury; SSI, surgical site infection.

Figure 4 Pooled postoperative complication rate after thoracoscopic lobectomy post chemoIO: random-effects forest plot. chemoIO, chemoimmunotherapy; CI, confidence interval.

Cohort/case series pathologic outcomes

Pathologic outcomes were frequently documented. R0 resection was achieved in 15 of 21 studies, with 14 having rates greater than 90%. The pooled MPR was 58.4% (95% CI: 51.1–65.7%), with substantial between-study heterogeneity (I²=73.3%, P<0.001), as shown in Figure 5. The pooled pCR was 33.7% (95% CI: 26.9–40.5%), with substantial between-study heterogeneity (I²=70.7%, P<0.001), as shown in Figure 6. Nodal downstaging was reported in only 7 of 21 (33.3%), ranging from 33.3% to 90.9%. Among the studies that stratified outcomes by VATS and RATS, there were no statistically significant differences in R0 resection, MPR, or pCR between the two approaches (13-15).

Figure 5 Pooled MPR after thoracoscopic lobectomy post chemoIO: random effects forest plot. chemoIO, chemoimmunotherapy; CI, confidence interval; MPR, major pathologic response.

Figure 6 Pooled pCR after thoracoscopic lobectomy post chemoIO: random effects forest plot. chemoIO, chemoimmunotherapy; CI, confidence interval; pCR, pathologic complete response.

Cohort/case series oncologic outcomes

Only 6 of 21 (28.6%) reported OS typically exceeding 90%. Similarly, secondary short-term survival metrics (DFS, RFS, EFS) were reported in 13 of 21 (61.9%), typically at a 1-year follow-up, with most survival rates exceeding 80%. Two studies reported survival metrics over an extended follow-up period. The only study to report outcomes at 3 years showed a DFS of 73.7% following surgical resection and an EFS of 73.5% from initiation of neoadjuvant therapy, whereas the only study to report outcomes at 4 years found RFS and OS rates at around 90% (19,20). The only cohort study stratifying VATS and RATS for oncologic outcomes showed comparable 1-year RFS rates of 85.2% and 83.0%, respectively (14).

Case report outcomes

Perioperative outcomes were sparsely reported across case reports. Operative time ranged from 90 to 180 minutes, and EBL was 50 mL. In studies from China, LOS was typically 3 to 7 days, with one outlier of 21 days due to a BPF diagnosed on post-operative day 10 (34). The only other report outside of China that documented LOS was from Japan, which reported a stay of 2 days (35). Eleven of 18 explicitly mentioned R0 resection outcomes. Among 14 reports documenting pathologic responses, 86% achieved MPR, 71% achieved pCR, and 93% demonstrated nodal downstaging. Follow-up duration in case reports ranged from 4 weeks to 24 months.

RCTs

The five major RCTs that included neoadjuvant chemoIO, CheckMate 816, CheckMate 77T, NADIM II, KEYNOTE-671, and AEGEAN, are summarized in Table 3 (6,8,52-55). All five studies included approximately a 1:1 ratio of SCC to non-SCC. Only two studies reported on surgical approach: in CheckMate 816, 41% and 37% in the chemoIO and control groups, respectively, underwent thoracoscopic resection; in AEGEAN, the rates were 40% and 38% (6,8,55). Only CheckMate 816 reported conversion rates, and they were slightly lower in the chemoIO group (11.4% compared to 15.6%) (6,8). In the two studies that reported operative time, the median operative time was about 3 to 3.5 hours (185 and 217 minutes in the chemoIO compared to 214 and 223 minutes in the control group, in CheckMate 816 and CheckMate 77T, respectively) (6,8,52). Among all RCTs reporting graded adverse events, grade 3+ adverse events occurred in 11.4% to 42.4% of patients in the chemoIO arms, such as anemia, PNA, fatigue and pain (procedural, incision-site, or unspecified). All RCTs broadly defined postoperative complications as any adverse event occurring after surgery, even if it was not directly caused by the surgical procedure itself. Among the pooled list of all perioperative complications reported by the cohort studies and case series, several important surgical complications such as empyema or return to OR were not reported by any of the 5 RCTs, and many more such as air leak or hemorrhage were reported by only 1 of the 5 (Table S5). MPR rates generally ranged from 30.2% to 46.8% in the chemoIO groups, compared to 11.0% to 12.7% in the control groups. pCR rates ranged from 17.2% to 30.5% in the chemoIO groups, compared to 3.2% to 4.7% in the controls. Notably, NADIM II demonstrated not only the highest pathologic response, with an MPR of 53% and a pCR of 37%, but also the highest 2-year RFS (53). The recent 5-year OS reported by CheckMate 816 evidences robust and sustained benefit following neoadjuvant chemoIO (6).

