Introduction
Background
Esophageal carcinoma was well described at the beginning of the 19th century, and the first successful resection was performed in 1913 by Frank Torek.1 In the 1930s, Ohsawa2 in Japan and Marshall3 in the United States were the first to perform successful 1-stage transthoracic esophagectomies with continent reconstruction.
Endoscopy demonstrating intraluminal esophageal c...
Endoscopy demonstrating intraluminal esophageal cancer.
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Endoscopy demonstrating intraluminal esophageal c...
Endoscopy demonstrating intraluminal esophageal cancer.
Pathophysiology
Esophageal carcinoma arises in the mucosa. Subsequently, it tends to invade the submucosa and the muscular layer and, eventually, contiguous structures such as the tracheobronchial tree, the aorta, or the recurrent laryngeal nerve. The tumor also tends to metastasize to the periesophageal lymph nodes and, eventually, to the liver, lungs, or both.
The image below shows the staging of the disease based on tumor invasion of the esophageal wall (T), involvement of lymph nodes (N), and the presence of metastases (M). Unfortunately, by the time the first symptoms manifest, the cancer has already spread to lymph nodes (mediastinal, cervical, celiac) in most patients.
TNM staging of esophageal cancer.
TNM staging of esophageal cancer.
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TNM staging of esophageal cancer.
TNM staging of esophageal cancer.
Frequency
United States
In the United States in 2008, the American Cancer Society estimates that there will be 16,470 new cases (12,970 men and 3,500 women) of esophageal cancer diagnosed; 14,280 persons (11,250 men and 3,030 women) are expected to die of the disease. Adenocarcinoma of the esophagus has the fastest growing incidence rate of all cancers in the United States. The incidence of esophageal carcinoma is approximately 3-6 cases per 100,000 persons, although certain endemic areas appear to have higher per-capita rates. The age-adjusted incidence is 5.8 cases per 100,000 persons.
The epidemiology of esophageal carcinoma has changed markedly over the past several decades in the United States. Until the 1970s, squamous cell carcinoma was the most common type of esophageal cancer (90-95%). It was located in the thoracic esophagus and affected mostly African American men who had a long history of smoking and alcohol consumption. Over the last 2 decades, the incidence of adenocarcinoma of the distal esophagus and gastroesophageal junction has progressively increased. Currently, it accounts for more than 50% of all new cases of esophageal cancer. Unlike squamous cell carcinoma, it affects mostly white men, and its pathogenesis is linked to gastroesophageal reflux disease (GERD) and the development of Barrett epithelium (see the image below).
Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
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Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
Cigarette smoking and alcohol may cause esophageal cancer and the two may act synergistically in this regard. A high-fat diet and obesity may increase the risk of esophageal cancer. Other risk factors include achalasia and Plummer-Vinson syndrome.
See related CME at Excess Body Weight Increases Risk for Many Cancers.
International
Esophageal cancer is the seventh leading cause of cancer death worldwide. Incidence of esophageal carcinoma can be as high as 30-800 cases per 100,000 persons in particular areas of northern Iran, some areas of southern Russia, and northern China. Unlike in the United States, squamous cell carcinoma is responsible for 95% of all esophageal cancers worldwide.
Race
In the United States, African-Americans have a higher incidence of esophageal cancer than whites.
Sex
Esophageal cancer is generally more common in men than in women, with a male-to-female ratio of 3-4:1.
Age
Esophageal cancer occurs most commonly during the sixth and seventh decades of life. The disease becomes more common with advancing age; it is about 20 times more common in those older than 65 years than in persons younger than 65 years.
Clinical
History
* Dysphagia is the most common presenting symptom.
o Dysphagia is initially experienced for solids, but eventually it progresses to include liquids.
o A complaint of dysphagia in an adult should always prompt an endoscopy to help rule out the presence of esophageal cancer. A barium swallow study is also indicated.
* Weight loss is the second most common symptom and occurs in more than 50% of people with esophageal carcinoma. Patients may experience bleeding.
* Pain can be felt in the epigastric or retrosternal area. It can also be felt over bony structures, representing a sign of metastatic disease.
* Hoarseness caused by invasion of the recurrent laryngeal nerve is a sign of unresectability. Patients may have a persisting cough.
