Esophageal Cancer Guidelines

Updated: Jun 20, 2017
  • Author: Muhammad Masab, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Guidelines

Screening and Surveillance

Recommendations for screening and surveillance of patients with GERD and/or Barrett esophagus have been issued by the following organizations:

  • American Society for Gastrointestinal Endoscopy (ASGE)
  • American Gastroenterological Association (AGA)
  • American College of Gastroenterology (ACG)
  • American College of Physicians (ACP)

None of the organizations recommend endoscopic screening of the general population with GERD. There is general agreement among the guidelines that patients with chronic GERD and multiple other risk factors associated with esophageal adenocarcinoma should undergo upper gastrointestinal endoscopy to screen for Barrett esophagus or esophageal adenocarcinoma. [129, 130, 131, 132, 133] Those additional risk factors include the following:

  • Male sex
  • Age 50 years or older
  • White race
  • Hiatal hernia
  • Obesity

The 2015 American Society for Gatrointestinal Endoscopy (ASGE) guidelines for the use of endoscopy in the management of GERD recommends endoscopic screening in select patients with multiple risk factors for Barrett esophagus be considered, but also advises that patients be informed that there is insufficient evidence that this practice prevents cancer or prolongs survival. [133]

The American College of Physicians' (ACP) best practice advice, issued in 2012, offers the following recommendations for upper endoscopy for GERD [132] :

  • Screening endoscopy is not recommended for women of any age or men younger than 50, regardless of other risk factors, because of the low incidence of cancer in these populations
  • Screening is recommended in both men and women with GERD symptoms despite medical treatment, and especially in those with GERD and dysphagia, bleeding, anemia, weight loss, or recurrent vomiting
  • No further surveillance is recommended if endoscopy shows negative results for Barrett esophagus
  • In patients with Barrett esophagus and no dysplasia, surveillance examinations should occur at intervals of 3 to 5 years; shorter intervals are indicated in patients with Barrett esophagus and dysplasia

The American College of Gastroenterology (ACG) guidelines for the surveillance and therapy of Barrett esophagus [131] are listed in the table below.

 

Table 6. ACG Recommendations on surveillance of Barrett esophagus (Open Table in a new window)

Biopsy Finding  Recommended Surveillance/Intervention
Barrett Esophagus (BE) without dysplasia Endoscopic surveillance every 3 years for patients with BE without dysplasia on 2 consecutive endoscopies with biopsies within a year. 
BE with low-grade dysplasia (LGD) For patients with confirmed low-grade dysplasia and without life-limiting comorbidity, endoscopic therapy is considered as the preferred treatment modality, although endoscopic surveillance is an acceptable alternative (Endoscopy within 6 months is warranted to ensure that no HGD is present in the esophagus. Follow-up endoscopy is recommended annually until no dysplasia is detected on 2 consecutive endoscopies with biopsies)
BE with high- grade dysplasia (HGD) Patients with confirmed high-grade dysplasia should be managed with endoscopic therapy. In case of life-limiting comorbidity endoscopy within 3 months is recommended to rule out adenocarcinoma of the esophagus. Follow-up endoscopy every 3 months is recommended thereafter. 

The ACG recommends that endoscopic ablative therapies should not be routinely used in patients with nondysplastic Barrett esophagus, because of their low risk of progression to esophageal adenocarcinoma (strong recommendation, very low level of evidence). However, endoscopic eradication therapy is the procedure of choice for patients with confirmed dysplasia, whether low or high grade.

The ACG advises that antireflux surgery should not be used as an antineoplastic measure. [131] Endoscopic resection (ER) and mucosal radiofrequency ablation (RFA) has become the preferred treatment for most patients with Barrett esophagus and HGD. Alternative strategies include cryoablation or photodynamic therapy (PDT) [134, 135] . Surgical resection is reserved for patients with HGD and characteristics that are unfavorable for non-surgical therapy, such as nodularity or long-segment involvement. For patients with metaplasia or LGD, gastroesophageal reflux is controlled with histamine receptor antagonists or proton pump inhibitors.

