Esophageal Cancer Treatment & Management
- Author: Keith M Baldwin, DO; Chief Editor: N Joseph Espat, MD, MS, FACS more...
Treatment of esophageal cancer varies by disease stage. Patients with stage I disease—particularly Tis and T1aN0 by endoscopic ultrasonography (EUS)—may be considered for endoscopic therapy, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), performed at a center with experience in these techniques.
In patients with T1b and any N, surgery may be the initial treatment; however, patients with stages beyond T1b should undergo multidisciplinary evaluation and be considered for multimodality therapy.
Trimodality (chemoradiation followed by surgery) is the recommended treatment for patients who can tolerate this regimen; this option is supported by strong level 1 evidence.[37, 38, 39, 40, 41, 42] 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.
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.
Stage IV disease is treated with chemotherapy or symptomatic and supportive care, as indicated. For patients who, because of their clinical condition or owing to advanced disease, are not candidates for curative treatment, 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.
Surgical Indications and Contraindications
Surgery remains the cornerstone of treatment for esophageal cancer. Indications for surgery include the following:
Esophageal cancer in a patient who is a candidate for surgery
High-grade dysplasia in a patient with Barrett esophagus that cannot be adequately treated endoscopically [1, 2]
Contraindications to surgery include the following:
Metastasis to N2 nodes (ie, cervical or supraclavicular lymph nodes) or solid organs (eg, liver, lungs); the treatment of patients with celiac lymph node involvement remains controversial 
Invasion of adjacent structures (eg, the recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium)
In addition, the presence of severe, associated comorbid conditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection. Consequently, cardiac and respiratory function must be carefully evaluated preoperatively. A forced expiratory volume in 1 second of less than 1.2 L and a left ventricular ejection fraction of less than 0.4 are relative contraindications to the operation.
Esophageal resection (esophagectomy) remains a critical component of multimodality therapy for patients with tumors of any stage. Endoscopic mucosal resection is an experimental approach to patients with T1a disease or high-grade dysplasia that is limited to certain centers and performed only under protocol. Esophagectomy is no longer is used for palliation of symptoms because other treatment modalities have become available for relieving dysphagia.
An esophagectomy can be performed by using an abdominal and a cervical incision with blunt mediastinal dissection through the esophageal hiatus (ie, transhiatal esophagectomy [THE]) or by using an abdominal and a right thoracic incision (ie, transthoracic esophagectomy [TTE]).
THE offers the advantage of avoiding a chest incision, which can cause prolonged discomfort and can further aggravate the condition of patients with compromised respiratory function. After removal of the esophagus, continuity of the gastrointestinal tract is usually reestablished using the stomach.
Some authors have questioned the validity of THE as a cancer operation because part of the operation is not performed under direct vision and fewer lymph nodes are removed than with TTE. However, many retrospective studies and 2 prospective ones have shown no difference in survival between the operations, suggesting that the factor influencing survival is not the type of operation but, rather, the stage of the cancer at the time the operation is performed.[24, 25, 45, 46, 47, 48]
Morbidity and mortality
Complications from esophagectomy occur in approximately 40% of patients. The morbidity associated with the surgery consists mostly of respiratory, cardiac, and septic complications, including the following:
Respiratory complications (15-20%) - Include atelectasis, pleural effusion, and pneumonia
Cardiac complications (15-20%) - Include cardiac arrhythmias and myocardial infarction
Septic complications (10%) - Include wound infection, anastomotic leak (breakdown of the new connection between the stomach and esophagus), and pneumonia
Anastomotic leaks and stricture may require dilatation (20%). Leaks may be treated with endoscopic placement of self-expanding, removable plastic stents.
Leak rates vary depending on whether the anastomosis was performed in the chest (3-12%) or the neck (10-25%). The choice of location for the anastomosis is based mostly on the location of the tumor and the surgeon’s assessment of the risks and benefits of a thoracic anastomosis. Such anastomoses have a lower leak rate, but an intrathoracic leak following esophagectomy can lead to sepsis and death.
A retrospective review of 1223 esophagectomies for cancer found that surgical management of intrathoracic leaks did not increase the patient mortality rate or effect long-term survival.
As with other complex operations (eg, cardiac operations, resection of the pancreas or liver), the lowest mortality rate with esophagectomy is achieved when the procedure is performed in high-volume centers by high-volume surgeons. In California from 1990-1994, for instance, 5 high-volume centers had a mortality rate of 5% or less for esophageal resection for cancer, while the state’s average mortality rate for this surgery was approximately 18%.
