Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

•This ESMO Clinical Practice Guideline provides key recommendations for managing oesophageal cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Algorithms for the management of locoregional and advanced/metastatic disease are provided.•The author group encompasses a multidisciplinary group of experts from different institutions in Europe and Australia.•Recommendations are based on available scientific data and the authors’ collective expert opinion. Oesophageal cancer is the seventh most common cancer worldwide, with 604 000 new cases diagnosed in 2020. It is the sixth most common cause of cancer-related mortality, with an estimated 544 000 deaths in 2020.1Sung H. Ferlay J. Siegel R.L. et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (37604) Google Scholar Approximately 70% of oesophageal cancer diagnoses occur in men; there is a twofold to threefold difference in incidence and mortality rates between the sexes. Rates of oesophageal cancer are higher in developing versus developed countries for men, but are comparable for women.2Arnold M. Abnet C.C. Neale R.E. et al.Global burden of 5 major types of gastrointestinal cancer.Gastroenterology. 2020; 159: 335-349Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar Eastern Asia exhibits the highest regional incidence, followed by Southern Africa, Eastern Africa, Northern Europe and South Central Asia.1Sung H. Ferlay J. Siegel R.L. et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (37604) Google Scholar Recent data from the US Surveillance, Epidemiology, and End Results database indicate an increased incidence of oesophageal adenocarcinoma (AC) in patients aged <50 years. In addition, young patients tend to be diagnosed in more advanced stages.3Codipilly D.C. Sawas T. Dhaliwal L. et al.Epidemiology and outcomes of young-onset esophageal adenocarcinoma: an analysis from a population-based database.Cancer Epidemiol Biomarkers Prev. 2021; 30: 142-149Crossref PubMed Scopus (25) Google Scholar There are two main subtypes of oesophageal cancer: oesophageal squamous-cell carcinoma (SCC) and oesophageal AC. Although SCC accounts for ∼90% of cases of oesophageal cancer worldwide, the incidence of AC is rising and has surpassed the incidence rate of SCC in several regions of Europe and North America, as well as certain high-risk areas of Asia, where this change was preceded by economic development and dietary changes (e.g. in China).2Arnold M. Abnet C.C. Neale R.E. et al.Global burden of 5 major types of gastrointestinal cancer.Gastroenterology. 2020; 159: 335-349Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar Heavy alcohol consumption, smoking and their synergistic effects are the major risk factors for oesophageal SCC in Western populations.4Thun M. Linet M.S. Cerhan J.R. et al.Cancer Epidemiology and Prevention.4th ed. Oxford University Press, New York2018Google Scholar In lower-income countries, including parts of Asia and sub-Saharan Africa, the major risk factors for oesophageal SCC have yet to be elucidated, although potential dietary components have been identified, including nutritional deficiencies and nitrosamines.5McCormack V.A. Menya D. Munishi M.O. et al.Informing etiologic research priorities for squamous cell esophageal cancer in Africa: a review of setting-specific exposures to known and putative risk factors.Int J Cancer. 2017; 140: 259-271Crossref PubMed Scopus (89) Google Scholar Additional suspected risk factors for oesophageal SCC are betel quid chewing in the Indian subcontinent, consumption of pickled vegetables (e.g. in China) and consumption of food and beverages at very hot temperatures (e.g. in Uruguay, Iran and Tanzania).4Thun M. Linet M.S. Cerhan J.R. et al.Cancer Epidemiology and Prevention.4th ed. Oxford University Press, New York2018Google Scholar AC represents roughly two-thirds of oesophageal cancer cases in high-income countries, with excess body weight, gastroesophageal reflux disease and oesophageal intestinal metaplasia among the key risk factors.4Thun M. Linet M.S. Cerhan J.R. et al.Cancer Epidemiology and Prevention.4th ed. Oxford University Press, New York2018Google Scholar,6El-Serag H.B. Hashmi A. Garcia J. et al.Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett’s oesophagus: a case-control study.Gut. 2014; 63: 220-229Crossref PubMed Scopus (102) Google Scholar,7O'Doherty M.G. Freedman N.D. Hollenbeck A.R. et al.A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.Gut. 2012; 61: 1261-1268Crossref PubMed Scopus (107) Google Scholar Across high-income countries, incidence rates of oesophageal AC are thus rising, partly due to the increasing prevalence of excess body weight and gastroesophageal reflux disease, and possibly because of decreasing incidence of chronic Helicobacter pylori (H. pylori) infection,8Parsonnet J. Friedman G.D. Vandersteen D.P. et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3658) Google Scholar which has been inversely associated with oesophageal AC.9Arnold M. Laversanne M. Brown L.M. et al.Predicting the future burden of esophageal cancer by histological subtype: international trends in incidence up to 2030.Am J Gastroenterol. 2017; 112: 1247-1255Crossref PubMed Scopus (252) Google Scholar These trends are predicted to continue in the near future, with incidence of oesophageal AC surpassing SCC in many high-income countries. Finally, the incidence of oesophagogastric junction (OGJ) AC seems to have moderately increased during recent decades, although this has not been uniformly classified.10Parfitt J.R. Miladinovic Z. Driman D.K. Increasing incidence of adenocarcinoma of the gastroesophageal junction and distal stomach in Canada -- an epidemiological study from 1964-2002.Can J Gastroenterol. 2006; 20: 271-276Crossref PubMed Scopus (41) Google Scholar Similar to oesophageal AC, obesity, gastroesophageal reflux disease and a high fat intake are risk factors for OGJ cancer,7O'Doherty M.G. Freedman N.D. Hollenbeck A.R. et al.A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.Gut. 2012; 61: 1261-1268Crossref PubMed Scopus (107) Google Scholar and H. pylori infection is inversely related.8Parsonnet J. Friedman G.D. Vandersteen D.P. et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3658) Google Scholar Screening for precursor lesions (oesophageal intestinal metaplasia) in high-risk patients, surveillance and endoscopic ablation of precursor lesions are not discussed in this guideline. The guidelines of the American College of Gastroenterology should be followed.11Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG clinical guideline: diagnosis and management of Barrett’s esophagus.Am J Gastroenterol. 2016; 111: 30-50Crossref PubMed Scopus (1073) Google Scholar The recommended diagnostic and staging investigations are detailed in Table 1. All patients with new dysphagia, gastrointestinal bleeding, recurrent aspiration or emesis and weight loss and/or loss of appetite should undergo an upper intestinal endoscopy. Approximately three-quarters of all oesophageal ACs are located in the distal oesophagus, whereas SCCs occur more frequently in the proximal-to-middle oesophagus.12Rustgi A.K. El-Serag H.B. Esophageal carcinoma.N Engl J Med. 2014; 371: 2499-2509Crossref PubMed Scopus (906) Google Scholar Biopsies should be taken from all suspicious areas. There is limited evidence for the optimal number of biopsies required to ensure a diagnosis where malignancy is present. The accepted convention is to obtain ≥6-8 representative biopsies of the lesion. The number of biopsies should be sufficient for pathological and molecular analysis.Table 1Diagnostic and staging investigations in oesophageal cancerProcedurePurposeFBCAssess for iron-deficiency anaemiaRenal and liver functionAssess renal and liver function to determine appropriate therapeutic optionsEndoscopy and biopsyObtain tissue for diagnosis, histological classification and molecular biomarkers, e.g. PD-L1 and HER2 status (AC)EUSAccurate assessment of T and N stage in potentially resectable tumoursBronchoscopy with endobronchial ultrasonographyAssess tumour growth towards central airways; complementary to EUS, especially when tumour stricture precludes EUSCT of thorax + abdomen ± pelvisStaging of tumour to detect local/distant lymphadenopathy and metastatic diseasePET–CT, if availableStaging of tumour to detect local/distant lymphadenopathy and metastatic diseaseLaparoscopy ± washingsExclude occult metastatic disease involving peritoneum/diaphragm, especially in locally advanced (T3/T4) ACs of the OGJ infiltrating the anatomical cardiaAC, adenocarcinoma; CT, computed tomography; EUS, endoscopic ultrasound; FBC, full blood count; HER2, human epidermal growth factor receptor 2; N, node; OGJ, oesophagogastric junction; PD-L1, programmed death-ligand 1; PET, positron emission tomography; T, tumour. Open table in a new tab AC, adenocarcinoma; CT, computed tomography; EUS, endoscopic ultrasound; FBC, full blood count; HER2, human epidermal growth factor receptor 2; N, node; OGJ, oesophagogastric junction; PD-L1, programmed death-ligand 1; PET, positron emission tomography; T, tumour. Diagnosis should be based on endoscopic biopsies with the histological tumour type classified according to the World Health Organization (WHO) criteria.13Nagtegaal I.D. Odze R.D. Klimstra D. et al.The 2019 WHO classification of tumours of the digestive system.Histopathology. 