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Robotic Esophagectomy Compared With Open Esophagectomy Reduces Sarcopenia within the First Postoperative Year: A Propensity Score-Matched Analysis

  • Felix Merboth
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Heiner Nebelung
    Affiliations
    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Institute and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Natalie Wotschel
    Affiliations
    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Institute and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Hendrik Liebscher
    Affiliations
    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Institute and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Franziska Eckert
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Janusz von Renesse
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Jasmin Hasanovic
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Thilo Welsch
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Current Address: Department of General, Visceral, and Thoracic Surgery, St. Elisabethen-Klinikum Ravensburg, Academic Teaching Hospital of the University of Ulm, Ulm, Germany
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  • Johannes Fritzmann
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Daniel E. Stange
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Verena Plodeck
    Affiliations
    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Institute and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Ralf-Thorsten Hoffmann
    Affiliations
    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

    Institute and Polyclinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Marius Distler
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Jürgen Weitz
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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  • Johanna Kirchberg
    Correspondence
    Corresponding author Address for correspondence: Johanna Kirchberg, MD, Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technical University Dresden Fetscherstraße 74, 01307 Dresden, Germany.
    Affiliations
    Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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Published:November 04, 2022DOI:https://doi.org/10.1016/j.jtho.2022.10.018

      Abstract

      Introduction

      Sarcopenia is a known risk factor for adverse outcomes after esophageal cancer (EC) surgery. Robot-assisted minimally invasive esophagectomy (RAMIE) offers numerous advantages, including reduced morbidity and mortality. However, no evidence exists to date comparing the development of sarcopenia after RAMIE and open esophagectomy (OE). The objective was to evaluate whether the development of sarcopenia within the first postoperative year after esophagectomy is associated with the surgical approach: RAMIE versus OE.

      Methods

      A total of 168 patients with EC were analyzed who either underwent total robotic or fully open Ivor Lewis esophagectomy in a propensity score-matched analysis. Sarcopenia was assessed using the skeletal muscle index (cm2/m2) and psoas muscle thickness per height (mm/m) on axial computed tomography scans during the first postoperative year; in total 540 computed tomography scans were evaluated.

      Results

      After 1-to-1 propensity score matching for confounders, 67 patients were allocated to RAMIE and OE groups, respectively. Skeletal muscle index in the OE group was significantly lower compared with the RAMIE group at the third (43.2 ± 7.6 cm2/m2 versus 49.1 ± 6.9 cm2/m2, p = 0.001), sixth (42.7 ± 7.8 cm2/m2 versus 51.5 ± 8.2 cm2/m2, p < 0.001) and ninth (43.0 ± 7.0 cm2/m2 versus 49.9 ± 6.6 cm2/m2, p = 0.015) postoperative month. Similar results were recorded for psoas muscle thickness per height.

      Conclusions

      To our knowledge, this study is the first to suggest a substantial benefit of RAMIE compared with open esophagectomy in terms of postoperative sarcopenia. These results add further evidence to support the implementation of the robotic approach in multimodal therapy of EC.

      Keywords

      Introduction

      Esophageal cancer (EC) is the sixth most common cause of cancer-related death worldwide.
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      Most cancers are catabolic diseases that can lead to deep changes in the body composition of lean muscle and adipose tissue owing to cancer-related malnutrition and activation of proinflammatory cytokines.
      • Anandavadivelan P.
      • Lagergren P.
      Cachexia in patients with oesophageal cancer.
      • Prado C.M.
      • Cushen S.J.
      • Orsso C.E.
      • Ryan A.M.
      Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.
      • Ryan A.M.
      • Power D.G.
      • Daly L.
      • Cushen S.J.
      • Ní Bhuachalla Ē
      • Prado C.M.
      Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later.
      This frequently leads to the development of sarcopenia, which has a prevalence of about 40% to 50% in newly diagnosed patients with cancer.
      • Prado C.M.
      • Cushen S.J.
      • Orsso C.E.
      • Ryan A.M.
      Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.
      ,
      • von Haehling S.
      • Morley J.E.
      • Anker S.D.
      An overview of sarcopenia: facts and numbers on prevalence and clinical impact.
      Especially in EC, changes in skeletal muscle mass are reinforced by the occurrence of dysphagia owing to tumor stenosis, aggravating the negative influence on metabolism.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      Sarcopenia is defined as low skeletal muscle mass and strength per international working groups such as the Asian Working Group for Sarcopenia or the European Working Group on Sarcopenia in Older People.
      • Chen L.K.
      • Woo J.
      • Assantachai P.
      • et al.
      Consensus update on sarcopenia diagnosis and treatment.
      ,
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Sarcopenia can be assessed and quantified in computed tomography (CT) scans as skeletal muscle index (SMI) (cm2/m2)
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      or as psoas muscle thickness per height (PMTH) (mm/m).
      • Durand F.
      • Buyse S.
      • Francoz C.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      The role of SMI and PMTH in measuring sarcopenia, their reproducibility and predictive potential have been described for many tumor types.
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      • Zhang S.
      • Tan S.
      • Jiang Y.
      • et al.
      Sarcopenia as a predictor of poor surgical and oncologic outcomes after abdominal surgery for digestive tract cancer: a prospective cohort study.
      • Tan B.H.
      • Birdsell L.A.
      • Martin L.
      • Baracos V.E.
      • Fearon K.C.
      Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.
      The cutoff values for sarcopenia measured by SMI
      • Chen L.K.
      • Woo J.
      • Assantachai P.
      • et al.
      Consensus update on sarcopenia diagnosis and treatment.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      ,
      • Cruz-Jentoft A.J.
      • Baeyens J.P.
      • Bauer J.M.
      • et al.
      Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People.
      and PMTH
      • Durand F.
      • Buyse S.
      • Francoz C.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      ,
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      have been established and validated but differ considerably among the various working groups.
      Esophagectomy, the accepted standard procedure for curative treatment of EC without distant metastasis,
      • Lordick F.
      • Mariette C.
      • Haustermans K.
      • Obermannová R.
      • Arnold D.
      ESMO Guidelines Committee
      Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      is a technically demanding procedure with a high incidence of perioperative morbidity and mortality.
      • Low D.E.
      • Kuppusamy M.K.
      • Alderson D.
      • et al.
      Benchmarking complications associated with esophagectomy.
      Recently, several studies have investigated the negative impact of cancer-related sarcopenia in EC on short-term
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Wang P.Y.
      • Xu L.D.
      • Chen X.K.
      • et al.
      Sarcopenia and short-term outcomes after esophagectomy: a meta-analysis.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      and long-term oncologic outcomes.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      ,
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      The influence of treatment (neoadjuvant chemotherapy or radiochemotherapy and surgery) on sarcopenia in patients with EC is well documented in most studies.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      ,
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      In particular, open esophagectomy (OE) can cause profound surgical trauma owing to the two-cavity procedure involving a transabdominal and transthoracic approach; it is well documented that open surgery leads to profound and long-standing postoperative sarcopenia. Numerous high-quality studies have revealed the superiority of minimally invasive and robotic esophagectomy over OE in reducing pulmonary complications with at least equivalent oncological radicality.
      • Mariette C.
      • Markar S.R.
      • Dabakuyo-Yonli T.S.
      • et al.
      Hybrid minimally invasive esophagectomy for esophageal cancer.
      ,
      • van der Sluis P.C.
      • van der Horst S.
      • May A.M.
      • et al.
      Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: a randomized controlled trial.
      The impact of total robotic approach for the postoperative development of sarcopenia as compared with OE remains unclear. Most studies have solely investigated sarcopenia in OE or a minimally invasive subgroup, without comparing approaches.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      ,
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      Further insights into sarcopenic changes dependent on the surgical approach to esophagectomy might help to identify patients at risk and might have the potential to improve short-term and oncological long-term outcomes in patients with EC by targeted interventions against sarcopenia and by choosing the surgical approach being the least associated with the development of postoperative sarcopenia.
      • Prado C.M.
      • Cushen S.J.
      • Orsso C.E.
      • Ryan A.M.
      Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.
      This study compared postoperative changes in skeletal muscle mass (SMI and PMTH) within the first 12 months after Ivor Lewis esophagectomy with gastric conduit reconstruction on the basis of an open or robotic surgical technique. In addition, univariate and multivariate analyses evaluated the potential factors influencing skeletal muscle loss within the first postoperative year.
      The basic hypothesis of this study is that, owing to less surgical trauma, the robot-assisted minimally invasive esophagectomy (RAMIE) will result in less sarcopenia in the first postoperative year compared with OE.

