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Video-Assisted Thoracoscopic Surgery Versus Thoracotomy Lymph Node Dissection in Clinical Stage I Lung Cancer: A Meta-Analysis and System Review

2016; Elsevier BV; Volume: 101; Issue: 6 Linguagem: Inglês

10.1016/j.athoracsur.2015.11.055

ISSN

1552-6259

Autores

Wenxiong Zhang, Yiping Wei, Han Jiang, Jianjun Xu, Dongliang Yu,

Tópico(s)

Pleural and Pulmonary Diseases

Resumo

Video-assisted thoracoscopic surgery (VATS) is the preferred surgical procedure, causing fewer injuries compared with thoracotomy, but whether VATS can achieve the same lymph node (LN) dissection efficacy is controversial. A systematic literature search was performed to identify studies comparing VATS and thoracotomy in LN dissection for clinical stage I lung cancer. Twenty articles met the inclusion criteria and involved 2,190 patients in the VATS group and 3,000 patients in the open group. Meta-analysis showed that fewer total LNs were dissected in the VATS group, although VATS harvested more left-side LNs. The same number of total LN stations, N2 LNs, N2 LN stations, N1 LNs, and right-side LNs was harvested in both groups. Our findings require further validation in more high-quality, large-scale randomized controlled trials. Video-assisted thoracoscopic surgery (VATS) is the preferred surgical procedure, causing fewer injuries compared with thoracotomy, but whether VATS can achieve the same lymph node (LN) dissection efficacy is controversial. A systematic literature search was performed to identify studies comparing VATS and thoracotomy in LN dissection for clinical stage I lung cancer. Twenty articles met the inclusion criteria and involved 2,190 patients in the VATS group and 3,000 patients in the open group. Meta-analysis showed that fewer total LNs were dissected in the VATS group, although VATS harvested more left-side LNs. The same number of total LN stations, N2 LNs, N2 LN stations, N1 LNs, and right-side LNs was harvested in both groups. Our findings require further validation in more high-quality, large-scale randomized controlled trials. Lung cancer is the leading cause of cancer death in many countries [1Surveillance, Epidemiology and End Results Program. SEER cancer statistics review, 1975–2007. Available at http://seer.cancer.gov/csr/1975_2007/. Accessed November 2009.Google Scholar, 2Chen W. Zhang S. Zou X. Estimation and projection of lung cancer incidence and mortality in China.Chin J Lung Cancer. 2010; 13: 488-493Google Scholar]. Surgical treatment is the preferred treatment for early-stage non-small cell lung cancer (NSCLC). Overall and disease-free survival are both associated with the number of lymph nodes (LNs) dissected [3Gajra A. Newman N. Gamble G.P. Kohman L.J. Graziano S.L. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small cell lung cancer.J Clin Oncol. 2003; 21: 1029-1034Crossref PubMed Scopus (263) Google Scholar, 4Ou S.H. Zell J.A. Prognostic significance of the number of lymph nodes removed at lobectomy in stage IA non-small cell lung cancer.J Thorac Oncol. 2008; 3: 880-886Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. As a consequence, current guidelines from the National Comprehensive Cancer Network (NCCN) and European Society of Thoracic Surgeons recommend that all patients with resectable NSCLC should undergo complete systematic nodal dissection, with at least 3 N2 LN stations (LNS) dissected [5Ettinger D.S. Akerley W. Bepler G. Blum M.G. Chang A. Cheney R.T. Non-small cell lung cancer.J Natl Compr Canc Netw. 2010; 8: 740-801PubMed Google Scholar, 6Lardinois D. De Leyn P. Van Schil P. et al.ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer.Eur J Cardiothorac Surg. 2006; 30: 787-792Crossref PubMed Scopus (499) Google Scholar]. Video-assisted thoracoscopic surgery (VATS) is the preferred surgical procedure, where there is reduced postoperative pain, better pulmonary function, shorter hospitalization, and higher long-term survival compared with thoracotomy [7Stephens N. Rice D. Correa A. et al.Thoracoscopic lobectomy is associated with improved short-term and equivalent oncological outcomes compared with open lobectomy for clinical stage I non-small-cell lung cancer: a propensity-matched analysis of 963 cases.Eur J Cardiothorac Surg. 2014; 46: 607-613Crossref PubMed Scopus (97) Google Scholar, 8Liu C. Li Z. Bai C. Wang L. Shi X. Song Y. Video-assisted thoracoscopic surgery and thoracotomy during lobectomy for clinical stage I non-small-cell lung cancer have equivalent oncological outcomes: a single-center experience of 212 consecutive resections.Oncol Lett. 2015; 9: 1364-1372PubMed Google Scholar, 9Nwogu C.E. D'Cunha J. Pang H. et al.VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance).Ann Thorac Surg. 2015; 99: 399-405Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Zhang Z. Zhang Y. Feng H. et al.Is video-assisted thoracic surgery lobectomy better than thoracotomy for early-stage non-small-cell lung cancer? A systematic review and meta-analysis.Eur J Cardiothorac Surg. 2013; 44: 407-414Crossref PubMed Scopus (81) Google Scholar]. However, whether VATS can achieve the same LN dissection efficacy is controversial. There remains a lack of large-scale clinical research of decisive significance or expert consensus. To optimize surgical procedures, we performed a systematic review and meta-analysis of LN dissection by VATS and thoracotomy for clinical stage I lung cancer. MEDLINE and manual searches were performed by 2 investigators independently and in duplicate to identify all relevant scientific literature published from January 1990 to July 2015. The MEDLINE search was performed using PubMed, Ovid MEDLINE, Embase, Web of Science, ScienceDirect, The Cochrane Library, Scopus, and Google Scholar. The medical subject heading terms "lung cancer or lung neoplasm," "thoracotomy or open surgery," "video-assisted thoracic surgery or VATS," and "comparative study" were used. The inclusion criteria were (1) published in English, (2) compared the LN dissection of VATS with thoracotomy in treating patients with lung cancer (including wedge resection, segmentectomy, and lobectomy), (3) only involved clinical stage I lung cancer, and (4) when data or data subsets were reported in more than one article, the article with the most detail or the most recent article was chosen. Excluded were case-only designs, case reports, systematic reviews, meta-analyses, animal studies, studies with duplicated data, and studies of robotic-assisted VATS. Two investigators independently extracted data from the eligible studies. The extracted data included first author, year of publication, geographic area, study design, duration of enrollment, information on preoperative staging, number of patients per group, LN number (LNN) and LNS number. Two investigators independently assessed the quality of each included study using the Newcastle-Ottawa Scale for nonrandomized studies and the Jadad scale for randomized controlled trials (RCT). The Newcastle-Ottawa Scale evaluates the quality of studies by analyzing three items: selection, comparability, and exposure. The scale assigns a maximum of 9 points to each study: a maximum of 4 points for selection, 2 points for comparability, and 3 points for exposure. Therefore, the highest-quality study would score 9 points. In our analysis, high-quality studies were defined as those that scored 8 or 9 points, and medium-quality studies were those that scored 6 or 7 points. The Jadad scale is scored according to the presence of three key methodologic features: randomization, blinding, and accountability of all patients, including withdrawals and dropouts. Studies were considered good quality if they scored 3 or more points. The data were analyzed using Review Manager 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and SPSS 18.0 software (IBM Corp, Armonk, NY). For continuous outcomes, we calculated the mean difference weighted by the inverse of the variance. The Cochrane Q and I2 statistics were introduced to evaluate heterogeneity. A fixed-effects model was adopted if heterogeneity was acceptable (p > 0.10, or p ≤ 0.10 but I2 ≤ 50%); otherwise, a random-effects model was adopted. A two-tailed p value of 0.05 or less was deemed statistically significant. For some studies, the original data were recalculated for analysis. Publication bias was explored through visual inspection of the funnel plots. We initially identified 2,298 publications from the database and reference list searches and reviewed 20 articles for final analysis (Fig 1). The articles involved 5,190 patients, of whom 2,190 underwent VATS and 3,000 