Esophageal cancer

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment for esophageal cancer is complex and depends on multiple factors, including disease stage, histology (squamous cell carcinoma or adenocarcinoma), tumor location, biomarker status (e.g., human epidermal receptor 2 [HER2]; metastatic microsatellite instability-high [MSI-H]; mismatch repair deficient [dMMR]; and programmed death-ligand 1 [PD-L1]), performance status, comorbidities, and patient preference.[88]

Initial treatment options include the following (some can be combined in certain patients):

Endoscopic therapy
Surgery (esophagectomy)
Radiation therapy
Chemotherapy
Chemoradiation therapy
Targeted therapy
Palliative/supportive care

The initial treatment approach is typically guided by clinical disease stage (i.e., limited [cT1, cN0, M0], localized [cT2, cN0, M0], locally advanced [cT3-4 or cN1-3, M0)], or metastatic [M1]), histology subtype, and suitability for surgery.

All patients require careful treatment planning that involves a multidisciplinary team (e.g., surgical oncology, medical oncology, radiation oncology, radiology, gastroenterology, pathology). Patients with locally advanced, metastatic, or recurrent disease may require a combination of local and systemic treatments (i.e., multimodality treatment).[135]

Endoscopic therapy

Endoscopic therapy includes endoscopic resection (using endoscopic mucosal resection [EMR] or endoscopic submucosal dissection [ESD]) and/or endoscopic ablation (using cryoablation or radiofrequency ablation). Endoscopic resection is recommended for the accurate staging of early-stage cancers (T1a or T1b based on endoscopic ultrasound [EUS]).[15]

Endoscopic therapy is considered to be a safe and effective treatment option for patients with limited (cT1) disease. Specifically, patients with T1a disease, superficial T1b tumors, and those lacking poor differentiation or lymphovascular invasion are candidates for endoscopic resection for curative intent. Procedures should be performed at a specialized center with appropriate expertise in gastrointestinal endoscopy, imaging, surgery, and pathology.[88][136][137] Endoscopic treatments can also be used in palliative care. Dilating balloons or bougies can be inserted for temporary relief from tumor obstruction or strictures, and dysphagia can be relieved by endoscopic tumor ablation or placement of self-expanding metal stents. Endoscopy can also be used to assist with the placement of feeding gastrostomy or jejunostomy tubes in the palliation of patients with anorexia, dysphagia, or malnutrition.[15]

EMR and ESD

EMR involves the use of an endoscopic snare device to resect lesions. In contrast, ESD involves dissecting lesions from the submucosa layer, followed by en bloc resection of the dissected lesions.[138]

EMR may be less time-consuming, and associated with a lower risk of severe adverse events, than ESD. However, its use is limited to smaller lesions.

For larger lesions, ESD is recommended.[122][139] ESD has been found to be associated with higher curative resection rates and lower local recurrence rates compared with EMR, particularly for large (≥20 mm) squamous cell carcinoma lesions.[122][139]

ESD is more useful than EMR for assessing lesion size, submucosa invasion, differentiation, and lymphovascular invasion. However, it is more time-consuming to perform and is associated with a higher risk of complications (e.g., bleeding, perforation) compared with EMR.[138][140][141]

The American Society for Gastrointestinal Endoscopy (ASGE) suggests selecting resection strategy on the basis of lesion size in patients with esophageal squamous cell dysplasia or early, well-differentiated, nonulcerated squamous cell carcinoma. Either ESD or EMR can be used when lesion size is ≤15 mm, while ESD is preferred over EMR when lesion size is >15 mm.[142] Further, in patients with early, well-differentiated, nonulcerated esophageal adenocarcinoma (T1 stage) or nodular Barrett dysplasia, the ASGE suggests using either ESD or EMR when lesion size is ≤20 mm, while ESD is preferred over EMR when lesion size is >20 mm.[142]

Endoscopic ablation

Involves thermal injury through heat (burning, coagulation necrosis) or freezing (cryotherapy) to destroy, rather than remove, neoplastic tissue.[143] Endoscopic ablation does not facilitate further diagnostic evaluation, but it is usually performed following EMR or ESD, after the resection site has healed, to help completely eliminate any residual dysplasia or treat nondysplastic Barrett esophagus.[15]