* Respiratory symptoms can be caused by aspiration of undigested food or by direct invasion of the tracheobronchial tree by the tumor. The latter is also a sign of unresectability.
Physical
* The goals of the workup are to establish the diagnosis and to stage the cancer.
* The examination findings are often normal. Hepatomegaly may result from hepatic metastases.
* Lymphadenopathy in the laterocervical or supraclavicular areas represents metastasis and, if confirmed by needle aspiration or biopsy findings, is a contraindication to surgery.
Causes
* The etiology of esophageal carcinoma is thought to be related to exposure of the esophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia to carcinoma in situ to carcinoma.
* Vitamin or nutritional deficiencies have been recognized as contributing factors. In a high-risk country such as China, deficiencies in vitamin or microelement levels may play a role in causation. Riboflavin deficiency in China may contribute to a high incidence of esophageal cancer.
* In Western cultures, retrospective evidence has implicated cigarette smoking and chronic alcohol exposure as the most common etiological factors for squamous cell carcinoma. In the Netherlands Cohort Study, Steevens et al explored this association prospectively in 120,852 participants. Among participants who drank ≥ 30 g ethanol daily, the multivariable adjusted incidence rate ratio (RR) for esophageal squamous cell carcinoma was 4.61 (95% confidence interval [CI], 2.24-9.50) compared with abstainers. The RR for current smokers who consumed >15 g/d of ethanol was 8.05 (95% CI, 3.89-16.60) when compared with never smokers who consumed <5 g/d of ethanol. No associations were found between alcohol consumption and esophageal adenocarcinoma. In contrast, the risk of esophageal squamous cell carcinoma and esophageal adenocarcinoma was increased among current smokers.4
* Human papillomavirus infection has been recognized as a contributing factor. Helicobacter pylori infection has not been found to be associated with esophageal cancer.
* Tylosis palmaris et plantaris is also implicated in esophageal cancer.
* Gastroesophageal reflux disease (GERD) is the most common predisposing factor for adenocarcinoma of the esophagus.
o As a consequence of the irritation caused by the reflux of acid and bile, 10-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium.
o Adenocarcinoma may develop in these patients, representing the last event of a sequence that starts with the development of GERD and progresses to (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma (see the image below).
o
Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
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Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
o In 1952, Morson and Belcher first described a patient with adenocarcinoma of the esophagus arising in a columnar epithelium with goblet cells.5 In 1975, Naef et al emphasized the malignant potential of Barrett esophagus.6 With the premalignant nature of Barrett esophagus well established, many investigators have searched for markers of esophageal carcinoma that could facilitate earlier diagnosis and follow-up of tumor recurrence.
o The risk of adenocarcinoma among patients with Barrett metaplasia has been estimated to be 30-60 times that of the general population.
o The prognosis of esophageal cancer is still poor, as these cancers are found late.
+ However, a better understanding of the molecular progression of Barrett metaplasia to dysplasia to adenocarcinoma sequence may improve the prognosis. Tilanus et al reviewed data from the published literature to address the molecular changes in the pathogenesis of Barrett esophagus-associated neoplastic lesions. He found that the progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure.7 The oncosuppressor gene TP53 and various oncogenes, particularly erb -b2, have been studied as potential markers.
+ Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.8 In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes. However, the exact sequence of events in the progression of Barrett esophagus to adenocarcinoma is not known. Probably multiple molecular pathways interact and are involved.
o A nationwide population-based case-control study performed in Sweden found an odds ratio of 7.7 (95% confidence interval, 5.3-11.4) for adenocarcinoma among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, and an odds ratio of 43.5 (95% confidence interval, 18.3-103.5) among patients with long-standing and severe symptoms of reflux.
* A large cohort study examined whether use of oral bisphosphonates was associated with an increased risk of esophageal or gastric cancers. No significant difference was observed for increased risk of esophageal or gastric cancers between the bisphosphonate cohort and the control group.Differential Diagnoses
Achalasia
Esophageal Stricture
Gastric Cancer
Other Problems to Be Considered
Peptic strictures due to reflux
Benign esophageal tumors
Workup
Laboratory Studies
* Complete blood cell count may demonstrate anemia secondary to iron deficiency or chronic disease.
