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Practice variation in anastomotic leak after esophagectomy: Unravelling differences in failure to rescue

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.ejso.2023.01.010

      Abstract

      Introduction

      Failure to rescue (FTR) is an important outcome measure after esophagectomy and reflects mortality after postoperative complications. Differences in FTR have been associated with hospital resection volume. However, insight into how centers manage complications and achieve their outcomes is lacking. Anastomotic leak (AL) is a main contributor to FTR. This study aimed to assess differences in FTR after AL between centers, and to identify factors that explain these differences.

      Methods

      TENTACLE – Esophagus is a multicenter, retrospective cohort study, which included 1509 patients with AL after esophagectomy. Differences in FTR were assessed between low-volume (<20 resections), middle-volume (20–60 resections) and high-volume centers (≥60 resections). Mediation analysis was performed using logistic regression, including possible mediators for FTR: case-mix, hospital resources, leak severity and treatment.

      Results

      FTR after AL was 11.7%. After adjustment for confounders, FTR was lower in high-volume vs. low-volume (OR 0.44, 95%CI 0.2–0.8), but not versus middle-volume centers (OR 0.67, 95%CI 0.5–1.0). After mediation analysis, differences in FTR were found to be explained by lower leak severity, lower secondary ICU readmission rate and higher availability of therapeutic modalities in high-volume centers. No statistically significant direct effect of hospital volume was found: high-volume vs. low-volume 0.86 (95%CI 0.4–1.7), high-volume vs. middle-volume OR 0.86 (95%CI 0.5–1.4).

      Conclusion

      Lower FTR in high-volume compared with low-volume centers was explained by lower leak severity, less secondary ICU readmissions and higher availability of therapeutic modalities. To reduce FTR after AL, future studies should investigate effective strategies to reduce leak severity and prevent secondary ICU readmission.

      Keywords

      1. Introduction

      In patients with curable esophageal cancer, surgery is an important component of multimodal treatment [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ,
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]. Despite advancements in surgical technique and perioperative care, esophagectomy is associated with substantial postoperative morbidity and mortality [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ,
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ,
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]. Differences in postoperative mortality rates between centers have been found to be related to hospital volume [
      • Markar S.R.
      • Karthikesalingam A.
      • Thrumurthy S.
      • Low D.E.
      Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011.
      ,
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]. Previous studies have suggested that differences in postoperative mortality between centers are not related to the incidence of complications, but rather to failure to rescue (FTR), i.e., patients dying after postoperative complications [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ,
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ,
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]. High-volume centers have been found to have lower FTR rates possibly due to earlier recognition and adequate treatment of complications [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ,
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ,
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ].
      Although these observations have been used as an argument for centralization of complex surgery in high-volume centers, centralization is not feasible in every health care system [
      • Markar S.R.
      • Karthikesalingam A.
      • Thrumurthy S.
      • Low D.E.
      Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011.
      ,
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ,
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]. Therefore, investigating how centers manage complications and rescue patients can provide important insights to reduce FTR and improve outcomes on a global scale. Hypothetically, the association between FTR and hospital volume could be explained by differences in management of complications, differences in patient selection and/or differences in available hospital resources. However, detailed insight into how centers manage complications and achieve their outcomes is lacking [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ,
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ].
      Anastomotic leak (AL) is a common complication contributing to postoperative mortality after esophagectomy [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ,
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research C
      Rates of anastomotic complications and their management following esophagectomy: results of the oesophago-gastric anastomosis audit (OGAA).
      ]. Previous studies have reported differences in diagnosis and treatment of patients with AL in relation to hospital volume [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ,
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ,
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]. However, the association between these differences and FTR has not been studied. The aim of this study was to evaluate the association of hospital volume with FTR in patients with AL after esophagectomy, and to identify factors that explain differences in FTR between centers.

      2. Methods

      This study was performed in the cohort of the TENTACLE – Esophagus study (NCT03829098), an international retrospective cohort study in 71 centers from Asia, Africa, Europe, South America and Oceania. Details regarding the study design and data collection were published previously [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]. In addition, data quality validation was performed by independent validators and showed a data accuracy of 96.5% [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]. The current analysis included 1509 patients with AL after esophagectomy between January 1st, 2011 until June 30th, 2019 enrolled consecutively in the TENTACLE – Esophagus study. AL was defined as a “full thickness gastrointestinal defect involving esophagus, anastomosis, staple line, or conduit irrespective of presentation or method of identification” [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ].

      2.1 Hospital volume

      Differences in FTR were assessed according to annual hospital volume. The annual hospital volume of centers and other site characteristics were recorded in a survey during data collection of the TENTACLE – Esophagus study (Supplementary Methods 1). Centers were stratified into three groups based on their annual resection volume: low-volume centers performing <20 resections, middle-volume centers performing 20–59 resections and high-volume centers performing ≥60 resections per year. Although various volume cut-offs have been used, these cut-offs are generally accepted in current literature and have been used as cut-offs for policies in different countries [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ,
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ,
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ,
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ,
      • van der Werf L.R.
      • Busweiler L.A.D.
      • van Sandick J.W.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.L.
      Reporting national outcomes after esophagectomy and gastrectomy according to the esophageal complications consensus group (ECCG).
      ].

      2.2 Outcome parameters

      The primary outcome was FTR, which was defined as mortality in patients with AL within 90-days after esophagectomy. The 90-day interval has been found to be the most reliable measure of mortality due to complications without including non-complication mortality (e.g., cancer recurrence) [
      • Damhuis R.A.
      • Wijnhoven B.P.
      • Plaisier P.W.
      • Kirkels W.J.
      • Kranse R.
      • van Lanschot J.J.
      Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types.
      ,
      • Talsma A.K.
      • Lingsma H.F.
      • Steyerberg E.W.
      • Wijnhoven B.P.
      • Van Lanschot J.J.
      The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.
      ,
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]. Secondary outcome parameters included length of hospital stay, intensive care unit (ICU) stay and leak healing (i.e., time to confirmed healing or non-clear liquid diet), and comprehensive complication index (CCI). The CCI is a scale ranging from 0 (no complications) to 100 (death) and represents the severity of all complications in a patient [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ].