Pathologic staging and histologic diagnosis

EMR and ESD facilitate pathologic staging and histologic diagnosis. This is particularly useful for staging patients with limited disease because clinical staging (using computed tomography or magnetic resonance imaging) cannot accurately differentiate T1a disease (no submucosa involvement) and T1b disease (with submucosa involvement).[91]

Endoscopic resected specimens obtained during EMR and ESD should be sent for histopathology assessment to determine pathologic stage and, importantly, depth of submucosal invasion. Depth of submucosal invasion is strongly associated with risk of lymph node metastases.[123] Additionally, deep margin status is important to determine if endoscopic therapy alone may be curative.

Surveillance

EUS has a high sensitivity for detecting recurrent disease post treatment. EUS-guided fine needle aspiration biopsy (EUS-FNA) should be undertaken if abnormalities are detected on cross-sectional imaging (e.g., suspicious lymph nodes or areas of wall thickening).[15]

Surgery (esophagectomy)

Surgery is the cornerstone of treatment for esophageal cancer. Surgery is usually carried out with curative intent. The main surgical approaches are:

Transthoracic esophagectomy (Ivor Lewis or Mckeown procedures)
Transhiatal esophagectomy

Transthoracic esophagectomy is often preferred because it allows direct visualization of the thoracic esophagus with extensive lymphadenectomy. Some data suggest improved survival compared with transhiatal esophagectomy in patients with resectable esophageal adenocarcinoma. However, historically, the morbidity of complications following Ivor Lewis esophagectomy (e.g., intrathoracic anastomotic leak) has led some surgeons to favor a cervical anastomosis via either McKeown or transhiatal approaches. With improved endoscopic options such as stent and endoluminal vacuum sponges, the morbidity of an intrathoracic leak may be reduced when managed at experienced centers.

In transthoracic esophagectomy, gastric tube reconstruction is performed with either an intrathoracic anastomosis (Ivor Lewis) or a cervical anastomosis (McKeown).[144] The Ivor Lewis procedure is most appropriate for distal thoracic lesions, whereas the McKeown procedure can be used for tumors more proximally in the esophagus (e.g., middle-third).[15]

A transhiatal esophagectomy involves a laparotomy and left cervical incision. It can be used for lesions at any thoracic location; however, transhiatal dissection of large middle-esophageal tumors adjacent to the trachea is difficult and may be associated with considerable risk.[15] European guidelines suggest a role for transhiatal esophagectomy in patients where morbidity from a thoracotomy incision may be considered excessive.[88]

The type of resection is dictated by the tumor location, and choices available for conduit, as well as the surgeon's experience and preference, whilst taking the patient's preference into consideration.[15]

Surgery should be carried out at high-volume centers and by surgeons experienced in performing esophagectomy.[15] Studies have found that high-volume centers have a lower mortality rate compared with low-volume centers.[145] There is also evidence to suggest that surgeon volume is a stronger prognostic factor than hospital volume.[145][146]

Minimally invasive surgery

Minimally invasive surgery involves performing esophagectomy under thoracoscopic and laparoscopic visualization. Minimally invasive surgery has been shown to have comparable outcomes to open esophagectomy for benign and non-locally advanced cancer.[147] [ ] In experienced centers, it is recommended as the surgical approach of choice.[88]

Techniques involve minimally invasive Ivor Lewis (laparoscopy and limited right thoracotomy) or McKeown (right thoracoscopy, limited laparotomy/laparoscopy, and cervical anastomosis) esophagectomies. However, hybrid techniques, which combine either thoracoscopy or laparoscopy with open surgery (for the abdominal or the thoracic component of the procedure, respectively), have also been described as minimally invasive.[148]

Laparoscopic and thoracoscopic or robotic-assisted minimally invasive esophagectomy offers benefits in terms of decreased perioperative pulmonary complications and postoperative complications, faster recovery, and improved short-term quality of life.[149][150][151]

Randomized studies demonstrate that, compared with standard transthoracic esophagectomy, both minimally-invasive transthoracic esophagectomy and hybrid minimally invasive esophagectomy (an Ivor Lewis procedure with laparoscopic gastric mobilization and limited open right thoracotomy) lead to significantly lower rates of postoperative complications and accelerated recovery, without compromising survival benefit.[152][153]

