Esophageal Cancer

Overview

Although still relatively uncommon in Western countries, esophageal cancer is fatal in the vast majority of cases. In the United States, an estimated 16,980 new cases will be diagnosed in 2015, and 15,590 deaths will result from the disease (although many cases at the gastroesophageal [GE] junction may be counted as gastric cancer). This high percentage of deaths rivals that of pancreatic cancer and is more than four times that of rectal cancer.

The esophagus extends from the cricopharyngeal sphincter to the gastroesophageal (GE) junction and is commonly divided into the cervical, upper- to mid-thoracic, and thoracic portions. This can be important, because histology and optimal treatment approaches may vary considerably according to the site of the cancer. It may not be possible to determine the site of origin if the cancer involves the GE junction itself.

Epidemiology

Gender

Esophageal cancer is four times more common and slightly more lethal in men than in women.

Age

In patients with adenocarcinoma of the esophagus (now more common in the United States than the squamous cell type, and typically involving the GE junction), the median age at diagnosis is 69 years. The incidence of squamous cell cancer of the esophagus increases with age as well and peaks in the seventh decade of life.

Race

The incidence of squamous cell esophageal cancer is three times higher in blacks than in whites, whereas adenocarcinomas are more common in white men.

Geography

Evidence of an association between environment and diet and esophageal cancer comes from the profound differences in incidence observed in various parts of the world. Esophageal cancer occurs at a rate 20 to 30 times higher in China than in the United States. An esophageal “cancer belt,” primarily squamous cell cancers, extends from northeast China to the Middle East.

Survival

Although the overall outlook for patients with esophageal cancer has improved in the past 30 years, most patients still present with advanced disease, and their survival remains poor. One-third to one-half of patients treated with either chemoradiation therapy or chemoradiation therapy plus surgery are alive at 2 years, without recurrence of esophageal cancer.

Disease Site

The rate of cancer of the distal esophagus is about equal to that of the more proximal two-thirds. In general, squamous cell carcinoma is found in the body of the esophagus, whereas adenocarcinoma predominates in lesions closer to the GE junction.

Etiology and Risk Factors

Cigarettes and Alcohol

Squamous cell carcinomas of the esophagus have been associated with cigarette smoking and/or excessive alcohol intake. Furthermore, cigarette smoking and alcohol intake appear to act synergistically, producing high relative risks in heavy users of tobacco and alcohol. Esophageal adenocarcinoma is increased twofold in smokers.

Diet

High-fat, low-protein, and low-calorie diets have been shown to increase the risk of esophageal cancer. Exposure to nitrosamines has been proposed as a factor in the development of both squamous cell carcinoma and adenocarcinoma of the esophagus. Elevated body mass index has also been associated with an increased incidence.

Barrett Esophagus and Other Factors

Gastroesophageal reflux disease (GERD) and Barrett esophagus (adenomatous metaplasia of the distal esophagus) have been linked to adenocarcinoma of the esophagus. Tylosis, Plummer-Vinson syndrome, history of head and neck cancer, and achalasia have also been associated with a higher than normal risk of developing squamous cell cancer of the esophagus.

Signs and Symptoms

Other than symptoms related to reflux disease, symptoms do not alert the patient until the disease is advanced; few esophageal cancers are diagnosed at an early stage.

Dysphagia

The most common presenting complaint is dysphagia which, because of esophageal elasticity, is generally not noted until the esophageal lumen is narrowed to one-half to one-third of normal.

Weight Loss

Weight loss is common and has a significant role in prognosis (> 10% of total body weight as poor prognosis).

Cough

Cough that is induced by swallowing is suggestive of local extension into the trachea with resultant tracheoesophageal fistula.

Odynophagia and Pain

Pain with swallowing (odynophagia) is an ominous sign. Patients who describe pain radiating to the back may well have extraesophageal spread. Supraclavicular, axillary, or cervical nodal metastases may be appreciated on examination.

Hoarseness

Hoarseness may be a sign of recurrent laryngeal nerve involvement due to extraesophageal spread.

Metastatic Disease

Metastatic disease may present as malignant pleural effusion or ascites. Bone metastasis can be identified by pain involving the affected site or by associated hypercalcemia. The most common metastatic sites are retroperitoneal or celiac lymph nodes, liver, and lungs.

The American College of Surgeons conducted a study using its national cancer database to assess the presentation, stage distribution, and treatment of patients with esophageal cancer between 1994 and 1997 (N = 5,044). The most common presenting symptoms were dysphagia (74%), weight loss (57.3%), reflux (20.5%), odynophagia (16.6%), and dyspnea (12.1%). The American College of Surgeons Database finds 50% of patients present with tumors in the lower third of the esophagus; 42% have adenocarcinoma histology and 52% have squamous histology. Barrett esophagus was found in 39% of patients with adenocarcinoma. Patients who underwent initial surgical resection had the following stage distribution: 13.3% stage I, 34.7% stage II, 35.7% stage III, and 12.3% stage IV.

Diagnosis

In Western countries, the diagnosis of esophageal cancer is generally made by endoscopic biopsy of the esophagus. In the Far East, cytologic evaluation is frequently used.

Endoscopy and Barium X-ray Films

Endoscopy allows for direct visualization of abnormalities and directed biopsies. Barium x-ray films are less invasive and may provide a good assessment of the extent of esophageal disease. However, the latter do not provide pathologic confirmation of malignancy.

Endoscopic Ultrasonography

Endoscopic ultrasonography (EUS) is extremely accurate (> 90%) in establishing the depth of tumor invasion (T stage) but less accurate (70% to 80%) in determining nodal involvement (N stage) unless combined with fine-needle aspiration (FNA) of the involved nodes (93% accuracy) when nodes larger than 5 mm are biopsied. The addition of FNA increases the sensitivity from 63% to 93% and the specificity from 81% to 100%. Because of its sensitivity, if available, EUS should be performed in patients with non-metastatic disease, to help direct treatment strategy. EUS is not reliable in determining the extent of response to neoadjuvant treatment.

Bronchoscopy

Bronchoscopy should be performed to detect tracheal invasion in all cases of esophageal cancer except adenocarcinoma of the distal third of the esophagus.

CT Scan

Once a diagnosis has been established and careful physical examination and routine blood tests have been performed, a computed tomography (CT) scan of the chest and abdomen should be obtained to help assess tumor extent, nodal involvement, and metastatic disease.

