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German guidelines for the diagnosis and treatment of squamous-cell carcinoma and adenocarcinoma of the esophagus—version 4.0

DGVS (OL) · 2025 · Germany

Source and licence

Authors
MP Ebert, W Fischbach, S Hollerbach et al.
Title
German guidelines for the diagnosis and treatment of squamous-cell carcinoma and adenocarcinoma of the esophagus—version 4.0
Journal
ESMO Gastrointestinal Oncology, 2025
DOI
10.1016/j.esmogo.2024.100112
Licence
CC BY 4.0
Changes
Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC12836548

Licence statement of the original publication

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This page reproduces excerpts of the original publication; the original is authoritative. It has not been reviewed by a physician, does not state a recommendation of Medelix and does not replace medical advice. The guideline may have been updated since.

Open the original publication →Full text on Europe PMC

Recommendations

Verbatim, with grade of recommendation or strength of consensus where given.

Primary diagnosis and staging

  • Recommendation 1(Expert Consensus, EC): All patients with new-onset dysphagia, gastrointestinal (GI) bleeding, recurrent aspiration, recurrent vomiting, dyspepsia, weight loss, and/or inappetence should be referred for early endoscopy [esophagogastrodudenoscopy (EGD)].Consensus strength: strong consensus
  • Recommendation 2(EC): Biopsies should be taken from all suspicious lesions during esophageal biopsy. In Barrett’s esophagus, additional four-quadrant biopsies should be taken. Suspect areas should be preserved separately and examined histopathologically.Consensus strength: strong consensus
  • Recommendation 3(EC): High-resolution video endoscopy has the highest sensitivity and specificity for the detection of neoplasms of the upper GI tract and should therefore be used as a standard diagnostic procedure.Consensus strength: strong consensus
  • Recommendation 4Chromoendoscopy (Lugol’s solution) or computer-assisted digital (filter) procedures ought to be used in patients at risk for esophageal cancer (= anamnestic squamous-cell carcinoma of the mouth/nose/pharynx/bronchial system, esophagus).Level of evidence: 2a. Grade of recommendation: B.
  • Recommendation 5Chromoendoscopy as well as new computer-assisted digital (filter, contrast, and artificial intelligence) techniques ought to be used to improve the detection of dysplasia/early carcinoma of the esophagus.Level of evidence: 1b. Grade of recommendation: B
  • Recommendation 6Endoscopic ultrasound (EUS) ought to be part of the staging in patients with curative therapy intention.Level of evidence: 1b. Grade of recommendation: B
  • Recommendation 7The assessment of a ‘complete remission’ after neoadjuvant tumor treatment is not possible with sufficient sensitivity and specificity using the current examination methods [endoscopy/biopsy, EUS-fine needle biopsy (FNP), computed tomography (CT)/magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT].Level of evidence2a. Consensus strength: strong consensus
  • Recommendation 8(EC): B-scan ultrasonography ought to be used as the first imaging modality to exclude liver metastases.Consensus strength: consensus
  • Recommendation 9(EC): B-scan ultrasonography of the neck can be used adjunctively to exclude cervical lymph node metastases for staging.Consensus strength: consensus
  • Recommendation 10(EC): The determination of circulating tumor markers for diagnosis or therapy monitoring of esophageal cancer shall not be carried out.Consensus strength: strong consensus
  • Recommendation 11(EC): The X-ray swallow shall not be used to diagnose esophageal cancer.Consensus strength: strong consensus
  • Recommendation 12(EC): For the diagnosis of local tumor complications (fistulas), an X-ray examination with oral, water-soluble contrast medium can be carried out.Consensus strength: strong consensus
  • Recommendation 13Patients with newly diagnosed esophageal cancer ought to undergo multidetector CT (MDCT) of the neck/thorax and abdomen (with multiplanar reconstructions and wall distension with oral negative contrast) and additional intravenous (i.v.) contrast for primary staging.Level of evidence: 4. Grade of recommendation: B
  • Recommendation 14In locally advanced tumors (cT 2-4 and cN+), a PET/CT examination may additionally be used for M-staging if the patient is potentially curatively treatable or the result has clinical consequences.Level of evidence: 1b. Grade of recommendation: 0
  • Recommendation 15Flexible bronchoscopy ought to be carried out for locally advanced tumors in contact with the tracheobronchial system at the level of—or above—the carina.Level of evidence: 4. Grade of recommendation: B
  • Recommendation 16(EC): For staging of esophageal cancer, rigid endoscopy of the upper air and food passages should not be carried out.Consensus strength: consensus
  • Recommendation 17Diagnostic laparoscopy may be carried out for adenocarcinomas of the distal esophagus and esophagogastric junction (EGJ) to exclude metastases to the liver and/or peritoneum in advanced stages (especially in the case of cT3, cT4 category).Level of evidence: 1b. Grade of recommendation: 0