2020; 76: 182-188Crossref PubMed Scopus (1441) Google Scholar The differentiation between oesophageal SCC and AC is of prognostic and therapeutic relevance. Immunohistochemical (IHC) staining is recommended in poorly differentiated and undifferentiated cancers [grade 3/4 American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th Edition] when differentiation between SCC and AC using morphological characteristics is not possible. In addition, other less frequently occurring tumour types, such as neuroendocrine tumours/carcinomas, lymphomas, mesenchymal tumours, melanomas or secondary tumours, must be identified separately from SCC and AC. The Cancer Genome Atlas research network identified three subtypes of oesophageal SCC (oesophageal SCC1, oesophageal SCC2 and oesophageal SCC3), which are each associated with defects in specific molecular pathways.14Cancer Genome Atlas Research NetworkIntegrated genomic characterization of oesophageal carcinoma.Nature. 2017; 541: 169-175Crossref PubMed Scopus (1103) Google Scholar So far, no distinct therapeutic options for these subtypes are available. Patients with oesophageal SCC have been shown to benefit from programmed cell death protein 1 (PD-1) blockade.15Kojima T. Shah M.A. Muro K. et al.Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer.J Clin Oncol. 2020; 38: 4138-4148Crossref PubMed Scopus (490) Google Scholar, 16Sun J.M. Shen L. Shah M.A. et al.Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.Lancet. 2021; 398: 759-771Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar, 17Kato K. Cho B.C. Takahashi M. et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar, 18Kelly R.J. Ajani J.A. Kuzdzal J. et al.Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.N Engl J Med. 2021; 384: 1191-1203Crossref PubMed Scopus (586) Google Scholar, 19Shen L. Kato K. Kim S.B. et al.RATIONALE 302: randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma.J Clin Oncol. 2021; 39: 4012Crossref Google Scholar, 20Luo H. Lu J. Bai Y. et al.Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized clinical trial.JAMA. 2021; 326: 916-925Crossref PubMed Scopus (205) Google Scholar, 21Huang J. Xu J. Chen Y. et al.Camrelizumab versus investigator’s choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study.Lancet Oncol. 2020; 21: 832-842Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 22Doki Y. Ajani J.A. Kato K. et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (257) Google Scholar, 23Shen L. Kato K. Kim S.B. et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study.J Clin Oncol. 2022; Jco2101926Google Scholar In patients who are candidates to receive first-line treatment with immune checkpoint inhibitors (ICIs), programmed death-ligand 1 (PD-L1) IHC is recommended [see the table of ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) scores for further details; Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2022.07.003]. PD-L1 expression is measured using tumour proportion score (TPS), which evaluates the percentage of viable tumour cells showing partial or complete membrane staining at any intensity (PD-L1 positivity is defined as TPS ≥1% in the case of first-line treatment with nivolumab and nivolumab–ipilimumab), or combined positive score (CPS), which is calculated by the total number of cells with PD-L1-positive plasma membrane staining (including tumour cells, lymphocytes and macrophages) divided by the number of vital tumour cells, multiplied by 100 (PD-L1 positivity is defined as CPS ≥10 in the case of first-line treatment with pembrolizumab). In the CheckMate 648 study, TPS was determined using the PD-L1 IHC 28-8 pharmDx assay, while in KEYNOTE-590, the PD-L1 IHC 22C3 assay was used for CPS. In several tumour types, the analytical concordance between the two assays has shown to be high, although conflicting data also exist.24Prince E.A. Sanzari J.K. Pandya D. et al.Analytical concordance of PD-L1 assays utilizing antibodies from FDA-approved diagnostics in advanced cancers: a systematic literature review.JCO Precis Oncol. 2021; 5: 953-973Crossref PubMed Scopus (22) Google Scholar,25Yeong J. Lum H.Y.J. Teo C.B. et al.Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy.Gastric Cancer. 