Positron Emission Tomography

A prospective trial designed to evaluate the utility of positron emission tomography (PET) vs CT and EUS was performed by obtaining these studies in 48 consecutive patients before esophagectomy. PET achieved a 57% sensitivity, a 97% specificity, and an 86% accuracy compared with CT, which was 99% sensitive, 18% specific, and 78% accurate. In terms of nodal staging, PET was correct in 83% of cases, compared with 60% of cases for CT and 58% for EUS (P = .006). This analysis suggests the improved accuracy of PET in the staging workup of patients with esophageal cancer. Numerous studies report the accuracy of PET scanning in determining the presence of metastatic disease, with sensitivity approaching 90% and specificity over 90%. Several studies have demonstrated that compared with CT scans alone, PET scans detect additional metastatic disease in 10% to 25% of patients with apparently non-metastatic disease at the time of evaluation. In addition, about 5% of patients who appeared to have metastatic disease to locoregional lymph nodes on CT scans, had non–fluorine-1-fluorodeoxyglucose–avid disease on PET scans that was confirmed to be non-metastatic disease. However, about 5% of patients had false-negative PET scans.

Another potential role for PET scans is in the evaluation of response to neoadjuvant therapy. However, data on the utility of PET in this regard have been mixed to date. While some studies suggest that PET response, admittedly defined in different ways in the different studies, has been correlated with pathologic response, and in some studies progression-free survival, PET response has not correlated with overall survival outcomes and has not been able to accurately correlate with a lack of response to neoadjuvant therapy. Therefore, PET scans should not routinely be used to make treatment decisions with regard to neoadjuvant therapy. The ongoing Cancer and Leukemia Group B (CALGB) 80803 study (ClinicalTrials.gov identifier: NCT 01333033) may help elucidate the role of PET scans in this setting.

Bone Scan

A bone scan should be obtained if the patient has bone pain or an elevated alkaline phosphatase level.

Thoracoscopy/Laparoscopy

Investigators have begun to examine the role of surgical staging before definitive therapy. These procedures are designed to allow pathologic review of regional lymph nodes and the accurate assessment of extraesophageal tumor spread by direct visualization. A multi-institution trial (CALGB 9380) published in 2001 found these procedures to be feasible in more than 70% of patients; they resulted in the upstaging of patients in 38% of cases reviewed. In current common practice, however, thoracoscopy and laparoscopy are reserved for suspicious findings on CT or PET scan.

Warning

Staging studies should be performed in a sequential manner. Invasive, lower-yield, and less accurate studies and procedures should only be undertaken if management would change on the basis of specific findings.

Screening and Surveillance

High-Risk Patients

Adenocarcinoma

The role of screening patients with GERD and surveillance of patients with Barrett esophagus by upper gastrointestinal endoscopy remains under investigation. In 833 patients studied by endoscopy, there was a 13% incidence of intestinal metaplasia (Barrett esophagus). Dysplasia or cancer was seen in 31% of patients with long-segment Barrett esophagus, in 10% with short-segment Barrett esophagus, and in 6% with GE junction intestinal metaplasia.

Squamous cell carcinoma

Mass screening in the high-risk areas of China and Japan is considered appropriate and feasible.

Pathology

The potential importance of the differences in histology on disease prognosis, and therefore treatment, which has been clinically recognized for several years, has resulted in differences in staging, based on histology in the seventh edition of the AJCC Cancer Staging Manual.

Adenocarcinoma

The incidence of esophageal adenocarcinoma involving the GE junction has risen 4% to 10% per year since 1976 in the United States and Europe. As a result, adenocarcinoma is now the predominant histologic subtype of esophageal cancer. The distal one-third of the esophagus is the site of origin of most adenocarcinomas.

Squamous Cell Carcinomas

Squamous cell carcinomas occur most often in the proximal two-thirds of the esophagus. Squamous cell carcinoma is still the most prevalent histologic subtype worldwide.

Other Tumor Types

Other, less frequently seen histologic subtypes include mucoepidermoid carcinoma, small-cell carcinoma, sarcoma, adenoid cystic leiomyosarcoma, and primary lymphoma of the esophagus. Occasionally, metastatic disease from another site may present as a mass in the esophagus or a mass pressing on the esophagus.

Metastatic Spread

The most common sites of metastatic disease are the regional lymph nodes, lungs, liver, bone, adrenal glands, and diaphragm. Adenocarcinoma can also metastasize to the brain.

Staging and Prognosis

TABLE 1: 1983 and 2010 AJCC TNM staging systems for esophageal cancer

On the basis of data demonstrating that the depth of penetration has important prognostic significance, the American Joint Committee on Cancer (AJCC) TNM staging system for esophageal cancer was changed from a clinical one (1983) to a pathologic one in 2002. The seventh edition of the AJCC Cancer Staging Manual became available in January 2010, and staging updates for esophageal cancer are listed in Table 1. Both the clinical and pathologic staging systems are shown in this table, because patients may be cured without an operation. Although pathologic information obtained from an esophagectomy specimen is of prognostic importance, postoperative therapy to improve prognosis has not been rigorously tested. Moreover, recurrence rates for stages I (30%) and II (70%) cancers suggest early systemic spread undetected by current noninvasive staging.

Pathologic information obtained from an esophagectomy specimen is of significant prognostic importance. Immunohistochemical analysis of the initial biopsy specimen may also have prognostic relevance. Clinical staging has been shown to be of prognostic importance, particularly in patients managed with primary radiotherapy or chemoradiation therapy.

Histology and Grade

Neither histology nor grade has been shown to be of prognostic importance in esophageal carcinoma.

Other Prognostic Factors

Patient age, performance status, and degree of weight loss are of prognostic importance. The prognostic implications of tumor-suppressor genes and oncogenes are an area of active investigation.

Treatment

Treatment options for the various disease stages are given in Table 2, along with 5-year survival rates.

Treatment of Localized Disease

Only 40% to 60% of patients with esophageal cancer present with clinically localized disease. The National Comprehensive Cancer Network guidelines state that patients with clinically localized disease may be treated with resection or chemotherapy plus irradiation (Tables 3 and 4). The overall 5-year survival rates for either surgery alone or combined chemotherapy and irradiation appear equivalent.

Chemoradiation therapy as primary management of localized or locoregionally confined esophageal cancer has been shown to be superior to irradiation alone. A series of randomized trials have demonstrated that adjuvant postoperative chemoradiation therapy does not offer a survival advantage to patients with esophageal cancer, save perhaps for those affected at the GE junction, as demonstrated in part in INT-0116. Adequate patient selection, tumor staging, and treatment standardization will be required before the optimal therapeutic modalities in these patients will be determined.

Surgery

Preoperative medical evaluation. Preoperative medical evaluation helps determine the patient’s risk of postoperative complications and mortality. In addition to the staging and nutritional status, it should include an evaluation of the pulmonary, cardiac, renal, and hepatic functions.

Extent of surgical resection. The extent of resection depends on the location of the primary tumor, histology of the tumor, and nature of the procedure (palliative vs curative). A retrospective study has reported that superficial mucosal lesions (T1a) may be treated via endoscopic mucosal resection, but those patients with submucosal invasion (T1b) require esophagectomy.

