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    Esophageal Cancer

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    Jan.02.2024

    Esophageal Cancer

    Synopsis

    Key Points

    • Esophageal cancer is any of several upper gastrointestinal tract cancers originating in the esophagus or esophagogastric junction; it often presents as locally advanced disease with poor prognosis
      • Squamous cell carcinoma and adenocarcinoma account for most cases (more than 95%) r1
    • Most common symptom is difficulty or pain in swallowing
    • Careful assessment of history with regard to risk factors and physical examination is critical to diagnose illness at earliest possible opportunity
    • Initial diagnostic evaluation is upper gastrointestinal tract endoscopy with biopsy
    • Accurate staging information obtained by CT, PET, PET-CT, and endoscopic ultrasonography is important for prognosis and determining treatment options
    • Management varies by histologic subtype, stage of disease, and medical fitness of patient
      • Multidisciplinary team is recommended to determine optimal management
      • Modalities can include endoscopic therapy, esophagectomy, chemoradiation therapy, immunotherapy, targeted therapy, and palliative interventions
    • Potential complications include esophageal obstruction, tracheoesophageal fistula with chronic aspiration, aortoesophageal fistula, and anastomotic leak
    • Prognosis depends on cancer stage at diagnosis

    Pitfalls

    • Failure to monitor Barrett esophagus for progressive dysplasia poses risk of delayed diagnosis of neoplasia c1

    Terminology

    Clinical Clarification r2

    • Esophageal cancer is any of several upper gastrointestinal tract cancers originating in the esophagus or esophagogastric junction
      • Squamous cell carcinoma and adenocarcinoma account for most cases (more than 95%) r1
    • Often presents as locally advanced disease with poor prognosis

    Classification

    • Cell of origin r3
      • Squamous cell carcinoma
        • Arises in squamous epithelial cells of inner lining of esophagus
        • Typically originates in proximal to middle esophagus
        • May be more sensitive to chemotherapy, chemoradiation therapy, and radiation therapy than adenocarcinoma, although long-term outcomes appear comparable r2
      • Adenocarcinoma
        • Arises in glandular or secretory epithelial cells that line esophagus
        • Occurs mainly in distal esophagus and esophagogastric junction
        • May be associated with better long-term prognosis after resection than squamous cell carcinoma r2
    • Staging
      • TNM staging classification (squamous cell carcinoma and adenocarcinoma) r4
        • Primary tumor (T)
          • TX: cannot be assessed
          • T0: no evidence of primary tumor
          • Tis: high-grade dysplasia (malignant cells confined to epithelium by basement membrane)
          • T1: tumor invades lamina propria, muscularis mucosae, or submucosa
            • T1a: tumor invades lamina propria or muscularis mucosae
            • T1b: tumor invades submucosa
          • T2: tumor invades muscularis propria
          • T3: tumor invades adventitia
          • T4: tumor invades adjacent structures
            • T4a: tumor invades pleura, pericardium, azygos vein, diaphragm, or peritoneum
            • T4b: tumor invades other adjacent structures (eg, aorta, trachea, vertebral body)
        • Regional lymph nodes (N)
          • NX: regional lymph nodes cannot be assessed
          • N0: no regional lymph node metastasis
          • N1: metastasis in 1 or 2 regional lymph nodes
          • N2: metastasis in 3 to 6 regional lymph nodes
          • N3: metastasis in 7 or more regional lymph nodes
        • Metastasis (M)
          • M0: no distant metastasis
          • M1: distant metastasis
        • Histologic grade (G)
          • GX: grade cannot be assessed
          • G1: well differentiated
          • G2: moderately differentiated
          • G3: poorly differentiated or undifferentiated
      • Location (L): position of tumor epicenter in esophagus in squamous cell carcinoma r4
        • X: location unknown
        • Upper: cervical esophagus to lower border of azygos vein
        • Middle: lower border of azygos vein to lower border of inferior pulmonary vein
        • Lower: lower border of inferior pulmonary vein to stomach, including esophagogastric junction
      • Prognostic stage groups r4
        • Clinical (cTNM): newly diagnosed, not treated patients
          • Squamous cell carcinoma
            • Stage 0: TisN0M0
            • Stage I: T1, N0 to N1, M0
            • Stage II:
              • T2, N0 to N1, M0
              • T3N0M0
            • Stage III:
              • T3N1M0
              • T1 to T3, N2, M0
            • Stage IVA
              • T4, N0 to N2, M0
              • Any T, N3, M0
            • Stage IVB: any T, any N, M1
          • Adenocarcinoma
            • Stage 0: TisN0M0
            • Stage I: T1N0M0
            • Stage IIA: T1N1M0
            • Stage IIB: T2N0M0
            • Stage III
              • T2N1M0
              • T3, N0 to N1, M0
              • T4a, N0 to N1, M0
            • Stage IVA
              • T1 to T4a, N2, M0
              • T4b, N0 to N2, M0
              • Any T, N3, M0
            • Stage IVB: any T, any N, M1
        • Pathologic staging (pTNM): for patients undergoing resection without prior treatment
          • Squamous cell carcinoma
            • Stage 0: Tis, N0, M0, G inapplicable, any L
            • Stage 1A
              • T1a, N0, M0, G1, any L
              • T1a, N0, M0, GX, any L
            • Stage IB
              • T1a, N0, M0, G2 to G3, any L
              • T1b, N0, M0, G1 to G3, any L
              • T1b, N0, M0, GX, any L
              • T2, N0, M0, G1, any L
            • Stage IIA
              • T2, N0, M0, G2 to G3, any L
              • T2, N0, M0, GX, any L
              • T3, N0, M0, any G, L: lower
              • T3, N0, M0, G1, L: upper/middle
            • Stage IIB
              • T3, N0, M0, G2 to G3, L: upper/middle
              • T3, N0, M0, GX, any L
              • T3, N0, M0, any G, L: X
              • T1, N1, M0, any G, any L
            • Stage IIIA
              • T1, N2, M0, any G, any L
              • T2, N1, M0, any G, any L
            • Stage IIIB
              • T2, N2, M0, any G, any L
              • T3, N1 to N2, M0, any G, any L
              • T4a, N0 to N1, M0, any G, any L
            • Stage IVA
              • T4a, N2, M0, any G, any L
              • T4b, N0 to N2, M0, any G, any L
              • Any T, N3, M0, any G, any L
            • Stage IVB: any T, any N, M1, any G, any L
          • Adenocarcinoma
            • Stage 0: Tis, N0, M0; G (grade) inapplicable
            • Stage 1A
              • T1a, N0, M0, G1
              • T1a, N0, M0, GX
            • Stage 1B
              • T1a, N0, M0, G2
              • T1b, N0, M0, G1 to G2
              • T1b, N0, M0, GX
            • Stage 1C
              • T1, N0, M0, G3
              • T2, N0, M0, G1 to G2
            • Stage IIA
              • T2, N0, M0, G3
              • T2, N0, M0, GX
            • Stage IIB
              • T1, N1, M0, any G
              • T3, N0, M0, any G
            • Stage IIIA
              • T1, N2, M0, any G
              • T2, N1, M0, any G
            • Stage IIIB
              • T2, N2, M0, any G
              • T3, N1 to N2, M0, any G
              • T4a, N0 to N1, M0, any G
            • Stage IVA
              • T4a, N2, M0, any G
              • T4b, N0 to N2, M0, any G
              • Any T, N3, M0, any G
            • Stage IVB: any T, any N, M1, any G
        • Postneoadjuvant therapy (ypTNM): for patients who have received preoperative therapy
          • Squamous cell carcinoma
            • Stage I: T0 to T2, N0, M0
            • Stage II: T3, N0, M0
            • Stage IIIA: T0 to T2, N1, M0
            • Stage IIIB
              • T3, N1, M0
              • T0 to T3, N2, M0
              • T4a, N0, M0
            • Stage IVA
              • T4a, N1 to N2, M0
              • T4a, NX, M0
              • T4b, N0 to N2, M0
              • Any T, N3, M0
            • Stage IVB: any T, any N, M1
          • Adenocarcinoma
            • Stage I: T0 to T2, N0, M0
            • Stage II: T3, N0, M0
            • Stage IIIA: T0 to T2, N1, M0
            • Stage IIIB
              • T3, N1, M0
              • T0 to T3, N2, M0
              • T4a, N0, M0
            • Stage IVA
              • T4a, N1 to N2, M0
              • T4a, NX, M0
              • T4b, N0 to N2, M0
              • Any T, N3, M0
            • Stage IVB: any T, any N, M1
      • Classification of esophagogastric junction tumors
        • Siewert classification r2
          • Applies to adenocarcinomas at or near esophagogastric junction
          • Type I: adenocarcinoma of distal esophagus, in which center of lesion is 1 to 5 cm above esophagogastric junction
          • Type II: true carcinoma of cardia, in which center of lesion is between 1 cm above and 2 cm below esophagogastric junction
          • Type III: subcardial carcinoma, in which center of lesion is 2 to 5 cm below esophagogastric junction but extends to junction or into esophagus from below
        • American Joint Committee on Cancer and Union for International Cancer Control define anatomic boundary between esophagus and stomach as follows: r4
          • Tumors involving esophagogastric junction with epicenter no more than 2 cm into proximal stomach are staged as esophageal cancers
          • Tumors with epicenter located more than 2 cm into proximal stomach are staged as stomach cancers, even if esophagogastric junction is involved

