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Hand-sewn versus stapled anastomoses for esophagectomy: We will probably never know which is better

Open AccessPublished:July 27, 2021DOI:https://doi.org/10.1016/j.xjon.2021.07.021

      Abstract

      Objective

      Esophagectomy remains the mainstay of treatment for nonmetastatic esophageal cancer. The optimal technique for anastomosis after esophagectomy remains unknown. The purpose of this systematic meta-analysis is to combine the available high-quality evidence to provide esophageal surgeons with an evidence base for their decision making.

      Methods

      A systematic search of multiple databases was conducted to find randomized controlled trials of esophageal anastomotic techniques. A meta-analysis of the pooled data was conducted.

      Results

      A total of 19 studies with 2123 patients were included in the meta-analysis. The pooled analysis revealed a 102% higher incidence of anastomotic leak after hand-sewn anastomosis compared with stapled anastomosis (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.48-2.75). Anastomotic stricture rate was also 31% higher with hand-sewn anastomosis (OR, 1.31; 95% CI, 1.00-1.7). Thirty-day mortality did not show statistical difference favoring one anastomosis technique to another (OR, 0.68; 95% CI, 0.45-1.04). None of anastomotic leak rate, anastomotic stricture rate, or 30-day overall survival differed between anastomotic techniques in studies with only thoracic anastomoses. In cervical position hand-sewn anastomosis was associated with higher rate of anastomotic leak (OR, 2.02; 95% CI, 1.33-3.05) and stricture (OR, 1.77; 95% CI, 1.15-2.72), but no difference in 30-day mortality.

      Conclusions

      This meta-analysis showed a signal of higher rate of leak and stricture in hand-sewn anastomoses, but sensitivity analyses did not show a consistent outcome, so these results should be interpreted with caution.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      AL (anastomotic leak), OS (overall survival), RCT (randomized controlled trial)
      Figure thumbnail fx2
      Forest plot for rate of anastomotic leakage between hand-sewn and stapled anastomosis.
      A higher rate of leakage and stricture with hand-sewn anastomotic technique was found in this meta-analysis. The studies were heterogeneous, and with variance in results of the sensitivity analyses.
      The rate of anastomotic leakage after esophagectomy remains significant, and there is no consensus on the optimal anastomotic technique. This meta-analysis provides a summary of the current evidence, highlighting the need for more quality studies, especially in minimally invasive settings.
      See Commentaries on pages 353 and 355.
      Esophagectomy—Ivor Lewis, McKeown, or transhiatal—is the established treatment for locoregional esophageal cancer. After esophageal resection, the reconstruction is generally performed by gastric pull-up and either intrathoracic or cervical esophagogastric anastomosis.
      • Lagergren J.
      • Smyth E.
      • Cunningham D.
      • Lagergren P.
      Oesophageal cancer.
      The standard approach has historically been open esophagectomy, but during the past few decades minimally invasive esophagectomy has gained popularity, with benefits over open esophagectomy in regard to overall and disease-specific survival, pulmonary complications, quality of life, and hospital stay.
      • Gottlieb-Vedi E.
      • Kauppila J.H.
      • Malietzis G.
      • Nilsson M.
      • Markar S.R.
      • Lagergren J.
      Long-term survival in esophageal cancer after minimally invasive compared to open esophagectomy a systematic review and meta-analysis.
      • Biere S.S.
      • van Berge Henegouwen M.I.
      • Maas K.W.
      • Bonavina L.
      • Rosman C.
      • Garcia J.R.
      • et al.
      Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial.
      • Maas K.W.
      • Cuesta M.A.
      • Henegouwen M.I.V.
      • Roig J.
      • Bonavina L.
      • Rosman C.
      • et al.
      Quality of life and late complications after minimally invasive compared to open esophagectomy: results of a randomized trial.
      Anastomotic leak (AL) is a devastating complication with a relatively high incidence; a recent meta-analysis of randomized trials reported an incidence of 11.2%.
      • Biere S.S.
      • Maas K.W.
      • Cuesta M.A.
      • van der Peet D.L.
      Cervical or thoracic anastomosis after esophagectomy for cancer: a systematic review and meta-analysis.
      ,
      • Alanezi K.
      • Urschel J.D.
      Mortality secondary to esophageal anastomotic leak.
      The development and adoption of minimally invasive techniques raises the questions regarding optimal anastomotic technique because hand-sewn anastomosis is challenging by the thoracoscopic/laparoscopic approach. There is a paucity of high-quality evidence examining the effect of anastomotic technique on the development of AL, particularly in the minimally invasive setting.
      The purpose of this meta-analysis was to determine whether contemporary evidence highlights superiority of 1 anastomotic technique (hand-sewn vs mechanical stapler) over another with respect to the development of AL, anastomotic stricture, and overall survival (OS).

      Methods

       Design

      This is a systematic literature review and meta-analysis that followed a predetermined study protocol according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews and meta-analyses.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Prisma Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.

       Literature Search Strategy

      Two independent investigators conducted a systematic literature search contemporary to June 2020 from multiple databases (Embase, Medline, and Cochrane library). The search was performed by combining medical subject headings and related free-text search terms with Boolean operators “AND” or “OR.” The MeSH terms used were esophageal neoplasms and anastomosis, surgical. A full description of the search strategy is available in Table E1.

       Study Selection

      The inclusion criteria were as follows: randomized controlled study, study patients underwent esophagectomy, study compared different anastomotic techniques, and study reported anastomotic leak and/or stricture outcomes. Exclusion criteria were English translation of the manuscript not available.

       Data Extraction

      Titles and abstracts were scrutinized by the first author (T.J.) and duplicates were identified simultaneously. Full texts of potential studies were analyzed by 2 authors (T.J. and I.I.). Summary data were extracted from included studies. Extracted data included publication year, sample size, tumor location and histology, operative technique, anastomosis technique, follow-up, 30-day mortality, hospital mortality, AL, and stricture rate.

