Esophageal cancer is associated with a poor prognosis with 5-year survival rates of approximately 15% to 20%. Although patients with early stage disease may adequately be treated with a single modality, combined therapy typically consisting of neoadjuvant chemoradiation followed by esophagectomy is being adopted increasingly in patients with locally advanced disease. In patients who are not surgical candidates, definitive chemoradiation is the preferred treatment approach. All patients with newly diagnosed esophageal cancer should be evaluated in the multidisciplinary setting by a surgeon, radiation oncologist, and medical oncologist owing to the importance of each specialty in the management of these patients.
Key points
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Esophageal cancer continues to be associated with poor treatment outcomes despite significant advances in treatment technique.
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There has been an increasing incidence of esophageal adenocarcinoma and decreasing esophageal squamous cell carcinoma owing to changes in diet and lifestyle factors.
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Owing to the adoption of endoscopic surveillance, there has been an increasing incidence of early stage esophageal cancer with potential treatment options including endomucosal therapy, esophagectomy, or chemoradiation.
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Trimodality therapy consisting of neoadjuvant chemoradiation followed by esophagectomy is the preferred treatment option for patients with locally advanced esophageal cancer.
Epidemiology
Esophageal cancer is the sixth most common cancer diagnosis in the world with more than 450,000 patients diagnosed each year. Although squamous cell carcinoma is the most common histology globally, adenocarcinoma is the most common histologic diagnosis in the United States. Despite significant advances in treatment techniques as well as the introduction of newer chemotherapy and targeted biologic agents, prognosis remains poor with 5-year survival rates of approximately 15% to 20%. When examining outcomes according to stage, patients with clinically localized disease have a 5-year survival of nearly 40% versus only 4% in patients with metastatic disease. Over the past decade, the use of endoscopic screening has increased the number of early stage cancers diagnosed each year, yet approximately one-third of patients are still diagnosed with advanced disease.
Epidemiology
Esophageal cancer is the sixth most common cancer diagnosis in the world with more than 450,000 patients diagnosed each year. Although squamous cell carcinoma is the most common histology globally, adenocarcinoma is the most common histologic diagnosis in the United States. Despite significant advances in treatment techniques as well as the introduction of newer chemotherapy and targeted biologic agents, prognosis remains poor with 5-year survival rates of approximately 15% to 20%. When examining outcomes according to stage, patients with clinically localized disease have a 5-year survival of nearly 40% versus only 4% in patients with metastatic disease. Over the past decade, the use of endoscopic screening has increased the number of early stage cancers diagnosed each year, yet approximately one-third of patients are still diagnosed with advanced disease.
Risk factors
Risk factors for the development of esophageal cancer are provided in Table 1 . Esophageal cancer peaks in late adulthood (60–70 years of age), and the incidence varies greatly according to gender, geography, and ethnicity. In general, esophageal cancer is diagnosed more commonly in males, although the patterns in diagnosis vary by geographic area. When examining histology, squamous cell carcinoma is far more common in black patients, and adenocarcinomas are more commonly seen in white patients.
| Adenocarcinoma | Squamous Cell Carcinoma |
|---|---|
| Obesity Smoking Gastroesophageal reflux disease Barrett’s esophagus Family history | Socioeconomic class Nitrosamine Polyaromatic hydrocarbons Tobacco smoking Poor oral hyenine Family history Alcohol |
The incidence of esophageal adenocarcinoma has increased dramatically in the United States over the past several decades, while the incidence of squamous cell carcinoma has been decreasing ( Fig. 1 ). The increase in esophageal adenocarcinoma has been attributed to changes in diet, with increased intake of high-fat foods and a decrease in fruit and vegetable consumption. Gastroesophageal reflux disease has been linked to esophageal adenocarcinoma (but not esophageal squamous cell carcinoma) in multiple population-based series. A large metaanalysis suggested that weekly symptoms of gastroesophageal reflux disease resulted in a dramatic increase in the risk for esophageal adenocarcinoma (odds ratio, 4.92; 95% confidence interval, 3.90–6.22) compared with asymptomatic controls. The decrease in squamous cell carcinoma incidence is likely owing to decreasing rates of smoking and alcohol use.