Pathology

  • Recommendation 18(EC): Dysplasia/intraepithelial neoplasia (IEN) should be graded according to the current World Health Organization (WHO) classification into negative, unclear/questionable, low-grade dysplasia (LGD) or high-grade dysplasia (HGD).Consensus strength: strong consensus
  • Recommendation 19(EC): In case of histological diagnosis of IEN/dysplasia in Barrett’s esophagus, the process of a competent (documented) pathological second opinion should be carried out in the sense of a four-eyes-principle. In case of dissent or uncertainty regarding the diagnosis of dysplasia, an external opinion should be obtained.Consensus strength: strong consensus
  • Recommendation 20(EC): The histopathological findings on the biopsy material shall include the following information: • Type of neoplastic lesion [LGD/low-grade IEN (LGIEN), HGD/high-grade IEN (HGIEN), carcinoma], in particular whether an invasive carcinoma is present [in the case of HGD/HGIEN: classification on the biopsy material as Tis according to the International Union Against Cancer (Union Internationale Contre le Cancer; UICC)]. • Histological type according to WHO (in particular differentiation between squamous cell versus adenocarcinoma) • For invasive adenocarcinomas: differentiation grade (grading) according to current WHO classification • For lesions in the distal esophagus: is a goblet cell-containing Barrett’s mucosa present?Consensus strength: strong consensus
  • Recommendation 21(EC): The histological classification and staging of esophageal cancers should be carried out according to the current WHO and TNM (tumor–node–metastasis) classification of the UICC. The pathological-anatomical assessment shall always be carried out completely and in a standardized form.Consensus strength: strong consensus
  • Recommendation 22(EC): The histopathological findings on local excisional data [endoscopic resection (ER)] shall include the following information: • Size of the neoplastic lesion (in three dimensions if possible) • Type of neoplastic lesion (LGD/LGIEN, HGD/HGIEN, carcinoma)—in particular, whether an invasive carcinoma is present (in the case of HGD/HGIEN: classification on the resectate as pTis according to UICC) • In case of carcinoma detection: histological type according to WHO (especially differentiation squamous-cell versus adenocarcinoma, other rare types) • In case of invasive adenocarcinoma: degree of differentiation (grading) according to current WHO classification • Maximum depth of infiltration: pT1a (m1, m2, m3, m4)/pT1b (sm1, sm2, sm3) plus infiltration depth in μm (or higher pT category) • Lymphatic vessel and/or vein invasion (L0 versus L1, V0 versus V1) • Summary assessment of the risk of lymph node metastasis: low-risk versus high-risk resection margins with regard to the neoplasia (for ER in toto circular and basal resection margin for ‘piecemeal’ ER basal resection margin, as here the circular resection margin must usually be evaluated histopathologically as RX)Consensus strength: strong consensus
  • Recommendation 23(EC): The histopathological findings on surgical resected specimens shall include the following information: • Size of the neoplastic lesion (in three dimensions if possible) • Localization of the tumor center in relation to the EGJ and whether the tumor crosses the EGJ (if possible) • Type of neoplastic lesion (LGD/LGIEN, HGD/HGIEN, carcinoma)—in particular, whether a carcinoma is present (for HGD/HGIEN: classification as pTis according to UICC) • If carcinoma is detected: histological type according to current WHO classification (especially differentiation between squamous-cell versus adenocarcinoma, other rare types) • Degree of differentiation (grading) • Maximum depth of infiltration (pT) • Lymphatic and/or venous invasion (L0 versus L1, V0 versus V1) • Resection margins: oral, aboral, and circumferential: R0 versus R1 • Status of regional lymph nodes according to current UICC classification (pN) and ratio of number of affected and examined lymph nodes (…/…lymph nodes).Consensus strength: strong consensus
  • Recommendation 24The histopathological findings on resected specimens ought to include additional statements on the regression score after preoperative therapy (neoadjuvant therapy).Level of evidence: 2b. Grade of recommendation: B
  • Recommendation 25(EC): Before the use of palliative systemic tumor therapy in adenocarcinoma, the human epidermal growth factor receptor 2 (HER2) status should be determined as a positive predictive factor for a potential therapy with trastuzumab. The histopathological determination on tumor tissue should be carried out in a quality-assured manner.Consensus strength: strong consensus

Nutritional medical care

  • Recommendation 26(EC): Nutritional medical care of patients with esophageal cancer should be an integral part of oncological diagnostics, therapy, and follow-up and should be an interdisciplinary task.Consensus strength: strong consensus