       Quality Assessment

      Quality of studies was assessed by 1 author (T.J.) using Cochrane Collaborations Risk of Bias Tool for randomized clinical trials, which is presented in Table E2.

       Informed Consent

      Because this was a meta-analysis that does not process individual patient data, no informed consent, as per Helsinki University Institutional Review Board guidelines, was needed.

       Outcome Measures and Statistical Analysis

      The primary outcome measures evaluated were odds ratios (OR) for AL rate and stricture. The secondary outcome measure was hazard ratio for 30-day mortality. Subset analyses dichotomizing patients according to anastomotic location (cervical vs thoracic) was performed.
      Meta-analysis of data was conducted using a random effects model due to high heterogeneity. Publication bias was assessed by funnel plots (plots of effect estimates against sample size) to detect outliers or asymmetry. Funnel plot asymmetry was analyzed visually and by Egger test for small-study effects and publication bias. The statistical significance for Egger test was set at P < .10, as originally described by Egger and colleagues.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      To maximize the number of patients included in the meta-analysis, studies that investigated subgroups within either only hand-sewn or only stapled anastomoses were included in the summary quantitative synthesis representing only a single group, either hand-sewn or stapled anastomosis, with the opposing group size being 0. Forest plots; that is, graphical display of estimated ORs and 95% confidence intervals (CIs) and summary statistics were used to elucidate the results of the studies. Post hoc sensitivity analyses were performed without the inclusion of these single-group studies to investigate the robustness of this analysis. Sensitivity analyses were also performed with studies containing only thoracic anastomoses or only cervical anastomoses and also without the inclusion of studies predating 2000 to elucidate the possible differences of outcomes within these subgroups.
      The I2 test was used to evaluate statistical heterogeneity, also known as the outcome variability in excess of what would be expected due to measurement error alone of the included studies, with levels of heterogeneity defined as not important (I2, 0%-25%), moderate (I2, 25%-50%), substantial (I2, 50%-75%), or considerable (I2, 75%-100%). Statistical analysis was done with R version 2020 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      The database search generated 3153 study titles, of which 19 studies met the inclusion criteria (Figure 1). The anastomotic approaches used were evenly distributed: 1160 (50.3%) hand-sewn anastomoses and 1148 (49.7%) mechanical stapler anastomoses. Eight of the 19 studies (42.1%) included only cervical anastomoses,
      • Zieren H.U.
      • Muller J.M.
      • Pichlmaier H.
      Prospective randomized study of one-layer or 2-layer anastomosis following esophageal resection and cervical esophagogastrostomy.
      • Bardini R.
      • Bonavina L.
      • Asolati M.
      • Ruol A.
      • Castoro C.
      • Tiso E.
      Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.
      • Laterza E.
      • de' Manzoni G.
      • Veraldi G.F.
      • Guglielmi A.
      • Tedesco P.
      • Cordiano C.
      Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.
      • Nederlof N.
      • Tilanus H.W.
      • Tran T.C.
      • Hop W.C.
      • Wijnhoven B.P.
      • de Jonge J.
      End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      • Cayi R.
      • Li M.
      • Xiong G.
      • Cai K.
      • Wang W.
      Comparative analysis of mechanical and manual cervical esophagogastric anastomosis following esophagectomy for esophageal cancer.
      • Hsu H.H.
      • Chen J.S.
      • Huang P.M.
      • Lee J.M.
      • Lee Y.C.
      Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      6 studies (31.6%) included only thoracic anastomoses,
      • Law S.
      • Fok M.
      • Chu K.M.
      • Wong J.
      Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.
      • Luechakiettisak P.
      • Kasetsunthorn S.
      Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.
      • Zhang Y.S.
      • Gao B.R.
      • Wang H.J.
      • Su Y.F.
      • Yang Y.Z.
      • Zhang J.H.
      • et al.
      Comparison of anastomotic leakage and stricture formation following layered and stapler oesophagogastric anastomosis for cancer: a prospective randomized controlled trial.
      • Aly A.
      • Jamieson G.G.
      • Watson D.I.
      • Devitt P.G.
      • Ackroyd R.
      • Stoddard C.J.
      An antireflux anastomosis following esophagectomy: a randomized controlled trial.
      • Liu J.F.
      • Wang J.D.
      • Liu X.B.
      • Sun Y.H.
      • Jiang T.
      • Wang F.S.
      • et al.
      Antireflux anastomosis following resection of esophageal cancer.
      • Wang W.P.
      • Gao Q.
      • Wang K.N.
      • Shi H.
      • Chen L.Q.
      A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.
      and 5 studies (26.3%) had both cervical and thoracic anastomoses.
      • Ribet M.
      • Debrueres B.
      • Lecomte-Houcke M.
      Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis? Late results of a prospective randomized study.
      • Valverde A.
      • Hay J.M.
      • Fingerhut A.
      • Elhadad A.
      Manual versus mechanical esophagogastric anastomosis after resection for carcinoma: a controlled trial. French Associations for Surgical Research.
      • Walther B.
      • Johansson J.
      • Johnsson F.
      • Von Holstein C.S.
      • Zilling T.
      Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
      • Okuyama M.
      • Motoyama S.
      • Suzuki H.
      • Saito R.
      • Maruyama K.
      • Ogawa J.
      Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
      • Ma R.D.
      • Zhang W.T.
      • Xu Q.R.
      • Chen L.Q.
      Esophagogastrostomy by side-to-side anastomosis in prevention of anastomotic stricture: a randomized clinical trial.
      Two of the studies were randomized trials of antireflux anastomotic techniques, of which 1 did not report any of the prespecified outcomes between hand-sewn and stapled groups and the other had no adequate text in English available, so both were excluded from the summary statistics.
      • Aly A.
      • Jamieson G.G.
      • Watson D.I.
      • Devitt P.G.
      • Ackroyd R.
      • Stoddard C.J.
      An antireflux anastomosis following esophagectomy: a randomized controlled trial.
      ,
      • Liu J.F.
      • Wang J.D.
      • Liu X.B.
      • Sun Y.H.
      • Jiang T.
      • Wang F.S.
      • et al.
      Antireflux anastomosis following resection of esophageal cancer.
      Remaining studies included 2230 patients across 17 studies. Characteristics of the studies are presented in Table 1.
      Figure thumbnail gr1
      Figure 1Flow chart of the literature search according to preferred reporting items for systematic reviews and meta-analyses statement. RCTs, Randomized controlled trials.
      Table 1Characteristics of included randomized controlled trials
      StudyCharacteristicN
      CountryLocation of the anastomosisSurgical approachesGroup AGroup BGroup CGroup AGroup BGroup C
      Ribet et al, 1992
      • Ribet M.
      • Debrueres B.
      • Lecomte-Houcke M.
      Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis? Late results of a prospective randomized study.
      FranceBothIL
      Ivor Lewis esophagectomy.
      and McK
      McKeown esophagectomy.
      Hand sewn, CervicalHand sewn, Thoracic3030
      Zieren et al, 1993
      • Zieren H.U.
      • Muller J.M.
      • Pichlmaier H.
      Prospective randomized study of one-layer or 2-layer anastomosis following esophageal resection and cervical esophagogastrostomy.
      GermanyCervicalIL
      Ivor Lewis esophagectomy.
      , McK
      McKeown esophagectomy.
      and TH
      Transhiatal esophagectomy
      1-layer hand sewn2-layer hand sewn5452
      Bardini et al, 1994
      • Bardini R.
      • Bonavina L.
      • Asolati M.
      • Ruol A.
      • Castoro C.
      • Tiso E.
      Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.
      ItalyCervicalTH
      Transhiatal esophagectomy
      Hand sewn, continuousHand sewn, interrupted2121
      Valverde et al, 1996
      • Valverde A.
      • Hay J.M.
      • Fingerhut A.
      • Elhadad A.
      Manual versus mechanical esophagogastric anastomosis after resection for carcinoma: a controlled trial. French Associations for Surgical Research.
      FranceBothIL
      Ivor Lewis esophagectomy.
      , McK
      McKeown esophagectomy.
      TH
      Transhiatal esophagectomy
      Hand sewnStapled7478
      Law et al, 1997
      • Law S.
      • Fok M.
      • Chu K.M.
      • Wong J.
      Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.
      ChinaThoracicIL
      Ivor Lewis esophagectomy.
      Hand sewnCircular stapled6161
      Laterza et al, 1999
      • Laterza E.
      • de' Manzoni G.
      • Veraldi G.F.
      • Guglielmi A.
      • Tedesco P.
      • Cordiano C.
      Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.
      ItalyCervicalMcK
      McKeown esophagectomy.
      Hand sewnStapled2120
      Walther et al, 2003
      • Walther B.
      • Johansson J.
      • Johnsson F.
      • Von Holstein C.S.
      • Zilling T.
      Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
      SwedenBothIL
      Ivor Lewis esophagectomy.
      and McK
      McKeown esophagectomy.
      Hand sewn, CervicalCircular stapled, Thoracic4142
      Hsu et al, 2004
      • Hsu H.H.
      • Chen J.S.
      • Huang P.M.
      • Lee J.M.
      • Lee Y.C.
      Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.
      TaiwanCervicalMcK
      McKeown esophagectomy.
      and TH
      Transhiatal esophagectomy
      Hand sewnCircular stapled3231
      Okuyama et al, 2007
      • Okuyama M.
      • Motoyama S.
      • Suzuki H.
      • Saito R.
      • Maruyama K.
      • Ogawa J.
      Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
      JapanBothIL
      Ivor Lewis esophagectomy.
      and McK
      McKeown esophagectomy.
      Hand sewn, CervicalCircular stapled, Thoracic1814
      Luechakiettisak et al, 2008
      • Luechakiettisak P.
      • Kasetsunthorn S.
      Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.
      ThailandThoracicIL
      Ivor Lewis esophagectomy.
      Hand sewnCircular stapled5958
      Zhang et al, 2010
      • Zhang Y.S.
      • Gao B.R.
      • Wang H.J.
      • Su Y.F.
      • Yang Y.Z.
      • Zhang J.H.
      • et al.
      Comparison of anastomotic leakage and stricture formation following layered and stapler oesophagogastric anastomosis for cancer: a prospective randomized controlled trial.
      ChinaThoracicL ThoracotomyHand sewnCircular stapled244272
      Aly et al, 2010
      • Aly A.
      • Jamieson G.G.
      • Watson D.I.
      • Devitt P.G.
      • Ackroyd R.
      • Stoddard C.J.
      An antireflux anastomosis following esophagectomy: a randomized controlled trial.
      AustraliaThoracicIL
      Ivor Lewis esophagectomy.
      Stapled with fundoplicationStapled without fundoplication2927
      Ma et al, 2010
      • Ma R.D.
      • Zhang W.T.
      • Xu Q.R.
      • Chen L.Q.
      Esophagogastrostomy by side-to-side anastomosis in prevention of anastomotic stricture: a randomized clinical trial.
      ChinaBothN/AHand sewnStapled, side-to-sideStapled, circular524547
      Nederlof et al, 2011
      • Nederlof N.
      • Tilanus H.W.
      • Tran T.C.
      • Hop W.C.
      • Wijnhoven B.P.
      • de Jonge J.