      Materials and Methods

      All patients who underwent fully open or fully robot-assisted esophagectomy at the Department for Visceral, Thoracic, and Vascular Surgery at the University Hospital Dresden between 2013 and 2020 were included in this retrospective analysis.
      Inclusion criteria were (1) biopsy-confirmed malignant esophageal or esophagogastric junction tumor (adenocarcinoma [AC], squamous cell carcinoma [SCC], other malignant tumors), (2) elective esophagectomy by means of an abdominothoracic approach (Ivor Lewis), (3) reconstruction with gastric conduit pull-up, (4) intrathoracic anastomosis using a circular stapler, and (5) availability of at least one pre- and postoperative CT scan within 12 months postoperatively. Exclusion criteria were benign histopathology, emergency operations, cervical anastomosis, colon conduit, intrathoracic anastomosis using a linear stapler, lack or insufficient quality of preoperative or postoperative CT scans, and patients’ death in-hospital or within the first 30 days postoperatively.
      The study protocol was reviewed by a local ethics committee (EK-109032022) and was performed in accordance with the Declaration of Helsinki and its later amendments. Some of the analyzed patient collectives have already been published regarding other end points.
      • Merboth F.
      • Hasanovic J.
      • Stange D.
      • et al.
      [Change of strategy to minimally invasive esophagectomy-Results at a certified center].

      Oncological Staging and Treatment Algorithms

      According to the guidelines of the local Comprehensive Cancer Center (National Center for Tumor Diseases), staging workup for all patients with histologically proven EC or esophageal junction cancer included esophagogastroduodenoscopy if possible with endosonography, CT scan of thorax, abdomen, and pelvis and in addition positron emission tomography–CT scan in SCC. After completion of staging evaluations, all patients were evaluated in the multidisciplinary tumor board (MTB).
      Neoadjuvant treatment was indicated when clinical staging revealed greater than or equal to cT3 or greater than or equal to cN1 disease. In AC or esophagogastric junction tumors, the standard chemotherapy regimen consisted of four cycles of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) preoperatively and postoperatively according to the FLOT4 protocol since 2017.
      • Al-Batran S.E.
      • Homann N.
      • Pauligk C.
      • et al.
      Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
      Before 2017, three cycles of ECF (Epirubicin, cisplatin, fluorouracil [Capecitabine]) preoperatively and postoperatively were standard regimen.
      In SCC, the standard radiochemotherapy regimen consisted of five cycles of carboplatin plus paclitaxel and concurrent radiation of 41.4 Gy given in 23 fractions of 1.8 Gy on 5 days per week according to CROSS-protocol.
      • Shapiro J.
      • van Lanschot JJB
      • Hulshof M.
      • et al.
      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
      Standard restaging CT scan was performed after completion of neoadjuvant therapy.
      Subsequently, surgery was recommended by the MTB when restaging CT scan did not reveal distant metastases or other contraindications were present. After surgery, the final histology was again discussed by the MTB. Adjuvant chemotherapy was regularly recommended in cases that had received preoperative chemotherapy. In the case of resection without neoadjuvant therapy, adjuvant treatment was discussed individually in the case of extended disease.
      Since 2021, adjuvant immunotherapy with nivolumab was administered in stage II/III EC and esophageal junction cancer with R0-resection after previous radiochemotherapy.
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      All patients underwent routine follow-up examinations after the completion of therapy.

      Surgical Technique

      In 2018, on the basis of documented evidence for reducing morbidity, our institute’s standard approach for esophagectomy was changed to a full RAMIE using Ivor Lewis esophagectomy with gastric conduit pull-up and intrathoracic circular stapler anastomosis.
      • Merboth F.
      • Hasanovic J.
      • Stange D.
      • et al.
      [Change of strategy to minimally invasive esophagectomy-Results at a certified center].
      • Grimminger P.P.
      • Hadzijusufovic E.
      • Ruurda J.P.
      • Lang H.
      • van Hillegersberg R.
      The da VINCI Xi robotic four-arm approach for robotic-assisted minimally invasive esophagectomy.
      Since 2018, only patients with locally advanced tumors (≥T4a) or previous extensive laparotomy/thoracotomy received hybrid RAMIE or OE.
      Before 2018, open Ivor Lewis esophagectomy was the standard approach at our institution, except for selected cases in which a minimally invasive procedure seemed feasible. Full or hybrid minimally invasive esophagectomies before 2018 were performed in the context of learning new surgical procedures and were not evaluated in the present study to avoid bias as the surgical learning curve was not yet completely overcome.

      Algorithm for Feeding Tube Implantation and Enteral Nutrition

      In the study cohort, preoperative enteral feeding by means of feeding tubes was not routinely administered, as preoperative tube feeding is not routine in our department. In selected cases with the inability to maintain adequate caloric intake solely through oral nutrition, a feeding tube was implanted before neoadjuvant therapy.
      According to the institutes` standard, a feeding tube was also not routinely implanted intraoperatively neither at RAMIE nor at OE. Only highly selected cases with a presumed high risk of anastomotic leakage received an enteral feeding tube during esophagectomy. Otherwise, oral intake was advanced postoperatively as tolerated by the patient under regular radiographic control of the gastric tube to exclude delayed gastric conduit emptying.

      Assessment of Skeletal Muscle Mass

      Skeletal muscle mass assessment was performed by three independent, experienced radiologists who were blinded to the time point of the CT scan and surgical approach. CT scans were routinely performed according to the guidelines of the local Comprehensive Cancer Center (National Center for Tumor Diseases). Standard time points for performing a staging CT scan were as follows: before initiation of any therapy (in case neoadjuvant therapy was recommended), preoperatively, and 3, 6, 9, and 12 months postoperatively. If there were no CT scans available at the exact time point, the CT scan closest to the defined time point was chosen for analysis.
      Measurement of skeletal muscle area (SMA; cm2) was performed on an axial CT scan at the level of the L3 vertebral body using the IMPAX tool (IMPAX EE R20, Agfa HealthCare, Mortsel, Belgium) to draw a contour with automatically supported edge detection (Fig. 1A). The SMA was normalized to the square of the patient’s height (m2) to calculate the SMI (cm2/m2).
      Figure thumbnail gr1
      Figure 1Determination of skeletal muscle mass. (A) Measurement of skeletal muscle area on an axial CT scan at the level of the L3 vertebral body. (B) Evaluation of transversal psoas muscle thickness on an axial CT scan at the level of the umbilicus. avg, average; CT, computed tomography; HU, Hounsfield unit; max, maximum; min, minimum.
      On an axial CT scan at the level of the umbilicus, the transverse psoas muscle thickness (mm) was evaluated. It was defined as the transverse diameter of the psoas muscle perpendicular to the largest diameter of the muscle on an axial view (Fig. 1B). Transversal psoas muscle thickness was normalized to the patient’s height (m) to calculate PMTH (mm/m).
      • Durand F.
      • Buyse S.
      • Francoz C.
      • et al.
      Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
      ,
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      Sarcopenia was defined according to Prado et al.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      as SMI less than 38.5 cm2/m2 for women and SMI less than 52.4/cm2/m2 for men (referred to as sarcopenic SMI) and according to Gu et al.
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      as PMTH less than 10.4 mm/m for women and less than 17.3 mm/m for men (referred to as sarcopenic PMTH).