      2.3 Statistical analysis

      Center characteristics (e.g., availability of therapeutic techniques), case-mix parameters, leak parameters, treatment parameters and outcomes were described stratified by hospital volume. Differences between patients in low-, middle- and high-volume centers were assessed using Chi-square test or Fisher's exact test, and one-way ANOVA or Kruskal-Wallis test where appropriate.
      The association between hospital volume and FTR found by previous studies resembles the total effect of hospital volume on FTR [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ,
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ,
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]. This total effect may consist of a direct effect of hospital volume and may also be explained by indirect effects (i.e., mediators): differences in parameters along the causal pathway between hospital volume and FTR [
      • Richiardi L.
      • Bellocco R.
      • Zugna D.
      Mediation analysis in epidemiology: methods, interpretation and bias.
      ]. For example, high-volume centers may treat complications differently, and may thus have different FTR rates. Mediation analysis is used to open the ‘black box’ of the total effect and gain insight into the underlying mechanism(s) of a total effect [
      • Cohen P.
      • West S.G.
      • Aiken L.S.
      Applied multiple regression/correlation analysis for the behavioral sciences.
      ,
      • Hafeman D.M.
      • Schwartz S.
      Opening the Black Box: a motivation for the assessment of mediation.
      ]. In current study, mediation analysis was performed to identify mediators explaining the relationship between hospital volume and FTR. Possible mediators for the association between hospital volume and FTR included differences in case-mix parameters, leak severity, treatment of AL and available hospital resources. The assumed causal pathways between hospital volume, possible mediators and FTR were visualized using a Directed Acyclic Graph (Fig. 1).
      Fig. 1
      Fig. 1Assumed relationships between hospital volume, possible mediators and Failure to Rescue.
      The continuous lines together represent the total effect of hospital volume on failure to rescue (FTR). The continuous line from hospital volume to FTR represents the possible direct effect of hospital volume on FTR. The continuous lines that connect hospital volume with FTR via case-mix, leak severity, available resources and treatment resemble possible indirect effects (i.e., mediators) which explain the total effect of hospital volume on FTR. The dotted lines represent possible confounding of year of surgery and country income on hospital volume and FTR. Case-mix parameters include age, comorbidity (i.e., ASA-classification), performance status (i.e., ECOG score) and tumor histology. Hospital resources include available diagnostic and therapeutic modalities. Leak severity is measured by the Severity of Esophageal Anastomotic Leak (SEAL) score, a score combining 12 clinical parameters at diagnosis into four classes of leak severity (i.e., mild, moderate, severe, critical). Treatment parameters include primary treatment strategy, primary reoperation, primary intensive care unit (ICU) readmission, secondary treatment, secondary reoperation and secondary ICU readmission.
      The total effect of hospital volume on FTR in patients with AL was assessed using multiple logistic regression, adjusting for relevant confounders: year of surgery and country income [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. Country income was dichotomized into low-/middle-income countries (LMIC) and high-income countries (HIC) based on the list published by the World bank [
      The World Bank
      Low and middle income | Data 2022.
      ]. Mediation analysis was performed using multiple logistic regression including relevant confounders (i.e., year of surgery, country income) and possible mediators: case-mix parameters, leak severity, AL treatment and available hospital resources. Case-mix parameters included age, comorbidity (i.e., American Society of Anesthesiologists (ASA) classification), performance status (i.e., Eastern Cooperative Oncology Group (ECOG) score) and tumor histology [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ,
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ,
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]. Leak severity at diagnosis was measured using the recently developed Severity of Esophageal Anastomotic Leak (SEAL) score [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]. This internally validated tool combines 12 clinical parameters at diagnosis (e.g., organ failure, circumference of the anastomotic defect) and differentiates four classes of leak severity (i.e., mild, moderate, severe and critical). The primary treatment strategy (i.e., within 48 h after diagnosis) was categorized according to the treatment principle: drainage of fluid collections, closure of the anastomotic defect (e.g., endoscopic stent, surgical closure), esophageal diversion and only supportive treatment [
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]. Primary reoperation and ICU readmission were included as measures for invasiveness of primary treatment. Secondary treatment (i.e., treatment due to failure of primary treatment or >48 h after diagnosis), secondary reoperation and secondary ICU readmission were included as measures for failure of primary treatment. The number of available diagnostic and therapeutic modalities were included (i.e., all available, 1 modality unavailable, ≥2 modalities unavailable).
      Estimates of the impact of hospital volume on FTR were expressed as odds ratios (OR) with 95% confidence interval (CI). A p-value <0.05 was considered statistically significant. Multiple imputation with chained equations was used to avoid bias due to missing data [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate imputation by chained equations in R.
      ]. Analyses were performed in each imputed dataset and pooled according to Rubin's rule, using R version 3.6.2 with packages ‘rms’ and ‘mice’ [
      • Wood A.M.
      • Royston P.
      • White I.R.
      The estimation and use of predictions for the assessment of model performance using large samples with multiply imputed data.
      ].

      3. Results

      In total, 1509 patients with AL after esophagectomy were included by 71 centers in 20 countries. Of the 1509 included patients, 139 patients (9%) were included by 19 low-volume centers, 959 patients (64%) by 38 middle-volume and 411 patients (27%) by 14 high-volume centers (Supplementary Table 1).