Radiofrequency ablation

RFA has been gaining popularity as a treatment for Barrett esophagus with dysplasia. Shaheen et al reported complete eradication of all dysplasia 2 years after RFA in 101 of 106 patients (95%). After 3 years, dysplasia remained eradicated in more than 85% of patients, without maintenance RFA. The rate of serious adverse events was 3.4%, and the rate of esophageal stricture was 7.6%. [136]

Photodynamic therapy

PDT involves the administration of photosensitizing chromophores, which are selectively retained by dysplastic malignant tissue. Light is then delivered in the area. The photosensitizer absorbs photons, becomes photoexcited, and transfers its energy to a chemical substrate that causes biologic damage to the abnormal tissue. A drawback of PDT is the formation of esophageal strictures in 34% of patients. The photosensitizer porfimer is FDA approved for ablation of high-grade dysplasia in Barrett esophagus.

Surveillance of Esophageal Cancer

Surveillance strategies after successful local therapy of esophageal cancers remain controversial since very limited prospective data is available on effective surveillance strategies.

In general, for asymptomatic patients, follow-up should include a complete history and physical examination every 3 to 6 months for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, and annually thereafter. CBC, comprehensive serum chemistry evaluation, upper GI endoscopy with biopsy, and imaging studies should be obtained as clinically indicated. In addition, some patients may require dilatation of an anastomotic or a chemoradiation-induced stricture. Nutritional assessment and counseling may be extremely valuable. 

The stage-specific recommendations for surveillance included in the NCCN Guidelines are based on the available evidence from retrospective studies [137, 138]  and the expertise of the panel members.

Stage (0-I / Tis, T1a, T1b): Evidence-based guidelines have not been established for all stages of completely treated early stage esophageal cancer. The recommendations outlined in the guidelines are based on available evidence from clinical trials and current practice. Endoscopic surveillance with upper GI endoscopy (EGD) is recommended for patients with Tis, T1a and T1b tumors, after completion of endoscopic therapy. It is recommended to perform EGD  every 3 months for the first year, every 4-6 months for the second year, and annually for 3 more years. In patients with T1b tumors treated with esophagectomy, endoscopic surveillance with EGD should be done as clinically indicated based on the symptoms and radiographic findings. Routine imaging studies are not recommended for patients with Tis and T1a tumors.

Stage (II-III / T2-T4, N0-N+, T4b): Locoregional recurrences are common after bimodality therapy. Therefore, EGD is a valuable surveillance tool following bimodality therapy. In patients treated with bimodality therapy, the majority of recurrences (95%) occur within 24 months. Thus, surveillance for at least 24 months is recommended following bimodality therapy [139]

Locoregional relpases are uncommon following trimodality therapy. [140] Therfore, EGD for surveillance is not recommended after trimodality therapy. Other imaging modalities (e.g., PET/CT or CT chest/abdomen with contrast) are used for most luminal recurrences. In patients treated with trimodality therapy, the majority of recurrences (90%) occur within 36 months of surgery. Therefore, surveillance for at least 36 months is recommended following trimodality therapy.

 

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Evaluation

In 2013, the Society of Thoracic Surgeons released clinical practice guidelines to assist in the diagnosis and treatment of localized esophageal cancer. Their recommendations include the following [64, 65] :

  • For the diagnosis of esophageal cancer, flexible endoscopy with biopsy is the primary method
  • For early-stage esophageal cancer, CT of the chest and abdomen is an optional test for staging; for locoregionalized esophageal cancer, CT of the chest and abdomen is a recommended test for staging
  • For early-stage esophageal cancer, PET is an optional test for staging. For locoregionalized esophageal cancer, PET is a recommended test for staging
  • In patients without metastatic disease, endoscopic ultrasonography is recommended to improve the accuracy of staging
  • In patients with small, discrete nodules or areas of dysplasia in whom disease appears limited to the mucosa or submucosa as assessed by endoscopic ultrasonography, endoscopic mucosal resection should be considered as a diagnostic/staging tool
  • In patients with locally advanced (T3/T4) adenocarcinoma of the esophagogastric junction infiltrating the anatomic cardia or Siewart type III esophagogastric tumors, laparoscopy is recommended to improve accuracy of staging.