Barrett’s esophagus is defined as a change in the normal squamous epithelium of the distal esophagus to a columnar type, with the classic appearance of a salmon-colored mucosa and the presence of goblet cells. These changes are thought to occur owing to a chronic inflammatory state that increases the risk for the development of esophageal adenocarcinoma. Patients diagnosed with Barrett’s esophagus have 11 times the risk of developing esophageal cancer versus those without Barrett’s. A large series from the Netherlands examined a cohort of 42,207 patients and found a risk of 0.4% of developing esophageal cancer with a history of Barrett’s. This study clearly illustrates that, although the risk of esophageal cancer in patients with Barrett’s is high relative to the general population, it is still relatively low.
Patients found to have Barrett’s esophagus typically undergo surveillance esophagogastroduodenoscopy owing to the increased risk of esophageal cancer. Typically, it is recommended that patients with Barrett’s undergo esophagogastroduodenoscopy every 3 to 5 years with standardized sampling and methodological documentation of the extent of disease. When a high-grade dysplastic lesion is identified, patients may undergo either endoscopic mucosal resection (EMR) or surgical resection. There is wide variation in the incidence of esophageal adenocarcinoma in this setting, ranging from 0% to 3.5% per year.
Anatomy
The esophagus is a hollow, viscus organ that extends inferiorly from the cricoid cartilage at the cricopharyngeus muscle to the gastroesophageal junction ( Fig. 2 ). The esophagus is further subdivided into cervical (15–18 cm from the incisors), upper thoracic (18–24 cm), middle thoracic (24–32 cm), and lower thoracic (32–40 cm) esophagus. Keratinizing squamous epithelium lines nearly the entire length of the esophagus, although the squamous epithelium can be replaced by intestinal-type glandular epithelium (Barrett’s esophagus). Beneath the epithelial layer of the esophagus is the basement membrane followed by the lamina propria, muscularis mucosa, submucosa, muscularis propria, and adventitia. Unlike other parts of the gastrointestinal tract, the esophagus lacks a true serosa and thus esophageal tumors have the ability to spread to adjacent organs and distal nodal regions relatively unhindered, without having to traverse a serosal layer.
The esophagus has a rich lymphatic system, with potential metastatic disease dependent on tumor location. Furthermore, because the submucosal lymphatics may traverse long distances along the length of the esophagus, radiation volumes are generally long to encompass these at-risk regions. The cervical esophagus may drain to cervical neck nodes and supraclavicular nodes. The upper thoracic esophagus drains to lymph nodes along the innominate artery and ligamentum arteriosium, in addition to paraesophageal and paratracheal nodes. The middle thoracic esophagus drains to the tracheobronchial, paraesophageal, and pulmonary hilar nodes. The gastroesophageal junction drains to nodes along the left gastric artery, celiac axis, common hepatic artery, splenic artery, lesser curvature of the stomach, and paracardial region. Although the potential nodal drainage patterns are extensive in patients with esophageal cancer, radiotherapy fields do not routinely prophylactically encompass all at risk nodal regions.
Staging and workup
Patients diagnosed with esophageal cancer most commonly present with symptoms of progressive dysphagia or odynophagia and weight loss. Other symptoms such as chest pain are less common, but may suggest involvement of adjacent mediastinal structures. Even less common are insidious findings such as anemia, lymphadenopathy, or hoarseness, suggesting recurrent laryngeal nerve involvement.
