10: Overview of Esophageal and Proximal Stomach Malignancy

Esophageal cancer is the eighth most frequent cancer worldwide. It is the sixth most common cause of cancer death, accounting for 5.4% of all cancer deaths.¹ Although the annual incidence of esophageal cancer in the United States is 4.5 per 100,000, some of the highest incidences are found in Asia, with roughly 100 per 100,000 individuals affected in the Linxian Province of central China.^2,3 Esophageal cancer remains one of the most lethal of all malignancies, with incidence and mortality rates roughly equal. Once a diagnosis is established, the prognosis is dismal, with a 5-year survival rate of 17%.⁴ The results of single-modality treatment have been poor, with the exception of surgery for early esophageal cancer. More recently, neoadjuvant chemotherapy, radiotherapy, and combined chemoradiation therapy have been added as treatment modalities to enhance local control, increase resectability rates, and improve disease-free survival.⁵ The initial results of these multimodality treatments have been encouraging. Since management of esophageal cancer and survival of patients is stage dependent, accuracy of clinical staging is vital. An array of technologies such as CT, MRI, and PET of the esophagus, as well as endoscopic ultrasound (EUS) and minimally invasive thoracoscopic/laparoscopic staging (Ts/Ls), offer more reliable preoperative diagnosis and staging of patients with esophageal cancer. This may result in allocation of patients to stage-specific regimens with resulting improved cure rates.

The boundaries of the esophagus are the inferior cricopharyngeal constrictor proximally and the esophagogastric junction distally. The esophagus is composed of four layers: mucosa, submucosa or lamina propria, muscularis propria, and adventitia (Fig. 10-1). The esophagus has no serosa, providing a teleologic explanation for the ease of spread of esophageal cancer. Familiarity with the histology of the esophageal wall is critical to understanding the staging system of esophageal cancer (see also Chapters 11 and 12).

Anatomically, the normal adult esophagus is approximately 35 cm in length and 2.5 cm in diameter, although it is not uniform throughout its course. The course of the esophagus begins in the midline in the upper neck at the level of the sixth cervical vertebra, which corresponds roughly to the level of the cricoid cartilage, and then deviates to the left in the lower neck and upper thorax. At the level of the tracheal bifurcation (24 cm from the incisors by endoscopic measurement), the esophagus again returns to the midline only to deviate to the left once again in the lower thorax, where it enters the abdomen through the diaphragmatic hiatus (40 cm from the incisors). Clinically, the esophagus is divided into three segments, the cervical, middle, and distal segments. The cervical segment ranges from the cricoid cartilage to the thoracic inlet (10–18 cm from the incisors). The middle esophageal segment ranges from the thoracic inlet to the midpoint between the tracheal bifurcation and the esophagogastric junction (19–34 cm). The distal esophageal segment extends from the midpoint between the tracheal bifurcation and the esophagogastric junction (35–44 cm). Three distinct narrowings are present in the esophagus. The first narrowing is formed by the cricopharyngeus muscle and is the narrowest segment of the gastrointestinal tract, located 12 to 15 cm from the incisors in the adult. The second narrowing is caused by the tracheal bifurcation and aortic arch at approximately 24 to 26 cm from the incisors. The last narrowing is located at the lower esophageal sphincter, approximately 40 to 44 cm from the incisors.⁶

The arterial blood supply of the esophagus is segmental (Fig. 10-2). The upper esophagus is supplied by branches from the inferior thyroid and subclavian arteries. The midesophagus receives blood from the bronchial arteries and direct branches from the thoracic aorta. The lower esophagus is supplied by branches of the inferior phrenic and gastric vessels. Venous drainage of the esophagus is segmental as well. The upper esophagus drains via the inferior thyroid veins. The midesophagus drains into the bronchial and azygos or hemiazygos veins. The lower esophagus drains into the coronary vein. As with the arterial network, the rich plexus of veins in the submucosa makes venous congestion unlikely.

Lymphatic drainage of the esophagus consists of two longitudinal interconnecting networks, the lymph channels and the lymph nodes. The intraesophageal or mucosal network of lymph channels is connected to the submucosa through transverse interconnections (Fig. 10-3). These collecting lymph channels merge, forming larger channels that feed into the extraesophageal lymph nodes (Fig. 10-4). It is estimated that the longitudinal flow is significant, which also may explain the frequency of spread of tumor along lymphatics. Flow proceeds in either direction freely and can be influenced by intrathoracic pressure differences and/or obstruction of lymphatic channels. The typical drainage pattern, however, is as follows: Cervical lymphatics drain into the internal jugular and supraclavicular nodes, the midesophagus drains into the paraesophageal and periesophageal nodes in the mediastinum, and the inferior esophagus drains below the diaphragm to the region of the cardia, left gastric vessels, lesser curve of the stomach, and celiac axis.^7,8

Esophageal cancer is a disease primarily of men (male:female ratio, 3:1) that occurs in the sixth and seventh decades of life with a median age of 67 years. In the United States, the incidence is 4.5 per 100,000 population, whereas in China it may be as high as 140 per 100,000 population. In addition, Russia, Japan, Scotland, and the Scandinavian countries have a higher incidence than the United States or Western Europe. In the United States, the incidence of adenocarcinoma of the esophagus is increasing dramatically across all socioeconomic boundaries. The incidence of adenocarcinoma in White men is roughly three times that in Black men, whereas the incidence of squamous cell carcinoma of the esophagus is six times higher in Blacks. Esophageal cancer rates have been declining in African Americans, a consequence of a decreasing incidence of squamous cell carcinoma. Incidence of esophageal adenocarcinoma has been increasing by an alarming rate of just under 2% per year.⁹ The reason for this is largely unknown, although the worsening obesity epidemic may be partially responsible.¹⁰ Several environmental factors have been implicated in the etiology of this disease, but none has been proved scientifically. Tobacco has been shown to increase the risk of esophageal cancer approximately 10-fold, whereas alcohol abuse increases the risk from 20- to 50-fold. Furthermore, the combination of tobacco and alcohol use may increase the risk 100-fold. Adenocarcinoma has a stronger association with tobacco use, whereas squamous cell carcinoma is more closely linked to alcohol use. In addition, diets high in nitrosamines and foods contaminated with molds (Fusarium) and fungus (Geotrichum candidum) also have been implicated, as well as diets in which hot liquids are consumed. Nutritional deficiencies also have been implicated. Diets low in beta carotene, vitamins B and C, magnesium, and zinc all have been implicated. Environmental exposure to asbestos, perchloroethylene, and radiation also has been shown to contribute to increased incidence.¹¹