TABLE 2: Treatment options and survival by stage in esophageal cancer

TABLE 3: Chemotherapy regimens for esophageal carcinoma

TABLE 4: Postoperative chemoradiation therapy for gastric/esophageal cancer

For tumors of the intrathoracic esophagus (squamous cell carcinomas) and tumors with extensive Barrett esophagus (adenocarcinomas), it is often necessary to perform a total esophagectomy with cervical anastomosis to achieve a complete resection. For distal lesions of the abdominal esophagus (adenocarcinomas) and cardia, it is often possible to perform an intrathoracic esophageal anastomosis, although many surgeons would prefer to perform a total esophagectomy.

The resected esophagus may be replaced with a tubularized stomach in patients with tumors of the intrathoracic esophagus or with a colon interposition in patients with tumors involving the proximal stomach, because such involvement can make this organ unsuitable for esophageal reconstruction. The esophageal replacement is usually brought up through the posterior mediastinum, although the retrosternal route is often used in palliative procedures.

Patient selection. The indications for esophagectomy in esophageal cancer vary from center to center. Clearly, patients with distant metastases, evidence of nodal metastases in more than one nodal basin, or tumor extension outside the esophagus (airway, mediastinum, vocal cord paralysis) are candidates for palliative therapy. Patients with disease limited to the esophagus and no evidence of nodal metastases (stages I and IIA) may be treated with esophagectomy, although these patients can also be considered for definitive treatment with chemoradiation therapy. Multiple retrospective studies in the United States and Europe document that short-term and even long-term outcomes are superior when esophageal resection is performed at high-volume centers (those performing approximately 8 to 12 procedures per year). Regionalization of surgical care of high-risk esophageal cancer patients may be even more beneficial.

Method of resection. Considerable controversy also exists among surgeons regarding the method of resection. To date, two randomized studies have compared transhiatal esophagectomy (without thoracotomy) with the Ivor-Lewis (transthoracic) esophagectomy (with thoracotomy). These studies failed to show differences between the two procedures with regard to operative morbidity and mortality. In a randomized trial of 220 patients treated with either an extended transthoracic esophagectomy or limited transhiatal esophageal resection, no significant overall survival benefit was found for either approach, although extended transthoracic esophagectomy showed a trend toward an improvement in 5-year survival. Over the past 5 years, successful attempts have been made to use minimally invasive approaches to esophageal cancer with thoracoscopy and laparoscopy. A recent randomized trial from the Netherlands comparing minimally invasive versus open esophagectomy has shown decreased pulmonary morbidity and reduced blood loss in the minimally invasive group. Retrospective studies suggest that the rate of positive margins and lymph node harvest are comparable between minimally invasive and open approaches, although randomized data are not yet available for comparing the endpoints of local recurrence, disease-free survival, and overall survival.

The need for pyloric drainage (pyloroplasty) following esophagectomy is another area of debate. A meta-analysis of nine randomized trials that included 553 patients showed a trend favoring pyloric drainage in improving gastric emptying and nutritional status, whereas bile reflux was better in the nondrainage group. The gastric emptying time evaluated by scintigraphy was twice as long in the nondrainage group as in the pyloric drainage groups.

Lymphadenectomy. Considerable controversy exists regarding the need for radical lymphadenectomy in esophageal disease. Much of the controversy is due to the fact that different diseases are being compared.

Japanese series include mostly patients with squamous cell carcinomas of the intrathoracic esophagus, with 80% of the tumors located in the proximal and middle sections of the esophagus. Americans report combined series, with at least 40% to 50% of patients with adenocarcinomas of the distal esophagus. Skinner and DeMeester favor en bloc esophagectomy with radical (mediastinal and abdominal) lymphadenectomy, based on 5-year survival rates of 40% to 50% in patients with stage II disease, as compared with rates of 14% to 22% in historical controls.

In a retrospective study, Akiyama found a 28% incidence of cervical node metastases in patients with squamous cell carcinomas located in the middle and distal portions of the esophagus, as opposed to 46% in those with tumors of the proximal third. Overall survival at 5 years was significantly better in patients who underwent extended lymphadenectomy (three fields) than in those who had conventional lymphadenectomy (two fields); this finding was true in patients with negative nodes (84% and 55%, respectively) and in those with positive nodes (43% and 28%, respectively). Extended lymphadenectomy was not associated with a survival advantage in patients with tumors in the distal third of the esophagus.

In a study of 1,000 patients with esophagogastric junction adenocarcinomas, the tumors were classified according to the location of the center of the tumor mass in adenocarcinomas of the distal esophagus, cardia, and subcardia. The tumors located in the cardia and subcardia regions spread primarily to the paragastric and left gastric vessel nodes and did not benefit from extended esophagectomy. Kato et al have studied the use of sentinel node mapping to improve the sensitivity of lymphadenectomy.

Preoperative chemotherapy

The frequency of metastatic disease as the cause of death in patients with esophageal cancer has resulted in exploration of the early application of systemic therapy for esophageal cancer. The first of the two large studies was RTOG (Radiation Therapy Oncology Group) trial 8911 (USA Intergroup 113). A total of 440 patients were treated with surgical resection alone or preceded by three cycles of cisplatin and fluorouracil (5-FU). Objective responses were reported in only 19% of patients who received chemotherapy. No difference in resectability, operative mortality, median survival (14.9 months with chemotherapy vs 16.1 months with surgery alone), or 2-year survival (35% vs 37%) was reported.

However, the Medical Research Council evaluated 802 patients with resectable esophageal cancer in a similar study. Patients randomized to receive chemotherapy were administered two cycles of cisplatin (80 mg/m²) and 5-FU (1 g/m²/d as a continuous infusion for 4 days). Microscopically complete resection was performed more frequently in patients receiving chemotherapy, with no difference found in postoperative complications or mortality. Moreover, patients who received neoadjuvant chemotherapy had significantly longer median survival (16.8 months vs 13.3 months) and 2-year survival (43% vs 34%) than patients treated with surgery alone. With a median follow-up of 6 years, the updated results of this study continued to demonstrate a significant difference in overall survival at 5 years: 23% for patients who received preoperative chemotherapy vs 17% for patients treated with surgery alone-and this benefit was present in both histologies. The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) study, which evaluated preoperative and postoperative chemotherapy with epirubicin, cisplatin, and infusional 5-FU in patients with GE cancer (about 25% had esophageal or GE junction tumors), also demonstrated a statistically significant improvement in survival with perioperative chemotherapy, with a hazard ratio [HR] of 0.75, suggesting a 25% increase in the likelihood of survival. Only about 40% of patients actually completed both preoperative and postoperative chemotherapy, but overall, this suggests that chemotherapy has benefit as preoperative therapy in esophageal cancer. The reasons for the differences in the outcomes are unclear but may be related to the chemotherapy regimen and schedule employed in the Intergroup study, patient population, or study design. As a result, the role of neoadjuvant chemotherapy remains in question but is promising, especially with the potentially more efficacious, newer-generation chemotherapy agents.