Radiation therapy

Radiation therapy (preoperative, postoperative, or palliative) can be used for both esophageal and esophagogastric junction tumors. Most patients should receive radiation therapy in combination with chemotherapy (chemoradiation therapy) due to significantly better outcomes than with radiation therapy alone; radiation therapy as a sole treatment should generally be reserved for palliation or for patients who are unable to receive chemotherapy.[15]

Treatment for Siewert Type 1 and 2 tumors generally follows guidelines for esophageal and esophagogastric tumors, whereas treatment for Siewert Type 3 tumors usually follows guidelines for radiation therapy of gastric cancer.[15]

Recommendations may be adapted according to location and bulk of the tumor.[15] A dose range of 41.4 to 50.4 Gy is recommended for preoperative therapy, and 45 to 50.4 Gy for postoperative therapy. Nonsurgical candidates can receive doses of 50 to 50.4 Gy.[15]

Chemotherapy

Preoperative and perioperative chemotherapy should only be used for adenocarcinoma of the thoracic esophagus or esophagogastric junction.[15]

The value of postoperative chemotherapy remains uncertain.

Chemoradiation therapy

Preoperative chemoradiation with paclitaxel and carboplatin plus radiation therapy is the preferred approach for localized resectable disease.[15][154] One Cochrane review found that preoperative chemotherapy followed by esophagectomy improved survival compared with surgery alone in patients with resectable thoracic esophageal cancer.[155] [ ] [Evidence B] Definitive chemoradiation should be reserved for those who have unresectable disease, decline surgery, or have prohibitive surgical risk.[15][156][157]

Patients undergoing upfront surgery for presumed limited disease found to have node positive on final pathology should be considered for adjuvant chemoradiation if poor nodal harvest was achieved and there is concern for suboptimal surgery.[15]

Targeted therapy

It is important that all patients with esophageal cancer undergo biomarker testing (e.g., for HER2, MSI-H, dMMR, and PD-L1 overexpression) to identify those suitable for targeted therapies.These agents may be used alone or in combination with chemotherapy, depending on the drug. Available preferred options recommended for unresectable locally advanced, recurrent, or metastatic disease include trastuzumab, nivolumab, and pembrolizumab. The preferred treatment options for MSI-H/dMMR tumors include pembrolizumab (alone or in combination with fluoropyrimidine- and platinum-based chemotherapy), dostarlimab, and nivolumab (in combination with ipilimumab or fluoropyrimidine- and platinum-based chemotherapy).

Trastuzumab (an anti-HER2 monoclonal antibody) is approved for use in patients with previously untreated metastatic HER2-positive adenocarcinoma, in combination with first-line platinum- and fluoropyrimidine-based chemotherapy.[15][114][158] In the ToGA trial, trastuzumab combined with chemotherapy (cisplatin plus either capecitabine or fluorouracil) improved survival (16.0 vs. 11.8 months) in patients with HER2-positive esophageal and gastric adenocarcinoma compared with chemotherapy alone.[114]

In the US, pembrolizumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line therapy with a fluoropyrimidine, a platinum agent, and trastuzumab for patients with HER2-positive adenocarcinoma.[15][159] Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy may be used for the first-line treatment of patients with squamous cell carcinoma or HER2-negative adenocarcinoma.[15][88][159] In Europe, this approval is limited to patients with combined positive score (CPS) ≥10. In the KEYNOTE-859 study comprising patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma, the combination of pembrolizumab with chemotherapy has shown significant and clinically meaningful improvement in overall survival with manageable toxicity, compared with placebo.[160]

Nivolumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line treatment with fluoropyrimidine- and platinum-based chemotherapy for patients with HER2-negative advanced esophageal or esophagogastric junction adenocarcinoma.[15][159] The National Institute for Health and Care Excellence (NICE) in the UK recommends nivolumab after fluoropyrimidine and platinum-based therapy for the treatment of previously treated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in adults.[161] NICE further recommends nivolumab plus fluoropyrimidine-based and platinum-based therapy as an option in adults with untreated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma whose tumors express PD‑L1 at a level of 1% or more when pembrolizumab plus chemotherapy is not found to be suitable.[162] Nivolumab is approved in combination with fluoropyrimidine- and platinum-based chemotherapy and in combination with ipilimumab for the first-line treatment of patients with advanced esophageal squamous cell carcinoma (ESCC).[15][159]

