The impact of Nutrition and Gastrointestinal Symptoms on Health-related Quality of Life in Survivorship after Oesophageal Cancer Surgery

Open AccessPublished:November 25, 2021DOI:https://doi.org/10.1016/j.nutos.2021.11.005

      Summary

      Background and Aims

      Oesophagectomy is the primary curative treatment for oesophageal cancer but is associated with considerable postoperative morbidity and mortality. To better understand the aetiology of impaired health-related quality of life (HRQL) in oesophageal cancer survivors (OCS), this study sought to determine the longitudinal changes in nutritional status, nutrition-impact symptoms (NIS), and HRQL in this cohort, and to determine which variables have the greatest impact on postoperative HRQL decline.

      Methods

      Data, derived from St. James' Hospital, Dublin, included patients who underwent oesophagectomy from October 2017 to May 2019 and attended clinic preoperatively and 6 months postoperatively. A subset attended a further 12-month appointment. HRQL and symptom data were collected using validated questionnaires and anthropometric measures were completed by clinicians. Data were analysed using SPSS.

      Results

      A total of 66 patients were studied preoperatively and 6 months postoperatively, of whom 37 were studied at 12 months postoperatively. Malnutrition remained prevalent at each time-point, although rates did not significantly change longitudinally. Conversely, the prevalence of malabsorption (7.6%–14.3%, P<0.001) and dumping syndrome (67.7%–74.3%, P=0.003) significantly increased with increasing time postoperatively. NIS were significantly associated with impaired HRQL function scores and were independent predictors of global quality of life (gQOL) score postoperatively (P=0.004). A diagnostic threshold of gastrointestinal symptom severity (11.5) that identifies patients at risk of impaired gQOL was therefore reported.

      Conclusion

      Malnutrition and NIS are prevalent post-oesophagectomy, the latter significantly associated with reduced HRQL. Targeted intervention in those with severe NIS could be highly beneficial, highlighting the need for dietetic input in OCS.

      KEYWORDS

      Abbreviations:

      HRQL (Health-related quality of life), NIS (Nutrition-impact symptoms), OC (Oesophageal Cancer)

      Introduction

      An oesophageal cancer (OC) diagnosis is commonly associated with a poor prognosis, often a reflection of presentation with advanced or metastatic disease. Even where patients can be treated with curative intent, the pathway may be arduous with extensive treatment requirements, including preoperative (neoadjuvant) therapy and major cancer surgery [
      • Lagergren J.
      • Smyth E.
      • Cunningham D.
      • Lagergren P.
      Oesophageal cancer.
      ]. The operation of oesophagectomy is the primary curative treatment for OC and is an exemplar of complex surgery [
      • Low D.E.
      • Allum W.
      • De Manzoni G.
      • Ferri L.
      • Immanuel A.
      • Kuppusamy M.
      • et al.
      Guidelines for Perioperative Care in Esophagectomy: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations.
      ,
      • Blencowe N.S.
      • Strong S.
      • McNair A.G.
      • Brookes S.T.
      • Crosby T.
      • Griffin S.M.
      • et al.
      Reporting of short-term clinical outcomes after esophagectomy: a systematic review.
      ], associated with considerable risk of major postoperative morbidity [
      • Murthy R.A.
      • Clarke N.S.
      • Kernstine Sr., K.H.
      Minimally Invasive and Robotic Esophagectomy: A Review.
      ] and health-related quality of life (HRQL) impairment [
      • Scarpa M.
      • Valente S.
      • Alfieri R.
      • Cagol M.
      • Diamantis G.
      • Ancona E.
      • et al.
      Systematic review of health-related quality of life after esophagectomy for esophageal cancer.
      ,
      • Jacobs M.
      • Macefield R.C.
      • Elbers R.G.
      • Sitnikova K.
      • Korfage I.J.
      • Smets E.M.
      • et al.
      Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery.
      ,
      • Taioli E.
      • Schwartz R.M.
      • Lieberman-Cribbin W.
      • Moskowitz G.
      • van Gerwen M.
      • Flores R.
      Quality of Life after Open or Minimally Invasive Esophagectomy in Patients With Esophageal Cancer-A Systematic Review.
      ,
      • Parameswaran R.
      • McNair A.
      • Avery K.N.
      • Berrisford R.G.
      • Wajed S.A.
      • Sprangers M.A.
      • et al.
      The role of health-related quality of life outcomes in clinical decision making in surgery for esophageal cancer: a systematic review.
      ]. Advances in the modern era [
      • Lagergren J.
      • Smyth E.
      • Cunningham D.
      • Lagergren P.
      Oesophageal cancer.
      ] have enabled improved 5-year survival rates in patients that undergo oesophagectomy [
      • Gavin A.T.
      • Francisci S.
      • Foschi R.
      • Donnelly D.W.
      • Lemmens V.
      • Brenner H.
      • et al.
      Oesophageal cancer survival in Europe: a EUROCARE-4 study.
      ] to approximately 50 per cent. Accordingly, with increased numbers of survivors, survivorship and HRQL have become important outcome measures [
      • Lagergren P.
      • Fayers P.
      • Conroy T.
      • Stein H.J.
      • Sezer O.
      • Hardwick R.
      • et al.
      Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach.
      ,
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Soriano T.T.
      • Eslick G.D.
      • Vanniasinkam T.
      Long-Term Nutritional Outcome and Health Related Quality of Life of Patients Following Esophageal Cancer Surgery: A Meta-Analysis.
      ,
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ,
      • Chang Y.L.
      • Tsai Y.F.
      • Chao Y.K.
      • Wu M.Y.
      Quality-of-life measures as predictors of post-esophagectomy survival of patients with esophageal cancer.
      ]; and in this context, nutritional health is a key metric [
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ].
      The importance of nutrition in survivorship of this cohort is highlighted in the Lasting Symptoms after Esophageal Resection (LASER) study, which found that two-thirds of oesophageal cancer survivors (OCS) have long-term, functional symptoms attributable to surgery, with many closely linked to nutritional issues [
      • Markar S.R.
      • Zaninotto G.
      • Castoro C.
      • Johar A.
      • Lagergren P.
      • Elliot J.A.
      • et al.
      Lasting Symptoms After Esophageal Resection (LASER): European Multicenter Cross-sectional Study.
      ]. The global health status and HRQL of these patients have thus been reported to be significantly lower than that of healthy populations, various cancer cohorts, and pre-treatment OC patients [
      • Donohoe C.L.
      • McGillycuddy E.
      • Reynolds J.V.
      Long-term health-related quality of life for disease-free esophageal cancer patients.
      ], and it is rare that they return to baseline. There is a spectrum of recovery; for instance, Sun et al. reported a HRQL recovery period of 6–12 months [
      • Sun V.
      • Kim J.
      • Kim J.Y.
      • Raz D.J.
      • Merchant S.
      • Chao J.
      • et al.
      Dietary alterations and restrictions following surgery for upper gastrointestinal cancers: Key components of a health-related quality of life intervention.
      ], while Derogar and Lagergren reported 6–36 months with a subgroup of patients whose HRQL deteriorates over time due to more symptoms and worse functioning [
      • Derogar M.
      • Lagergren P.
      Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study.
      ]. Symptoms mainly comprise those which impede oral intake, known as nutrition-impact symptoms (NIS) [
      • Omlin A.
      • Blum D.
      • Wierecky J.
      • Haile S.R.
      • Ottery F.D.
      • Strasser F.
      Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a case-control study.
      ]. These are long-lasting [
      • Sun V.
      • Kim J.
      • Kim J.Y.
      • Raz D.J.
      • Merchant S.
      • Chao J.
      • et al.
      Dietary alterations and restrictions following surgery for upper gastrointestinal cancers: Key components of a health-related quality of life intervention.
      ,
      • Mantoan S.
      • Cavallin F.
      • Pinto E.
      • Saadeh L.M.
      • Alfieri R.
      • Cagol M.
      • et al.
      Long-term quality of life after esophagectomy with gastric pull-up.
      ] and associated with poor survival [
      • Djärv T.
      • Lagergren P.
      Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery.
      ]; highlighting the prognostic value of their identification [
      • Anandavadivelan P.
      • Martin L.
      • Djärv T.
      • Johar A.
      • Lagergren P.
      Nutrition Impact Symptoms Are Prognostic of Quality of Life and Mortality after Surgery for Oesophageal Cancer.
      ].
      Weight loss, dumping syndrome (DS) and malabsorption are key factors underpinning NIS. Body weight loss (BWL) is almost universal in this cohort, despite dietetic support and supplementation [
      • Donohoe C.L.
      • Healy L.A.
      • Fanning M.
      • Doyle S.L.
      • Hugh A.M.
      • Moore J.
      • et al.
      Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
      ]. The inability to swallow (dysphagia), which characterises the presentation of OC in many patients, is a key factor, as well as tumour-mediated cachexia and the consequences of neoadjuvant therapies [
      • Martin L.
      • Jia C.
      • Rouvelas I.
      • Lagergren P.
      Risk factors for malnutrition after oesophageal and cardia cancer surgery.
      ,
      • Stahl M.
      • Mariette C.
      • Haustermans K.
      • Cervantes A.
      • Arnold D.
      Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Postoperatively, changes in anatomy and physiology, particularly gastrointestinal and hormonal physiology, underpin the pathophysiological BWL observed [
      • Donohoe C.L.
      • Healy L.A.
      • Fanning M.
      • Doyle S.L.
      • Hugh A.M.
      • Moore J.
      • et al.
      Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
      ,
      • Elliott J.A.
      • Docherty N.G.
      • Eckhardt H.G.
      • Doyle S.L.
      • Guinan E.M.
      • Ravi N.
      • et al.
      Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study.
      ]. Significant reductions in weight, including fat mass, skeletal muscle mass (SMM), and bone mineral density, at postoperative time-points compared to preoperatively are consistently reported [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ,
      • Donohoe C.L.
      • Healy L.A.
      • Fanning M.
      • Doyle S.L.
      • Hugh A.M.
      • Moore J.
      • et al.
      Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
      ,
      • Heneghan H.M.
      • Zaborowski A.
      • Fanning M.
      • McHugh A.
      • Doyle S.
      • Moore J.
      • et al.
      Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
      ,
      • Elliott J.A.
      • Docherty N.G.
      • Murphy C.F.
      • Eckhardt H.G.
      • Doyle S.L.
      • Guinan E.M.
      • et al.
      Changes in gut hormones, glycaemic response and symptoms after oesophagectomy.
      ,
      • Elliott J.A.
      • Casey S.
      • Murphy C.F.
      • Docherty N.G.
      • Ravi N.
      • Beddy P.
      • et al.
      Risk factors for loss of bone mineral density after curative esophagectomy.
      ,
      • Guinan E.M.
      • Bennett A.E.
      • Doyle S.L.
      • O’Neill L.
      • Gannon J.
      • Foley G.
      • et al.
      Measuring the impact of oesophagectomy on physical functioning and physical activity participation: a prospective study.
      ,
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • King S.
      • Guinan E.M.
      • Beddy P.
      • et al.
      Sarcopenia: Prevalence, and Impact on Operative and Oncologic Outcomes in the Multimodal Management of Locally Advanced Esophageal Cancer.
      ]. Weight loss is most pronounced in the immediate 6 months post-oesophagectomy [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Anandavadivelan P.
      • Wikman A.
      • Johar A.
      • Lagergren P.
      Impact of weight loss and eating difficulties on health-related quality of life up to 10yearsafter oesophagectomy for cancer.
      ] with a reported 40–62% of patients losing greater than 10% of body weight and BMI during this time [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Soriano T.T.
      • Eslick G.D.
      • Vanniasinkam T.
      Long-Term Nutritional Outcome and Health Related Quality of Life of Patients Following Esophageal Cancer Surgery: A Meta-Analysis.
      ,
      • Donohoe C.L.
      • Healy L.A.
      • Fanning M.
      • Doyle S.L.
      • Hugh A.M.
      • Moore J.
      • et al.
      Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
      ,
      • Martin L.
      • Lagergren J.
      • Lindblad M.
      • Rouvelas I.
      • Lagergren P.
      Malnutrition after oesophageal cancer surgery in Sweden.
      ]. Loss of SMM is a key component, reported in 75% of patients at 6 months postoperatively [
      • Nakashima Y.
      • Saeki H.
      • Hu Q.
      • Tsuda Y.
      • Zaitsu Y.
      • Hisamatsu Y.
      • et al.
      Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer.
      ]. Following this time-period, however, BWL [
      • Heneghan H.M.
      • Zaborowski A.
      • Fanning M.
      • McHugh A.
      • Doyle S.
      • Moore J.
      • et al.
      Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
      ] and SMM loss [
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • King S.
      • Guinan E.M.
      • Beddy P.
      • et al.
      Sarcopenia: Prevalence, and Impact on Operative and Oncologic Outcomes in the Multimodal Management of Locally Advanced Esophageal Cancer.
      ] can continue with a negative impact on prognosis and survival [
      • Donohoe C.L.
      • Healy L.A.
      • Fanning M.
      • Doyle S.L.
      • Hugh A.M.
      • Moore J.
      • et al.
      Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
      ,
      • Nakashima Y.
      • Saeki H.
      • Hu Q.
      • Tsuda Y.
      • Zaitsu Y.
      • Hisamatsu Y.
      • et al.
      Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer.
      ,
      • Martin L.
      • Lagergren P.
      Long-term weight change after oesophageal cancer surgery.
      ].
      A NIS-related consequence of the mechanics of oesophagectomy, including a vagotomy and pyloroplasty, is DS [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Tack J.
      • Arts J.
      • Caenepeel P.
      • De Wulf D.
      • Bisschops R.
      Pathophysiology, diagnosis and management of postoperative dumping syndrome.
      ]. The symptoms manifest as early or late DS with distinct pathophysiology [
      • Tack J.
      • Arts J.
      • Caenepeel P.
      • De Wulf D.
      • Bisschops R.
      Pathophysiology, diagnosis and management of postoperative dumping syndrome.
      ]. In early DS, reduced stomach reservoir capacity results in rapid transit of voluminous and hyperosmotic chyme into the intestinal luminal space after food ingestion. This triggers duodenal distension, intravascular fluid shifts, activation of the sympathetic nervous system and gastrointestinal hormone hypersecretion; jointly resulting in gastrointestinal, vasomotor, and haemodynamic symptoms which occur within 10–60 minutes post-prandially [
      • Tack J.
      • Arts J.
      • Caenepeel P.
      • De Wulf D.
      • Bisschops R.
      Pathophysiology, diagnosis and management of postoperative dumping syndrome.
      ,
      • Berg P.
      • McCallum R.
      Dumping Syndrome: A Review of the Current Concepts of Pathophysiology, Diagnosis, and Treatment.
      ,
      • van Beek A.P.
      • Emous M.
      • Laville M.
      • Tack J.
      Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management.
      ]. Late DS, also called reactive hypoglycaemia, occurs after 60–120 minutes of ingestion. Insulin hypersecretion, caused by early and excessive concentrations of glucose in the small intestine followed by a rapid rise in blood glucose levels, results in delayed hypoglycaemia and the precipitation of adrenergic and/or neuroglycopenic symptoms. This is augmented by the incretin-mediated increase in insulin production and sensitivity [
      • Tack J.
      • Arts J.
      • Caenepeel P.
      • De Wulf D.
      • Bisschops R.
      Pathophysiology, diagnosis and management of postoperative dumping syndrome.
      ,
      • van Beek A.P.
      • Emous M.
      • Laville M.
      • Tack J.
      Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management.
      ,
      • Miholic J.
      • Orskov C.
      • Holst J.J.
      • Kotzerke J.
      • Pichlmayr R.
      Postprandial release of glucagon-like peptide-1, pancreatic glucagon, and insulin after esophageal resection.
      ,
      • Burrows W.M.
      Gastrointestinal function and related problems following esophagectomy.
      ,
      • Tack J.
      • Deloose E.
      Complications of bariatric surgery: dumping syndrome, reflux and vitamin deficiencies.
      ,
      • Vavricka S.R.
      • Greuter T.
      Gastroparesis and Dumping Syndrome: Current Concepts and Management.
      ].
      In this National Centre, a Nutrition and Survivorship Clinic was established to monitor outcomes after OC surgery. It included detailed recording of nutritional symptoms, HRQL, and relevant laboratory measurements of nutritional well-being at a number of time-points. The aim of this report is to investigate the associations between nutritional status, NIS and HRQL in a cohort of OCS from the clinic. The objectives were threefold: first, to describe the prevalence of and longitudinal changes in malnutrition and NIS in survivorship after curative intent OC surgery; second, to investigate whether anthropometric/nutritional measures or NIS are associated with HRQL; and third, to identify predictors of impaired HRQL in OCS.