    Diagnosis

    Clinical Presentation

    History

    • Early stages of esophageal cancer may be asymptomatic c2
    • Patients may report a long history of heartburn from gastric reflux r5c3
    • Dysphagia, with or without unintentional weight loss, is most common presentation of esophageal cancer r1c4
    • Early symptoms
      • May be subtle and nonspecific
      • Pain or difficulty swallowing solid food and eventually liquids c5c6
      • Weight loss
        • Unintended loss of 10% or more body weight in preceding 3 to 6 months r1c7
    • Late symptoms
      • Pain, burning sensation, or chest discomfort when swallowing c8c9c10
      • Coughing or hoarseness c11c12
      • Halitosis c13
      • Sudden onset of hiccups is common when tumor spreads to diaphragm c14c15

    Physical examination

    • In most cases, physical examination is unrevealing; cervical lymphadenopathy may be palpable r1c16
    • Hepatomegaly may be found in advanced disease c17

    Causes and Risk Factors

    Causes

    • Specific causes of esophageal cancer are unknown, but several factors are known to increase risk of developing the disease c18

    Risk factors and/or associations

    Age
    • Adenocarcinoma of esophagus typically presents in patients older than 50 years r1c19
    • Squamous cell carcinoma of esophagus typically presents in patients aged 60 to 70 years r1c20
    • Esophageal cancer is rare in young people r5c21c22
    Sex
    Genetics
    • Although various genes are associated with esophageal cancer, no single specific variant is known to be involved in most esophageal cancers r5c25
    • Several hereditary cancer risk syndromes are associated with increased risk for esophageal carcinoma r2c26
      • Tylosis: rare autosomal dominant syndrome caused by variants in RHBDF2 gene (rhomboid 5 homolog 2) c27
      • Bloom syndrome: rare autosomal recessive syndrome caused by variants in BLM gene (RECQL3; BLM RecQ like helicase) c28
      • Fanconi anemia: autosomal recessive disorder that may be caused by variants in various genes of the Fanconi anemia complementation group (eg, FANCA, FANCC, FANCG, FANCD2) c29
      • Familial Barrett esophagus: rare autosomal dominant susceptibility associated with various germline variants c30
    Ethnicity/race
    • Adenocarcinoma
      • More prevalent in White populations than in Black populations r7c31c32
      • Predominant subtype in North America and Europe
    • Squamous cell carcinoma
      • More prevalent in Black populations than in White populations r7c33c34
      • Predominant subtype outside the United States (90% of cases worldwide); highest rates in China, central Asia, and eastern and southern Africa r1
    Other risk factors/associations r8
    • Squamous cell carcinoma r9
      • Tobacco use (associated with 3- to 7-fold increased risk) c35
        • Risk of developing squamous cell carcinoma is dramatically reduced after smoking cessation
        • Smoking cessation does not significantly reduce risk for developing adenocarcinoma
      • Excessive alcohol consumption (associated with 3- to 5-fold increased risk) c36
      • Esophageal diverticula c37
      • Caustic injury to esophagus c38
      • Frequent consumption of extremely hot beverages c39
      • Plummer-Vinson syndrome c40
      • History of head and neck cancer c41c42
      • Achalasia r10
      • Exposure to thoracic radiation r10
      • Tylosis (nonepidermolytic palmoplantar keratoderma) r10
    • Adenocarcinoma r9
      • Most common risk factor is obesity (considered causal association) c43
        • Visceral fat is more closely associated than BMI c44
      • Gastroesophageal reflux disease (increases risk of developing adenocarcinoma by 5-fold) c45
        • Barrett esophagus is one of the most common predisposing risk factors c46
      • Tobacco use (associated with 2-fold increased risk) c47
      • Previous use of β-blockers, anticholinergic agents, or aminophylline c48c49c50
      • Variants of enzymes that metabolize alcohol (eg, loci at PLCE1, C20orf54, ADH1B, and ALDH2) in combination with alcohol consumption and smoking r10
      • Chronic Helicobacter pylori infection is associated with reduced risk r11
    • Squamous cell carcinoma and adenocarcinoma
      • Achalasia r5c51
      • Mediastinal radiation r3c52
      • Diet high in red meat, fat, and processed foods r5c53c54

    Diagnostic Procedures

    Primary diagnostic tools

    • Evaluation begins with patient history, including symptoms (eg, dysphagia, weight loss) and risk factors, and careful physical examination (although findings thereof are usually unremarkable) r3c55
    • Perform upper gastrointestinal tract endoscopy with biopsy as initial diagnostic evaluation r1r2c56
      • Evaluates for presence and location of neoplasia and allows for biopsy of suspicious lesions
      • Double-contrast barium esophagography is optional; it is reserved for patients who cannot undergo endoscopy r1r2c57c58
    • Patients whose biopsy shows histologic evidence of malignancy undergo further evaluation for staging
      • Obtain CBC and comprehensive chemistry panel r2c59c60
      • Perform CT of chest and abdomen for evidence of metastasis; may be extended to pelvis if clinically indicated r12c61c62
      • If CT results are negative for evidence of metastasis, obtain PET scan to evaluate for occult metastases not detected by CT r12r13c63
        • Superior to CT for detecting distant metastatic disease r1
        • F-18 fluorodeoxyglucose-PET-CT evaluation (skull base to midthigh) is useful technique for initial staging r2r13c64
          • Improves detection of stage IV disease and lymph node staging
      • In the absence of metastatic disease, perform endoscopic ultrasonography r2r12
        • Recommended for better locoregional tumor staging; perform before any treatment r12c65
        • Combination with fine-needle aspiration of suspicious nodes for cytology assessment provides greater accuracy in metastatic evaluation than endoscopic ultrasonography alone r2c66
      • Endoscopic mucosal resection should be performed for small nodular lesions (2 cm or smaller) to provide accurate staging of early-stage cancers; it may also be curative r2c67
      • If esophageal lesion is at or above level of carina and no evidence of metastatic disease is found, perform bronchoscopy; obtain endobronchial biopsies if suspect lesions are observed r2r12c68c69
      • Microsatellite instability or mismatch repair testing and PD-L1 (programmed cell death ligand 1) protein expression is recommended for all newly diagnosed patients r2r14c70c71
      • The following testing is recommended for patients with documented or suspected metastatic or inoperable disease to aid in choosing chemotherapeutic agents: r2r15
        • HER2 (human epidermal growth factor receptor 2) expression (adenocarcinomas) r14c72
        • Next generation sequencing, including identification of NTRK gene fusions, tumor mutational burden, HER2 amplification, MSI status (microsatellite instability), MMR deficiency (DNA mismatch repair), RET gene fusions (rearranged during transfection), and BRAF V600E variants, may be considered r2
      • In suspected metastatic disease, obtain tissue biopsy in at least 1 suspect site to confirm metastasis r3c73
      • Laparoscopy, with or without peritoneal washings, may be useful for detection of radiographically occult metastatic disease involving peritoneum or diaphragm in select patients, especially in locally advanced adenocarcinoma of esophagogastric junction r11c74

