Guideline sources The following summarized guidelines for the evaluation and management of esophageal cancer are prepared by our editorial team based on guidelines from the Society for Immunotherapy of Cancer (SITC 2023), the Japan Endocrine Society (JES 2023), the American Society of Clinical Oncology (ASCO 2023; 2021; 2020), the Perioperative Quality Initiative (POQI/AUGIS 2022), the European Society of Medical Oncology (ESMO 2022), the American College of Radiology (ACR 2022), the American Association for Thoracic Surgery (AATS/ESTS 2022), the College of American Pathologists (CAP/AMP/FCC 2022), the American College of Gastroenterology (ACG 2022; 2016), the European Society of Gastrointestinal Endoscopy (ESGE 2021; 2017), the Canadian Task Force on Preventive Health Care (CTFPHC 2020), the American Society for Gastrointestinal Endoscopy (ASGE 2019; 2018; 2013), the British Society of Gastroenterology (BSG 2018), the American Society for Clinical Pathology (ASCP/CAP/ASCO 2017), the Society of Thoracic Surgeons (STS 2013), and the American Gastroenterological Association (AGA 2012). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 27 28 Definition https://web.pathway.md/diseases/recGMUdC2zPetYflS 1/12 6/29/23, 4:19 AM t o e Esophageal cancer Pathway Esophageal cancer refers to malignant disease arising from the esophageal epithelium, and principally comprises SCC and adenocarcinoma. 25 Epidemiology Exposure to various carcinogens, genetic susceptibility, and repeated insults to the esophageal mucosa increase the risk of malignant transformation of esophageal epithelial cells, with the subsequent development of esophageal cancer. 27 Pathophysiology The overall annual incidence of esophageal cancer in the United States is 4.7 cases per 100,000 person-years. 26 Disease course Predominant changes in the squamous mucosa of the proximal esophagus predispose to esophageal SCC, while intestinal metaplasia of the mucosa of the distal esophagus predisposes to esophageal adenocarcinoma. 27 Prognosis and risk of recurrence The overall 5-year survival rate of patients with esophageal cancer is estimated at 15-20%. 28 Calculator Calculator Calculat Assess Respiratory Risk in Surgi Eastern Cooperative Oncology G Karnof Guidelines 1. Screening and diagnosis Indications for screening (GERD): do not screen adult patients with chronic GERD for esophageal adenocarcinoma or precursor conditions (Barrett's esophagus or dysplasia). D Indications for screening, Barrett's esophagus, general principles: As per ACG 2022 guidelines, perform both white light endoscopy and chromoendoscopy in patients undergoing endoscopic surveillance of Barrett's esophagus. B Show 6 more As per ASGE 2019 guidelines, perform chromoendoscopy, including virtual chromoendoscopy and Seattle protocol biopsy sampling, in patients with Barrett's esophagus undergoing surveillance. B Show 3 more As per ESGE 2017 guidelines, obtain endoscopic surveillance in patients with Barrett's esophagus. B Show 4 more https://web.pathway.md/diseases/recGMUdC2zPetYflS 2/12 6/29/23, 4:19 AM Esophageal cancer Pathway As per AGA 2012 guidelines, do not obtain surveillance examination within 3 years in patients with Barrett's esophagus with a second endoscopy confirming the absence of dysplasia on biopsy. D Indications for screening, Barrett's esophagus, without dysplasia: As per ASGE 2019 guidelines, consider performing surveillance endoscopy in patients with nondysplastic Barrett's esophagus. C As per ACG 2016 guidelines: Consider performing repeat endoscopy at 1-2 years to rule out Barrett's esophagus in patients with suspected Barrett's esophagus and lack of intestinal metaplasia on histology. C Do not perform repeat endoscopy if the initial endoscopy is negative for Barrett's esophagus. Perform repeat endoscopy after PPI therapy for 8-12 weeks if endoscopy reveals esophagitis (Los Angeles Classification B, C, or D), to ensure healing of esophagitis and exclude the presence of underlying Barrett's esophagus. D Indications for screening, Barrett's esophagus, with dysplasia: As per ASGE 2019 guidelines, do not obtain routine EUS to differentiate mucosal versus submucosal disease in patients with Barrett's esophagus with high-grade dysplasia/intramucosal cancer or nodules. D As per ASGE 2018 guidelines, consider obtaining surveillance over endoscopic eradication therapy in patients with low-grade dysplasia placing a high value on avoiding adverse events related to endoscopic eradication therapy. C As per BSG 2018 guidelines: Perform a repeat endoscopy at 6 months in patients with low-grade dysplasia. B