2022; 25: 741-750Crossref PubMed Scopus (25) Google Scholar Currently, data on their interchangeability specifically in oesophageal SCC are awaited. Use of a validated test that is subject to a quality assurance programme is recommended. In the RATIONALE 302 study, PD-L1 expression was assessed using the VENTANA PD-L1 (SP 263) assay with tumour area positivity (TAP) score. TAP is defined as the total percentage of the tumour area covered by tumour cells with any membrane staining above the background and tumour-associated immune cells with any staining above the background. Only patients with a TAP score ≥10 were defined as PD-L1 positive.23Shen L. Kato K. Kim S.B. et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study.J Clin Oncol. 2022; Jco2101926Google Scholar Molecular pathology assessment in oesophageal and OGJ AC should follow the recommendations provided in the ESMO Clinical Practice Guideline (CPG) for gastric cancer.26Lordick F. Carneiro F. Cascinu S. et al.Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.[published online ahead of print, 2022 Jul 29]. Ann Oncol. 2022; https://doi.org/10.1016/j.annonc.2022.07.004Abstract Full Text Full Text PDF Scopus (127) Google Scholar •Patients with new dysphagia, gastrointestinal bleeding, recurrent aspiration or emesis and weight loss and/or loss of appetite should undergo an upper intestinal endoscopy [III, A]. Diagnosis should be made by histopathological assessment of multiple (≥6) endoscopic biopsies to guarantee an adequate representation of the tumour and sufficient tissue for molecular analysis [I, B].•Histological diagnosis should be reported according to the WHO criteria [IV, A].•IHC staining is recommended in poorly differentiated and undifferentiated cancers when differentiation between SCC and AC using morphological characteristics is not possible [V, B].•For oesophageal SCC, PD-L1 expression by IHC according to the TPS or CPS is a validated predictive biomarker for ICI therapy [I-II, A]. Decisions about initial treatment for oesophageal cancer are based on clinical staging, which should be carried out with the highest degree of accuracy possible. Staging should include a complete clinical examination, endoscopy and computed tomography (CT) or positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-d-glucose (FDG). Endoscopic ultrasound (EUS) can be used for tumour (T) and node (N) staging, but has low accuracy for T1 tumours; in these cases, endoscopic resection offers more precise staging in addition to therapeutic benefit.27Catalano M.F. Van Dam J. Sivak M.V. Malignant esophageal strictures: staging accuracy of endoscopic ultrasonography.Gastrointest Endosc. 1995; 41: 535-539Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,28Krill T. Baliss M. Roark R. et al.Accuracy of endoscopic ultrasound in esophageal cancer staging.J Thorac Dis. 2019; 11: s1602-s1609Crossref PubMed Scopus (34) Google Scholar EUS is particularly useful to determine the therapeutic strategy in two ways: (i) for assessment of T4b status with invasion towards the airways, pericardium or aorta, and (ii) for identification and biopsy of suspected lymph node metastases outside the regular radiation field or beyond the planned resection limits. In advanced T stages, tumour stricture may preclude the use of EUS. In the assessment of tumour growth towards central airways, bronchoscopy with endobronchial ultrasonography is a useful complement to EUS, especially when tumour stricture precludes EUS use. FDG–PET (typically carried out as PET–CT) is helpful to identify otherwise undetected distant metastases. FDG–PET should therefore be carried out in patients who are candidates for oesophagectomy, as the finding of otherwise unknown distant metastases can help to avoid futile surgery; however, the availability of PET–CT differs between countries and centres.29van Vliet E.P.M. Heijenbrok-Kal M.H. Hunink M.G.M. et al.Staging investigations for oesophageal cancer: a meta-analysis.Br J Cancer. 2008; 98: 547-557Crossref PubMed Scopus (414) Google Scholar, 30Flamen P. Lerut A. Van Cutsem E. et al.Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma.J Clin Oncol. 