Dostarlimab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) is approved for the treatment of patients with DNA mismatch repair-deficiency recurrent or advanced solid tumors that have progressed on or following prior treatment, who have no alternative treatment options, and who have not previously received a PD-1 or PD-L1 inhibitor.[15] The nonrandomized phase-1 multi-cohort GARNET trial evaluated the safety and efficacy of dostarlimab in 209 patients with dMMR solid tumors (the majority of which were endometrial or gastrointestinal cancers) who had not received previous PD-1 or PD-L1 inhibitors. At 12 months of follow-up the overall response rate was 38.7%, with a 7.5% complete response rate.[163]

Palliative/supportive care

The focus of palliative/supportive care should be to prevent and relieve suffering primarily due to dysphagia, obstruction, pain, bleeding, and nausea and vomiting.[15] Early palliative care referral and nutritional support should be offered.[88]

Photodynamic therapy (PDT) involves the activation of an exogenously administered, or an endogenously generated, photosensitizer with light to produce localized tissue destruction.[164] Palliative laser and PDT for esophageal obstruction has been associated with stricture formation.[165][166][167]

Cryotherapy (using liquid nitrogen) is under investigation for the treatment of squamous dysplasia of the esophagus (especially in patients who are high-risk for surgery).[168][169]

Insertion of self-expanding metal stents combined with brachytherapy provides comparable palliative relief of dysphagia to endoscopic ablation techniques.[170] It is associated with a reduced requirement for reinterventions. Various other techniques, including rigid plastic tube insertion, dilation alone or in combination with other therapies, chemotherapy or chemoradiation, and bypass surgery, are associated with a high rate of delayed complications and recurrence of dysphagia.[170]

Limited disease (cT1, cN0, M0)

Endoscopic therapy (EMR or ESD, with or without endoscopic ablation) or surgery (esophagectomy) are the recommended initial treatment options for patients with limited disease (both squamous cell carcinoma and adenocarcinoma).[15][88][137][171] The goal of treatment is complete disease eradication and cure.

T1a disease

Endoscopic therapy alone is recommended for most patients with cT1a disease (i.e., disease limited to the lamina propria and muscularis mucosae).[15][88] No further surgical treatment is required. Endoscopic resection can usually be considered curative in all T1a adenocarcinomas.[88] Esophageal squamous cell carcinomas (ESCC) have a higher risk of lymph node metastasis and features such as differentiation and lymphovascular invasion should be considered. Esophagectomy is indicated for patients with extensive T1a ESCC, particularly nodular disease that is not controlled with endoscopic therapy.[15][88]

In a SEER database analysis of 1458 patients with T1N0 esophageal cancer, the overall survival rates were similar after treatment with surgery or endoscopic therapy, but those treated with endoscopic therapy had improved cancer-specific survival and decreased morbidity.[172]

Residual Barrett esophagus should be ablated following endoscopic therapy to minimize the risk of subsequent cancer.[15][88] Following endoscopic therapy, patients require continuous monitoring with routine interval endoscopies.

T1b disease

Esophagectomy is recommended for patients with cT1b disease (squamous cell carcinoma or adenocarcinoma) who are suitable for surgery.[15][88][137][173][174]

Patients with superficial T1b adenocarcinomas may be considered for initial treatment with endoscopic therapy instead of surgery.[88] If histopathologic assessment of endoscopic resected specimens confirms superficial T1b disease (i.e., submucosa invasion <500 micrometers), no ulceration, and the presence of low-risk lesions (i.e., no lymphovascular invasion, well-differentiated histology, negative margins) then no further surgical treatment is required. The ASGE suggests that patients with esophageal squamous cell dysplasia or early, well-differentiated, nonulcerated ESCC who do not show overt signs of submucosal invasion need not undergo surgical resection.[142] Surgery is required if histopathologic assessment confirms deep submucosa invasion and/or high-risk lesions (i.e., lymphovascular invasion, poorly differentiated histology, positive margins).[88]