      3.1 Hospital volume

      Patients with AL in middle- and high-volume centers had less comorbidity and a higher incidence of adenocarcinoma than patients in low-volume centers (Table 1). Availability of computed tomography (CT) guided drainage and endoscopic vacuum assisted closure (endoVAC) was lower in low-volume centers compared with middle- and high-volume centers. The FTR rate was lower in middle- and high-volume centers (low-volume 20% vs. middle-volume 12% vs. high-volume 8%, p = 0.001) (Table 2).
      Table 1Center and patient characteristics.
      ParametersLow-volumeMiddle-volumeHigh-volumeP-value
      Center characteristics
      Centers (%)19 [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ]
      38 (54)14 [
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]
      Country Income (%)
       LMIC6 [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate imputation by chained equations in R.
      ]
      2 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      1 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      0.023
       HIC13 (68)36 (95)13 (93)
      Hospital type (%)
       General hospital7 [
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]
      14 [
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]
      0 (0)0.042
       University hospital11 (58)20 (53)12 (86)
       Cancer center1 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      4 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      2 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
      Preferred anastomosis location (%)
       Intrathoracic16 (84)25 (66)13 (93)0.087
       Cervical3 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      13 [
      • Dikken J.L.
      • Dassen A.E.
      • Lemmens V.E.
      • Putter H.
      • Krijnen P.
      • van der Geest L.
      • et al.
      Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in The Netherlands between 1989 and 2009.
      ]
      1 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      Availability of diagnostic tests (%)
       Clinical leak test, Methylene blue17 (90)36 (95)13 (93)0.828
       X-ray swallow18 (95)36 (95)14 (100)1.000
       CT-scan19 (100)38 (100)14 (100)
       CT-scan, oral contrast17 (90)38 (100)14 (100)0.105
       Endoscopy18 (95)38 (100)14 (100)0.465
      Availability of treatment (%)
       Ultrasound-guided drainage19 (100)38 (100)14 (100)
       CT-guided drainage15 (79)38 (100)14 (100)0.005
       Endoscopic drainage18 (95)37 (97)14 (100)1.000
       Stent17 (90)38 (100)14 (100)0.105
       EndoVAC7 [
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]
      33 (87)11 (79)<0.001
       Endoclip17 (90)37 (97)14 (100)0.270
       Thoracoscopy/VATS16 (84)35 (92)14 (100)0.332
       Laparoscopy18 (95)38 (100)14 (100)0.465
      Patient characteristics
      Patients139 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      959 (64)411 [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ]
      Year of surgery (median [IQR])2015 [’13, ‘17]2015 [’13, ‘17]2015 [’14, ‘18]<0.001
      Age (median [IQR])66 [59, 71]66 [59, 72]66 [58, 71]0.512
      Comorbidity (%)
       ASA I3 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      111 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      29 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      <0.001
       ASA II60 (44)539 (58)246 (60)
       ≥ASA III75 (54)277 [
      • Hafeman D.M.
      • Schwartz S.
      Opening the Black Box: a motivation for the assessment of mediation.
      ]
      136 [
      • Wood A.M.
      • Royston P.
      • White I.R.
      The estimation and use of predictions for the assessment of model performance using large samples with multiply imputed data.
      ]
       Missing1 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      32 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      0 (0)
      Performance status (%)
       ECOG 059 (42)435 (45)172 (42)0.053
       ECOG 161 (44)259 [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ]
      105 [
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]
       ≥ECOG 213 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      57 [
      • Markar S.R.
      • Karthikesalingam A.
      • Thrumurthy S.
      • Low D.E.
      Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011.
      ]
      29 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
       Missing6 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      208 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      105 [
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]
      Tumor histology (%)
       Adenocarcinoma84 (60)705 (74)299 (73)0.022
       Squamous cell carcinoma51 [
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]
      228 [
      • Damhuis R.A.
      • Wijnhoven B.P.
      • Plaisier P.W.
      • Kirkels W.J.
      • Kranse R.
      • van Lanschot J.J.
      Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types.
      ]
      98 [
      • Damhuis R.A.
      • Wijnhoven B.P.
      • Plaisier P.W.
      • Kirkels W.J.
      • Kranse R.
      • van Lanschot J.J.
      Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types.
      ]
       Other3 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      24 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      11 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
       Missing1 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      2 (0.2)3 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      Abbreviations: LMIC, low-/middle-income country; HIC, high-income country; CT, computed tomography; VATS, video-assisted thoracoscopic surgery ASA, American Society of Anesthesiologists; ECOG, Eastern Collaborative Oncology Group.
      Table 2Outcomes of patients with AL in low-, middle- and high-volume centers.
      ParametersLow-volumeMiddle-volumeHigh-volumeP-value
      Patients139959411
      Failure to rescue (%)27 (19.4)115 (12.0)34 (8.3)0.001
      LOS, hospital (days, median [IQR])32 [20, 52]30 [19, 48]31 [21, 51]0.087
      LOS, ICU (days, median [IQR])7 [3, 18]5 [2, 15]6 [3, 14]0.008
      Healing time (days, median [IQR])17 [8, 33]28 [15, 48]23 [12, 40]<0.001
      CCI (median [IQR])45 [34, 72]43 [30, 62]45 [34, 66]0.083
      Abbreviations: LOS, length of stay; ICU, intensive care unit; IQR, interquartile range; CCI, comprehensive complication index; LMIC, low-/middle-income countries; HIC, high-income countries.