* Findings from a chemistry 18 panel may demonstrate liver function abnormalities due to ingestion of alcohol or may reflect hepatic metastases. Patients with squamous cell carcinomas may demonstrate hypercalcemia.
* Prothrombin time and activated partial thromboplastin time coagulation study findings may demonstrate hepatic insufficiency or nutritional deficiencies and are part of preoperative screening.
Imaging Studies
* Barium swallow is very sensitive for helping detect strictures (see the first image below) and intraluminal masses (see the second image below).
*
Barium swallow demonstrating stricture due to can...
Barium swallow demonstrating stricture due to cancer.
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Barium swallow demonstrating stricture due to can...
Barium swallow demonstrating stricture due to cancer.
*
Barium swallow demonstrating an endoluminal mass ...
Barium swallow demonstrating an endoluminal mass in the mid esophagus.
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Barium swallow demonstrating an endoluminal mass ...
Barium swallow demonstrating an endoluminal mass in the mid esophagus.
* Performing esophagogastroduodenoscopy allows direct visualization and biopsies of the tumor (see the image below).
*
Endoscopy demonstrating intraluminal esophageal c...
Endoscopy demonstrating intraluminal esophageal cancer.
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Endoscopy demonstrating intraluminal esophageal c...
Endoscopy demonstrating intraluminal esophageal cancer.
* Endoscopic ultrasound is the most sensitive test to help determine the depth of penetration of the tumor (T staging) and the presence of enlarged periesophageal lymph nodes (N staging).
* Abdominal and chest CT scans are useful to help exclude the presence of metastases (M staging) to the lungs and liver and may be useful to help determine if adjacent structures have been invaded (see the image below).
*
Chest CT scan showing invasion of the trachea by ...
Chest CT scan showing invasion of the trachea by esophageal cancer.
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Chest CT scan showing invasion of the trachea by ...
Chest CT scan showing invasion of the trachea by esophageal cancer.
* Bronchoscopy is indicated for cancers of the middle and upper third of the thoracic esophagus to help exclude invasion of the trachea or bronchi.
* Bone scan is indicated in patients with complaints suggestive of bone metastases.
* Laparoscopy and thoracoscopy have a greater than 92% accuracy in staging regional nodes.
* A new modality for staging is positron emission tomography scanning, which can help elucidate hypermetabolic foci of disease activity. It may be particularly useful in detecting lymph node metastases and bone spread.Treatment
Medical Care
Nonoperative therapy is usually reserved for patients who have esophageal carcinoma and are not candidates for surgery. The goal of therapy for these patients is palliation of dysphagia, allowing them to eat. A single best method of palliation cannot be applied to every situation. Most patients require more than one palliative method to sustain lumen patency during the course of their disease.
* The most appropriate method to control dysphagia should be tailored 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:
o Chemotherapy as a single modality has limited use. Only a few patients achieve a modest and short-lived response.
o 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, Herskovich and colleagues reported a 2-year survival rate of 38%, with a median survival of 12.5 months.10 See the practice guideline Combined Modality Radiotherapy and Chemotherapy in Nonsurgical Management of Localized Carcinoma of the Esophagus.11
o Laser therapy (Nd:YAG laser) can help achieve temporary relief of dysphagia in as many as 70% of patients. Multiple sessions are usually required to keep the esophageal lumen patent.
o Patients may be intubated with expandable metallic stents, which can be deployed by endoscopy under fluoroscopic guidance and can keep the esophageal lumen patent. They are particularly useful when a tracheoesophageal fistula is present.
o In 2006, a Cochrane review tried to assess the effectiveness of chemotherapy versus best supportive care or different chemotherapy regimens against each other, in metastatic esophageal carcinoma. The authors found that there was no consistent benefit of any specific chemotherapy regimen.12 Chemotherapy agents with promising response rates and tolerable toxicity are cisplatin, 5-fluorouracil (5-FU), paclitaxel, and anthracyclines. Future trials comparing palliative treatment modalities should assess quality of life with validated quality of life measures.