Patients who are unsuitable for or decline surgery can be offered definitive chemoradiation therapy. The radiation component should be delivered at a dose of 50.4 Gy. The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; fluorouracil plus oxaliplatin; or leucovorin plus fluorouracil plus oxaliplatin (FOLFOX). Other options include: cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.[15][88][154][156][175][176] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Definitive chemoradiation therapy has been shown to increase the survival of patients who have squamous cell carcinoma or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with radiation therapy alone.[177][178] The landmark RTOG 85-01 trial randomized patients to receive either chemoradiation therapy (fluorouracil plus cisplatin plus radiation therapy) or radiation therapy alone. At 5 years of follow-up, the overall survival for combined therapy was 26% (95% CI 15% to 37%) compared with 0% following radiation therapy.[178] Median survival in one phase 3 study (n=121) was 12.5 months in patients treated with chemoradiation therapy compared with 8.9 months in the patients treated with radiation therapy alone.[177]

Endoscopic therapy is an alternative to chemoradiation, but only for patients with superficial adenocarcinomas.[88]

Localized disease (cT2, cN0, M0)

Esophagectomy is recommended as part of the treatment plan for patients with localized disease (cT2, cN0, M0) who are suitable for surgery.[15][88][135]

Certain patients may be considered for surgery with either preoperative chemoradiation therapy or perioperative (i.e., pre- and postoperative) chemotherapy, depending on histology subtype and histopathologic findings.

Preoperative treatment is used to reduce the size of the primary tumor and remove micrometastatic disease, with the aim of improving R0 (no residual disease) resection rates, reducing the risk of recurrence and metastases, and improving survival rates.[179]

Localized disease and low-risk lesions

Patients with cT2 disease and low-risk lesions (i.e., no lymphovascular invasion, tumor size <30 mm, well-differentiated histology) can be treated with surgery alone if there is confidence in the accuracy of the clinical stage.[15][135][180][181] European guidelines note that there is insufficient evidence to make firm recommendations regarding the use of preoperative chemoradiation therapy or chemotherapy for T2 N0 cancers, advising that each case should be discussed by a multidisciplinary team with careful consideration of the risks and benefits.[88]

Localized disease and high-risk lesions: squamous cell carcinoma

Patients with localized esophageal squamous cell carcinoma (ESCC) and high-risk lesions (i.e., lymphovascular invasion, tumor size ≥30 mm, poorly differentiated histology) can be considered for preoperative chemoradiation therapy followed by surgery.[15][88][135][182] This has been shown to improve survival compared with surgery alone in patients with localized or locally advanced ESCC.[154][182][183][184][185]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy), based on the results from the CROSS trial (which enrolled patients with cT1, N1 disease or cT2-3, N0-1 disease).[154][184][185] The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.[15][88][175][176] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Localized disease and high-risk lesions: adenocarcinoma

Patients with localized esophageal adenocarcinoma (EAC) and high-risk lesions can be considered for surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.[135] Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy in 23 fractions), based on the results from the CROSS trial.[154][184][185] The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.[15][88][175][176] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Patients with resectable disease should proceed to surgery even after complete clinical tumor response to preoperative chemoradiation therapy, as data for a watch-and-wait strategy are limited.[88]

Perioperative chemotherapy is an alternative treatment, with data strongly suggesting noninferiority compared to preoperative chemoradiation.[15] The survival benefit of perioperative chemotherapy was first demonstrated in the phase 3 MAGIC trial, which compared perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil (ECF) to surgery alone. It found that perioperative chemotherapy improves progression-free and overall survival in patients with nonmetastatic stage 2 and higher gastric or esophagogastric junction adenocarcinoma.[188] The phase 3 Neo-AEGIS trial directly compared preoperative chemoradiation (CROSS regimen) to perioperative chemotherapy (modified MAGIC or FLOT regimen) in patients with locoregional adenocarcinoma of the esophagus or esophagogastric junction.[189] Both treatment arms showed similar 3-year survival and no major differences in operative and health-related quality of life outcomes. The trial was prematurely terminated due to similar survival metrics and the impact of the COVID-19 pandemic.[189]