      Materials and methods

       Data source and data collection

      The data was derived from the Nutrition and Survivorship Clinic at the National Oesophageal and Gastric Cancer Centre at St. James' Hospital, Dublin. This study includes patients who underwent oesophagectomy for OC between October 2017 and May 2019 and attended clinic preoperatively and 6 months postoperatively. A subset of patients attended a further 12-month clinic appointment. The preoperative and perioperative care of patients at this centre has been previously described [
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ]. Standard nutritional therapy involved exclusive jejunostomy feeding for 5 days postoperatively, commencing on the first postoperative day, which progressed slowly to half portions of easy to chew texture diet [
      International Dysphagia Diet Standardisation Initiative
      IDDSI Framework and Detailed Level Definitions.
      ]. Patients were discharged on consuming half portions, overnight jejunostomy feeding, and oral nutritional supplements as required. Participant exclusion criteria included non-carcinoma related oesophagectomy, and disease recurrence or death prior to the 6-month postoperative appointment.
      All patient data was collected prospectively at clinic visits. Ethical approval was obtained from the Hospital ethics committee. Reference population HRQL data was obtained from the European Centre for Research and Treatment of Cancer (EORTC) and other publications considered most appropriate [
      • Scott N.W.
      • Fayers P.M.
      • Aaronson N.K.
      • Bottomly A.
      • de Graeff A.
      • Groenvold M.
      • et al.
      EORTC QLQ-C30 reference values manual.
      ,
      • Nolte S.
      • Liegl G.
      • Petersen M.A.
      • Aaronson N.K.
      • Costantini A.
      • Fayers P.M.
      • et al.
      General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States.
      ]. Prior to clinic visits, patients had HRQL and symptom questionnaires posted to them to be completed before arrival. These included the general EORTC Quality of Life Questionnaire C30 (QLQ-C30), the OC specific EORTC QLQ-OG25, a modified Gastrointestinal Symptom Rating Scale (mGSRS), and the Sigstad dumping questionnaire [
      • Sigstad H.
      A clinical diagnostic index in the diagnosis of the dumping syndrome. Changes in plasma volume and blood sugar after a test meal.
      ]. At the survivorship clinic, anthropometric measurements and micronutrient screening were completed, and treatment and follow-up arranged as appropriate.

       Nutritional and quality of life outcomes

      BWL was classified according to the Blackburn criteria [
      • Blackburn G.L.
      • Bistrian B.R.
      • Maini B.S.
      • Schlamm H.T.
      • Smith M.F.
      Nutritional and metabolic assessment of the hospitalized patient.
      ] and BMI was categorized according to the World Health Organisation [

      World Health Organisation. Body Mass Index - BMI. Available from: https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthylifestyle/body-mass-index-bmi [Accessed 23/03/2021].

      ]. Malnutrition was defined by nutritional risk index (NRI); (1.489∗serum albumin [g/L])+(41.7∗current weight/usual weight) [
      • Bouillanne O.
      • Morineau G.
      • Dupont C.
      • Coulombel I.
      • Vincent J.P.
      • Nicolis I.
      • et al.
      Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients.
      ], which has previously defined malnutrition in gastrointestinal cohorts [
      • Schiesser M.
      • Kirchhoff P.
      • Müller M.K.
      • Schäfer M.
      • Clavien P.A.
      The correlation of nutrition risk index, nutrition risk score, and bioimpedance analysis with postoperative complications in patients undergoing gastrointestinal surgery.
      ,
      • Oh C.A.
      • Kim D.H.
      • Oh S.J.
      • Choi M.G.
      • Noh J.H.
      • Sohn T.S.
      • et al.
      Nutritional risk index as a predictor of postoperative wound complications after gastrectomy.
      ,
      • Fujiya K.
      • Kawamura T.
      • Omae K.
      • Nishiwaki N.
      • Kaji S.
      • Hikage M.
      • et al.
      Post-gastrectomy nutrition risk index can be a good predictive factor for survival.
      ]. Thresholds for classification of nutritional status are as follows; ≥100, well-nourished; 97.5–100, mild malnutrition; 83.5–97.5, moderate malnutrition; <83.5, severe malnutrition [
      Veterans Affairs Total Parenteral Nutrition Cooperative Study Group
      Perioperative total parenteral nutrition in surgical patients.
      ]. Malabsorption was indicated by a steatorrhoea-specific score >7, as assessed by specific questions in the mGSRS [
      • Heneghan H.M.
      • Zaborowski A.
      • Fanning M.
      • McHugh A.
      • Doyle S.
      • Moore J.
      • et al.
      Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
      ]. Finally, hand grip strength was measured on each hand three times, and the highest value was used as a functional surrogate for ‘probable sarcopenia’ using previously described sex-specific and BMI-dependant thresholds [
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      ].
      Assessment of NIS was limited to those assessed in the mGSRS (cramps, bloating, wind, belching, borborygmi, reflux, anorexia, nausea, vomiting, urgency to open bowels, incomplete passing of stool, oily stools, floating stools, and foul-smelling stools). Symptoms were assessed using a 4-point Likert scale and an estimate of symptom frequency and severity was found by totalling the scores. Dumping syndrome (DS) was assessed using Sigstad's scoring system where points are allocated to specific symptoms whose presence or absence were indicated by patients. Those with a total score greater than 7 were defined as having DS whereas those with a score less than or equal to 7 were defined as not having DS [
      • Scarpellini E.
      • Arts J.
      • Karamanolis G.
      • Laurenius A.
      • Siquini W.
      • Suzuki H.
      • et al.
      International consensus on the diagnosis and management of dumping syndrome.
      ].
      Quality of life outcomes included HRQL, which is an indication of one's function and level of symptomology [
      • Karimi M.
      • Brazier J.
      Health
      Health-Related Quality of Life, and Quality of Life: What is the Difference?.
      ], and global quality of life (gQOL), a measure of self-perceived health status. These were both recorded using the disease-specific and validated EORTC QLQ-C30 and QLQ-25 scales [
      • Rejeski W.J.
      • Mihalko S.L.
      Physical Activity and Quality of Life in Older Adults.
      ].