      Outcome Measures

      The primary outcome was the longitudinal early postoperative changes in skeletal muscle mass (SMI and PMTH) within the first 12 months postoperatively comparing the open with the robotic surgical technique.

      Statistical Analysis

      Statistical analyses were performed using the Statistical Package for the Social Sciences software (SPSS, version 28.0, IBM Corp., Armonk, NY). Continuous variables were presented as mean (± SD) or median with an interquartile range (IQR). Continuous data were compared using Student’s t test when the variables were normally distributed. The Mann-Whitney U test was used to compare continuous nonparametric variables. One-way analysis of variance was used to compare longitudinal variation in continuous variables. Categorical variables were compared using chi-square or Fisher’s exact tests. The significance level was set at a p value equal to 0.05. Univariate and multivariate analyses for the development of sarcopenia according to Prado et al.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      or Gu et al.
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      were performed using binary logistic regression. Variables with p value less than 0.1 in univariate analysis were included in the multivariate analysis.
      To ensure better comparability between OE and RAMIE, a 1-to-1 propensity score matching was performed. The following variables were used to calculate the propensity score using the following regression models: sarcopenic SMI preoperatively as defined by Prado et al.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      , sarcopenic PMTH preoperatively as defined by Gu et al.,
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      sex, age, body mass index (BMI), American Society of Anaesthesiologists Classification (ASA), postoperative severity of complications using the comprehensive complication index (CCI), neoadjuvant treatment, adjuvant treatment, histology, and pathologic Union internationale contre le cancer (UICC) stage. Subsequently, the nearest neighbor method with a caliber width of 0.1 was used to find matching pairs.

      Results

      Patient Characteristics

      Between 2013 and 2020, a total of 303 patients underwent Ivor Lewis esophagectomy for the malignant disease at our center. A total of 168 patients met the inclusion criteria and were included in the study. A total of 90 (53.6%) underwent OE and 78 (46.4%) underwent robotic-assisted esophagectomy. Patient characteristics are presented in Supplementary Table 1.
      Patient baseline characteristics including age, BMI, CCI, ASA classification, comorbidities, histology, neoadjuvant therapy, and UICC clinical stage were comparable within the open and RAMIE groups.
      Patients were predominantly men (89.3%), 62.7 (±8.7) years old, and most had AC (62.5%). Most patients underwent neoadjuvant therapy (81.0%), 35.1% received chemotherapy, and 45.8% received chemoradiation with a mean radiation dose of 40.13 Gy.
      The most often used chemotherapy regimens were carboplatin and paclitaxel in 32.4% (44 of 136), usually in combination with radiation, FLOT regimen in 27.2% (37 of 136), and 5-fluorouracil with cisplatin in 26.5% (36 of 136). Adjuvant therapy was administered to 21.1% of the patients in the open group and 26.9% in the RAMIE group (p = 0.468). Overall, the FLOT regimen was most frequently used (35.0%, 14 of 40), followed by folinic acid, fluorouracil, and oxaliplatin regimen in 17.5% (7 of 40) and 5-fluorouracil with cisplatin in 15.0% (6 of 40). In clinical trials, in addition to adjuvant chemotherapy, pembrolizumab was administered to five patients, and trastuzumab and nivolumab/ipilimumab to one patient each.
      A sarcopenic SMI was present preoperatively in 52.3% of the patients in the open group and 46.8% in the robotic group (p = 0.532). A sarcopenic PMTH was present preoperatively in 25.6% of the patients in the open group and 15.6% in the robotic group (p = 0.084). The interval from the time of diagnosis to the start of therapy (neoadjuvant therapy or primary surgery) did not differ between patients with preoperatively sarcopenic SMI (44 d, IQR: 32–58 d) or PMTH (46 d, IQR: 35–59 d) compared with patients with preoperatively normal SMI (47 d, IQR: 35–57 d, p = 0.356) or PMTH (45 d, IQR: 32–59 d, p = 0.925). In contrast, the time from diagnosis to preoperative CT was longer in patients with sarcopenic SMI (83 d, IQR: 64–106 d versus 74 d, IQR: 50–99 d, p = 0.084), although not significantly. The same was also seen for PMTH (85 d, IQR: 70–104 d versus 76 d, IQR: 58–103 d, p = 0.153). However, a regression analysis revealed a 6% higher risk of obtaining a sarcopenic SMI value (OR = 1.060, 95% confidence interval [CI]: 1.005–1.118, p = 0.032) or PMTH value (OR = 1.059, 95% CI: 1.002–1.119, p = 0.043) per week delay from diagnosis to preoperative CT. A total of 96.3% of patients (77 of 80) with an interval of up to 3 months between diagnosis and preoperative CT received neoadjuvant therapy. Neoadjuvant treatment also proved to be a significant risk factor for preoperative sarcopenic SMI (OR = 2.933, 95% CI: 1.256–6.848, p = 0.013) or PMTH (OR = 4.460, 95% CI: 1.049–20.530, p = 0.043).
      After propensity score matching for sarcopenic SMI, sarcopenic PMTH, sex, age, BMI, ASA, CCI, neoadjuvant treatment, adjuvant treatment, histology, and pathologic UICC stage, 67 patients were allocated to the open and RAMIE groups, respectively. Patient characteristics and surgical and histopathologic findings of these patients are found in Table 1. Even after matching, patients who underwent OE had significantly higher blood loss with a median of 500 ml (IQR: 350–800 ml) than with a median of 300 ml (IQR: 100–400 ml, p < 0.001) in the RAMIE group. In addition, the median hospital stay after OE was 20 days (IQR: 15–35 d), compared with only 14 days (IQR: 12–21 d, p < 0.001) after RAMIE. None of the other parameters was significantly different (Table 1).
      Table 1Patient Characteristics, Histopathologic, and Surgical Findings
      Patient Characteristics, Histopathologic, and Surgical FindingsOpenRAMIEp Value
      n = 67n = 67
      Age [years]63.6 (±9.0)62.7 (±7.5)0.528
      t test.
      Sex1.000
       female5 (7.5)5 (7.5)
       male62 (92.5)62 (92.5)
      BMI [kg/m2]26.6 (±4.7)27.4 (±4.8)0.303
      t test.
      Smoking25 (37.3)30 (44.8)0.483
      Alcohol18 (26.9)16 (23.9)0.843
      Diabetes mellitus20 (29.9)14 (20.9)0.321
      CAD9 (13.4)9 (13.4)1.000
      Respiratory diseases12 (17.8)8 (11.9)0.468
      Neurologic disorders10 (14.9)8 (11.9)0.801
      Cardiac arrhythmias6 (9.0)11 (16.4)0.299
      Metabolic diseases24 (35.8)25 (37.3)1.000
      Arterial hypertension38 (56.7)45 (67.2)0.286
      Vascular diseases13 (19.4)11 (16.4)0.822
      Chronic liver diseases5 (7.5)11 (16.4)0.182
      Chronic renal insufficiency6 (9.0)8 (11.9)0.779
      ASA0.927
       10 (0.0)0 (0.0)
       224 (35.8)22 (32.8)
       342 (62.7)44 (65.7)
       41 (1.5)1 (1.5)
      Preoperative use of feeding tube3 (4.5)0 (0.0)0.244
      Histology0.784
       Adenocarcinoma42 (67.7)44 (65.7)
       Squamous cell carcinoma24 (35.8)21 (31.3)
       Others1 (1.5)2 (3.0)
      Neoadjuvant treatment0.494
       None16 (23.9)12 (17.9)
       Chemotherapy20 (29.9)26 (38.8)
       Chemoradiotherapy31 (46.3)29 (43.3)
      Adjuvant treatment0.689
       None52 (77.6)49 (73.1)
       Chemotherapy15 (22.4)18 (26.9)
      pT stage0.790
       011 (16.4)10 (14.9)
       117 (25.4)21 (31.3)
       214 (20.9)15 (22.4)
       325 (37.3)20 (29.9)
       40 (0.0)1 (1.5)
      pN stage0.085
       041 (61.2)39 (58.2)
       110 (14.9)19 (28.4)
       210 (14.9)8 (11.9)
       36 (9.0)1 (1.5)
      pM stage0.744
       061 (91.0)63 (94.0)
       16 (9.0)4 (6.0)
      R-status1.000
       065 (97.0)66 (98.5)
       12 (3.0)1 (1.5)
      UICC stage0.578
       128 (41.8)29 (43.3)
       211 (16.4)11 (16.4)
       318 (26.9)22 (32.8)
       410 (14.9)5 (7.5)
      Lymph nodes harvested20 (15-24)22 (17-26)0.115
      Mann-Whitney U test.
      Blood loss [ml]500 (350-800)300 (100-400)<0.001
      Mann-Whitney U test.
      CCI25.1 (±23.2)22.5 (±19.7)0.591
      Mann-Whitney U test.
      CDC ≥3a29 (43.3)29 (43.3)1.000
      Length of hospital stay [d]20 (15-35)14 (12-21)<0.001
      Mann-Whitney U test.
      Note: n (%), mean (± SD) or median (IQR), Fisher’s exact test.
      ASA, American Society of Anesthesiologists Classification; BMI, body mass index; CAD, coronary artery disease; CCI, Comprehensive Complication Index; CDC, Clavien-Dindo-Classification; IQR, interquartile range; UICC, Union internationale contre le cancer.
      a t test.
      b Mann-Whitney U test.
      In the open group, anastomotic leakage (26.9% versus 9.0%, p = 0.012) and wound infections (17.9% versus 3.0%, p = 0.009) occurred more frequently. The incidence of other typical complications such as pneumonia (16.4% versus 9.0%, p = 0.299), chyle leak (1.5% versus 6.0%, p = 0.365), or anastomotic strictures (4.5% versus 0.0%, p = 0.244) was not different in the two groups.
      In binary logistic regression, preoperative sarcopenia did not prove to be a risk factor for the postoperative occurrence of anastomotic leakage or pneumonia. In addition, the overall severity of complications measured by CCI was independent of the presence of preoperative sarcopenia (data not shown).