The better results in high-volume centers are due to a team approach. In these facilities, expert surgeons work with intensivists, cardiologists, pulmonologists, radiologists, and nurses who have experience and expertise.
For TTE, the patient is placed supine on the operating room table. An arterial line, a central venous catheter, a Foley catheter, and a dual-lumen endotracheal tube are placed. Preoperative antibiotics are administered. An upper midline incision is made.
After exploring the peritoneal cavity for metastatic disease (if metastases are found, the operation is not continued), the stomach is mobilized. The right gastric and the right gastroepiploic arteries are preserved, while the short gastric vessels and the left gastric artery are divided.
Next, the gastroesophageal junction is mobilized, and the esophageal hiatus is enlarged. A pyloromyotomy is performed, and a feeding jejunostomy is placed for postoperative nutritional support.
After closure of the abdominal incision, the patient is repositioned in the left lateral decubitus position and a right posterolateral thoracotomy is performed in the fifth intercostal space.
The azygos vein is divided to allow full mobilization of the esophagus. The stomach is delivered into the chest through the hiatus and is then divided approximately 5 cm below the gastroesophageal junction.
An anastomosis (hand-sewn or stapled) is performed between the esophagus and the stomach at the apex of the right chest cavity. Then, the chest incision is closed.
For THE, the preoperative details are similar to those of TTE, except that a single-lumen, rather than a double-lumen, endotracheal tube is used. The neck is prepared in the operative field.
The abdominal part of the operation is identical to the TTE; however, dissection of the esophagus is performed through the enlarged esophageal hiatus without opening the right chest. The esophagus is mobilized in this fashion all the way to the thoracic inlet.
Then, a 6-cm incision is made in the left side of the neck. The internal jugular vein and carotid artery are retracted laterally, and the esophagus is identified and isolated posterior to the airway. To prevent injury to the left recurrent laryngeal nerve, no mechanical retractors are used to retract the trachea.
Next, after resection of the proximal stomach and thoracic esophagus, the remaining stomach is pulled up through the posterior mediastinum until it reaches the remaining esophagus at the cervical level. Then, a hand-sewn anastomosis is performed, and a small drain is placed in the neck alongside the anastomosis. The abdominal and neck incisions are closed. (See the image below.)
Minimally invasive surgery techniques in esophagectomy
The use of laparoscopic and thoracoscopic techniques has revolutionized the treatment of benign esophageal disorders such as achalasia and gastroesophageal reflux disease (GERD). Advantages of minimally invasive surgery include a shorter hospital stay, less postoperative discomfort, and much faster recovery time than with open surgery. These techniques are finding a place in the treatment of esophageal cancer.
Video-assisted thoracoscopy (VATS) is being used in many centers for the thoracic mobilization of the esophagus, reducing the size of the chest incision. In addition, laparoscopy can be used to mobilize the gastric conduit in the abdomen, reducing abdominal incision size as well.
A study by Uenosono et al found that sentinel node mapping can be applied to patients with clinical T1 and N0 esophageal cancer. Use of this technique may facilitate less invasive surgery, with reduction of lymphadenectomy.
Endoscopic mucosal resection (EMR) is a modern, attractive option for the treatment of superficial esophageal cancers. High-grade dysplasia and mucosa-limited neoplasms are candidates for EMR, because of the low risk of node metastasis in these cases. A population-based study of 1618 patients with grade Tis, T1a, or T1b esophageal cancer found that overall survival times and esophageal-cancer-specific survival times with endoscopic therapy were similar to those with surgery, after adjustment for patient and tumor factors.[54, 55]
Salvage endoscopic resection
In patients with local failure after definitive chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC), salvage endoscopic treatment (SET) may be a viable option, according to a study reported at the 2014 Gastrointestinal Cancers Symposium. The study included 716 ESCC patients treated with CRT, 417 of whom experienced local failure (incomplete response or local recurrence); of these 417 patients, 164 underwent SET (either photodynamic therapy or endoscopic resection).
Curative resection was achieved in 88% of the patients who underwent endoscopic resection, and a complete response was achieved in 57.5% of those who underwent photodynamic therapy. Overall survival and relapse-free survival rates at 5 years were 38.6% and 28%, respectively. The factors most strongly predictive of improved survival were (1) an absence of lymph node metastasis before CRT and (2) an elapsed time of 6 months or longer between the initiation of CRT and the performance of SET.