       Statistical analysis

      Data were analysed using SPSS software (IBM 27.0 for Windows, SPSS Inc, Chicago, IL). Continuous variables were assessed for normality using the Shapiro-Wilk test, and data are reported as mean, standard deviation (SD) or median, range as appropriate. Frequency data are presented as number (n), valid percent (%); where missing values are excluded from the prevalence analysis. Comparison of prevalence between groups was performed using the Chi-squared test. All EORTC questionnaire responses were previously linearly transformed as per the scoring manual [
      • Fayers P.M.
      • Aaronson N.K.
      • Bjordal K.
      • Groenvold M.
      • Curran D.
      • Bottomley A.
      EORTC QLQC30 scoring manual.
      ]. Average differences in HRQL scores were classed as clinically relevant as per the evidence-based interpretation guidelines, available for inter- [
      • Cocks K.
      • King M.T.
      • Velikova G.
      • Martyn St-James M.
      • Fayers P.M.
      • Brown J.M.
      Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
      ] and intra-group [
      • Cocks K.
      • King M.T.
      • Velikova G.
      • de Castro Jr., G.
      • Martyn St-James M.
      • Fayers P.M.
      • et al.
      Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
      ] comparison. These guidelines were developed using robust methodology to improve clinical interpretation of score differences, and, in the present study, differences were classed as clinically relevant if within the medium or large range [
      • Cocks K.
      • King M.T.
      • Velikova G.
      • Martyn St-James M.
      • Fayers P.M.
      • Brown J.M.
      Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
      ].
      Spearman's rank correlation was used in correlation analyses, as, consistently, at least one variable was non-normally distributed. Univariable comparisons within groups over two time-points were performed using paired t-tests or Wilcoxon signed-rank tests for continuous variables, and McNemar's test for dichotomous variables. For between group comparisons, the Mann-Whitney U test was used. For comparing data over three time-points, Cochran's Q test, one-way repeated measure ANOVA, or Friedman's test were performed, as appropriate. Receiver operating characteristic (ROC) curves were used to determine thresholds of continuous variables that may predict dichotomous outcomes. Standard single or multiple linear regression was used to investigate predictors of continuous outcomes, with independent variables inputted into the model based on their perceived clinical relevance. A significance level of 0.05 was used for all analyses and reported P values are two-tailed.

      Results

       Characteristics of the study cohort

      The characteristics of the 6-month and 12-month cohort are shown in Table 1. Sixty-six patients were studied at the 6-month time-point, of whom 37 attended at 12 months postoperatively. Preoperative data was originally collected on 75 patients [
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ], resulting in an inclusion rate of 88% at 6 months and 49% at 12 months. The primary documented reasons for drop-out were disease recurrence and participants not reaching the 12-month postoperative time-point at the time of analysis. Their mean age was 63.3, the majority were male, and approximately half were ex-smokers. For more than 80% of patients in each cohort, OC was their first malignancy diagnosis with adenocarcinoma being the primary histological subtype. Neoadjuvant therapy and surgery was the main treatment approach, with preoperative chemotherapy and radiation therapy (CROSS protocol) and radical 2-stage en bloc oesophagectomy the most common combination. Over half the patients experienced a postoperative complication, and 22.7% and 18.9% of the 6 and 12-month cohort, respectively, experienced a complication classified as ≥3 according to the Clavien-Dindo Classification (CDC) system [
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      ]. Tumour recurrence after last clinic appointment was documented in 15.2% at 6 months and 8.1% at 12 months postoperatively.
      Table 1Demographic, clinicopathologic and treatment characteristics of the cohort of patients who attended their preoperative, 6-month postoperative, and 12-month postoperative appointment at the Nutrition and Survivorship Clinic
      VariablePreoperative cohort (n=75)6-month cohort (n=66)12-month cohort (n=37)
      Demographic Characteristics
      Sex
       Male (n, %)63, 84.0%55, 83.3%32, 86.5%
       Female (n, %)12, 16.0%11, 16.7%5, 13.5%
      Age at surgery (mean, SD)62.7, 10.3%63.3, 9.963.3, 9.9
      Smoking status
       Current smoker (n, %)13, 17.3%10, 15.2%5, 13.5%
       Ex-smoker >1year (n, %)35, 46.7%31, 47.0%19, 51.4%
       Never smoked (n, %)24, 32.0%22, 33.3%13, 35.1%
       Unknown/not specified (n, %)3, 4.0%3, 4.5%0, 0.0%
      Alcohol intake
       Non-drinker (n, %)12, 16.0%8, 12.1%4, 10.8%
       Ex-drinker (n, %)9, 12.0%9, 13.6%5, 13.5%
       Heavy drinker (>14/21UPW) (n, %)17, 22.7%15, 22.7%7, 18.9%
       Social drinker (<14/21UPW) (n, %)35, 46.7%32, 48.5%21, 56.8%
       Unknown/not specified (n, %)2, 2.7%2, 3.0%0, 0.0%
      Clinicopathologic and Treatment Characteristics
      ASA grade at diagnosis
       1 (n, %)8, 10.7%8, 12.1%4, 10.8%
       2 (n, %)51, 68.0%44, 66.7%24, 64.9%
       3 (n, %)16, 21.3%14, 21.2%9, 24.3%
      Previous malignancy
       Yes (n, %)10, 13.3%10, 15.2%6, 16.2%
       No (n, %)62, 82.7%53, 80.3%31, 83.8%
       Unknown/not specified (n, %)3, 4.0%3, 4.5%0, 0.0%
      Barrett's oesophagus (n, %)29, 38.7%26, 39.4%17, 45.9%
      Tumour histology
       Adenocarcinoma (n, %)64, 85.3%56, 84.8%31, 83.8%
       Squamous cell carcinoma (n, %)11, 14.7%10, 15.2%6, 16.2%
      Main curative treatment
       Surgery (n, %)13, 17.3%13, 19.7%8, 21.6%
       Neoadjuvant therapy and surgery (n, %)57, 76.0%48, 72.7%26, 70.3%
       Surgery and endoscopic treatments (n, %)3, 4.0%3, 4.5%2, 5.4%
       Surgery and adjuvant therapy (n, %)1, 1.3%1, 1.5%1, 2.7%
       Surgery and radical CT/RT (n, %)1, 1.3%1, 1.5%0, 0.0%
      Neoadjuvant therapy type
       CROSS (n, %)25, 33.3%22, 33.3%8, 21.6%
       MAGIC (n, %)8, 10.7%6, 9.1%6, 16.2%
       FLOT (n, %)20, 26.7%15, 22.7 %7, 18.9%
       Not specified/Did not receive (n, %)22, 29.3%23, 34.8%16, 43.2%
      Surgery type
       Transhiatal oesophagectomy (n, %)20, 26.7%19, 28.8%12, 32.4%
       2-Stage oesophagectomy (n, %)42, 56.0%36, 54.5%20, 54.1%
       3-Stage oesophagectomy (n, %)13, 17.3%11, 16.7%5, 13.5%
      Postoperative complication
       Yes (n, %)44, 58.7%38, 57.6%20, 54.1%
       No (n, %)31, 41.3%28, 42.4%17, 45.9%
       CDC ≥3 (n, %)18, 24.3%15, 22.7%7, 18.9%
      Postoperative readmission
       Yes (n, %)11, 14.7%10, 15.2%7, 18.9%
       No (n, %)64, 85.3%56, 84.8%30, 81.1%
      Recurrence
       Yes (n, %)12, 16.0%10, 15.2%3, 8.1%
       No (n, %)63, 84.0%56, 84.8%34, 91.9%
      ASA indicates American Society of Anaesthesiologists; CDC, Clavien-Dindo Classification; CT/RT, chemotherapy/radiotherapy; SD, standard deviation; UPW, units per week.
      CROSS protocol: weekly carboplatin and paclitaxel administration with concurrent Gy radiotherapy for 5 weeks. MAGIC protocol: perioperative triplet regimen of epirubicin, cisplatin, and fluorouracil. FLOT protocol: perioperative triplet regimen of docetaxel, oxaliplatin, leucovorin, and fluorouracil.
      The prevalence of malnutrition, as per NRI, was 24.2% preoperatively and 37.9% 6 months postoperatively in the 6-month cohort, and was 29.7% at 12 months postoperatively. Longitudinal changes in anthropometric and nutritional measurements in the 12-month cohort are shown in Table 2. Mean weight and BMI significantly decreased over time, reflected by a significant decrease in the prevalence of overweight/obesity. Mean NRI score also significantly decreased from preoperatively to 6 months, yet the majority of malnourished patients remained in the ‘mild malnutrition’ category. Severe BWL was identified in 37.8% at 6 months and 43.2% at 12 months, and probable sarcopenia was diagnosed in 35%, 32.4% and 29.7% at the respective time-points.
      Table 2Longitudinal anthropometric changes in the 12-month cohort
      VariablePreop (n=37)6 months (n=37)12 months (n=37)PP (preop vs 6m)P (preop vs 12m)P (6m vs 12m)
      Weight, kg (mean, SD)80.3, 14.673.2, 12.072.9, 12.7<0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      <0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      <0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      1.000
      One-way repeated measures ANOVA and post-hoc test significance result.
      BMI, kg/m2 (mean, SD)27.4, 4.624.9, 3.424.8, 3.8<0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      <0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      <0.001
      One-way repeated measures ANOVA and post-hoc test significance result.
      1.000
      One-way repeated measures ANOVA and post-hoc test significance result.
      BMI >25 kg/m2 (n, %)26, 70.3%19, 51.4%17, 45.9%0.001
      Cochran's Q and post-hoc test significance result.
      0.007
      Cochran's Q and post-hoc test significance result.
      <0.001
      Cochran's Q and post-hoc test significance result.
      0.439
      Cochran's Q and post-hoc test significance result.
      NRI (mean, SD)105.5, 7.1102.5, 5.0103.1, 4.90.039
      One-way repeated measures ANOVA and post-hoc test significance result.
      0.040
      One-way repeated measures ANOVA and post-hoc test significance result.
      0.164
      One-way repeated measures ANOVA and post-hoc test significance result.
      0.737
      One-way repeated measures ANOVA and post-hoc test significance result.
      Mild Malnutrition (n, %)4, 10.8%9, 24.3%7, 18.9%0.257
      Cochran's Q and post-hoc test significance result.
      Moderate Malnutrition (n, %)2, 5.4%4, 10.8%4, 10.8%0.641
      Cochran's Q and post-hoc test significance result.
      Severe Malnutrition (n, %)1, 2.7%0, 0%0, 0%0.368
      Cochran's Q and post-hoc test significance result.
      Grip Strength (r), kg (mean, SD)33.0, 7.831.2, 7.332.6, 8.10.217
      One-way repeated measures ANOVA and post-hoc test significance result.
      Grip Strength (l), kg (mean, SD)30.7, 8.331.2, 6.930.6, 8.40.897
      One-way repeated measures ANOVA and post-hoc test significance result.
      MUAC, cm (mean, SD)26.9, 2.226.9, 2.50.852
      Paired sample t-test significance result.
      Waist Circumference, cm94.0, 64–106+90.9, 11.9#0.704
      Wilcoxon signed-rank test significance result.
      Hip Circumference, cm96.7, 65–108+97.5, 6.6#0.992
      Wilcoxon signed-rank test significance result.
      Waist: Hip ratio, (median, range)0.9, 0.8–1.00.9, 0.8–1.20.629
      Wilcoxon signed-rank test significance result.
      % BWL (mean, SD)8.4, 5.88.8, 7.10.487
      Paired sample t-test significance result.
      >10% BWL (n, %)14, 37.8%16, 43.2%0.727
      McNemar's test significance result.
      Probable Sarcopenia (n, %)7, 35%
      Probable sarcopenia measures available in n=20 preoperatively.
      12, 32.4%11, 29.7%0.472
      Cochran's Q and post-hoc test significance result.
      BMI indicates body mass index; BWL, body weight loss; l, left; MUAC, mid-upper arm circumference; NRI, nutritional risk index; Preop, preoperatively; r, right; SD, standard deviation; vs, versus. Bold indicates where longitudinal changes are significant (P<0.05).
      #mean, SD, +median, range.
      a Probable sarcopenia measures available in n=20 preoperatively.
      b One-way repeated measures ANOVA and post-hoc test significance result.
      c Cochran's Q and post-hoc test significance result.
      d Paired sample t-test significance result.
      e Wilcoxon signed-rank test significance result.
      f McNemar's test significance result.