      Longitudinal Evaluation of Sarcopenia Within the First Postoperative Year Depending on Surgical Technique

      In total, 540 CT scans were evaluated, with a mean of 3.2 CT scans per patient. A total of 126 CT scans were assessable before neoadjuvant therapy; 163 preoperatively; and 84, 85, 36, and 46 scans at 3, 6, 9, and 12 months postoperatively.
      In the matched cohort preoperative SMI did not differ significantly between the open and RAMIE group (50.1 ± 9.1 cm2/m2 versus 52.0 ± 8.4 cm2/m2, p = 0.156). SMI in the open group was significantly lower at three (43.2 ± 7.6 cm2/m2 versus 49.1 ± 6.9 cm2/m2, p = 0.001), six (42.7 ± 7.8 cm2/m2 versus 51.5 ± 8.2 cm2/m2, p < 0.001) and nine (43.0 ± 7.2 cm2/m2 versus 49.9 ± 6.6 cm2/m2, p = 0.015) months postoperative. Similar results were recorded for the PMTH: there was no significant difference between both groups preoperative (19.9 ± 4.1 mm/m versus 21.0 ± 4.1 mm/m, p = 0.191) but lower PMTH values in the open group at three (17.3 ± 3.5 mm/m versus 19.6 ± 3.5 mm/m, p = 0.015), six (17.9 ± 3.6 mm/m versus 20.2 ± 4.2 mm/m, p = 0.039) and nine (17.2 ± 4.8 mm/m versus 20.8 ± 3.2 mm/m, p = 0.055) months postoperatively were depicted (Table 2 and Fig. 2A and B).
      Table 2Longitudinal Evaluation of Sarcopenia Within the First Postoperative Year Depending on Surgical Technique
      Parameters of SarcopeniaPreoperative3M postoperative6M postoperative9M postoperative12M postoperative
      OpenRAMIEp ValueOpenRAMIEp ValueOpenRAMIEp ValueOpenRAMIEp ValueOpenRAMIEp Value
      SMI [cm2/m2]50.1 (±9.1)52.0 (±8.4)0.156
      Mann-Whitney U test
      43.2 (±7.6)49.1 (±6.9)0.001
      Mann-Whitney U test
      42.7 (±7.8)51.5 (±8.2)<0.001
      Mann-Whitney U test
      43.0 (±7.2)49.9 (±6.6)0.015
      Mann-Whitney U test
      47.1 (±7.7)49.1 (±8.9)0.443
      Mann-Whitney U test
      Sarcopenic SMI
      Defined by Prado et al.9
      37 (55.2)31 (46.3)0.38826 (78.8)19 (55.9)0.06824 (80.0)17 (47.2)0.0108 (66.7)10 (62.5)1.00011 (61.1)11 (61.1)1.000
      SMI loss [%]------12.54.10.001
      Mann-Whitney U test
      12.91.4<0.001
      Mann-Whitney U test
      5.94.60.568
      Mann-Whitney U test
      8.62.60.152
      Mann-Whitney U test
      PMTH [mm/m]19.9 (±4.1)21.0 (±4.1)0.191
      Mann-Whitney U test
      17.3 (±3.5)19.6 (±3.5)0.015
      Mann-Whitney U test
      17.9 (±3.6)20.2 (±4.2)0.039
      Mann-Whitney U test
      17.2 (±4.8)20.8 (±3.2)0.055
      Mann-Whitney U test
      18.3 (±4.2)20.6 (±3.6)0.116
      Mann-Whitney U test
      Sarcopenic PMTH
      Defined by Gu et al.15
      15 (22.4)12 (17.9)0.66714 (42.4)8 (23.5)0.12313 (44.8)8 (22.2)0.0665 (41.7)2 (12.5)0.1038 (44.4)3 (16.7)0.146
      PMTH loss [%]------11.05.20.078
      Mann-Whitney U test
      10.72.70.006
      Mann-Whitney U test
      6.21.70.828
      Mann-Whitney U test
      9.7−0.10.056
      Mann-Whitney U test
      Note: n (%), mean (± SD); Fisher’s exact test.
      M, months; PMTH, psoas muscle thickness per height; SMI, skeletal muscle index.
      a Mann-Whitney U test
      b Defined by Prado et al.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      c Defined by Gu et al.
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      Figure thumbnail gr2
      Figure 2The course of SMI (A) and PMTH (B) within the first 12 months postoperatively and percent loss of SMI (C) and PMTH (D) compared with baseline values preoperatively for each patient within the first 12 months postoperatively. The black line represents the RAMIE group and the gray line represents the open group. PMTH, psoas muscle thickness per height; RAMIE, robot-assisted minimally invasive esophagectomy; SMI, skeletal muscle index.
      A total of 37 patients (55.2%) in the open group and 31 (46.3%) in the RAMIE group had sarcopenic SMI values preoperatively (p = 0.388). Three (78.8% versus 55.9%, p = 0.068) and six (80.0% versus 47.2%, p = 0.010) months postoperatively, more patients in the open group were considered sarcopenic. If sarcopenia thresholds for PMTH were used, only half of the patients were classified as sarcopenic in both groups. According to PMTH values, there were more patients with sarcopenia in the open group, but the difference did not reach significance at any of the time points (Table 2).
      To determine the patient-specific loss of muscle mass over time, the percentage loss of both SMI and PMTH relative to the preoperative value was determined for each patient. The percentage of SMI loss was significantly greater in the open group at three (12.5% versus 4.1%, p = 0.001) and six (12.9% versus 1.4%, p < 0.001) months postoperatively compared with the RAMIE group. Similar results were also observed for the percentage of PMTH loss at three (11.0% versus 5.2%, p = 0.078) and six (10.7% versus 2.7%, p = 0.006) months postoperatively (Table 2 and Fig. 2C and D).
      Twelve months postoperatively, SMI (47.1 ± 7.7 cm2/m2 versus 49.1 ± 8.9 cm2/m2, p = 0.443) and PMTH (18.3 ± 4.2 mm/m versus 20.6 ± 3.6 mm/m, p = 0.116) values converged in both groups (Table 2).

