A Comparative Analysis of Video-Assisted Thoracoscopic Surgery and Thoracotomy in Non-Small-Cell Lung Cancer in Terms of Their Oncological Efficacy in Resection: A Systematic Review

Video-assisted thoracoscopic surgery (VATS) is considered the standard procedure for surgical resection in non-small-cell lung cancer (NSCLC). However, there is still lingering speculation on its adequacy of lymph node (LN) dissection or sampling and the long-term survival benefits when compared to open thoracotomy. Given the above, we conducted a systematic review comparing VATS and thoracotomy in terms of their oncological effectiveness in resection. We explored major research literature databases and search engines such as MEDLINE, PubMed, PubMed Central, Google Scholar, and ResearchGate to find pertinent articles. After the meticulous screening, quality check, and applying relevant filters according to our eligibility criteria, we identified 16 studies relevant to our research question, out of which one was a randomized controlled trial, one meta-analysis, and 14 were observational studies. The study comprised 44,673 patients with NSCLC, out of whom 15,093 patients were operated by VATS and the remaining 29,580 patients by thoracotomy. The results indicate that VATS is equivalent to thoracotomy in total LNs (N1 + N2) and LN stations dissected. However, a thoracotomy may achieve slightly better mediastinal lymph node dissection (N2) in terms of assessing a greater number of mediastinal lymph nodes and nodal stations. This may be attributed to a better visual field during mediastinal nodal clearance by an open approach. Also, nodal upstaging was consistently more common with an open approach. In terms of long-term outcomes, both overall survival and disease-free survival rates were similar between the two groups, with VATS offering a slightly better survival benefit. Irrespective of the increased rates of nodal upstaging by an open approach, we conclude that VATS should be considered a highly efficient alternative to thoracotomy in both early and locally advanced NSCLC.


Introduction And Background
Lung cancer is the most prevalent type of cancer in both sexes and accounts for 18.4% of all cancer-related mortality globally [1]. Non-small-cell lung cancer (NSCLC) is by far the most common type comprising a majority of all lung cancer diagnoses. The treatment modality for early-stage NSCLC consists of surgical resection and lymph node (LN) dissection or sampling [2,3]. Historically, surgical intervention has involved open approaches, including open lobectomy, segmentectomy, or wedge resection. However, these ribspreading invasive approaches are associated with many post-operative morbidities [4].
In this prelude, minimally invasive surgical techniques such as video-assisted thoracoscopic surgery (VATS) are being readily used nowadays to reduce surgical trauma associated with open procedures. The first documented evidence of VATS for lung cancer resection and mediastinal lymph node dissection (MLND) was provided by McKenna in 1994 [5]. Since its inception, there has been a gradual and widespread adoption of VATS as the standard operative procedure for early-stage NSCLC [6,7]. Many studies are delineating the efficacy of VATS over open thoracotomy concerning reduced post-operative pain, improved post-operative pulmonary function, shorter chest tube duration, shorter hospital stay as well as decreased incidence of other post-operative morbidities, including supraventricular arrhythmias, myocardial infarction, pulmonary embolism, and empyema [6,[8][9][10].

Analysis of Study Quality/Bias
We critically evaluated 17 selected studies for quality, using standardized quality assessment tools, and 16 studies qualified as medium or high quality, which were included in the review. The following tools were used: (1) for observational studies, Newcastle-Ottawa scale; (2) for systematic reviews and meta-analyses, Assessment of Multiple Systematic Reviews (AMSTAR) tool; (3) for traditional reviews, Scale for the Assessment of Narrative Review Articles (SANRA) checklist; (4) for RCTs, Cochrane risk-of-bias assessment tool.

Data Extraction
Two investigators independently extracted data from the eligible studies and examined them for the following: (1) type of study, (2) number of participants, (3) number of LNs and LN stations dissected, (4) rates of nodal upstaging and (5) long-term outcomes.

Results
A total of 5013 articles were identified in our initial search of MEDLINE, PubMed, and PMC databases. Out of them, 3851 articles were discarded after applying relevant filters as per our eligibility criteria (last 10 years, human studies, English papers) and duplicates were removed. Two individual investigators then screened the remaining articles (n=1162) based on titles, abstracts, full-text, and detailed inclusionexclusion criteria. After the meticulous screening, we were left with 14 articles about our research question. Additional three articles were added by searching the relevant keywords in Google Scholar and ResearchGate directly relevant to our topic. A total of 17 studies were included for a thorough quality/bias assessment using standardized quality assessment tools. One study was excluded after quality appraisal, and the final 16 studies were included in this systematic review. The PRISMA 2020 flow diagram is depicted in Figure 1 [17].