underwent thoracotomy. Of these 20 publications, three studies were RCTs and 17 were retrospective studies. According to the Newcastle-Ottawa Scale and Jadad scales assessment scores, 16 articles were of good quality, and the remaining four were medium quality. The baseline characteristics of these articles are listed in Table 1 [11Kirby T.J. Mack M.J. Landreneau R.J. Rice T.W. Lobectomy video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial.J Thorac Cardiovasc Surg. 1995; 109: 997-1001Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 12Ohbuchi T. Morikawa T. Takeuchi E. Kato H. Lobectomy: video-assisted thoracic surgery versus posterolateral thoracotomy.Jpn J Thorac Cardiovasc Surg. 1998; 46: 519-522Crossref PubMed Scopus (49) Google Scholar, 13Luketich J.D. Meehan M.A. Landreneau R.J. et al.Total videothoracoscopic lobectomy versus open thoracotomy for early-stage non small-cell lung cancer.Clin Lung Cancer. 2000; 2: 56-60Abstract Full Text PDF PubMed Scopus (18) Google Scholar, 14Sugi K. Kaneda Y. Esato K. Video-assisted thoracoscopic lobectomy achieves a satisfactory long-term prognosis in patients with clinical stage IA lung cancer.World J Surg. 2000; 24: 27-30Crossref PubMed Scopus (304) Google Scholar, 15Nomori H. Horio H. Naruke T. Suemasu K. What is the advantage of a thoracoscopic lobectomy over a limited thoracotomy procedure for lung cancer surgery?.Ann Thorac Surg. 2001; 72: 879-884Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 16Watanabe A. Koyanagi T. Obama T. et al.Assessment of node dissection for clinical stage I primary lung cancer by VATS.Eur J Cardiothorac Surg. 2005; 27: 745-752Crossref PubMed Scopus (52) Google Scholar, 17Shiraishi T. Shirakusa T. Miyoshi T. Hiratsuka M. Yamamoto S. Iwasaki A. A completely thoracoscopic lobectomy/segmentectomy for primary lung cancer—technique, feasibility, and advantages.Thorac Cardiovasc Surg. 2006; 54: 202-207Crossref PubMed Scopus (22) Google Scholar, 18Shigemura N. Akashi A. Funaki S. et al.Long-term outcomes after a variety of video-assisted thoracoscopic lobectomy approaches for clinical stage IA lung cancer: a multi-institutional study.J Thorac Cardiovasc Surg. 2006; 132: 507-512Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 19Watanabe A. Mishina T. Ohori S. et al.Is video-assisted thoracoscopic surgery a feasible approach for clinical N0 and postoperatively pathological N2 non-small cell lung cancer?.Eur J Cardiothorac Surg. 2008; 33: 812-818Crossref PubMed Scopus (68) Google Scholar, 20Okur E. Baysungur V. Tezel Ç. Ergene G. Sevilgen G. Halezeroglu S. Comparison of perioperative results of conventional versus thoracoscopic lobectomy for clinical stage I lung carcinoma.Turkish J Thorac Cardiovasc Surg. 2009; 17: 191-197Google Scholar, 21Denlinger C.E. Fernandez F. Meyers B.F. et al.Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.Ann Thorac Surg. 2010; 89: 1730-1735Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 22Ilonen I.K. Rasanen J.V. Knuuttila A. Salo J.A. Sihvo E.I. Anatomic thoracoscopic lung resection for non-small cell lung cancer in stage I is associated with less morbidity and shorter hospitalization than thoracotomy.Acta Oncol. 2011; 50: 1126-1132Crossref PubMed Scopus (41) Google Scholar, 23Licht P.B. Jorgensen O.D. Ladegaard L. Jakobsen E. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.Ann Thorac Surg. 2013; 96: 943-949Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 24Zhong C. Yao F. Zhao H. Clinical outcomes of thoracoscopic lobectomy for patients with clinical N0 and pathologic N2 non-small cell lung cancer.Ann Thorac Surg. 2013; 95: 987-992Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 25Zhou W. Chen X. Zhang H. Zhang H. Zhao M. Video-assisted thoracic surgery lobectomy for unexpected pathologic N2 non-small cell lung cancer.Thorac Cancer. 