    Laboratory

    • CBC and comprehensive chemistry profile r2c75c76
      • Establish baseline values before decisions about surgery and/or chemotherapy; may suggest metastasis r1
        • CBC can evaluate for anemia
        • Elevated hepatic transaminase or alkaline phosphatase levels may be evidence of liver or bone metastasis, respectively c77c78c79
    • HER2 biomarker testing r2c80c81
      • Useful in patients with inoperable locally advanced, recurrent, or metastatic adenocarcinoma
      • Assess for overexpression by immunohistochemistry or fluorescence in situ hybridization c82c83
      • Influences selection of chemotherapy agents

    Imaging

    • CT scan of chest and abdomen r16c84c85c86c87c88c89
      • Obtained for staging, with and without oral and IV contrast material
      • Aids in investigating the possibility of distant metastatic disease, such as the following:
        • Lung or liver metastases c90
        • Celiac, aortic, or retroperitoneal lymph node spread
      • May be extended into pelvis if clinically indicated and in cases of adenocarcinoma r17
    • F-18 fluorodeoxyglucose-PET-CT scan r2c91
      • Alternative to CT for initial staging r13
      • Recommended if metastatic disease is not evident on CT scan
        • More sensitive than CT at detecting metastatic disease r13c92
      • Useful in evaluating response to chemotherapy or chemoradiation therapy
    • Endoscopic ultrasonography r1c93
      • Recommended for patients who appear to have early localized disease (no distant metastasis)
        • Can provide prognostic information and guide therapeutic options
        • More accurate than CT or PET to determine extent of tumor invasion and nodal involvement
      • May be combined with fine-needle aspiration of adjacent lymph nodes for cytology to increase diagnostic accuracy c94c95

    Procedures

    Upper gastrointestinal tract endoscopy c96
    General explanation
    • Fiberoptic examination of esophagus and stomach c97
    • Useful in diagnosis, staging, treatment, and surveillance of esophageal cancer r2
    • Determines presence and location of esophageal neoplasia; the following are noted: r2
      • Detailed description of length, circumferential involvement, and degree of obstruction
      • Location relative to teeth and esophagogastric junction
    • Biopsies of suspicious lesions are taken for histologic interpretation r2c98
      • Cytologic brushing or washings are typically inadequate for initial diagnosis
    • For small nodular lesions (2 cm or smaller), endoscopic resection is performed to more accurately measure depth of invasion, and it is also potentially curative c99
    Indication
    • Initial evaluation of dysphagia or follow-up of barium esophagogram c100c101c102
    Contraindications
    • Esophageal stricture precluding passage of scope
    Complications
    • Bleeding
    • Aspiration
    • Perforation
    Interpretation of results
    • Histologic analysis distinguishes between benign and malignant lesions and characterizes malignant lesions as squamous cell carcinoma or adenocarcinoma
    • Molecular pathology assessment includes PD-L1 and HER2 status r11
    Bronchoscopy c103
    General explanation
    • Bronchofiberscope is passed through nose or mouth, down trachea, and into lung
    • Lung tissue is visually examined
    • Biopsies of abnormalities and cytology of washings are obtained
      • Sterile saline is injected into lung, then aspirated and collected for analysis
    Indication
    • Need for visual examination of tracheal and alveolar tissue in cases in which esophageal lesion occurs at level of carina r2
    Contraindications
    • Patient is unable to support ventilation during procedure
    Complications
    • Fever
    • Bronchospasm or bronchoconstriction
    • Hypoxia
    • Pneumothorax
    • Cardiac arrhythmias
    • Laryngeal edema, injury, or spasm
    Interpretation of results
    • Visual and/or histopathologic evidence of tumor
    Endoscopic ultrasonography c104
    General explanation
    • Endoscope fitted with linear-plane sonographic probe is passed into esophagus and stomach
    Indication
    • Perform before any treatment to provide evidence of depth of invasion of tumor, presence of abnormal lymph nodes, and possibly signs of distant metastasis r2
    Contraindications
    • Esophageal stricture precluding passage of scope
    Complications
    • Aspiration
    Interpretation of results
    • Identifies mediastinal and perigastric lymph nodes
      • Appearance of enlarged, hypoechoic, rounded, well-circumscribed, homogeneous structures in these areas identifies inflammatory or malignant nodes
    • Findings indicate whether lesion is apparently confined to esophagus or whether there is evidence of regional extension
    Laparoscopy c105
    General explanation
    • Fiberoptic laparoscope is inserted through small incision in abdominal wall for inspection of extraluminal surfaces of esophagogastric junction, stomach, and adjacent organs
    • Peritoneal fluid is collected for cytology, and any suspicious lesions are biopsied c106c107c108c109
    Indication
    • Consider in patient with adenocarcinoma for staging of advanced, clinical stage T3 or node-positive tumors r2
    • Consider for detection of radiographically occult metastatic disease in select patients, especially patients with Siewert type II or III tumors of esophagogastric junction r2
    Complications
    • Perforation or laceration
    • Peritonitis
    • Bleeding
    Interpretation of results
    • Evidence of metastatic disease, including positive cytology findings in peritoneal fluid, may limit treatment options and worsen prognosis r2

    Differential Diagnosis

    Most common

    • Benign stricture c110
      • Esophageal narrowing that may result in difficulty swallowing
      • Associated with long history of heartburn
      • Like esophageal cancer, may cause dysphagia and/or pain; optical endoscopic appearance may resemble that of malignant esophageal cancer
      • Differentiated by biopsy showing absence of malignant structures
    • Achalasia c111d1
      • Rare inability to properly relax the lower esophageal sphincter, preventing food from moving to stomach
      • Dysphagia is common to both conditions c112
      • Patients with achalasia are more likely to have halitosis and to regurgitate retained esophageal contents
      • Differentiated by esophagography and/or endoscopy showing absence of obstructive tumor or inflammation; manometry shows characteristic dysfunction of lower esophageal sphincter and impaired esophageal motility
    • Barrett esophagus c113d2
      • Replacement of healthy esophageal epithelium with metaplastic columnar cells as a result of gastroesophageal reflux disease
      • Presents with long-standing reflux, as do many esophageal cancers; dysphagia is rare
      • Esophagogastroduodenoscopy with biopsy is required to diagnose Barrett esophagus and to differentiate from esophageal malignancy
        • Because Barrett esophagus predisposes to malignancy, the 2 conditions may coexist
    • Eosinophilic esophagitis c114d3
      • Characterized by dense esophageal eosinophilia with severe squamous epithelial hyperplasia occurring in association with esophageal symptoms
      • Principal symptoms are dysphagia and food impaction
      • Differentiated by characteristic histopathologic findings on biopsy of esophageal mucosa (including more than 15 eosinophils per high-power field)