      End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.
      The NetherlandsCervicalIL
      Ivor Lewis esophagectomy.
      & TH
      Transhiatal esophagectomy
      Hand sewn, end to sideHand sewn, end-to-end6464
      Liu et al, 2011
      • Liu J.F.
      • Wang J.D.
      • Liu X.B.
      • Sun Y.H.
      • Jiang T.
      • Wang F.S.
      • et al.
      Antireflux anastomosis following resection of esophageal cancer.
      ChinaThoracicN/AStapled with fundoplicationStapled without fundoplication3535
      Saluja et al, 2012
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      IndiaCervicalMcK
      McKeown esophagectomy.
      Hand sewnSide to side stapled8787
      Cayi et al, 2012
      • Cayi R.
      • Li M.
      • Xiong G.
      • Cai K.
      • Wang W.
      Comparative analysis of mechanical and manual cervical esophagogastric anastomosis following esophagectomy for esophageal cancer.
      ChinaCervicalN/AHand sewnStapled125125
      Wang et al, 2013
      • Wang W.P.
      • Gao Q.
      • Wang K.N.
      • Shi H.
      • Chen L.Q.
      A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.
      ChinaThoracicL ThoracotomyHand sewnCircular stapledSemi-mechanical524745
      Hayata et al, 2017
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      JapanCervicalHybrid & McK
      McKeown esophagectomy.
      Ciruclar stapledTriangular linear stapled4951
      IL, Ivor Lewis; McK, McKeown; TH, transhiatal; N/A, not available.
      Ivor Lewis esophagectomy.
      McKeown esophagectomy.
      Transhiatal esophagectomy
      The studies had somewhat differing definitions for AL, although all of the studies used routine radiographic imaging on postoperative day 3 through 10. Stricture definitions differed somewhat between studies, the most common definitions being the inability to pass a small diameter (9-10 mm) enteroscope past the anastomosis, a small diameter of the anastomosis (<8-10 mm) in imaging or the need for dilatation based on symptoms. The definitions of AL and anastomotic stricture and related methods of diagnosis of each study are presented in Table 2.
      Table 2Identification and definition of anastomotic leak and anastomotic stricture in the included studies
      StudyAnastomotic leak diagnosisRoutine postoperative anastomotic assessmentStricture diagnosisLast follow-up
      Ribet et al, 1992
      • Ribet M.
      • Debrueres B.
      • Lecomte-Houcke M.
      Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis? Late results of a prospective randomized study.
      Any radiographic evidence7th day postoperative swallow study
      Swallow esophagogram with either water-soluble or barium contrast.
      N/AN/A
      Zieren et al, 1993
      • Zieren H.U.
      • Muller J.M.
      • Pichlmaier H.
      Prospective randomized study of one-layer or 2-layer anastomosis following esophageal resection and cervical esophagogastrostomy.
      Any radiographic evidence7th day postoperative swallow study
      • Any form of anastomotic narrowing requiring endoscopic dilatation or operative revision
      • Inability to proceed into the gastric tube with a 9 mm endoscope
      N/A (mean follow-up of 44 wk)
      Bardini et al, 1994
      • Bardini R.
      • Bonavina L.
      • Asolati M.
      • Ruol A.
      • Castoro C.
      • Tiso E.
      Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.
      Any radiographic evidence10th day postoperative swallow study
      • Radiographic anastomotic diameter <1 cm
      • Any dysphagia
      3 mo
      Valverde et al, 1996
      • Valverde A.
      • Hay J.M.
      • Fingerhut A.
      • Elhadad A.
      Manual versus mechanical esophagogastric anastomosis after resection for carcinoma: a controlled trial. French Associations for Surgical Research.
      • Drain output of intestinal fluids or orally ingested methylene blue
      • Any radiographic evidence
      • Repeat operation or autopsy
      3-8 postoperative swallow study and methylene blue
      • Any form of anastomotic narrowing requiring endoscopic dilatation or operative revision
      3 mo
      Law et al, 1997
      • Law S.
      • Fok M.
      • Chu K.M.
      • Wong J.
      Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.
      • Any radiographic evidence
      • Any endoscopic evidence
      7th day postoperative swallow study and endoscopy
      • Inability to proceed into the gastric tube with a 10 mm endoscope
      1 y
      Laterza et al, 1999
      • Laterza E.
      • de' Manzoni G.
      • Veraldi G.F.
      • Guglielmi A.
      • Tedesco P.
      • Cordiano C.
      Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.
      • Drain output of intestinal fluids or orally ingested methylene blue
      • Any radiographic evidence
      postoperative day 9-10 swallow study and methylene blue
      • Any form of anastomotic narrowing requiring endoscopic dilatation or operative revision
      At least 6 mo
      Walther et al, 2003
      • Walther B.
      • Johansson J.
      • Johnsson F.
      • Von Holstein C.S.
      • Zilling T.
      Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
      • Drain output of intestinal fluids
      • Any radiographic evidence
      5th day postoperative swallow study
      • Inability to proceed into the gastric tube with a 9 mm endoscope
      1 y
      Hsu et al, 2004
      • Hsu H.H.
      • Chen J.S.
      • Huang P.M.
      • Lee J.M.
      • Lee Y.C.
      Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.
      • Drain output of intestinal fluids
      • Any radiographic evidence
      7-10 d postoperative swallow study
      • Inability to proceed into the gastric tube with a 10 mm endoscope
      N/A (24 mo follow-up mean)
      Okuyama et al, 2007
      • Okuyama M.
      • Motoyama S.
      • Suzuki H.
      • Saito R.