Curative therapy

  • Recommendation 27(EC): Therapy recommendations should be made in an interdisciplinary tumor conference. Staging information, patient comorbidities, nutritional status, and patient preference should be taken into account as the basis for the therapy recommendation.Consensus strength: strong consensus
  • Recommendation 28(EC): • If HGIEN or mucosal carcinoma (L0, V0, no ulceration, grading G1/G2) is detected in Barrett’s esophagus, endoscopic resection should be carried out, as this provides staging of the lesion with the question of deep infiltration in addition to therapy. • Therefore, an endoscopic complete resection with curative intention should be aimed for. • In patients with superficial submucosal infiltration of adenocarcinoma and no risk criteria (pT1sm1; <500 μm deep invasion, L0, V0, G1/2, <20 mm, no ulceration), endoscopic resection can be regarded as a sufficient alternative to surgery. • After successful resection of neoplasms in Barrett’s esophagus, the non-neoplastic Barrett’s mucosa should be thermally ablated to decrease the rate of metachronous neoplasms.Consensus strength: strong consensus
  • Recommendation 29(EC): • If there is evidence of HGIEN or mucosal carcinoma (L0, V0, no ulceration, grading G1/G2, infiltration depth m1/m2) in the squamous epithelium, endoscopic en bloc resection should be attempted, as this will provide staging of the lesion with the question of deep infiltration in addition to therapy. • Therefore, resection with curative intention and R0 resection should be aimed for.Consensus strength: strong consensus
  • Recommendation 30(EC): • If endoscopically nonlocalizable LGIEN is detected in Barrett’s esophagus and confirmed by a reference pathologist, follow-up visits shall occur at 6 months and then annually. • Radiofrequency ablation (RFA) of the entire Barrett’s segment to prevent progression of the LGIEN may be carried out. • If HGIEN cannot be localized endoscopically, an ablative procedure ought to be used.Consensus strength: strong consensus
  • Recommendation 31(EC): Local recurrence confined to the mucosa (crT1a cN0 cM0) after previous endoscopic resection of mucosal carcinoma in Barrett’s esophagus can be treated again endoscopically. If R0 resection is not possible with this, a surgical procedure should be chosen.Consensus strength: consensus
  • Recommendation 32(EC): After successful endoscopic therapy of HGIEN or early carcinoma, regular control endoscopies should be carried out (after 3 months, then every 6 months for 2 years, and then annually).Consensus strength: strong consensus
  • Recommendation 33(EC): Surgical treatment of esophageal tumors should be carried out in hospitals with at least 20 complex esophageal surgeries per year and a center for surgeons who are experienced in this type of procedure.Consensus strength: consensus
  • Recommendation 34(EC): Before planned esophagectomy, a risk analysis of important organ functions of the patient should be carried out. In case of functional inoperability despite oncological resectability, other therapeutic procedures should be used.Consensus strength: strong consensus
  • Recommendation 35(EC): The goal of surgical resection for squamous-cell carcinoma and adenocarcinoma is complete removal of the tumor (oral, aboral, and circumferential) and regional lymph nodes.Consensus strength: strong consensus
  • Recommendation 36(EC): In case of localization of the tumor
  • Recommendation 37(EC): The extent of the lymphadenectomy depends on the location of the primary tumor, whereby three fields (abdominal, thoracic, and cervical) are distinguished. Two-field lymphadenectomy (abdominal, thoracic) is the standard approach.Consensus strength: strong consensus
  • Recommendation 38(EC): Reconstruction after transhiatal extended gastrectomy and distal esophagectomy should include end-to-side Roux-en-Y esophagojejunostomy. Subtotal esophagectomy should be followed by gastric elevation with high intrathoracic esophagogastrostomy, and total esophagectomy with cervical anastomosis. In case of unsuitable gastric interposition or after total esophagogastrectomy, colonic interposition should be carried out.Consensus strength: consensus
  • Recommendation 39(EC): Esophagectomy and reconstruction of the esophagus should be carried out minimally invasive or in combination with open procedures (hybrid technique) if there are no contraindications against this approach.Consensus strength: strong consensus
  • Recommendation 40(EC): In case of preoperative evidence of distant metastases, surgery shall not be carried out. In case of intraoperative findings of previously unknown, very limited distant metastases, these can be removed together with the primary tumor.Consensus strength: consensus
  • Recommendation 41(EC): Screening for malnutrition should be carried out as part of the preoperative risk stratification.Consensus strength: strong consensus
  • Recommendation 42(EC): Regardless of nutritional status, nutritional counseling should be offered concomitantly during neoadjuvant therapy.Consensus strength: strong consensus
  • Recommendation 43(EC): Patients with severe malnutrition, i.e. high metabolic risk, should receive nutritional therapy before surgery, even if surgery has to be postponed.Level of evidence: 1a. Grade of recommendation: A
  • Recommendation 44(EC): After esophageal resection, enteral nutrition should be started within 24 h due to metabolic risk, if the patient’s clinical condition allows this. Parenteral supplementation may be recommended if <50% of the energy can be supplied by enteral means.Consensus strength: strong consensus
  • Recommendation 45(EC): In the case of an intraoperatively proven R1 resection, the possibility of a curative resection should first be examined independently of preoperative therapy. If this is not possible, post-operative radiochemotherapy should be carried out after discussion in the interdisciplinary tumor conference. In the case of a post-operatively detected R1 resection, radiochemotherapy should be given because the conditions for a postresection are unfavorable. In individual cases, a ‘wait and see’ strategy may be recommended.Consensus strength: strong consensus
  • Recommendation 46(EC): In case of a locoregional R2 resection, post-operative radiochemotherapy can be carried out after discussion in the interdisciplinary tumor conference.Consensus strength: strong consensus