    Treatment

    Goals

    • For a localized tumor, the goal of treatment is cure
    • For a metastatic tumor, the goals include:
      • Slow disease progression
      • Ease symptoms
      • Improve quality of life

    Disposition

    Admission criteria

    • Patients requiring esophageal resection

    Recommendations for specialist referral r2

    • Multidisciplinary team is recommended to determine optimal management; it typically includes medical, radiation, and surgical oncologists; radiologists; gastroenterologists; and pathologists
    • Referral to supporting services, such as social workers, palliative care specialists, and nutritional services, may also be beneficial
    • Referral to cancer geneticist is recommended for those with known high-risk syndrome associated with esophageal cancers

    Treatment Options

    Treatment options depend on histologic subtype (squamous cell carcinoma or adenocarcinoma), stage at diagnosis, and medical fitness of patient r1

    Consider preoperative nutritional support via nasoduodenal or jejunostomy tube; percutaneous endoscopic gastrostomy is not recommended r2

    Patients may be classified into 2 groups after initial workup r2

    • Locoregional cancer (stages I-IVA, except T4b or unresectable N3)
      • Can be subclassified by medical fitness after additional evaluation (eg, nutritional, cardiac, and pulmonary studies)
        • Medically fit for surgery
        • Nonsurgical candidate
    • Unresectable locally advanced or metastatic cancer (stage IVA -T4b or unresectable N3 only, and IVB)

    Locoregional cancer

    • Offer multimodality therapy to most patients with locally advanced esophageal carcinoma r18
      • Surgery alone may be considered for patients with clinical earlier-stage esophageal cancer (T2N0)
    • Primary treatment options for patients with squamous cell carcinoma who are medically fit for surgery r2
      • Endoscopic therapy (endoscopic mucosal resection or endoscopic submucosal dissection), with or without ablation r19
        • Preferred treatment option for most superficial lesions (Tis or T1a tumors); may also be considered for T1b lesions that have a low risk of metastasis (ie, smaller than 2 cm, localized to superficial submucosa, well differentiated, and without lymphovascular invasion)r19
        • Ablation alone is option for Tis lesions
      • Esophagectomy
        • Patients with extensive Tis or T1a disease, especially nodular disease not adequately controlled by ablation or endoscopic resection with or without ablation, and those with T1b to T2, N0, low-risk, well-differentiated lesions smaller than 2 cm are candidates for esophagectomy alone
      • Preoperative chemoradiation therapy or chemoradiation therapy alone (without surgery) r18
        • Patients with T1b, N1 to N3 tumors, and locally advanced resectable tumors (T2-T4a, any N) should undergo preoperative chemoradiation therapy r20
        • Definitive chemoradiation therapy is preferred for patients who decline surgery and those with unresectable T4b tumors
          • Chemotherapy alone is considered with invasion of trachea, great vessels, vertebrae, or heart r2
        • Fluoropyrimidine- or taxane-based regimens are recommended for preoperative and definitive chemoradiation therapy
          • Preoperative chemoradiation therapy r2c115
            • Preferred regimens (fluorouracil can be replaced with capecitabine)
          • Definitive chemoradiation therapy r2c120
            • Preferred regimens (fluorouracil can be replaced with capecitabine)
    • Primary treatment options for patients with adenocarcinoma who are medically fit for surgery r2
      • Endoscopic therapy (endoscopic mucosal resection or endoscopic submucosal dissection), with or without ablation
        • Preferred treatment option for most superficial lesions (includes Tis-T1b, N0 tumors)
        • Ablation alone is option for Tis lesions
      • Esophagectomy r2
        • Patients with extensive Tis, T1a, or superficial T1b disease, especially nodular disease not adequately controlled by ablation or endoscopic resection with or without ablation, and those with T1b to T2, N0, low-risk, well-differentiated lesions less than 3 cm are candidates for esophagectomy alone
      • Preoperative chemoradiation before esophagectomy is the preferred approach for localized adenocarcinoma of the thoracic esophagus or esophagogastric junction r18
        • Perioperative systemic therapy followed by esophagectomy is an alternative option for distal esophagus and esophagogastric junction before esophagectomy
          • Adenocarcinomas are significantly less sensitive to radiation therapy than squamous cell carcinoma; chemoradiation therapy may offer no benefit over chemotherapy alone followed by surgery r21
        • Preferred regimens (3 cycles preoperative; 3 cycles postoperative)
          • Fluorouracil, leucovorin, oxaliplatin, and docetaxel (only if patient medically fit) c125c126c127
          • Fluoropyrimidine and oxaliplatin c128c129
      • Neoadjuvant or perioperative therapy with an immune checkpoint inhibitor can be considered if tumor is MSI-H/dMMR (high-MSI/MMR deficient) r2
        • Role of subsequent surgery in patients with complete radiologic and metabolic response to neoadjuvant immunotherapy is unclear
      • Definitive chemoradiation therapy is preferred for unresectable T4b tumors (same regimens as squamous cell)
        • Chemotherapy alone is considered with invasion of trachea, great vessels, or heart r2
    • Postoperative treatment options are based on surgical margins, histology, and nodal status r2
      • For patients with adenocarcinoma
        • Postoperative fluoropyrimidine-based chemoradiation therapy or chemotherapy is recommended after R0 resection for patients with node-positive tumors who have not received preoperative therapy, and it may be considered in those with node-negative T2 tumors with high-risk features, as well as those with T2, T3, and T4a tumors
      • For patients with adenocarcinoma or squamous cell carcinoma
        • Postoperative treatment with nivolumab is recommended after R0 resection for patients with node-positive disease and/or those who remained T-positive after preoperative chemoradiation r14
        • Nivolumab is preferred postoperative systemic therapy for patients who have positive margins on resection after preoperative chemoradiation therapy and surgery; fluoropyrimidine-based regimens are also recommended
        • Postoperative fluoropyrimidine-based chemoradiation therapy is recommended for patients with residual disease at surgical margin only if they did not receive preoperative chemoradiation therapy
    • Treatment options for patients with squamous cell carcinoma or adenocarcinoma who are not candidates for surgery r2
      • Endoscopic therapy (endoscopic mucosal resection or endoscopic submucosal dissection), with or without ablation, is recommended for patients with Tis to T1b, N0 tumors; ablation alone is an option for Tis lesions
      • Definitive chemoradiation therapy (fluoropyrimidine- or taxane-based) is preferred for technically resectable locally advanced cancer (T2-T4a, any N) in patients able to tolerate treatment
      • Palliative radiation therapy or best supportive care are appropriate options in patients unable to tolerate chemotherapy or chemoradiation therapy