The 2013 American Society for Gastrointestinal Endoscopy (ASGE) guidelines for use of endoscopy in the assessment and treatment of esophageal cancer make the following recommendations for accurate staging [141] :

  • Endoscopic ultrasound and fine needle aspiration (FNA), when indicated, in conjunction with cross-sectional imaging is preferred over CT
  • Endoscopic mucosal or submucosal dissection is indicated for the treatment and staging of nodular Barrett esophagus and suspected squamous cell carcinoma and adenocarcinoma

Guidelines from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology, issued in 2016, include the following recommendations for clinicians [142] :

  • Request HER2 testing on tumor tissue in patients with advanced esophageal adenocarcinoma who are potential candidates for HER2-targeted therapy.
  • Request HER2 testing on tumor tissue in the biopsy or resection specimens (primary or metastasis), preferably before starting trastuzumab therapy, if such specimens are available and adequate; an acceptable alternative is HER2 testing on fine-needle aspiration specimens.

National Comprehensive Cancer Network (NCCN) guidelines for HER2 testing include the following  [81] :

  • Assessment for tumor HER2 overexpression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is recommended for inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the esophagus [143] .
  • Based on the results of the ToGA trial, trastuzumab should be added to first-line chemotherapy (category 1 for combination with cisplatin and fluoropyrimidine; category 2B for combination with other chemotherapy agents) for patients with HER2- overexpressing advanced or metastatic adenocarcinoma (a tumor Immunohistochemistry (IHC) score of  3+ or 2+ with the evidence of HER2 amplification by FISH) [82]
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Management

American College of Gastroenterology (ACG) recommendations regarding endoscopic treatment of Barrett esophagus include the following [131] :

  • In patients with T1a esophageal adenocarcinoma, endoscopic therapy is the preferred therapeutic approach (strong recommendation, moderate level of evidence)
  • In patients with T1b esophageal adenocarcinoma, consultation with multidisciplinary surgical oncology team should occur before embarking on endoscopic therapy; in such patients, endoscopic therapy may be an alternative strategy to esophagectomy, especially in those with superficial (sm1) disease with a well-differentiated neoplasm lacking lymphovascular invasion, as well as those who are poor surgical candidates (strong recommendation, low level of evidence)
  • In patients with known T1b disease, EUS may have a role in assessing and sampling regional lymph nodes, given the increased prevalence of lymph node involvement in these patients compared with less advanced disease (strong recommendation, moderate level of evidence)
  • In patients with dysplastic Barrett esophagus who are to undergo endoscopic ablative therapy for nonnodular disease, radiofrequency ablation is currently the preferred endoscopic ablative therapy (strong recommendation, moderate level of evidence).

National Comprehensive Cancer Network (NCCN) treatment recommendations for esophageal cancer include the following [81] :