  • Recommendation 47(EC): In case of an isolated local recurrence after curatively intended surgery, surgery can be carried out again after discussion in an interdisciplinary tumor conference. Careful evaluation of operability and resectability should be carried out by a treatment team experienced in esophageal surgery. Alternatively, radiochemotherapy should be offered if there has been no previous irradiation in the recurrent area or if there is sufficient normal tissue tolerance.Consensus strength: strong consensus
  • Recommendation 48(EC): If neoadjuvant therapy is planned, a risk analysis of important organ functions and a screening for malnutrition should be carried out in patients before starting therapy.Consensus strength: strong consensus
  • Recommendation 49Preoperative radiotherapy alone may not be recommended in operable patients with resectable esophageal cancer.Level of evidence: 2a. Grade of recommendation: 0
  • Recommendation 50For localized adenocarcinomas of the esophagus and EGJ of category cT2, preoperative chemotherapy may be given and continued post-operatively.Level of evidence: 1b. Grade of recommendation: 0
  • Recommendation 51In operable patients with a locally advanced adenocarcinoma of the esophagus or EGJ (category cT3/T4 resectable or category cN1-3), perioperative chemotherapy or preoperative radiochemotherapy should be given.Level of evidence: 1a. Grade of recommendation: A
  • Recommendation 52The use of neoadjuvant chemotherapy alone without simultaneous radiotherapy for squamous-cell carcinoma of the esophagus cannot be recommended.Level of evidence: 1a. Grade of recommendation: B
  • Recommendation 53(EC): In operable patients with cT2 squamous-cell carcinoma of the esophagus, preoperative radiochemotherapy followed by complete resection can be carried out.Consensus strength: strong consensus
  • Recommendation 54In operable patients with a locally advanced squamous-cell carcinoma of the esophagus (category cT3/T4 resectable or category cN1-3), preoperative radiochemotherapy followed by complete resection should be carried out. See also Recommendation 59 ‘Indication for definitive radiochemotherapy’.Level of evidence: 1a. Grade of recommendation: A
  • Recommendation 55Self-expanding metal stents (SEMS) ought not to be used due to an increased complication rate with planned neoadjuvant radiochemotherapy or as a bridge to surgery.Level of evidence: 4. Grade of recommendation: B
  • Recommendation 56(EC): After completion of a preoperative therapy, a new exclusion of distant metastases should be carried out. Restaging of the local findings can be carried out for planning the surgery.Consensus strength: strong consensus
  • Recommendation 57(EC): If clinical signs of tumor progression occur during preoperative therapy, symptom-based diagnostics should be carried out. If endoscopic or imaging evidence of local tumor progression is present, surgery should be carried out early.Consensus strength: strong consensus
  • Recommendation 58(EC): The clinical utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)–PET for response assessment of chemotherapy or radiochemotherapy before surgery is controversial, which is why FDG–PET/CT should not be routinely carried out in this setting.Consensus strength: strong consensus
  • Recommendation 59Definitive radiochemotherapy should be given irrespective of the histological entity of the esophageal cancer if the tumor is deemed surgically/endoscopically unresectable at an interdisciplinary tumor conference or if a patient is functionally inoperable, or declines surgery after detailed explanation.Level of evidence: 1b. Grade of recommendation: A
  • Recommendation 60In patients with localized squamous-cell carcinoma of the cervical esophagus, definitive radiochemotherapy should be preferred over primary surgical resection.Consensus strength: strong consensus
  • Recommendation 61In patients with resectable squamous-cell carcinoma of the intrathoracic esophagus of category cT3/cT4, definitive radiochemotherapy ought to be carried out as an alternative to surgical resection. See also Recommendation 54.Level of evidence: 1a. Grade of recommendation: B
  • Recommendation 62(EC): In case of tumor persistence or local recurrence without distant metastases after radiochemotherapy, salvage surgery can be attempted with curative intent. Careful evaluation of operability and resectability should be carried out by a treatment team experienced in esophageal surgery.Consensus strength: strong consensus
  • Recommendation 63(EC): Antibodies and small molecules shall not be used in preoperative therapy.Consensus strength: consensus
  • Recommendation 64After R0 resection of squamous-cell carcinoma, adjuvant radiotherapy or radiochemotherapy should not be carried out.Level of evidence: 1a (radiotherapy); 4 (radiochemotherapy). Grade of recommendation: B
  • Recommendation 65After primary R0 resection of a non-pretreated adenocarcinoma in the EGJ, adjuvant radiochemotherapy or chemotherapy may be carried out if there is an increased risk of recurrence (pN1-3).Level of evidence: 1b. Grade of recommendation: 0
  • Recommendation 66If residual tumor cells can still be detected histologically in the resection specimen (≥ypT1 or ≥ypN1) following neoadjuvant radiochemotherapy and R0 resection of squamous-cell carcinoma in the esophagus or adenocarcinoma in the esophagus or gastroesophageal (GE) junction, adjuvant immunotherapy with nivolumab ought to be carried out for 1 year.Level of evidence: 2. Grade of recommendation: B
  • Recommendation 67(EC): Patients with esophageal cancer who have undergone potentially curative treatment should be offered structured follow-up care, provided that treatment decisions can be derived from this. In other cases, symptom-oriented follow-up care should be provided.Consensus strength: strong consensus
  • Recommendation 68(EC): In the first 6 months, regular follow-up checks of the nutritional status including dietary advice should be carried out. Supplementation of oral energy intake with drinkable solution or even tube feeding via an initially left fine-needle catheter jejunostomy can be recommended.Consensus strength: strong consensus
  • Recommendation 69(EC): Patients with esophageal cancer should be motivated—within their means—to engage in physical activity. After completing primary therapy, all patients capable of rehabilitation should be offered follow-up treatment. The rehabilitative therapy should include medical, nursing, and educational, training and psychosocial measures adapted to the individual rehabilitation needs. In order to reduce the fatigue syndrome caused by cancer or tumor therapy, endurance training should be carried out that is geared to the individual’s ability to cope with stress.Consensus strength: consensus