FIGURE 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram
Of the 16 included studies, there were 14 observational studies, one RCT and one meta-analysis. They included 44,673 patients with NSCLC, out of whom 15,093 patients underwent VATS, and 29,580 patients underwent thoracotomy. We identified 14 studies that compared the efficacy of lymph node dissection and rates of nodal upstaging following VATS or thoracotomy. They included 44,413 patients, of whom 14,923 belonged to the VATS group, and 29,490 belonged to the thoracotomy group. There was no significant difference in the total number of lymph nodes (N1 + N2) and lymph node stations resected between the VATS and thoracotomy groups. However, a thoracotomy may be slightly better than VATS in terms of MLND (N2) alone. Nodal upstaging (N1/N2) was also moderately more common with an open approach.
In another sub-group, we analysed the long-term outcomes of surgery by comparing the three-year and fiveyear OS and DFS rates between VATS and thoracotomy. We identified 10 studies comparing the two groups' five-year OS, five-year DFS, three-year OS, and three-year DFS. They included 9164 patients, of whom 2674 patients underwent VATS and 6490 patients underwent open procedures. OS and DFS were nearly similar between the two groups, with VATS conferring a slightly better survival benefit.

Discussion
We analysed the oncological efficacy of resection conferred by VATS and open thoracotomy by comparing the completeness of lymph node dissection or sampling and the survival rates in patients with NSCLC.
In patients with lung cancer, a pre-operative staging routinely done by computed tomography (CT) scan, positron emission tomography (PET) scan or mediastinoscopy may not always be accurate. This is evident by post-operative nodal upstaging after lobectomy with systematic lymph node dissection. In a prospective trial including 502 clinical Stage I NSCLC patients, who underwent surgical resection and complete lymph node dissection, D'Cunha et al. demonstrated that 38.3% were upstaged post-operatively or had inaccuracies in diagnosis [33]. An extensive and complete lymph node assessment is vital for lung cancer surgery. It helps in accurate post-operative staging and minimize the chance of leaving behind occult malignancy. This, in turn, has implications in guiding adjuvant chemotherapy, if required, which has proven beneficial in upstaged NSCLC patients [34,35].
Also, the number of dissected lymph nodes directly correlates with the OS. In a retrospective study conducted by Jeon et al. including 211 patients with clinical Stage I NSCLC, patients were divided into two groups. One group underwent lobectomy with complete mediastinal lymph node dissection (14.09 ± 7.57 LNs), and the other underwent lobectomy with selective lymph node sampling (7.50 ± 5.44 LNs). The results favored the group with greater resected lymph nodes in overall survival [36]. Ou et al. also demonstrated a definite survival benefit in patients with more dissected lymph nodes [37]. A recent large retrospective study by David et al. reported that the number of dissected lymph nodes served as a significant positive prognostic factor [38]. The current NCCN guidelines also vouch for a minimum of three N2 nodal station dissections or sampling.
Although the short-term benefits of VATS lobectomy are well documented, the efficacy of lymph node dissection and subsequent long-term outcomes is questionable when compared to thoracotomy lobectomy. With this in mind, we selected 16 studies for our systematic review that compared VATS and open thoracotomy for the effectiveness of nodal dissection and overall and disease-free survival.