Discussion

Key findings

Most studies originated from China, limiting generalizability to Western surgical contexts. Moreover, the predominant histology was SCC, contrasting with its comparatively lower incidence elsewhere and in the included RCTs. We observed considerable variation in reported outcomes, though operative time, LOS, perioperative mortality, and pathologic response were consistent across studies. Conversion rates varied widely, with common reasons for conversion being adhesions, bleeding, and fibrosis. The most common and frequently reported complications were PNA, air leak, arrhythmia, chylothorax, PTX, and BPF. High rates of MPR and pCR were observed across studies. Although short-term oncologic outcomes were limited, those that were reported compared favorably to the major RCTs. Notably, long-term oncologic outcomes were lacking across all studies.

Strengths and limitations

This is the first study to evaluate the current body of evidence on this emerging area of importance. The data, though limited, represent early real-world experiences and offer valuable information on the safety and efficacy of thoracoscopic lobectomy after neoadjuvant chemoIO for NSCLC.

The predominance of studies from China limits generalizability to Western practice, given differences in healthcare systems, institutional practice patterns, available therapies, and disease epidemiology. Another major limitation of this review was the lack of RCTs and only one prospective, non-randomized study that reported outcomes specific to thoracoscopic approaches. Variability in defining and reporting of key outcomes across studies also made direct comparisons challenging. Although all included studies performed thoracoscopic lobectomy, the specific surgical techniques varied. Additionally, several studies had small sample sizes, making their event rates highly sensitive to single events. Finally, given that FDA approval of the first neoadjuvant chemoIO regimen occurred only 3 years ago, follow-up is inherently limited, and only CheckMate 816 reported recent mature survival data (6,8).

Comparison with similar research

RCTs and other review articles have predominantly focused on overall outcomes following surgical resection after neoadjuvant chemoIO, rather than analyzing specific surgical approaches separately (6,8,52-58). As such, there is a paucity of data examining outcomes associated with thoracoscopic or open surgery after chemoIO for NSCLC in the literature. Our review is the first to summarize and assess outcomes specific to thoracoscopic resection.

Explanation of findings

Several interesting patterns emerged from this review. The substantial number of articles originating from China reflects the differences in Western and Chinese healthcare systems, surgical care, and disease burden. China’s highly centralized healthcare model concentrates surgical care and research at large academic hospitals in urban regions. Surgical care is more conservative, with longer lengths of stay and higher hospital bed density compared to Western healthcare systems, allowing for close health surveillance and early detection programs (59). In the United States, healthcare delivery is decentralized, with surgical care distributed across community hospitals and academic centers. The high costs of surgical care come with a greater emphasis on research-driven practices and advanced technologies to improve perioperative outcomes (60). Disease burden significantly differs between these two countries, with China combating lung cancer due to high tobacco use and air pollution, while the United States manages more cases of cardiovascular disease. The incidence in China is approximately 828,100 new cases and 657,000 deaths annually, compared with 228,820 new cases and 135,720 deaths in the United States (61,62). This high disease burden in China has driven greater investment in research, leading to the development of many early detection screening programs and greater training of surgeons (62-64). Ultimately, this national public health crisis has contributed to China’s disproportionate representation in literature.

Surprisingly, SCC was the predominant histology in most studies, with an incidence ranging from 52% to 100%, followed by adenocarcinoma. The RCTs demonstrated a roughly equal distribution between SCC and non-SCC. This contrasts with global epidemiologic data for NSCLC, in which adenocarcinoma accounts for more than half of cases and SCC for only approximately one-third (65). In the United States, 54% of NSCLC cases are adenocarcinoma, whereas 30% are SCC (66); in China, adenocarcinoma accounts for 45% and SCC for 28% (67). A possible reason for this discrepancy is that SCC is disproportionately overrepresented in Chinese thoracoscopic and chemoIO studies due to specific trial designs and patient selection factors. In particular, Chinese patients with adenocarcinoma have a higher rate of epidermal growth factor receptor (EGFR) driver mutation (38–50%) compared to patients in the United States (14–21%), increasing the likelihood of receiving targeted therapy rather than chemoIO (68-71). This skews the study population toward SCC, which is more common in male smokers and less likely to have targetable mutations (72). This difference in histology is salient, as it directly influences the responsiveness and efficacy of chemoIO therapy. Additionally, regional practice variations, such as the use of immunotherapy agents available only in China and longer postoperative hospitalization may further bias reported outcomes. These aspects are discussed in greater detail in the subsequent sections.