Chemotherapy and radiotherapy for esophageal cancer are delivered preoperatively. No survival benefit is obtained when radiation and chemotherapy are administered postoperatively; however, postoperative continuance of chemotherapy started preoperatively may be beneficial. The aims of preoperative (neoadjuvant) chemotherapy and radiotherapy are to reduce the bulk of the primary tumor before surgery to facilitate higher curative resection rates and to eliminate or delay the appearance of distant metastases.
Most chemotherapy that is currently used for the treatment of esophageal cancer, including alkylating, antimetabolite, anthracycline, and antimicrotubular agents, are not approved for this indication by the US Food and Drug Administration (FDA). Chemotherapy for squamous cell esophageal carcinoma, as with squamous cell carcinomas in general, is based on cisplatin, while chemotherapy for esophageal adenocarcinoma has been extrapolated from experience in patients with adenocarcinoma of the stomach.
Neoadjuvant chemotherapy alone appears to offer a limited benefit at best. A North American randomized trial found that preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with squamous cell cancer or adenocarcinoma of the esophagus. In a larger trial, British investigators found that preoperative chemotherapy with those 2 agents resulted in a 5-year survival rate of 23.0%, compared with 17.1% for surgery alone.
In contrast, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated considerable benefit from preoperative chemoradiation over surgery alone in selected patients with esophageal or esophagogastric-junction cancer (tumor stage T1N1 or T2–T3 with any N). Median overall survival with chemoradiation therapy followed by surgery was 49.4 months, compared with 24.0 months with surgery alone.
An analysis of data from CROSS I and II showed that preoperative chemoradiotherapy (CRT) plus surgery was superior to surgery alone in preventing local, regional, and distant recurrence, particularly hematogenous metastasis and peritoneal carcinomatosis.[60, 61, 62] Overall recurrence rates were 35% for CRT plus surgery and 58% for surgery alone. The rates of locoregional recurrence, peritoneal carcinomatosis, and hematogenous dissemination were all lower for the former as well (14% vs 34%, 4% vs 14%, and 29% vs 35%, respectively).
Neoadjuvant therapy consists of a combination of radiotherapy (approximately 45 Gy) and chemotherapy with cisplatin and 5-fluorouracil. While the radiotherapy acts locally at the tumor site, the chemotherapy acts on tumor cells that have already spread. This combination therapy is usually administered over a 45-day period; esophageal resection is performed after an interval of approximately 4 weeks.
Rohatgi et al reported that the response to preoperative chemoradiotherapy correlated strongly with overall survival and disease-free survival in patients with esophageal cancer. In their review of 235 cases, survival decreased progressively between patients who achieved a pathologic complete response, those who had a partial response (1-50% residual carcinoma in the resected specimen), and those with no response (greater than 50% residual carcinoma).
A study by Rao et al identified groups of esophageal tumors with distinct gene expression profiles, which in future may allow for tailored treatment protocols. Similarly, Alexander et al identified DNA-repair biomarkers that predict response to neoadjuvant chemotherapy.
A trial involving 111 patients undergoing chemoradiotherapy for head-and-neck or esophageal cancer indicated that enteral nutrition enriched with n-3 fatty acids helps to preserve body mass and improve nutritional and functional status parameters during chemoradiotherapy.[66, 67]
In patients who, because of their clinical condition or advanced disease, are not candidates for surgery, treatment focuses on control of dysphagia. The most appropriate method to control dysphagia should be determined for each patient individually, depending on tumor characteristics, patient preference, and the specific expertise of the physician.
The following treatment modalities are available to help achieve this goal:
Chemotherapy as a single modality has limited use. Only a few patients achieve a modest and short-lived response.
A phase 3 study from the United Kingdom suggests that docetaxel may be useful as a second-line treatment for patients with esophageal cancer who have progressed after first-line chemotherapy.[69, 70] Median overall survival was significantly better in patients treated with docetaxel than in those managed with active symptom control (5.2 versus 3.6 months, respectively).
Because survival in these patients is measured in months, quality of life is an important consideration. In the UK study, quality-of-life questionnaires demonstrated no differences between the 2 groups on global and functioning scores but did indicate an improvement in symptom scores, with the docetaxel group reporting less pain.[69, 70]
In 2006, a Cochrane review tried to assess the effectiveness of chemotherapy versus best supportive care, as well as that of different chemotherapy regimens against each other, in metastatic esophageal carcinoma. The authors found that no consistent benefit with any specific chemotherapy regimen. Cisplatin, 5-fluorouracil (5-FU), paclitaxel, and anthracyclines had promising response rates and tolerable toxicity.