2013; 4: 287-294Crossref Scopus (10) Google Scholar, 26Palade E. Passlick B. Osei-Agyemang T. Günter J. Wiesemann S. Video-assisted vs open mediastinal lymphadenectomy for stage I non-small-cell lung cancer: results of a prospective randomized trial.Eur J Cardiothorac Surg. 2013; 44: 244-249Crossref PubMed Scopus (62) Google Scholar, 27Kuritzky A.M. Aswad B.I. Jones R.N. Ng T. Lobectomy by video-assisted thoracic surgery vs muscle-sparing thoracotomy for stage I lung cancer: a critical evaluation of short- and long-term outcomes.J Am Coll Surg. 2015; 220: 1044-1053Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 28Murakawa T. Ichinose J. Hino H. Kitano K. Konoeda C. Nakajima J. Long-term outcomes of open and video-assisted thoracoscopic lung lobectomy for the treatment of early stage non-small cell lung cancer are similar: a propensity-matched study.World J Surg. 2015; 39: 1084-1091Crossref PubMed Scopus (31) Google Scholar, 29Zhang S. Pan S.B. Lyu Q.H. et al.Postoperative regulatory T-cells and natural killer cells in stage I nonsmall cell lung cancer underwent video-assisted thoracoscopic lobectomy or thoracotomy.Chin Med J (Engl). 2015; 128: 1502-1509Crossref PubMed Scopus (13) Google Scholar].Table 1Summary of the 20 Studies Included in the Present Meta-AnalysisStudyCountryInstitutionEnrolled (month/year)Patients (No.)Clinical StageOutcomeDesignQuality(score)First AuthorYearVATSOpenVATSOpenKirby 11Kirby T.J. Mack M.J. Landreneau R.J. Rice T.W. Lobectomy video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial.J Thorac Cardiovasc Surg. 1995; 109: 997-1001Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar1995JapanSingle10/1991–12/199110/1991–12/19932530I①RCT3Ohbuchi 12Ohbuchi T. Morikawa T. Takeuchi E. Kato H. Lobectomy: video-assisted thoracic surgery versus posterolateral thoracotomy.Jpn J Thorac Cardiovasc Surg. 1998; 46: 519-522Crossref PubMed Scopus (49) Google Scholar1998JapanSingle1/1996–12/19964/1994–12/19953535I③Retrospective7Luketich 13Luketich J.D. Meehan M.A. Landreneau R.J. et al.Total videothoracoscopic lobectomy versus open thoracotomy for early-stage non small-cell lung cancer.Clin Lung Cancer. 2000; 2: 56-60Abstract Full Text PDF PubMed Scopus (18) Google Scholar2000USASingleNot mentionedNot mentioned3131I①Retrospective7Sugi 14Sugi K. Kaneda Y. Esato K. Video-assisted thoracoscopic lobectomy achieves a satisfactory long-term prognosis in patients with clinical stage IA lung cancer.World J Surg. 2000; 24: 27-30Crossref PubMed Scopus (304) Google Scholar2000JapanSingle1/1993–6/19941/1993–6/19944852Ia③, ⑤RCT3Nomori 15Nomori H. Horio H. Naruke T. Suemasu K. What is the advantage of a thoracoscopic lobectomy over a limited thoracotomy procedure for lung cancer surgery?.Ann Thorac Surg. 2001; 72: 879-884Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar2001JapanSingle8/1999–12/20004/1998–7/19993333I①, ⑦, ⑧Retrospective7Watanabe 16Watanabe A. Koyanagi T. Obama T. et al.Assessment of node dissection for clinical stage I primary lung cancer by VATS.Eur J Cardiothorac Surg. 2005; 27: 745-752Crossref PubMed Scopus (52) Google Scholar2005JapanSingle1997–20041997–2004221190I①, ③, ⑦, ⑧Retrospective8Shiraishi 17Shiraishi T. Shirakusa T. Miyoshi T. Hiratsuka M. Yamamoto S. Iwasaki A. A completely thoracoscopic lobectomy/segmentectomy for primary lung cancer—technique, feasibility, and advantages.Thorac Cardiovasc Surg. 2006; 54: 202-207Crossref PubMed Scopus (22) Google Scholar2006JapanSingle1/2003–12/20041/2003–12/20041019Ia①, ⑦, ⑧Retrospective7Shigemura 18Shigemura N. Akashi A. Funaki S. et al.Long-term outcomes after a variety of video-assisted thoracoscopic lobectomy approaches for clinical stage IA lung cancer: a multi-institutional study.J Thorac Cardiovasc Surg. 2006; 132: 507-512Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar2006JapanMulti1/1999–1/20041/1999–1/20045055Ia①Retrospective9Watanabe 19Watanabe A. Mishina T. Ohori S. et al.Is video-assisted thoracoscopic surgery a feasible approach for clinical N0 and postoperatively pathological N2 non-small cell lung cancer?.Eur J Cardiothorac Surg. 2008; 33: 812-818Crossref PubMed Scopus (68) Google Scholar2008JapanSingle1997–20061997–20063732I①, ②, ③, ④Retrospective8Okur 20Okur E. Baysungur V. Tezel Ç. Ergene G. Sevilgen G. Halezeroglu S. Comparison of perioperative results of conventional versus thoracoscopic lobectomy for clinical stage I lung carcinoma.Turkish J Thorac Cardiovasc Surg. 2009; 17: 191-197Google Scholar2009TurkeySingle1/2007–11/20071/2007–11/20072028I②Retrospective8Denlinger 21Denlinger C.E. Fernandez F. Meyers B.F. et al.Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.Ann Thorac Surg. 2010; 89: 1730-1735Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar2010USASingle1/2000–8/20081/2000–8/200879464I①, ③, ⑤Retrospective8Ilonen 22Ilonen I.K. Rasanen J.V. Knuuttila A. Salo J.A. Sihvo E.I. Anatomic thoracoscopic lung resection for non-small cell lung cancer in stage I is associated with less morbidity and shorter hospitalization than thoracotomy.Acta Oncol. 2011; 50: 1126-1132Crossref PubMed Scopus (41) Google Scholar2011FinlandSingle1/2000–2/20101/2000–2/2010116212I②Retrospective8Licht 23Licht P.B. Jorgensen O.D. Ladegaard L. Jakobsen E. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.Ann Thorac Surg. 2013; 96: 943-949Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar2012DNKMulti1/2007–12/20111/2007–12/2011717796I②Retrospective8Zhong 24Zhong C. Yao F. Zhao H. Clinical outcomes of thoracoscopic lobectomy for patients with clinical N0 and pathologic N2 non-small cell lung cancer.Ann Thorac Surg. 2013; 95: 987-992Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar2013ChinaSingle3/2006–8/20113/2006–8/20116790I①, ②, ③, ④Retrospective8Zhou 25Zhou W. Chen X. Zhang H. Zhang H. Zhao M. Video-assisted thoracic surgery lobectomy for unexpected pathologic N2 non-small cell lung cancer.Thorac Cancer. 2013; 4: 287-294Crossref Scopus (10) Google Scholar2013ChinaSingle1/2004–12/20081/2004–12/2008117241I③, ④, ⑤, ⑥Retrospective8Palade 26Palade E. Passlick B. Osei-Agyemang T. Günter J. Wiesemann S. Video-assisted vs open mediastinal lymphadenectomy for stage I non-small-cell lung cancer: results of a prospective randomized trial.Eur J Cardiothorac Surg. 2013; 44: 244-249Crossref PubMed Scopus (62) Google Scholar2013GERSingle5/2008–12/20115/2008–12/20113232I①, ⑦, ⑧RCT3Stephens 7Stephens N. Rice D. Correa A. et al.Thoracoscopic lobectomy is associated with improved short-term and equivalent oncological outcomes compared with open lobectomy for clinical stage I non-small-cell lung cancer: a propensity-matched analysis of 963 cases.Eur J Cardiothorac Surg. 2014; 46: 607-613Crossref PubMed Scopus (97) Google Scholar2014USASingle1/2002–12/20111/2002–12/2011307307I②Retrospective8Kuritzky 27Kuritzky A.M. Aswad B.I. Jones R.N. Ng T. Lobectomy by video-assisted thoracic surgery vs muscle-sparing thoracotomy for stage I lung cancer: a critical evaluation of short- and long-term outcomes.J Am Coll Surg. 2015; 220: 1044-1053Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar2015USASingle2007–20122007–201274224I②Retrospective8Murakawa 28Murakawa T. Ichinose J. Hino H. Kitano K. Konoeda C. Nakajima J. Long-term outcomes of open and video-assisted thoracoscopic lung lobectomy for the treatment of early stage non-small cell lung cancer are similar: a propensity-matched study.World J Surg. 2015; 39: 1084-1091Crossref PubMed Scopus (31) Google Scholar2015DNKSingle2001–20102001–2010101101I①, ②Retrospective8Zhang 29Zhang S. Pan S.B. Lyu Q.H. et al.Postoperative regulatory T-cells and natural killer cells in stage I nonsmall cell lung cancer underwent video-assisted thoracoscopic lobectomy or thoracotomy.Chin Med J (Engl). 2015; 128: 1502-1509Crossref PubMed Scopus (13) Google Scholar2015ChinaSingle10/2012–11/201310/2012–11/20137028I①Retrospective9① = total lymph node number (LNN); ② = total lymph node station number (LNS); ③ = N2 LNN; ④ = N2 LNS; ⑤ = N1 LNN; ⑥ = N1 LNS; ⑦ = left-side LNN; ⑧ = right-side LNN; DNK = Denmark; GER = Germany; RCT = randomized controlled trial; USA = United States of America. Open table in a new tab ① = total lymph node number (LNN); ② = total lymph node station number (LNS); ③ = N2 LNN; ④ = N2 LNS; ⑤ = N1 LNN; ⑥ = N1 LNS; ⑦ = left-side LNN; ⑧ = right-side LNN; DNK = Denmark; GER = Germany; RCT = randomized controlled trial; USA = United States of America. We identified 11 articles for total LNN comparison. They involved 746 patients in the VATS group and 1,086 patients in the open (thoracotomy) group. The heterogeneity between these studies was acceptable (I2 = 40%, p = 0.08). The mean difference in total LNN between the two groups was significant (95% confidence interval [CI], –1.67 to –0.61; p < 0.0001), which demonstrated more favorable LN dissection efficacy by thoracotomy (Fig 2A). Eight articles were identified for total LNS comparison. They involved 1,439 patients in the VATS group and 1,790 patients in the open group. The mean difference in total LNS between the two groups was not significant (95% CI, –0.62 to 0.02; p = 0.07), with significant heterogeneity across studies (I2 = 95%, p < 0.00001; Fig 2B). Seven articles were identified for N2 LNN comparison. They involved 604 patients in the VATS group and 1,104 patients in the open group. The results showed significant heterogeneity between these studies (I2 = 71%, p = 0.002). The mean difference in N2 LNN between the two groups was not significant (95% CI, –1.04 to 0.43; p = 0.42; Fig 3A). Three articles were identified for N2 LNS comparison. They involved 221 patients in the VATS group and 363 patients in the open group. There was no evidence of heterogeneity between these studies (I2 = 0%, p = 0.60). The mean difference in N2 LNS between the two groups was not significant (95% CI, –0.20 to 0.14; p = 0.76; Fig 3B). Three articles were identified for N1 LNN comparison. They involved 224 patients in the VATS group and 757 patients in the open group. There was no evidence of heterogeneity among these studies (I2 = 0%, p = 0.54). The mean difference in N1 LNS between the two groups was not significant (95% CI, –0.28 to 0.03; p = 0.12; Fig 4). Only one article was identified for N1 LNS comparison. It involved 48 patients in the VATS group and 52 patients in the open group. The mean difference between the two groups was not significant (8.2 ± 1.5 vs 8.4 ± 1.0, p = 0.88). Three articles were identified for left-side and right-side LNN comparison. They involved 286 patients in the VATS group and 255 patients in the open group. There was no evidence of heterogeneity among these studies for both sides (I2 = 0%). The mean difference in right-side LNN between the two groups was not significant (95% CI, –1.52 to 2.23; p = 0.71; Fig 5A). In the comparison of left-side LNN, the VATS group had better efficiency (95% CI, 0.51 to 3.32; p = 0.007; Fig 5B). The funnel plot for publication bias (standard error by total LNN comparison) demonstrated marked evidence of symmetry (Fig 6), indicating no publication bias. The combined effect size yielded a z value of 4.23, with a corresponding p of less than 0.0001. This result indicates that the fail-safe N value was relevant. Unsuspected LN metastases are found in the surgical specimens of 10% to 28% clinical stage I lung cancers [30Boffa D.J. Kosinski A.S. Paul S. Mitchell J.D. Onaitis M. Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.Ann Thorac Surg. 2012; 94: 347-353Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 31D'Cunha J. Herndon J.E. Herzan D.L. et al.Poor correspondence between clinical and pathologic staging in stage I non-small cell lung cancer: results from CALGB 9761, a prospective trial.Lung Cancer. 2005; 48: 241-246Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. Noninvasive staging modalities, such as computed tomography and positron emission tomography scanning, are insufficient because they fail to identify nodal metastases in more than 20% of patients with primary lung cancer [32Silvestri G.A. Gould M.K. Margolis M.L. et al.Noninvasive staging of non-small cell lung cancer: ACCP evidenced based clinical practice guidelines (2nd edition).Chest. 2007; 132: 178-201Crossref PubMed Scopus (561) Google Scholar]. Although VATS is associated with many benefits compared with thoracotomy, whether VATS can achieve the same LN dissection efficacy in patients with early-stage lung cancer remains controversial [7Stephens N. Rice D. Correa A. et al.Thoracoscopic lobectomy is associated with improved short-term and equivalent oncological outcomes compared with open lobectomy for clinical stage I non-small-cell lung cancer: a propensity-matched analysis of 963 cases.Eur J Cardiothorac Surg. 2014; 46: 607-613Crossref PubMed Scopus (97) Google Scholar, 8Liu C. Li Z. Bai C. Wang L. Shi X. Song Y. Video-assisted thoracoscopic surgery and thoracotomy during lobectomy for clinical stage I non-small-cell lung cancer have equivalent oncological outcomes: a single-center experience of 212 consecutive resections.Oncol Lett. 2015; 9: 1364-1372PubMed Google Scholar, 9Nwogu C.E. D'Cunha J. Pang H. et al.VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance).Ann Thorac Surg. 2015; 99: 399-405Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. Flores [33Flores R.M. Video-assisted thoracic surgery (VATS) lobectomy: focus on technique.World J Surg. 2010; 34: 616-620Crossref PubMed Scopus (28) Google Scholar] reported that the surgical field