The diagnosis and management of esophageal cancer is currently the focus of considerable clinical investigation. In the presence of localized disease, advances in the operative and postoperative management and rational applications of multimodality therapy have failed to significantly improve survival rates over the last 25 years.¹ In this chapter, we will review recent changes in the histologic composition of esophageal cancers and how this may relate to tumor biologic and epidemiologic factors. We will also discuss the evolving impact of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) for the staging and treatment of esophageal cancer. We will review the rationale for novel combined-modality approaches and the results of clinical trials testing both single-modality and combined-modality therapies, as well as the use of palliative therapies for disease that cannot be cured. We will conclude with a summary of the data and the current treatment recommendations and a discussion of several important clinical trials in progress.

Etiology and Epidemiology

Esophageal cancer is a highly aggressive neoplasm. In 2010, 16,640 Americans were diagnosed with esophageal cancer, representing a 14.6% increase in incidence over the previous 5 years. Approximately 87% of patients died of their disease; this fact indicates that no significant improvement in outcome has been seen over the same time period.^1,² Local invasion and early metastases are common in newly diagnosed esophageal cancers because the esophagus has a rich lymphatic and vascular supply. Approximately half of newly diagnosed patients will present with locally advanced disease, with a 20% to 30% 5-year survival rate after surgical resection or multimodality therapy.³ Cure rates of 60% to 80% can be achieved in only the 10% or so of patients with node-negative disease confined to the esophagus that has been treated with surgical resection.⁴

The incidence of adenocarcinoma of the distal esophagus and gastroesophageal junction is increasing in the Western world and currently represents approximately 60% of all esophageal carcinomas in the United States, but squamous cell carcinoma remains dominant in underdeveloped parts of the world.5,6,7 Data from the Surveillance Epidemiology and End Results (SEER) program of the National Cancer Institute (1975 to 2004) demonstrate that in the United States, the incidence of esophageal cancer in white males has steadily risen from 5.76 per 10,000 person-years during the years 1975 to 1979 to 8.34 per 10,000 person-years during the years 2000 to 2004. The adenocarcinoma incidence rate has increased by 463%, from 1.01 to 5.69 per 10,000 person-years, but the incidence rate of squamous cell cancers has declined by 50%, from 3.81 to 1.90 per 10,000 person-years.⁸ Among white females, the incidence of esophageal cancer has remained constant at 2 per 10,000 person-years, with a 29% decrease in squamous cell cancers (0.98 per 10,000 person-years) and a 335% increase in adenocarcinomas (9.74 per 10,000 person-years from 1975 to 2004).^8,⁹ Similarly, the incidence of squamous cell carcinoma has shown a significant decline in black males beginning in 1992,¹⁰ but it remains the most common cell type among blacks in the United States,¹¹ despite the twofold to threefold increase in incidence of adenocarcinomas in black males and females.

Data reported by Hesketh ¹² in a review of the New England tumor registries show that the incidence of adenocarcinoma has increased even when tumors located at the esophagogastric junction have been excluded. Table 43-1 reflects recent changes in the prevalence of adenocarcinoma of the esophagus over the span of several decades. Pohl and colleagues^7,13,14,15 extracted information from the National Cancer Institute’s SEER database from 1973 to 2001 to counter a number of suggested possibilities for the recent increase in adenocarcinomas of the esophagus, and found no evidence for either histologic reclassification of esophageal squamous cancers or anatomic reclassification of adenocarcinomas of the gastric cardia.

TABLE 43-1 Incidence of Adenocarcinoma of the Esophagus

Investigator	Years	Adenocarcinoma (%)
Smithers²¹¹	1936-1951	7.3
Hesketh/Conn. Register¹²	1983-1986	22.9
Birgisson²¹²	1987-1994	73.5
Steyerberg¹⁶	1991-1999	52.0
Brown⁸	2000-2004	61.1*

* White males and females only.

Esophageal cancer is more commonly seen in men than women; of the more than 16,000 cases of esophageal cancer diagnosed in the United States in 2010, approximately 13,000 were found in men.^1,² Esophageal cancer is the seventh leading cause of cancer deaths among males in the United States. Black males are more likely to present with advanced and/or metastatic disease, resulting in a survival rate that is 60% of that for white males.^1,² In a multivariate regression analysis controlling for age, gender, marital status, tumor histologic type, and tumor location, black race was associated with worse survival rates. In this study analyzing SEER data, when the tumor status, surgical technique, and radiotherapeutic modality were added to the model, race was no longer significantly associated with survival rates.¹¹ Provocative data from Steyerberg and associates¹⁶ also suggested that the underuse of potentially curative surgery may, in part, explain the poorer survival rates observed for black patients with locally advanced disease; in a population-based analysis, the authors observed that once the data had been corrected for treatment received, there was no difference in survival rates between white and black patients. It has been postulated that the increased incidence of disease and increased mortality rates observed in black patients are reflections of socioeconomic status and dietary risk factors but not ethnicity. Squamous cell carcinoma remains the most common histologic type among black males and may be associated with worse outcomes, facts that could explain some of the observed racial disparities in survival rates.¹¹ Data from Brown and colleagues¹⁷ support a correlation between an increased rate of squamous cancers in black males with known risk factors. In this population-based case-control study, there appeared to be a risk for developing esophageal cancer in black patients beyond what could be attributed to alcohol and tobacco use.¹⁷ The reasons for the apparent racial difference in risk from the same level of alcohol and tobacco use could be associated, in part, with increased mutations in the TP53 gene in esophageal cancers found in black patients, as reported by Baron and colleagues.¹⁸