Palliative therapy

  • Recommendation 70All patients should be offered palliative care following the diagnosis of a non-curable cancer, regardless of whether tumor-specific therapy is undertaken.Level of evidence: 1. Grade of recommendation: A
  • Recommendation 71Patients with metastatic or locally advanced adenocarcinoma of the esophagus and EGJ that cannot be treated curatively should be offered systemic therapy. The therapeutic goal is to prolong survival and maintain quality of life.Level of evidence: 1a. Grade of recommendation: A
  • Recommendation 72(EC): Before initiation of palliative systemic therapy in adenocarcinoma of the esophagus, HER2 status should be determined as a predictive factor for therapy with trastuzumab and programmed death-ligand 1 (PD-L1) combined positive score (CPS) should be determined as a predictive factor for therapy with an immune checkpoint inhibitor.Consensus strength: strong consensus
  • Recommendation 73If HER2 status is negative and PD-L1 CPS < 5, a platinum (oxaliplatin or cisplatin)/fluoropyrimidine-containing two- or three-drug combination should be used.Level of evidence: 1a. Grade of recommendation: A
  • Recommendation 74In case of negative HER2 status and an elevated PD-L1 CPS cut-off value (for nivolumab PD-L1 CPS ≥ 5, for pembrolizumab PD-L1 CPS ≥ 10), a platinum (oxaliplatin or cisplatin)/fluoropyrimidine combination should be used together with one of the mentioned immune checkpoint inhibitors.Level of evidence: 1b. Grade of recommendation: A
  • Recommendation 75For HER2-overexpressing tumors [immunohistochemistry (IHC)3+ or IHC2+ and FISH+], first-line cisplatin/fluoropyrimidine-based chemotherapy should be supplemented with trastuzumab.Level of evidence: 2. Grade of recommendation: A
  • Recommendation 76(EC): Before initiation of palliative systemic therapy of squamous-cell carcinoma, PD-L1 CPS should be determined as a predictive factor for therapy with an immune checkpoint inhibitor.Consensus strength: strong consensus
  • Recommendation 77(EC): Patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus with a PD-L1 CPS < 10 and a PD-L1 tumor proportion score (TPS) < 1% that cannot be treated curatively may be offered palliative systemic chemotherapy. The therapeutic goal is to maintain quality of life. Here, a combination therapy of a platinum derivative with a fluoropyrimidine or a taxane can be used.Consensus strength: strong consensus
  • Recommendation 78In patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus that is not curatively treatable and has a PD-L1 CPS ≥ 10 or PD-L1 TPS ≥ 1%, platinum/fluoropyrimidine chemotherapy should be used in conjunction with an immune checkpoint inhibitorpembrolizumab PD-L1 CPS ≥ 10, nivolumab PD-L1 TPS ≥ 1%
  • Recommendation 79In patients with metastatic or locally advanced, non-curatively treatable squamous-cell carcinoma of the esophagus with a PD-L1 TPS ≥1%, the combination of nivolumab/ipilimumab can be used as the sole immunotherapy.Level of evidence: 2. Grade of recommendation: B
  • Recommendation 80In patients with metastatic or locally advanced adenocarcinoma of the esophagus not amenable to curative treatment and adequate general condition, second- and third-line systemic therapy ought to be given.Level of evidence: 1b. Grade of recommendation: B
  • Recommendation 81In patients with metastatic or locally advanced, non-curatively treatable adenocarcinoma of the esophagus and sufficient general condition, the high-frequency microsatellite instability (MSI-high) and/or mismatch repair deficiency (dMMR) status should be determined in the event of tumor progression under or recurrence after first-line therapy. Due to the high efficacy of immune checkpoint inhibitors in tumors with MSI-high or with a dMMR, these patients should be offered treatment with a checkpoint inhibitor after failure of first-line therapy if no immunotherapy has been used previously.
  • Recommendation 82Patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus that cannot be treated curatively and sufficient general condition ought to receive second-line therapy with an immune checkpoint inhibitor, if there has been no previous immunotherapy.Level of evidence: 2. Grade of recommendation: B
  • Recommendation 83(EC): Percutaneous radiotherapy of esophageal cancer—if necessary in combination with simultaneous chemotherapy—can be used for local symptoms (e.g. bleeding, stenosis, compression) as part of multidisciplinary care.Consensus strength: consensus
  • Recommendation 84Palliative brachytherapy ought to be offered as part of the multidisciplinary care of patients with esophageal cancer to relieve dysphagia, in combination with percutaneous radiochemotherapy, or stent implantation when appropriate.Level of evidence: 1a. Grade of recommendation: B
  • Recommendation 85A self-expanding metal stent ought to be used for rapid relief of dysphagia in patients with esophageal cancer.Level of evidence: 1a. Grade of recommendation: B
  • Recommendation 86With an inserted SEMS, simultaneous percutaneous radiotherapy ought to be avoided because it is associated with an increased complication rate.Level of evidence: 4. Grade of recommendation: B
  • Recommendation 87(EC): Intraluminal thermoablative therapy in patients with exophytic esophageal cancer in the palliative setting can be considered.