      3.2 Diagnosis and management of AL

      Table 3 presents clinical parameters and AL treatment of patients in low-, middle- and high-volume centers. High-volume centers confirmed AL one postoperative day (POD) later than low- and middle-volume centers (median POD low-volume 7, middle-volume, high-volume 8). Leak severity at diagnosis was the lowest in high-volume centers, as more patients had a mild or moderate leak as measured by the SEAL score (low-volume 68% vs. middle-volume 76% vs. high-volume 80%, p = 0.001). Patients in high-volume centers less frequently had hemodynamic or pulmonary organ failure compared with low- and middle-volume centers.
      Table 3Clinical parameters at diagnosis and treatment of patients with AL per hospital volume.
      ParametersLow-volumeMiddle-volumeHigh-volumeP-value
      Patients139 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      959 (64)411 [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ]
      Resection type (%)
       TTE-CA43 [
      The World Bank
      Low and middle income | Data 2022.
      ]
      233 [
      • Damhuis R.A.
      • Wijnhoven B.P.
      • Plaisier P.W.
      • Kirkels W.J.
      • Kranse R.
      • van Lanschot J.J.
      Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types.
      ]
      131 [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate imputation by chained equations in R.
      ]
      <0.001
       TTE-IA65 (47)558 (58)226 (55)
       THE-CA27 [
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ]
      161 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research C
      Rates of anastomotic complications and their management following esophagectomy: results of the oesophago-gastric anastomosis audit (OGAA).
      ]
      53 [
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ]
       Missing4 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      7 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      1 (0.2)
      POD of diagnosis (median [IQR])7 [5, 10]7 [5, 11]8 [6, 11]0.002
       Missing (%)13 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      52 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      75 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]
      Modality confirming AL (%)
       Endoscopy13 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      129 [
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ]
      40 [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ]
      <0.001
       Esophagram32 [
      • van der Werf L.R.
      • Busweiler L.A.D.
      • van Sandick J.W.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.L.
      Reporting national outcomes after esophagectomy and gastrectomy according to the esophageal complications consensus group (ECCG).
      ]
      99 [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ]
      74 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]
       CT66 (48)451 (47)226 (55)
       Drain21 [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ]
      208 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      31 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ]
       Reoperation1 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      20 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      2 (0.4)
       Other4 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      41 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      9 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
       None0 (0)3 (0.3)11 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
       Missing2 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      8 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      18 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      Number of different assessments in 48h before diagnosis (%)
       062 (45)304 [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate imputation by chained equations in R.
      ]
      161 [
      • Johnston M.J.
      • Arora S.
      • King D.
      • Bouras G.
      • Almoudaris A.M.
      • Davis R.
      • et al.
      A systematic review to identify the factors that affect failure to rescue and escalation of care in surgery.
      ]
      <0.001
       170 (50)494 (52)146 [
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Workum F.
      • Ten Broek R.
      • Siersema P.D.
      • Rovers M.
      • et al.
      Management of intrathoracic and cervical anastomotic leakage after esophagectomy for esophageal cancer: a systematic review.
      ]
       ≥27 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      133 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
      33 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ]
       Missing (%)028 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      71 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research C
      Rates of anastomotic complications and their management following esophagectomy: results of the oesophago-gastric anastomosis audit (OGAA).
      ]
      Leak severity, SEAL score (%)
       Mild20 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
      239 [
      • Talsma A.K.
      • Lingsma H.F.
      • Steyerberg E.W.
      • Wijnhoven B.P.
      • Van Lanschot J.J.
      The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.
      ]
      85 [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]
      0.001
       Moderate74 (53)494 (52)243 (59)
       Severe29 [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]
      119 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      54 [
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ]
       Critical16 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      107 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      29 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      Ward at diagnosis (%)
       Ward62 (45)551 (58)249 (61)0.002
       ICU/MC/HC/PACU68 (49)342 [
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Workum F.
      • Ten Broek R.
      • Siersema P.D.
      • Rovers M.
      • et al.
      Management of intrathoracic and cervical anastomotic leakage after esophagectomy for esophageal cancer: a systematic review.
      ]
      133 [
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate imputation by chained equations in R.
      ]
       ED/Other6 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      46 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      9 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
       Missing3 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      20 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      20 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      Diet at diagnosis (%)
       No restrictions16 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      113 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      39 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      0.350
       Liquid37 [
      • Slankamenac K.
      • Graf R.
      • Barkun J.
      • Puhan M.A.
      • Clavien P.A.
      The comprehensive complication index: a novel continuous scale to measure surgical morbidity.
      ]
      255 [
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]
      79 [
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ]
       Water10 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      102 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      46 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
       Nil per mouth66 (47)391 (41)155 [
      • Ghaferi A.A.
      • Dimick J.B.
      Importance of teamwork, communication and culture on failure-to-rescue in the elderly.
      ]
       Missing10 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      98 [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ]
      92 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      Antibiotics prescribed before diagnosis (%)79 (57)445 (46)187 (46)0.089
      Leukocyte count at diagnosis (median [IQR])12.7 [8.6, 16]12.3 [9.4, 16]12.5 [9.4, 17]0.937
      qSOFA score (mean (SD))0.7 (0.9)0.5 (0.8)0.4 (0.8)0.030
       Missing (%)20 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
      246 [
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]
      150 [
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]
      Pulmonary failure (%)30 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      176 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]
      49 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      0.051
       Missing (%)6 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      46 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      67 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      Hemodynamic failure (%)22 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      89 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      26 [
      • Markar S.R.
      • Karthikesalingam A.
      • Thrumurthy S.
      • Low D.E.
      Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011.
      ]
      0.009
       Missing (%)10 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      71 [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ]
      65 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      Renal failure (%)11 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ]