    Unresectable or metastatic disease r2

    • Decision to use best supportive care alone or with systemic therapy depends on performance status, comorbidities, and toxicity profile r2
      • Performance status scales are commonly used to assess functional impairment, to compare effectiveness of therapies, and to assess prognosis
        • Karnofsky performance status scale r22
          • Ordered scale with 11 levels (0-100) based on health status; low scores are associated with severe illness and poor survival r2
        • Eastern Cooperative Oncology Group performance status scale (from ECOG-ACRIN Cancer Research Group) r23
          • 5-point scale (0-4) based on level of symptom interference with normal activity; higher scores correlate with poor performance status r2
      • Patients with Karnofsky performance status of 60% or more or ECOG performance status of 2 or less may be offered systemic therapy and/or best supportive care
      • For patients with Karnofsky performance status less than 60% or ECOG performance status of 3 or more, offer palliative, best supportive care only
    • First line systemic therapy r2
      • 2 drug cytotoxic regimens are preferred owing to lower toxicity; 3 drug regimens are reserved for patients who are medically fit with excellent performance status and easy access to frequent toxicity evaluations
      • Both nivolumab and pembrolizumab, in addition to chemotherapy, improved overall survival and progression-free survival in patients with PD-L1–positive tumors r24r25r26
        • US Food and Drug Administration has approved pembrolizumab and nivolumab in combination with chemotherapy for patients with metastatic or locally advanced esophageal carcinoma who are not candidates for surgical resection or definitive chemoradiation r27r28
      • Preferred regimens for squamous cell carcinoma and HER2 overexpression–negative adenocarcinoma
        • Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and nivolumab r29r30
        • Fluoropyrimidine (fluorouracil or capecitabine), cisplatin, and nivolumab (for squamous cell carcinoma) r31
        • Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and pembrolizumab
        • Fluoropyrimidine (fluorouracil or capecitabine), cisplatin, and pembrolizumab
        • Fluoropyrimidine (fluorouracil or capecitabine) and oxaliplatin
        • Fluoropyrimidine (fluorouracil or capecitabine) and cisplatin
        • Nivolumab and ipilimumab (for squamous cell carcinoma) r30r32
      • Add trastuzumab to first line chemotherapy for HER2-overexpressing advanced or metastatic adenocarcinoma r2r33
        • Pembrolizumab may also be added irrespective of PD-L1 expression r14r30r34
        • Preferred regimens if HER2 overexpression–positive
          • Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and trastuzumab, with or without pembrolizumab c130c131c132c133
          • Fluoropyrimidine (fluorouracil or capecitabine), cisplatin, and trastuzumab, with or without pembrolizumab c134c135c136c137
      • Preferred regimens for MSI-H/dMMR tumors (independent of PD-L1 status)
        • Pembrolizumab
        • Dostarlimab-gxly
        • Nivolumab and ipilimumab
        • Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and nivolumab
        • Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and pembrolizumab
      • Emerging regimen
        • Zolbetuximab, an investigational monoclonal antibody targeting CLDN18.2 (expressed by gastric and gastroesophageal cancers), plus oxaliplatin-based chemotherapy may represent a new first line treatment for previously untreated locally advanced or unresectable, HER2-negative, CLDN18.2-positive esophagogastric junction adenocarcinoma r35
          • Improved progression-free and overall survival compared to oxaliplatin-based chemotherapy alone
    • Second line or subsequent therapy choices depend on prior therapy and performance status; no specific regimen is currently supported r2
      • Preferred options r2
        • Paclitaxel with ramucirumab (for adenocarcinoma) c138
        • Fam-trastuzumab deruxtecan (for HER2 overexpression–positive adenocarcinoma)
        • Docetaxel c139c140
        • Paclitaxel
        • Irinotecan c141c142c143
        • Fluorouracil and irinotecan
        • Trifluridine and tipiricil (third line for adenocarcinoma of esophagogastric junction) c144
        • Nivolumab (for squamous cell carcinoma)
        • Entrectinib or larotrectinib (for NTKR gene fusion–positive tumors) r2c145c146
        • Pembrolizumab for MSI-H, dMMR, or high tumor variant burden (10 or more variants/megabase) tumors r2c147
        • Dostarlimab for tumors with MSI-H, dMMR, or high tumor variant burden (10 or more variants per megabase)
        • Dabrafenib and trametinib for BRAF V600E mutated tumors
        • Selpercatinib for RET gene fusion–positive tumors