The American Joint Committee on Cancer TNM classification and staging has been directly linked to outcomes in patients diagnosed and treated for esophageal cancer. The most recent seventh edition has several important changes from the previous version of the staging manual. In particular, the American Joint Committee on Cancer TNM staging now separates squamous cell carcinoma from adenocarcinoma, reflecting the increasing understanding that these are 2 separate entities with substantially different outcomes and prognosis. Other changes in the seventh edition include the subclassification of T4 tumors into resectable (T4a) or unresectable (T4b) disease. Furthermore, the staging system adds location and grade into the classification system. The nodal classification was also altered; the current system uses the number of lymph nodes positive instead of location of the disease. In addition, celiac lymph node involvement, previously considered metastatic disease, is now classified as regional. Table 2 details the stage groupings according to the American Joint Committee on Cancer TNM seventh edition.
| Description | |
|---|---|
| Primary tumor | |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | High-grade dysplasia |
| 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 | Resectable tumor invading pleura, pericardium, or diaphragm |
| T4b | Unresectable tumor invading other adjacent structures, such as aorta, vertebral body or trachea |
| Regional lymph nodes | |
| NX | Regional nodes not assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in 1–2 regional lymph nodes ∗ |
| N2 | Metastasis in 3–6 regional lymph nodes ∗ |
| N3 | Metastasis in 7 or more regional lymph nodes |
| Distant metastasis | |
| MX | Distant metastasis cannot be assessed |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Stage grouping (adenocarcinoma) | |
| Stage 0 | Tis, N0, M0, grade 1 or X |
| Stage IA | T1, N0, M0, grade 1–2 or X |
| Stage IB | T1, N0, M0, grade 3 |
| T2, N0, M0, grade 1–2 or X | |
| Stage IIA | T2, N0, M0, grade 3 |
| Stage IIB | T3, N0, M0, any grade |
| T1-2, N1, M0, any grade | |
| Stage IIIA | T1-2, N2, M0, any grade |
| T3, N1, M0, any grade | |
| T4a, N0, M0, any grade | |
| Stage IIIB | T3, N2, M0, any grade |
| Stage IIIC | T4a, N1-2, M0, any grade |
| T4b, any N, M0, any grade | |
| Any T, N3, M0, any grade | |
| Stage IV | Any T, any N, M1, any grade |
| Stage grouping (squamous cell carcinoma) | |
| Stage 0 | Tis, N0, M0, grade 1 or X, any location |
| Stage IA | T1, N0, M0, grade 1 or X, any location |
| Stage IB | T1, N0, M0, grade 2 or 3, any location |
| T2-3, N0, M0, grade 1 or X, lower esophagus or X | |
| Stage IIA | T2-3, N0, M0, grade 1 or X, upper and middle esophagus |
| T2-3, N0, M0, grade 2 or 3, lower esophagus or X | |
| Stage IIB | Stage IIB T2-3, N0, M0, grade 2 or 3, upper and middle esophagus |
| T1-2, N1, M0, any grade, any location | |
| Stage IIIA | T1-2, N2, M0, any grade, any location |
| T3, N1, M0, any grade, any location | |
| T4a, N0, M0, any grade, any location | |
| Stage IIIB | T3, N2, M0, any grade, any location |
| Stage IIIC | T4a, N1-2, M0, any grade, any location |
| T4b, any N, M0, any grade, any location | |
| Any T, N3, M0, any grade, any location | |
| Stage IV | Any T, any N, M1, any grade, any location |
∗ Regional lymph nodes extend from cervical nodes to celiac nodes.
Accurate staging is essential in esophageal cancer, because the treatment modality of choice varies greatly according to the extent of disease. The initial diagnostic method is typically an endoscopy with biopsy, providing a histologic diagnosis and demonstrating the extent of disease. The use of endoscopic ultrasound provides the depth of infiltration and has 60% to 90% accuracy for T staging and 50% to 90% accuracy for nodal staging ( Fig. 3 ). In patients with proximal esophageal cancers, tracheobronchoscopy is indicated with biopsies and brushings to rule out tumor infiltration into the trachea or mainstem bronchus. Patients with tumors adherent to the mediastinum are typically considered unresectable.