The role of perioperative chemotherapy versus upfront chemoradiation is under active investigation. The phase 3 ESOPEC trial, which compared the efficacy of neoadjuvant chemoradiation (CROSS protocol) followed by surgery with perioperative chemotherapy (FLOT protocol) and surgery in patients with resectable, locally advanced adenocarcinoma, found a 29-month improvement in median overall survival with perioperative chemotherapy regimen compared with neoadjuvant chemoradiation regimen.[190][191] Similar surgical complications and postoperative mortality were reported in both arms. These results suggest the superiority of perioperative FLOT protocol over neoadjuvant CROSS protocol in patients with resectable, locally advanced adenocarcinoma.[191]

The preferred perioperative chemotherapy regimens are fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), or a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin. The other option is fluorouracil plus cisplatin.[15][88]

Localized disease: unsuitable for surgery

Patients with localized squamous cell carcinoma or adenocarcinoma who are unsuitable for surgery (e.g., those with tumors located in the cervical esophagus, where surgery would entail a laryngectomy) or who decline surgery can be considered for definitive chemoradiation therapy.[15][88]

Randomized trials comparing definitive chemoradiation therapy versus surgery plus preoperative chemoradiation therapy in patients with locally advanced disease have reported similar survival outcomes, particularly among those with squamous cell carcinoma who achieved a complete response with chemoradiation therapy.[192][193][194]

Close monitoring is required following definitive chemoradiation therapy due to the risk of local tumor recurrence.[192][193]

Salvage esophagectomy can be considered in patients with persistent or progressive disease post definitive chemoradiation therapy. It has been shown to be comparable in terms of outcomes to those with planned trimodality therapy in the setting of adenocarcinoma.[88][195][196] However, some data suggest increased morbidity for patients with ESCC.[197]

Radiation therapy should be delivered at a dose of 50.4 Gy. The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; fluorouracil plus oxaliplatin; or leucovorin plus fluorouracil plus oxaliplatin (FOLFOX). Other options include: cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.[15][88][154][156][175][176] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Locally advanced disease (cT3-T4 or cN1-3, M0)

Multimodality treatment comprising surgery combined with preoperative chemoradiation therapy, preoperative chemotherapy, or perioperative (i.e., pre- and postoperative) chemotherapy is recommended for patients with locally advanced disease (cT3-T4 or cN1-3, M0) who are suitable for surgery.[15][88][135][182]

Decisions regarding the use of preoperative or perioperative treatment can be guided by histology subtype (squamous cell carcinoma or adenocarcinoma).

Similar to patients with localized (cT2) disease, the goal of preoperative and perioperative treatment in patients with locally advanced disease is to improve R0 resection rates, reduce the risk of recurrence and metastases, and improve survival.[179] Preoperative treatment is particularly important for locally advanced disease because approximately 30% to 40% of patients have resectable disease at presentation.[198]

Furthermore, survival rates are relatively low for those treated with surgery alone.[199][200]

Locally advanced disease: squamous cell carcinoma

The recommended initial treatment for patients with locally advanced ESCC is surgery plus preoperative chemoradiation therapy.[15][88][135][151][182] This has been shown to improve survival compared with surgery alone in patients with localized or locally advanced ESCC.[135][154][183][184][185]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy), based on the results from the CROSS trial (which enrolled patients with cT1, N1 disease or cT2-3, N0-1 disease).[154][184][185] The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.[15][175][176] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Locally advanced disease: adenocarcinoma

The recommended initial treatment for patients with locally advanced EAC is surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.[15][88][135][151] Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

Perioperative chemotherapy is an alternative treatment for locally advanced EAC, with data strongly suggesting noninferiority compared to preoperative chemoradiation.[15] The role of perioperative chemotherapy versus upfront chemoradiation is under active investigation. The phase 3 ESOPEC trial, which compared the efficacy of neoadjuvant chemoradiation (CROSS protocol) followed by surgery with perioperative chemotherapy (FLOT protocol) and surgery in patients with resectable, locally advanced adenocarcinoma, found a 29-month improvement in median overall survival with perioperative chemotherapy regimen compared with neoadjuvant chemoradiation regimen.[190][191] Similar surgical complications and postoperative mortality were reported in both arms. These results suggest the superiority of perioperative FLOT protocol over neoadjuvant CROSS protocol in patients with resectable, locally advanced adenocarcinoma.[191]

Patients with resectable disease should proceed to surgery even after complete clinical tumor response to preoperative chemoradiation therapy, as data for a watch-and-wait strategy are limited.[88]