Several premalignant conditions have been shown to predispose to esophageal carcinoma. Achalasia causes esophageal irritation and is associated with a 5% to 10% incidence in squamous cell carcinoma over 15 to 25 years. This tumor tends to occur in younger individuals and carries a poor prognosis. Gastroesophageal reflux disease causing distal esophageal metaplasia (Barrett esophagus) appears to be related to the increased incidence of adenocarcinoma in White males. Patients with Barrett esophagus have an 11-fold risk of developing esophageal adenocarcinoma, with an annualized risk of 0.12%.¹² It is noteworthy that these patients also have a high incidence of hiatal hernia and duodenal ulcer disease. Finally, obesity now has been shown to increase the incidence of adenocarcinoma dramatically.¹⁰

The majority of esophageal carcinomas are either squamous cell carcinomas or adenocarcinomas. Squamous cell carcinoma most commonly arises in the midportion of the esophagus, whereas adenocarcinoma usually arises in the lower third, close to the esophagogastric junction. Although squamous cell carcinoma remains the dominant histology worldwide, the incidence of adenocarcinoma is rising dramatically in the West. There is a geographic heterogeneity in the distribution of these two histologic entities. In the United States, squamous cell carcinoma accounted for roughly 90% of esophageal cancers in the 1960s. However, recent data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database indicate that the incidence of adenocarcinoma actually has surpassed that of squamous cell carcinoma. Based on correlative data, this is unlikely to be the result of the reclassification of squamous cell carcinoma or adjacent gastric adenocarcinoma or as an overdiagnosis of adenocarcinoma. The importance of tumor histology and tumor grade is apparent with the advent of the new AJCC staging system (see Chapters 11 and 12).

Esophageal cancer often presents in an insidious and nonspecific manner, with indigestion, retrosternal discomfort, and transient dysphagia comprising the leading complaints. Often patients may present late because they have been able to compensate subconsciously for symptoms of dysphagia by eating softer foods or chewing their food more thoroughly. Dysphagia is the most commonly presenting symptom of esophageal carcinoma. It can progress to odynophagia and eventually to complete obstruction. Pain may be transient, associated with swallowing, or constant. It may be retrosternal or epigastric in location. Weight loss may be due to dietary changes, starvation, or tumor anorexia. Patients may experience regurgitation of undigested food, that is, food that has not been tainted with acidic gastric secretions. Patients also may develop respiratory sequelae primarily from aspiration but also from other causes such as direct invasion of tumor into the tracheobronchial tree or even a tracheoesophageal fistula, usually involving the left mainstem bronchus. Symptoms may include cough, dyspnea, and pleuritic pain. Hoarseness can result from direct involvement of the recurrent laryngeal nerve, a poor prognostic sign. Also, in advanced cases of near-complete or complete esophageal obstruction, patients may become severely dehydrated, even hypokalemic, because of their inability to swallow potassium-rich saliva.

The most commonly used diagnostic and staging modalities are the barium swallow study, chest radiography, esophagoscopy, bronchoscopy, CT, MRI, and EUS with fine-needle aspiration (FNA). Additional adjuncts include thoracoscopic and laparoscopic staging, and PET scan. Usually, the first diagnostic method is a barium swallow, followed by endoscopy with biopsy. After a histologic diagnosis of carcinoma is confirmed, a CT scan of the thorax and abdomen should be obtained for the purpose of staging, paying particular attention to tumor extension, lymphadenopathy, and distant metastases. In some countries, abdominal ultrasound is often performed instead of CT to diagnose liver or celiac lymphatic metastasis.

Chest radiography has a minimal role in the modern diagnosis and staging of esophageal cancer, although it can reveal an abnormal finding in almost half of the patients with esophageal cancer. However, in some countries it is still used routinely to identify hilar or mediastinal adenopathy, evidence of pulmonary metastases, secondary pulmonary infiltrates caused by aspiration, elevation of the bronchus by midesophageal tumors and pleural effusion.¹³ Bronchoscopy is often necessary to determine involvement of the tracheobronchial tree for patients with middle- and upper-third disease.^14,15 Gallium scanning can be useful for the detection of bony metastases but generally has been replaced by PET scan in the United States. Endoscopy remains the method of choice for the confirmation of esophageal cancer.¹⁶ Its ability to detect early lesions can be improved with the use of staining techniques and, more recently, narrow-band imaging.¹⁷

Although the role of CT in evaluating esophageal cancer has been studied thoroughly, questions regarding its utility still remain. Although CT is highly effective in the assessment of mediastinal esophageal carcinomas, it is less helpful in the staging of cervical or gastroesophageal junction carcinomas. It plays a key role in assessing initial tumor bulk for radiation therapy planning and is also useful in monitoring tumor response to the cytoreductive therapy. CT is also helpful in depicting extraesophageal tumor spread to contiguous structures and distant metastases. CT evaluation is performed from the thoracic inlet through the liver to include the upper abdominal lymph node groups. Either thin barium or water-soluble oral contrast agents are administered routinely. Adequate distention of the esophagogastric junction is essential to exclude tumor involvement of this anatomic segment. Intravenous contrast material should be administered by the dynamic bolus technique to ensure optimal opacification of the heart, mediastinal vessels, and liver. Measurements of esophageal wall thickness greater than 5 mm are abnormal regardless of the degree of distention. Intraluminal air is seen in 60% of normal patients. CT staging of esophageal cancer includes assessment of (1) the extent of involvement of the esophageal wall by tumor, (2) tumor invasion of the periesophageal fat and adjacent structures, and (3) metastases to regional lymph nodes or distant organs.