Prevention and Early Detection

Smoking is an established risk factor for squamous cell carcinoma of the esophagus and also for adenocarcinoma but to a lesser extent; smoking cessation reduces the risk of only squamous cell carcinoma, however.¹⁹ Chronic esophagitis is also thought to be a precursor for the development of squamous cell cancers.²⁰ Other environmental factors associated with the development of squamous cell cancers include thermal injury and exposure to nitrates and potentially carcinogenic nitrosamines, asbestos fibers, or water contaminated with petroleum products.²¹^–²³ Data from several laboratories have implicated genital-mucosal strains of human papillomaviruses (HPV-16 and HPV-18) as risk factors for the development of cancers of the esophagus.^24,²⁵

Alcohol consumption has been shown to be a risk factor for squamous cell carcinoma but not adenocarcinoma.¹⁹ Gastroesophageal reflux disease (GERD) predisposes to Barrett’s esophagus and is associated with an increased risk of adenocarcinoma of the esophagus, with severe long-standing disease.¹⁹ It has been postulated that the incidence of GERD is increasing in the United States; however, it is not clear whether this increase is contributing to the increase in adenocarcinomas.¹⁹ An increasing body mass index is also strongly associated with adenocarcinoma risk.²⁶ Diet has been demonstrated to affect both types of esophageal carcinoma, with increased intake of fruits and vegetables associated with a reduced incidence of cancer.²⁷ Lifestyle changes, including weight loss and exercise, postulated to reduce the risk of developing esophageal adenocarcinoma, are currently being investigated.

Barrett’s esophagus is known to be associated with GERD and is a precursor lesion for esophageal adenocarcinoma, although most Barrett’s lesions do not proceed to carcinoma. Although families with Barrett’s esophagus have been described, most cases are sporadic and thought to be caused by chronic gastroesophageal reflux. Suleiman and associates ²⁸ have postulated that the use of pharmaceutical agents for the treatment of gastroesophageal reflux (i.e., antisecretory agents and therapies to relax the lower esophageal sphincter) may preclude the surveillance required for the detection and management of Barrett’s esophagus and that their use is therefore related to the recent increase in the incidence of Barrett’s esophagus–associated adenocarcinomas.

Although the molecular understanding of the premalignant conditions associated with Barrett’s esophagus continues to expand, efforts to improve early detection and incorporation of chemoprevention efforts are under investigation. Nguyen ²⁹ reported the results of a retrospective observational study of 344 patients with Barrett’s esophagus that examined the association between prescription use of proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, or statins and the risk of developing esophageal dysplasia or adenocarcinoma. In this study, PPI use was associated with a reduced risk of high-grade dysplasia or cancer with adjustment for gender, age, and the length of duration of Barrett’s esophagus. Use of NSAIDs or aspirin resulted in a nonsignificant trend toward a lower incidence of high-grade dysplasia and cancer, whereas statin use was not significantly associated with the risk of developing neoplasia.²⁹ A meta-analysis supports these findings, demonstrating that the use of NSAIDs decreases the risk of both squamous cell carcinoma and adenocarcinoma, with odds ratios of 0.58 and 0.67, respectively.³⁰ Vaughan and associates³¹ demonstrated similar results in a prospective cohort study, and currently, there is a large multicenter, randomized controlled clinical trial (AspECT) evaluating the long-term chemopreventive effect of esomeprazole with or without aspirin.³²

Adenocarcinomas and, more recently, squamous cancers of the esophagus have been shown to overexpress the cyclooxygenase-2 (COX-2) enzyme.^33,³⁴ Data from Shamma and colleagues³⁵ demonstrates that COX-2 expression is correlated with the proliferative activity in dysplastic lesions of the esophagus. In this study, the COX-2 level was found to be increased, in a stepwise fashion, with the transition from normal esophageal tissue to low-grade dysplasia to high-grade dysplasia, suggesting that COX-2 is involved in the early stages of carcinogenesis and that interruptions in the dysplasia-carcinoma sequence could prove to be an important part of a chemoprevention strategy. In addition, the HER2/neu oncogene is overexpressed and/or amplified in preneoplastic lesions and in adenocarcinoma of the esophagus and has been associated with a poor prognosis.³⁶ Translational approaches with targeted therapies, such as trastuzumab, are being investigated based on preclinical evidence.³⁷ Precancerous lesions of the esophagus have also been shown to overexpress TP53,^36,^38,³⁹ cyclin D1,⁴⁰ and P16,⁴¹ which may be targeted by chemoprevention agents in the future.