  • Medically fit patients with locoregional SCC stage Tis (in situ) and T1a  are treated with endoscopic therapies like endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) with or without ablation. For stage T1b, N0 tumors, esophagectomy is the recommended primary treatment option [80] . Primary treatment options for patients with T1b,N+ and locally advanced resectable tumors (T2-T4a with any N) include preoperative chemoradiation (for non-cervical esophagus), definitive chemoradiation (for cervical esophagus) or esophagectomy (for non-cervical esophagus) [144, 145, 146] . Definitive chemoradiation is the preferred treatment modality for stage T4b (unresectable) tumors. [147]
  • Medically fit patients with locoregional adenocarcinoma stage Tis (in situ), T1a or T1b,N0 are treated with similar modalities as for SCC. Primary treatment options for patients with T1b,N+ and locally advanced resectable tumors (T2-T4a with any N) include preoperative chemoradiation (preferred) [148] , definitive chemoradiation (for patients who refuse surgery) [145, 146] , perioperative chemotherapy [149]  or esophagectomy (for low risk patients with well differentiated lesions under 2 cm).
  • Chemoradiation followed by surgery is supported by strong level 1 evidence. [150, 151, 152, 153, 154, 155] In fact, 15%-30% of patients undergoing neoadjuvant chemoradiation will have a complete pathologic response (pCR), meaning that the tumor will have completely disappeared when the esophagus is examined after surgery. Patients with a pCR have a 3-year survival rate of approximately 50%, as opposed to 27% for those without a pCR. [156] Fluoropyrimidine- or taxane-based regimens are recommended for preoperative and definitive chemoradiation.
  • Definitive chemoradiation is the preferred treatment modality for stage T4b (unresectable) tumors. [147]
  • Preoperative chemotherapy followed by surgery is another option. However, the evidence for this approach is weak; the chance of increase in 2-year overall survival is less than 6%, compared with approximately 13% with trimodality therapy.
  • Postoperative treatment is based on the surgical margins, nodal status, and histology. The efficacy of postoperative treatment has not been established in randomized trials for patients with esophageal cancer. Available evidence for the use of postoperative chemoradiation (only for patients who have not received preoperative therapy) and perioperative chemotherapy for patients with adenocarcinoma of the distal esophagus or EGJ comes from prospective randomized clinical trials involving patients with gastric cancer that have included patients with adenocarcinoma of the distal esophagus or EGJ. [149, 157]
  • For patients with SCC who have not received preoperative therapy, no further treatment is necessary (irrespective of their nodal status) if there is no residual disease at surgical margins (R0 resection). Patients with microscopic (R1 resection) or macroscopic (R2 resection) residual disease should be treated with fluoropyrimidine-based chemoradiation. Palliative therapy is an alternative option for patients with macroscopic residual disease.
  • For patients with adenocarcinoma who have not received preoperative therapy, no further treatment is necessary for patients with Tis and T1, N0 tumors, if there is no residual disease at surgical margins (R0 resection). Based on the results of the INT-0116 trial, postoperative fluoropyrimidine-based chemoradiation (following R0 resection) is recommended for all patients with T3-T4 tumors, node-positive T1-T2 tumors, and selected patients with T2, N0 tumors with high-risk features (poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion, or age younger than 50 years). [157]
  • Perioperative chemotherapy is recommended following R0 resection for all patients with adenocarcinoma, irrespective of the nodal status (category 1). Patients with microscopic (R1 resection) or macroscopic residual disease with no distant metastatic disease (R2 resection) should be treated with fluoropyrimidine-based chemoradiation. Palliative therapy is an alternative option for patients with macroscopic residual disease.
  • For the management of locally advanced  locoregional cancer (T2-T4a, any regional N) in non-surgical candidates, fluoropyrimidine-based or taxane-based definitive chemoradiation is the preferred treatment option. Alternatively, these patients can also be treated with chemotherapy or radiation therapy (RT) or supportive care. Palliative RT or supportive care are the appropriate options for non-surgical candidates who are unable to tolerate chemotherapy or chemoradiation (patients with poor performance status).
  • Based on the results of the ToGA trial, trastuzumab should be added to first-line chemotherapy (category 1 for combination with cisplatin and fluoropyrimidine; category 2B for combination with other chemotherapy agents) for patients with HER2- overexpressing advanced or metastatic adenocarcinoma (a tumor Immunohistochemistry (IHC) score of  3+ or 2+ with the evidence of HER2 amplification by FISH). [82]
  • Ramucirumab, a VEGFR-2 antibody, has shown promising results in the treatment of patients with previously treated advanced or metastatic gastric or EGJ cancers in phase III clinical trials. [158, 159] An international, randomized, multicenter, placebo-controlled, phase III trial (REGARD trial) demonstrated a survival benefit for ramucirumab for patients with advanced gastric or EGJ adenocarcinoma progressing after first-line chemotherapy [158] . In a more recent international phase III randomized trial (RAINBOW trial) that evaluated paclitaxel with or without ramucirumab in patients with metastatic gastric or EGJ adenocarcinoma progressing on first-line chemotherapy, the combination of paclitaxel with ramucirumab resulted in significantly higher survival rate [159] . Based on the results of these two studies, ramucirumab either as a single agent or in combination with paclitaxel was recently approved by the FDA for the treatment for patients with advanced EGJ adenocarcinoma refractory to or progressive following first-line therapy with platinum- or fluoropyrimidine-based chemotherapy.
  • Stage IV disease is treated with chemotherapy or symptomatic and supportive care, as indicated. There are two scoring methods commonly used by Oncologists to assess performace status in cancer patients: Karnofsky Performance Score (KPS) and Eastern Cooperative Oncology Group performance score (ECOG PS). For patients with poor performance status (ie, KPS score <60 and ECOG PS score >2) or with advanced disease, curative treatment is not an option and the goal of therapy is palliation of dysphagia, so that these patients can eat. No single method of palliation is best for every situation. Most patients require more than 1 kind of palliative treatment to sustain esophageal patency during the course of their disease.