The two key prognostic features of esophageal cancer are (1) the depth of tumor infiltration into or through the esophageal wall and (2) the presence or absence of visceral metastasis. Although the thickness of the esophageal wall often can be determined by CT, the individual layers of the esophageal wall cannot.¹⁸ T1 and T2 lesions generally show an esophageal mass thickness between 5 and 15 mm, and T3 lesions show a thickness greater than 15 mm. T4 lesions show invasion of contiguous structures on CT. Specific findings of tracheobronchial invasion include demonstration of a tracheobronchial fistula or extension of tumor into the airway lumen. If an esophageal tumor indents or displaces the adjacent airway, luminal invasion is likely. Thickening of the wall of the tracheobronchial tree also suggests invasion. Generally, direct visualization with bronchoscopy is necessary to rule out airway invasion (usually distal trachea or left mainstem bronchus) for upper- and middle-third tumors. Although CT is useful in determining the extent of local disease, it is not as accurate in the staging of lymph node involvement; it is limited in differentiating between small normal nodes and nodes invaded by tumor but small in size. It has been suggested that mediastinal nodes greater than 10 mm in diameter in the short axis should be classified as pathologic and that subdiaphragmatic nodes greater than 8 mm in diameter should be considered abnormal. The accuracy of CT in predicting lymph node involvement ranges from 83% to 87% for abdominal lymph nodes but only 51% to 70% for mediastinal nodes.

MRI offers an alternative to CT for the evaluation of esophageal cancer. Its application in esophageal carcinoma has received scant attention. Like CT, MRI is highly accurate for detecting distant metastases of esophageal cancer, especially to the liver, and for determining advanced local spread (T4). However, it is less reliable in defining early infiltration (T1–3). MRI appears to be as sensitive as CT in predicting mediastinal invasion. One advantage of MRI is the loss of signal in the vessels and the air-filled trachea and bronchi, which may provide a clear delineation between the tumor and the aorta and the tracheobronchial tree. Like CT, MRI is poor at detecting tumors restricted to mucosa or submucosa and also tends to understage the regional lymph nodes.¹⁹ MRI is not customarily used in the evaluation of esophageal cancer, as alternative modalities are often more reliable for determining local invasion and distant disease.

EUS has now become routine for the staging of esophageal cancer. EUS combines the technologies of flexible endoscopy and ultrasonic imaging. Tio et al.²⁰ found that the accuracy of EUS for T1a and T1b cancer was 85% versus 12% for CT. Luminal stenosis is a definite limiting factor for EUS, as it is occasionally not possible to traverse the tumor with the endoscope. Lymph nodes at a distance of more than 2 cm from the esophageal lumen cannot be imaged because of the very limited penetration depth of ultrasound. For patients with severe stenosis, a nonoptical, wire-guided echoendoscope can markedly reduce the occurrence of incomplete esophageal cancer staging and improve the detection of metastatic disease. EUS is also of help in the assessment of unresectability. The most important findings of unresectability are tumor invasion into the left atrium (with loss of smooth, flexible movement of the pericardium on real-time EUS), the wall of the descending aorta, the spinal body, the pulmonary vein or artery, or the tracheobronchial system. The latter should be confirmed with bronchoscopy with transbronchial FNA. EUS appears most helpful in predicting the superficial T1 tumors as well as the T3/4 tumors with greater depth of penetration. The positive predictive value of EUS for T2 tumors, however, is only 23%, with most tumors overstaged.²¹ Clinically, T1N0 and T2N0 tumors are found to have unanticipated nodal disease 24% and 39% of the time, respectively.²² Furthermore, for clinically T2 tumors, EUS understages nodal disease roughly two-thirds of the time.²³ It is possible to enhance specificity with ultrasound-guided needle biopsies through the EUS endoscope. The use of EUS-guided FNA was first reported in the diagnosis of esophageal cancer recurrence after distal esophageal resection in 1989.²⁴ One must use caution to avoid traversing the primary tumor with a needle resulting in a false-positive lymph node biopsy. At this time, EUS, especially when combined with FNA, is the most accurate imaging modality for locoregional staging of esophageal cancer.

Since multimodal neoadjuvant treatment for esophageal cancer has been used with increased frequency, tumor restaging remains fundamental in evaluating the response to therapy and in planning an operation. Many studies have evaluated the role of EUS in this setting. Although EUS is extremely accurate for staging untreated esophageal cancer, its accuracy in staging tumors after neoadjuvant chemoradiotherapy is relatively poor, with most errors caused by overstaging.²⁵ Although EUS is close to 90% accurate in predicting initial T stage, after neoadjuvant therapy, accuracy ranges from 27% to 82%. N stage is from 38% to 73% accurate after neoadjuvant therapy, whereas FNA can be expected to increase the accuracy further. Errors in posttherapy staging are likely due to the similar echogenic appearance of fibrosis and residual tumor. Residual nodal disease is an ominous finding. EUS, when combined with FNA, is very useful in detecting residual cancer within the lymph nodes. Others have found that ultrasound evidence of tumor regression is predictive of pathologic response to neoadjuvant therapy.