Molecular Characteristics of Esophageal Cancer

Mutations in the TP53 gene are present in up to 80% of esophageal cancers. Interestingly, the mutations for squamous tumors, which are int A-T base pairs, are very different from the mutations usually seen in adenocarcinomas.⁴² Data from Montesano⁴² indicate that the mutations common to squamous tumors are correlated with smoking. Mutations in the TP53 gene are an early event in the carcinogenic process from Barrett’s esophagus mucosa to high-grade dysplasia and esophageal adenocarcinoma. In data from Coggi and associates,⁴³ TP53 gene mutations in exons 5 to 8 were detected in 53% of 74 esophageal cancers. Interestingly, there was no concordance between TP53 gene mutations and the accumulation of the TP53 protein nor were the mutations in the TP53 gene independently predictive of clinical outcome. In vitro data evaluating the sensitivity of esophageal adenocarcinoma cell lines to chemotherapeutic agents (e.g., 5-FU; mitomycin C, and cisplatin) showed that wild-type TP53 protein levels increased after treatment with each of the agents via post-translational and or translational processes. Schrump and collaborators⁴⁴ also confirmed a positive correlation with drug sensitivity and the increased expression of wild-type TP53 protein versus a negative in vitro sensitivity effect with deficient TP53 protein expression or expression of mutated TP53 protein.

Additional molecular abnormalities include cyclin D1, a cell cycle-regulating protein involved in the G₁ phase to S phase transition. Overexpression of cyclin D1 has been observed in approximately 30% to 40% of esophageal adenocarcinomas and squamous cell carcinomas.⁴⁵ Inactivation of the P16 gene, a tumor supressor gene, occurs in a significant number of esophageal cancers,⁴¹ and restoring P16 expression appears to markedly inhibit the proliferation and tumorgenicity of esophageal cancers.⁴⁴ These represent but a few of the potential molecular targets for directing therapies in future clinical studies.

Overexpression of the epidermal growth factor receptor (EGFR) is found in both esophageal squamous cell carcinomas and esophageal adenocarcinomas, as well as their precursor lesions, such as squamous dysplasia and Barrett’s esophagus.⁴⁶^–⁴⁸ Overexpression of EGFR on immunohistochemical testing occurs in approximately 80% of patients with esophageal adenocarcinoma and squamous cell carcinoma.⁴⁹ Additionally, amplification of the EGFR gene has been detected by fluorescence in situ hybridization (FISH) analysis in 8% to 30% of esophageal adenocarcinomas.⁴⁹^–⁵² Clinical studies have shown that increased EGFR expression is associated with an overall decrease in survival rates in patients with esophageal cancer⁵³ (Table 43-2).

TABLE 43-2 Endothelial Growth Factor Receptor (EGFR) Expression in Esophageal Cancer and Outcome

Pathologic Findings and Pathways of Spread

The predominant histologic types of esophageal cancer are squamous cell carcinomas and adenocarcinomas. Approximately 20% of esophageal squamous tumors involve the upper “cervical” esophagus, while the majority (50%) are found in the middle esophagus, defined as the segment of esophagus from the aortic arch to the inferior pulmonary vein and usually representing the segment at 25 to 32 cm from the incisors. The remaining 30% of squamous tumors are found in the distal esophagus (at 33 to 42 cm from the incisors). In contrast, over 90% of adenocarcinomas are found in the distal esophagus and gastroesophageal junction. Other malignant histologic types are unusual but include adenosquamous, mucoepidermoid, and adenoid cystic tumors and malignant tumors with endocrine differentiation (small cell cancers). Histologic review of esophagectomy specimens with early-stage disease revealed little difference between the rate of submucosal spread and the rate of lymph node metastasis for squamous cell carcinomas and adenocarcinomas.⁵⁴ In addition, no difference in survival rates has been correlated with histologic subtype for patients who undergo surgery for esophageal cancer.^54,55,56

The esophagus is a hollow tube approximately 25 cm in length that extends from the pharynx to the stomach and consists of three parts: the cervical, thoracic, and distal esophagus. The cervical esophagus lies just left of the midline behind the larynx and trachea. The upper portion of the thoracic esophagus passes behind the tracheal bifurcation and left main stem bronchus, and the lower thoracic esophagus runs behind the left atrium. The distal esophagus is an area approximately 6 to 8 cm in length merging into the gastroesophageal junction. In the esophagus, mucosal lymphatics merge with a submucosal plexus, which then merges with lymphatic channels in the muscularis. These channels communicate with an extensive network of cooperating lymphatics that extend longitudinally throughout the esophagus and eventually drain into nodal groups as caudal as the internal jugular lymph nodes and as cephalad as the celiac lymph nodes. The nodal groups at risk for involvement in cancers of the cervical esophagus include the supraclavicular and right upper paratracheal nodes. The nodes at risk for gastroesophageal tumors include the pulmonary ligament, paracardial, left gastric, common hepatic, splenic, and celiac nodes. The esophagus lacks a serosal surface and is only separated from adjacent structures by a loose connective tissue, the adventitia. The adventitia provides little barrier to local spread, and as a consequence, tracheoesophageal and esophagobronchial fistulas develop in 5% to 10% of patients with cancer of the esophagus.

Clinical Manifestations, Patient Evaluation, and Staging

Box 43-1 lists the most common clinical symptoms associated with esophageal cancer at presentation. Over 90% of patients present with progressive and worsening dysphagia often resulting in significant weight loss. Other findings include odynophagia, chest pain, cough, and fever associated with possible respiratory fistulas, hoarseness associated with tumor involvement of the recurrent laryngeal nerve, and melena resulting from intraluminal bleeding. Recommended staging tests are outlined in Box 43-2.