* Photodynamic therapy (PDT) offers an interesting nonsurgical form of therapy.
o PDT refers to the administration of photosensitizing chromophores, which are selectively retained by dysplastic malignant tissue. Light is delivered in the area where the photons are absorbed by the photosensitizer. The photosensitizer becomes photoexcited and transfers its energy to a chemical substrate that causes biologic damage to the abnormal tissue.
o Recent studies have demonstrated that PDT alone or with Nd:YAG laser thermal ablation combined with long-term acid inhibition provides an effective endoscopic therapy to (1) eliminate Barrett mucosal dysplasia and superficial esophageal cancer and (2) reduce the extent of and, in some cases, eliminate Barrett mucosa. A drawback of PDT is the formation of esophageal strictures in 34% of patients. Therefore, even though the initial results are encouraging, this form of treatment is still considered experimental.
See related CME at Highlights in Head and Neck Cancer.
Surgical Care
Esophageal resection (esophagectomy) remains a crucial part of the treatment of esophageal cancer. It is used in patients who are considered candidates for surgery. It no longer is used for palliation of symptoms because other treatment modalities are now available for relieving dysphagia (see Medical Care). 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 be a prolonged cause of discomfort and can further aggravate the condition of patients with compromised respiratory function.
o After removal of the esophagus, continuity of the gastrointestinal tract is usually reestablished using the stomach.
o 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 compared to TTE. However, many retrospective and 2 prospective studies have shown no difference in survival between the operations, suggesting that the type of operation is not the factor influencing survival but, rather, the stage of the cancer at the time the operation is performed.
o The morbidity associated with the operation is due mostly to cardiac, respiratory, and septic complications. As with other complex operations (eg, cardiac operations, resection of the pancreas or liver), a low mortality rate is achieved in centers with personnel who have more clinical experience (ie, those in high-volume centers). The better results (as compared to low-volume centers) are due to a team approach, during which expert surgeons work with intensivists, cardiologists, pulmonologists, radiologists, and nurses who have experience and expertise. For instance, in California from 1990-1994, only 5 centers had a mortality rate of 5% or less for esophageal resection for cancer, while the average mortality rate in the state was approximately 18%.
* Relevant anatomy includes the following:
o The esophagus is a muscular tube that extends from the level of the 7th cervical vertebra to the 11th thoracic vertebra. The esophagus can be divided into 3 anatomic parts: the cervical esophagus, the thoracic esophagus, and the abdominal esophagus.
o The blood supply of the cervical esophagus is derived from the inferior thyroid artery, while the blood supply for the thoracic esophagus comes from the bronchial arteries and the aorta. The abdominal esophagus is supplied by branches of the left gastric artery and inferior phrenic artery.
o Venous drainage of the cervical esophagus is through the inferior thyroid vein, while the thoracic esophagus drains via the azygous vein, the hemiazygous vein, or the bronchial veins. The abdominal esophagus drains through the coronary vein.
o The esophagus is characterized by a rich network of lymphatic channels in the submucosa that can facilitate the longitudinal spread of neoplastic cells along the esophageal wall. Lymphatic drainage is to cervical nodes, tracheobronchial and mediastinal nodes, and gastric and celiac nodes.
* Indications for surgery include the following:
o Diagnosis of esophageal cancer must be made in a patient who is a candidate for surgery.
o Surgery is indicated when high-grade dysplasia is present in a patient with Barrett esophagus. As many as 50-70% of such patients are found to have cancer when the esophagus is resected.
* Contraindications to surgery include the following:
o Metastasis to N2 nodes (ie, celiac, cervical, or supraclavicular lymph nodes) or solid organs (eg, liver, lungs) is a contraindication.
o Invasion of adjacent structures (eg, recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium) is a contraindication.
o Severe associated comorbid conditions (eg, cardiovascular disease, respiratory disease) can decrease a patient's chances of surviving an esophageal resection.
o Cardiac function and respiratory function are 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.
* TTE involves the following:
o 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.
o 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.
o 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.
o 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.
o 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.
o 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.
* THE involves the following:
o Preoperative details are similar to those of TTE, with the exception of a single rather than a double-lumen endotracheal tube. The neck is prepared in the operative field.
o 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.
o 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.
o 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.
o 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.
* Advantages of minimally invasive surgery include the following:
o The use of laparoscopic or thoracoscopic techniques has revolutionized the treatment of benign esophageal disorders such as achalasia and GERD.
o When compared to open surgery, the hospital stay is shorter, the postoperative discomfort is reduced, and the recovery time is much faster. In the near future, these techniques might find a place in the treatment of esophageal cancer, reducing the morbidity due to cardiac and respiratory complications.Follow-up
Further Inpatient Care
* The average length of postoperative hospital stay 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.
o If no leak is present, patients start oral feedings.
o 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.