      Risk Factors for the Development of Sarcopenia Within 6 Months Postoperatively

      Univariate analysis revealed that the male sex (OR = 3.840, 95% CI: 1.213–12.153, p = 0.022) and the preoperative presence of sarcopenia (OR = 8.587, 95% CI: 2.984–24.708, p < 0.001) were associated with the development of sarcopenic SMI within the first 6 months postoperative. In contrast, a higher preoperative BMI (OR = 0.905, 95% CI: 0.829–0.989, p = 0.027) and RAMIE procedure (OR = 0.257, 95% CI: 0.107–0.616, p = 0.002) were found to be potential protective factors. In multivariate analysis, the only independent factor being associated with the development of postoperative sarcopenia was the preoperative presence of sarcopenia (OR = 7.449, 95% CI: 2.254–24.617, p < 0.001), and the only potential protective factor was the RAMIE procedure (OR = 0.222, 95% CI: 0.081–0.611, p = 0.004) (Table 3).
      Table 3Univariate and Multivariate Analysis for Sarcopenic SMI Within 6 Months Postoperative
      Risk Factors for SarcopeniaUnivariateMultivariate
      N = 111OR95% CIp ValueOR95% CIp Value
      Age1.0310.985–1.0800.185
      Sex (f:m)3.8401.21312.1530.0223.6930.908–15.0280.068
      BMI0.9050.8290.9890.0270.9470.847–1.0600.347
      Smoking0.5310.232–1.2170.531
      Alcohol0.5480.216–1.3900.205
      Diabetes mellitus1.6540.658–4.1630.285
      ASA1.2270.500–2.7390.617
      Use of feeding tube2.1920.246–19.5230.482
      Histology (SCC:AC)1.0540.599–1.8570.584
      Neoadjuvant treatment1.3000.774–2.1830.322
      Adjuvant treatment1.1510.450–2.9480.769
      UICC stage1.2140.820–1.7960.333
      CCI1.0070.988–1.0260.491
      CDC >21.4290.629–3.2460.394
      RAMIE0.2570.107–0.6160.0020.2220.081–0.6110.004
      Sarcopenic SMI
      Defined by Prado et al.9
      preoperative
      8.5872.984–24.708<0.0017.4492.254–24.617<0.001
      Note: Binary logistic regression. Parameters that were significant in univariate or mutlivariate analysis were boldfaced.
      95% CI: 95% confidence interval; AC, adenocarcinoma; ASA, American Society of Anesthesiologists; BMI, body mass index; CCI, Comprehensive Complications Index; CDC, Clavien-Dindo-Classification; f, female; m, male; RAMIE, robot-assisted minimally invasive esophagectomy; SCC, squamous cell carcinoma; SMI, skeletal muscle index; UICC, Union internationale contre le cancer.
      a Defined by Prado et al.
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      Univariate and multivariate analyses revealed similar results for sarcopenic PMTH. A higher BMI (OR = 0.887, 95% CI: 0.801–0.982, p = 0.021) was the only protective factor for the development of sarcopenia within the first six months postoperative, whereas the preoperative presence of sarcopenia (OR = 9.474, 95% CI: 2.350–38.193, p = 0.002) was the only risk factor (Table 4).
      Table 4Univariate and Multivariate Analysis for Sarcopenic PMTH Within 6 Months Postoperative
      Risk Factors for SarcopeniaUnivariateMultivariate
      N = 111OR95% CIp ValueOR95% CIp Value
      Age1.0340.990–1.0810.134
      Sex (f:m)0.7530.242–2.3460.624
      BMI0.8710.791–0.9600.0050.8870.801–0.9820.021
      Smoking1.7650.800–3.8920.159
      Alcohol1.4670.593–3.6280.407
      Diabetes mellitus1.0130.442–2.3210.976
      ASA1.8260.832–4.0090.133
      Use of feeding tube1.7630.339–9.1720.500
      Histology (SCC:AC)1.0230.606–1.7250.933
      Neoadjuvant treatment1.3680.817–2.2930.234
      Adjuvant treatment1.2900.542–3.0690.565
      UICC stage1.0350.720–1.4870.853
      CCI1.0030.985–1.0210.761
      CDC >21.1770.544–2.5460.678
      RAMIE0.6040.276–1.3230.208
      Sarcopenic PMTH
      Defined by Gu et al.15
      preoperative
      11.2352.985–42.277<0.0019.4742.350–38.1930.002
      Note: Binary logistic regression. Parameters that were significant in univariate or mutlivariate analysis were boldfaced.
      95% CI: 95% confidence interval; AC, adenocarcinoma; ASA, American Society of Anesthesiologists; BMI, body mass index; CCI, Comprehensive Complications Index; CDC, Clavien-Dindo-Classification; f, female; m, male; PMTH, psoas muscle thickness per height; RAMIE, robot-assisted minimally invasive esophagectomy; SCC, squamous cell carcinoma; UICC, Union internationale contre le cancer.
      a Defined by Gu et al.
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.