Recent evidence regarding the use of endoscopic mucosal resection (EMR) (see Chapter 173) particularly for early-stage tumors has emphasized the importance of this technology in determining the correct stage and differentiating T1a from T1b tumors when a superficial carcinoma is suspected.²⁶

As with many other malignancies, [¹⁸F]fluoro-2-deoxy-d-glucose (FDG)-PET is becoming a useful adjunct to conventional radiographic staging. PET improves staging and facilitates selection of patients for operation by detecting distant disease not identified by CT scanning alone. PET and CT are effective in showing the primary tumor and are equally sensitive in the demonstration of periesophageal nodes. The American College of Surgeons Oncology Group embarked on a prospective trial (Z0060) investigating the utility of PET scanning in the initial staging of esophageal cancer.²⁷ With 189 patients evaluated, roughly 5% of patients had a biopsy-confirmed distant metastasis detected with PET over CT alone. However, an additional 9.5% of patients had unconfirmed PET findings accepted by the treating surgeon as sufficient evidence to preclude resection. This particular study did not utilize PET/CT composite technology, which may have hampered the results. PET/CT is now accepted to have a routine role in esophageal cancer staging, with additional studies reporting the ability to detect distant metastatic disease in a significant number of patients.^28-30 Recent evidence suggests that PET scanning also may be used to measure the biologic activity of a tumor and thereby assess response to neoadjuvant therapy, stratifying survival after resection.³¹ Maximal standard uptake values (SUVmax) have been shown to be independent predictors of prognosis.³² The clinical relevance of this finding is most powerful in those patients with early-stage disease and high SUVmax who may be predicted to benefit from induction therapy.

Brain metastases are very rare in patients presenting with esophageal carcinoma. Autopsy studies reveal the prevalence of brain metastases in patients who died from esophageal cancer to be 0% to 1.8%. They tend to occur in patients with large tumors or aggressive nodal disease. Brain imaging is not generally performed during the evaluation of an esophageal cancer patient in the absence of neurologic symptoms.^33,34

The treatment of esophageal cancer is rigorously stage-driven. Patients with early-stage esophageal cancer may have a 5-year survival of over 75%, yet with more advanced disease, survival drops precipitously. The ability to recommend effective treatment algorithms and predict prognosis relies on the determination of a clinical stage for each patient with current technology.

The sixth edition of the AJCC staging system for esophageal cancer was introduced in 2002, and was not significantly different from an earlier version from 1987 because of lack of convincing survival data. Our cancer staging systems need to evolve as newer diagnostic modalities and treatments emerge, and as knowledge of the disease accumulates. As such, the staging system for esophageal carcinoma was recently revised with the introduction of the 7th edition of the AJCC staging manual (see Chapter 12) (Tables 10-1, 10-2A, and 10-2B).³⁵ Data used to generate the new staging system were assembled by a worldwide esophageal cancer collaboration, which included over 4600 patients.³⁶ Although the previous system was logical, straightforward, and simple, modifications were necessary as limitations became apparent (Table 10-3). The most important change pertains to the N descriptor. In the previous edition, the N descriptor was binary—N0 indicated no known nodal metastasis and N1 indicated any metastasis, regardless of tumor burden. The distinction was somewhat arbitrary an N1 node versus a distant M1a nodal metastasis which was not supported by recent data. The N descriptor in the new system now ranks lymph node burden with gradations from N0 through N3.

The staging system for gastric cancer includes groupings within the N descriptor based on number of involved lymph nodes. This has been shown to be relevant to prognostication for esophageal cancer as well.^37-39 The number of involved lymph nodes correlates with survival, irrespective of tumor depth of invasion. The prior subgrouping of M1 as M1a and M1b appears unfounded. The former M1a indicated distant nodal disease, but may have simply been a surrogate for large lymph node burden. This distinction has been eliminated in the new system. The seventh edition of the AJCC cancer staging manual also recommends harvesting a minimum number of lymph nodes based on the T descriptor. Ten nodes must be resected for T1, 20 for T2, and at least 30 for T3 or T4. These numbers are supported by data indicating that survival improves as a greater number of nodes are resected with the specimen.⁴⁰ This may be due at least in part to stage migration rather than resection of nodal micrometastases. It has been reported, however, that most resections fail to harvest an adequate number of lymph nodes.⁴¹ The harvest is improved when the surgeon takes the time to individually submit lymph node stations distinct from the resected esophagogastric specimen.

Histologic tumor type also has been shown to be of prognostic significance, with adenocarcinoma having a somewhat better prognosis than squamous cell carcinoma.⁴² These two tumor types now have their own stage groupings (see Tables 10-2A and 10-2B). Histologic grade was introduced as an important variable, as well-differentiated (G1) yet higher T-stage tumors have a similar prognosis to less well-differentiated tumors that are of lower T-stage.

Many surgical studies show a significant stratification of survival after resection of esophageal cancer based on accurate pathologic staging. Multimodality treatment of this disease has been introduced; however, it is difficult to compare different treatment modalities because of the lack of precise preoperative staging. Preoperative minimally invasive surgical staging in esophageal cancer may solve this problem, just as the successful use of mediastinoscopy in preoperative staging has solved this problem for lung cancer. Such staging in esophageal cancer may separate advanced disease from early local disease. Prognostication in patients with esophageal cancer may allow more appropriate allocation of chemotherapy and/or radiation therapy, thus reducing the morbidity and mortality associated with esophageal cancer treatment.