Further Outpatient Care
* 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.
Complications
* Complications occur in approximately 40% of patients.
* 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, and pneumonia.
* Anastomotic stricture may require dilatation (20%).
* The mortality rate depends on the functional status of the patient and the experience of the surgeon and the team taking care of the patient. A mortality rate of less than 5% should be the goal for esophagectomy for cancer. With rare exceptions, this mortality rate is usually achieved only in tertiary care centers.
* An intrathoracic leak following esophagectomy is a known tragic complication of the procedure that can lead to sepsis and death. A retrospective review of 1223 esophagectomies for cancer showed that modern surgical management of intrathoracic leaks results in no increased mortality and has no impact on long-term survival.
Prognosis
* Survival depends on the stage of the disease. Lymph node metastases or solid organ metastases are associated with low survival rates.
* A recent report of 1085 patients who underwent THE for cancer showed that the operation was associated with a 4% operative mortality rate and a 23% 5-year survival rate. A subgroup of patients with a better 5-year survival rate (48%) was identified. These patients received preoperative radiation and chemotherapy (ie, neoadjuvant therapy), with complete response (ie, disappearance of the tumor).
* The overall 5-year survival rate for esophageal cancer remains approximately 20-25% for all stages.
o Patients without lymph node involvement have a significantly better prognosis and 5-year survival rate compared to patients with involved lymph nodes.
o Stage IV lesions are associated with a 5-year survival rate of less than 5% (see the image below).
o
TNM staging of esophageal cancer.
TNM staging of esophageal cancer.
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TNM staging of esophageal cancer.
TNM staging of esophageal cancer.
* THE and TTE have equivalent survival rates.
* Squamous cell carcinoma and adenocarcinoma, stage-by-stage, have equivalent survival rates.
Patient Education
For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article, Cancer of the Esophagus.
Miscellaneous
Special Concerns
* Because most patients undergo surgery when lymph node metastases are already present, the 5-year survival rate for this disease remains quite low. Chemotherapy and radiotherapy (alone or in combination) have been used before or after surgery in the attempt to improve survival.
o The aims of preoperative (neoadjuvant) chemotherapy 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. Note that chemotherapy concurrently administered with radiotherapy has demonstrated a pathologic response rate of as high as 30% but has been associated with increased operative morbidity and mortality. While chemotherapeutic management of squamous cell malignancies is generally based on cisplatin use, the chemotherapeutic choices in esophageal adenocarcinoma have been extrapolated from the chemotherapy experience in patients with adenocarcinoma of the stomach.
o No completely satisfactory method is available to clinically stage esophageal cancer. The difficulty of clinically assessing the disease is reflected by the American Joint Committee staging system.
+ The 1983 staging system was based on the length of the intraluminal esophageal tumor, the presence of esophageal obstruction, and the involvement of palpable lymph nodes. This clinical staging system proved to be limited.
+ The 1988 revision now defines a clinical and pathologic staging system based entirely on the depth of esophageal wall invasion and the presence or absence of local nodal involvement. Neither of these parameters is assessed easily on a clinical basis.
+ To help overcome these problems Hofstatter proposed recently a modification of the American Joint Committee on Cancer (AJCC) nodal classification system to incorporate the number of involved lymph nodes with regional and nonregional node location. This seems to simplify and better predict long-term survival than does the current AJCC nodal system.
o Conventional staging tools such as esophagoscopy or barium esophagogram can demonstrate only intraluminal disease extent, and CT scan of the chest is relatively insensitive, except for the presence of extensive local disease. Esophageal ultrasound allows the visualization of both the esophageal wall and local lymph nodes. As such, it allows a clinical determination of both T and N stage in most patients.
o Previous reports of induction chemotherapy in esophageal cancer often are difficult to interpret because of varying definitions of response (eg, symptomatic improvement, decrease in tumor length after barium esophagram, subjective determination of improvement at endoscopy or CT scan). Even the complete response, often defined as endoscopic biopsies or cytologies with negative findings, is hampered by the inability to assess the true extent of the transmural disease. Not surprisingly, reported responses are quite variable, ranging from 20-65%, with clinical complete responses in as many as 40% of patients.