Box 43-1 Presenting Signs and Symptoms of Esophageal Cancer

The use of 18-fluorodeoxy-D-glucose (FDG) positron emission tomography (PET) or PET-CT for staging in esophageal cancer continues to evolve. The addition of PET to standard staging techniques has improved the detection of occult metastatic disease 57–60,61 and can result in up to 15% upstaging from M0 to M1 compared with CT and endoscopic ultrasonography.⁵⁸ In a meta-analysis reported by van Westreenen and colleagues,⁶² PET showed limited sensitivity (0.51) and reasonable specificity (0.81) for the detection of locoregional metastases. These statistics were improved, however, for detecting distant lymphatic and hematogenous metastasis, with a sensitivity and specificity of 0.67 and 0.97, respectively.⁶² Taken in total, these data are compelling and have resulted in an increasing use of PET for the routine staging of patients with esophageal cancer.

The initial PET maximum standardized uptake value (SUVmax) has not proven to be predictive of survival times in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy; patients with a high initial SUVmax demonstrate a better response to preoperative therapy, however.⁶³ The use of PET to provide an early assessment of response and response-adapted treatment has been under investigation. In the MUNICON trial, locally advanced distal esophageal adenocarcinoma or gastric cardial adenocarcinoma patients were assigned to 2 weeks of platinum- and fluorouracil-based induction chemotherapy. After completion of induction chemotherapy, patients found to have an SUV decrease of 35% or more on PET imaging, who were defined as metabolic responders, continued to receive additional 5-FU-based neoadjuvant chemotherapy for 12 weeks, followed by surgery. Metabolic nonresponders discontinued chemotherapy and proceeded directly to surgery. Of the 49% of patients who were metabolic responders, median overall survival was not reached by 2.3 years, whereas median overall survival was 25.8 months in the nonresponders. Major histologic remissions (<10% of residual tumor) were noted in the 58% who were metabolic responders, but no histologic response was noted in metabolic nonresponders.⁶⁴ A similar adaptive treatment strategy has been adopted by the Cancer and Leukemia Group B (CALGB) for investigation.

The TNM staging system for esophageal cancer according to the American Joint Committee on Cancer (AJCC) staging manual, seventh edition, is shown in Box 43-3. As reflected in the staging, patients with regional and/or celiac axis lymphadenopathy should not necessarily be considered to have metastatic disease. Some difficulties have arisen because this is a surgical staging system and many patients are now treated initially without resection, making accurate pathologic staging impossible. Esophageal cancers are staged according to the depth of invasion, presence of regional lymph nodes or distant metastatic disease, and grade and location of tumor. Diagnostic tools relevant to determining the locoregional stage include endoscopic ultrasound and thoracoscopic staging.

Box 43-3

Staging and Prognosis for Esophageal Cancer

TNM Staging of Esophageal Cancer

Primary Tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	High-grade dysplasia
T1	Tumor invades lamina propria, muscularis mucosae, or submucosa
T1a	Tumor invades lamina propria or muscularis mucosae
T1b	Tumor invades submucosa
T2	Tumor invades muscularis propria
T3	Tumor invades adventitia
T4	Tumor invades adjacent structures
T4a	Resectable tumor invading pleura, pericardium, or diaphragm
T4b	Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea
Regional Lymph Nodes
Nx	Regional nodes not assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1-2 regional lymph nodes*
N2	Metastasis in 3-6 regional lymph nodes*
N3	Metastasis in 7 or more regional lymph nodes*
Distant Metastasis
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

Stage and Prognostic Groupings for Esophageal Cancer

Adenocarcinoma
Stage 0	Tis, N0, M0, grade 1 or X
Stage I A	T1, N0, M0, grade 1-2 or X
Stage I B	T1, N0, M0, grade 3
	T2, N0, M0, grade 1-2 or X
Stage IIA	T2, N0, M0, grade 3
Stage IIB	T3, N0, M0, any grade
	T1-2, N1, M0, any grade
Stage IIIA	T1-2, N2, M0, any grade
	T3, N1, M0, any grade
	T4a, N0, M0, any grade
Stage IIIB	T3, N2, M0, any grade
Stage IIIC	T4a, N1-2, M0, any grade
	T4b, any N, M0, any grade
	Any T, N3, M0, any grade
Stage IV	Any T, any N, M1, any grade
Squamous Cell Carcinoma
Stage 0	Tis, N0, M0, grade 1 or X, any location
Stage I A	T1, N0, M0, grade 1 or X, any location
Stage I B	T1, N0, M0, grade 2 or 3, any location
	T2-3, N0, M0, grade 1 or X, lower esophagus or X
Stage IIA	T2-3, N0, M0, grade 1 or X, upper and middle esophagus
	T2-3, N0, M0, grade 2 or 3, lower esophagus or X
Stage IIB	T2-3, N0, M0, grade 2 or 3, upper and middle esophagus
	T1-2, N1, M0, any grade, any location
Stage IIIA	T1-2, N2, M0, any grade, any location
	T3, N1, M0, any grade, any location
	T4a, N0, M0, any grade, any location
Stage IIIB	T3, N2, M0, any grade, any location
Stage IIIC	T4a, N1-2, M0, any grade, any location
	T4b, any N, M0, any grade, any location
	Any T, N3, M0, any grade, any location
Stage IV	Any T, any N, M1, any grade, any location

*Regional lymph nodes extend from cervical nodes to celiac nodes.