    Drug therapy

    • Drug Therapy: Esophageal CancerCTLA-4, cytotoxic T-lymphocyte antigen 4; FLOT, fluorouracil + oxaliplatin + docetaxel; ILD, Interstitial lung disease; PD-1, programmed death receptor-1; PRES, Posterior reversible encephalopathy syndrome; VEGFR2, Vascular endothelial growth factor receptor 2.Data from Accord Healthcare, Inc.: Carboplatin Injection. Drug Label Information. National Library of Medicine DailyMed website. Updated April 13, 2020. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=48aa7ef3-9f44-2a08-e054-00144ff88e88; Celltrion USA, Inc.: Capecitabine 150MG--Capecitabine Tablet, Film Coated. Capecitabine 500MG--Capecitabine Tablet, Film Coated. National Library of Medicine DailyMed website. Updated November 7, 2019. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=56ada01c-b033-4108-85e5-ebe5f2bd9ee9; Accord Healthcare, Inc.: Fluorouracil Injection, Solution. National Library of Medicine DailyMed website. Updated September 9, 2020. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66d451fe-2436-494c-80c5-4528c8e34369; Genentech, Inc.: Herceptin Hylecta--Trastuzumab And Hyaluronidase-Oysk Injection, Solution. National Library of Medicine DailyMed website. Updated October 19, 2020. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf30894-41cf-480c-8bc3-56f592a13813; Daiichi Sankyo, Inc.: Enhertu--Fam-Trastuzumab Deruxtecan-Nxki Injection, Powder, Lyophilized, for Solution. National Library of Medicine DailyMed website. Updated February 8, 2023. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6; Genentech, Inc.: Rozlytrek- Entrectinib Capsule. National Library of Medicine DailyMed website. Updated June 8, 2020. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908; Bayer HealthCare Pharmaceuticals Inc.: Vitrakvi--Larotrectinib Capsule Vitrakvi- Larotrectinib Solution, Concentrate. National Library of Medicine DailyMed website. Updated December 6, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd; Eli Lilly and Company: Retevmo--Selpercatinib Capsule. National Library of Medicine DailyMed website. Updated September 21, 2022. Accessed April, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7fa848ba-a59c-4144-9f52-64d090f4d828; Curae Pharma360 Inc.: Docetaxel Anhydrous Injection. National Library of Medicine DailyMed website. Updated October 18, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=84aa26ea-5d61-4a15-9530-7d156c0dc746; Alembic Pharmaceuticals Inc.: Paclitaxel Injection. National Library of Medicine DailyMed website. Updated October 27, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c12c77c-5fd4-48dc-a318-e96892233992; GlaxoSmithKline LLC: Jemperli--Dostarlimab Injection. National Library of Medicine DailyMed website. Updated February 9, 2023. Accessed April 7, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=095eab9f-545a-4f12-bfb7-19477fb901a5; Merck Sharp & Dohme LLC: Keytruda--Pembrolizumab Injection, Powder, Lyophilized, for Solution Keytruda--Pembrolizumab Injection, Solution. National Library of Medicine DailyMed website. Updated March 7, 2023. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287; E.R. Squibb & Sons, L.L.C.: Yervoy--Ipilimumab Injection. National Library of Medicine DailyMed website. Updated February 15, 2023. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2265ef30-253e-11df-8a39-0800200c9a66; Eli Lilly and Company: Cyramza--Ramucirumab Solution. National Library of Medicine DailyMed website. Updated November 8, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6080942-dee6-423e-b688-1272c2ae90d4; Pharmacia & Upjohn Company LLC: Camptosar--Irinotecan Hydrochloride Injection, Solution. National Library of Medicine DailyMed website. Updated May 11, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e518dfc6-7e93-4fee-a66c-51e1ab71c056; Novartis Pharmaceuticals Corporation: Mekinist--Trametinib Tablet, Film Coated Mekinist--Trametinib Powder, For Solution. National Library of Medicine DailyMed website. Updated March 16, 2023. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0002ad27-779d-42ab-83b5-bc65453412a1; Taiho Pharmaceutical Co., Ltd.: Lonsurf--Trifluridine And Tipiracil Tablet, Film Coated. National Library of Medicine DailyMed website. Updated January 19, 2022. Accessed April 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5beed22-d71d-4c0d-8dca-2c7317d65d85; Accord Healthcare: Cisplatin Injection. National Library of Medicine DailyMed website. Updated June 8, 2021. Accessed April 7, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b2b029f5-0d7e-4e7f-accc-b722aec34c68; Sandoz Inc.: Oxaliplatin Injection, Solution. National Library of Medicine DailyMed website. Updated August 16, 2021. Accessed April 11, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86f6c19d-30d1-42e3-8d46-5e3f45776e85; Novartis Pharmaceuticals Corporation: Tafinlar--Dabrafenib Capsule Tafinlar--Dabrafenib Tablet, For Suspension. Updated March 16, 2023. Accessed April 7, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea; Novartis Pharmaceuticals Corporation: Tafinlar--Dabrafenib Capsule Tafinlar--Dabrafenib Tablet, For Suspension. National Library of Medicine DailyMed website. Updated March 16, 2023. Accessed April 7, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea; E.R. Squibb & Sons, L.L.C.: Opdivo--Nivolumab Injection. National Library of Medicine DailyMed website. Updated February 15, 2023. Accessed April 11, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394
      MedicationCommon regimensLife-threatening or dose-limiting adverse reactionsNotable or nonemergent adverse reactionsSpecial considerations
      Alkylating agent - platinum
      Carboplatin• Carboplatin + paclitaxel •
      Anaphylaxis
      • Bone marrow suppression
      • Nausea
      or vomiting
      •Nephrotoxicity
      		•
      Electrolyte loss
      • Ototoxicity
      • Peripheral neuropathy
      • Secondary malignancy      		•
      Avoid coadministering nephrotoxic or ototoxic agents
      • Ensure adequate hydration
      Cisplatin• Capecitabine + cisplatin +/- trastuzumab +/- pembrolizumab
      • Cisplatin + irinotecan
      • Fluorouracil + cisplatin +/- trastuzumab +/- pembrolizumab      		•
      Anaphylaxis
      • Bone marrow suppression
      • Nausea
      • Vomiting
      •Nephrotoxicity
      • Ocular toxicity
      		•
      Electrolyte loss
      • Ototoxicity
      • Peripheral neuropathy
      • Secondary malignancy      		•
      Avoid coadministering nephrotoxic or ototoxic agents
      • Ensure adequate hydration
      • Cisplatin has been associated with optic neuritis, papilledema, vision
      loss
      • Effective contraception required during and after therapy for 14 months
      for females of reproductive potential and for 11 months for males with female
      partners of reproductive potential
      Oxaliplatin• Capecitabine + oxaliplatin + nivolumab
      • Capecitabine + oxaliplatin + trastuzumab +/- pembrolizumab
      • Fluorouracil + oxaliplatin + nivolumab
      • Fluorouracil + oxaliplatin +/- trastuzumab +/- pembrolizumab
      • FLOT       		•
      Anaphylaxis
      • Bleeding
      • Bone marrow suppression
      • Nausea/vomiting
      • PRES
      • Pulmonary fibrosis
      • QT prolongation and ventricular arrhythmias
      • Rhabdomyolysis      		•
      Diarrhea
      • Fatigue
      • Increased hepatic enzymes
      • Peripheral sensory neuropathy
      • Stomatitis      		•
      Effective contraception required during and after therapy for 9 months for
      females of reproductive potential and for 6 months for males with female
      partners of reproductive potential
      Antimetabolite - nucleoside metabolic inhibitor
      Capecitabine• Capecitabine + oxaliplatin +/- trastuzumab +/- pembrolizumab
      • Capecitabine + cisplatin +/- trastuzumab +/- pembrolizumab
      • Capecitabine + oxaliplatin + nivolumab      		• Bone
      marrow suppression
      • Cardiotoxicity
      • Dehydration
      • Dermatologic toxicity
      • Hyperbilirubinemia
      • Renal failure      		•
      Abdominal pain
      • Diarrhea
      • Fatigue/weakness
      • Nausea
      • Vomiting       		•
      Increased risk of serious or fatal adverse reactions in patients with low or
      absent dihydropyrimidine dehydrogenase activity
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential and for 3 months for males with female
      partners of reproductive potential
      Fluorouracil• Fluorouracil + irinotecan
      • Fluorouracil + oxaliplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + cisplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + oxaliplatin + nivolumab
      • FLOT       		• Bone
      marrow suppression
      • Cardiotoxicity
      • Diarrhea
      • Hyperammonemic encephalopathy
      • Mucositis
      • Neurotoxicity
      • Palmar-plantar erythrodysesthesia (hand-foot syndrome)      		•
      Increased risk of serious or fatal adverse reactions in patients with low or
      absent dihydropyrimidine dehydrogenase activity
      • Effective contraception required during and after therapy for 3 months
      for females of reproductive potential and males with female partners of
      reproductive potential
      HER2/neu receptor antagonist
      Trastuzumab• Capecitabine + cisplatin +/- trastuzumab +/- pembrolizumab
      • Capecitabine + oxaliplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + cisplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + oxaliplatin +/- trastuzumab +/- pembrolizumab      		•
      Cardiomyopathy
      • Infusion-related reactions
      • Neutropenia
      • Pulmonary toxicity      		•
      Anemia
      • Chills
      • Cough
      • Diarrhea
      • Dysgeusia
      • Fatigue
      • Fever
      • Headache
      • Infection
      • Insomnia
      • Mucosal inflammation
      • Nasopharyngitis
      • Nausea
      • Rash
      • Stomatitis
      • Thrombocytopenia
      • Weight loss      		•
      Effective contraception required during and after therapy for 7 months for
      females of reproductive potential
      HER2-directed antibody and topoisomerase inhibitor conjugate
      Fam-trastuzumab deruxtecan• Fam-trastuzumab deruxtecan monotherapy• Bone
      marrow suppression
      • Cardiomyopathy
      • ILD/pneumonitis      		•
      Alopecia
      • Anorexia
      • Constipation
      • Diarrhea
      • Fatigue
      • Fever
      • Hyperbilirubinemia
      • Hypokalemia
      • Increased hepatic enzymes
      • Musculoskeletal pain
      • Nausea
      • Vomiting
      • Respiratory infection
      		•
      Effective contraception required during and after therapy for 7 months for
      females of reproductive potential and for 4 months for males with female
      partners of reproductive potential
      Human CTLA-4–blocking antibody
      Ipilimumab• Nivolumab + ipilimumab•
      Adrenal insufficiency
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Infusion-related reactions
      • Myocarditis
      • Nephritis
      • Neurotoxicity
      • Ocular toxicity
      • Pneumonitis
      • Thyroiditis      		•
      Anorexia
      • Diarrhea
      • Fatigue
      • Fever
      • Headache
      • Insomnia
      • Nausea
      • Vomiting
      • Pruritus
      • Rash
      • Weight loss
      		•
      Effective contraception required during and after therapy for 3 months for
      females of reproductive potential
      Kinase inhibitor
      Dabrafenib• Dabrafenib + trametinib•
      Bleeding
      • Cardiomyopathy
      • Dermatologic toxicity
      • Fever
      • New primary malignancy
      • Uveitis      		•
      Alopecia
      • Arthralgia
      • Headache
      • Hyperglycemia
      • Hyperkeratosis
      • Papilloma      		•
      Potential risk of hemolytic anemia in patients with glucose-6-phosphate
      dehydrogenase deficiency
      • Effective nonhormonal contraception required during and after therapy
      for at least 2 weeks for females of reproductive potential and males with female partners of reproductive potential
      Entrectinib• Entrectinib monotherapy• Bone
      marrow suppression
      • Heart failure
      • Hepatotoxicity
      • Hyperuricemia
      • Neurotoxicity
      • QT prolongation
      • Skeletal fractures
      • Vision disorders       		•
      Arthralgia
      • Cognitive impairment
      • Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Dysesthesia
      • Dysgeusia
      • Dyspnea
      • Edema
      • Fatigue
      • Fever
      • Increased hepatic enzymes
      • Myalgia
      • Nausea
      • Vomiting
      • Weight gain
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Effective contraception required during and after therapy for at least 5
      weeks for females of reproductive potential and for 3 months for males with
      female partners of reproductive potential
      Larotrectinib• Larotrectinib monotherapy•
      Hepatotoxicity
      • Neurotoxicity      		•
      Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Fatigue
      • Increased hepatic enzymes
      • Nausea
      • Vomiting
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Effective contraception required during and after therapy for at least 1
      week for females of reproductive potential and males with female partners of
      reproductive potential
      Selpercatinib• Selpercatinib monotherapy•
      Bleeding
      • Hepatotoxicity
      • Hypersensitivity reactions
      • Hypertension
      • Hypothyroidism
      • Impaired wound healing
      • ILD/pneumonitis
      • QT prolongation
      • Tumor lysis syndrome      		•
      Abdominal pain
      • Constipation
      • Diarrhea
      • Dry mouth
      • Edema
      • Fatigue
      • Headache
      • Hypertension
      • Hypocalcemia
      • Hyponatremia
      • Increased hepatic enzymes
      • Lymphopenia
      • Nausea
      • Rash      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Withhold therapy for at least 1 week before elective surgery and at
      least 2 weeks after major surgery and until adequate wound healing
      • Effective contraception required during and after therapy for 1 week for
      females of reproductive potential and males with female partners of reproductive potential
      Trametinib• Dabrafenib + trametinib•
      Bleeding
      • Cardiomyopathy
      • Colitis and gastrointestinal perforation
      • Dermatologic toxicity
      • Fever
      • ILD/pneumonitis
      • New primary malignancy
      • Retinal pigment epithelial detachment
      • Retinal vein occlusion
      • Venous thromboembolism      		•
      Diarrhea
      • Hyperglycemia
      • Lymphedema
      • Rash      		•
      Effective contraception required during and after therapy for 4 months for
      females of reproductive potential and males with female partners of
      reproductive potential
      Microtubule inhibitor
      Docetaxel• Docetaxel monotherapy
      • FLOT       		•
      Asthenia
      • Bone marrow suppression
      • Cystoid macular edema
      • Dermatologic toxicity
      • Diarrhea
      • Edema
      • Enterocolitis and neutropenic colitis
      • Febrile neutropenia
      • Hepatotoxicity
      • Hypersensitivity reactions
      • Infections
      • Neurotoxicity
      • Stomatitis/mucositis
      • Toxic deaths      		•
      Alopecia
      • Anorexia
      • Constipation
      • Dysgeusia
      • Dyspnea
      • Myalgia
      • Nail disorders
      • Nausea
      • Vomiting
      • Pain
      • Secondary malignancy
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Some docetaxel injection formulations contain alcohol and may affect the
      central nervous system and ability to drive or operate machinery
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential and for 3 months for males with female
      partners of reproductive potential
      Paclitaxel• Carboplatin + paclitaxel
      • Ramucirumab + paclitaxel       		•
      Anaphylaxis
      • Bone marrow suppression
      • Cardiotoxicity
      • Neurotoxicity      		•
      Alopecia
      • Arthralgia
      • Diarrhea
      • Increased hepatic enzymes
      • Injection site reactions
      • Mucositis
      • Myalgia
      • Nausea
      • Vomiting
      		• Some
      paclitaxel formulations contain alcohol and may affect the central nervous
      system and ability to drive or operate machinery
      Nucleoside metabolic inhibitor and thymidine phosphorylase inhibitor
      Trifluridine and tipiracil• Trifluridine and tipiracil monotherapy• Bone
      marrow suppression
      • Diarrhea
      • Febrile neutropenia
      • Nausea
      • Vomiting
      		•
      Anorexia
      • Asthenia/fatigue
      • Fever      		• Effective contraception required during and after therapy for at least 6 months for females of reproductive potential and for at least 3 months for males with female partners of reproductive potential
      PD-1 blocking antibody
      Dostarlimab• Dostarlimab monotherapy •
      Adrenal insufficiency
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Infusion-related reactions
      • Myocarditis
      • Nephritis
      • Pneumonitis
      • Thyroiditis      		•
      Anemia
      • Asthenia
      • Diarrhea
      • Fatigue
      • Nausea      		•
      Effective contraception required during and after therapy for 4 months for
      females of reproductive potential
      Nivolumab• Capecitabine + oxaliplatin + nivolumab
      • Fluorouracil + oxaliplatin + nivolumab
      • Nivolumab + ipilimumab      		•
      Adrenal insufficiency
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Infusion-related reactions
      • Myocarditis
      • Nephritis
      • Neurotoxicity
      • Pneumonitis
      • Thyroiditis      		•
      Abdominal pain
      • Anorexia
      • Arthralgia
      • Asthenia
      • Back pain
      • Constipation
      • Cough
      • Diarrhea
      • Dyspnea
      • Fatigue
      • Fever
      • Headache
      • Myalgia
      • Nausea
      • Vomiting
      • Pruritus
      • Rash
      • Upper respiratory tract infection
      • Urinary tract infection
      		•
      Effective contraception required during and after therapy for at least 5
      months for females of reproductive potential
      Pembrolizumab• Capecitabine + cisplatin +/- trastuzumab +/- pembrolizumab
      • Capecitabine + oxaliplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + cisplatin +/- trastuzumab +/- pembrolizumab
      • Fluorouracil + oxaliplatin +/- trastuzumab +/- pembrolizumab      		•
      Adrenal insufficiency
      • Anaphylaxis
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Myocarditis
      • Nephritis
      • Pneumonitis
      • Thyroiditis      		•
      Abdominal pain
      • Anorexia
      • Constipation
      • Cough
      • Diarrhea
      • Dyspnea
      • Fatigue
      • Fever
      • Myalgia
      • Nausea
      • Pruritus
      • Rash      		•
      Effective contraception required during and after therapy for at least 4
      months for females of reproductive potential
      Topoisomerase I inhibitor
      Irinotecan• Cisplatin + irinotecan
      • Fluorouracil + irinotecan