Psycho-oncology

  • Recommendation 1(EC): The psycho-oncological care of patients with esophageal cancer should be an integral part of oncological diagnostics, therapy, and aftercare and pose an interdisciplinary task for all professional groups involved in oncology.Consensus strength: strong consensus

Primary diagnosis

  • Recommendation 1(EC): All patients with new-onset dysphagia, GI bleeding, recurrent aspiration, recurrent vomiting, dyspepsia, weight loss, and/or inappetence should be referred for early endoscopy (EGD).Consensus strength: strong consensus

Advanced diagnostics

  • Recommendation 5Chromoendoscopy as well as new computer-assisted digital (filter, contrast, and AI) techniques ought to be used to improve the detection of dysplasia/early carcinoma of the esophagus.Level of evidence: 1b. Grade of recommendation: B

Staging of esophageal cancer

  • Recommendation 7(EC): The assessment of a ‘complete remission’ after neoadjuvant tumor treatment is not possible with sufficient sensitivity and specificity using the current examination methods (endoscopy/biopsy, EUS-FNP, CT/MRI, and PET–CT).Level of evidence: 2a.
  • Recommendation 8B-scan ultrasonography ought to be used as the first imaging modality to exclude liver metastases.Consensus strength: consensus
  • Recommendation 13Patients with newly diagnosed esophageal cancer ought to undergo multidetector CT (MDCT) of the neck/thorax and abdomen (with multiplanar reconstructions and wall distension with oral negative contrast) and additional i.v. contrast for primary staging.Level of evidence: 4. Grade of recommendation: B

Diagnostic laparoscopy and thoracoscopy (staging)

  • Recommendation 17Diagnostic laparoscopy may be carried out for adenocarcinomas of the distal esophagus and EGJ to exclude metastases to the liver and/or peritoneum in advanced stages (especially in the case of cT3, cT4 category).Level of evidence: 1b. Grade of recommendation: 0

Pathology

  • Recommendation 18(EC): Dysplasia/IEN should be graded according to the current WHO classification into negative, unclear/questionable, LGD or HGD.Consensus strength: strong consensus

Barrett’s mucosa

  • Recommendation 20(EC): The histopathological findings on the biopsy material shall include the following information: • Type of neoplastic lesion (LGD/LGIEN, HGD/HGIEN, carcinoma), in particular whether an invasive carcinoma is present (in the case of HGD/HGIEN: classification on the biopsy material as Tis according to UICC). • Histological type according to WHO (in particular differentiation between squamous-cell versus adenocarcinoma) • For invasive adenocarcinomas: differentiation grade (grading) according to current WHO classification • For lesions in the distal esophagus: is a goblet cell-containing Barrett’s mucosa present?Consensus strength: strong consensus
  • Recommendation 21(EC): The histological classification and staging of esophageal cancers should be carried out according to the current WHO and TNM classification of the UICC. The pathological-anatomical assessment shall always be carried out completely and in a standardized form.Consensus strength: strong consensus

Regional lymph nodes

  • Recommendation 22(EC): The histopathological findings on local excisional data (ER) shall include the following information: • Size of the neoplastic lesion (in three dimensions if possible) • Type of neoplastic lesion (LGD/LGIEN, HGD/HGIEN, carcinoma)—in particular, whether an invasive carcinoma is present (in the case of HGD/HGIEN: classification on the resectate as pTis according to UICC) • In case of carcinoma detection: histological type according to WHO (especially differentiation squamous-cell versus adenocarcinoma, other rare types) • In case of invasive adenocarcinoma: degree of differentiation (grading) according to current WHO classification • Maximum depth of infiltration: pT1a (m1, m2, m3, m4)/pT1b (sm1, sm2, sm3) plus infiltration depth in μm (or higher pT category) • Lymphatic vessel and/or vein invasion (L0 versus L1, V0 versus V1) • Summary assessment of the risk of lymph node metastasis: low-risk versus high-risk resection margins with regard to the neoplasia (for ER in toto circular and basal resection margin for ‘piecemeal’ ER basal resection margin, as here the circular resection margin must usually be evaluated histopathologically as RX)Consensus strength: strong consensus

Histological determination of tumor regression after neoadjuvant therapy

  • Recommendation 25(EC): Before the use of palliative systemic tumor therapy in adenocarcinoma, the HER2 status should be determined as a positive predictive factor for a potential therapy with trastuzumab. The histopathological determination on tumor tissue should be carried out in a quality-assured manner.Consensus strength: strong consensus

Endoscopic resection (ER) and local ablative procedures

  • Recommendation 30(EC): • If endoscopically nonlocalizable LGIEN is detected in Barrett’s esophagus and confirmed by a reference pathologist, follow-up visits shall occur at 6 months and then annually. • RFA of the entire Barrett’s segment to prevent progression of the LGIEN may be carried out. • If HGIEN cannot be localized endoscopically, an ablative procedure ought to be used.