From the American Joint Committee on Cancer: AJCC Cancer Staging Manual, ed 7. New York, 2009, Springer-Verlag.

Hiele and associates,⁶⁵ in a prospective review, found that preoperative endoscopic ultrasound reflected an accurate T stage in 59% of patients subsequently taken to surgery and an accuracy of 82% in patients with transmural tumor extension. Natsugoe and colleagues⁶⁶ found the accuracy of endoscopic ultrasound to be 87% for detecting mediastinal nodal disease. The CALGB, in a multi-institutional trial of thoracoscopic staging, found thoracoscopic determination of tumor penetration and lymph node staging to be accurate in 88% of patients later taken to resection. The accuracy of overall staging further improved with concomitant laparoscopic lymph node staging.⁶⁷ Although endoscopic ultrasound is recommended for the staging of esophageal cancers by current National Comprehensive Cancer Network (NCCN) guidelines, the precise role of endoscopic ultrasound is not well defined, because the results often do not affect the clinical management. Similarly, thoracoscopic staging studies were done before the common use of PET scans, and thoracoscopy and laparoscopy are now infrequently used. Studies have demonstrated that the diagnostic accuracy of re-endoscopy with rebiopsy and endoscopic ultrasound is inadequate for objective pathologic response evaluation after neoadjuvant chemoradiation.^68,69

Cancers confined to the epithelium and muscularis mucosa and without nodal involvement are considered stage I and II tumors. In a clinicopathologic review of 165 patients with esophageal cancer treated with resection only, Holscher and colleagues ⁷⁰ observed 0% lymph node metastases in patients with disease confined to the mucosa compared with 18% for tumors with submucosal spread. The 5-year overall survival rate reported for patients with node-negative disease was 63%. Tumors invading the adventitia or surrounding structures have a worse outcome than more limited disease, and there is almost always associated nodal involvement.

Primary Therapy

Single-Modality Therapy

Surgery

In 1913, Dr. Franz Torek ⁷¹ used a transpleural approach to perform the first successful resection of an esophageal carcinoma, reconstructed with an external rubber esophagus. With improvements in anesthesia, subsequent surgeons used mainly a transthoracic approach with primary esophagogastric anastomosis, and in 1933, Ohsawa⁷² reported extended survival rates in 8 of 20 patients who had a resection. In 1938, Adams and Phernister⁷³ were the first Western surgeons to successfully adopt the Japanese transthoracic technique. The results of these studies, however, revealed a discouraging 5-year survival rate of 5% to 10%.

Despite recent advances in surgical and anesthetic techniques, the results with surgery alone have produced only modest improvements in outcome. Moertel ⁷⁴ reviewed 18 surgical series involving 4109 patients treated with resection and found an 5-year overall survival rate of 9.6% (range, 3% to 20%). Our review of more recently published surgical series reveals slightly more encouraging results, but there has been careful patient selection in some of these trials. Mariette and colleagues,⁷⁵ in a series of 179 patients with stage 0 to II esophageal cancer treated with surgery alone between 1982 and 2002, observed an overall actuarial survival rate at 5 years of 59%. The investigators report, however, that no long-term survivors were observed among a subset of patients with locally advanced disease.

Analysis of surgical pathology shows that a significant number of patients present with disease involving the regional lymph nodes and that such involvement results in a worse outcome. In 156 patients evaluated by Frunberger and colleagues,⁷⁶ 53% had nodal disease at surgery. Sun and associates⁷⁷ found that of 474 operable patients, 211 (44.5%) had involved regional lymph nodes at the time of surgery. The overall survival rate for the entire group was 31%; but only 13% of patients with nodal disease were alive at 5 years versus 44% for node-negative patients. Similar results have been reported by Collard and associates⁷⁸; the 5-year survival rate after surgery alone fell from 57% for node-negative patients to 15% in patients with positive nodes. Holscher and colleagues,⁷⁰ in an evaluation of 165 patients treated with en bloc esophagectomy, found that no patient with more than 30% regional nodal tumor involvement was alive at 5 years, whereas 45% of patients with less than 30% nodal disease were alive at 5 years.

These data indicate that in the limited cohort of patients who present without regional nodal involvement, many will do well with surgery alone. Equally important, however, is the fact that patients found to have nodal disease at the time of resection are rarely treated successfully with surgery alone. Unfortunately, the current diagnostic tools for determining regional nodal status are not very sensitive, and a significant percentage of patients with esophageal cancer will present with locally advanced, node-positive tumors. Despite its modest success, surgical resection remains the standard of care for the treatment of early-stage esophageal cancer.