* Neoadjuvant therapy consists of a combination of radiotherapy (approximately 45 Gy) and chemotherapy (cisplatin and 5-fluorouracil).
o 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 and is followed by esophageal resection after an interval of approximately 4 weeks.
o The results of many studies suggest that approximately 15-20% of patients have a complete response to therapy because no tumor is found in the specimen by the pathologists; these patients have a definite improvement in survival. The remaining patients, in whom a partial response or no response has occurred, have no benefit.
+ A randomized trial conducted by Urba that compared preoperative chemoradiation (ie, cisplatin, fluorouracil, and vinblastine) versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.
+ Walsh conducted a prospective randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery and reported that patients who received induction chemotherapy (ie, 2 courses of cisplatin and fluorouracil, 1 course of radiotherapy at 40 Gy) followed by surgery had improved survival compared to those who had surgery alone. Of the patients who underwent surgery after multimodal therapy, 25% had complete responses as determined pathologically. Their median survival was 16 months, as compared with 11 months for those assigned to surgery alone. The survival advantage was even more evident at 3 years (32% vs 6%, P = .01).13
+ Bosset treated patients with induction chemoradiotherapy (ie, cisplatin and 18.5 Gy) and surgery and with surgery alone, reporting that in patients with squamous cell carcinoma of the esophagus, preoperative chemoradiotherapy did not improve overall survival, but it did prolong disease-free survival and survival deemed free of local disease.14
+ Herskovic reported that combined therapy increased the survival of patients with squamous cell carcinoma or adenocarcinoma of the esophagus, stages T1-3 N0-1 M0, compared with radiotherapy alone.10
+ A recent meta-analysis of randomized trial data identified 10 randomized comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and 8 trials of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable esophageal carcinoma. The authors found that the hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumor types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those withadenocarcinoma(0.78[0.64-0.95]; p=0.014). The authors concluded that significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the esophagus.
o The goal for the future is to identify patients who are likely to benefit from neoadjuvant therapy.
* Adjuvant therapy does not appear to improve survival. No survival benefit is obtained when radiation and chemotherapy are administered postoperatively.
* GERD may lead to esophageal cancer.
o Because most esophageal cancers today are adenocarcinomas that originated from Barrett esophagus, stopping the sequence of events leading from GERD to adenocarcinoma is now possible (see the image below).
o
Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
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Cascade of events that lead from gastroesophageal...
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
o Better control of gastroesophageal reflux can prevent the development of Barrett metaplasia in patients with GERD and the development of high-grade dysplasia in patients with metaplasia.
o Endoscopic follow-up evaluations should be performed at 1- to 2-year intervals to detect the presence of high-grade dysplasia, allowing intervention before cancer develops.
* Follow-up of patients with Barrett esophagus includes the following:
o For metaplasia, the common recommendation is to perform routine endoscopy every 12-24 months because no evidence suggests that either medical or surgical therapy can stop the progression to high-grade dysplasia and cancer. In addition, routine endoscopy can detect a tumor at an early stage, thereby increasing the possibility of a curative resection.
o For high-grade dysplasia, the protocol suggested by investigators at the University of Washington in Seattle proposes endoscopy every 3 months with jumbo forceps and 4-quadrant biopsy samples taken at 1-cm intervals. The rationale is to avoid esophagectomy in patients who will not progress to cancer, based on the belief that this protocol will identify carcinoma in situ before it becomes invasive with lymph node metastases. This protocol has 2 major problems, as follows:
+ The protocol can rarely be followed in the average clinical practice, that is, outside of tertiary care centers, because of poor patient compliance and reluctance by the gastroenterologists to perform such extensive biopsies. In addition, there is a risk of missing an in situ lesion. Once the tumor is invasive, lymph node metastases are common and the chance of cure is lost.
+ When an esophagectomy is performed for high-grade dysplasia detected using endoscopy, adenocarcinoma is found in approximately 40% of cases (range of 30-73%).
o Based on these considerations, the authors and others strongly recommend that esophagectomy be performed once high-grade dysplasia is detected. The operation must be performed by experienced surgeons in high-volume centers in order to keep the mortality rate at less than 5%.