Offer endoscopic ablation therapy, preferably with radiofrequency ablation and after a review by a specialist multidisciplinary team, in patients with low-grade dysplasia in any of the follow-up endoscopy (confirmed by an expert gastrointestinal pathologist in at least 2 sets of biopsies). Offer 6-monthly surveillance if ablation is not performed. A As per ESGE 2017 guidelines, optimize antireflux therapy and perform repeated endoscopy at 6 months in patients with a diagnosis of "indefinite for dysplasia" confirmed by a second expert gastrointestinal pathologist. Obtain surveillance as in patients with nondysplastic Barrett's esophagus if no definite dysplasia is found in subsequent biopsy samples (including if the biopsies are again classified as "indefinite for dysplasia"). B Show 2 more As per ACG 2016 guidelines, obtain endoscopic surveillance at intervals of 3-5 years in patients with Barrett's esophagus without dysplasia. B Show 2 more Indications for screening, Barrett's esophagus, post-treatment: As per ACG 2022 guidelines, obtain endoscopic surveillance in patients with Barrett's esophagus successfully completed endoscopic eradication therapy. B As per ASGE 2018 guidelines, consider performing surveillance endoscopy in patients with dysplasia and intramural cancer achieved complete eradication of intestinal metaplasia after endoscopic eradication therapy. C https://web.pathway.md/diseases/recGMUdC2zPetYflS 3/12 6/29/23, 4:19 AM Esophageal cancer Pathway As per ACG 2016 guidelines, continue endoscopic surveillance to detect recurrent intestinal metaplasia and/or dysplasia following successful endoscopic therapy and complete eradication of intestinal metaplasia. B Show 3 more 2. Classification and risk stratification Staging: As per ACR 2022 guidelines, obtain CT of the chest and abdomen with IV contrast or FDG- positron emission tomography/CT of the skull base to mid-thigh for initial staging of patients with newly diagnosed esophageal cancer. B As per ESMO 2022 guidelines, perform a physical examination, gastrointestinal endoscopy, and obtain contrast-enhanced CT or FDG-positron emission tomography-CT of the chest, abdomen pelvis during initial staging and risk assessment. Consider obtaining EUS for tumor and nodal staging. B Show 2 more As per ESGE 2017 guidelines: Consider performing EUS-guided sampling for the assessment of regional lymph nodes in T1 (and, depending on local treatment policy, T2) adenocarcinoma and of lesions suspicious for metastasis, such as distant lymph nodes, left liver lobe lesions, and suspected peritoneal carcinomatosis. C Obtain integrated FDG-positron emission tomography-CT over EUS for lymph node restaging and for predicting complete pathological response after neoadjuvant therapy. Consider performing EUS-guided sampling only in highly selected cases. B As per ASGE 2013 guidelines: Perform EUS and FNA (when indicated), in conjunction with cross-sectional imaging, for accurate staging of esophageal carcinoma. B Consider performing endoscopic mucosal resection or endoscopic submucosal dissection for the staging and treatment of nodular Barrett's esophagus and suspected intramucosal SCC and adenocarcinoma. C As per STS 2013 guidelines, consider obtaining CT of the chest and abdomen B and positron emission tomography for the staging of early-stage esophageal cancer. C Show 4 more 3. Diagnostic procedures Upper gastrointestinal endoscopy: As per ESMO 2022 guidelines, perform upper gastrointestinal endoscopy in patients with new dysphagia, gastrointestinal bleeding, recurrent aspiration or emesis and weight loss and/or loss of appetite. B As per STS 2013 guidelines, perform flexible endoscopy with biopsy as the primary method for the diagnosis of esophageal carcinoma. B Biopsy and histopathology: https://web.pathway.md/diseases/recGMUdC2zPetYflS 4/12 6/29/23, 4:19 AM Esophageal cancer Pathway As per ESMO 2022 guidelines, establish the diagnosis of esophageal cancer by histopathological assessment of multiple ( 6) endoscopic biopsies to guarantee an adequate representation of the tumor and sufficient tissue for molecular analysis. B Show 2 more As per ESGE 2021 guidelines: Take at least 6 biopsies in patients with suspected advanced esophageal cancer. B Take only 1-2 targeted biopsies for esophageal lesions potentially amenable to endoscopic resection (Paris classification 0-I, 0-II) to confirm the diagnosis and not compromise subsequent endoscopic resection. B As per ESGE 2017 guidelines, consider performing EUS-guided sampling aiming at a core biopsy after the failure of standard biopsy techniques in