       Nutrition-impact symptoms (NIS) and dumping syndrome (DS)

      Nutrition-impact symptoms remained prevalent throughout the postoperative period, with 41% and 36% of patients reporting >2 bothersome symptoms (scored a 2 or 3 on a 0–3 Likert scale) at 6 and 12 months, respectively. In the 12-month cohort, scores for individual symptoms did not significantly change from 6 to 12 months (Table 3), nor did average total mGSRS score (11.1 versus 10, P=0.523). The prevalence of malabsorption increased from 7.6% at 6 months to 14.3% at 12 months (P<0.001).
      Table 3Gastrointestinal Symptoms as measured by the mGSRS at 6 and 12 months postoperatively
      Symptomn, % of patients who scored 2 or 3Sig of the difference in scores from 6-12 months in 12-month cohort
      6 months (n=66)12 months (n=36
      n=1 missing data at 12 months postoperatively.
      )
      P
      Cramps9, 13.6%(n=35) 4, 11.4%0.513
      Bloating9, 13.6%(n=35) 3, 8.6%0.090
      Wind17, 25.7%8, 22.2%0.467
      Belching12, 18.2%8, 22.3%0.132
      Borborygmus10, 15.5%3, 8.4%0.808
      Reflux(n=65) 9, 13.8%2, 5.6%0.739
      Anorexia(n=65) 12, 18.4%(n=35) 4, 11.5%0.109
      Nausea11, 13.6%3, 8.4%0.475
      Vomiting0, 0%0, 0%0.655
      Urgency to open bowels5, 7.6%4, 11.1%0.467
      Incomplete passing of stool5, 7.5%(n=35) 4, 11.5%0.660
      Oily stool(n=65) 6, 9.2%(n=35) 4, 11.4%0.564
      Floating stool7, 10.6%2, 5.6%0.480
      Foul-smelling stool9, 13.7%6, 16.6%0.218
      Sleep disturbance due to bowels0, 0%(n=35) 1, 2.9%0.739
      P, significance result of Wilcoxon signed-rank test; Sig, significance.
      a n=1 missing data at 12 months postoperatively.
      Mean Sigstad score (SS) was 9.45 at 6 months and 8.91 at 12 months. The prevalence of DS, defined by SS>7, significantly increased from 67.7% (44/65) to 74.3% (26/35) from 6 to 12 months (P=0.003). There were no significant differences in the prevalence of DS between sexes.

       Health-related quality of life

      Mean HRQL scores of various populations are shown in supporting information Table 1, and clinically relevant differences between groups [
      • Cocks K.
      • King M.T.
      • Velikova G.
      • Martyn St-James M.
      • Fayers P.M.
      • Brown J.M.
      Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
      ] are marked. Clinically relevant improvements [
      • Cocks K.
      • King M.T.
      • Velikova G.
      • de Castro Jr., G.
      • Martyn St-James M.
      • Fayers P.M.
      • et al.
      Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
      ] in dyspnoea and appetite loss were found from 6 to 12 months in the 12-month cohort, whereas statistically significant improvements were found for emotional function, nausea and vomiting, dyspnoea, appetite loss, dysphagia, and taste changes.
      A gQOL score of <66.1, the general population reference score [
      • Nolte S.
      • Liegl G.
      • Petersen M.A.
      • Aaronson N.K.
      • Costantini A.
      • Fayers P.M.
      • et al.
      General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States.
      ], was set as the threshold for impaired gQOL. This was found in 20% and 14.3% of the population at 6 and 12 months, respectively. The demographic and clinicopathologic characteristics of those with and without impaired gQOL were compared (data not shown). At both time-points, patients with impaired gQOL had higher Sigstad, steatorrhoea-specific, and total mGSRS scores. All other variables assessed, including sex, age, smoking/alcohol status, and anthropometric measurements, did not differ significantly between those with and without impaired gQOL.

       Nutritional status and HRQL

      HRQL did not differ between those with and without a BMI ≥25kg/m2, apart from ‘worry about weight loss’ at 6 months, which was significantly higher in the under/normal weight cohort compared to the overweight/obese cohort (P=0.022). Sarcopenic patients had several higher symptom scores postoperatively, and an increased gQOL at 6 months (P=0.029), compared to non-sarcopenic patients (supporting information Table 2). Several weak correlations (<0.4) were found between NRI score and HRQL scores, suggesting worsening of HRQL with decreasing NRI score (supporting information Table 3).

       Dumping syndrome and HRQL

      Numerous HRQL scores significantly differed at each postoperative time-point, both statistically as well as clinically, between those with and without DS, as shown in Table 4. Items that scored worse in patients with DS at both time-points were physical function (P=0.005/0.046), social function (P=0.001/0.011), fatigue (P<0.001/=0.004), dyspnoea (P=0.001/0.016), eating restrictions (P=0.011/0.038), trouble enjoying meals (P=0.007/0.028), and pain and discomfort (P=0.001/0.038). Similarly, several significant correlations were found between SS and HRQL scores which showed that increasing SS has a negative impact on HRQL (supporting information Table 4). Strong correlations (≥0.5) were found between SS and fatigue at 6 months (0.649, P<0.001), and social function (-0.518, P=0.001), fatigue (0.506, P=0.002), and dyspnoea (0.522, P=0.001) at 12 months.
      Table 4The clinical relevance of statistically significant differences in HRQL scores between patients with and without dumping syndrome
      HRQL item6 months (n=65)12 months (n=35)
      Dumping syndrome (median)Non-dumping syndrome (median)PMedian score differenceClinically relevant (EBIG)Dumping syndrome (median)Non-dumping syndrome (median)PMedian score differenceClinically relevant (EBIG)
      Physical function83.331000.00516.67Yes83.331000.04616.67No
      Social function66.671000.00133.33Yes83.331000.01116.67Yes
      Fatigue33.3311.11<0.00122.22Yes33.3311.110.00422.22Yes
      Dyspnoea33.3300.00133.33Yes33.3300.01633.33Yes
      Eating restrictions25.008.330.01116.67Yes258.330.03816.67Yes
      Trouble enjoying meals33.3300.00733.33Yes33.3300.02833.33Yes
      Pain and discomfort33.3316.670.00116.66Yes33.3316.670.03816.66Yes
      P, significance result of Mann-Whitney U test.
      EBIG, Evidence-based Interpretation Guidelines (Fig. 1).

       Nutrition-impact symptoms and HRQL

      Supporting information Table 4 displays the correlations between total mGSRS score and HRQL scores. At both postoperative time-points, strong correlations (≥0.5) were found between mGSRS score and gQOL score (-0.526, P<0.001; -0.582, P<0.001 [Figure 2]), cognitive function (-0.538, P<0.001; -0.636, P<0.001), insomnia (0.566, P<0.001; 0.506, P=0.002), eating restrictions (0.546, P<0.001; 0.672, P<0.001), and odynophagia (0.516, P<0.001; 0.599, P<0.001). These correlations suggested worsening of HRQL with increased NIS. Malabsorption also had a significant negative impact on several HRQL items (supporting information Table 5), including cognitive function (P=0.031/0.014).
      Figure 1
      Figure 1A clinic visit flow diagram outlining patient attendance at the Survivorship clinic.
      Figure 2
      Figure 2Simple scatter plots of the correlations between total mGSRS score and global QOL score at 6 and 12 months postoperatively.
      ROC curves were used to determine a threshold for total mGSRS score that indicates impaired gQOL (<66.1). As shown in Figure 3, the area under the curve (AUC) between total mGSRS score and impaired gQOL at 6 and 12 months was 0.804 (CI:0.677–0.931, P=0.001) and 0.843 (CI:0.666–1.00, P=0.015), supporting it as a good diagnostic test. A threshold of 11.5 was selected as the sum of sensitivity and specificity was as closest to, or above, 1.5 at each time-point, as recommended by Power et al. [
      • Power M.
      • Fell G.
      • Wright M.
      Principles for high-quality, high-value testing.
      ] (sensitivity/specificity: 76.9%/71.2% at 6 months, 80%/80% at 12 months).
      Figure 3
      Figure 3Receiver operating characteristic curves between total mGSRS score and impaired global QOL at 6 and 12 months postoperatively.
      A bivariate regression analysis was conducted to examine how well 6-month total mGSRS score could predict gQOL score at 12 months. The scatterplot between these two variables, shown in Figure 4, revealed one outlier which was removed from the analysis: resulting in a sample size of 34. The Spearman correlation between the two variables was -0.586 (P<0.001), the regression equation for predicting 12-month gQOL score was 98.589-1.861(6-month mGSRS score) (P<0.001), and the adjusted r2 was 0.508.
      Figure 4
      Figure 4Simple scatter plot of 6-month total mGSRS score and 12-month global QOL score in the 12-month cohort.

       Predictors of HRQL

      Standard multiple linear regression was performed to assess the impact of a set of predictor variables on gQOL score (Table 5). Predictor variables were selected based on plausibility to impact HRQL and results of previous analyses, and included NRI, Sigstad score (SS), steatorrhoea-specific score, mGSRS score, whether the patient had a postoperative complication of CDC≥3 and whether the patient had a preoperative ASA grade of 3. At 6 months, the model explained 41.1% of variance in gQOL score (P<0.001). Total mGSRS score (β [CI]: -0.572 [-3.163 – -0.628], P=0.004) and ASA grade equalling 3 (β [CI]: -0.285 [-22.228 – -3.898], P=0.006) independently contributed to the model equation and, together, explained 15.75% of gQOL variance. At 12 months, the model explained 38.7% of variance in gQOL score (P=0.003), with SS independently contributing to the model equation (β [CI]: -0.401 [-2.251 – -0.301], P=0.012) and explaining 13.40% of gQOL variance.
      Table 5Multiple linear regression analysis of predictor variables for global quality of life score at 6 and 12 months postoperatively
      Predictor Variable6 months12 months
      BetaCIP[Part]2 x100BetaCIP[Part] [
      • Low D.E.
      • Allum W.
      • De Manzoni G.
      • Ferri L.
      • Immanuel A.
      • Kuppusamy M.
      • et al.
      Guidelines for Perioperative Care in Esophagectomy: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations.
      ] x100
      Nutritional risk index0.033-0.588–0.8210.7410.100.199-0.336–1.5920.1923.31
      Sigstad score-0.127-1.195–0.3350.2651.17-0.401-2.251–-0.3010.01213.40
      Steatorrhoea-specific score0.079-1.573–2.5570.6350.21-0.342-4.515–0.9900.2003.20
      mGSRS score-0.572-3.163–-0.6280.0048.24-0.095-1.697–1.2250.7430.20
      CDC≥30.189-0.889–17.7850.0753.03-0.026-11.117–13.1960.8620.06
      ASA grade of 3-0.285-22.228–-3.8980.0067.51-0.136-15.482–5.7310.3541.66
      Model SummaryAdjusted R square: 0.411 (P<0.001)Adjusted R square: 0.387 (P=0.003)
      ASA, American Society of Anaestheologists; Beta, standardised beta coefficient; CDC, Clavien-Dindo Classification; CI, confidence interval; mGSRS, modified Gastrointestinal Symptom Rating Scale; P, significance value; Part, semipartial correlation coefficient. Bold indicates where longitudinal changes are significant (P<0.05).