Given the uncertainty about the efficacy of preoperative chemotherapy and chemoradiation therapy, some investigators have administered preoperative chemotherapy, followed by chemoradiation therapy, then surgery. The true utility of this approach will need to be defined by randomized studies (that carefully match for histology, anatomic location, radiation techniques, and chemotherapy), but clearly it is feasible, without a significant increase in toxicity or operative morbidity. Interestingly, these reports have also demonstrated that most patients had significant improvement or resolution of dysphagia with the induction chemotherapy alone.

Adjuvant/postoperative chemotherapy

Because the most common source of treatment failure in patients with esophageal cancer who have undergone surgical resection is distant metastatic disease, postoperative chemotherapy has also undergone limited investigation. The Japanese Cooperative Oncology Group has compared preoperative and postoperative chemotherapy in 330 patients with stage II or III esophageal squamous cell carcinomas. Patients received two courses of either preoperative or postoperative chemotherapy with cisplatin/5-FU. The patients who received preoperative chemotherapy demonstrated a significant improvement in progression-free survival (2.9 years vs 2 years). Thus, the investigators determined that preoperative therapy would be the new standard therapy. However, the fact that preoperative chemotherapy was superior to postoperative chemotherapy does not necessarily mean that there is no benefit to postoperative chemotherapy. Moreover, the role of adjuvant chemotherapy alone in esophageal adenocarcinomas is uncertain.

Radiotherapy

Although radiotherapy alone is inferior to chemoradiation therapy in the primary management of locoregionally confined esophageal cancer, it may offer palliation to patients with advanced local disease who are too frail to be managed with chemotherapy.

Preoperative radiotherapy. Preoperative radiotherapy has been shown to be of little value in converting unresectable cancers into resectable ones or in improving survival. However, it decreases the incidence of locoregional tumor recurrence.

Postoperative radiotherapy. Postoperative radiotherapy (usually to 50 or 60 Gy) can decrease locoregional failure following curative resection, but it has no effect on survival.

Brachytherapy. Intraluminal isotope radiotherapy (intracavitary brachytherapy) allows high doses of radiation to be delivered to a small volume of tissue. Retrospective studies suggest that a brachytherapy boost may result in improved rates of local tumor control and survival over external beam radiation therapy (EBRT) alone. This technique can be associated with a high rate of morbidity if not used carefully.

A multi-institution prospective phase I/II trial of 49 patients was conducted by the RTOG to determine the feasibility and toxicity of chemotherapy, EBRT, and esophageal brachytherapy in potentially curable patients with esophageal cancer. Nearly 70% of patients in RTOG study 9207 were able to complete EBRT, brachytherapy, and at least two cycles of 5-FU/cisplatin. The median survival time was 11 months, and the 1-year survival rate was 49%. Because of the 12% incidence of fistula formation, the investigators (Gaspar et al: Cancer J 2001) urged caution in the routine application of brachytherapy as part of a definitive treatment plan.

Chemoradiation therapy

Preoperative chemoradiation therapy. Initial trials of preoperative chemoradiation therapy reported unacceptably high operative mortality (approximately 26%). Subsequent trials reported operative mortality of 4% to 11%, median survival as long as 29 months, and 5-year survival rates as high as 34%. In general, 25% to 30% of patients have no residual tumor in the resected specimen, and this group tends to have a higher survival rate than those who have a residual tumor discovered by the pathologist.

The superiority of preoperative chemoradiation therapy over surgery alone in esophageal adenocarcinoma has been investigated in several prospective trials. The first trial (Walsh et al: N Engl J Med 1996), in Ireland, included 113 patients with adenocarcinoma of the esophagus. These patients were randomized to receive either preoperative chemoradiation therapy (two courses of 5-FU and cisplatin given concurrently with 40 Gy of radiotherapy in 15 fractions) or surgery alone. Median survival was statistically superior in the combined-modality arm compared with the surgery-alone arm (16 months vs 11 months). Rates of 3-year survival again statistically favored the combined-modality arm (32% vs 6%). Although toxicity was not severe, the short survival duration in the surgery control arm has minimized the impact of these results in the United States.

An American cooperative group study, CALGB 9781, was closed early after enrollment of 56 patients, because of poor accrual, but the reported long-term results of the study supported a significant survival benefit (5-year survival 39% vs 16%) with chemoradiation (cisplatin 100 mg/m² on days 1 and 29; 5-FU 1,000 mg/m²/d IV continuous infusion from days 1 to 4 and 29 to 32 and 50.4 Gy of radiation) followed by surgery, compared with surgery alone.

More recently, van Hagen et al investigators studied radiation therapy (41.4 Gy) with weekly (for 5 weeks) carboplatin (area under the curve [AUC]=2), with paclitaxel (50 mg/m²) followed by surgery vs surgery alone. Most of the 363 patients enrolled in this study, all of whom had potentially resectable disease at the time of enrollment, had adenocarcinoma (75% vs 23% squamous cell carcinoma). The pathologic complete response rate was 29% in those who underwent preoperative therapy. The addition of neoadjuvant chemoradiation increased the likelihood of a complete resection (from 64.9% to 92.3% with neoadjuvant chemoradiation) and survival, both median (24 months vs 49.4 months with neoadjuvant therapy) and at 3 years (48% vs 59% with neoadjuvant therapy). There was no difference in postoperative complications or in-hospital mortality between the two arms.

A meta-analysis of randomized trials comparing neoadjuvant chemoradiation therapy followed by surgery with surgery alone found that neoadjuvant concurrent chemoradiation therapy improved 3-year survival (odds ratio, 0.66) compared with surgery alone, with a nonsignificant trend toward increased treatment mortality with neoadjuvant chemoradiation.

The most widely accepted recent study is the CROSS trial, reported by Van Hagen et al, which assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (with doses titrated to achieve an area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m² of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 d/wk), followed by surgery. Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P < .001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy–surgery group versus 24 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy–surgery group (HR, 0.657; 95% CI, 0.495–0.871; P = .003).

Newer chemotherapy agents are active and may improve outcome over these older trials.

A phase II trial from Memorial Sloan Kettering Cancer Center combined cisplatin and irinotecan with 50.4 Gy of radiation therapy followed by surgery. Twenty-five percent of patients had a pathologic complete response.