      Discussion

      To our knowledge, this study is the first to compare the changes in skeletal muscle mass during the first year after surgery between open and robotic Ivor Lewis esophagectomy in a matched cohort of patients with EC. We reported, for the first time, that RAMIE potentially results in significantly less sarcopenia after surgery than OE. This represents an important additional benefit of RAMIE, aside from its known benefits of reduced perioperative morbidity and mortality.
      • Mariette C.
      • Markar S.R.
      • Dabakuyo-Yonli T.S.
      • et al.
      Hybrid minimally invasive esophagectomy for esophageal cancer.
      ,
      • van der Sluis P.C.
      • van der Horst S.
      • May A.M.
      • et al.
      Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: a randomized controlled trial.
      The principal findings of this study are in detail:
      • 1.
        RAMIE is associated with less postoperative muscle loss compared with OE at three and six months after surgery.
      • 2.
        The surgical approach, not neoadjuvant or adjuvant treatment, is a key driver of sarcopenia within six months postoperatively in EC in univariate and multivariate analyses. Notably, this effect seems to be independent of perioperative complications, as complications were included as a factor in propensity score matching.
      In current literature, to our knowledge, no study group has analyzed changes in skeletal muscle mass depending on the surgical approach yet. Yoshida et al.
      • Yoshida S.
      • Nishigori T.
      • Tsunoda S.
      • et al.
      Chronological changes in skeletal muscle mass two years after minimally invasive esophagectomy: a prospective cohort study.
      described the influence of skeletal muscle mass measured by bioimpedance analysis and SMI on postoperative complications in 71 patients 2 years after minimally invasive esophagectomy exclusively but without any control group. They described an SMI nadir as early as two months after minimally invasive surgery and stabilization between 6 and 24 months postoperatively. In our study, minimal values for SMI and PMTH were observed later than in the cohort of Yoshida et al,
      • Yoshida S.
      • Nishigori T.
      • Tsunoda S.
      • et al.
      Chronological changes in skeletal muscle mass two years after minimally invasive esophagectomy: a prospective cohort study.
      particularly in the open subgroup. The SMI reached its minimum after three months in the robotic group and after six months in the open group. PMTH was also minimized after three months in the robotic group and as late as nine months after surgery in the open group.
      In multivariate analysis, our study established significant evidence that only the surgical approach, and not neoadjuvant or adjuvant treatment, seems to be the key driver of sarcopenia in EC. Even when neoadjuvant therapy seems to have a significant impact on the development of sarcopenia preoperatively, the influence of the chosen surgical approach seems to dominate postoperatively.
      Other groups have found conflicting results regarding the influence of neoadjuvant therapy on sarcopenia; most have revealed adverse effects of neoadjuvant chemo- or radiotherapy, including two meta-analyses.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      ,
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      ,
      • Deng H.Y.
      • Zha P.
      • Peng L.
      • Hou L.
      • Huang K.L.
      • Li X.Y.
      Preoperative sarcopenia is a predictor of poor prognosis of esophageal cancer after esophagectomy: a comprehensive systematic review and meta-analysis.
      In these studies, the proportion of minimally invasive, hybrid, or robotic esophagectomies was limited and ranged between 0% and 40%. Consequently, the influence of minimally invasive or robotic approaches in a multimodal setting compared with an open approach has not been analyzed in any of these studies. Only Grotenhuis et al.
      • Grotenhuis B.A.
      • Shapiro J.
      • van Adrichem S.
      • et al.
      Sarcopenia/muscle mass is not a prognostic factor for short- and long-term outcome after esophagectomy for cancer.
      found no adverse effects after chemoradiation in their collective of 120 patients who underwent open surgery
      • Grotenhuis B.A.
      • Shapiro J.
      • van Adrichem S.
      • et al.
      Sarcopenia/muscle mass is not a prognostic factor for short- and long-term outcome after esophagectomy for cancer.
      treated during the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) 1 and 2.
      • van Meerten E.
      • Muller K.
      • Tilanus H.W.
      • et al.
      Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study.
      ,
      • van Hagen P.
      • Hulshof M.C.
      • van Lanschot J.J.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      The mechanism of reduced skeletal muscle loss in robotic esophagectomy compared with open surgery has not yet been clarified, and this study did not evaluate the possible causes. There are some potential explanations for this finding.
      First, the minimally invasive approach in robotic esophagectomy is associated with reduced surgical trauma compared with surgical trauma caused by laparotomy and thoracotomy in OE. This fact is reflected by reduced C-reactive protein levels postoperatively in robotic esophagectomy compared with OE.
      • Babic B.
      • Tagkalos E.
      • Gockel I.
      • et al.
      C-reactive protein levels after esophagectomy are associated with increased surgical trauma and complications.
      ,
      • Scarpa M.
      • Cavallin F.
      • Saadeh L.M.
      • et al.
      Hybrid minimally invasive esophagectomy for cancer: impact on postoperative inflammatory and nutritional status.
      In addition, some authors have reported less activation of immune and inflammatory responses in minimally invasive esophagectomy.
      • Scheepers J.J.
      • Sietses C.
      • Bos D.G.
      • et al.
      Immunological consequences of laparoscopic versus open transhiatal resection for malignancies of the distal esophagus and gastroesophageal junction.
      ,
      • Tan J.T.
      • Zhong J.H.
      • Yang Y.
      • et al.
      Comparison of postoperative immune function in patients with thoracic esophageal cancer after video-assisted thoracoscopic surgery or conventional open esophagectomy.
      The reverse relationship between higher circulating inflammatory markers and lower skeletal muscle strength and muscle mass has been described in a recent meta-analysis by Tuttle et al.
      • Tuttle C.S.L.
      • Thang L.A.N.
      • Maier A.B.
      Markers of inflammation and their association with muscle strength and mass: a systematic review and meta-analysis.
      Second, mobility and physical activity are reduced to a greater extent after open surgery than after minimally invasive surgery.
      • Wolk S.
      • Linke S.
      • Bogner A.
      • et al.
      Use of activity tracking in major visceral surgery-the enhanced perioperative mobilization trial: a randomized controlled trial.
      One primary reason for this might be the reduced postoperative pain after minimally invasive surgery. This was illustrated after robotic esophagectomy compared with OE by van der Sluis et al.
      • van der Sluis P.C.
      • van der Horst S.
      • May A.M.
      • et al.
      Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: a randomized controlled trial.
      in the ROBOT trial. Short-term disuse of skeletal muscle leads to an approximately 0.5% decrease in skeletal muscle mass per day.
      • Dirks M.L.
      • Wall B.T.
      • Snijders T.
      • Ottenbros C.L.
      • Verdijk L.B.
      • van Loon L.J.
      Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans.