      Discussion

      With improved survival rates in OC treated with curative intent, HRQL has become a major focus of research and an intervention target to enhance recovery and optimise survivorship [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ,
      • Nakashima Y.
      • Saeki H.
      • Hu Q.
      • Tsuda Y.
      • Zaitsu Y.
      • Hisamatsu Y.
      • et al.
      Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer.
      ]. Nutritional health is central to this goal in this cohort of patients. An understanding of nutrition in HRQL will also provide evidence-based information for clinical decision-making and for resourcing optimal care pathways [
      • Lagergren P.
      • Avery K.N.
      • Hughes R.
      • Barham C.P.
      • Alderson D.
      • Falk S.J.
      • et al.
      Health-related quality of life among patients cured by surgery for esophageal cancer.
      ]. This study has shown that malnutrition, NIS, and DS are prevalent in OCS, and that NIS and DS are significantly associated with reduced HRQL. This highlights numerous modifiable targets.
      Collection of information on outcomes from a patient perspective is an accepted part of oncological research [
      • Blazeby J.M.
      • Farndon J.R.
      • Donovan J.
      • Alderson D.
      A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma.
      ], particularly in OC [
      • Djärv T.
      • Blazeby J.M.
      • Lagergren P.
      Predictors of postoperative quality of life after esophagectomy for cancer.
      ], and is facilitated through HRQL questionnaires. Responses can inform preoperative patients on what to expect postoperatively, guide standard advice [
      • Scarpa M.
      • Valente S.
      • Alfieri R.
      • Cagol M.
      • Diamantis G.
      • Ancona E.
      • et al.
      Systematic review of health-related quality of life after esophagectomy for esophageal cancer.
      ,
      • Lagergren P.
      • Avery K.N.
      • Hughes R.
      • Barham C.P.
      • Alderson D.
      • Falk S.J.
      • et al.
      Health-related quality of life among patients cured by surgery for esophageal cancer.
      ], and identify patients requiring further intervention [
      • Djärv T.
      • Lagergren P.
      Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery.
      ]. Moreover, postoperative HRQL scores, including gQOL and physical function, are independent predictors of long-term survival in OCS [
      • Djärv T.
      • Lagergren P.
      Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery.
      ,
      • van Heijl M.
      • Sprangers M.A.G.
      • de Boer A.G.E.M.
      • Lagarde S.M.
      • Reitsma H.B.
      • Busch O.R.C.
      • et al.
      Preoperative and Early Postoperative Quality of Life Predict Survival in Potentially Curable Patients with Esophageal Cancer.
      ]. The HRQL of this cohort was comparable to the reference general population, which is an unusual finding compared to previous publications [
      • Donohoe C.L.
      • McGillycuddy E.
      • Reynolds J.V.
      Long-term health-related quality of life for disease-free esophageal cancer patients.
      ,
      • Courrech Staal E.F.
      • van Sandick J.W.
      • van Tinteren H.
      • Cats A.
      • Aaronson N.K.
      Health-related quality of life in long-term esophageal cancer survivors after potentially curative treatment.
      ], particularly regarding physical function [
      • Scarpa M.
      • Valente S.
      • Alfieri R.
      • Cagol M.
      • Diamantis G.
      • Ancona E.
      • et al.
      Systematic review of health-related quality of life after esophagectomy for esophageal cancer.
      ,
      • Reynolds J.V.
      • McLaughlin R.
      • Moore J.
      • Rowley S.
      • Ravi N.
      • Byrne P.J.
      Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone.
      ,
      • Alghamedi A.
      • Buduhan G.
      • Tan L.
      • Srinathan S.K.
      • Sulman J.
      • Darling G.
      • et al.
      Quality of life assessment in esophagectomy patients.
      ,
      • McLarty A.J.
      • Deschamps C.
      • Trastek V.F.
      • Allen M.S.
      • Pairolero P.C.
      • Harmsen W.S.
      Esophageal resection for cancer of the esophagus: long-term function and quality of life.
      ]. The survivorship clinic may be a factor, which provided contact with dietetic professionals through the first year of survivorship. This is consistent with increases in gQOL and physical function reported in other cancer types when patients have this level of nutritional and dietetic support [
      • Isenring E.A.
      • Capra S.
      • Bauer J.D.
      Nutrition intervention is beneficial in oncology outpatients receiving radiotherapy to the gastrointestinal or head and neck area.
      ]. Emotional function was higher in the sample cohort compared to reference populations at 12 months postoperatively, and it significantly improved from 6-month scores. This effect of treatment completion on emotional function has been reported elsewhere [
      • Scarpa M.
      • Valente S.
      • Alfieri R.
      • Cagol M.
      • Diamantis G.
      • Ancona E.
      • et al.
      Systematic review of health-related quality of life after esophagectomy for esophageal cancer.
      ,
      • Lagergren P.
      • Avery K.N.
      • Hughes R.
      • Barham C.P.
      • Alderson D.
      • Falk S.J.
      • et al.
      Health-related quality of life among patients cured by surgery for esophageal cancer.
      ,
      • Conroy T.
      • Marchal F.
      • Blazeby J.M.
      Quality of life in patients with oesophageal and gastric cancer: an overview.
      ], and is possibly related to the feeling of optimism from the recovery process after they have undergone curative intent surgery [
      • Lagergren P.
      • Avery K.N.
      • Hughes R.
      • Barham C.P.
      • Alderson D.
      • Falk S.J.
      • et al.
      Health-related quality of life among patients cured by surgery for esophageal cancer.
      ].
      Notwithstanding encouraging gQOL and function scores observed, most patients have a considerable symptom burden. Some patients with a high level of symptomology report good HRQL scores, however a subset still reported impaired gQOL. Independent risk factors for this included increased Sigstad, steatorrhoea-specific, and mGSRS score, but neither demographic nor clinicopathologic factors. As these risk factors are all related to gastrointestinal function, the benefit of comprehensive and intensive nutritional management in this cohort is further highlighted.
      Extensive gastrointestinal resection and reconstruction, an inherent consequence of oesophagectomy, increases the risk of malnutrition postoperatively [
      • Martin L.
      • Lagergren J.
      • Lindblad M.
      • Rouvelas I.
      • Lagergren P.
      Malnutrition after oesophageal cancer surgery in Sweden.
      ,
      • Nakashima Y.
      • Saeki H.
      • Hu Q.
      • Tsuda Y.
      • Zaitsu Y.
      • Hisamatsu Y.
      • et al.
      Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer.
      ], which is associated with reduced HRQL and survival [
      • Donohoe C.L.
      • McGillycuddy E.
      • Reynolds J.V.
      Long-term health-related quality of life for disease-free esophageal cancer patients.
      ,
      • Kitagawa H.
      • Namikawa T.
      • Munekage M.
      • Fujisawa K.
      • Munekage E.
      • Kawanishi Y.
      • et al.
      Analysis of Factors Associated with Weight Loss After Esophagectomy for Esophageal Cancer.
      ,
      • D'Journo X.B.
      • Ouattara M.
      • Loundou A.
      • Trousse D.
      • Dahan L.
      • Nathalie T.
      • et al.
      Prognostic impact of weight loss in 1-year survivors after transthoracic esophagectomy for cancer.
      ,
      • Schandl A.
      • Johar A.
      • Anandavadivelan P.
      • Vikström K.
      • Mälberg K.
      • Lagergren P.
      Patient-reported outcomes 1 year after oesophageal cancer surgery.
      ,
      • Steenhagen E.
      • van Vulpen J.K.
      • van Hillegersberg R.
      • May A.M.
      • Siersema P.D.
      Nutrition in peri-operative esophageal cancer management.
      ]. At 1-year postoperatively, the prevalence of malnutrition in this cohort was 43.2% when defined by BWL >10%, and 29.7% as per NRI. This is lower than what is reported in similar studies [
      • Martin L.
      • Lagergren J.
      • Lindblad M.
      • Rouvelas I.
      • Lagergren P.
      Malnutrition after oesophageal cancer surgery in Sweden.
      ,
      • D'Journo X.B.
      • Ouattara M.
      • Loundou A.
      • Trousse D.
      • Dahan L.
      • Nathalie T.
      • et al.
      Prognostic impact of weight loss in 1-year survivors after transthoracic esophagectomy for cancer.
      ,
      • Park S.Y.
      • Kim D.J.
      • Suh J.W.
      • Byun G.E.
      Risk Factors for Weight Loss 1 Year After Esophagectomy and Gastric Pull-up for Esophageal Cancer.
      ], possibly achieved through postoperative jejunostomy feeding for typically one month post-discharge, dietetic interventions, and increased monitoring via the survivorship clinic. It is worth noting that evidence supporting the use of malnutrition assessment tools such as the Patient-Generated Subjective Global Assessment tool [
      • Ottery F.D.
      Definition of standardized nutritional assessment and interventional pathways in oncology.
      ] and the Global Leadership Initiative on Malnutrition tool [
      • Cederholm T.
      • Jensen G.L.
      • Correia M.
      • Gonzalez M.C.
      • Fukushima R.
      • Higashiguchi T.
      • et al.
      GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.
      ] is superior to the NRI [
      • Jager-Wittenaar H.
      • Ottery F.D.
      Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment.
      ,
      • De Groot L.M.
      • Lee G.
      • Ackerie A.
      • van der Meij B.S.
      Malnutrition Screening and Assessment in the Cancer Care Ambulatory Setting: Mortality Predictability and Validity of the Patient-Generated Subjective Global Assessment Short form (PG-SGA SF) and the GLIM Criteria.
      ]. However, the NRI was used to allow for comparisons with previous publications on oesophageal cancer cohorts from this [
      • Heneghan H.M.
      • Zaborowski A.
      • Fanning M.
      • McHugh A.
      • Doyle S.
      • Moore J.
      • et al.
      Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
      ] and other centres nationally [
      • Ryan A.M.
      • Reynolds J.V.
      • Healy L.
      • Byrne M.
      • Moore J.
      • Brannelly N.
      • 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.
      ,
      • Healy L.A.
      • Ryan A.
      • Doyle S.L.
      • Éb N.B.
      • Cushen S.
      • Segurado R.
      • et al.
      Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial.
      ]. Furthermore, the volume of subjective participant questionnaires employed in this study indicated use of a straightforward, objective malnutrition screening tool such as the NRI, which carries limited evidence suggesting its utility [
      • Tyner B.C.B.
      • O’Neill M.
      • Philips M.
      • Marshall L.
      • Smith S.M.
      • Ryan M.
      Systematic review of nutritional screening tools for adult patients in acute hospital settings.
      ,
      • Faramarzi E.
      • Mahdavi R.
      • Mohammad-Zadeh M.
      • Nasirimotlagh B.
      Validation of nutritional risk index method against patient-generated subjective global assessment in screening malnutrition in colorectal cancer patients.
      ,
      • Duguet A.
      • Bachmann P.
      • Lallemand Y.
      • Blanc-Vincent M.P.
      Summary report of the Standards, Options and Recommendations for malnutrition and nutritional assessment in patients with cancer (1999).
      ].
      Probable sarcopenia prevalence did not significantly increase postoperatively despite postoperative BWL, suggesting loss of fat mass was greater than SMM in this cohort. As sarcopenia is negatively associated with overall survival [
      • Srpcic M.
      • Jordan T.
      • Popuri K.
      • Sok M.
      Sarcopenia and myosteatosis at presentation adversely affect survival after esophagectomy for esophageal cancer.
      ,
      • 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.
      ] and major morbidity [
      • Elliott J.A.
      • Doyle S.L.
      • Murphy C.F.
      • King S.
      • Guinan E.M.
      • Beddy P.
      • et al.
      Sarcopenia: Prevalence, and Impact on Operative and Oncologic Outcomes in the Multimodal Management of Locally Advanced Esophageal Cancer.
      ], this is a positive, clinically relevant finding. Notwithstanding, it is worth considering that using hand grip strength as a surrogate for sarcopenia does not follow European clinical consensus guidelines [
      • Cruz-Jentoft A.J.
      • Baeyens J.P.
      • Bauer J.M.
      • Boirie Y.
      • Cederholm T.
      • Landi F.
      • et al.
      Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People.
      ] and may have underestimated its prevalence. It was for this reason that the term ‘probable sarcopenia’ was used throughout the present study.
      Vagal denervation and endogenous neuroendocrine signal loss can result in exocrine pancreas insufficiency post-oesophagectomy [
      • Steenhagen E.
      • van Vulpen J.K.
      • van Hillegersberg R.
      • May A.M.
      • Siersema P.D.
      Nutrition in peri-operative esophageal cancer management.
      ]. In this study, the prevalence of malabsorption significantly increased from 6 to 12 months postoperatively. Malabsorption and steatorrhoea contribute to malnutrition through nutrient loss, especially of fat soluble vitamins, so identifying patients and treatment with pancreatic enzymes is both essential and effective [
      • Heneghan H.M.
      • Zaborowski A.
      • Fanning M.
      • McHugh A.
      • Doyle S.
      • Moore J.
      • et al.
      Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
      ]. It has not been previously investigated whether the overall effect of steatorrhoea reduces HRQL [
      • Blonk L.
      • Wierdsma N.J.
      • Jansma E.P.
      • Kazemier G.
      • van der Peet D.L.
      • Straatman J.
      Exocrine pancreatic insufficiency after esophagectomy: a systematic review of literature.
      ], where present study found a reduction in several HRQL scores, including cognitive function. This association warrants further investigation and may be related to fat soluble vitamin [
      • Grimm M.O.W.
      • Mett J.
      • Hartmann T.
      The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease.
      ] and/or other micronutrient deficiency [
      • Araújo J.R.
      • Martel F.
      • Borges N.
      • Araújo J.M.
      • Keating E.
      Folates and aging: Role in mild cognitive impairment, dementia and depression.
      ,
      • van Hagen P.
      • de Jonge R.
      • van Berge Henegouwen M.I.
      • Hötte G.J.
      • van der Stok E.P.
      • Lindemans J.
      • et al.
      Vitamin B12 deficiency after esophagectomy with gastric tube reconstruction for esophageal cancer.
      ].
      Although many nutritional parameters were better than reported in previous studies, the prevalence of DS was high. There may be many contributing factors, including the routine use of pyloroplasty in patients at this centre, which may accelerate gastric emptying. A key element is likely the detailed prospective evaluation of relevant symptoms in each patient, something which we suspect is not standard practice outside of such structures and clinical research [
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ]. Moreover, it is clear that an inconsistency in assessment and diagnostic methods for DS limits reliable comparisons between studies [
      • Boshier P.R.
      • Huddy J.R.
      • Zaninotto G.
      • Hanna G.B.
      Dumping syndrome after esophagectomy: a systematic review of the literature.
      ]. Importantly, DS was strongly associated with HRQL, principally fatigue and social function. Social function recovery is essential as it allows OCS to separate themselves from the identity of a ‘cancer patient’ [
      • Thong M.S.Y.
      • Wolschon E.-M.
      • Koch-Gallenkamp L.
      • Waldmann A.
      • Waldeyer-Sauerland M.
      • Pritzkuleit R.
      • et al.
      “Still a Cancer Patient”—Associations of Cancer Identity With Patient-Reported Outcomes and Health Care Use Among Cancer Survivors.
      ], but unpleasant social interactions and anxiety associated with DS may impede this [
      • van Beek A.P.
      • Emous M.
      • Laville M.
      • Tack J.
      Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management.
      ]. Taken together, these findings confirm that dumping syndrome is a major, prevalent problem after oesophagectomy that requires objective, evidence-based diagnosis, management, and treatment guidelines. Management and treatment may be aided by novel interventions, such as continuous glucose monitoring, which could be a useful tool in the diagnosis and management of reactive hypoglycaemia [
      • Malik S.
      • Mitchell J.E.
      • Steffen K.
      • Engel S.
      • Wiisanen R.
      • Garcia L.
      • et al.
      Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery.
      ]. It may also facilitate strategies to reduce the impact of dumping on HRQL, especially social and cognitive function [
      • Sheehan A.
      • Patti M.E.
      Hypoglycemia After Upper Gastrointestinal Surgery: Clinical Approach to Assessment, Diagnosis, and Treatment.
      ].
      Nutrition-impact symptoms are key contributors to malnutrition [
      • Baker M.
      • Halliday V.
      • Williams R.N.
      • Bowrey D.J.
      A systematic review of the nutritional consequences of esophagectomy.
      ], and it is known that they reduce HRQL [
      • Tielemans M.M.
      • Jaspers Focks J.
      • van Rossum L.G.
      • Eikendal T.
      • Jansen J.B.
      • Laheij R.J.
      • et al.
      Gastrointestinal symptoms are still prevalent and negatively impact health-related quality of life: a large cross-sectional population based study in The Netherlands.
      ,
      • Sweed M.R.
      • Schiech L.
      • Barsevick A.
      • Babb J.S.
      • Goldberg M.
      Quality of life after esophagectomy for cancer.
      ,
      • Haverkort E.B.
      • Binnekade J.M.
      • Busch O.R.
      • van Berge Henegouwen M.I.
      • de Haan R.J.
      • Gouma D.J.
      Presence and persistence of nutrition-related symptoms during the first year following esophagectomy with gastric tube reconstruction in clinically disease-free patients.
      ,
      • Gupta V.
      • Allen-Ayodabo C.
      • Davis L.
      • Zhao H.
      • Hallet J.
      • Mahar A.L.
      • et al.
      Patient-Reported Symptoms for Esophageal Cancer Patients Undergoing Curative Intent Treatment.
      ]. However, this has rarely been explicitly studied in OCS. This may be because the symptom pattern of OCS as they recover is unclear [
      • Ginex P.
      • Thom B.
      • Jingeleski M.
      • Vincent A.
      • Plourde G.
      • Rizk N.
      • et al.
      Patterns of symptoms following surgery for esophageal cancer.
      ] and holds inter-individual variability. The present study found that symptoms do not improve from 6 to 12 months postoperatively, suggesting lack of adaption of the gastrointestinal tract to anatomical changes in the first year after surgery. Total mGSRS score was strongly correlated with numerous HRQL scores at both postoperative time-points, including gQOL, and it independently contributed to variance in gQOL at 6 months. Therefore, a total mGSRS score threshold for identifying those whose HRQL could benefit from specialised nutritional input was determined. This mGSRS test is patient-centred, timely, and efficient; thus fulfilling the requirements of a high-quality test as reported by Power et al. [
      • Power M.
      • Fell G.
      • Wright M.
      Principles for high-quality, high-value testing.
      ]. This study also revealed it to be a sensitive and specific screening tool for use in clinical practice, allowing those at highest risk of impaired gQOL to be referred for targeted symptom management intervention. It was also found that 12-month gQOL score could be predicted by the 6-month mGSRS score using the reported equation. This would allow an opportunity for early intervention in those identified as high risk of impaired HRQL with the aim of reducing their symptom burden by the 12-month postoperative time-point.
      The strengths of this study include detailed, prospective data collection at a dedicated structured clinic [
      • Murphy C.F.
      • Fanning M.
      • Raftery N.
      • Elliott J.A.
      • Docherty N.G.
      • Donohoe C.L.
      • et al.
      Early experience with a nutrition and survivorship clinic in esophageal cancer.
      ] and the use of validated questionnaires [
      • Lagergren P.
      • Fayers P.
      • Conroy T.
      • Stein H.J.
      • Sezer O.
      • Hardwick R.
      • et al.
      Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach.
      ,
      • Groenvold M.
      • Klee M.C.
      • Sprangers M.A.
      • Aaronson N.K.
      Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement.
      ], which minimise information bias. Additionally, assessment at two postoperative time-points allowed for more rigorous evaluations of postoperative contributors to HRQL. We acknowledge some limitations, including a relatively modest sample size from a single institution, and encourage result validation in a larger study group, including the regression analyses and mGSRS threshold. Sources of potential bias include participant drop-out, self-reporting of symptoms, and the sole inclusion of patients who remained recurrence-free throughout the study period, introducing a survivorship bias. Notably, correction for multiple comparisons was not employed in this analysis. Tools such as Bonferroni have been criticised for being overly restrictive and increasing the risk of Type 2 errors. In this analysis, we explored a wide spectrum of patient outcomes and the results have been interpretated in a holistic manner, rather than focusing on single results of significance.