Several schedules of oxaliplatin (Eloxatin) and 5-FU concurrently with radiation have been investigated. None of the studies have been large enough or the results conclusive enough to result in the widespread adoption of oxaliplatin in place of carboplatin or cisplatin with radiation in esophageal cancer. The Southwest Oncology Group (SWOG) has investigated a schedule of oxaliplatin 85 mg/m² every other week, with a continuous infusion of 5-FU 180 mg/m²/d continuously through radiation, followed by surgery (SWOG 0356). The regimen was regarded as tolerable, with two patients (2.2% of 93 evaluable) dying of chemoradiation, and two as a result of surgical complications (2.2%). Most patients (79/93 evaluable patients, 84.9%) underwent resection, including R0 resection in 67% of patients, and 28% of the patients achieved a pathologic complete response, lower than the endpoint of the study to proceed to a phase III study, but interesting nonetheless. The FOLFOX (oxaliplatin, leucovorin, 5-FU) schedule concurrent with radiation has also been studied. Conroy et al presented a randomized phase III study at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) that compared FOLFOX/radiation therapy with cisplatin/5-FU/radiation therapy. The study included 267 patients, of which 86% had squamous histology and 52% had stage III disease. Three-year progression-free survival was 18.2% and 17.4%, respectively, showing no benefit to FOLFOX in progression-free survival.

Adding anti-EGFR (epidermal growth factor receptor) therapy with cetuximab or panitumumab to neoadjuvant chemoradiation appears to be feasible in small phase I and II studies, but it has not clearly been shown to improve pathologic complete response rates, and the large randomized trial known as REAL-3 failed to show any benefit from perioperative chemotherapy with panitumumab.

Primary chemoradiation therapy. Patients with locally advanced esophageal cancer (T1-4 N0-1 M0) may be cured with definitive chemoradiation therapy. Randomized trials have demonstrated a survival advantage for chemoradiation therapy over radiotherapy alone in the treatment of esophageal cancer. In an RTOG randomized trial involving 129 patients with esophageal cancer, 80% of whom had squamous cell cancers, irradiation (50 Gy) with concurrent cisplatin and 5-FU provided a significant survival advantage (27% vs 0% at 5 years) and improved local tumor control over radiation therapy alone (64 Gy). Median survival also was significantly better in the combined-therapy arm than in the irradiation arm (14.1 months vs 9.3 months). Survival outcomes were also somewhat better for squamous cell cancers. These data were confirmed in a similar study by the Eastern Cooperative Oncology Group using mitomycin-C rather than cisplatin with infusional 5-FU.

RTOG 94-05/Intergroup 0123 randomized patients to conventional-dose radiotherapy (50.4 Gy) or high-dose radiotherapy (64.8 Gy), both with 5-FU/cisplatin chemotherapy. The study was closed early because of increased morbidity of the high-dose arm. Kachnic et al reported a subsequent quality-of-life analysis that confirmed lower mean quality of life in the high-dose radiotherapy arm, providing further data that 50.4 Gy is the recommended dose of radiation therapy in the definitive setting.

The EGFR antagonist cetuximab has been demonstrated to have radiation sensitization effects in squamous cell carcinomas of the head and neck. Naturally, agents of this class are being evaluated in esophageal cancers. De Vita et al employed cetuximab with radiation after induction therapy with FOLFOX/cetuximab. Overall, the preoperative therapy was fairly well tolerated, and a pathologic compete response was found in 27% of patients. Cisplatin, docetaxel, and cetuximab were combined with radiation therapy by Ruhstaller et al prior to surgery, and this was found to be tolerable, with a complete or near complete pathologic regression in 68% of the patients. In addition, Li et al reported on a small series of patients who received cisplatin, paclitaxel, and radiation therapy with erlotinib, 150 mg daily. The 2-year overall survival was 70.1%, and relapse-free survival was 57.4%, with acceptable tolerability.

Bedenne et al presented results of a randomized trial of preoperative chemoradiation therapy vs chemoradiation therapy alone, in which there was no difference in median or 2-year overall survival rates. A randomized intergroup trial was designed to investigate the role of high-dose irradiation in conjunction with systemic therapy. This study compared doses of 50.4 Gy with doses of 64.8 Gy. Both treatment arms of the study administered concurrent 5-FU and cisplatin. This trial was stopped after an interim analysis revealed no statistically significant difference in survival between the two groups. The authors concluded that higher-dose radiation therapy did not offer any survival benefit over the 50.4-Gy dose.

Newer forms of radiation therapy, such as proton beam therapy, are being studied in combination with chemotherapy. Lin et al published a single-institution experience of treating 62 patients with proton beam radiotherapy/chemotherapy, of which 29 went on to surgery. With a median relative biologic equivalence dose of 50.4 Gy, toxicities were similar to those in previous photon beam radiotherapy/chemotherapy studies. The pathologic complete response rate was 28% in those who underwent surgery. Prospective comparison of proton beam radiotherapy/chemotherapy vs conventional photon beam radiotherapy is awaited.

• Patient selection-Patients with disease involving the mid to proximal esophagus are excellent candidates for definitive chemoradiation therapy because resection in this area can be associated with greater morbidity than resection of more distal tumors.

Most of the trials demonstrating the efficacy of chemoradiation therapy have had a high proportion of patients with squamous cell cancers. Chemoradiation therapy has thus become standard treatment of locoregionally confined squamous cell cancer of the esophagus. It is essential that chemotherapy be given concurrently with irradiation when this approach is chosen as primary treatment for esophageal cancer. A typical regimen is 50 to 60 Gy over 5 to 6 weeks, with cisplatin (75 mg/m²) and 5-FU (1 g/m²/24 hours for 4 days) on weeks 1, 5, 8, and 11.

The literature also supports offering primary surgery, preoperative chemoradiation therapy, or primary chemoradiation therapy with surgical salvage if necessary to patients with adenocarcinoma. Entering these patients on protocols will allow us to further define standard treatment.

Sidebar: Ilson and colleagues reported on initial results of RTOG 0436, a randomized phase III trial comparing definitive chemoradiation with weekly cisplatin/paclitaxel/RT against RT at 50.4 Gy with or without weekly cetuximab. Of 328 eligible patients, 80% had T3/T4 disease and 66% had N1 disease. The 24-month overall survival rate was similar between those treated with cetuximab (44%) and those not (42%), as was cCR rates (56% vs 59%). This suggests that EGFR-targeted agents will only be useful if a biomarker test can identify susceptible tumors (Ilson DH, et al: J Clin Oncol 32[suppl 5s]: abstract 4007, 2014).

Sequential preoperative chemotherapy and radiation therapy. Only modest benefits have been found with preoperative chemoradiation therapy to date, with systemic failure continuing to be an important problem. Thus, sequential therapy with chemotherapy followed by chemoradiation therapy has been explored.