To look at the feasibility of thoracoscopic surgery following chemoIO, we conducted a meta-analysis and found a pooled conversion rate of 9.2%, with summary statistics showing similar central tendency. These findings are comparable to Checkmate 816 of 11.4% and the National Cancer Database (NCDB) of 15.3% (6,8,73). However, substantial heterogeneity was observed, with some studies reporting markedly higher rates, up to 38.9%. These outlier studies were typically characterized by small sample sizes, and with an inclusion of a study with a complex resection that is not represented in the major RCTs. These findings underscore the potential gap between RCTs and real-world surgical experience, which captures a broader surgical spectrum where conversion risk may be higher.

In our review, operative times ranged from 90 to 268.3 minutes, which closely aligns with those in CheckMate 77T and CheckMate 816 (216.5 and 185 minutes, respectively). Only one study from the United States and one from Japan reported LOS, documenting a considerably shorter stay compared to the remaining studies, most originating from China. The varying LOS may arise from differences in healthcare system models. United States healthcare systems are incentivized by value-based care models, insurance practices that minimize unnecessary hospitalizations, and the adoption of the Enhanced Recovery After Surgery (ERAS) approach, leading to shorter LOS of around 3–4 days on average for minimally invasive surgeries (74-76). In China, however, cultural expectations for comprehensive care and family support have heavily contributed to longer LOS (77). Chinese hospitals typically have a more conservative discharge criterion compared to Western counterparts and often place less emphasis on early mobilization after treatment to monitor patients for a longer duration (78,79). Moreover, the only study from Japan reporting an LOS was a case report documenting a 2-day post-surgical stay (35); however, this is not representative of the typical LOS in Japan, which tends to be around 6 days and is therefore comparable to that of China (80). Therefore, differences in healthcare systems should be considered when comparing LOS across studies as it may reflect systemic practices rather than a measure of surgical complexity or complication rate. Interestingly, the LOS specific to lobectomy in CheckMate 816 exceeded the range typically reported in our review but may reflect the inclusion of thoracotomy cases in their reported outcomes. This conclusion aligns with the literature demonstrating shorter LOS associated with thoracoscopy (74).

Commonly reported complications in our review included PNA, air leak, arrhythmia, chylothorax, PTX, and BPF. PNA, air leak, arrhythmia, and PTX were also frequently reported in the Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD), while chylothorax and BPF were much rarer (0.5% and 0.23%) (81,82). In contrast, the RCTs most frequently reported anemia, PNA, and pain. The complication rate in our review varied from 0% to 38.7%, which is comparable to the variation seen in the RCTs from 11.4% to 42.4%. However, interpretation of complication rates in the RCTs is confounded by the inclusion of subjective or low-acuity adverse events such as postoperative pain, which may artificially inflate the rates, as well as by their focus largely on extensive lists of systemic therapy-related complications like diarrhea or leukopenia. Meanwhile, many surgically relevant complications like BPF or recurrent laryngeal nerve injury were often conspicuously absent, causing doubt as to whether these were rigorously recorded. It seems highly unlikely that these complications never occurred in these large trials, and rates of 0% for these complications would be inconsistent with national database outcomes. Importantly, none of the RCTs stratified results, including complications, by surgical approach. CheckMate 816, CheckMate 77T, AEGEAN, and KEYNOTE-671 also only reported adverse events with an incidence greater than 5%. As many surgical complications are relatively rare, they may have been underreported or omitted. Consequently, a divergence in data relevance is observed between these trials and real-world thoracic surgery reports, highlighting the value of real-world studies, which focused more on perioperative morbidity germane to a surgeon’s perspective on procedural safety and feasibility.

Short-term mortality (30-day and 90-day) were generally low. 30-day mortality rates ranged from 0% to 1.2%, and compared favorably with the rate of 1.0% after lobectomy in the 2023 STS GTSD report (83). There were two outliers at 3.2% and 3.0%, each derived from a single death in small studies (31 and 33 patients, respectively) (14,15). The 90-day mortality was even lower, mostly 0%, with one study reporting 1.6%. This outlier may similarly be disproportionately influenced by a single death due to its small sample size of 62 patients (18). Despite this, the 90-day mortality was still lower than the typical 3.1%, further highlighting the safety of the intervention (84,85).

The R0 resection rates, generally ≥90% in our review, were similar to those reported by the five RCTs, which exceeded 83%. The MPR and pCR varied widely in our review, which may be attributed to the inclusion of smaller studies that are more susceptible to the influence of outliers. The pooled MPR and pCR were 58.4% and 33.7%, respectively. Both are higher than most rates reported in the RCTs, with MPR ranging from 30.2–46.8% and pCR from 17.2–30.5%. Even large cohort studies demonstrated considerably higher pCR and MPR rates. These unusually high pathological response rates may stem from the inherent nature of real-world studies to report favorable outcomes compared with RCTs that are specifically designed to minimize such bias. Furthermore, the discrepancy may reflect differences in how clinical trials and retrospective studies define pathologic outcomes. RCTs apply an intent-to-treat principle, whereby patients who received at least one cycle of therapy but did not undergo resection are still counted as not achieving a response. Consequently, this inflates the denominator and yields lower response rates compared with retrospective analyses that restrict evaluation to patients who underwent surgery. Moreover, the heterogeneity in histological distribution between our review and the RCTs may account for a higher response to therapy in this regimen. A multicenter study found that patients with SCC achieved markedly higher pCR and MPR rates compared with those with adenocarcinoma (86). As previously established, most studies were conducted in China, so the differences may be partially explained by the use of immunotherapy agents available exclusively in China.