NCCN guidelines for surgical therapy of esophageal cancer are as follows [81] :

  • Prior to surgery, clinical staging should be performed to assess resectability with CT scan of the chest and abdomen, whole-body PET and endoscopic ultrasound (EUS).
  • Prior to starting therapy, all patients should should be be assessed for by an esophageal surgeon for physiologic ability to undergo esophageal resection. Esophageal resection should be considered for all physiologically fit patients with resectable esophageal cancer (ie, >5 cm from cricopharyngeus).
  • Siewert Siewert Classification tumor type should be assessed in all patients with adenocarcinomas involving the EGJ. Siewert Type I is adenocarcinoma of the lower esophagus with the center located within 1 cm to 5 cm above the anatomic EGJ. Siewert Type II is true carcinoma of the cardia with the tumor center within 1 cm above and 2 cm below the EGJ. Siewert Type III is subcardial carcinoma with the tumor center 2 to 5 cm below the EGJ that infiltrates the EGJ and lower esophagus from below.
  • Laparoscopy may be useful in select patients in detecting radiographically occult metastatic disease, especially in patients with Siewert II and III tumors.
  • Positive peritoneal cytology (performed in the absence of visible peritoneal implants) is associated with poor prognosis and is defined as M1 disease. In patients with advanced tumors, clinical T3 or N+ disease should be considered for laparoscopic staging with peritoneal washings.
  • Cervical or cervicothoracic esophageal carcinomas <5 cm from the cricopharyngeus should be treated with definitive chemoradiation.
  • Resectable esophageal or EGJ cancer: T1a tumors, defined as tumors involving the mucosa but not invading the submucosa, may be considered for EMR + ablation or esophagectomy in experienced centers.Tumors in the submucosa (T1b) or deeper may be treated with esophagectomy. T1-T3 tumors are resectable even with regional nodal metastases (N+), although bulky; multi-station lymphatic involvement is a relative contraindication to surgery, to be considered in conjunction with age and performance status. T4a tumors with involvement of pericardium, pleura, or diaphragm are resectable.
  • Unresectable esophageal cancer: T4b tumors with involvement of the heart, great vessels, trachea, or adjacent organs including liver, pancreas, lung, and spleen are unresectable. Most patients with multi-station, bulky lymphadenopathy should be considered unresectable, although lymph node involvement should be considered in conjunction with other factors, including age and performance status and response to therapy.
  • Disease in patients with EGJ and supraclavicular lymph node involvement should be considered unresectable.
  • Esophageal cancers in patients with distant (including nonregional lymph nodes) metastases (stage IV) are unresectable.
  • The type of esophageal resection is dictated by the location of the tumor and the available choices for conduit, as well as by the surgeon's experience and preference and the patient's preference.
  • In patients who are unable to swallow well enough to maintain nutrition during induction therapy, esophageal dilatation or a feeding jejunostomy tube are preferred to a gastrostomy (which may compromise the integrity of gastric conduit for reconstruction).
  • Acceptable operative approaches for resectable esophageal or EGJ cancer: Ivor Lewis esophagogastrectomy (laparotomy + right thoracotomy; McKeown esophagogastrectomy (right thoracotomy + laparotomy + cervical anastomosis); minimally invasive Ivor Lewis esophagogastrectomy (laparoscopic approach); minimally invasive McKeown esophagogastrectomy (laparoscopic approach); robotic minimally invasive esophagogastrectomy; transhiatal esophagectomy (THE); and transthoracic/transabdominal esophagectomy with anastomosis in chest or neck. 
  • Acceptable conduits: gastric (preferred), colon, and jejunum.  
  • Acceptable lymph node dissections: standard and extended (en bloc)
  • In patients undergoing esophagectomy without induction chemoradiation, at least 15 lymph nodes should be removed to achieve adequate nodal staging. The optimum number of nodes to remove after preoperative chemoradiation is unknown, although similar lymph node resection is recommended. 
  • Patients who develop localized, resectable esophageal cancer after defintive chemoradiation can be considered for esophagectomy if they do not have distant recurrence. 
  • Patients with potentially resectable esophageal cancer should undergo multidisciplinary review. Esophageal resection, EMR, and other ablative techniques should be performed in high-volume esophageal centers by experienced surgeons and endoscopists. 