in VATS facilitated the dissection of LNs adjacent to blood vessels and the trachea and found smaller nodes to achieve better LN dissection. Ramos and colleagues [34Ramos R. Girard P. Masuet C. Validire P. Gossot D. Mediastinal lymph node dissection in early-stage non-small cell lung cancer: totally thoracoscopic vs thoracotomy.Eur J Cardiothorac Surg. 2012; 41: 1342-1348Crossref PubMed Scopus (42) Google Scholar] showed that VATS dissected more total LNS (5.1 ± 1.1 vs 4.5 ± 1.2, p < 0.001) and mediastinal LNS (3.4 ± 0.9 vs 3.2 ± 0.9, p = 0.022) compared with thoracotomy. Denlinger and colleagues [21Denlinger C.E. Fernandez F. Meyers B.F. et al.Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.Ann Thorac Surg. 2010; 89: 1730-1735Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] reported significantly more overall LNs were dissected in the open group than in the VATS group (8.9 ± 5.2 vs 7.1 ± 5.2, p = 0.0006). Similar results were reported by Merritt and colleagues [35Merritt R.E. Hoang C.D. Shrager J.B. Lymph node evaluation achieved by open lobectomy compared with thoracoscopic lobectomy for N0 lung cancer.Ann Thorac Surg. 2013; 96: 1171-1177Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] in their retrospective study of LN evaluation achieved by VATS lobectomy compared with open lobectomy. A secondary analysis involving 752 original participants of the American College of Surgeons Oncology Group Z0030 trial compared patients who underwent VATS lobectomy with patients who underwent thoracotomy. The results showed no statistical difference in the overall number of LNs retrieved between the two groups (15 vs 19, p = 0.147) [36Scott W.J. Allen M.S. Darling G. et al.Video-assisted thoracic surgery versus open lobectomy for lung cancer: a secondary analysis of data from the American College of Surgeons Oncology Group Z0030 randomized clinical trial.J Thorac Cardiovasc Surg. 2010; 139: 976-981Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. The present study included 5,190 patients with clinical stage I lung cancer from 7 countries, providing the most comprehensive evidence for LN dissection efficacy by VATS. Our results showed that VATS harvested fewer total LNN. In the 11 pertinent articles, only the study by Denlinger and colleagues [21Denlinger C.E. Fernandez F. Meyers B.F. et al.Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.Ann Thorac Surg. 2010; 89: 1730-1735Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar] supported this conclusion (7.1 ± 5.2 vs 8.9 ± 5.2, p = 0.006), while the others showed no significant difference. We believe that the reason might be related to the incomplete dissection of LNS 7 in the VATS group, especially for left-side and early resection. No significant difference in total LNS was found between the two groups, and only one of the eight pertinent articles (Ilonen and colleagues [22Ilonen I.K. Rasanen J.V. Knuuttila A. Salo J.A. Sihvo E.I. Anatomic thoracoscopic lung resection for non-small cell lung cancer in stage I is associated with less morbidity and shorter hospitalization than thoracotomy.Acta Oncol. 2011; 50: 1126-1132Crossref PubMed Scopus (41) Google Scholar]) reported better LN dissection in the open group (2.8 ± 1.7 vs 4.6 ± 1.8, p = 0.001). In the comparison of the N1 and N2 LNs, our results showed that similar LNN and LNS were harvested by VATS compared with thoracotomy. Only one article (Zhou and colleagues [25Zhou W. Chen X. Zhang H. Zhang H. Zhao M. Video-assisted thoracic surgery lobectomy for unexpected pathologic N2 non-small cell lung cancer.Thorac Cancer. 2013; 4: 287-294Crossref Scopus (10) Google Scholar]) reported N1 LNS comparison between the two groups, and no significant difference was found (2.51 ± 0.57 vs 2.59 ± 0.68, p = 0.284). A meta-analysis by Zhang and colleagues [37Zhang Z. Feng H. Wang X. Liang C. Liu D. Can lymph node evaluation be performed well by video-assisted thoracic surgery?.J Cancer Res Clin Oncol. 2015; 141: 143-151Crossref PubMed Scopus (3) Google Scholar] compared LN evaluation efficacy between 2015 patients in the VATS group and 3250 patients in the open group for lung cancer. Their results showed that VATS harvested fewer N2 LNs (95% CI, –1.81 to –0.24; p = 0.01) [37Zhang Z. Feng H. Wang X. Liang C. Liu D. Can lymph node evaluation be performed well by video-assisted thoracic surgery?.J Cancer Res Clin Oncol. 