In addition to locoregional staging, computed tomography (CT) of the chest and abdomen allow for the evaluation of distant metastatic disease as well as infiltration of adjacent organs. More recently, PET has become a critical component in the staging workup for esophageal cancers, because 15% of patients may have distant metastasis not otherwise detected. Before proceeding with multimodality therapy, all patients should undergo a PET/CT scan to evaluate for potential distant metastatic disease ( Fig. 4 ). The role of PET/CT in an adaptive treatment strategy is an area of active investigation. The role of laparoscopy in preoperative staging is based on institutional preference. Although many institutions have moved away from routine laparoscopies in these patients, pretreatment surgical staging has been shown to be more accurate versus imaging techniques. In a study conducted by the Cancer and Leukemia Group B, invasive staging more accurately identified lymph node positivity or advanced locoregional disease, although it should be noted that this study was conducted in the pre-PET/CT era.
Treatment modalities
Treatment of esophageal cancer necessitates maximizing survival while offering symptomatic improvement, because a significant number of patients present with dysphagia or related symptoms. Although surgery alone may be curative in select patients with early disease (cT1N0), a combined approach is indicated typically for most patients with locally advanced disease. Endoscopic procedures for superficial mucosal lesions can be curative, although patients with more invasive lymph node negative tumors may require esophagectomy as well as chemotherapy with or without radiation. Historically, the appropriate management for locally advanced esophageal cancers has been controversial, with potential options including esophagectomy, chemotherapy followed by esophagectomy, chemoradiation followed by esophagectomy, or esophagectomy alone. More recently, a trimodality approach consisting of chemoradiation followed by surgery has been increasingly accepted as the preferred treatment option for these patients.
Surgery
The majority of patients diagnosed with esophageal cancer have penetration of the submucosal tissue and surgical evaluation is recommended. In general, surgery consists of a transthoracic en bloc esophagectomy and lymphadenectomy. The resected esophagus is replaced by a conduit and anastomosed to the remaining esophagus. There are several methods of esophagectomy described in the literature. Each one differs by the site of anastomosis and may be preferred according to the site of the tumor.
A transhiatal esophagectomy consists of dissecting the upper portion of the esophagus using a cervical approach along with an abdominal incision; this procedure does not require a thoracotomy. A blunt dissection technique is used to minimize risk of injury to the esophagus or surrounding tissue, and a cervical esophagogastrostomy anastomosis is performed in the left neck. Owing to the location of the left recurrent laryngeal nerve, care must be taken to minimize the risk of injury. A transthoracic (Ivor-Lewis) approach is the most commonly used method, consisting of a right thoracotomy and a laparotomy. This approach allows good access to middle and distal esophageal lesions. The transhiatal approach allows for a more thorough dissection of the paraesophageal lymph nodes owing to better visualization. A disadvantage of this approach is that there is a potential for an anastomotic leak into the thorax or a thoracic duct leak, either of which can be significant complications. The McKeown or “3-field” esophagectomy consists of all 3 incisions (cervical, right thoracotomy, and laparotomy) and has resulted in similar outcomes compared with the other approaches. Recent advances in technology have also allowed for the adoption of minimally invasive techniques that consist of a combination of laparoscopic, thorascopic, and robotic approaches. Early series examining minimally invasive esophagectomy have demonstrated excellent clinical outcomes.
In patients undergoing esophagectomy, there are data suggesting that an increased lymph node harvest during surgery improves treatment outcomes. Greenstein and colleagues retrospectively reviewed a cohort of 972 patients and found a stepwise increase in 5-year disease-specific survival with increasing lymph nodes dissected; 55% with less than 11, 66% with 11 to 17, and 75% with 18 or more. Other series have also demonstrated an association between number of lymph nodes removed and treatment outcomes. Current guidelines suggest at least 15 lymph nodes dissected at the time of esophagectomy, and the location of these lymph nodes varies by tumor site. Upper and middle esophageal lesions typically require a dissection of the lymph nodes in the surrounding adventitia, whereas distal esophageal lesions require a dissection of paraesophageal nodes along the paracardiac and gastrohepatic ligament and along the left gastric artery.