      Consequently, early mobilization is a key player in “enhanced recovery after surgery” concepts. In recent decades, enhanced recovery after surgery has exhibited a high potential for optimizing patient outcomes, even in highly complex surgical procedures such as robotic esophagectomy.
      • Chen L.
      • Sun L.
      • Lang Y.
      • et al.
      Fast-track surgery improves postoperative clinical recovery and cellular and humoral immunity after esophagectomy for esophageal cancer.
      ,
      • Triantafyllou T.
      • Olson M.T.
      • Theodorou D.
      • Schizas D.
      • Singhal S.
      Enhanced recovery pathways vs standard care pathways in esophageal cancer surgery: systematic review and meta-analysis.
      Our findings have high clinical relevance. The evaluation of sarcopenia using SMI and PMTH is technically easy without additional radiation exposure, as peritherapeutic CT scans are routinely obtained regularly. We used SMI and PMTH because both can be determined in the same CT scan and there is good evidence for both parameters reflecting total body muscle mass. We relied on previously published cutoff values for both parameters. PMTH classified fewer patients as sarcopenic in our analysis. However, our study did not address whether SMI or PMTH was the most sensitive factor for analyzing postoperative sarcopenia. Further studies are necessary to determine the parameters that are more useful in clinical practice. It would be interesting to evaluate which parameter correlates better with the clinical and paraclinical data. For example, a study by Paternostro et al.
      • Paternostro R.
      • Lampichler K.
      • Bardach C.
      • et al.
      The value of different CT-based methods for diagnosing low muscle mass and predicting mortality in patients with cirrhosis.
      was conducted on patients with liver cirrhosis and evaluated four CT-based methods for diagnosing low muscle mass, including SMI and PMTH. Only PMTH emerged as an independent risk factor for mortality. This is a relevant finding as measuring SMA requires specialized radiologic software and expertise, whereas psoas muscle thickness is very easy to measure. In addition, it is equally important to establish uniform sex- and race-specific cutoff values for both methods to ensure better comparability.
      Consequently, early detection of sarcopenia can be used to respond in a straightforward manner to nutritional interventions, easily preventing or at least reducing skeletal muscle loss.
      • Ryan A.M.
      • Reynolds J.V.
      • Healy L.
      • et al.
      Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.
      ,
      • Baldwin C.
      • Spiro A.
      • Ahern R.
      • Emery P.W.
      Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis.
      Numerous studies have linked sarcopenia in patients with cancer, including EC, with dismal oncological outcomes.
      • Boshier P.R.
      • Heneghan R.
      • Markar S.R.
      • Baracos V.E.
      • Low D.E.
      Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
      ,
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • et al.
      Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
      ,
      • Deng H.Y.
      • Zha P.
      • Peng L.
      • Hou L.
      • Huang K.L.
      • Li X.Y.
      Preoperative sarcopenia is a predictor of poor prognosis of esophageal cancer after esophagectomy: a comprehensive systematic review and meta-analysis.
      Although in this study cohort sarcopenia exhibits a trend to normalize after 12 months after esophagectomy as described by other groups, loss of muscle mass within the first months after esophagectomy has been found by several groups to have a significant impact on long-term survival and recurrence rates. Specifically, Boshier et al.
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      revealed that the presence of sarcopenia at the time of EC diagnosis did not affect overall survival, but the development of sarcopenia within the first postoperative year was associated with lower 5-year survival. In addition, multivariate analysis revealed SMI loss within the first postoperative year as a risk factor for worse survival.
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      The negative impact on overall survival of the development of sarcopenia after esophagectomy was confirmed by several groups within 12 months,
      • Park S.Y.
      • Yoon J.K.
      • Lee S.J.
      • Haam S.
      • Jung J.
      Postoperative change of the psoas muscle area as a predictor of survival in surgically treated esophageal cancer patients.
      6 months,
      • Nakashima Y.
      • Saeki H.
      • Hu Q.
      • et al.
      Skeletal muscle loss after esophagectomy is an independent risk factor for patients with esophageal cancer.
      4 months,
      • Mayanagi S.
      • Tsubosa Y.
      • Omae K.
      • et al.
      Negative impact of skeletal muscle wasting after neoadjuvant chemotherapy followed by surgery on survival for patients with thoracic esophageal cancer.
      ,
      • Takahashi K.
      • Watanabe M.
      • Kozuki R.
      • et al.
      Prognostic significance of skeletal muscle loss during early postoperative period in elderly patients with esophageal cancer.
      and 3 months
      • Kawakita Y.
      • Motoyama S.
      • Sato Y.
      • et al.
      Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
      postoperatively. There is even evidence that loss of muscle mass within the first 7 days after esophagectomy negatively affects long-term prognosis.
      • Matsui K.
      • Kawakubo H.
      • Hirata Y.
      • et al.
      Relationship between early postoperative change in total psoas muscle area and long-term prognosis in esophagectomy for patients with esophageal cancer.
      The percentage loss of muscle mass compared with preoperative values seems to play a decisive role. It was described that an SMI loss of more than 9% to 10% leads to a worse overall and relapse-free survival.
      • Boshier P.R.
      • Klevebro F.
      • Jenq W.
      • et al.
      Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
      ,
      • Takahashi K.
      • Watanabe M.
      • Kozuki R.
      • et al.
      Prognostic significance of skeletal muscle loss during early postoperative period in elderly patients with esophageal cancer.
      In our open surgery group, we saw an SMI loss of 12.5% and 12.9% at 3 and 6 months, respectively. In the RAMIE group, SMI loss was only 4.1% and 1.4% (p = 0.001).
      Hence, robotic esophagectomy in combination with early nutritional or hormonal interventions in patients with sarcopenia might have the potential to reduce surgery-related sarcopenia and possibly further optimize patient survival in the future. As a recent example of hormonal intervention, Nose et al.
      • Nose Y.
      • Yamashita K.
      • Takeoka T.
      • et al.
      Perioperative ghrelin administration attenuates postoperative skeletal muscle loss in patients undergoing esophagectomy for esophageal cancer: secondary analysis of a randomized controlled trial.
      reported that continuous administration of ghrelin attenuates skeletal muscle loss in patients with EC during postoperative starvation.
      The limitations of this study are its retrospective nature and lack of oncologic long-term outcome data. Sarcopenia was identified by SMI and PMTH, and technical and clinical aspects such as bioimpedance analysis, muscle strength, and physical function should be considered in further studies. Furthermore, the study was performed in a single institution with a white patient cohort. Thus, our findings may not apply to other countries and ethnic groups. These data should be validated in a prospective multicentric setting.
      Nevertheless, our data for the first time, suggest very strongly that RAMIE offers important benefits over OE in terms of reduced postoperative sarcopenia. These results strongly support the implementation of the robotic approach in multimodal therapy of EC.