2000; 18: 3202-3210Crossref PubMed Scopus (524) Google Scholar, 31Heeren P.A.M. Jager P.L. Bongaerts F. et al.Detection of distant metastases in esophageal cancer with 18F-FDG PET.J Nucl Med. 2004; 45: 980-987PubMed Google Scholar, 32Findlay J.M. Bradley K.M. Maile E.J. et al.Pragmatic staging of oesophageal cancer using decision theory involving selective endoscopic ultrasonography, PET and laparoscopy.Br J Surg. 2015; 102: 1488-1499Crossref PubMed Scopus (45) Google Scholar Oesophageal SCCs are often accompanied by head and neck second primary tumours (HNSPTs). The prognosis of patients with an additional HNSPT is worse than patients with only oesophageal SCC. The pooled prevalence of HNSPT in patients with oesophageal SCC is 6.7%. Therefore, early detection of HNSPTs may improve the overall outcome of patients with oesophageal SCC.33van de Ven S. Bugter O. Hardillo J.A. et al.Screening for head and neck second primary tumors in patients with esophageal squamous cell cancer: a systematic review and meta-analysis.United European Gastroenterol J. 2019; 7: 1304-1311Crossref PubMed Scopus (12) Google Scholar Patients with oesophageal SCC should undergo a qualified clinical examination of the head and neck region to exclude HNSPTs. In locally advanced (T3/T4) ACs of the OGJ infiltrating the anatomical cardia, laparoscopy should be carried out to rule out peritoneal metastases, which are found in ∼15% of patients.34Gertsen E.C. Brenkman H.J.F. van Hillegersberg R. et al.18F-fludeoxyglucose-positron emission tomography/computed tomography and laparoscopy for staging of locally advanced gastric cancer: a multicenter prospective Dutch cohort study (PLASTIC).JAMA Surg. 2021; 156e215340Crossref PubMed Scopus (22) Google Scholar The finding of otherwise unknown peritoneal metastases may prevent patients from undergoing futile surgery. Oesophageal cancer should be staged according to the American Joint Committee on Cancer AJCC/UICC TNM (tumour–node–metastasis) 8th edition staging system (see Supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.annonc.2022.07.003).35Rice T.W. Ishwaran H. Blackstone E.H. et al.Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.Dis Esophagus. 2016; 29: 913-919Crossref PubMed Scopus (87) Google Scholar Anatomic staging should be complemented by medical risk assessment, especially in patients who are scheduled for multimodal therapy and/or surgery. Medical risk assessment should comprise a differential blood count as well as liver, pulmonary, cardiac and renal function tests. Nutritional status and history of weight loss should be assessed according to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines.36Cederholm T. Barazzoni R. Austin P. et al.ESPEN guidelines on definitions and terminology of clinical nutrition.Clin Nutr. 2017; 36: 49-64Abstract Full Text Full Text PDF PubMed Scopus (1198) Google Scholar More than half of patients lose >5% of their body weight before admission for oesophagectomy, and 40% lose >10%. Independent from body mass index, weight loss confers an increased operative risk, worsens a patient’s quality of life (QoL) and is associated with poor survival in advanced disease. Therefore, nutritional support according to the ESPEN guidelines37Bischoff S.C. Austin P. Boeykens K. et al.ESPEN guideline on home enteral nutrition.Clin Nutr. 2020; 39: 5-22Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar is an integral part of medical care for patients with oesophageal cancer, in both curative and palliative settings. Reduced physical activity is associated with worse outcomes following perioperative treatment. In addition, lower physical fitness is a negative predictor of long-term survival in oesophagogastric cancer.38Sinclair R. Navidi M. Griffin S.M. et al.The impact of neoadjuvant chemotherapy on cardiopulmonary physical fitness in gastro-oesophageal adenocarcinoma.Ann R Coll Surg Engl. 2016; 98: 396-400Crossref PubMed Scopus (39) Google Scholar,39Whibley J. Peters C.J. Halliday L.J. et al.Poor performance in incremental shuttle walk and cardiopulmonary exercise testing predicts poor overall survival for patients undergoing esophago-gastric resection.Eur J Surg Oncol. 2018; 44: 594-599Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar A supervised exercise programme has been shown to improve cardiorespiratory fitness and aspects of QoL in patients who have undergone an oesophagectomy and can therefore be recommended.40van Vulpen J.K. Hiensch A.E. van Hillegersberg R. et al.Supervised exercise after oesophageal cancer surgery: the PERFECT multicentre randomized clinical trial.Br J Surg. 2021; 108: 786-796Crossref PubMed Scopus (9) Google Scholar Other studies are investigating whether the addition of a perioperative exercise regimen to neoadjuvant chemotherapy (ChT) improves outcomes.41Tully R. Loughney L. Bolger J. et al.The effect of a pre- and post-operative exercise programme versus standard care on physical fitness of patients with oesophageal and gastric cancer undergoing neoadjuvant treatment prior to surgery (The PERIOP-OG Trial): study protocol for a randomised controlled trial.Trials. 