Murray et al.⁴³ first reported their experience with minimally invasive surgical staging for esophageal cancer in 1977. They used mediastinoscopy and minilaparotomy prospectively in 30 esophageal cancer patients. Seven were found to have positive lymph nodes by mediastinoscopy, and celiac lymph nodes were identified in 16. Dagnini et al.⁴⁴ did routine laparoscopy in 369 esophageal cancer patients, and they noted intra-abdominal metastases in 14% and celiac lymph node metastases in 9.7%. All these patients with metastasis avoided unnecessary resection.

Diagnostic laparoscopy with laparoscopic ultrasound revealed previously unknown findings, particularly in patients with locally advanced adenocarcinoma of the distal esophagus or cardia (hepatic metastases in 22% and peritoneal tumor spread or free tumor cells in the abdominal cavity in 25%), whereas the diagnostic gain was low in patients with squamous cell esophageal cancer.⁴⁵

With the advances in thoracoscopic (Ts) and laparoscopic (Ls) techniques, Ts/Ls has been used for staging esophageal cancer in some centers. Recent reports show that Ts/Ls staging can correctly predict nodal metastasis for esophageal cancer, as mediastinoscopy does for lung cancer. Krasna and McLaughlin⁴⁶ first described the efficacy of thoracoscopic lymph node staging in esophageal cancer. They further reported their successful experience with combined Ts/Ls for staging disease in the chest and abdomen in a follow-up series from three institutions of the Cancer and Leukemia Group B with an accuracy of over 90%.⁴⁷ A more recent report of 65 patients showed 94% accuracy with laparoscopy and 91% accuracy with thoracoscopy in esophageal cancer staging.⁴⁸ When compared with EUS, Ts/Ls staging is superior for detecting lymph node metastases. The study also demonstrated that clinical stage evaluation based on noninvasive diagnostic methods including CT, MRI, and EUS may be used to guide surgeons to focus on suspicious areas for the most high-yield biopsy targets when doing Ts/Ls staging.⁴⁹ The main advantage of Ts/Ls staging is that it provides greater accuracy in evaluation of regional and celiac lymph nodes. Such information is very important in patient stratification and selection of therapy, especially in the setting of new treatment protocols. Furthermore, the histologic status of mediastinal and abdominal lymph nodes is critical for design of the field for irradiation. It permits one to maximize the dose delivery to areas of known disease while minimizing dose to surrounding sensitive, normal tissue. Minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve the ability to stage cancer patients. Reverse transcriptase-polymerase chain reaction of carcinoembryonic antigen mRNA has been used to increase the detection of micrometastases in lymph nodes from esophageal cancer patients with minimally invasive staging.⁵⁰ Krasna et al.⁵¹ found that immunohistochemistry study of the molecular marker of p53 also can be used for this purpose; immunohistochemistry study of cytokeratin, an antibody to epithelial cells, also can be used to detect occult micrometastasis in Ts/Ls lymph nodes, and patients with positive cytokeratin findings tend to have poor survival.

Recently, the task force of the Society of Thoracic Surgeons (STS) conducted an evidence-based evaluation of diagnostic studies for esophageal cancer (Table 10-4).¹⁶ Based on this analysis, a Class I recommendation was made for flexible endoscopy with biopsy (level of evidence B).¹⁶ The task force also evaluated the efficacy of diagnostic tools for staging based on the current stage groupings published in the 7th edition of the AJCC staging manual for esophageal cancer (see also Chapter 12). In making these recommendations, esophageal cancer was defined as early-stage (T1a), locoregionalized (T2b-T4, any N, and M0), and distant (M1 disease). A class I recommendation (level of evidence B) was made for the use of computed tomography (CT) of the chest and abdomen as an optional test for staging. CT of the chest and abdomen was recognized as the recommended test for staging of locoregionalized esophageal cancer (Class I recommendation; level of evidence B). A Class IIA recommendation was made for the use of positron emission tomography (PET) as an optional test for early-stage cancer. A class IIA recommendation also was made for endosonography (EUS) in the absence of metastatic disease as a tool for improving the accuracy of clinical staging.

Esophageal cancer can metastasize to virtually any organ in the body. Widespread distant metastases are almost always present at the time of death. The extensive lymphatic drainage pathways in the esophagus and the long-time interval during which tumors typically remain asymptomatic may contribute to the high incidence of lymph node metastases. For all but the earliest stage tumors, surgical resection alone is inadequate. In fact, as many as 30% of patients with early (T1) lesions may have lymph node metastases. For this reason, multimodality regimens have been designed to achieve better survival in this disease.

Neoadjuvant Radiotherapy

The rationale for using preoperative radiotherapy is to reduce marginally resectable tumors to a more resectable size, to reduce the risk of tumor spread during surgical manipulation, and to treat extension of tumor beyond the surgical specimen. Surgery then removes the central, more radioresistant tumor mass. It does not appear that preoperative radiotherapy has an adverse effect on resectability or surgical morbidity.