Locally advanced disease: unsuitable for surgery

Patients with locally advanced squamous cell carcinoma or adenocarcinoma who are unsuitable for surgery (e.g., those with tumors located in the cervical esophagus, where surgery would entail a laryngectomy) or who decline surgery can be considered for definitive chemoradiation therapy.[15][88][135]

Close monitoring is required following definitive chemoradiation therapy due to the risk of local tumor recurrence.[192][193] In the case of complete response to definitive chemoradiation therapy, a 3-month follow-up with endoscopy, biopsies, and computed tomography (CT) scan should be considered.[88]

Salvage esophagectomy can be considered in patients with persistent or progressive disease post chemoradiation therapy. It has been shown to be comparable in terms of outcomes to those with planned trimodality therapy in the setting of adenocarcinoma.[88][195][196] However, some data suggest increased morbidity for patients with ESCC.[197]

The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; oxaliplatin plus fluorouracil; or fluorouracil plus leucovorin plus oxaliplatin (FOLFOX). Other options include cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.[15][88][154][156][175][176] In one randomized trial, chemoradiation with FOLFOX did not increase progression-free survival compared with chemoradiation with fluorouracil plus cisplatin; however, FOLFOX might be a more convenient option for patients with localized esophageal cancer unsuitable for surgery.[156] Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

The radiation component of the treatment should be delivered using 3D conformal radiation treatment (RT) as a minimum, but intensity-modulated RT or volumetric arc therapy are preferred to better minimize the radiation dose to normal tissues such as the heart and lungs. There is little evidence to support the use of RT doses >50.4 Gy in the definitive treatment of esophageal cancer.[88]

Targeted therapy may be added to chemotherapy regimens for certain subtypes of unresectable, locally advanced esophageal cancer. It is important that all patients with esophageal cancer undergo biomarker testing (e.g., for HER2, MSI-H, dMMR, and PD-L1 overexpression) to identify those suitable for targeted therapies.The preferred options include trastuzumab, nivolumab, and pembrolizumab. The preferred treatment options for MSI-H/dMMR tumors include pembrolizumab (alone or in combination with fluoropyrimidine- and platinum-based chemotherapy), dostarlimab, and nivolumab (in combination with ipilimumab or fluoropyrimidine- and platinum-based chemotherapy).

Second-line or subsequent therapy depends on prior therapy and performance status.[15] If patients are unable to tolerate chemoradiation therapy they should be offered palliative radiation therapy or best supportive care.[15]

Postoperative residual pathologic disease

Patients with localized or locally advanced disease (both squamous cell carcinoma and adenocarcinoma) who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203] Other recommended regimens are capecitabine and oxaliplatin or fluorouracil and oxaliplatin.[15]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202] PD-L1 testing is not required for this indication.[88]

Metastatic (M1) disease

Patients presenting with distant metastatic disease are considered to have unresectable disease. Early palliative therapy and best supportive care are recommended for these patients.[15][88][203][204]

Patients may have symptoms secondary to the local and systemic effects of malignancy, such as dysphagia, esophageal obstruction, pain, bleeding, and malaise, in addition to underlying comorbidities. Palliation of symptoms and maintaining quality of life is, therefore, central to managing patients with metastatic disease.

Dysphagia and esophageal obstruction may be relieved using palliative radiation therapy (external beam radiation therapy or brachytherapy) or self-expanding metallic stent insertion, depending on the degree of dysphagia and its impact on nutrition, quality of life, performance status, and prognosis.[15][88][137] The National Institute for Health and Care Excellence in the UK advises against routine use of external beam radiation therapy after stent placement in patients with esophageal cancer and recommends that it should only be used in those with esophageal cancer having prolonged post-interventional bleeding or a known bleeding disorder.[137] If there is complete obstruction, endoscopic lumen restoration should be performed via simultaneous retrograde and anterograde enteroscopy.[15] Severe obstruction should be relieved with wire-guided dilation or balloon dilation and insertion of an expandable metal stent.[15] These options should be considered for moderate obstruction, balancing the associated risks and benefits.[15] Photodynamic therapy may be effective but is less commonly used due to associated photosensitivity and costs.[15] Surgery may be useful in carefully selected patients.[15]

Nutritional status should be optimized with dietetic input (including dietary advice, nutritional supplements, and, if appropriate, short-term enteral feeding).