patients with diffuse esophageal wall thickening. Consider using newly developed biopsy techniques under optical endoscopic guidance as an alternative. C Show 3 more Ancillary testing (flow cytometry): obtain flow cytometry in patients with suspected gastrointestinal lymphoma, such as diffuse esophageal wall thickening. B Ancillary testing, PD-L1 testing: As per SITC 2023 guidelines: Obtain tumor testing for PD-L1 expression (using a validated antibody) in all patients with gastroesophageal cancer. B Use the CPS to quantify PD-L1 expression in patients with gastroesophageal adenocarcinoma. Use the CPS or the TPS to determine eligibility for immune checkpoint inhibitor therapy in patients with esophageal SCC. B As per ESMO 2022 guidelines, assess the PD-L1 expression by immunohistochemistry according to the TPS or CPS as a validated predictive biomarker for immune checkpoint inhibitor therapy for esophageal SCC. B Ancillary testing, HER2 testing: As per SITC 2023 guidelines, obtain HER2 testing on tumor tissue in patients with gastroesophageal adenocarcinoma. B As per ASCO/ASCP/CAP 2017 guidelines: Obtain HER2 testing on tumor tissue in patients with advanced esophageal adenocarcinoma being potential candidates for HER2-targeted therapy. A Obtain request HER2 testing on tumor tissue of the biopsy or resection specimens (primary or metastasis), if such specimens are available and adequate, or on FNA specimens (cell blocks) as an acceptable alternative, preferably before initiating trastuzumab therapy. B Ancillary testing, MMR/MSI: As per SITC 2023 guidelines, assess high MSI/mismatch repair deficiency status in all patients with gastroesophageal cancers. B Consider obtaining MSI status testing by next- generation sequencing. Consider obtaining mismatch repair status testing by immunohistochemistry. As per FCC/AMP/CAP 2022 guidelines, obtain mismatch repair-immunohistochemistry and/or MSI testing by PCR over MSI testing by next-generation sequencing to detect https://web.pathway.md/diseases/recGMUdC2zPetYflS 5/12 6/29/23, 4:19 AM Esophageal cancer Pathway deoxyRNA mismatch repair defects in patients with gastroesophageal cancer suitable for immune checkpoint inhibitor therapy. A Ancillary testing (tumor mutational burden): consider obtaining tumor mutational burden testing in patients with gastroesophageal cancer. C Consider obtaining tumor mutational burden testing by next-generation sequencing. Ancillary testing (genomic testing): insufficient evidence to recommend for or against genomic testing in patients with gastroesophageal adenocarcinoma. I Ancillary testing (EBV testing): do not obtain routine EBV testing for immune checkpoint inhibitor treatment determination in patients with gastroesophageal cancer. 4. Medical management General principles: As per ESMO 2022 guidelines, ensure multidisciplinary assessment and planning before commencing any treatment. B As per ASCO 2020 guidelines, offer multimodality therapy in patients with locally advanced esophageal carcinoma. B Management of locally advanced disease, surgery: As per JES 2023 guidelines, consider performing esophagectomy in patients with clinical stage I (T1bN0M0) esophageal cancer. C Show 3 more As per ESMO 2022 guidelines, perform surgery in patients with resectable esophageal adenocarcinoma, even after complete clinical tumor response to preoperative chemoradiotherapy or chemotherapy. B As per ASCO 2020 guidelines, decide on surgery in patients with esophageal SCC in the context of shared decision-making, taking into account age, comorbidities, patient preference, caregiver support, and other factors. A Management of locally advanced disease, chemoradiotherapy: As per JES 2023 guidelines, consider offering definitive chemoradiotherapy with adequate follow-up and salvage therapy in patients with clinical stage I (T1bN0M0) esophageal cancer desiring esophageal preservation. C Show 3 more As per ESMO 2022 guidelines, consider offering preoperative/perioperative chemotherapy or chemoradiotherapy in all patients with locally advanced resectable disease. B Show 5 more As per ASCO 2020 guidelines: Offer preoperative chemoradiotherapy or chemoradiotherapy without surgery (definitive chemoradiotherapy) in patients with locally advanced esophageal SCC. B Offer preoperative chemoradiotherapy or perioperative chemotherapy in patients with locally advanced esophageal adenocarcinoma. B Management of locally advanced disease, immunotherapy: As per JES 2023 guidelines: https://web.pathway.md/diseases/recGMUdC2zPetYflS 6/12 6/29/23, 4:19 AM Esophageal cancer Pathway Offer postoperative