The optimum number of lymph nodes to be removed and examined at the time of resection remains unclear. A recent retrospective analysis performed on SEER data demonstrated that the number of lymph nodes removed at the time of surgery was an independent predictor of survival time and that the optimal threshold predicted by Cox regression analysis for this survival benefit was removal of 23 nodes.⁷⁹ Another recent study suggested that 18 lymph nodes should be removed.⁸⁰

Currently, there are two standard surgical approaches for resecting tumors with potentially curable disease. The transthoracic resection, or Ivor-Lewis procedure, allows better access to lesions in the upper two-thirds of the esophagus and complete visualization of the esophagus. For distal tumors, this approach allows for resecting a substantial proximal margin and placing the anastomosis high in the chest, a technique that is thought to result in fewer anastomotic leaks and less postoperative reflux. The initial laparotomy is for exploring the abdomen for distant disease and mobilization of the stomach. The second and, sometimes, third thoracotomy incisions are for exposure and dissection of the esophagus. Once the tumor is resected, the stomach is pulled through the hiatus for an intrathoracic anastomosis.

Orringer and others have reintroduced the transhiatal procedure as an alternative to the transthoracic approach. The advantages for this technique include eliminating the morbidity associated with a thoracotomy by performing the operation through a laparotomy and left neck incision. The esophagus is removed via blunt dissection and continuity is reestablished with a cervical esophagogastric anastomosis, which eliminates an anastomosis in the chest and the risk of a leak producing mediastinitis.

At present, there are no definitive data to suggest that one technique is superior to the others. Fok and colleagues,⁸¹ in a review of 210 patients treated with either a transthoracic resection (n = 172) versus a transhiatal resection (n = 38), reported an increased incidence of tumor perforation (18%) and injuries to the recurrent laryngeal nerve (13%) following the transhiatal approach. In a retrospective study of 238 patients, Pac and associates⁸² observed increased rates of wound infections, pneumothorax, and hospital mortality for patients treated with transthoracic resection. In contrast, Stark and associates⁸³ observed increased rates of respiratory complications and hospital mortality following transhiatal resection. Others have identified little or no difference in overall complication rates or operative mortality rates between the two surgical approaches.^84,⁸⁵ These findings are consistent with a meta-analysis reported by Hulscher and colleagues,⁸⁶ who observed that the 5-year survival rate with surgery alone was approximately 20% after both transthoracic and transhiatal resections.

Esophagectomy remains the standard of care for high-grade dysplasia and superficial cancers; surgical morbidity and mortality may be substantial for patients who are medically unfit, however. More recently, minimally invasive esophagectomy (MIE) and endoscopic treatments have become treatment options for selected patients with early-stage localized esophageal cancer. A recent meta-analysis using data from 10 studies to evaluate the effects of MIE versus open esophagectomy on outcome demonstrated trends in favor of MIE, with reductions in morbidity, pulmonary complications, anastomotic leakage, mortality, length of hospital stay, operating time, and blood loss.⁸⁷ Similarly, laparoscopic inversion esophagectomy (LIE) has been shown to be comparable to open transhiatal esophagectomy (THE), with potential benefits related to the use of minimally invasive techniques, and is associated with less blood loss and a shorter operative time and length of hospital stay without increased morbidity or mortality.^88,89 It must be recognized, however, that not all patients are candidates for minimally invasive procedures.

Photodynamic therapy has been reported to provide local control in early esophageal cancers arising from Barrett’s esophagus, ranging from 17% to 100%, and high-grade dysplasia, ranging from 75% to 100%.^90,⁹¹ Complete remission rates of more than 90% have also been reported with endoscopic mucosal resection.⁹¹ Recurrence rates are higher than with esophagectomy, however, and require close endoscopic surveillance and retreatment in some patients.

Chemotherapy

It has been observed in several autopsy series that esophageal cancer has a distant failure rate of more than 70%. A large number of chemotherapy agents have been evaluated for response in cancer of the esophagus (Table 43-3), but unfortunately, the response rates remain very low, with only about 20% of patients having an objective response to a variety of single agents. Combination chemotherapeutic regimens have shown a higher response rate, the best responses being seen in patients receiving combinations with cisplatin (Table 43-4). Although the increased response rate has been gratifying, the duration of response has been short and comparable to that seen with single-agent chemotherapy. Current drugs under intense investigation include oxaliplatin, irinotecan, and gemcitabine in combination with cisplatin and the targeted therapies.

TABLE 43-3 Single-Agent Activity in Chemotherapy of Esophageal Cancer*

TABLE 43-4 Combination-Agent Activity in Chemotherapy of Esophageal Cancer *

Combination	No. Patients	Overall Response Rate (%)
Cisplatin + bleomycin²²⁷	61	15
Cisplatin + vindesine + bleomycin²²⁸	68	53
Taxol + cisplatin²²⁹	20	40
5-Fluorouracil + cisplatin + doxorubicin²³⁰	21	33
Cisplatin + etoposide²³¹	73	48
5-Fluorouracil + cisplatin²³²	88	35
Bleomycin + doxorubicin²³³	16	19
Irinotecan + cisplatin¹⁷⁴	35	57
Gemcitabine + cisplatin²³⁴	36	41
Gemcitabine + irinotecan²³⁵	61	NS
Bevacizumab + irinotecan + cisplatin¹¹⁴	47	65
Trastuzumab + 5-fluorouracil + cisplatin¹⁰⁴	594	47.3

NS, not significant.