      CRediT Authorship Contribution Statement

      Felix Merboth: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing - original draft, Visualization, Project administration.
      Heiner Nebelung: Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - original draft.
      Natalie Wotschel: Software, Validation, Formal analysis, Investigation, Writing - original draft.
      Hendrik Liebscher: Software, Validation, Formal analysis, Investigation, Writing - review & editing.
      Franziska Eckert, Janusz von Renesse, Jasmin Hasanovic: Investigation, Data curation, Writing - original draft.
      Thilo Welsch, Johannes Fritzmann: Conceptualization, Resources, Writing - review & editing.
      Daniel E. Stange, Verena Plodeck, Ralf-Thorsten Hoffmann: Conceptualization, Methodology, Resources, Writing - review & editing.
      Marius Distler: Conceptualization, Resources, Writing - review & editing.
      Jürgen Weitz: Conceptualization, Writing - review & editing, Supervision, Project administration.
      Johanna Kirchberg: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing - original draft, Supervision, Project administration.

      Acknowledgments

      The authors thank all patients and study nurses who were involved in the present study.

      Supplementary Data

      References

        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Anandavadivelan P.
        • Lagergren P.
        Cachexia in patients with oesophageal cancer.
        Nat Rev Clin Oncol. 2016; 13: 185-198
        • Prado C.M.
        • Cushen S.J.
        • Orsso C.E.
        • Ryan A.M.
        Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact.
        Proc Nutr Soc. 2016; 75: 188-198
        • Ryan A.M.
        • Power D.G.
        • Daly L.
        • Cushen S.J.
        • Ní Bhuachalla Ē
        • Prado C.M.
        Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later.
        Proc Nutr Soc. 2016; 75: 199-211
        • von Haehling S.
        • Morley J.E.
        • Anker S.D.
        An overview of sarcopenia: facts and numbers on prevalence and clinical impact.
        J Cachexia Sarcopenia Muscle. 2010; 1: 129-133
        • Boshier P.R.
        • Heneghan R.
        • Markar S.R.
        • Baracos V.E.
        • Low D.E.
        Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.
        Dis Esophagus. 2018; 31 (10.1093/dote/doy047)
        doi:10.1093/dote/doy047
        • Chen L.K.
        • Woo J.
        • Assantachai P.
        • et al.
        Consensus update on sarcopenia diagnosis and treatment.
        J Am Med Dir Assoc. 2019; 21: 300-307.e302
        • Cruz-Jentoft A.J.
        • Bahat G.
        • Bauer J.
        • et al.
        Sarcopenia: revised European consensus on definition and diagnosis.
        Age Ageing. 2019; 48: 16-31
        • Prado C.M.
        • Lieffers J.R.
        • McCargar L.J.
        • et al.
        Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
        Lancet Oncol. 2008; 9: 629-635
        • Durand F.
        • Buyse S.
        • Francoz C.
        • et al.
        Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.
        J Hepatol. 2014; 60: 1151-1157
        • Kawakita Y.
        • Motoyama S.
        • Sato Y.
        • et al.
        Decreases in the psoas muscle index correlate more strongly with survival than other prognostic markers in esophageal cancer after neoadjuvant chemoradiotherapy plus esophagectomy.
        World J Surg. 2020; 44: 1559-1568
        • Zhang S.
        • Tan S.
        • Jiang Y.
        • et al.
        Sarcopenia as a predictor of poor surgical and oncologic outcomes after abdominal surgery for digestive tract cancer: a prospective cohort study.
        Clin Nutr. 2019; 38: 2881-2888
        • Tan B.H.
        • Birdsell L.A.
        • Martin L.
        • Baracos V.E.
        • Fearon K.C.
        Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.
        Clin Cancer Res. 2009; 15: 6973-6979
        • Cruz-Jentoft A.J.
        • Baeyens J.P.
        • Bauer J.M.
        • et al.
        Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People.
        Age Ageing. 2010; 39: 412-423
        • Gu D.H.
        • Kim M.Y.
        • Seo Y.S.
        • et al.
        Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
        Clin Mol Hepatol. 2018; 24: 319-330
        • Lordick F.
        • Mariette C.
        • Haustermans K.
        • Obermannová R.
        • Arnold D.
        • ESMO Guidelines Committee
        Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27: v50-v57
        • Low D.E.
        • Kuppusamy M.K.
        • Alderson D.
        • et al.
        Benchmarking complications associated with esophagectomy.
        Ann Surg. 2019; 269: 291-298
        • Wang P.Y.
        • Xu L.D.
        • Chen X.K.
        • et al.
        Sarcopenia and short-term outcomes after esophagectomy: a meta-analysis.
        Ann Surg Oncol. 2020; 27: 3041-3051
        • Elliott J.A.
        • Doyle S.L.
        • Murphy C.F.
        • et al.
        Sarcopenia: prevalence, and impact on operative and oncologic outcomes in the multimodal management of locally advanced esophageal cancer.
        Ann Surg. 2017; 266: 822-830
        • Boshier P.R.
        • Klevebro F.
        • Jenq W.
        • et al.
        Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.
        Dis Esophagus. 2021; 34: doab016
        • Mariette C.
        • Markar S.R.
        • Dabakuyo-Yonli T.S.
        • et al.
        Hybrid minimally invasive esophagectomy for esophageal cancer.
        N Engl J Med. 2019; 380: 152-162
        • van der Sluis P.C.
        • van der Horst S.
        • May A.M.
        • et al.
        Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: a randomized controlled trial.
        Ann Surg. 2019; 269: 621-630
        • Merboth F.
        • Hasanovic J.
        • Stange D.
        • et al.
        [Change of strategy to minimally invasive esophagectomy-Results at a certified center].
        Chirurgie (Heidelb). 2022; 93: 694-701
        • Al-Batran S.E.
        • Homann N.
        • Pauligk C.
        • et al.
        Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
        Lancet. 2019; 393: 1948-1957
        • Shapiro J.
        • van Lanschot JJB
        • Hulshof M.
        • et al.
        Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
        Lancet Oncol. 2015; 16: 1090-1098
        • Kelly R.J.
        • Ajani J.A.
        • Kuzdzal J.
        • et al.
        Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
        N Engl J Med. 2021; 384: 1191-1203
        • Grimminger P.P.
        • Hadzijusufovic E.
        • Ruurda J.P.
        • Lang H.
        • van Hillegersberg R.
        The da VINCI Xi robotic four-arm approach for robotic-assisted minimally invasive esophagectomy.
        Thorac Cardiovasc Surg. 2018; 66: 407-409
        • Yoshida S.
        • Nishigori T.
        • Tsunoda S.
        • et al.
        Chronological changes in skeletal muscle mass two years after minimally invasive esophagectomy: a prospective cohort study.
        Surg Endosc. 2022; 36: 1527-1535
        • Deng H.Y.
        • Zha P.
        • Peng L.
        • Hou L.
        • Huang K.L.
        • Li X.Y.
        Preoperative sarcopenia is a predictor of poor prognosis of esophageal cancer after esophagectomy: a comprehensive systematic review and meta-analysis.
        Dis Esophagus. 2019; 32: doy115
        • Grotenhuis B.A.
        • Shapiro J.
        • van Adrichem S.
        • et al.
        Sarcopenia/muscle mass is not a prognostic factor for short- and long-term outcome after esophagectomy for cancer.
        World J Surg. 2016; 40: 2698-2704
        • van Meerten E.
        • Muller K.
        • Tilanus H.W.
        • et al.
        Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study.
        Br J Cancer. 2006; 94: 1389-1394
        • van Hagen P.
        • Hulshof M.C.
        • van Lanschot J.J.
        • et al.
        Preoperative chemoradiotherapy for esophageal or junctional cancer.
        N Engl J Med. 2012; 366: 2074-2084
        • Babic B.
        • Tagkalos E.
        • Gockel I.
        • et al.
        C-reactive protein levels after esophagectomy are associated with increased surgical trauma and complications.
        Ann Thorac Surg. 2020; 109: 1574-1583
        • Scarpa M.
        • Cavallin F.
        • Saadeh L.M.
        • et al.
        Hybrid minimally invasive esophagectomy for cancer: impact on postoperative inflammatory and nutritional status.
        Dis Esophagus. 2016; 29: 1064-1070
        • Scheepers J.J.
        • Sietses C.
        • Bos D.G.
        • et al.
        Immunological consequences of laparoscopic versus open transhiatal resection for malignancies of the distal esophagus and gastroesophageal junction.
        Dig Surg. 2008; 25: 140-147
        • Tan J.T.
        • Zhong J.H.
        • Yang Y.
        • et al.
        Comparison of postoperative immune function in patients with thoracic esophageal cancer after video-assisted thoracoscopic surgery or conventional open esophagectomy.
        Int J Surg. 2016; 30: 155-160
        • Tuttle C.S.L.
        • Thang L.A.N.
        • Maier A.B.
        Markers of inflammation and their association with muscle strength and mass: a systematic review and meta-analysis.
        Ageing Res Rev. 2020; 64101185
        • Wolk S.
        • Linke S.
        • Bogner A.
        • et al.
        Use of activity tracking in major visceral surgery-the enhanced perioperative mobilization trial: a randomized controlled trial.
        J Gastrointest Surg. 2019; 23: 1218-1226
        • Dirks M.L.
        • Wall B.T.
        • Snijders T.
        • Ottenbros C.L.
        • Verdijk L.B.
        • van Loon L.J.
        Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans.
        Acta Physiol (Oxf). 2014; 210: 628-641
        • Chen L.
        • Sun L.
        • Lang Y.
        • et al.
        Fast-track surgery improves postoperative clinical recovery and cellular and humoral immunity after esophagectomy for esophageal cancer.
        BMC Cancer. 2016; 16: 449
        • Triantafyllou T.
        • Olson M.T.
        • Theodorou D.
        • Schizas D.
        • Singhal S.
        Enhanced recovery pathways vs standard care pathways in esophageal cancer surgery: systematic review and meta-analysis.
        Esophagus. 2020; 17: 100-112
        • Paternostro R.
        • Lampichler K.
        • Bardach C.
        • et al.
        The value of different CT-based methods for diagnosing low muscle mass and predicting mortality in patients with cirrhosis.
        Liver Int. 2019; 39: 2374-2385
        • Ryan A.M.
        • Reynolds J.V.
        • Healy L.
        • et al.
        Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.
        Ann Surg. 2009; 249: 355-363
        • Baldwin C.
        • Spiro A.
        • Ahern R.
        • Emery P.W.
        Oral nutritional interventions in malnourished patients with cancer: a systematic review and meta-analysis.
        J Natl Cancer Inst. 2012; 104: 371-385
        • Park S.Y.
        • Yoon J.K.
        • Lee S.J.
        • Haam S.
        • Jung J.
        Postoperative change of the psoas muscle area as a predictor of survival in surgically treated esophageal cancer patients.
        J Thorac Dis. 2017; 9: 355-361
        • Nakashima Y.
        • Saeki H.
        • Hu Q.
        • et al.
        Skeletal muscle loss after esophagectomy is an independent risk factor for patients with esophageal cancer.
        Ann Surg Oncol. 2020; 27: 492-498
        • Mayanagi S.
        • Tsubosa Y.
        • Omae K.
        • et al.
        Negative impact of skeletal muscle wasting after neoadjuvant chemotherapy followed by surgery on survival for patients with thoracic esophageal cancer.
        Ann Surg Oncol. 2017; 24: 3741-3747
        • Takahashi K.
        • Watanabe M.
        • Kozuki R.
        • et al.
        Prognostic significance of skeletal muscle loss during early postoperative period in elderly patients with esophageal cancer.
        Ann Surg Oncol. 2019; 26: 3727-3735
        • Matsui K.
        • Kawakubo H.
        • Hirata Y.
        • et al.
        Relationship between early postoperative change in total psoas muscle area and long-term prognosis in esophagectomy for patients with esophageal cancer.
        Ann Surg Oncol. 2021; 28: 6378-6387
        • Nose Y.
        • Yamashita K.
        • Takeoka T.
        • et al.
        Perioperative ghrelin administration attenuates postoperative skeletal muscle loss in patients undergoing esophagectomy for esophageal cancer: secondary analysis of a randomized controlled trial.
        Ann Surg Oncol. 2022; 29: 3604-3612