Procedure for R1/R2 resection

  • Recommendation 45(EC): In the case of an intraoperatively proven R1 resection, the possibility of a curative resection should first be examined independently of preoperative therapy. A retrospective study indicates that adjuvant chemo(radio)therapy improves survival and reduces distant recurrence in patients with R1 resection, but without affecting locoregional recurrence.315 If this is not possible, post-operative radiochemotherapy should be carried out after discussion in the interdisciplinary tumor conference. In the case of a post-operatively detected R1 resection, radiochemotherapy should be given because the conditions for a postresection are unfavorable. In individual cases, a ‘wait and see’ strategy may be recommended.Consensus strength: strong consensus

Preoperative radiochemotherapy and perioperative chemotherapy

  • Recommendation 51In operable patients with a locally advanced adenocarcinoma of the esophagus or EGJ (category cT3/T4 resectable or category cN1-3), perioperative chemotherapy or preoperative radiochemotherapy should be given (Figure 4).Level of evidence: 1a. Grade of recommendation: A

R0 resection rate

  • Recommendation 55SEMS ought not to be used due to an increased complication rate with planned neoadjuvant radiochemotherapy or as a bridge to surgery.Level of evidence: 4. Grade of recommendation: B

Response prediction

  • Recommendation 58(EC): The clinical utility of FDG–PET for response assessment of chemotherapy or radiochemotherapy before surgery is controversial, which is why FDG–PET/CT should not be routinely carried out in this setting.Consensus strength: strong consensus

Indication for definitive radiochemotherapy

  • Recommendation 60In patients with localized squamous-cell carcinoma of the cervical esophagus, definitive radiochemotherapy should be preferred over primary surgical resection (Figure 5).Consensus strength: strong consensus

Value of post-operative adjuvant radiotherapy or radiochemotherapy

  • Recommendation 64After R0 resection of squamous-cell carcinoma, adjuvant radiotherapy or radiochemotherapy ought not to be carried out.Level of evidence: 1a (radiotherapy); 4 (radiochemotherapy). Grade of recommendation: B
  • Recommendation 64applies to a small group of patients who, on the one hand, were staged too low preoperatively and, on the other hand, are capable of receiving further therapy post-operatively. For those patients who already have locally advanced squamous-cell carcinoma at initial staging (cT3-4 or cN1-3), this recommendation explicitly does not apply (see instead recommendation 54).

Value of adjuvant immunotherapy

  • Recommendation 66If residual tumor cells can still be detected histologically in the resection specimen (≥ypT1 or ≥ypN1) following neoadjuvant radiochemotherapy and R0 resection of squamous-cell carcinoma in the esophagus or adenocarcinoma in the esophagus or GE junction, adjuvant immunotherapy with nivolumab ought to be carried out for 1 year.Level of evidence: 2. Grade of recommendation: B

Aftercare and rehabilitation

  • Recommendation 68(EC): In the first 6 months, regular follow-up checks of the nutritional status including dietary advice should be carried out. Supplementation of oral energy intake with oral nutritional supplements or even tube feeding via an initially left fine-needle catheter jejunostomy can be recommended.Consensus strength: strong consensus
  • Recommendation 69(EC): Patients with esophageal cancer should be motivated—within their means—to engage in physical activity. After completing primary therapy, all patients capable of rehabilitation should be offered follow-up treatment. The rehabilitative therapy should include medical, nursing, educational, training, and psychosocial measures adapted to the individual rehabilitation needs. In order to reduce the fatigue syndrome caused by cancer or tumor therapy, endurance training should be carried out that is geared to the individual’s ability to cope with stress.Consensus strength: consensus

Palliative first-line therapy: adenocarcinoma of the esophagus and esophagogastric junction

  • Recommendation 72(EC): Before initiation of palliative systemic therapy of adenocarcinoma of the esophagus, HER2 status should be determined as a predictive factor for therapy with trastuzumab and PD-L1 CPS should be determined as a predictive factor for therapy with an immune checkpoint inhibitor.Consensus strength: strong consensus
  • Recommendation 74In case of negative HER2 status and an elevated PD-L1 CPS cut-off value (for nivolumab PD-L1 CPS ≥ 5, for pembrolizumab PD-L1 CPS ≥ 10), a platinum (oxaliplatin or cisplatin)/fluoropyrimidine combination should be used together with one of the mentioned immune checkpoint inhibitors (Figure 6).Level of evidence: 1b. Grade of recommendation: A
  • Recommendation 75For HER2-overexpressing tumors (IHC3+ or IHC2+ and FISH+), first-line cisplatin/fluoropyrimidine-based chemotherapy should be supplemented with trastuzumab.Level of evidence: 2. Grade of recommendation: A