* Response as determined by radiographic and/or endoscopic methods.

Targeted Biologic Therapy

It is estimated that up to 80% of esophageal adenocarcinomas and squamous cell carcinomas demonstrate increased EGFR expression, which is associated with a decrease in overall survival rates in patients with esophageal cancer. Investigations looking into molecular predictors of sensitivity to EGFR inhibitors for patients with esophageal and gastroesophageal junction cancers are under investigation.⁹² Multiple phase II trials have been reported for the tyrosine kinase inhibitors erlotinib and gefitinib and for the anti-EGFR antibody cetuximab. These agents appear to have minimal activity in adenocarcinomas and limited activity in squamous cell carcinomas.⁹²^–⁹⁹ Furthermore, there has been no correlation of change in expression of EGFR or downstream markers with response.^94,^95,^97,⁹⁹ There is preclinical evidence that EGFR inhibition may enhance radiosensitivity of esophageal cancers.¹⁰⁰ Clinical trials evaluating the efficacy of adding EGFR inhibition during preoperative chemotherapy and irradiation are under way. One phase II multicenter trial using cetuximab with paclitaxel, carboplatin, and irradiation for patients with esophageal cancer has demonstrated tolerability without increased radiation toxicity and a 70% complete clinical response rate. The pathologic response rate has not yet been reported.¹⁰¹

Overexpression of HER2/neu ranges from 0% to 52% in squamous cell carcinomas of the esophagus and 0% to 73% in adenocarcinomas.¹⁰² Although there is some suggestion that HER2/neu overexpression is important in the progression of dysplasia to cancer, resistance to therapy, and extramucosal invasion, its value as a prognostic factor is uncertain.¹⁰³ The ToGa trial screened tumors from 3807 patients with advanced esophagogastric disease, and 22.1% were found to be HER2/neu-positive.¹⁰⁴ Patients with HER2/neu-positive tumors were randomized to receive cisplatin and 5-FU with or without trastuzumab. The addition of trastuzumab resulted in an increase in progression-free survival rates.^104,¹⁰⁵ A phase I and II study of full-dose trastuzumab, paclitaxel, cisplatin, and irradiation for locally advanced, stage II to III or higher, HER2-overexpressing esophageal adenocarcinomas reported a median survival time of 24 months and a 2-year survival rate of 50%, similar to prior studies and without an increase in toxicity.¹⁰⁵ Further evaluations of trastuzumab for esophageal cancer are needed to clarify the utility of targeting HER2/neu in this setting.

Vascular Endothelial Growth Factor (VEGF)

Data suggest a role for vascular endothelial growth factor (VEGF), an agiogenic factor, in the development of esophageal cancer. VEGF expression levels and microvessel density are significantly higher in cancerous tissues compared with normal tissues and Barrett’s dysplastic tissues.¹⁰⁶ VEGF is overexpressed in 30% to 60% of esophageal cancers, and studies have demonstrated a correlation between high levels of VEGF expression, advanced stage, and poor overall survival rates in esophageal cancer patients.^{101,107–112,113} Trials combining VEGF-targeted therapy are ongoing in the treatment of locally advanced esophageal cancer. A recent phase II trial combined bevacizumab with irinotecan and cisplatin in metastatic gastroesophageal junction and gastric cancers, resulting in a response rate of 65% with 8.9 months as the median time to progression, significantly better results than those with historical controls.¹¹⁴ Further phase II and III trials of bevacizumab in esophageal cancer are under way. There are no clinical data on the use of oral tyrosine kinase inhibitors that target VEGF (sorafenib, sunitinib, and AG13736) in esophageal cancer to date. Similar to EGFR, VEGF inhibition has demonstrated enhanced radiosensitivity in preclinical trials.^115,¹¹⁶ The impact of VEGF inhibition in combination with chemotherapy and irradiation in patients with esophageal cancer is currently being investigated.

Cyclooxygenase-2 (COX-2)

COX-2 is another molecular target that has been shown to have significance in cancer development and progression. Selective inhibition of COX-2 has been shown to alter the development and progression of cancer in clinical trials.¹¹⁷ In addition, inhibition of COX-2 activity results in enhanced radiosensitization of tumor tissue but not normal tissue.^118,¹¹⁹ Selective COX-2 inhibition has also been shown to directly inhibit tumor neovascularization.^{118,119,120,121–123} The combination of these effects suggests potential enhancement of selective tumor targeting by COX-2 inhibition. Studies combining COX-2 inhibition with neoadjuvant chemotherapy and radiation have demonstrated tolerability but fail to demonstrate an improvement in the pathologic response over standard neoadjuvant combined-modality treatment.^124,125 Pretreatment VEGF expression does not correlate with treatment response, and pretreatment COX-2 expression has been shown to correlate with treatment response only in the subset of patients with squamous cell carcinoma, although patients whose tumors expressed high levels of VEGF and COX-2 tended to have shorter overall survival times.¹²⁵