      26 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      18 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      0.009
       Missing (%)6 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      84 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      35 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      Intrathoracic fluid collections (%)
       None43 [
      The World Bank
      Low and middle income | Data 2022.
      ]
      330 [
      • Dikken J.L.
      • Dassen A.E.
      • Lemmens V.E.
      • Putter H.
      • Krijnen P.
      • van der Geest L.
      • et al.
      Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in The Netherlands between 1989 and 2009.
      ]
      146 [
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Workum F.
      • Ten Broek R.
      • Siersema P.D.
      • Rovers M.
      • et al.
      Management of intrathoracic and cervical anastomotic leakage after esophagectomy for esophageal cancer: a systematic review.
      ]
      0.046
       Drained21 [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ]
      84 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      34 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ]
       Undrained74 (53)395 (41)217 (53)
       Missing1 [
      • van Hagen P.
      • Hulshof M.C.C.M.
      • van Lanschot Jjb
      • Steyerberg E.W.
      • MivB Henegouwen
      • Wijnhoven B.P.L.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      ]
      150 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      14 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      Defect circumference (%)
       < 25%72 (52)322 [
      • Dikken J.L.
      • Dassen A.E.
      • Lemmens V.E.
      • Putter H.
      • Krijnen P.
      • van der Geest L.
      • et al.
      Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in The Netherlands between 1989 and 2009.
      ]
      176 (43)0.797
       ≥ 25%28 [
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]
      106 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      59 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
       Not available39 [
      • Richiardi L.
      • Bellocco R.
      • Zugna D.
      Mediation analysis in epidemiology: methods, interpretation and bias.
      ]
      531 (55)176 (43)
       Missing0 (0)1 (0.1)0 (0)
      Overall tube condition (%)
       Viable104 (75)683 (71)297 (72)0.293
       Ischemic/necrotic12 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Complications, failure to rescue, and mortality with major inpatient surgery in medicare patients.
      ]
      103 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      33 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ]
       Missing23 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research C
      Rates of anastomotic complications and their management following esophagectomy: results of the oesophago-gastric anastomosis audit (OGAA).
      ]
      173 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]
      81 [
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]
      Primary treatment
      Primary strategy (%)
       Supportive only28 [
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ]
      203 [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]
      104 [
      • Talsma A.K.
      • Lingsma H.F.
      • Steyerberg E.W.
      • Wijnhoven B.P.
      • Van Lanschot J.J.
      The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.
      ]
      0.006
       Drainage54 [
      • Johnston M.J.
      • Arora S.
      • King D.
      • Bouras G.
      • Almoudaris A.M.
      • Davis R.
      • et al.
      A systematic review to identify the factors that affect failure to rescue and escalation of care in surgery.
      ]
      380 (40)156 [
      • Ghaferi A.A.
      • Dimick J.B.
      Importance of teamwork, communication and culture on failure-to-rescue in the elderly.
      ]
       Defect closure15 [
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Hospital volume and failure to rescue with high-risk surgery.
      ]
      45 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      8 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
       Drainage and defect closure30 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      184 [
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ]
      75 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]
       Esophageal Diversion6 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      32 [
      • Goense L.
      • Meziani J.
      • Ruurda J.P.
      • van Hillegersberg R.
      Impact of postoperative complications on outcomes after oesophagectomy for cancer.
      ]
      19 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      Stent placement (%)35 [
      • Talsma A.K.
      • Lingsma H.F.
      • Steyerberg E.W.
      • Wijnhoven B.P.
      • Van Lanschot J.J.
      The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.
      ]
      187 [
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ]
      41 [
      • Liou D.Z.
      • Serna-Gallegos D.
      • Mirocha J.
      • Bairamian V.
      • Alban R.F.
      • Soukiasian H.J.
      Predictors of failure to rescue after esophagectomy.
      ]
      <0.001
      EndoVAC (%)5 [
      • van Workum F.
      • Verstegen M.H.P.
      • Klarenbeek B.R.
      • Bouwense S.A.W.
      • van Berge Henegouwen M.I.
      • Daams F.
      • et al.
      Intrathoracic vs cervical anastomosis after totally or hybrid minimally invasive esophagectomy for esophageal cancer: a randomized clinical trial.
      ]
      21 [
      • Al-Batran S.-E.
      • Homann N.
      • Schmalenberg H.
      • Kopp H.-G.
      • Haag G.M.
      • Luley K.B.
      • et al.
      Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.
      ]
      22 [
      • Puccetti F.
      • Wijnhoven B.P.L.
      • Kuppusamy M.
      • Hubka M.
      • Low D.E.
      Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.
      ]
      0.009
      Primary Reoperation (%)30 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      248 [
      • In H.
      • Palis B.E.
      • Merkow R.P.
      • Posner M.C.
      • Ferguson M.K.
      • Winchester D.P.
      • et al.
      Doubling of 30-day mortality by 90 Days after esophagectomy: a critical measure of outcomes for quality improvement.
      ]
      87 [
      • Ubels S.
      • Verstegen M.
      • Klarenbeek B.
      • Bouwense S.
      • van Berge Henegouwen M.
      • Daams F.
      • et al.
      Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score.
      ]
      0.130
      Antibiotics (%)129 (93)751 (78)385 (94)<0.001
      Feeding support (%)17 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      140 [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ]
      64 [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]
      0.673
      Primary ICU readmission (%)61 (44)295 [
      The World Bank
      Low and middle income | Data 2022.
      ]
      128 [
      The World Bank
      Low and middle income | Data 2022.
      ]
      0.005
      Secondary treatment
      Need for secondary treatment (%)86 (62)554 (58)248 (60)0.755
      Secondary ICU readmission (%)30 [
      • Low D.E.
      • Alderson D.
      • Cecconello I.
      • Chang A.C.
      • Darling G.E.
      • D'Journo X.B.
      • et al.
      International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG).
      ]
      137 [
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]
      49 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      0.015
      Secondary reoperation (%)24 [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research C
      Rates of anastomotic complications and their management following esophagectomy: results of the oesophago-gastric anastomosis audit (OGAA).
      ]
      123 [
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ]
      49 [
      • Henneman D.
      • Dikken J.L.
      • Putter H.
      • Lemmens V.E.
      • Van der Geest L.G.
      • van Hillegersberg R.
      • et al.
      Centralization of esophagectomy: how far should we go?.
      ]
      0.245
      Abbreviations: AL; anastomotic leak TTE, transthoracic esophagectomy; CA, cervical anastomosis; IA, intrathoracic anastomosis; THE, transhiatal esophagectomy; POD, postoperative day; IQR, interquartile range; SD, standard deviation; CT, computed tomography; SEAL, severity of esophageal anastomotic leak; ICU, intensive care unit; MC, medium care; HC, high care; PACU, post anesthesia care unit; ED, emergency department; qSOFA, quick sequential organ failure assessment; EndoVAC, endoscopic vacuum assisted closure.
      The primary treatment strategy differed between low-, middle- and high-volume centers: more patients in high-volume centers were only treated supportively, whereas defect closure was performed more often in low-volume centers. The primary ICU readmission rate was higher in low-volume centers compared with middle- and high-volume centers. Although, a similar percentage of patients underwent secondary treatment (i.e., treatment due to failure of primary treatment or >48 h after diagnosis) in low-, middle- and high-volume centers, in low-volume centers the secondary ICU readmission rate was higher, and more patients underwent secondary reoperation.