nivolumab therapy, regardless of the histologic type or tumor expression level of PD-L1, in patients with clinical stage II-III esophageal cancer failed to show a pathologic complete response after preoperative chemoradiotherapy plus surgery with radical resection. A Insufficient evidence to recommend postoperative nivolumab therapy in patients with clinical stage II-III esophageal failed to show a pathologic complete response after preoperative chemotherapy plus surgery with radical resection. I As per SITC 2023 guidelines, offer adjuvant nivolumab as the standard of care in patients with resected (R0) stage II or III esophageal or GEJ cancer with residual pathological disease following neoadjuvant chemoradiotherapy. B As per ESMO 2022 guidelines, offer adjuvant nivolumab following neoadjuvant chemoradiotherapy in patients with SCC or adenocarcinoma of the esophagus or GEJ showing evidence of residual pathological disease in the resection specimen ( ypT1 and/or ypN1). A As per ESMO 2022 guidelines, offer trastuzumab-chemotherapy in patients with HER2- positive tumors. A Show 2 more As per ASCO 2021 guidelines, offer nivolumab following neoadjuvant chemoradiotherapy and surgery in patients with locally advanced esophageal carcinoma with ECOG status 0-1 failed to experience a pathological complete response (with a residual disease of at least ypT1 or ypN1 in resected specimens). B Management of advanced/metastatic disease, immunotherapy/targeted therapy: As per ASCO 2023 guidelines, offer pembrolizumab plus fluoropyrimidine- and platinum- based chemotherapy in patients with HER2-negative esophageal SCC and PD-L1 CPS 10. A Show 5 more As per JES 2023 guidelines, offer pembrolizumab, cisplatin, and 5-fluorouracil regimen as first-line therapy in patients with unresectable, advanced/recurrent esophageal cancer. A Show 6 more As per SITC 2023 guidelines, do not offer single-agent immune checkpoint inhibitor therapy in patients with untreated, advanced, microsatellite stable/mismatch repair-proficient gastroesophageal cancer. Consider offering single-agent anti-PD-1 therapy as an option in patients with untreated, advanced, high MSI/mismatch repair-deficient gastroesophageal cancer ineligible for chemotherapy. D Show 6 more As per ESMO 2022 guidelines, offer platinum and fluoropyrimidine as first-line chemotherapy in patients with advanced, untreated esophageal SCC. B Offer dose-reduced oxaliplatin- capecitabine as an alternative option in patients unsuitable for full-dose chemotherapy. A Show 5 more As per ASCO/ASCP/CAP 2017 guidelines, offer combination chemotherapy and HER2- targeted therapy as initial treatment in appropriate patients with HER2-positive advanced esophageal adenocarcinoma. B Management of advanced/metastatic disease (chemoradiotherapy): https://web.pathway.md/diseases/recGMUdC2zPetYflS 7/12 6/29/23, 4:19 AM Esophageal cancer Pathway Consider offering definitive chemoradiotherapy in patients with unresectable clinical stage IVA esophageal cancer. C Consider offering additional chemotherapy in patients with clinical stage IVA esophageal carcinoma showing complete response to definitive chemoradiotherapy. C Management of advanced/metastatic disease (surgery): consider performing surgical resection in patients with unresectable, locally advanced esophageal cancer (cT4 N0-3M0) becoming resectable after definitive chemoradiotherapy or induction chemotherapy. C Palliative care: As per JES 2023 guidelines: Offer oral prednisolone, submucosal triamcinolone injection, or concurrent oral prednisolone and submucosal triamcinolone injection to prevent stenosis after endoscopic resection. B Consider offering palliative radiotherapy in patients with clinical stage IVB esophageal cancer presenting with obstruction. C As per ESMO 2022 guidelines, offer early palliative care referral and nutritional support in patients with advanced esophageal cancer. A As per ASGE 2013 guidelines, perform esophageal stent placement as the preferred method for palliation of dysphagia and fistulae secondary to esophageal cancer in the majority of patients, to provide immediate and durable symptom relief. B 5. Nonpharmacologic interventions Nutritional support: assess nutritional status and history of weight loss B and provide nutritional support as appropriate. B 6. Perioperative care Analgesia: perform either thoracic epidural or paravertebral blockade as the primary method of analgesia for esophagectomy to reduce pulmonary complications. B Perioperative thromboprophylaxis: consider administering parenteral anticoagulation with subcutaneous LMWH or UFH for VTE