      Conclusion

      This study has shown that malnutrition and DS are prevalent after OC surgery, and that NIS reduce HRQL. The clinic structure and the study data support such programmes for these cohorts of patients, in particular those with severe NIS. We have proposed a mGSRS threshold of >11.5, however validation of this in a larger sample is needed. The high prevalence of DS is noted, and its detailed assessment complimented by continuous glucose monitoring to diagnose and manage reactive hypoglycaemia represents an important area to study. These data show that nutritional health is inextricably linked to symptoms, HRQL, and recovery and survivorship after oesophageal cancer surgery, and strategies to optimise the patient pathway through the treatment cycle into survivorship should create clinics with a major focus on dietetics/nutritional health to accommodate these significant patient needs.

      Funding statement

      This research was completed as part of a university thesis project. As such, it did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Author contributions

      Sarah Bennett: Formal analysis, Investigation, Methodology, Visualization; Roles/Writing - original draft Conor F Murphy: Data Curation, Investigation, Writing - review & editing, Resources. Michelle Fanning: Conceptualization, Writing - review & editing. John V Reynolds: Writing - review & editing. Suzanne L Doyle: Project administration, Visualization; Roles/Writing - original draft, Resources, Supervision Claire L Donohoe: Conceptualization, Writing - review & editing.

      Not relevant

      Software, Validation, Funding Acquisition.