Radiation therapy is successful in relieving dysphagia in approximately 50% of patients. In patients with advanced esophageal cancer, the preoperative combination of chemotherapy and radiotherapy has shown good results.
In a large, multicenter study, Herskovic and colleagues reported a 2-year survival rate of 38%, with a median survival period of 12.5 months, for patients treated with radiotherapy in combination with chemotherapy (fluorouracil and cisplatin), compared with a 2-year-survival rate of 10% and a median survival period of 8.5 months in patients treated with radiotherapy alone.[68, 72]
In a study, Folkert et al found that high-dose-rate (HDR) endoluminal brachytherapy was well tolerated in medically inoperable patients with superficial primary or recurrent esophageal cancer. Over the course of 3 years, 14 patients were treated with HDR intraluminal brachytherapy; 10 had recurrent esophageal cancer and 4 had previously unirradiated lesions. The overall freedom from failure (OFFF) and the overall survival (OS) rate at 18 months were 30.8% and 72.7%, respectively. Patients with recurrent disease had an 11.1% OFFF and a 55.6% OS rate at 18 months. For patients with previously unirradiated disease, the OFFF was 75% and the OS rate was 100%.
Laser therapy (Nd:YAG laser) can help to achieve temporary relief of dysphagia in as many as 70% of patients. Multiple sessions are usually required to keep the esophageal lumen patent. The photosensitizer porfimer (Photofrin) is FDA approved for palliation of patients with completely obstructing esophageal cancer or partially obstructing cancer that cannot be satisfactorily treated with Nd:YAG laser therapy. Intravenous injection of porfimer is followed 40–50 hours later with delivery of 630 nm wavelength laser light; a second laser light treatment may be given 96–120 hours after the injection.
Patients may be intubated with expandable metallic stents, which can be deployed by endoscopy under fluoroscopic guidance and can keep the esophageal lumen patent. Stents are particularly useful for patients with a tracheoesophageal fistula.
Postoperative Care and Follow-up
The average length of postoperative hospital stay for patients with esophageal cancer is 9-14 days. Patients usually spend the first postoperative night in the intensive care unit (ICU).
Patients can be extubated immediately after the operation, but mechanical ventilation should be continued if any concerns about the respiratory status are present. Respiratory complications (eg, atelectasis, pleural effusion, pneumonia) and cardiac complications (eg, cardiac arrhythmias) usually occur in the first postoperative days. Patients leave the ICU and are transferred to the surgical ward only when their respiratory status and cardiac status are satisfactory.
Feeding through the feeding jejunostomy begins on postoperative day 1. On postoperative day 6, a swallow study is performed to check for anastomotic leakage. If no leak is present, patients start oral feedings. If a leak is present, the drainage tubes are left in place and nutrition is provided entirely through the feeding jejunostomy until the leak closes spontaneously.
Approximately 85-90% of patients go home after discharge. The remaining patients may need additional time in a skilled nursing facility if they live alone and if they cannot take care of themselves.
Patients are seen by the responsible surgeon at 2 weeks and 4 weeks after discharge from the hospital and subsequently every 6 months by an oncologist. Most patients return to their regular level of activities within 2 months.
Prevention of Esophageal Cancer
For squamous cell carcinoma, prevention consists of smoking cessation, efforts to reduce alcohol abuse, and consumption of a diet containing an adequate amount of fruits, vegetables, and vitamins. For esophageal adenocarcinomas, prevention involves stopping the sequence of events leading from gastroesophageal reflux disease (GERD) to Barrett esophagus to adenocarcinoma.
Better control of gastroesophageal reflux can prevent the development of Barrett metaplasia in patients with GERD and can discourage the development of high-grade dysplasia in patients with metaplasia. Endoscopic follow-up evaluations should be performed at 1- to 2-year intervals to detect the presence of dysplasia, allowing intervention before cancer develops.
Dysplasia in Barrett esophagus can be treated with endoscopic ablation, using radiofrequency ablation (RFA), photodynamic therapy (PDT), or cryotherapy.
If high-grade dysplasia does develop, esophagectomy is indicated. The operation must be performed by experienced surgeons in high-volume centers in order to keep the mortality rate at less than 5%.
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%.
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.
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|Stage IV||Any T||Any N||M1|
|Stage IV||Any T||Any N||M1|