In 2014, the Society of Thoracic Surgeons (STS) released clinical practice guidelines for multimodal treatment of esophageal cancer with the following recommendations [160] :

  • Locally advanced disease should be treated in a multidisciplinary setting
  • Restaging should be performed after neoadjuvant therapy and before surgery
  • Endoscopic ultrasound restaging for residual local disease is inaccurate and can be omitted
  • A PET scan should be used for restaging after neoadjuvant therapy to detect interval development of distant metastatic disease
  • Neoadjuvant chemoradiation therapy should be used for locally advanced squamous cell cancer and either neoadjuvant chemotherapy or chemoradiation therapy for locally advanced adenocarcinoma; multimodality therapy has advantages over surgical resection alone
  • For patients with adenocarcinoma who have not received neoadjuvant therapy, adjuvant chemoradiotherapy is an option for regional lymph node disease.

The 2013 American Society for Gastrointestinal Endoscopy (ASGE) guidelines note that argon plasma coagulation (APC), heater probe, cryotherapy, or radiofrequency ablation should not be used as monotherapy with curative intent for T1a tumors. However, those techniques may have a role in ablation of remaining high-risk tissue following resection [141] .

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Metastatic Disease and Palliative Care

NCCN guidelines recommend the following for treatment of metastatic or recurrent disease [81] :

  • Recurrence after esophagectomy can be treated with fluoropyrimidine-based or taxane-based concurrent chemoradiation in patients who did not receive prior chemoradiation.
  • Selected patients with recurrences can undergo repeat resection.
  • Recurrence after chemoradiation without esophagectomy in medically fit patients with resectable tumors, can be treated with esophagectomy.
  • Palliative care is indicated for medically unfit patients, or those with unresectable or metastatic recurrence.
  • First-line therapy with two-drug chemotherapy regimens is preferred for advanced or metastatic disease.
  • Docetaxel and irinotecan are options for second-line therapy for locally advanced or metastatic disease.

NCCN guidelines recommend the following for palliative/best supportive care [81] :

  • Patients with complete esophageal obstruction can be treated with endoscopic lumen restoration, external beam radiation therapy (EBRT), chemotherapy, or surgery.
  • Surgical or radiologic placement of jejunostomy or gastronomy tubes may be necessary to provide adequate hydration and nutrition, if endoscopic lumen restoration is not undertaken or is unsuccessful.
  • Brachytherapy may be considered instead of EBRT, if lumen can be restored using appropriate applicators during the delivery of brachytherapy to avoid excessive dose on mucosal surfaces. In a multicenter randomized trial, single-dose brachytherapy was associated with fewer complications and better long-term relief of dysphagia compared with metal stents. [109]  
  • For patients with severe esophageal obstruction (those able to swallow liquids only), some additional options include endoscopic lumen enhancement (wire-guided or balloon dilation) and endoscopy or fluoroscopy-guided placement of covered expandable metal stents. While some data suggest a lower migration and re-obstruction rate with the larger-diameter covered expandable metal stents, there may be a higher risk of stent-related complications. [110]  

The 2013 American Society for Gastrointestinal Endoscopy (ASGE) guidelines have following recommendations for palliative care [141] :

  • Esophageal stent placement is the preferred method for palliation of dysphagia and fistulae.
  • Patient preferences, quality of life, and prognosis should be addressed with the patient and family before initiating endoscopic palliation.
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