      • Maruyama K.
      • Ogawa J.
      Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
      Any radiographic evidence9-10 d postoperative swallow study
      • Any form of anastomotic narrowing requiring endoscopic dilatation or operative revision
      6 mo
      Luechakiettisak et al, 2008
      • Luechakiettisak P.
      • Kasetsunthorn S.
      Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.
      Any radiographic evidence7th day postoperative swallow study
      • Inability to proceed into the gastric tube with an endoscope
      3 mo
      Zhang et al, 2010
      • Zhang Y.S.
      • Gao B.R.
      • Wang H.J.
      • Su Y.F.
      • Yang Y.Z.
      • Zhang J.H.
      • et al.
      Comparison of anastomotic leakage and stricture formation following layered and stapler oesophagogastric anastomosis for cancer: a prospective randomized controlled trial.
      • Drain output of intestinal fluids
      • Any radiographic evidence
      5-10 d postoperative swallow study
      • Inability to proceed into the gastric tube with a 10 mm endoscope
      1 y
      Aly et al, 2010
      • Aly A.
      • Jamieson G.G.
      • Watson D.I.
      • Devitt P.G.
      • Ackroyd R.
      • Stoddard C.J.
      An antireflux anastomosis following esophagectomy: a randomized controlled trial.
      Not describedN/A
      • Dysphagia was assessed using a previously validated scoring system based on a 9-item graded food scale with no dysphagia scoring 0 and a maximum score of 457 as well as a 0-10 analog scale.
      • Any form of anastomotic narrowing requiring endoscopic dilatation or operative revision
      1 y
      Ma et al, 2010
      • Ma R.D.
      • Zhang W.T.
      • Xu Q.R.
      • Chen L.Q.
      Esophagogastrostomy by side-to-side anastomosis in prevention of anastomotic stricture: a randomized clinical trial.
      N/AN/A
      • Radiographic anastomotic diameter <0.8 cm
      3 mo
      Nederlof et al, 2011
      • Nederlof N.
      • Tilanus H.W.
      • Tran T.C.
      • Hop W.C.
      • Wijnhoven B.P.
      • de Jonge J.
      End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.
      • Drain output of intestinal fluids
      • Any radiographic
      • Any endoscopic evidence
      6th postoperative day swallow study and 7th postoperative day endoscopy
      • Inability to proceed into the gastric tube with a 9 mm endoscope
      12 mo
      Liu et al, 2011
      • Liu J.F.
      • Wang J.D.
      • Liu X.B.
      • Sun Y.H.
      • Jiang T.
      • Wang F.S.
      • et al.
      Antireflux anastomosis following resection of esophageal cancer.
      N/AN/AN/AN/A
      Saluja et al, 2012
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      • Drain output of intestinal fluids
      • Any radiographic evidence
      7th postoperative day swallow studyNot described3 y
      Cayi et al, 2012
      • Cayi R.
      • Li M.
      • Xiong G.
      • Cai K.
      • Wang W.
      Comparative analysis of mechanical and manual cervical esophagogastric anastomosis following esophagectomy for esophageal cancer.
      N/AN/AN/AN/A
      Wang et al, 2013
      • Wang W.P.
      • Gao Q.
      • Wang K.N.
      • Shi H.
      • Chen L.Q.
      A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.
      N/AN/A
      • Radiographic anastomotic diameter <0.8 cm
      3 mo after surgery
      Hayata et al, 2017
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      • Drain output of intestinal fluids
      • Any radiographic evidence
      • Any endoscopic evidence
      7th postoperative day swallow study, endoscopy and CT
      • Inability to proceed into the gastric tube with a 9 mm endoscope
      12 mo
      N/A, Not available; CT, computed tomography.
      Swallow esophagogram with either water-soluble or barium contrast.
      All 17 studies reported AL rates. The pooled analysis revealed a 102% higher incidence of AL after hand-sewn anastomosis compared with stapled anastomosis (OR, 2.02; 95% CI, 1.48-2.75). Figure 2 shows the associated forest plot. Statistical heterogeneity of the studies was moderate (I2, 42%; P = .08). Funnel plot showed symmetry visually and statistically (Egger test, 0.87). The funnel plot is displayed in Figure 3, A.
      Figure thumbnail gr2
      Figure 2Forest plot for anastomotic leak comparing hand-sewn anastomosis to stapled anastomosis. OR, Odds ratio; CI, confidence interval; NA, not available.
      Figure thumbnail gr3
      Figure 3Funnel plots for (A) anastomotic leak, (B) anastomotic stricture, and (C) 30-day mortality.
      Anastomotic stricture rates were reported by all but 1 study. Hand-sewn anastomosis group had a 31% increased incidence of anastomotic stricture; however, the statistical significance was borderline significant (OR, 1.31; 95% CI, 1.00-1.7). The forest plot is presented in Figure 4. Statistical heterogeneity was substantial (I2, 58%; P = .006). Visual and statistical symmetry was confirmed by funnel plot (Egger test, 0.20). The funnel plot is presented in Figure 3, B.
      Figure thumbnail gr4
      Figure 4Forest plot for anastomotic stricture comparing hand-sewn anastomosis to stapled anastomosis. OR, Odds ratio; CI, confidence interval; NA, not available.
      Thirty-day mortality was reported only by 9 (52.9%) studies. Thirty-day mortality did not show statistical difference favoring 1 anastomosis technique over another (OR, 0.68; 95% CI, 0.45-1.04). Figure 5 displays the related forest plot. Statistical heterogeneity of these studies was not important (I2, 22%; P = .35). Funnel plot was symmetrical visually and by statistical analysis (Egger test, 0.39). Figure 3, C, presents the funnel plot.
      Figure thumbnail gr5
      Figure 5Forest plot for 30-day mortality comparing hand-sewn anastomosis to stapled anastomosis. OR, Odds ratio; CI, confidence interval; NA, not available.