Preoperative radiation doses of 30 to 45 Gy have been reported to result in a complete pathologic response rate of 15% to 30%. It is important to note that precise reporting of the rates of tumor sterilization is not possible, because not all patients who are irradiated undergo surgery and not all those operated on are resectable. Some clinical trials have suggested that survival after preoperative radiotherapy is correlated with the extent of tumor destruction seen in the resected specimen. A multicenter randomized controlled trial conducted by the European Organization for Research and Treatment of Cancer involved the administration of 33 Gy in 10 fractions in the treatment arm, followed by esophagectomy within 8 days. There were no significant differences in resectability or operative mortality between the study arms. Locoregional failure was decreased significantly in the radiotherapy arm from 67% to 46%. This was not associated with a survival benefit.⁵² Current consensus sees no role for neoadjuvant XRT alone.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy in patients with esophageal cancer who appear to have locoregional disease may diminish the incidence of unrecognized systemic metastases. The potential benefits of preoperative chemotherapy include downstaging the disease to facilitate surgical resection, improving local control, and eradicating micrometastatic disease. Surgical resection subsequently provides an opportunity to assess the tumor response to chemotherapy and to evaluate the patient for possible postoperative adjuvant therapy. In patients with localized, resectable tumors, chemotherapy-related toxicity occasionally can result in prolonged delay or even cancellation of planned surgical resection, risking further spread of disease. The resulting need for careful patient selection for participation in clinical trials of preoperative chemotherapy can bias treatment results. An American multi-institutional randomized trial of 440 patients compared surgery alone versus neoadjuvant chemotherapy followed by surgery. Preoperative chemotherapy consisted of three cycles of fluorouracil (5-fluorouracil or 5-FU) and cisplatin. Surgical resection followed 2 to 4 weeks later. Patients received two additional cycles of chemotherapy postoperatively. There was no significant difference in perioperative morbidity and mortality between the two groups. There was no significant difference in 1-year survival (60%), 2-year survival (35%), or local or distant recurrence rates. Survival did not differ between patients with squamous cell carcinoma and adenocarcinoma. Median survival time was 15 to 16 months in both treatment arms.⁵³ A smaller randomized trial comprising 147 esophageal cancer patients from Hong Kong demonstrated a higher rate of curative resection, yet failed to show a survival benefit with neoadjuvant chemotherapy.⁵⁴

A British randomized controlled trial of 802 patients also studied the use of preoperative 5-fluorouracil and cisplatin. The rate of microscopically complete resection was significantly higher for patients undergoing preoperative chemotherapy than for those undergoing surgery alone (60% vs. 54%). Postoperative complication rates were similar in both groups (41% vs. 42%). Patients undergoing preoperative chemotherapy achieved significantly improved median survival (16.8 vs. 13.3 months) and 2-year survival (43% vs. 34%).⁵⁵ Results of this trial were updated in 2009, reporting 5-year survival of 23% for the neoadjuvant chemotherapy group versus 17% for the surgery alone group.⁵⁶ The results of this trial, however, are potentially confounded by the fact that clinicians were allowed the option of giving preoperative radiotherapy to their patients irrespective of randomization.

An oft-quoted study is the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial which randomized 503 patients with gastroesophageal cancer to either perioperative chemotherapy or surgery alone.⁵⁷ The chemotherapy was comprised of three cycles of epirubicin, cisplatin, and 5-fluorouracil followed by surgery and three additional cycles of the same regimen. It was originally designed to include gastric cancer only, but inclusion criteria were later extended to include cancers of the lower third of the esophagus. There was a survival benefit for perioperative chemotherapy (36% 5-year survival vs. 23%). It should be kept in mind, however, that only a quarter of these patients had tumors of the lower esophagus or gastroesophageal junction; the remainder were gastric cancers. Another more recent multicenter randomized study by Ychou et al.⁵⁸ investigated a similar question of perioperative chemotherapy (cisplatin and 5-fluorouracil) versus resection alone for cancers of the esophagogastric junction. Of 224 patients, 11% involved the lower esophagus, 25% the stomach, and the remainder were true gastroesophageal junction tumors. There was again a survival benefit conferred by perioperative chemotherapy. Although some are conflicting, the majority of recent data, suggest a benefit of perioperative chemotherapy over surgery alone for the treatment of esophageal cancer.

Neoadjuvant Chemoradiotherapy

Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when administered preoperatively. The notion of downstaging esophageal cancer before surgical resection is appealing. In an attempt to improve resectability and survival in esophageal cancer, chemotherapy has been combined with radiotherapy in the neoadjuvant setting. Most reports of so-called trimodality therapy for esophageal carcinoma describe concurrent neoadjuvant chemoradiation using combinations of cisplatin and 5-fluorouracil while administering 30 to 45 Gy of radiation. Some studies have used additional postoperative chemotherapy. The results appear comparable at most experienced centers.

In an Irish study of 113 patients who had esophageal adenocarcinoma, patients were randomly allocated to surgery alone versus trimodality therapy with neoadjuvant chemoradiation.⁵⁹ Patients randomized to the trimodality arm received two cycles of 5-fluoruracil and cisplatin given concurrently with 40 Gy of radiation, followed by surgery. Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 25%. Trimodality therapy was associated with significantly increased median survival (16 vs. 11 months) and 3-year survival (32% vs. 6%). It should be noted that, at the time of surgery, the incidence of lymph node involvement was significantly higher in the group undergoing surgery alone. Survival with surgery alone was lower than that reported in most other series.

A French randomized trial of 282 patients compared surgery alone with two cycles of cisplatin chemotherapy and concurrent radiotherapy (total 37 Gy) followed 2 to 4 weeks later by surgery.⁶⁰ Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 26% but with significantly increased operative mortality (12.3% vs. 3.6%). Despite a significantly increased rate of microscopically complete resection, longer local disease-free survival time, longer overall disease-free survival time, and fewer cancer-related deaths in the trimodality arm, overall survival time was 18.6 months in both treatment arms. A randomized trial from the University of Michigan looked at 100 patients receiving either preoperative chemoradiation (total 45 Gy) or surgery alone.⁶¹ All resections were performed using a transhiatal approach. With a median follow-up of 8 years, there was no difference in survival.