Palliative first-line therapy: squamous-cell carcinoma of the esophagus

  • Recommendation 77(EC): Patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus with a PD-L1 CPS < 10 and a PD-L1 TPS < 1% that cannot be treated curatively may be offered palliative systemic chemotherapy (Figure 7). The therapeutic goal is to maintain quality of life. Here, a combination therapy of a platinum derivative with a fluoropyrimidine or a taxane can be used.Consensus strength: strong consensus
  • Recommendation 78In patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus that is not curatively treatable and has a PD-L1 CPS ≥ 10 or PD-L1 TPS ≥ 1%, platinum/fluoropyrimidine chemotherapy should be used in conjunction with an immune checkpoint inhibitor (pembrolizumab PD-L1 CPS ≥ 10, nivolumab PD-L1 TPS ≥ 1%) (Figure 7).Level of evidence: 2. Grade of recommendation: A
  • Recommendation 79In patients with metastatic or locally advanced, non-curatively treatable squamous-cell carcinoma of the esophagus with a PD-L1 TPS ≥ 1%, the combination of nivolumab/ipilimumab ought to be used as the sole immunotherapy.Level of evidence: 2. Grade of recommendation: B

Palliative system therapy: second- and third-line therapy

  • Recommendation 81In patients with metastatic or locally advanced, non-curatively treatable adenocarcinoma of the esophagus and sufficient general condition, the MSI-high and/or dMMR status should be determined in the event of tumor progression under or recurrence after first-line therapy. Due to the high efficacy of immune checkpoint inhibitors in tumors with MSI-high or with dMMR, these patients ought to be offered treatment with a checkpoint inhibitor after failure of first-line therapy if no immunotherapy has been used previously.

Abstract

This guideline for the diagnosis and treatment of squamous-cell carcinoma and adenocarcinoma of the esophagus was developed and managed by the German Guideline Program in Oncology (GGPO) of the Association of the Scientific Medical Societies in Germany (AWMF), German Cancer Society (DKG), and German Cancer Aid (DKH). The guideline commission comprised multidisciplinary experts from various professional associations and organizations involved in the management of esophageal cancer, as well as a patient representative. Quality of the evidence is presented using Oxford evidence-based medicine system, and recommendations were graded in a formal consensus process using a recommendation grading scheme.

Contents of the original publication

The section headings of the original.

  • Executive summary and list of recommendations
  • Primary diagnosis and staging
  • Pathology
  • Nutritional medical care
  • Curative therapy
  • Palliative therapy
  • Psycho-oncology
  • Scope and purpose
  • Methodology
  • Level of evidence
  • Grade of recommendation
  • Statement
  • Expert consensus (EC)
  • Background
  • Risk factors and prevention
  • Primary diagnosis and staging
  • Primary diagnosis
  • Advanced diagnostics
  • Staging of esophageal cancer
  • MRI for staging of esophageal cancer
  • Diagnostic laparoscopy and thoracoscopy (staging)
  • Pathology
  • Squamous epithelium
  • Barrett’s mucosa
  • Anatomical subdivisions
  • Regional lymph nodes
  • Squamous-cell carcinoma
  • Barrett’s adenocarcinoma
  • Histological determination of tumor regression after neoadjuvant therapy
  • Nutritional medical care
  • Curative intended therapy
  • General therapy decision
  • Endoscopic therapy
  • Procedure for local recurrences after endoscopic therapy
  • Follow-up after endoscopic therapy
  • Surgical therapy
  • Preoperative risk analysis
  • Surgical technique
  • Resection extent
  • Extent of lymphadenectomy
  • Reconstruction
  • Minimally invasive procedures (MIP)
  • Carcinomas of the middle and distal third of the esophagus including AEG type I
  • AEG type II and III
  • Squamous-cell carcinomas
  • Lymphadenectomy
  • Limited distal esophageal and proximal gastric resection
  • Special case of cervical esophageal cancer
  • Reconstruction
  • Pyloroplasty
  • Hiatoplasty
  • Minimally invasive esophagectomy (MIS)
  • Perioperative complications
  • Procedure for oligometastasis
  • Perioperative nutrition
  • Procedure for R1/R2 resection
  • Procedure for local recurrence after surgery
  • Multimodal therapy concepts
  • Preoperative radiotherapy
  • Preoperative radiochemotherapy and perioperative chemotherapy
  • Preoperative radiochemotherapy
  • Adenocarcinoma
  • Squamous-cell carcinoma
  • Restaging after preoperative multimodal therapy
  • Response prediction
  • Indication for definitive radiochemotherapy
  • Procedure for tumor persistence/local recurrence after radiochemotherapy
  • Importance of targeted therapies for preoperative concepts
  • Value of post-operative adjuvant radiotherapy or radiochemotherapy
  • Value of adjuvant immunotherapy
  • Aftercare and rehabilitation
  • Palliative therapy
  • Palliative systemic therapy: general
  • Palliative first-line therapy: adenocarcinoma of the esophagus and esophagogastric junction
  • Palliative first-line therapy: squamous-cell carcinoma of the esophagus
  • Palliative system therapy: second- and third-line therapy
  • Palliative radio(chemo)therapy
  • Palliative brachytherapy
  • Endoscopic stent application
  • Value of intraluminal local therapy
  • Psycho-oncology
  • Supplementary data

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