       Sensitivity Analyses

      Figure 6 shows the summary statistics of the sensitivity analyses. Without single-group studies, the leak rate and stricture rate were not statistically different, but the 30-day mortality rate favored the hand-sewn anastomosis (OR, 0.52; 95% CI, 0.33-0.84). When studies predating 2000 were excluded, the results did not change from the original analysis: leak rate favored stapled anastomosis (OR, 2.37; 95% CI, 1.63-3.43), no difference in stricture rate or mortality.
      Figure thumbnail gr6
      Figure 6Sensitivity analyses of the anastomotic leak, anastomotic stricture, and 30-day mortality analyses. Sensitivity analyses included were analyses without single-group studies, thoracic anastomoses only, and cervical anastomoses only. OR, Odds ratio; CI, confidence interval.
      When analyzing thoracic anastomoses only, including 4 studies, neither AL rate (OR, 1.74; 95% CI, 0.95-3.17), anastomotic stricture rate (OR, 0.73; 95% CI, 0.42-1.28) nor 30-day OS rate (OR, 0.48; 95% CI, 0.15-1.57) differed between anastomotic techniques.
      • Law S.
      • Fok M.
      • Chu K.M.
      • Wong J.
      Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.
      • Luechakiettisak P.
      • Kasetsunthorn S.
      Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.
      • Zhang Y.S.
      • Gao B.R.
      • Wang H.J.
      • Su Y.F.
      • Yang Y.Z.
      • Zhang J.H.
      • et al.
      Comparison of anastomotic leakage and stricture formation following layered and stapler oesophagogastric anastomosis for cancer: a prospective randomized controlled trial.
      ,
      • Wang W.P.
      • Gao Q.
      • Wang K.N.
      • Shi H.
      • Chen L.Q.
      A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.
      Figure E1 shows the associated forest plot.
      In cervical position, analysis of 8 studies showed that hand-sewn anastomosis was associated with higher rate of AL (OR, 2.02; 95% CI, 1.33-3.05) and stricture (OR, 1.77; 95% CI, 1.15-2.72), but no difference in 30-day OS (OR, 0.95; 95% CI, 0.51-177).
      • Zieren H.U.
      • Muller J.M.
      • Pichlmaier H.
      Prospective randomized study of one-layer or 2-layer anastomosis following esophageal resection and cervical esophagogastrostomy.
      • Bardini R.
      • Bonavina L.
      • Asolati M.
      • Ruol A.
      • Castoro C.
      • Tiso E.
      Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.
      • Laterza E.
      • de' Manzoni G.
      • Veraldi G.F.
      • Guglielmi A.
      • Tedesco P.
      • Cordiano C.
      Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.
      • Nederlof N.
      • Tilanus H.W.
      • Tran T.C.
      • Hop W.C.
      • Wijnhoven B.P.
      • de Jonge J.
      End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      • Cayi R.
      • Li M.
      • Xiong G.
      • Cai K.
      • Wang W.
      Comparative analysis of mechanical and manual cervical esophagogastric anastomosis following esophagectomy for esophageal cancer.
      • Hsu H.H.
      • Chen J.S.
      • Huang P.M.
      • Lee J.M.
      • Lee Y.C.
      Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      The full forest plot of these studies can be appreciated in Figure E2.

      Discussion

      This systematic review and meta-analysis of 17 randomized controlled trials (RCTs) with 2230 patients shows that hand-sewn anastomosis is associated with a higher rate of AL and anastomotic stricture, but no difference in 30-day mortality as illustrated in Figure 7 and summarized in Figure 8 and Video 1.
      Figure thumbnail fx3
      Video 1The corresponding author, Tommi Järvinen, summarizes the results of the meta-analysis. Video available at: https://www.jtcvs.org/article/S2666-2736(21)00207-2/fulltext.
      Figure thumbnail gr7
      Figure 7Forest plot showing the summary results for anastomotic leak, anastomotic stricture, and 30-day mortality.
      Figure thumbnail gr8
      Figure 8Graphical abstract summarizing the results of the study. From the left to right, Amount of randomized controlled trials (RCTs) and patients involved, number of patients in hand-sewn and stapled anastomosis groups, comparison of groups in anastomotic leak rates, and comparison of groups in anastomotic stricture rates. OR, Odds ratio; CI, confidence interval.
      The strengths of this study are inclusion of only RCTs and the associated extensive literature search, resulting in a large number of applicants and minimal confounding by patient-related prognostic factors. Limitations include the heterogeneity of reported outcomes in the RCTs, especially in regard to mortality, which was either not reported, reported as in-hospital mortality, or 30-day mortality. To facilitate comparisons among groups, 30-day all-cause mortality was used. The studies included were performed over a 25-year time span, which introduces more heterogeneity in the form of different neoadjuvant, perioperative oncologic therapies and overall postoperative treatment protocols. The difference of patient populations and disease characteristics between Asian and Western studies is a probable source of bias. Studies that used either only hand-sewn or stapled anastomoses were included in the meta-analysis, which might exaggerate different reporting criteria between the studies. Different surgical methods were employed (eg, single-layer or 2-layer anastomosis, circular [end-to-end anastomosis] or side-stapled anastomosis), and the effects of these variations in methods are hard to quantify. Moreover, the superiority between these specific techniques cannot be established from this study and should be further investigated in future studies/reports.