Meta-analyses of randomized trials of trimodality therapy versus surgery alone for esophageal carcinoma have revealed a trend toward increased treatment-related mortality and slightly increased overall survival. Among patients treated with trimodality therapy for esophageal carcinoma, the best predictor of survival appears to be the finding of a pathologic complete response at the time of surgical resection.^62,63

Cancer and Leukemia Group B 9781 was a prospective, randomized intergroup trial of trimodality therapy versus surgery alone for the treatment of stages I to III esophageal cancer.⁶⁴ Patients were randomized to treatment with either surgery alone or cisplatin (100 mg/m²) and 5-fluorouracil (1000 mg/m² per day × 4 days) during weeks 1 and 5 concurrent with radiation therapy (50.4 Gy at 1.8 Gy/daily fraction over 5.6 weeks) followed by esophagectomy with lymph node dissection. A total of 56 patients were entered into the study between October 1997 and March 2000 when the trial was closed as a consequence of poor accrual. Thirty patients were randomized to trimodality therapy and 26 to surgery alone. An intent-to-treat analysis showed a median survival of 4.5 versus 1.8 years in favor of trimodality therapy (log rank p = 0.02). A log-rank test with stratifications by N stage, staging approach, and histology demonstrated a p value of 0.005. The 5-year survival was 39% (95% confidence interval: 21%–57%) versus 16% (95% confidence interval: 5%–33%) in favor of trimodality therapy.

Van der Gaast et al.⁶⁵ presented results in 2010 of the largest randomized study to date looking at neoadjuvant chemoradiotherapy compared to surgery alone. The multicenter phase III CROSS trial investigated 363 esophageal cancer patients undergoing neoadjuvant chemoradiation (utilizing a different chemotherapy regimen and a total of 41.4 Gy) versus surgery alone. The R0 resection rate was 92% in the neoadjuvant arm versus 65% in the surgery alone arm. Median survival was 49 months compared to 26 months in favor of trimodality therapy. The benefit was most pronounced in patients with squamous cell histology. The final results have recently been published in manuscript form and confirm these findings.⁶⁶

An Australian randomized phase II trial investigated whether the addition of concurrent radiation to a preoperative chemotherapy regimen is advantageous.⁷⁰ Seventy-five patients with esophageal adenocarcinoma received either neoadjuvant chemotherapy or chemoradiotherapy. There was no statistically significant difference in survival. The major pathologic response rate (pCR + <10% viable cells) was significantly improved in the arm receiving radiation (8% vs. 31%; p = 0.01). However, the advantage in 5-year survival was not statistically significant, suggesting that the study may have been underpowered.

To date, there is no completely reliable preoperative method for identifying a pathologic complete response after neoadjuvant chemoradiation. There is conflicting evidence regarding whether a restaging PET scan is a reliable predictor of a complete pathologic response prior to resection.^67,68 However, we now know that the survival of patients with microscopic residual disease approaches that of patients with a complete pathologic response, whereas gross residual disease is a poor prognostic factor.⁶⁹

At this point, there is adequate prospective evidence that the addition of radiation to a neoadjuvant chemotherapy regimen improves survival, as well as the rate of a complete pathologic response.⁶⁶

Adjuvant Radiotherapy

Radiotherapy is commonly considered postoperatively to “sterilize” residual microscopic disease and to control gross residual locoregional tumor. As an advantage, reserving radiotherapy for postoperative use avoids the necessity of subjecting all patients with completely resectable disease to the damaging effects of radiation. As a disadvantage, the use of postoperative radiation in patients who have undergone gastric pull-up or colonic interposition exposes large volumes of normal tissue to harm and is a potential cause of late morbidity. A French randomized trial of 221 patients with squamous cell carcinoma arising in the distal two-thirds of the esophagus compared surgical resection alone versus surgery followed by postoperative radiotherapy doses of 45 to 55 Gy in daily fractions of 1.8 Gy. Among patients with negative lymph nodes, local recurrence rates were lower in the group that received postoperative radiotherapy. There was no significant difference in survival between the two groups.⁷¹ A randomized trial from Hong Kong studied 130 patients undergoing either palliative or curative resection for esophageal cancer. Patients randomized to the postoperative radiotherapy arm of the study received doses of 49 to 52.5 Gy in daily fractions of 3.5 Gy. The very high daily radiation dose used in this study was associated with a significantly decreased median survival compared with surgery alone (8.7 vs. 15.2 months). In patients undergoing curative resection, postoperative radiotherapy was not associated with any improvement in local control. Although postoperative radiotherapy was associated with improved local control in patients undergoing palliative resection with gross residual disease, there was no survival benefit.⁷² A prospective Chinese study of 495 patients who had undergone surgical resection of esophageal cancer randomized patients to a postoperative radiotherapy group or a control group. A midplane dose of 50 to 60 Gy was administered in daily fractions of 2 Gy. A trend toward improved 5-year survival in patients who received postoperative radiotherapy (41.3% vs. 31.7%) was not statistically significant. This trend was somewhat stronger in patients with positive lymph nodes (29.2% vs. 14.7%, p = 0.07). Postoperative radiotherapy was associated with a statistically significant improvement in 5-year survival only among patients with stage III disease (35.1% vs. 13.1%).⁷³ This is corroborated by a more recent retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) database suggesting a survival benefit for stage III patients with either squamous cell carcinoma or adenocarcinoma who receive postoperative radiation as opposed to resection alone. There was no benefit associated with postoperative radiation among stage II patients.⁷⁴

Adjuvant Chemotherapy

Adjuvant chemotherapy also has been studied. A multi-institutional Japanese randomized controlled trial of 242 patients who had undergone complete surgical resection for esophageal squamous cell carcinoma studied the effects of adjuvant chemotherapy with two cycles of cisplatin and 5-fluorouracil. Adjuvant chemotherapy was associated with significantly improved 5-year disease-free survival in patients with lymph node involvement (52% vs. 38%). Despite improved disease-free survival, there was no significant improvement in overall survival. Among node-negative patients receiving adjuvant chemotherapy, a trend toward improved 5-year disease-free survival (76% vs. 70%) was not statistically significant.⁷⁵ To date, there are no published North American data suggesting that postoperative chemotherapy in the absence of documented metastatic disease is associated with prolonged survival.