2015; 141: 143-151Crossref PubMed Scopus (3) Google Scholar]. The difference in results might be related to the fact that only patients with clinical stage I lung cancer were included in our study. This conclusion is somewhat supported, and it is indirectly suggested that larger tumors or enlarged mediastinal LNs increase the difficulty of N2 node dissection [10Zhang Z. Zhang Y. Feng H. et al.Is video-assisted thoracic surgery lobectomy better than thoracotomy for early-stage non-small-cell lung cancer? A systematic review and meta-analysis.Eur J Cardiothorac Surg. 2013; 44: 407-414Crossref PubMed Scopus (81) Google Scholar]. Some scholars have suggested that LN dissection is more effective for improving survival in right lung cancer. The first reason is that more lymph returns to the contralateral side though the carinal LNs from the lower left lung compared with other lobes. Second, right upper mediastinal LN dissection is more complete and easier than that of left [38Kan Q.W. Liu L.X. Current status and progress of lymphadenectomy in lung cancer operation.Chin J Cardiovasc Surg. 2009; 16: 467-472Google Scholar]. However, we found no significant difference between the two groups in right-side LN dissection, and VATS harvested more LNs on the left side (95% CI, 0.51 to 3.22; p = 0.007), but no significant difference was found between the two groups in the three pertinent articles. In a large prospective controlled study, Boffa and colleagues [30Boffa D.J. Kosinski A.S. Paul S. Mitchell J.D. Onaitis M. Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.Ann Thorac Surg. 2012; 94: 347-353Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar] compared the completeness of surgical LN evaluation during anatomic resection of primary lung cancer by open and VATS approach in 11,531 patients from The Society of Thoracic Surgeons General Thoracic Database. The results showed nodal upstaging in 14.3% (1,024 patients) of the open group and in 11.6% (508 patients) of the VATS group (p < 0.001). Upstaging from N0 to N1 was more common in the open group (9.3% vs 6.7%, p < 0.001); however, upstaging from N0 to N2 was similar between the open and VATS groups (5.0% vs 4.9%, p = 0.52). The study suggested that surgeons should be encouraged to apply a systematic approach to hilar and peribronchial LN dissection during VATS lobectomy for lung cancer, particularly as they were adopting this approach [30Boffa D.J. Kosinski A.S. Paul S. Mitchell J.D. Onaitis M. Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.Ann Thorac Surg. 2012; 94: 347-353Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar]. The possible limitations of our study must be considered when interpreting the findings described. First, including only English papers might have resulted in language bias. Second, including 5,190 participants from 20 studies with only three RCTs might have weakened the quality of the results. Third, different physicians have different understandings of LN dissection and might be at different stages of learning curve. Some data did not meet the NCCN guide requirements for lung cancer surgical treatment of systematic LN dissection, which affected the reliability of the results. Fourth, mediastinoscopy was not or was partly performed in 16 articles, which affected the clinical staging. Finally, there is great potential for LN fragmentation during dissection. Different pathologists and different counting procedures might lead to false LNN counts, which might increase the heterogeneity between studies but would not alter the overall results. In conclusion, whether VATS can achieve the same LN dissection efficacy as thoracotomy remains undetermined. As found in the present study, VATS evaluated fewer total LNs and more left-side LNs. Both approaches harvested similar number of N1, N2, and right-side LNs. However, due to possible existing bias in the original studies, interstudy heterogeneity, and the inherent limitations of our meta-analysis, this conclusion requires further validation by more high-quality and large-scale RCTs. The authors are grateful to all of the investigators, surgeons, and patients who participated in the studies assessed in this meta-analysis.

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