      Conflicts of interest

      The authors declare no conflict of interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Lagergren J.
        • Smyth E.
        • Cunningham D.
        • Lagergren P.
        Oesophageal cancer.
        Lancet. 2017; 390: 2383-2396
        • Low D.E.
        • Allum W.
        • De Manzoni G.
        • Ferri L.
        • Immanuel A.
        • Kuppusamy M.
        • et al.
        Guidelines for Perioperative Care in Esophagectomy: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations.
        World J Surg. 2019; 43: 299-330
        • Blencowe N.S.
        • Strong S.
        • McNair A.G.
        • Brookes S.T.
        • Crosby T.
        • Griffin S.M.
        • et al.
        Reporting of short-term clinical outcomes after esophagectomy: a systematic review.
        Ann Surg. 2012; 255: 658-666
        • Murthy R.A.
        • Clarke N.S.
        • Kernstine Sr., K.H.
        Minimally Invasive and Robotic Esophagectomy: A Review.
        Innovations (Phila). 2018; 13: 391-403
        • Scarpa M.
        • Valente S.
        • Alfieri R.
        • Cagol M.
        • Diamantis G.
        • Ancona E.
        • et al.
        Systematic review of health-related quality of life after esophagectomy for esophageal cancer.
        World J Gastroenterol. 2011; 17: 4660-4674
        • Jacobs M.
        • Macefield R.C.
        • Elbers R.G.
        • Sitnikova K.
        • Korfage I.J.
        • Smets E.M.
        • et al.
        Meta-analysis shows clinically relevant and long-lasting deterioration in health-related quality of life after esophageal cancer surgery.
        Qual Life Res. 2014; 23: 1097-1115
        • Taioli E.
        • Schwartz R.M.
        • Lieberman-Cribbin W.
        • Moskowitz G.
        • van Gerwen M.
        • Flores R.
        Quality of Life after Open or Minimally Invasive Esophagectomy in Patients With Esophageal Cancer-A Systematic Review.
        Semin Thorac Cardiovasc Surg. 2017; 29: 377-390
        • Parameswaran R.
        • McNair A.
        • Avery K.N.
        • Berrisford R.G.
        • Wajed S.A.
        • Sprangers M.A.
        • et al.
        The role of health-related quality of life outcomes in clinical decision making in surgery for esophageal cancer: a systematic review.
        Ann Surg Oncol. 2008; 15: 2372-2379
        • Gavin A.T.
        • Francisci S.
        • Foschi R.
        • Donnelly D.W.
        • Lemmens V.
        • Brenner H.
        • et al.
        Oesophageal cancer survival in Europe: a EUROCARE-4 study.
        Cancer Epidemiol. 2012; 36: 505-512
        • Lagergren P.
        • Fayers P.
        • Conroy T.
        • Stein H.J.
        • Sezer O.
        • Hardwick R.
        • et al.
        Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach.
        Eur J Cancer. 2007; 43: 2066-2073
        • Baker M.
        • Halliday V.
        • Williams R.N.
        • Bowrey D.J.
        A systematic review of the nutritional consequences of esophagectomy.
        Clin Nutr. 2016; 35: 987-994
        • Soriano T.T.
        • Eslick G.D.
        • Vanniasinkam T.
        Long-Term Nutritional Outcome and Health Related Quality of Life of Patients Following Esophageal Cancer Surgery: A Meta-Analysis.
        Nutr Cancer. 2018; 70: 192-203
        • Murphy C.F.
        • Fanning M.
        • Raftery N.
        • Elliott J.A.
        • Docherty N.G.
        • Donohoe C.L.
        • et al.
        Early experience with a nutrition and survivorship clinic in esophageal cancer.
        Dis Esophagus. 2021; 34: doaa061
        • Chang Y.L.
        • Tsai Y.F.
        • Chao Y.K.
        • Wu M.Y.
        Quality-of-life measures as predictors of post-esophagectomy survival of patients with esophageal cancer.
        Qual Life Res. 2016; 25: 465-475
        • Markar S.R.
        • Zaninotto G.
        • Castoro C.
        • Johar A.
        • Lagergren P.
        • Elliot J.A.
        • et al.
        Lasting Symptoms After Esophageal Resection (LASER): European Multicenter Cross-sectional Study.
        Ann Surg. 2020; ([Preprint] Available from:)https://doi.org/10.1097/sla.0000000000003917
        • Donohoe C.L.
        • McGillycuddy E.
        • Reynolds J.V.
        Long-term health-related quality of life for disease-free esophageal cancer patients.
        World J Surg. 2011; 35: 1853-1860
        • Sun V.
        • Kim J.
        • Kim J.Y.
        • Raz D.J.
        • Merchant S.
        • Chao J.
        • et al.
        Dietary alterations and restrictions following surgery for upper gastrointestinal cancers: Key components of a health-related quality of life intervention.
        Eur J Oncol Nurs. 2015; 19: 343-348
        • Derogar M.
        • Lagergren P.
        Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study.
        J Clin Oncol. 2012; 30: 413-418
        • Omlin A.
        • Blum D.
        • Wierecky J.
        • Haile S.R.
        • Ottery F.D.
        • Strasser F.
        Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a case-control study.
        J Cachexia Sarcopenia Muscle. 2013; 4: 55-61
        • Mantoan S.
        • Cavallin F.
        • Pinto E.
        • Saadeh L.M.
        • Alfieri R.
        • Cagol M.
        • et al.
        Long-term quality of life after esophagectomy with gastric pull-up.
        J Surg Oncol. 2018; 117: 970-976
        • Djärv T.
        • Lagergren P.
        Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery.
        Eur J Cancer. 2011; 47: 530-535
        • Anandavadivelan P.
        • Martin L.
        • Djärv T.
        • Johar A.
        • Lagergren P.
        Nutrition Impact Symptoms Are Prognostic of Quality of Life and Mortality after Surgery for Oesophageal Cancer.
        Cancers (Basel). 2018; 10: 318-327
        • Donohoe C.L.
        • Healy L.A.
        • Fanning M.
        • Doyle S.L.
        • Hugh A.M.
        • Moore J.
        • et al.
        Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.
        Dis Esophagus. 2017; 30: 1-9
        • Martin L.
        • Jia C.
        • Rouvelas I.
        • Lagergren P.
        Risk factors for malnutrition after oesophageal and cardia cancer surgery.
        Br J Surg. 2008; 95: 1362-1368
        • Stahl M.
        • Mariette C.
        • Haustermans K.
        • Cervantes A.
        • Arnold D.
        Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi51-56
        • Elliott J.A.
        • Docherty N.G.
        • Eckhardt H.G.
        • Doyle S.L.
        • Guinan E.M.
        • Ravi N.
        • et al.
        Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study.
        Ann Surg. 2017; 266: 82-90
        • Heneghan H.M.
        • Zaborowski A.
        • Fanning M.
        • McHugh A.
        • Doyle S.
        • Moore J.
        • et al.
        Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery.
        Ann Surg. 2015; 262: 803-808
        • Elliott J.A.
        • Docherty N.G.
        • Murphy C.F.
        • Eckhardt H.G.
        • Doyle S.L.
        • Guinan E.M.
        • et al.
        Changes in gut hormones, glycaemic response and symptoms after oesophagectomy.
        Br J Surg. 2019; 106: 735-746
        • Elliott J.A.
        • Casey S.
        • Murphy C.F.
        • Docherty N.G.
        • Ravi N.
        • Beddy P.
        • et al.
        Risk factors for loss of bone mineral density after curative esophagectomy.
        Arch Osteoporos. 2019; 14: 6
        • Guinan E.M.
        • Bennett A.E.
        • Doyle S.L.
        • O’Neill L.
        • Gannon J.
        • Foley G.
        • et al.
        Measuring the impact of oesophagectomy on physical functioning and physical activity participation: a prospective study.
        BMC Cancer. 2019; 19: 682
        • Elliott J.A.
        • Doyle S.L.
        • Murphy C.F.
        • King S.
        • Guinan E.M.
        • Beddy P.
        • 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
        • Anandavadivelan P.
        • Wikman A.
        • Johar A.
        • Lagergren P.
        Impact of weight loss and eating difficulties on health-related quality of life up to 10yearsafter oesophagectomy for cancer.
        Br J Surg. 2018; 105: 410-418
        • Martin L.
        • Lagergren J.
        • Lindblad M.
        • Rouvelas I.
        • Lagergren P.
        Malnutrition after oesophageal cancer surgery in Sweden.
        Br J Surg. 2007; 94: 1496-1500
        • Nakashima Y.
        • Saeki H.
        • Hu Q.
        • Tsuda Y.
        • Zaitsu Y.
        • Hisamatsu Y.
        • et al.
        Skeletal Muscle Loss After Esophagectomy Is an Independent Risk Factor for Patients with Esophageal Cancer.
        Ann Surg Oncol. 2020; 27: 492-498
        • Martin L.
        • Lagergren P.
        Long-term weight change after oesophageal cancer surgery.
        Br J Surg. 2009; 96: 1308-1314
        • Tack J.
        • Arts J.
        • Caenepeel P.
        • De Wulf D.
        • Bisschops R.
        Pathophysiology, diagnosis and management of postoperative dumping syndrome.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 583-590
        • Berg P.
        • McCallum R.
        Dumping Syndrome: A Review of the Current Concepts of Pathophysiology, Diagnosis, and Treatment.
        Dig Dis Sci. 2016; 61: 11-18
        • van Beek A.P.
        • Emous M.
        • Laville M.
        • Tack J.
        Dumping syndrome after esophageal, gastric or bariatric surgery: pathophysiology, diagnosis, and management.
        Obes Rev. 2017; 18: 68-85
        • Miholic J.
        • Orskov C.
        • Holst J.J.
        • Kotzerke J.
        • Pichlmayr R.
        Postprandial release of glucagon-like peptide-1, pancreatic glucagon, and insulin after esophageal resection.
        Digestion. 1993; 54: 73-78
        • Burrows W.M.
        Gastrointestinal function and related problems following esophagectomy.
        Semin Thorac Cardiovasc Surg. 2004; 16: 142-151
        • Tack J.
        • Deloose E.
        Complications of bariatric surgery: dumping syndrome, reflux and vitamin deficiencies.
        Best Pract Res Clin Gastroenterol. 2014; 28: 741-749
        • Vavricka S.R.
        • Greuter T.
        Gastroparesis and Dumping Syndrome: Current Concepts and Management.
        J Clin Med. 2019; 8: 1127
        • International Dysphagia Diet Standardisation Initiative
        IDDSI Framework and Detailed Level Definitions.
        2019 (Available from:)
        https://iddsi.org/framework/
        Date accessed: October 14, 2021
        • Scott N.W.
        • Fayers P.M.
        • Aaronson N.K.
        • Bottomly A.
        • de Graeff A.
        • Groenvold M.
        • et al.
        EORTC QLQ-C30 reference values manual.
        2nd ed. EORTC Quality of Life Group, Brussels, Belgium2008
        • Nolte S.
        • Liegl G.
        • Petersen M.A.
        • Aaronson N.K.
        • Costantini A.
        • Fayers P.M.
        • et al.
        General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States.
        Eur J Cancer. 2019; 107: 153-163
        • Sigstad H.
        A clinical diagnostic index in the diagnosis of the dumping syndrome. Changes in plasma volume and blood sugar after a test meal.
        Acta Med Scand. 1970; 188: 479-486
        • Blackburn G.L.
        • Bistrian B.R.
        • Maini B.S.
        • Schlamm H.T.
        • Smith M.F.
        Nutritional and metabolic assessment of the hospitalized patient.
        J Parenter Enteral Nutr. 1977; 1: 11-22
      1. World Health Organisation. Body Mass Index - BMI. Available from: https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthylifestyle/body-mass-index-bmi [Accessed 23/03/2021].