      Studies included in this trial had mostly a moderate risk of bias, as shown with Cochrane Collaborations Risk of Bias Tool analysis because with surgical clinical studies, the masking of the intervention from the subjects and the care team is difficult or even impossible. No studies tried to analyze or to account for this bias. Very limited description of the randomization process was available and use of blinded investigators in the analysis of data was rare.
      The sensitivity analyses show some variance in results compared with the original meta-analysis. The inclusion of the single group-studies into the quantitative analysis favored the stapled anastomosis groups because without these groups in the analysis, intergroup differences in AL rate become nonsignificant and 30-day mortality then favors hand-sewn anastomoses. When interpreting these results, one must note that some of the included RCTs compared intrathoracic stapled anastomoses to hand-sewn cervical anastomoses.
      • Ribet M.
      • Debrueres B.
      • Lecomte-Houcke M.
      Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis? Late results of a prospective randomized study.
      ,
      • Walther B.
      • Johansson J.
      • Johnsson F.
      • Von Holstein C.S.
      • Zilling T.
      Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
      ,
      • Okuyama M.
      • Motoyama S.
      • Suzuki H.
      • Saito R.
      • Maruyama K.
      • Ogawa J.
      Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
      Intrathoracic anastomosis requires intrathoracic entry, and because many of these studies were done before the widespread use of minimally invasive techniques, this meant performing a thoracotomy, which has been shown to negatively influence outcomes compared with minimally invasive techniques.
      • Gottlieb-Vedi E.
      • Kauppila J.H.
      • Malietzis G.
      • Nilsson M.
      • Markar S.R.
      • Lagergren J.
      Long-term survival in esophageal cancer after minimally invasive compared to open esophagectomy a systematic review and meta-analysis.
      In fact, among the studies included, only 1 study applied minimally invasive techniques.
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      In contrast, the majority of cervical anastomosis were done via a transhiatal approach (390 transhiatal esophagectomies vs 287 McKeown esophagectomies), which spares the patient thoracotomy-related morbidity, but at the expense of thoracic lymph node yield, possibly sacrificing long-term survival.
      • Peyre C.G.
      • Hagen J.A.
      • DeMeester S.R.
      • Altorki N.K.
      • Ancona E.
      • Griffin S.M.
      • et al.
      The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection.
      ,
      • Kutup A.
      • Nentwich M.F.
      • Bollschweiler E.
      • Bogoevski D.
      • Izbicki J.R.
      • Holscher A.H.
      What should be the gold standard for the surgical component in the treatment of locally advanced esophageal cancer transthoracic versus transhiatal esophagectomy.
      This might bias the results of the 30-day mortality to favor the hand-sewn anastomosis group because the comparison is between operations and surgical risk with thoracotomy and transhiatal esophagectomies. When observing only thoracic anastomoses, no difference between the anastomotic techniques could be established in any of the outcomes. The results of the sensitivity analyses of thoracic-only anastomoses are subject to possible random error because only 4 studies used exclusively thoracic anastomoses. The same can be said of the OS results of cervical anastomoses because only 2 studies of this group reported 30-day mortality. Exclusion of studies conducted before the turn of the millennium did not change the summary statistics results, speaking against any significant confounding effect of studies published earlier.
      The reported rates of AL between the studies varied between 1.2% and 31.3%. Definitions for AL were heterogeneous, or not elucidated in the article, which most likely explains the variability of the incidence and produces more heterogeneity to this analysis. Explanation for high degree of difference for the difference in stricture rates between the techniques when used in the thorax or in the cervical region is not known to the authors. It may be possible that circular stapling and side-to-side stapling provide different rates of stricture and/or AL, which may confound the findings of this meta-analysis. Unfortunately, due to the low amount of studies reporting the use of side-to-side stapling, such a separate analysis between the techniques is not feasible.
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      ,
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      ,
      • Ma R.D.
      • Zhang W.T.
      • Xu Q.R.
      • Chen L.Q.
      Esophagogastrostomy by side-to-side anastomosis in prevention of anastomotic stricture: a randomized clinical trial.
      Studies did not report whether their institutions, or the surgeons, had a preferred anastomotic technique. If there is a preferred technique that is in routine use at the institution, the alternative anastomotic technique used in the study might be subject to higher rate of complication and/or observation bias.
      Although this meta-analysis includes a fair number of randomized controlled studies (n = 19) and patients (n = 2308) there is clearly need for better quality data, if a definitive answer to the superiority of an anastomotic technique is to be proven. A large-scale multi-institutional RCT with clearly characterized and clinically meaningful outcomes could provide us with an answer, but for now the data can be interpreted in a multitude of ways. It could also be the case that the difference between the techniques is so subtle that a massive number of patients would be needed to ferret out a statistical difference between the anastomotic technique, in which case the difference would probably not be clinically significant.