      3.3 Regression analyses

      After adjusting for confounders, lower FTR was found in high-volume centers vs. low-volume centers (OR 0.44, 95%CI 0.2–0.8), but no statistically significant differences in FTR were found between high-volume vs. middle-volume centers (OR 0.67, 95%CI 0.5–1.0) (Table 4).
      Table 4Multivariable regression identifying parameters underlying differences in FTR.
      ParametersTotal effect
      Hospital volume was corrected for confounders: year of surgery, country income.
      OR (95%CI)
      Mediation analysis
      OR of parameters other than hospital volume should be interpreted with caution due to the ‘Table 2 fallacy’. (Westreich & Greenland, 2013).
      OR (95%CI)
      Hospital volume
       Low11
       Middle0.64 (0.4–1.0)1.01 (0.6–1.8)
       High0.44 (0.2–0.8)0.86 (0.4–1.7)
      Country income status
       Low/Middle11
       High0.27 (0.1–0.5)0.28 (0.1–0.7)
      Year of surgery
       2011–201311
       2014–20161.05 (0.7–1.6)1.19 (0.8–1.9)
       2017–20190.83 (0.6–1.3)0.90 (0.6–1.5)
      Available diagnostic modalities
      Interquartile odds ratio, interquartile range: 59–71 years.
       All modalities available1
       1 unavailable1.30 (0.6–2.8)
       ≥ 2 unavailable1.25 (0.5–3.3)
      Available treatment modalities
      Interquartile odds ratio, interquartile range: 59–71 years.
       All modalities available1
       1 unavailable1.27 (0.8–2.1)
       ≥ 2 unavailable2.59 (1.2–5.8)
       Age
      Interquartile odds ratio, interquartile range: 59–71 years.
      1.42 (1.1–1.9)
      Comorbidity
       ASA I1
       ASA II1.67 (0.6–4.5)
       ≥ASA III1.77 (0.6–4.9)
      Performance status
       ECOG 01
       ECOG 11.57 (1.0–2.5)
       ≥ECOG 22.00 (1.0–3.9)
      Tumor histology
       Adenocarcinoma1
       Squamous cell carcinoma1.44 (1.0–2.1)
       Other0.41 (0.1–2.0)
      Leak severity, SEAL score
       Mild1
       Moderate2.44 (1.2–4.9)
       Severe6.13 (2.8–13.4)
       Critical10.66 (5.0–22.6)
      Primary strategy
       Supportive only1
       Drainage1.15 (0.6–2.1)
       Defect closure0.98 (0.4–2.4)
       Drainage & defect closure1.53 (0.8–3.0)
       Esophageal diversion1.32 (0.5–3.5)
      Primary reoperation1.24 (0.8–2.0)
      Primary ICU readmission1.05 (0.7–1.6)
      Secondary treatment1.04 (0.6–1.7)
      Secondary reoperation1.44 (0.9–2.3)
      Secondary ICU readmission3.43 (2.1–5.5)
      Abbreviations: FTR, failure to rescue; LMIC, low-/middle-income countries; HIC, high-income countries; AL, anastomotic leak; OR, odds ratio; CI, confidence interval; ASA, American Society of Anesthesiologists; ECOG, Eastern Collaborative Oncology Group; SEAL, severity of esophageal anastomotic leak; ICU, intensive care unit.
      Recorded diagnostic modalities are methylene blue, swallow X-ray, computed tomography (CT), contract CT) and endoscopy; Recorded therapeutic modalities are ultrasound-guided drainage, CT-guided drainage, endoscopic drainage, stent treatment, endoscopic vacuum-assisted closure (endoVAC), endoscopic clipping (endoclip), video-assisted thoracoscopic surgery (VATS) and laparoscopy.
      a Hospital volume was corrected for confounders: year of surgery, country income.
      b OR of parameters other than hospital volume should be interpreted with caution due to the ‘Table 2 fallacy’. (Westreich & Greenland, 2013).
      c Interquartile odds ratio, interquartile range: 59–71 years.
      During mediation analysis, three parameters were found to mediate the total effect of hospital volume on FTR: leak severity as measured by the SEAL score (moderate OR 2.4, 95%CI 1.2–4.9; severe OR 6.1, 95%CI 2.8–13.4; critical OR 10.7, 95%CI 5.0–22.6), secondary ICU readmission (OR 3.4, 95%CI 2.1–5.5) and availability of therapeutic modalities (one modality unavailable vs. all modalities available: OR 1.3, 95%CI 0.8–2.1; two or more modalities unavailable vs. all modalities available: OR 2.6, 95%CI 1.2–5.8). The primary treatment strategy had no statistically significant impact on FTR. In addition, no statistically significant direct effect was found between hospital volume and FTR: high-volume vs. low-volume 0.86 (95%CI 0.4–1.7), high-volume vs. middle-volume OR 0.86 (95%CI 0.5–1.4). This indicates the lower FTR rate in high-volume centers compared with low-volume centers was explained by lower leak severity, lower secondary ICU readmission rates and higher availability of therapeutic modalities in high-volume centers.