Patients with metastatic disease can be considered for chemotherapy, in addition to best supportive care. The decision to proceed with chemotherapy should be based on performance status, comorbidities, and patient preference.

Chemotherapy may improve symptoms, survival, and quality of life compared with best supportive care alone in patients with metastatic disease.[205][206] Most of the evidence supporting the use of chemotherapy in metastatic disease is extrapolated from randomized studies in patients with advanced/metastatic gastric adenocarcinoma.[205][206]

Two-drug chemotherapy regimens comprising a platinum agent (e.g., oxaliplatin or cisplatin) plus a fluoropyrimidine (e.g., fluorouracil or capecitabine) are typically recommended for first-line treatment in patients with metastatic disease.[15][88] Studies suggest equivalence for oxaliplatin and cisplatin.[88] Oxaliplatin is usually preferred to cisplatin due to lower toxicity.[15][207] A reduced-dose oxaliplatin plus capecitabine regime is an option for older or frail patients who may be unsuitable for full-dose treatment.[88]

Adding a taxane (docetaxel) or anthracycline (epirubicin) to a two-drug regimen (i.e., triplet therapy) may be considered if a rapid response is required (e.g., to treat bulky and/or symptomatic disease). However, triplet therapy is associated with an increased risk of toxicity and adverse effects (e.g., myelosuppression, gastrointestinal toxicity, neuropathy, neutropenia); therefore, it is only suitable for fit patients with good performance status.[208][209][210]

Docetaxel combined with cisplatin plus fluorouracil has been shown to improve survival compared with cisplatin plus fluorouracil alone in patients with untreated advanced gastric cancer, although at the expense of increased toxicity.[209]

Epirubicin combined with cisplatin plus fluorouracil has been shown to improve survival compared with other triplet regimens (e.g., fluorouracil plus doxorubicin plus methotrexate; and mitomycin plus cisplatin plus fluorouracil) in patients with advanced esophagogastric cancer.[211][212] However, there is controversy regarding the efficacy and safety of epirubicin-containing regimens, particularly when compared with standard two-drug regimens.[213]

Other triplet therapy regimens that can be considered for first-line treatment include leucovorin plus fluorouracil plus oxaliplatin (FOLFOX), and leucovorin plus fluorouracil plus irinotecan (FOLFIRI).[214][215][216]Guimbaud R, Louvet C, Ries P, et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6.

Despite the benefits of triplet therapy, two-drug regimens are generally preferred due to lower toxicity.

Other options for first-line therapy include docetaxel plus cisplatin; paclitaxel plus cisplatin; paclitaxel plus carboplatin; or single-agent capecitabine, fluorouracil, docetaxel, or paclitaxel.[15]

Several targeted therapies can be used in patients with metastatic esophageal and esophageal junction cancer.

It is important that all patients with esophageal cancer undergo biomarker testing (e.g., for HER2, MSI-H, dMMR, and PD-L1 overexpression) to identify those suitable for targeted therapies. The preferred options include trastuzumab, pembrolizumab, and nivolumab. Trastuzumab is added to chemotherapy for HER2 overexpression positive tumors. The preferred treatment options for MSI-H/dMMR tumors include pembrolizumab (alone or in combination with fluoropyrimidine- and platinum-based chemotherapy), dostarlimab, and nivolumab (in combination with ipilimumab or fluoropyrimidine- and platinum-based chemotherapy). Second-line or subsequent therapy depends on prior therapy and performance status.[15]

Recurrent disease

Treatment decisions for patients with recurrent or refractory disease are informed by prior treatment history.

Patients with locoregional recurrence that occurs subsequent to chemoradiation therapy can be considered for surgery if the tumor is resectable (depending on performance status and patient preference).

Patients with locoregional recurrence that occurs following surgery without the use of chemoradiation therapy can be considered for chemoradiation therapy, surgery, chemotherapy, and palliative care/best supportive care (depending on performance status and patient preference).

Patients with unresectable recurrent disease or metastatic disease that occurs following treatment can be considered for palliative/best supportive care (including systemic and targeted therapies).

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