Ajani et al reported on a series of 43 patients who received 12 weeks of cisplatin and irinotecan followed by weekly paclitaxel with infusional 5-FU and concurrent radiation therapy (4,500 cGy) and then esophagectomy. Therapy was well tolerated, with no deaths from chemotherapy or chemoradiation therapy, and an operative mortality rate of 5%. Cisplatin and irinotecan induced responses in 37% of patients, and 91% of patients underwent complete resection. Pathologic complete responses occurred in 26% of patients, and some tumor shrinkage was noted in 63% of patients. With a median follow-up of more than 30 months, the median progression-free survival was 10.2 months, the median survival was 22.1 months, and the 2-year survival was 42%. The patients who had a pathologic response to therapy had significantly better outcomes than the rest of the study population. However, systemic recurrences remained a prominent cause of failure, with five patients experiencing recurrence first in the brain and an additional five patients, in the liver.

Despite the logical rationale and promise of this approach, a subsequent randomized phase II study also conducted by Ajani et al at the MD Anderson Cancer Center did not demonstrate any improvement in outcomes after induction chemotherapy with an oxaliplatin/infusional 5-FU regimen, followed by oxaliplatin/infusional 5-FU/radiation surgery, or chemoradiation alone, followed by surgery. However, there was no significant difference in operative morbidity or mortality between the two approaches at this high-volume referral center. Nonetheless, this approach cannot be recommended for use outside the context of a clinical trial.

After definitive therapy for esophageal cancer, the optimal surveillance strategy for recurrent or second primary disease is uncertain. Because of the primary threat to survival, CT scans are often ordered at 6- to 12-month intervals. Endoscopies are often performed to evaluate for local recurrence. However, a retrospective evaluation of patients with esophageal adenocarcinoma who were treated with trimodality therapy including chemotherapy, radiation, and surgery at the MD Anderson Cancer Center from 2000 to 2010 suggested that anastomotic recurrence alone, without distant metastatic disease, is an infrequent event, occurring in 5% of patients, compared with 36% of patients who had anastomotic recurrence with distant metastatic disease. Moreover, 70% of patients developed recurrence within 3 years of surgery. These findings suggest that surveillance for recurrent or metastatic disease that is amenable to treatment may focus on the history and physical examination, with radiographic imaging primarily during the first 3 years, and then with decreasing intensity.

Esophagectomy following induction chemotherapy and chemoradiation therapy for squamous cell carcinoma. Controversy exists regarding the need for esophagectomy following chemoradiation therapy in patients with squamous cell carcinoma, which tends to respond well to chemoradiation. Although previously described studies randomized patients to receive surgery with or without preoperative chemoradiation therapy, Stahl et al randomized patients to receive chemoradiation therapy with or without surgery. Also, all 172 patients in the study underwent initial induction chemotherapy (bolus 5-FU, leucovorin, etoposide, and cisplatin for three cycles). Those randomized to receive preoperative chemoradiation therapy received cisplatin/etoposide with 40 Gy of radiation, followed by surgery 3 to 4 weeks later. Those randomized to receive definitive chemoradiation therapy received cisplatin/etoposide with 65 Gy of radiation. After a 6-year median follow-up, the local progression-free survival favored the group that underwent surgery (64% vs 41%). However, the treatment-related mortality was higher in those patients who underwent surgery (13% vs 4%), and so overall survival was statistically equivalent (at 3 years, 31% vs 24%). Since induction chemotherapy was used in all patients, these results should not be extrapolated to indicate the value of esophagectomy following chemoradiotherapy alone. In addition, the surgical mortality rate in this trial was significantly higher than in modern series from high-volume institutions, suggesting that if surgery can be performed with low operative risk, the risk/benefit balance may tilt in favor of trimodality therapy (chemoradiotherapy and surgery).

Stahl et al reported on a randomized trial comparing preoperative chemotherapy with chemoradiotherapy in 126 patients with T3-4 NX adenocarcinoma of the lower esophagus/gastric cardia. Pathologic complete response was higher (15.6% vs 2%) and 3-year survival was trending toward improvement (47% vs 28%) in patients who received preoperative chemoradiotherapy.

At ASCO 2013, Alberts et al reported on North Central Cancer Treatment Group N0849, which examines the use of extended neoadjuvant chemotherapy, since delivery of post-chemotherapy may be difficult. Patients were randomized to arm A: docetaxel/oxaliplatin followed by 5-FU/oxaliplatin/50.4 Gy radiation therapy or arm B: 5-FU/oxaliplatin/50.4 Gy radiation therapy. Both arms then proceed to surgery. Forty-two patients were included in the interim analysis. Of the 21 patients in arm A, 2 did not proceed to chemoradiation and 2 died before proceeding to surgery. The pathologic complete response rate was 33% in arm A and 48% in arm B, so extended neoadjuvant chemotherapy did not improve the pathologic complete response rate, and survival/recurrence data are pending.

The incidence of residual disease in patients who have a complete clinical response to chemoradiation therapy is 40% to 50%, and those patients who have a pathologic complete response to chemoradiation therapy have the best survival rates with surgery.

Treatment in elderly patients. Since esophageal cancer is being diagnosed in more patients at older ages, research is ongoing as how best to treat elderly patients. Retrospective studies from Nallapareddy et al have found chemoradiaton therapy is tolerable in elderly patients, whereas Rice et al have found a trimodality approach of chemoradiation therapy followed by surgery is also tolerable in the elderly. Close monitoring for toxicities such as dehydration, nutritional concerns, anemia, and postoperative arrhythmia was recommended in these two studies.

Treatment of Advanced Disease

The goal of esophageal cancer treatment is generally palliative for patients with bulky or extensive retroperitoneal lymph nodes or distant metastatic disease. Therapeutic approaches should temper treatment-related morbidity with the overall dismal outlook. Most data relating to the treatment of unresectable and metastatic esophageal cancer are often derived from clinical trials in which patients with esophageal and gastric and gastroesophageal carcinomas are enrolled. Similarly, patients in such studies may have either squamous cell carcinomas or adenocarcinomas. However, although subset analysis of data suggests a similar survival outcome in both histologic subsets, it is possible that there is a difference in response rates, by histology.

Local treatment

In patients with a good performance status, the combination of 5-FU/mitomycin, or 5-FU/cisplatin, and radiotherapy (50 Gy) results in a median survival of 7 months to 9 months. This regimen usually renders patients free of dysphagia until death.

Photodynamic therapy

Porfimer (Photofrin) and an argon-pumped dye laser can provide effective palliation of dysphagia in patients with esophageal cancer. A prospective, randomized multicenter trial comparing photodynamic therapy (PDT) with neodymium/yttrium-aluminum-garnet (Nd:YAG) laser therapy in 236 patients with advanced esophageal cancer found that improvement of dysphagia was equivalent with the two treatments.

A review of 119 patients treated with endoluminal palliation reported a significant improvement in dysphagia scores and an increased ability to relieve stenosis caused by tumor when PDT was used in conjunction with laser therapy and irradiation.

Other approaches

Other approaches include EBRT with or without an intracavitary brachytherapy boost, simple dilatation, placement of stents, and laser recannulization of the esophageal lumen.