prevention in patients undergoing esophagectomy. C Consider preferring LMWH over UFH. C Show 6 more Perioperative supportive care: Target normovolemia to reduce pulmonary complications during esophagectomies. B Use a lung protective ventilation strategy throughout the operation comprising minimization of peak pressure, limiting tidal volume, optimizing PEEP, and using recruitment maneuvers to reduce pulmonary complications. B Perioperative nutrition: Do not place nasogastric tubes routinely during esophagectomies to reduce the risk of pulmonary complications. D Initiate clear oral fluids in the immediate postoperative phase after esophagectomy. B https://web.pathway.md/diseases/recGMUdC2zPetYflS 8/12 6/29/23, 4:19 AM Esophageal cancer Pathway Postoperative rehabilitation: offer chest physiotherapy and early mobilization to reduce pulmonary complications after esophagectomy. B 7. Surgical interventions Technical considerations for surgery: As per ESMO 2022 guidelines, perform laparoscopy in patients with locally advanced (T3/T4) adenocarcinoma of the GEJ crossing the diaphragm to infiltrate the anatomical cardia. B Show 3 more As per AUGIS 2022 guidelines: Perform either minimally invasive esophagectomy B or robot-assisted minimally invasive esophagectomy over open esophagectomy to reduce the risk of pulmonary complications. B Do not perform routine pyloric drainage procedures to reduce pulmonary complications. D As per ASGE 2013 guidelines, consider performing endoscopic mucosal resection or endoscopic submucosal dissection for the treatment and staging of nodular Barrett's esophagus and suspected intramucosal SCC and adenocarcinoma. C Show 2 more 8. Patient education General counseling: consider a variety of factors, including patient preferences, quality of life, and prognosis with the patient and family before initiating endoscopic palliation for esophageal malignancy. C 9. Follow-up and surveillance Follow-up: As per ACR 2022 guidelines, obtain FDG-positron emission tomography/CT of the skull base to mid-thigh for the evaluation of patients with esophageal cancer undergoing treatment. B Show 2 more As per ESMO 2022 guidelines: Recognize that the majority ( 90%) of relapses occur within the first 2 years after completion of local therapy. Focus on symptoms, nutrition, and psychosocial support during follow-up visits. B Consider obtaining a 3-month follow-up based on endoscopy, biopsies, and CT to detect early recurrence in case of complete response to definitive chemoradiotherapy. C Clinical findings Symptoms Past medical history Acid reflux Aspiration pneumonia https://web.pathway.md/diseases/recGMUdC2zPetYflS 9/12 6/29/23, 4:19 AM Esophageal cancer Pathway Chest pain Barrett's esophagus Cough Bloom syndrome Dysphagia Bone metastasis Epigastric pain Brain metastasis Fatigue Exposure to radiation therapy Heartburn Fanconi anemia Hematemesis GERD Hoarseness HPV infection Melena Howel-evans syndrome Nausea Liver metastasis Odynophagia Lung metastasis Vomiting Obesity Weight loss Peritoneal metastasis Upper gastrointestinal bleeding Social history Abdominal exam Alcohol consumption Consumption of hot food and beverage Epigastric mass Integument exam High red meat consumption Tobacco use Digital clubbing Lymphatic exam Hematological findings Supraclavicular lymphadenopathy Anemia Lab findings Iron deficiency Studies 2023 ANTICIPUSC In patients at high risk of postoperative pulmonary complications after elective or semi-urgent surgery with an Assess Respiratory Risk in Surgical Patients in Catalonia score 45, prophylactic noninvasive ventilation was not superior to usual postoperative care with respect to the rate of in-hospital acute respiratory failure within 7 days after surgery. Stanislas Abrard et al. Br J Anaesth. 2023 Jan. 2006 MAGIC In patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus, perioperative chemotherapy plus surgery was superior to surgery alone with respect to overall survival. David Cunningham et al. N Engl J Med. 2006 Jul 6. References https://web.pathway.md/diseases/recGMUdC2zPetYflS 10/12 6/29/23, 4:19 AM Esophageal cancer Pathway 1. Ronan J Kelly, Katherine Bever, Joseph Chao et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer. 2023 Jun;11 6):e006658. Open 2. Pritam Singh, James Gossage, Sheraz Markar et al. Association of Upper Gastrointestinal Surgery of Great Britain and Ireland AUGIS /Perioperative Quality Initiative POQI consensus statement on intraoperative and postoperative interventions to reduce pulmonary complications after oesophagectomy. 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