Surgical resection margin status is a key driver of tumor recurrence, and safely obtaining negative margins is crucial when planning surgery. In concept, there are 3 margins that must be assessed at the time of surgery, the proximal tumor margin, the distal tumor margin, and the circumferential tumor margin. The proximal and distal tumor margins should generally be at least 4 to 5 cm and the circumferential tumor margin should be 1 mm or greater. A recent metaanalysis of 14 studies found significantly higher mortality rates in patients with positive circumferential resection margins and found a survival advantage with a resection margin of more than 1 mm.
Esophagectomy continues to be one of the most morbid procedures in oncology, although mortality rates have improved from 10% in the 1970s to 3% in the 1990s. Data has suggested that high-volume centers having significantly improved treatment outcomes. A recent metaanalysis demonstrated that overall mortality is decreased in treatment centers performing a high number of esophagectomy cases. Patients who will undergo an esophagectomy should be referred to a high-volume center owing to improved outcomes.
Systemic Therapy
Systemic therapy plays an important role in the management of patients with both localized and metastatic disease. Although surgical resection alone may be an acceptable treatment approach for patients with early stage (Tis or T1) esophageal cancer, patients with locally advanced disease generally require multimodality therapy. The dual role of cytotoxic chemotherapy is to sterilize micrometastatic disease owing to the high rates of distant failure as well as to potentiate the effectiveness of radiotherapy in patients receiving chemoradiation. In the landmark Herskovic study, patients randomized to chemotherapy and radiation had a significant survival advantage of 12.5 months versus 8.9 months in the radiation alone arm.
Chemotherapy for metastatic esophageal and gastroesophageal cancers has evolved significantly over the past several decades. Whereas historical treatment approaches consisted of single agents, more recent treatment approaches involve at least doublets with improved overall survival with dual therapy. A large metaanalysis demonstrated a significant survival benefit with combination chemotherapy versus single-agent chemotherapy (hazard ratio, 0.82; 95% confidence interval, 0.74–0.90).
Recent advances have also allowed for the recognition of targetable mutations in the management of metastatic esophageal cancer. In particular, approximately 20% of esophageal cancers have overexpression of HER2, a transmembrane tyrosine kinase receptor. Trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2, has been found to improve overall survival in patients with metastatic HER-2–positive gastroesophageal junction or gastric adenocarcinoma. Other ongoing research efforts are examining targetable epidermal growth factor receptor, cMET, and other mutations in esophageal cancer.
Radiotherapy
Radiotherapy is part of the curative treatment approach in patients with locally advanced esophageal cancer. Radiotherapy can also be used for palliation in patients with metastatic disease. In patients with nonmetastatic disease, radiotherapy may be used in conjunction with chemotherapy as definitive treatment or preoperatively with chemotherapy before esophagectomy. In general, patients with nonmetastatic disease receiving radiotherapy should also receive systemic therapy owing to the poor outcomes in patients receiving radiation alone. In Radiation Therapy Oncology Group (RTOG) 85-01, there were no 5-year survivors after radiotherapy alone versus a 5-year survival of 27% after chemoradiation. Therefore, concurrent chemoradiation is the preferred treatment approach in patients receiving definitive treatment.
Multimodality therapy consisting of chemoradiation followed by surgery has been increasingly adopted in the management of esophageal cancer. There are 7 randomized trials that have examined preoperative chemoradiation versus surgical resection. The trials have demonstrated mixed results, with some series demonstrating a benefit from neoadjuvant therapy while others demonstrated no difference. Most recently, the landmark CROSS trial (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study) randomized 366 patients to neoadjuvant chemoradiation with carboplatin and paclitaxel or surgery alone. The results demonstrated a significant survival advantage in patients receiving trimodality therapy (median survival: 24 vs 49 months). Because this trial was well-powered, used modern surgery and chemotherapy, and treated a contemporary mix of patients, trimodality therapy consisting of chemoradiation followed by esophagectomy has become the preferred treatment option for patients with locally advanced esophageal cancer.