      • Irinotecan monotherapy      		•
      Anaphylaxis
      • Bone marrow suppression
      • Diarrhea
      • Interstitial pulmonary disease
      • Renal failure      		•
      Abdominal pain
      • Alopecia
      • Anorexia
      • Asthenia
      • Constipation
      • Fever
      • Nausea
      • Vomiting
      • Weight loss
      		•
      Increased risk of neutropenia in patients with reduced UGT1A1 activity
      • Effective contraception required during and after therapy for at least 6
      months for females of reproductive potential and for 3 months for males with
      female partners of reproductive potential
      VEGFR2 antagonist
      Ramucirumab• Ramucirumab + paclitaxel•
      Arterial thromboembolic events
      • Bleeding
      • Gastrointestinal perforation
      • Hepatotoxicity
      • Hypertension
      • Hypothyroidism
      • Impaired wound healing
      • Infusion-related reactions
      • Nephrotoxicity and proteinuria
      • PRES      		•
      Abdominal pain
      • Anorexia
      • Ascites
      • Diarrhea
      • Fatigue
      • Hypoalbuminemia
      • Hyponatremia
      • Peripheral edema
      • Nausea
      • Thrombocytopenia      		•
      Withhold therapy for at least 28 days before elective surgery and for at
      least 2 weeks after major surgery and until adequate wound healing
      • Effective contraception required during and after therapy for 3 months
      for females of reproductive potential