      Conclusions

      This meta-analysis shows that RCTs of esophageal anastomotic techniques are heterogeneous with a risk of bias, and paucity of data in the minimally invasive setting. Our main finding is that there seems to be a signal favoring stapled anastomoses; however, these results show some discrepancy when subjected to sensitivity analyses and thus, no real recommendation of a preferred anastomotic technique can be made. We hope that this meta-analysis underscores the need for modern, well-performed RCTs. In the end, the authors all agree that the most important factor in anastomotic technique is a well-vascularized anastomosis constructed without tension rather than a specific anastomotic technique.

       Conflict of Interest Statement

      The authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

      Supplementary Data

      Appendix

      Figure thumbnail fx4
      Figure E1Forest plots of thoracic anastomosis-only studies. OR, Odds ratio; CI, confidence interval; NA, not available.
      Figure thumbnail fx5
      Figure E2Forest plots of cervical anastomosis-only studies. OR, Odds ratio; CI, confidence interval; NA, not available.
      Table E1Electronic search strategies
      MedlineScopus
      1. exp Esophageal neoplasms/1. TITLE-ABS-KEY ( esoph∗ )
      2. ((esophag∗ or oesophag∗) adj3 (cancer∗ or neoplas∗ or carcin∗ or adenocarcin∗ or tumour∗ or tumor∗ or malig∗)).ti,ab,kf.2. TITLE-ABS-KEY(cancer OR carc∗ OR malig∗ OR neoplas∗ )
      3. or/1-23. 1 and 2
      4. exp Anastomosis, surgical/4. TITLE-ABS-KEY ( anastomo∗ )
      5. (anastomo∗).ti,ab,kf5. 3 and 4
      6. or/4-56. TITLE-ABS-KEY ( ( clinic∗ W/1 trial∗ ) OR (randomi∗ W/1 control∗ ) OR ( randomi∗ W/2 trial∗ ) OR ( random∗ W/1 assign∗ ) OR ( random∗ W/1 allocat∗ ) OR ( control∗ W/1 clinic∗ ) OR ( control∗ W/1 trial ) OR placebo∗ OR ( quantitat∗ W/1 stud∗ ) OR ( control∗ W/1 stud∗ ) OR ( randomi∗ W/1 stud∗ ) OR ( singl∗ W/1 blind∗ ) OR ( singl∗ W/1 mask∗ ) OR ( doubl∗ W/1 blind∗ ) OR ( doubl∗ W/1 mask∗ ) OR ( tripl∗ W/1 blind∗ ) OR ( tripl∗ W/1 mask∗ ) OR ( trebl∗ W/1 blind∗ ) OR ( trebl∗ W/1 mask∗ ) ) AND NOT ( SRCTYPE ( b ) OR SRCTYPE ( k ) OR SRCTYPE ( p ) OR SRCTYPE ( r ) OR SRCTYPE ( d ) OR DOCTYPE ( ab ) OR DOCTYPE ( bk ) OR DOCTYPE ( ch ) OR DOCTYPE ( bz ) OR DOCTYPE ( cr ) OR DOCTYPE ( ed ) OR DOCTYPE ( er ) OR DOCTYPE ( le ) OR DOCTYPE ( no ) OR DOCTYPE ( pr ) OR DOCTYPE ( rp ) OR DOCTYPE ( re ) OR DOCTYPE ( sh ) )
      7. 3 and 67. 5 and 6
      OvidSpCENTRAL
      1. exp Esophageal neoplasms/1. ((esophag∗ or oesophag∗ or gastroesophag∗ or gastrooesophag∗) near/3 (cancer∗ or neoplas∗ or carcin∗ or adenocarcin∗ or tumour∗ or tumor∗ or malig∗)):ab,ti,kw
      2. ((esophag∗ or oesophag∗) adj3 (cancer∗ or neoplas∗ or carcin∗ or adenocarcin∗ or tumour∗ or tumor∗ or malig∗)).ti,ab,kf.2. (anastom∗):ab,ti,kw
      3. or/1-23. #1 and #2
      4. exp Anastomosis, surgical/
      5. (anastomo∗).ti,ab,kf
      6. or/4-5
      7. 3 and 6
      Table E2Risk of bias using Cochrane Collaborations Risk of Bias Tool
      Study IDAuthor and yearRandomization processDeviations from intended interventionsMissing outcome dataMeasurement of the outcomeSelection of the reported resultOverall bias
      1Hsu et al, 2004
      • Hsu H.H.
      • Chen J.S.
      • Huang P.M.
      • Lee J.M.
      • Lee Y.C.
      Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.
      Some concernsSome concernsLowSome concernsLowSome concerns
      2Law et al, 1997
      • Law S.
      • Fok M.
      • Chu K.M.
      • Wong J.
      Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.
      Some concernsSome concernsLowLowLowSome concerns
      3Okuyama et al, 2007
      • Okuyama M.
      • Motoyama S.
      • Suzuki H.
      • Saito R.
      • Maruyama K.
      • Ogawa J.
      Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.
      Some concernsHighLowLowLowHigh
      4Luechakiettisak et al, 2008
      • Luechakiettisak P.
      • Kasetsunthorn S.
      Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.
      Some concernsSome concernsSome concernsLowSome concernsSome concerns
      5Wang et al, 2013
      • Wang W.P.
      • Gao Q.
      • Wang K.N.
      • Shi H.
      • Chen L.Q.
      A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture.
      HighSome concernsLowLowLowHigh
      6Zhang et al, 2010
      • Zhang Y.S.
      • Gao B.R.
      • Wang H.J.
      • Su Y.F.
      • Yang Y.Z.
      • Zhang J.H.
      • et al.
      Comparison of anastomotic leakage and stricture formation following layered and stapler oesophagogastric anastomosis for cancer: a prospective randomized controlled trial.
      Some concernsSome concernsLowLowLowSome concerns
      7Zieren et al, 1993
      • Zieren H.U.
      • Muller J.M.
      • Pichlmaier H.
      Prospective randomized study of one-layer or 2-layer anastomosis following esophageal resection and cervical esophagogastrostomy.
      LowSome concernsLowSome concernsSome concernsSome concerns
      9Saluja et al, 2012
      • Saluja S.S.
      • Ray S.
      • Pal S.
      • Sanyal S.
      • Agrawal N.
      • Dash N.R.
      • et al.
      Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck.
      Some concernsSome concernsLowSome concernsSome concernsSome concerns
      10Walther et al, 2003
      • Walther B.
      • Johansson J.
      • Johnsson F.
      • Von Holstein C.S.
      • Zilling T.
      Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.
      Some concernsSome concernsLowSome concernsSome concernsSome concerns
      11Nederlof et al, 2011
      • Nederlof N.
      • Tilanus H.W.
      • Tran T.C.
      • Hop W.C.
      • Wijnhoven B.P.
      • de Jonge J.
      End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.
      LowSome concernsLowLowLowLow
      12Ma et al, 2010
      • Ma R.D.
      • Zhang W.T.
      • Xu Q.R.
      • Chen L.Q.
      Esophagogastrostomy by side-to-side anastomosis in prevention of anastomotic stricture: a randomized clinical trial.
      Some concernsSome concernsLowSome concernsSome concernsSome concerns
      13Ribet et al, 1992
      • Ribet M.
      • Debrueres B.
      • Lecomte-Houcke M.
      Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis? Late results of a prospective randomized study.
      HighHighLowSome concernsSome concernsHigh
      14Valverde et al, 1996
      • Valverde A.
      • Hay J.M.
      • Fingerhut A.
      • Elhadad A.
      Manual versus mechanical esophagogastric anastomosis after resection for carcinoma: a controlled trial. French Associations for Surgical Research.
      LowSome concernsLowLowSome concernsSome concerns
      17Bardini et al, 1994
      • Bardini R.
      • Bonavina L.
      • Asolati M.
      • Ruol A.
      • Castoro C.
      • Tiso E.
      Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.
      Some concernsSome concernsLowLowSome concernsSome concerns
      18Laterza et al, 1999
      • Laterza E.
      • de' Manzoni G.
      • Veraldi G.F.
      • Guglielmi A.
      • Tedesco P.
      • Cordiano C.
      Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.
      LowSome concernsLowLowSome concernsSome concerns
      20Hayata et al, 2017
      • Hayata K.
      • Nakamori M.
      • Nakamura M.
      • Ojima T.
      • Iwahashi M.
      • Katsuda M.
      • et al.
      Circular stapling versus triangulating stapling for the cervical esophagogastric anastomosis after esophagectomy in patients with thoracic esophageal cancer: a prospective, randomized, controlled trial.
      LowSome concernsLowLowLowLow
      21Cayi et al, 2012
      • Cayi R.
      • Li M.
      • Xiong G.
      • Cai K.
      • Wang W.
      Comparative analysis of mechanical and manual cervical esophagogastric anastomosis following esophagectomy for esophageal cancer.
      Some concernsSome concernsLowLowSome concernsSome concerns

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