2020; 21: 638PubMed Google Scholar Geriatric screening and assessment may help to identify patients who need additional support and/or are at increased risk of ChT-associated side-effects.42Kotzerke D. Moritz F. Mantovani L. et al.The performance of three oncogeriatric screening tools - G8, optimised G8 and CARG - in predicting chemotherapy-related toxicity in older patients with cancer. A prospective clinical study.J Geriatr Oncol. 2019; 10: 937-943Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar •Initial staging and risk assessment should include physical examination, endoscopy and contrast-enhanced CT or FDG–PET–CT scan of the thorax, abdomen ± pelvis. EUS can be used for T and N staging [III, A].•FDG–PET should be carried out in candidates for oesophagectomy [III, B].•In locally advanced (T3/T4) ACs of the OGJ which cross the diaphragm to infiltrate the anatomical cardia, laparoscopy should be carried out [IV, B].•The TNM stage should be recorded according to the latest edition of the AJCC/UICC guidelines and staging manual [IV, A].•Nutritional status and history of weight loss should be assessed [III, A] and nutritional support provided [II, A] according to ESPEN guidelines. Multidisciplinary assessment and planning of treatment are mandatory. Treatment is determined together with the patient based on histological subtype, clinical TNM stage, tumour location and the patient’s predicted treatment tolerance, which considers performance status and comorbidities, and may be supplemented by functional testing. Correction of malnutrition is often warranted before curative-intent therapy can be started. Occasionally, enteral feeding is necessary, either via feeding jejunostomy or via nasogastric tube. Endoscopic stenting should be avoided in patients undergoing treatment with curative intent as this may worsen prognosis.43Mariette C. Gronnier C. Duhamel A. et al.Self-expanding covered metallic stent as a bridge to surgery in esophageal cancer: impact on oncologic outcomes.J Am Coll Surg. 2015; 220: 287-296Crossref PubMed Scopus (54) Google Scholar A proposed algorithm for the treatment of localised oesophageal and OGJ cancer is shown in Figure 1. Endoscopic en bloc resection, using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), is the treatment of choice for lesions with intraepithelial high-grade dysplasia and most T1 tumours.44di Pietro M. Canto M.I. Fitzgerald R.C. Endoscopic management of early adenocarcinoma and squamous cell carcinoma of the esophagus: screening, diagnosis, and therapy.Gastroenterology. 2018; 154: 421-436Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,45Weusten B. Bisschops R. Coron E. et al.Endoscopic management of Barrett’s esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.Endoscopy. 2017; 49: 191-198Crossref PubMed Scopus (379) Google Scholar Examination of the specimen provides accurate staging and, unless the deep resection margin is involved or there are significant risk factors for lymph node metastases, endoscopic resection can be considered definitive treatment.44di Pietro M. Canto M.I. Fitzgerald R.C. Endoscopic management of early adenocarcinoma and squamous cell carcinoma of the esophagus: screening, diagnosis, and therapy.Gastroenterology. 2018; 154: 421-436Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,45Weusten B. Bisschops R. Coron E. et al.Endoscopic management of Barrett’s esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.Endoscopy. 2017; 49: 191-198Crossref PubMed Scopus (379) Google Scholar The strongest risk factors for lymph node metastasis are depth of invasion, lymphovascular invasion, low differentiation grade, ulceration and large tumour size.46Pimentel-Nunes P. Dinis-Ribeiro M. Ponchon T. et al.Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.Endoscopy. 2015; 47: 829-854Crossref PubMed Scopus (883) Google Scholar,47Yamashina T. Ishihara R. Nagai K. et al.Long-term outcome and metastatic risk after endoscopic resection of superficial esophageal squamous cell carcinoma.Am J Gastroenterol. 2013; 108: 544-551Crossref PubMed Scopus (202) Google Scholar For oesophageal AC, which often occurs in the context of oesophageal intestinal metaplasia, endoscopic resection can usually be considered curative in all T1a cancers and, in the absence of other risk factors for lymph node metastasis, also in the most superficial submucosally involved T1b cancers (sm1, invasion depth <500 μm, no ulceration).45Weusten B. Bisschops R. Coron E. et al.Endoscopic management of Barrett’s esophagus: European Society of Gastrointestina