    Nondrug and supportive care

    Radiation therapy r2c148c149

    • Modalities include brachytherapy and external beam radiation therapy r36c150c151
    • May be used preoperatively, postoperatively, or palliatively
    • Used in combination with chemotherapy as neoadjuvant treatment (chemoradiation therapy)
    • Used alone only for palliation or when patients are unfit to receive chemotherapy

    Nutritional therapy r2c152

    • Patients are often malnourished at diagnosis owing to symptoms caused by tumor
    • Malnutrition is associated with poorer cancer treatment outcomes and survival
    • Assess nutritional status and provide nutritional therapy preoperatively r11
    • Early oral feeding may enhance recovery after esophagectomy r37r38c153
    • If intake is less than 1500 kcal/day, consider oral or enteral nutrition r2

    Advise smoking cessation and counseling, if indicated r2

    Palliative interventions r2r39

    • For dysphagia, which is the most common symptom, palliation is most commonly achieved with placement of esophageal stent r2c154
      • Brachytherapy alone or in addition to stenting is an alternative for esophageal cancer patients with dysphagia and a longer life expectancy r40
    • For esophageal obstruction, options include endoscopic lumen restoration, external beam radiation therapy, brachytherapy, photodynamic therapy, chemotherapy, esophageal dilation, feeding tube placement, or surgery r41
    • Malignant tracheoesophageal or bronchoesophageal fistulas may be sealed with self-expandable metal stents r40
    • Bleeding from tumor surface may be controlled with bipolar electrocoagulation or argon plasma coagulation; brisk bleeding related to tumor-related aortoesophageal fistulization may require surgery, external beam radiation therapy, and/or endoscopic therapy

    Supportive care

    • Indicated for all patients with locally advanced, metastatic, or recurrent disease to improve quality of life and relieve pain c155c156
    • Treat nausea and vomiting according to guidelines for antiemesis by National Comprehensive Cancer Network r42c157
    • Pain is best managed according to guidelines for adult cancer pain by National Comprehensive Cancer Network r41
    Procedures
    Esophagectomy r2c158c159c160c161
    General explanation
    • Surgical removal of esophagus, with gastric pull-through or interposition of portion of jejunum or colon to create conduit
      • Various approaches exist for surgical resection and lymph node dissection
      • Minimally invasive approach is appropriate for many patients and results in fewer complications r43r44
    Indication
    • Definitive treatment of more advanced tumors, such as those with submucosal invasion, positive lymph nodes, or involvement of more than one-third of circumference of esophagus r45c162
    Contraindications
    • Location less than 5 cm from cricopharyngeus muscle r2
    • Local invasion of unresectable structures r2
    • Widespread metastasis r2
    Interpretation of results
    • Histopathology should show clear surgical margins
    Endoscopic therapy c163c164
    General explanation
    • Removal of mucosal and submucosal lesions via endoscope while preserving the esophagus itself r46c165
    • Range of definitive approaches, including endoscopic mucosal resection, endoscopic submucosal dissection, and ablation r41r46r47c166c167c168c169
      • Endoscopic mucosal resection has significantly lower morbidity and mortality compared with esophagectomy r46
      • Ablation methods include radiofrequency ablation, cryoablation, and photodynamic therapy c170c171c172
    • Palliative therapies include esophageal dilation, tumor ablation, and endoscopic stenting c173c174c175
    Indication
    • Preferred for patients with limited early stage disease (Tis and T1a, moderately to well-differentiated tumors, no more than 2 cm) r41
    Contraindications
    • Widespread metastasis
    Brachytherapy r2c176c177c178
    General explanation
    • A sealed radiation source (seed) is placed close to tumor to shrink it c179
    Indication
    • Intolerable dysphagia c180
    • Nonresectable tumor c181
    Contraindications
    • Tracheal or bronchial involvement
    • Cervical esophagus location
    • Stenosis that cannot be bypassed

    Comorbidities

    • Patients with severe cardiac or pulmonary disease may not be able to tolerate esophagectomy r2c182c183

    Monitoring

    • All patients require systematic surveillance r2c184
      • Stage-specific recommendations for surveillance after completion of local therapy are available r2
        • Vary according to stage, depth of invasion, and treatment modality
      • General surveillance recommendation for asymptomatic patients as follows: r2c185
        • Complete history and physical examination c186
          • Every 3 to 6 months for 1 to 2 years, then c187
          • Every 6 to 12 months for next 3 to 5 years, then c188
          • Annually thereafter c189
        • Obtain further studies as clinically indicated (eg, CBC, serum chemistry, endoscopy with biopsy, imaging studies) c190c191c192

    Complications and Prognosis

    Complications

    • Complications of esophageal cancer r39
      • Dysphagia is most common r2c193
      • Esophageal obstruction, resulting in inadequate nutritional intake, weight loss, regurgitation, and aspiration c194
      • Tracheoesophageal fistula, resulting in chronic aspiration and pneumonia c195
      • Fistulization to pleural space, aorta, or other mediastinal structures
      • Malnutrition
    • Complications of treatment
      • Anastomotic leak, leading to mediastinal and pulmonary infections c196c197c198
      • Postoperative or postirradiation strictures c199c200
      • Aortoesophageal fistula c201c202

    Prognosis

    • Esophageal cancer is one of the most lethal malignancies r7
    • Overall 5-year survival rate is 20.6% in the United States r6
    • Approximately 90% of recurrences occur within the first 2 years after completion of local therapy r2
    • Prognosis depends on cancer stage at diagnosis r6
      • For localized cancer (confined to primary site), 5-year survival rate is 48.8%
      • For regionalized cancer (spread to regional lymph nodes), 5-year survival rate is 27.7%
      • For metastatic cancer, 5-year survival rate is 5.6%
    • Adenocarcinoma is associated with better long-term prognosis after resection than squamous cell carcinoma

    Screening and Prevention

    Screening

    At-risk populations

    • Some guidelines recommend screening for precursor conditions (Barrett esophagus or dysplasia) in patients with multiple of the following risk factors for esophageal cancer (adenocarcinoma): r48r49r50r51c203
      • Aged 50 years or older
      • Male sex
      • White race
      • Chronic gastroesophageal reflux disease
      • Hiatal hernia
      • Elevated BMI
      • Intra-abdominal distribution of body fat
      • Tobacco smoking
      • Family history of Barrett esophagus or esophageal cancer
    • Screening for esophageal cancer or precursor conditions (Barrett esophagus or dysplasia) is not recommended for patients in the general population with chronic gastroesophageal reflux disease r50r51r52r53

    Screening tests

    • Endoscopic surveillance r2c204
      • Chromoendoscopy with Seattle protocol biopsy sampling is the recommended technique for patients with Barrett esophagus who are undergoing screening for dysplasia r54c205c206
      • Frequency is determined by presence and degree of dysplasia on biopsy (ranges from 3 to 5 years)r54

    Prevention

    • Cessation of smoking and excessive alcohol intake r10c207c208
    • Abstinence from betel quid chewing r10
    • Increased consumption of fruits and vegetables intake and avoidance of meat, processed food, and very hot beverages r10
    • Early identification, appropriate treatment, and aggressive monitoring of associated conditions (eg, persistent reflux symptoms despite 4- to 8-week course of proton pump inhibitors,r55Barrett esophagusr54) c209c210
      • Although indefinite use of proton pump inhibitors is recommendedr56 for patients with gastroesophageal reflux, evidencer51 does not show that they slow the rate of progression to dysplasia or cancer
      • Endoscopic resection or ablation of Barrett esophagus epithelium reduces the risk of progression to esophageal adenocarcinoma r57c211c212
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