Radiation Therapy

Early attempts to cure esophageal cancer with irradiation were generally restricted to patients with middle and upper esophageal lesions, whereas lesions of the distal esophagus were managed with surgical resection. In the 1950s, Buschke ¹²⁶ reported a 5-year survival rate of 5% for patients with lesions of the mid-esophagus treated with irradiation, similar to the surgical results being reported at that time. The outcome following primary radiation therapy alone in the treatment of clinically localized esophageal cancer still remains poor, with a 2-year survival rate of approximately 10% to 20% and a 5-year survival rate of approximately 5% (Table 43-5). Several autopsy studies demonstrate that 50% to 89% of patients harbor both local and undetected distant disease.¹²⁷ Review of the literature examining patterns of failure following irradiation alone demonstrate local failure rates of 50% to 91% following doses greater than 5000 cGy^128,129,130 and a distant failure rate of 23% to 66%.¹²⁸

TABLE 43-5 Results with Irradiation Alone in Treatment of Esophageal Cancer

Radiation Therapy Followed by Surgery

Early attempts to improve local control and survival rates combined radiation and surgery. At the Memorial Sloan-Kettering Cancer Center from 1956 through 1966, 85 patients were treated with preoperative radiation and surgery, with 47 patients ultimately going on to resection. The overall crude 5-year survival rate was 6 % and the median survival rate was 14 months. No tumor was seen in the surgical specimen in 7 (14%) of the tumors resected.¹³¹ Nakayama and colleagues¹³² compared the outcomes for patients who underwent staging laparotomy, gastrostomy, and nutritional supplementation prior to preoperative radiation (20 to 25 Gy in 4 to 5 fractions) followed by a total esophagectomy with the outcomes for patients who underwent either irradiation or surgery alone. The 3-year survival rate was 27% for patients treated with combined therapy versus 22% for those treated with surgery alone and 6% with irradiation alone,¹³² but updated data showed a 5-year survival rate of 13% for the combined-modality cohort.¹³³ Others report a 5-year survival rate of 25% for patients receiving 50 Gy preoperatively versus 14% for patients treated with surgery alone.¹³⁴ These studies, however, were all retrospective reviews that did not allow direct comparisons of treatments. Prospective randomized trials evaluating outcomes for patients treated with either surgery alone or 40 Gy of preoperative irradiation demonstrated no benefit to the addition of preoperative radiotherapy; reported 5-year survival rates ranged from 9.5% to 45% for the irradiation and surgery group and from 11.5% to 25% for patients treated with surgery alone.^{135,136,137,138} Table 43-6 summarizes the results of EBRT alone followed by surgical resection.

TABLE 43-6 Results of Randomized Prospective Trials of Preoperative Irradiation

With the addition of preoperative irradiation, local failure rates are reduced from 50% to 91% following irradiation alone and to 20% to 58% following combined irradiation and surgery. Because these modest improvements in local control rates have not resulted in significant improvements in overall survival rates, there is now little enthusiasm for the routine use of regimens employing only radiation therapy and surgery. In the setting of curative therapy for esophageal cancer and in light of the positive results observed with multimodality therapies, irradiation alone or preoperative radiation therapy should be restricted to patients who are medically unable to receive combined-modality therapy.

Combined-Modality Therapy

Chemoradiotherapy

Numerous single institutions and cooperative groups have investigated the use of concurrent chemotherapy and radiotherapy in the management of patients with localized esophageal cancer, either as definitive treatment or as preoperative therapy. It is not known whether the benefits of combined-modality therapy in esophageal cancer result more from an additive effect of two partially effective modalities or whether a synergism exists between the two therapies. However, a significant body of information suggests that chemotherapeutic agents such as 5-FU, cisplatin, mitomycin C, gemcitabine, irinotecan, oxaliplatin, and taxol have a greater than additive effect when used in combination with radiation therapy. Therefore, most studies testing the safety and efficacy of multimodality therapy have used these agents in a concurrent schedule. The mechanism of the interaction between irradiation and these chemotherapeutic agents is complex and not entirely understood. Because of the uncertainty of these interactions, it seems sensible to use both modalities with treatment schemes and at drug dose levels that are optimum when each is used alone rather than rely on a synergistic effect. The use of concurrent radiation therapy and chemotherapy in esophageal cancer is modeled primarily on the successful use of combined-modality therapy with 5-FU and mitomycin C in carcinomas of the anal canal.

Sequential Chemotherapy and Irradiation

The usefulness of sequential chemotherapy followed by a course of definitive radiation therapy alone has been evaluated on a limited scale. Izquierdo and colleagues ¹³⁹ treated patients with sequential cisplatin/bleomycin chemotherapy for three courses followed by definitive thoracic irradiation and reported a partial response rate of 52% and a complete response rate of 16% as determined by CT scanning and endoscopy. The 1-year and 4-year survival rates were disappointing at 20% and 8%, respectively.¹³⁹ Valerdi and colleagues¹⁴⁰ reported the results of two cycles of induction cisplatin-vindesine-bleomycin chemotherapy followed by definitive radiotherapy and found a discouraging 15% overall survival rate at 5 years. A more recent phase II sequential study reported by Sharma and associates,¹⁴¹ testing multiple cycles of 5-FU plus cisplatin followed by a definitive course of irradiation (60 Gy) was equally disappointing, with a median survival time of 39 weeks. This approach has generated relatively little interest because it does not take advantage of the probable benefit of chemotherapy and irradiation given in combination.