Comparison of Efficacy of Lymph Node Dissection
Fourteen of our included studies compared the effectiveness of nodal dissection achieved by VATS versus thoracotomy. They included 12 retrospective cohort studies, one RCT and one meta-analysis. They all assessed the number of lymph nodes and stations dissected and rates of nodal upstaging. Still, they differed regarding study design, sample size, geographic and demographic aspects of the participants, and certain eligibility criteria.
In a retrospective study conducted by Ramos et al., 296 patients with clinical Stage I-II NSCLC from a single institution in France were enrolled [23]. Out of them, 96 surgical resections and LND were via VATS and the remaining 200 via posterolateral thoracotomy. Pre-operative assessments for both the groups were the same, and there was comparability between them concerning age, gender, and existing comorbidities except cardiopathy. The study showed that VATS achieved a better total (5.  [43]. There was no significant difference in any of the zonal dissection also. However, this RCT was limited by the small number of its participants. This finding was supported by a Canadian retrospective study conducted by Hanna et al. in the same year including a larger cohort size of 608 NSCLC patients [30]. The study showed no statistical difference between VATS and thoracotomy in nodal sampling at different stations. The IASLC nodal mapping is depicted below in Figure 2. The figure is adapted from Refs [43,44] and was created by the first author.  [25]. Both procedures harvested similar number of total LNs (15.6 ± 9.2 vs. 14.7 ± 7.9), hilar and peribronchial nodes (5.3 ± 4 vs. 5.3 ± 3.7) and mediastinal nodes (10.3 ± 7 vs. 9.4 ± 5.8).
Interestingly, the number of LNs resected by VATS improved with more operative time.
On interpreting and analysing the studies mentioned above, we found that despite VATS offering a more or less equivalent nodal dissection, nodal upstaging was consistently more common with thoracotomy. This may be explained by the open approach's more targeted and meticulous clearance of suspected LNs, owing to the better visual field. This may also have been affected by facility type. Also, as most of our included studies were observational studies, an inherent selection bias might have led to larger tumors with a greater tendency of a positive nodal burden being operated openly.
The brief descriptions of each study, including the year of publication, author name, number of patients, type of study, results, and conclusions of the authors regarding LN assessment/dissection, are listed in Table  4.

Author and year of publication
Interventions studied  ). This should be correlated with a previous finding stating that the efficacy of LN dissection was similar between the two groups. This study was more generalizable as it was larger than the previously mentioned ones regarding participants. Selection bias was also somewhat diminished by propensity matching of cohorts. Another point to mention is that the study accounted for Stages IB, II and IA, but no deductions can be made about the more advanced disease (Stage III or more).

Number of patients
To include a perspective of surgical efficacy of resection in advanced disease, we included a multi-  [13]. However, this study was limited by its small sample size. Also, a point worth mentioning is that more patients in the open group received adjuvant chemotherapy, which should have tilted the benefit of thoracotomy. Still, the results showed otherwise. Lee and colleagues also did not report significantly different long-term survival rates between VATS and thoracotomy in their study [16]. They concluded that VATS was not inferior to thoracotomy in conferring a better oncological prognosis. In a consensus, our analysis showed that irrespective of LN evaluation status, VATS offers an equivalent if not slightly better long-term survival benefit in patients with NSCLC. The detailed descriptions of each study, including the year of publication, author name, number of patients, type of study, results, and authors' conclusions regarding the long-term survival rates (OS, DFS), are listed in Table 5. Author

Limitations
Our study had a few limitations, and hence the results should be interpreted keeping them in mind. Most importantly, there was only one RCT out of the 16 studies included in our systematic review. This might lessen the quality of evidence and raise concerns about the lack of prospective RCTs on the topic. Second, we included only English papers that might have led to language bias. Third, as most of our studies were observational, that calls for inherent selection bias as larger, more central tumors tend to be operated by open lobectomy by most surgeons. Also, we must take into account that a surgeon's preferred practice and expertise might also have led to selection bias. However, this aspect was somewhat lessened as most of the studies showed results after propensity matching of the cohorts. Fourth, we must account for information bias due to the non-availability and non-uniformity of certain data collected from various databases worldwide. Finally, the ideology and methodology of LN dissection or sampling and levels of expertise may vary between different surgeons, which may also have implications for the results.

Conclusions
This systematic review was carried out to compare a minimally invasive VATS procedure with open thoracotomy in terms of their resection potential and long-term prognosis in patients with NSCLC to find out the surgical approach deemed more suitable ultimately. VATS is equivalent to thoracotomy in surgical resection of total LNs and LN stations. However, the data collected suggests that if only MLND is considered, a thoracotomy may offer a slightly better result. Also, nodal upstaging was more common with an open approach. On analysis of another aspect of long-term outcomes or survival rates, the evidence showed that VATS offered an equivalent if not slightly better result in overall survival and disease-free survival.
This review study will prove helpful in guiding practicing surgeons who are ambivalent regarding the optimal surgical technique. Irrespective of increased rates of nodal upstaging by thoracotomy, VATS should be considered a highly efficient alternative in both early and locally advanced NSCLC because of the marginally better survival benefit conferred. However, we found that very few RCTs have been conducted on the topic, and thus these findings should be ideally validated by a high-quality RCT.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.