The role of surgery in patients with locally advanced esophageal cancer has also been tested with the theory that an organ preservation approach may result in similar outcomes without subjecting patients to surgical morbidity. Two trials conducted in Europe addressed the role for surgery after chemoradiation in squamous cell carcinoma patients. Stahl and colleagues randomized patients who had received induction chemotherapy to either definitive chemoradiation or chemoradiation followed by surgery. The Federation Francophone de Cancerologie Digestive randomized patients who responded to chemoradiation to either observation or surgery. Neither trial demonstrated a difference in overall survival, although there were higher rates of treatment-related mortality in the surgical arms. In patients with adenocarcinoma, pathologic complete response rates are substantially lower (23% vs 49% in the CROSS trial) and, therefore, the risk of persistent disease is much greater. Given the decline in surgical morbidity and mortality, trimodality therapy remains a commonly used strategy.
Another investigational approach is reservation of surgery as a salvage option, in an effort to better select those patients who will benefit from surgery. RTOG 0246 tested chemoradiation consisting of induction 5-fluoracil (5-FU), cisplatin, and paclitaxel, followed by concurrent chemoradiation with 50.4 Gy and 5-FU, and cisplatin with surgical salvage for patients with residual or recurrent disease without systemic disease. The 1-year survival (71%) did not achieve the trial’s prespecified endpoint of 1-year survival of 77.5%, although this may have owing to the higher than expected neoadjuvant treatment-related mortality.
Because persistent or recurrent local disease is still relatively common after definitive chemoradiation, dose-escalated radiotherapy has been tested to examine whether local control and survival can be improved with an increasing dose to the tumor volume. In the Intergroup 0123 trial, patients were randomized to either 64.8 Gy or 50.4 Gy with concurrent cisplatin and 5-FU. There was no difference in overall survival (13 months vs 18.1 months) or locoregional failure (56% vs 52%) with high-dose radiation. Another attempt at dose escalation was via a brachytherapy boost in RTOG 9207, where patients received concurrent chemoradiation followed by intraluminal brachytherapy along with concurrent 5-FU. Unfortunately, owing to a high rate of treatment-related morbidity, this technique is not recommended typically.
In patients diagnosed with cervical esophageal cancer, the surgery required to remove the tumor adequately is comprehensive and can lead to significant morbidity and mortality. As a result, the tumor is commonly treated similarly to a primary head and neck cancer with definitive chemoradiation being the treatment modality of choice. Definitive chemoradiation allows for organ preservation while resulting in similar treatment efficacy. Unfortunately, there are relatively few data in this realm. In a series of 34 patients treated with concurrent chemoradiation with cisplatin and 5-FU, the local control rate was 88%, although 2 patients died from treatment-related toxicity. Similar outcomes have been demonstrated by other institutions, although higher doses were used in these series.
Although radiotherapy is an effective treatment modality, dose delivery to surrounding structures can lead to a significant risk for toxicity. Over the past decade, there have been significant technological advances in the realm of radiotherapy that allow for image-guided radiotherapy and intensity-modulated radiotherapy. Image-guided radiotherapy integrates imaging to allow for anatomic visualization of the tumor and surrounding structures to improve the accuracy and precision of radiation delivery. The use of 4-dimensional planning also allows for more accurate target delineation by creating an internal target volume that accounts for respiratory motion and allows for more conformal treatment planning volumes. Intensity-modulated radiotherapy consists of modulating the intensity of each radiation beam to improve target volume coverage while minimizing dose to organs at risk ( Fig. 5 ). Several series have suggested that intensity-modulated radiotherapy is safe and effective and will likely be increasingly adopted in the coming years. Similarly, proton therapy has the theoretic advantage of further improving dose distribution owing with a sharp dose falloff provided that clinical trials demonstrate either improved overall survival or reduced toxicity. As a result, proton therapy may allow for a further decrease in the dose to the surrounding structures. Additional data are necessary to establish the efficacy and toxicity benefit of proton therapy treatment for esophageal cancer.
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