Definitive Chemoradiotherapy

In light of the relatively high morbidity and mortality rates associated with esophageal resection, definitive chemoradiation has been advocated as a reasonable approach for the treatment of esophageal cancer. Two similar phase III studies compared the efficacy of neoadjuvant chemoradiotherapy and definitive chemoradiotherapy, with concordant results. A French study only randomized chemoradiotherapy nonresponders (of 444 eligible patients, only 259 were randomized). Of the remaining patients who responded clinically to chemoradiation, there was no difference in survival when surgery was added to the treatment regimen. However, the surgical arm had more early deaths yet better local control and palliation of dysphagia.⁷⁶ A German study also failed to reveal a survival difference between treatment arms, yet resected patients had better progression-free survival. Clinical response to induction chemotherapy was a good prognostic factor in each group.⁷⁷ For elderly patients, however, definitive chemoradiation is associated with significant morbidity and poor survival.⁷⁸ It may be reasonable to consider resection alone for elderly patients who are of acceptable surgical risk.

It is clear from patterns-of-care study surveys that a multimodality approach is increasing in popularity across the country.⁷⁹ Novel restaging techniques, as well as further study of the risks and benefits of neoadjuvant chemoradiotherapy, are needed.

Although patients with early localized disease benefit from complete surgical resection, there is increasing evidence that multimodality therapy (neoadjuvant chemoradiation followed by surgical resection) has increased survival benefits when compared to surgery alone for more advanced stages.⁵⁹

The success rate for treatment of esophageal cancer with surgery alone is related to the disease stage. If the depth of tumor invasion is limited to the submucosa without regional lymph node involvement or distant metastases (T1N0M0), most patients undergoing complete resection will survive 5 years. In most cases of esophageal cancer presenting with dysphagia, however, management is complicated by the prevalence of locally advanced disease (T3 or T4), involvement of regional lymph nodes (N1–3), or distant (often occult) metastases (M1). Curative treatment of esophageal cancer must address local control of the primary lesion as well as the control and/or prevention of metastases.

There has been a significant variation within the literature with regard to morbidity and mortality rates after esophagectomy. A Veterans Affairs National Surgical Quality Improvement Program database of 1777 patients undergoing esophagectomy revealed morbidity and mortality rates of 50% and 10%, respectively.⁸⁰ A more recent study gleaned from 2315 patients entered into the Society of Thoracic Surgeons (STS) General Thoracic Database revealed a much lower mortality rate of 2.7%.⁸¹ This difference may be due, in part, to the fact that participation in the STS database is voluntary and comprised mostly of board-certified thoracic surgeons. Nevertheless, risk factors for poor outcomes were identified to include congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes, hypertension, steroid use, smoking status, and a high American Society of Anesthesiology (ASA) score. Interestingly, induction therapy was found not to be a risk factor for increased morbidity. Several recent studies have documented the importance of institution and surgeon experience as measured by volume of esophagectomies.^82-86

Although esophagectomy remains the preferred treatment for the earliest stage intramucosal tumors (T1aN0), endoscopic approaches are gaining in popularity. Endoscopic radiofrequency ablation and EMR have been used for metaplasia and dysplasia of the mucosa, and indications are now broadening to include these superficial tumors. Studies have shown successful treatment of T1aN0 tumors using EMR.^87,88 These series are highly selective, comprised of small tumors staged with EUS and excluding poorly differentiated tumors. Patients were followed endoscopically and some required repeated treatments. Although endoscopic treatment of these highly selected lower-risk tumors may be reasonable, there must be a commitment by both patients and their physicians to rigorous long-term surveillance.⁸⁹ Endoscopic treatment is certainly a good option for the high-risk surgical patient.

For most patients with localized esophageal cancer, surgical resection affords the best chance for local control and the best means of palliation of dysphagia. In all but the earliest stages of esophageal cancer (T1N0M0 or T2N0M0), however, both local and systemic recurrence of disease is common when surgical resection is performed as the sole treatment modality. With the exception of these early lesions, surgery alone with complete resection of all grossly apparent disease is associated with median survival ranging from 12 to 18 months in most centers and 5-year survival rarely exceeding 20%. Because of the low cure rates associated with the treatment of esophageal cancer by surgery alone, other modalities have been added to the treatment regimen.^90,91

Esophageal cancer is the fastest growing malignancy in terms of incidence in the North American and the Western nations. A multimodality approach generally is needed to treat this disease. With newer imaging and minimally invasive staging techniques, careful determination of pathologic TNM staging can be achieved before treatment. Patients can receive stage-specific treatment regimens, including chemotherapy, radiation therapy, and surgery, appropriate to their disease. With further advances in the identification of molecular markers, patients with esophageal cancer will be able to receive treatments based on a specific profile of genome expression, as is currently being done for patients with cancers of the breast and lung.

The main message from this chapter is that esophageal cancer must be approached in a stage-specific fashion, just as one would approach any other solid-organ malignancy. New diagnostic and staging algorithms, recently endorsed by the STS Taskforce, suggest the use of EGD, PET, and EUS with FNA for all but the most superficial tumors. Using the revised TNM staging system, surgeons should carefully allocate treatment (resection, neoadjuvant and adjuvant therapy) as appropriate for each subgroup based on stage. The results of two recent randomized trials (CALGB 9781 and the CROSS study) have codified neoadjuvant chemoradiation as the approach of choice for locoregional disease. Until a definitive method of restaging patients postchemo/radiation induction therapy is developed, surgery should always be considered as part of the multimodality regimen in nonmetastatic patients.