        • Bouillanne O.
        • Morineau G.
        • Dupont C.
        • Coulombel I.
        • Vincent J.P.
        • Nicolis I.
        • et al.
        Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients.
        Am J Clin Nutr. 2005; 82: 777-783
        • Schiesser M.
        • Kirchhoff P.
        • Müller M.K.
        • Schäfer M.
        • Clavien P.A.
        The correlation of nutrition risk index, nutrition risk score, and bioimpedance analysis with postoperative complications in patients undergoing gastrointestinal surgery.
        Surgery. 2009; 145: 519-526
        • Oh C.A.
        • Kim D.H.
        • Oh S.J.
        • Choi M.G.
        • Noh J.H.
        • Sohn T.S.
        • et al.
        Nutritional risk index as a predictor of postoperative wound complications after gastrectomy.
        World J Gastroenterol. 2012; 18: 673-678
        • Fujiya K.
        • Kawamura T.
        • Omae K.
        • Nishiwaki N.
        • Kaji S.
        • Hikage M.
        • et al.
        Post-gastrectomy nutrition risk index can be a good predictive factor for survival.
        J Clin Oncol. 2017; 35 (101): 101
        • Veterans Affairs Total Parenteral Nutrition Cooperative Study Group
        Perioperative total parenteral nutrition in surgical patients.
        N Engl J Med. 1991; 325: 525-532
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • Newman A.B.
        • Hirsch C.
        • Gottdiener J.
        • et al.
        Frailty in older adults: evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: 146-156
        • Scarpellini E.
        • Arts J.
        • Karamanolis G.
        • Laurenius A.
        • Siquini W.
        • Suzuki H.
        • et al.
        International consensus on the diagnosis and management of dumping syndrome.
        Nat Rev Endocrinol. 2020; 16: 448-466
        • Karimi M.
        • Brazier J.
        • Health
        Health-Related Quality of Life, and Quality of Life: What is the Difference?.
        Pharmacoeconomics. 2016; 34: 645-649
        • Rejeski W.J.
        • Mihalko S.L.
        Physical Activity and Quality of Life in Older Adults.
        J Gerontol: Series A. 2001; 56: 23-35
        • Fayers P.M.
        • Aaronson N.K.
        • Bjordal K.
        • Groenvold M.
        • Curran D.
        • Bottomley A.
        EORTC QLQC30 scoring manual.
        3rd ed. European Organisation for Research and Treatment of Cancer, Brussels, Belgium2001
        • Cocks K.
        • King M.T.
        • Velikova G.
        • Martyn St-James M.
        • Fayers P.M.
        • Brown J.M.
        Evidence-based guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
        J Clin Oncol. 2011; 29: 89-96
        • Cocks K.
        • King M.T.
        • Velikova G.
        • de Castro Jr., G.
        • Martyn St-James M.
        • Fayers P.M.
        • et al.
        Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
        Eur J Cancer. 2012; 48: 1713-1721
        • Dindo D.
        • Demartines N.
        • Clavien P.A.
        Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
        Ann Surg. 2004; 240: 205-213
        • Power M.
        • Fell G.
        • Wright M.
        Principles for high-quality, high-value testing.
        Evid Based Med. 2013; 18: 5-10
        • Lagergren P.
        • Avery K.N.
        • Hughes R.
        • Barham C.P.
        • Alderson D.
        • Falk S.J.
        • et al.
        Health-related quality of life among patients cured by surgery for esophageal cancer.
        Cancer. 2007; 110: 686-693
        • Blazeby J.M.
        • Farndon J.R.
        • Donovan J.
        • Alderson D.
        A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma.
        Cancer. 2000; 88: 1781-1787
        • Djärv T.
        • Blazeby J.M.
        • Lagergren P.
        Predictors of postoperative quality of life after esophagectomy for cancer.
        J Clin Oncol. 2009; 27: 1963-1968
        • van Heijl M.
        • Sprangers M.A.G.
        • de Boer A.G.E.M.
        • Lagarde S.M.
        • Reitsma H.B.
        • Busch O.R.C.
        • et al.
        Preoperative and Early Postoperative Quality of Life Predict Survival in Potentially Curable Patients with Esophageal Cancer.
        Ann Surg Oncol. 2010; 17: 23-30
        • Courrech Staal E.F.
        • van Sandick J.W.
        • van Tinteren H.
        • Cats A.
        • Aaronson N.K.
        Health-related quality of life in long-term esophageal cancer survivors after potentially curative treatment.
        J Thorac Cardiovasc Surg. 2010; 140: 777-783
        • Reynolds J.V.
        • McLaughlin R.
        • Moore J.
        • Rowley S.
        • Ravi N.
        • Byrne P.J.
        Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone.
        Br J Surg. 2006; 93: 1084-1090
        • Alghamedi A.
        • Buduhan G.
        • Tan L.
        • Srinathan S.K.
        • Sulman J.
        • Darling G.
        • et al.
        Quality of life assessment in esophagectomy patients.
        Ann Transl Med. 2018; 6: 84
        • McLarty A.J.
        • Deschamps C.
        • Trastek V.F.
        • Allen M.S.
        • Pairolero P.C.
        • Harmsen W.S.
        Esophageal resection for cancer of the esophagus: long-term function and quality of life.
        Ann Thorac Surg. 1997; 63: 1568-1572
        • Isenring E.A.
        • Capra S.
        • Bauer J.D.
        Nutrition intervention is beneficial in oncology outpatients receiving radiotherapy to the gastrointestinal or head and neck area.
        Br J Cancer. 2004; 91: 447-452
        • Conroy T.
        • Marchal F.
        • Blazeby J.M.
        Quality of life in patients with oesophageal and gastric cancer: an overview.
        Oncology. 2006; 70: 391-402
        • Kitagawa H.
        • Namikawa T.
        • Munekage M.
        • Fujisawa K.
        • Munekage E.
        • Kawanishi Y.
        • et al.
        Analysis of Factors Associated with Weight Loss After Esophagectomy for Esophageal Cancer.
        Anticancer Res. 2016; 36: 5409-5412
        • D'Journo X.B.
        • Ouattara M.
        • Loundou A.
        • Trousse D.
        • Dahan L.
        • Nathalie T.
        • et al.
        Prognostic impact of weight loss in 1-year survivors after transthoracic esophagectomy for cancer.
        Dis Esophagus. 2012; 25: 527-534
        • Schandl A.
        • Johar A.
        • Anandavadivelan P.
        • Vikström K.
        • Mälberg K.
        • Lagergren P.
        Patient-reported outcomes 1 year after oesophageal cancer surgery.
        Acta Oncol. 2020; 59: 613-619
        • Steenhagen E.
        • van Vulpen J.K.
        • van Hillegersberg R.
        • May A.M.
        • Siersema P.D.
        Nutrition in peri-operative esophageal cancer management.
        Expert Rev Gastroenterol Hepatol. 2017; 11: 663-672
        • Park S.Y.
        • Kim D.J.
        • Suh J.W.
        • Byun G.E.
        Risk Factors for Weight Loss 1 Year After Esophagectomy and Gastric Pull-up for Esophageal Cancer.
        J Gastrointest Surg. 2018; 22: 1137-1143
        • Ottery F.D.
        Definition of standardized nutritional assessment and interventional pathways in oncology.
        Nutrition. 1996; 12: 15-19
        • Cederholm T.
        • Jensen G.L.
        • Correia M.
        • Gonzalez M.C.
        • Fukushima R.
        • Higashiguchi T.
        • et al.
        GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community.
        J Cachexia Sarcopenia Muscle. 2019; 10: 207-217
        • Jager-Wittenaar H.
        • Ottery F.D.
        Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment.
        Curr Opin Clin Nutr Metab Care. 2017; 20: 322-329
        • De Groot L.M.
        • Lee G.
        • Ackerie A.
        • van der Meij B.S.
        Malnutrition Screening and Assessment in the Cancer Care Ambulatory Setting: Mortality Predictability and Validity of the Patient-Generated Subjective Global Assessment Short form (PG-SGA SF) and the GLIM Criteria.
        Nutrients. 2020; 12: 2287
        • Ryan A.M.
        • Reynolds J.V.
        • Healy L.
        • Byrne M.
        • Moore J.
        • Brannelly N.
        • 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
        • Healy L.A.
        • Ryan A.
        • Doyle S.L.
        • Éb N.B.
        • Cushen S.
        • Segurado R.
        • et al.
        Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial.
        Ann Surg. 2017; 266: 720-728
        • Tyner B.C.B.
        • O’Neill M.
        • Philips M.
        • Marshall L.
        • Smith S.M.
        • Ryan M.
        Systematic review of nutritional screening tools for adult patients in acute hospital settings.
        Department of Health, 2020 (Available from:)
        • Faramarzi E.
        • Mahdavi R.
        • Mohammad-Zadeh M.
        • Nasirimotlagh B.
        Validation of nutritional risk index method against patient-generated subjective global assessment in screening malnutrition in colorectal cancer patients.
        Chin J Cancer Res. 2013; 25: 544-548
        • Duguet A.
        • Bachmann P.
        • Lallemand Y.
        • Blanc-Vincent M.P.
        Summary report of the Standards, Options and Recommendations for malnutrition and nutritional assessment in patients with cancer (1999).
        Br J Cancer. 2003; 89: 92-97
        • Srpcic M.
        • Jordan T.
        • Popuri K.
        • Sok M.
        Sarcopenia and myosteatosis at presentation adversely affect survival after esophagectomy for esophageal cancer.
        Radiol Oncol. 2020; 54: 237-246
        • 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: 1-11
        • Cruz-Jentoft A.J.
        • Baeyens J.P.
        • Bauer J.M.
        • Boirie Y.
        • Cederholm T.
        • Landi F.
        • 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
        • Blonk L.
        • Wierdsma N.J.
        • Jansma E.P.
        • Kazemier G.
        • van der Peet D.L.
        • Straatman J.
        Exocrine pancreatic insufficiency after esophagectomy: a systematic review of literature.
        Dis Esophagus. 2021;
        • Grimm M.O.W.
        • Mett J.
        • Hartmann T.
        The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease.
        Int J Mol Sci. 2016; 17: 1785
        • Araújo J.R.
        • Martel F.
        • Borges N.
        • Araújo J.M.
        • Keating E.
        Folates and aging: Role in mild cognitive impairment, dementia and depression.
        Ageing Res Rev. 2015; 22: 9-19
        • van Hagen P.
        • de Jonge R.
        • van Berge Henegouwen M.I.
        • Hötte G.J.
        • van der Stok E.P.
        • Lindemans J.
        • et al.
        Vitamin B12 deficiency after esophagectomy with gastric tube reconstruction for esophageal cancer.
        Dis Esophagus. 2017; 30: 1-8
        • Boshier P.R.
        • Huddy J.R.
        • Zaninotto G.
        • Hanna G.B.
        Dumping syndrome after esophagectomy: a systematic review of the literature.
        Dis Esophagus. 2017; 30: 1-9
        • Thong M.S.Y.
        • Wolschon E.-M.
        • Koch-Gallenkamp L.
        • Waldmann A.
        • Waldeyer-Sauerland M.
        • Pritzkuleit R.
        • et al.
        “Still a Cancer Patient”—Associations of Cancer Identity With Patient-Reported Outcomes and Health Care Use Among Cancer Survivors.
        JNCI Cancer Spectrum. 2018; 2: pky031
        • Malik S.
        • Mitchell J.E.
        • Steffen K.
        • Engel S.
        • Wiisanen R.
        • Garcia L.
        • et al.
        Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery.
        Obes Res Clin Pract. 2016; 10: 1-14
        • Sheehan A.
        • Patti M.E.
        Hypoglycemia After Upper Gastrointestinal Surgery: Clinical Approach to Assessment, Diagnosis, and Treatment.
        Diabetes Metab Syndr Obes. 2020; 13: 4469-4482
        • Tielemans M.M.
        • Jaspers Focks J.
        • van Rossum L.G.
        • Eikendal T.
        • Jansen J.B.
        • Laheij R.J.
        • et al.
        Gastrointestinal symptoms are still prevalent and negatively impact health-related quality of life: a large cross-sectional population based study in The Netherlands.
        PLoS One. 2013; 8e69876
        • Sweed M.R.
        • Schiech L.
        • Barsevick A.
        • Babb J.S.
        • Goldberg M.
        Quality of life after esophagectomy for cancer.
        Oncol Nurs Forum. 2002; 29: 1127-1131
        • Haverkort E.B.
        • Binnekade J.M.
        • Busch O.R.
        • van Berge Henegouwen M.I.
        • de Haan R.J.
        • Gouma D.J.
        Presence and persistence of nutrition-related symptoms during the first year following esophagectomy with gastric tube reconstruction in clinically disease-free patients.
        World J Surg. 2010; 34: 2844-2852
        • Gupta V.
        • Allen-Ayodabo C.
        • Davis L.
        • Zhao H.
        • Hallet J.
        • Mahar A.L.
        • et al.
        Patient-Reported Symptoms for Esophageal Cancer Patients Undergoing Curative Intent Treatment.
        Ann Thorac Surg. 2020; 109: 367-374
        • Ginex P.
        • Thom B.
        • Jingeleski M.
        • Vincent A.
        • Plourde G.
        • Rizk N.
        • et al.
        Patterns of symptoms following surgery for esophageal cancer.
        Oncol Nurs Forum. 2013; 40: E101-E107
        • Groenvold M.
        • Klee M.C.
        • Sprangers M.A.
        • Aaronson N.K.
        Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement.
        J Clin Epidemiol. 1997; 50: 441-450