Palliative resection

Palliative resection for esophageal cancer is rarely warranted, although it does provide relief from dysphagia in some patients.

Chemotherapy

At this time, most studies in esophageal and GE junction cancers categorize them by histology: gastric and GE junction adenocarcinomas, or esophageal squamous cell carcinomas. The data are from studies that include a substantial proportion of patients with metastatic gastric cancer, as opposed to esophageal or GE junction adenocarcinomas.

Phase I and II studies have demonstrated moderate response rates to chemotherapy in esophageal cancer.

Although chemotherapy alone may produce an occasional long-term remission, there is no standard regimen for patients with metastatic cancer. Patients with advanced disease should be encouraged to participate in well-designed trials exploring novel agents and chemotherapy combinations.

Chemotherapy in Advanced Esophageal Cancer

In Britain, the ECF regimen, a combination of epirubicin (50 mg/m²) and cisplatin (60 mg/m²), both repeated every 21 days, with continuous infusion of 5-FU (200 mg/m²/d), is considered to be a standard regimen for advanced esophagogastric cancers. However, in the remainder of the world, there is no regimen that is considered to be the standard treatment of metastatic esophageal cancer. Difficulties in determining optimal therapy for this disease include the possible differences between esophageal squamous cell cancers and adenocarcinomas. Moreover, most of the available data regarding the treatment of metastatic esophageal cancer are derived from studies in which most patients had gastric cancer or from small phase II studies.

Although the regimen has been fairly well tolerated, infusional 5-FU has rendered the combination unpopular in other countries. Several phase III studies have been performed and consistently demonstrated objective responses in about 40% of patients, with a median survival of 9 months and a 1-year survival of 36% to 40%. The main severe toxicities of this regimen are neutropenia, in about one-third of patients (32% to 36%), lethargy (18%), and nausea and vomiting (11% to 17%). The REAL-2 study evaluated 1,002 patients (60% esophageal or GE junction cancer) with advanced esophagogastric cancers. They were randomly assigned to receive epirubicin (50 mg/m² every 21 days) with either cisplatin (60 mg/m²) or oxaliplatin (130 mg/m²) every 21 days, and either infusional 5-FU (200 mg/m²/d) or capecitabine (Xeloda; 625 mg/m² twice daily). In this study, the outcomes were similar in the resultant treatment groups, with median survivals of about 10 months and 1-year survivals between 39% and 45%. Indeed, the single best-performing arm was EOX (epirubicin, oxaliplatin, Xeloda [capecitabine]), with a median survival of 11.2 months and a 1-year survival of 46.8%, although these results were not significantly superior to the other arms.

With the advent of many new chemotherapeutic agents (the taxoids, paclitaxel and docetaxel [Taxotere], irinotecan, and gemcitabine [Gemzar]) with varying mechanisms of activity, further studies have been conducted, and each of these drugs has demonstrated activity, with responses achieved in approximately 15% to 30% of patients.

However, the primary route of investigation for these new agents has been in combination with cisplatin and/or 5-FU. The results available to date suggest promising activity, with response rates often around 50% in phase II studies. Irinotecan (65 mg/m²) and cisplatin (30 mg/m²) administered weekly for 4 weeks every 6 weeks have also been active, with responses in 20 of 35 patients (57%) and an impressive median survival of 14.6 months. A Korean phase II study did not confirm these results but did suggest the combination was active, with a response rate of 31% of 32 patients, and a median survival of 9.6 months.

TABLE 5: Combination chemotherapy in advanced disease

Paclitaxel (180 mg/m² over 3 hours) and cisplatin (60 mg/m² over 3 hours) administered every 14 days have been extensively evaluated in Europe. They were reported to produce objective responses in 43% of 51 patients, including two complete responses, and 43% of patients were alive 1 year after initiation of therapy (Table 5).

Because of the toxic and logistic difficulties of using cisplatin, carboplatin has become a popular chemotherapeutic drug. Several studies of carboplatin with paclitaxel in esophageal cancer have been undertaken. El-Rayes et al administered carboplatin (at an AUC of 5) with paclitaxel (200 mg/m² over 3 hours) every 3 weeks in 33 chemotherapy-naive patients. Objective responses were reported in 45% of patients, with a median survival of 9 months and 1-year and 2-year survival rates of 43% and 17%, respectively.

Polee et al explored a weekly schedule of these drugs in a phase I study. With therapy administered for 3 consecutive weeks, followed by a 1-week break, a dose of carboplatin (at AUC 4) with paclitaxel (100 mg/m²) was recommended for further investigation. Responses were noted in half of the 40 patients, with a median survival of 11 months and a 1-year survival of 46%. Both of these combinations were well tolerated, with the primary toxicity of myelosuppression.

The combination of docetaxel, cisplatin, and infusional 5-FU (DCF) has been approved by the US Food and Drug Administration for the treatment of metastatic gastric and GE junction adenocarcinomas. The activity of this regimen in esophageal cancers is unclear. Tebbutt et al performed a randomized phase II study in 106 patients with advanced esophagogastric cancers. Two different modifications of the DCF regimen were evaluated, either docetaxel (30 mg/m², 2 weeks on, 1 week off) with capecitabine (1,600 mg/m² daily, divided into two separate doses), or a similar docetaxel with cisplatin at a lower dose (60 mg/m²) and a continuous infusion of 5-FU. This study demonstrated that the modified DCF appeared to have a better response rate (47% vs 26%) but similar overall survival (11.2 months and 10.1 months, respectively) and progression-free survival (5.9 months vs 41 months).

Another response to the toxicity of the DCF regimen has been the elimination of the 5-FU, and exploration of cisplatin and docetaxel alone or substitution of oxaliplatin for cisplatin. Kim et al evaluated this combination, with a dose of 70 mg/m² of each agent, administered every 21 days in 39 Korean patients with squamous cell carcinomas of the esophagus. They reported a 33% response rate, which included three complete responses (7.7%), and a median survival time of 8.3 months. The regimen was reported as well tolerated, with about one-third of patients experiencing grade 3 or 4 neutropenia.

The antimetabolite gemcitabine has also been evaluated in combination with cisplatin in esophageal cancer. A SWOG study, reported by Urba et al, combined 1,000 mg/m² of gemcitabine on days 1, 8, and 15 with 100 mg/m² of cisplatin on day 15 in 64 patients. Approximately one-quarter of these patients had received prior chemotherapy. Therapy was well tolerated, with severe neutropenia occurring in 31% of patients. The median survival of patients treated on this study was 7.3 months, and the 1-year survival rate was 20%. However, the heterogeneity of the patient population makes the efficacy of the therapy somewhat difficult to assess.