      4. Discussion

      This large retrospective study has explored differences FTR between centers in patients with AL after esophagectomy. A lower FTR rate was found in high-volume centers compared with low-volume centers, but not compared with middle-volume centers. The higher FTR in low-volume centers was found to be explained by higher leak severity at diagnosis of AL, higher ICU readmission rate during secondary treatment and lower availability of therapeutic modalities.
      In line with other studies, the current study observed an 11.7% FTR rate in patients with AL and found substantial differences in FTR related to hospital volume [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ,
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ]. Patients in high-volume centers were found to have less comorbidity and better performance status, corroborating previous findings [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ,
      • Dikken J.L.
      • Dassen A.E.
      • Lemmens V.E.
      • Putter H.
      • Krijnen P.
      • van der Geest L.
      • et al.
      Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in The Netherlands between 1989 and 2009.
      ]. Potentially, this may be related to differences in patient selection between different centers. In addition, it has to be considered that more patients treated in low-volume centers were from low-/middle-income countries, which may contribute to differences in comorbidity and performance status. However, these explanations could not be substantiated in current data as this was not the topic of the TENTACLE – Esophagus study and the study did not include patients undergoing esophagectomy that did not develop AL.
      Besides case-mix parameters, previous studies have not further investigated factors that underly differences in FTR related to hospital volume. We found that differences in FTR were explained by lower leak severity at diagnosis in high-volume centers, especially due to lower incidence of organ failure and ICU admission at diagnosis. From a theoretical perspective, the lower leak severity may be related to earlier diagnosis of AL or more standardized postoperative care, as suggested by a previous study [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. However, current data did not support this hypothesis: rather than earlier, AL was diagnosed one day later in high-volume centers compared with low- and medium-volume centers. Furthermore, there was no difference in proportion of patients already prescribed antibiotics before diagnosis (i.e., during suspicion of AL). Unfortunately, data on the events before diagnosis of AL were not available. Therefore, differences in leak severity between centers could not be fully explained and should be further investigated.
      Regarding treatment of AL, although there was a difference in the primary treatment strategy between low-, middle- and high-volume centers, this difference was not found to explain differences in FTR. In addition, there was no difference in the overall proportion of patients that underwent secondary treatment between low-, middle- and high-volume centers. However, the rate of ICU readmission and reoperation during secondary treatment was lower in middle- and high-volume centers compared with low-volume centers, and secondary ICU readmission was identified as a factor explaining differences in FTR between centers. These findings indicate that middle- and high-volume centers may monitor the course of treatment more effectively and change their treatment strategy more effectively.
      Corroborating previous findings, the availability of therapeutic modalities (i.e., endoVAC and CT-guided drainage) was lower in low-volume centers compared with middle- and high-volume centers [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. The availability of therapeutic modalities was identified as a factor explaining the differences in FTR between centers. Extending availability of therapeutic resources could improve outcomes, however, new modalities should be carefully introduced, and implementation requires broad expertise of surgeons, gastroenterologists and radiologists. Moreover, whereas endoVAC was the modality with the largest differences in availability, this modality was scarcely used across all centers. Consequently, it may be questioned whether the mediating effect is truly attributable to the availability of treatment modalities or whether it reflects a higher level of specialized care in middle- and high-volume centers such as on-call esophageal teams and interventional radiology services [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ].
      Differences in postoperative outcomes in relation to hospital volume have been an argument for centralization of esophageal surgery [
      • Markar S.R.
      • Karthikesalingam A.
      • Thrumurthy S.
      • Low D.E.
      Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000-2011.
      ,
      • Brusselaers N.
      • Mattsson F.
      • Lagergren J.
      Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
      ,
      • van Lanschot J.J.
      • Hulscher J.B.
      • Buskens C.J.
      • Tilanus H.W.
      • ten Kate F.J.
      • Obertop H.
      Hospital volume and hospital mortality for esophagectomy.
      ]. However, centralization may not be possible in every setting or country. Therefore, our study investigated what factors underly differences in FTR and found that differences in FTR in relation to hospital volume are attributable to leak severity at diagnosis, secondary ICU readmission and available therapeutic resources. Although leak severity and secondary ICU admission rates are not directly modifiable, strategies to reduce leak severity and prevent secondary ICU readmission should be further explored to improve outcomes. Standardization of diagnostic and therapeutic strategies may be an important tool to improve outcomes and recently standardization of post-operative care after pancreatic surgery led to a substantial reduction in postoperative morbidity and mortality [
      • Smits F.J.
      • Henry A.C.
      • Besselink M.G.
      • Busch O.R.
      • van Eijck C.H.
      • Arntz M.
      • et al.
      Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in The Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.
      ]. However, high-quality evidence to support guidelines for diagnosis and treatment of AL after esophagectomy is still lacking [
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ,
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Workum F.
      • Ten Broek R.
      • Siersema P.D.
      • Rovers M.
      • et al.
      Management of intrathoracic and cervical anastomotic leakage after esophagectomy for esophageal cancer: a systematic review.
      ]. In absence of high-quality evidence, qualitative approaches may be useful and centers may engage in sharing experiences to identify best practices in diagnosis and management of AL [
      • Abdelsattar Z.M.
      • Habermann E.
      • Borah B.J.
      • Moriarty J.P.
      • Rojas R.L.
      • Blackmon S.H.
      Understanding failure to rescue after esophagectomy in the United States.
      ,
      • Ubels S.
      • Lubbers M.
      • Verstegen M.H.P.
      • Bouwense S.A.W.
      • van Daele E.
      • Ferri L.
      • et al.
      Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
      ].
      The main strength of this study is the detailed data on clinical parameters, treatment and outcome of AL in combination with data on hospital volume. Previous studies were not able to investigate practice variation in relation to outcomes due to the lack of detailed data [
      • Busweiler L.A.
      • Henneman D.
      • Dikken J.L.
      • Fiocco M.
      • van Berge Henegouwen M.I.
      • Wijnhoven B.P.
      • et al.
      Failure-to-rescue in patients undergoing surgery for esophageal or gastric cancer.
      ,
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. Our study identified explanations for differences in FTR, which can be further explored to improve outcomes of AL after esophagectomy. Some limitations of this study need to be addressed. First, as the current study only included patients with AL, differences in overall postoperative mortality and incidence of AL could not be assessed. Although differences in incidence of AL related to hospital volume have been reported, other studies have found that differences in postoperative mortality were not related to incidence of complications but to FTR [
      Oesophago-Gastric Anastomotic Audit (OGAA) Collaborative
      Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: an international cohort study.
      ,
      • Ghaferi A.A.
      • Birkmeyer J.D.
      • Dimick J.B.
      Variation in hospital mortality associated with inpatient surgery.
      ,
      • Voeten D.M.
      • Gisbertz S.S.
      • Ruurda J.P.
      • Wilschut J.A.
      • Ferri L.E.
      • van Hillegersberg R.
      • et al.
      Overall volume trends in esophageal cancer surgery results from the Dutch upper gastrointestinal cancer audit.
      ]. Second, there is large variation in diagnosis and treatment of AL and management of AL may have changed during the 8.5-year study period [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ,
      • Hagens E.R.C.
      • Anderegg M.C.J.
      • van Berge Henegouwen M.I.
      • Gisbertz S.S.
      International survey on the management of anastomotic leakage after esophageal resection.
      ]. Differences in treatment of AL related to country income have been previously reported [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. Although analysis on the relationship between country income and FTR could have been insightful, no detailed analysis could be performed as current cohort only included 41 patients from low/middle-income countries. Nonetheless, analyses on hospital volume were corrected for country income and year of surgery, bias due to temporal and geographic variation was minimized. Third, previous studies have suggested that micro-level factors such as teamwork, and leadership are associated with FTR [
      • Ghaferi A.A.
      • Dimick J.B.
      Importance of teamwork, communication and culture on failure-to-rescue in the elderly.
      ,
      • Johnston M.J.
      • Arora S.
      • King D.
      • Bouras G.
      • Almoudaris A.M.
      • Davis R.
      • et al.
      A systematic review to identify the factors that affect failure to rescue and escalation of care in surgery.
      ]. In addition, organizational factors may also affect FTR and high-volume centers have been found to use perioperative protocols more often and have a higher availability of specialized on-call teams [
      Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative
      International variation in surgical practices in units performing oesophagectomy for oesophageal cancer: a unit survey from the oesophago-gastric anastomosis audit (OGAA).
      ]. The impact of micro-level and organizational factors on FTR could not be assessed as these data were not available from the current study. Future research may evaluate the impact of organizational and micro-level factors on outcomes of care.
      In conclusion, substantial differences were found in the FTR rates related to hospital volume in patients with AL after esophagectomy. Lower FTR rate in high-volume centers compared with low-volume centers was explained by lower leak severity, lower secondary ICU readmission rate and higher availability of therapeutic modalities. Future studies should identify effective strategies to reduce leak severity and prevent secondary ICU readmission in order to improve outcomes of patients with AL after esophagectomy globally.