The OS was generally over 90% at 1-year for the included studies. Comparison of oncologic outcomes was challenging due to limited reporting of the secondary survival metrics (DFS, RFS, EFS) and significant variability in definitions, even within individual metrics. As a result, we grouped these three metrics and compared them collectively to the EFS reported in the RCTs. The secondary 1-year survival metrics identified in our review were generally around 80%, comparable to those of the RCTs, specifically, 73.4% in AEGEAN and 76.1% in CheckMate 816. The slightly lower EFS observed in the RCTs may be partly explained by the difference in definitions. The RCTs used a broader definition of EFS, which encompassed pre-surgical progression, whereas our review measured survival metrics from the date of surgery, thus possibly missing preoperative events. None of the studies in our review had long-term follow-up, underscoring a clear area of scarcity in survival data on this specific treatment regimen.

The thoracoscopic approach (RATS versus VATS) was evaluated to identify potential differences in outcomes. In our review, over two-thirds of patients underwent VATS. Only three studies directly compared the two techniques. No significant differences were observed in perioperative, pathologic, or oncologic outcomes. However, one study found a significantly lower conversion rate with RATS, whereas the other two studies reported lower but non-significant rates. As previously mentioned, conversion rates ranged from 0% to 39% overall, with VATS spanning the full range and RATS consistently lower at 0% to 7%. Although based on only four studies, three comparative and one cohort, this pattern may suggest a potential benefit of robotic surgery. Other studies have similarly shown a difference in conversion rates between VATS and RATS, attributing it to the enhanced advantages of robotic surgery, which allow for superior visualization of anatomical structures and greater maneuverability in challenging operating environments (76,87).

Implications and actions needed

We identified a total of 1,138 cases of thoracoscopic lobectomy following neoadjuvant chemoIO for NSCLC. Perioperative safety appears to be reasonable, but there may be some differences in the type and frequency of complications compared to standard lobectomy. The pooled conversion rate of 9.2% was comparable to those reported in CheckMate 816 (11% in chemoIO group) and in the STS GTSD (15.3% in treatment-naïve patients undergoing thoracoscopic lobectomy), but varied widely across individual studies and ranged up to 39% (6,8,73). Throughout the studies, the R0 resection and pathologic responses compared favorably to the RCTs. However, it is important to acknowledge the significant limitations of the available data.

More studies of real-world outcomes are needed. High-volume centers should prioritize reporting their safety and oncologic results as follow-up accrues and should include outcomes stratified by surgical approach, intervention, and therapeutic treatment. There is a need for more studies in the United States and other Western countries to increase the generalizability of the data. To enhance comparability across future studies, definitions for oncologic outcomes and follow-up intervals should be clearly defined and reported. Major national databases such as the NCDB and STS GTSD should likewise move quickly to incorporate/improve variables related to chemoIO (including differentiating immunotherapy from targeted therapies) to enable the collection of large-scale data for study on this topic. Importantly, we have also identified a need for more detailed reporting of surgical outcomes from major RCTs. None of the five RCTs reported outcomes by surgical approach, and some did not even report the approach. Surgical morbidity was likely under-reported and no trial specified tracked surgical complications (e.g., STS GTSD major morbidity). Thus, despite the existence of five large, high-quality trials, results were reported in a format that does not permit surgeons to evaluate the outcomes of thoracoscopic approaches in this setting.

Although long-term oncologic outcomes remain limited, our review findings, combined with the favorable long-term results of the RCTs and the known advantages of minimally invasive surgery, suggest that thoracoscopic approaches are appropriate following neoadjuvant chemoIO.

Conclusions

Thoracoscopic lobectomy after neoadjuvant chemoIO for NSCLC is associated with reasonable safety and early outcomes in this review, although significant variability in reporting and outcomes was observed. Notably, conversion rates are likely higher after chemoIO, and there may be differences in the complication profile. We call on surgeons to report their real-world experiences and on trial authors to report detailed, approach-stratified surgical outcomes. And, of course, we all eagerly await mature long-term data from the RCTs and other reports.

Acknowledgments

The authors appreciate the resources offered at The George Washington School of Medicine and Health Sciences.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-25-33/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-25-33/prf

Funding: None.

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