      Funding

      The TENTACLE – Esophagus study received funding from Medtronic company. The study was performed independently, and Medtronic had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit to manuscript.

      Ethical approval

      TENTACLE – Esophagus was approved by the institutional review board of Radboud university medical center (reference number 2018–4585).

      CRediT authorship contribution statement

      Sander Ubels: Funding acquisition, Formal analysis, Data curation, Writing – original draft, or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Statistical analysis: Administrative, technical or material support. Eric Matthée: Funding acquisition, Formal analysis, Data curation, Writing – original draft, Acquisition, analysis or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Administrative, technical or material support. Moniek Verstegen: Funding acquisition, Formal analysis, Data curation, Writing – original draft, Acquisition, analysis or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Concept and design: Obtained funding. Bastiaan Klarenbeek: Funding acquisition, Formal analysis, Writing – original draft, Conceptualization, and design: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Statistical analysis: Obtained funding, Supervision. Stefan Bouwense: Funding acquisition, Conceptualization, and design: Critical revision of the manuscript for important intellectual content: Obtained funding. Mark I. van Berge Henegouwen: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Freek Daams: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Jan Willem T. Dekker: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content. Marc J. van Det: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Stijn van Esser: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content. Ewen A. Griffiths: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Jan Willem Haveman: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Grard Nieuwenhuijzen: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Peter D. Siersema: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content, Conceptualization, and design. Bas Wijnhoven: Funding acquisition, Formal analysis, Data curation, Acquisition, analysis or interpretation of data: Critical revision of the manuscript for important intellectual content: Obtained funding, Conceptualization, and design. Gerjon Hannink: Funding acquisition, Formal analysis, Data curation, Writing – original draft, Acquisition, analysis or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Statistical analysis: Administrative, technical or material support, Supervision, Conceptualization, and design. Frans van Workum: Funding acquisition, Formal analysis, Data curation, Writing – original draft, Acquisition, analysis or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Statistical analysis: Obtained funding: Administrative, technical or material support, Supervision, Conceptualization, and design. Camiel Rosman: Funding acquisition, Formal analysis, Data curation, Writing – original draft, Acquisition, analysis or interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: Statistical analysis: Obtained funding, Supervision, Conceptualization, and design.

      Declaration of competing interest

      All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare funding by Medtronic for the submitted work. PS reports grants from The Enose Company, grants and other from Motus GI, grants from Pentax, grants from Micro-Tech, other from Boston Scientific outside the submitted work; BK reports grants from Medtronic, grants from ZonMw, outside the submitted work; MIvBH reports other from Mylan, other from Alesi Surgical, other from Johnson and Johnson, other from BBraun, other from Medtronic, grants from Olympus, grants from Stryker, outside the submitted work; all fees unrelated to submitted work, paid to institution.

      Acknowledgments

      We thank all people involved in the TENTACLE – Esophagus study for their contribution to this large international study.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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