Oxaliplatin may also have a role in the treatment of esophageal cancer, both as a radiosensitizer and an agent in advanced disease. Mauer and colleagues reported the results of treatment with oxaliplatin, 5-FU, and leucovorin according to the FOLFOX4 schedule (oxaliplatin, 85 mg/m² on day 1; leucovorin, 500 mg/m² over 2 hours on days 1 and 2; and 5-FU, 400 mg/m² bolus, then 600 mg/m² over 22 hours on days 1 and 2, repeated every 14 days). Of 35 patients who were treated, objective responses were noted in 40%. The median survival rate was 7.1 months, the 1-year survival rate was 31%, and the 2-year survival rate was 11%. The median progression-free survival was 4.6 months. Although differences in patient populations were noted, these results are similar to those of other reported combinations.

The combination of oxaliplatin (130 mg/m² on day 1) with capecitabine (1,000 mg/m² twice daily on days 1 to 14) repeated every 21 days has also been studied in esophageal cancer. Thirty-eight percent of the 51 treated patients had objective responses, with a median survival of 8 months and a 1-year survival rate of 26%. This study was conducted in the Netherlands, and the tolerability and efficacy of this regimen in American patients remain to be determined.

The primary toxicity of these regimens is severe neutropenia, occurring in about 40% to 70% of patients. Severe diarrhea, nausea, and vomiting occur in approximately 10% to 15% of patients in many studies. Fatigue and asthenia also were significant side effects with both therapies.

With improving toxicity profiles and modest improvements in therapeutic outcomes, second-line therapy for advanced esophageal cancer is also increasingly being explored. Muro et al treated 28 Japanese patients with squamous cell carcinoma of the esophagus with docetaxel (70 mg/m²) every 3 weeks; these patients had previously received cisplatin and 5-FU. As expected, severe neutropenia was the dominant toxicity (88%, including nine episodes of febrile neutropenia), with severe anorexia, fatigue, and anemia also reported. Objective responses were noted in 16% of these patients.

In addition, Lordick et al determined that irinotecan (55 mg/m²) and docetaxel (25 mg/m²) given on days 1, 8, and 15, with cycles repeated every 28 days, were tolerable, with severe asthenia in 21% of 24 patients and severe diarrhea in 13%. However, only three partial responses (13%) and eight patients with stable disease were noted, with a resultant median survival of 26 weeks. Although these studies suggest the feasibility of second-line cytotoxic chemotherapy in esophageal cancer, the significant toxicity and limited objective response rate warrant its use only with caution and preferably on a clinical study. In another study of second-line chemotherapy, Shim et al treated 38 patients who had previously been treated with cisplatin/5-FU, with cisplatin 75 mg/m² and docetaxel 70 mg/m² IV every 3 weeks. In this setting, a response rate of 35% was reported, with a median survival of 7.4 months.

Oral tyrosine kinase inhibitors of the EGFR have also been investigated in esophageal cancer. Gefitinib (Iressa), at a daily dose of 500 mg, as second-line therapy in patients with esophageal adenocarcinomas was evaluated by Ferry et al. It produced partial responses in 11% of 27 patients, and an additional seven patients had stable disease. In patients with esophageal cancer that had previously been treated with platinum-based chemotherapy, Janmaat et al treated 37 patients with the same regimen. They reported a confirmed response in only one patient and stable disease in another 10, although 18% of patients were free of disease progression at 6 months, suggesting that some patients indeed experience disease control and benefit from this therapy. However, Radovich et al reported only one response in 23 patients treated with erlotinib (Tarceva; 150 mg daily). The toxicities were as expected, including rash, diarrhea, vomiting, and elevation in transaminase levels. As with lung and colon cancers, the optimal population for treatment with these targeted agents remains to be defined.

The other class of agents that target the EGFR pathway, monoclonal antibodies such as cetuximab, has provided mixed results in patients with esophageal cancer. For example, a German study of cisplatin/5-FU with or without cetuximab (Erbitux) as initial therapy in patients with metastatic esophageal squamous cell cancers with EGFR expression by immunohistochemistry suggested an improvement in patient outcomes. Sixty-two patients were randomized in a non-blinded fashion on the study, and crossover to cetuximab with cisplatin/5-FU was allowed in the patients who received initial cisplatin/5-FU alone. The response rates were similar in the two arms (33% with cetuximab, vs 30%), but patients who received the additional cetuximab had a superior disease-control rate (75% vs 57%), median time to disease progression (5.9 months vs 3.6 months), and median overall survival (9.5 months vs 5.5 months). Moreover, of the five patients who crossed over to second-line cetuximab, two had partial responses (one with single-agent therapy), and one had stable disease. However, given the sample size, and the unblinded nature of the study with crossover, caution must be exercised when interpreting these results.

More recently, the CALGB performed a randomized phase II study combining cetuximab with several other typical chemotherapy regimens, including ECF, cisplatin/irinotecan, and FOLFOX, in patients with metastastic esophageal and GE junction cancers. Each arm included about 80 patients; the response rates were 58%, 38%, and 51%, respectively, and median survivals were 8 to 10 months. Each arm surpassed the prespecified endpoint, suggesting enough promise to further explore in phase III studies. Again, however, the number of patients treated was too low to consider any of the regimens to be a standard at this time. Both cetuximab and panitumumab have been evaluated in large randomized phase III studies in patients with advanced or metastatic esophagogastric adenocarcinoma in the first-line setting. Neither study demonstrated a survival benefit with the addition of anti-EGFR therapy to platinum/fluoropyrimidine combination. Indeed, the outcomes were worse in the experimental arms of both studies, perhaps because of the increased toxicity, including diarrhea and dermatologic reactions, engendered by the additional drugs.

The SWOG studied cetuximab as a single agent as second-line therapy for metastatic esophageal adenocarcinoma. Of the 55 eligible and evaluable patients, only one (2%) had a partial response, and six (11%) had stable disease. The median progression-free survival was 1.8 months, the median survival was 4 months, and the 6-month survival rate was 36%. The authors concluded that although the drug was well tolerated as single-agent therapy, it did not meet its primary endpoint and so could not be recommended as second-line therapy in esophageal cancer. The discordant results represented in these studies, between histologies and drugs, may reflect the differing biologies of esophageal adenocarcinomas and squamous cell carcinomas. Alternatively, they may reflect alterations in cancers after undergoing chemotherapy.

The role of the vascular endothelial growth factor (VEGF) pathway in esophageal cancer also remains unclear. A phase II study of a modified DCF with bevacizumab demonstrated a response rate of 67% and median survival of 16.8 months in 44 patients with GE cancer, which is superior to DCF alone, suggesting a potential utility of bevacizumab in this disease. In addition, a study of sorafenib, 400 mg twice daily, demonstrated one complete response and one prolonged stable disease in 20 patients. Taken together, these data suggest that inhibiting the VEGF pathway may improve outcomes in metastatic disease, and further investigation is ongoing.

In addition to the EGFR and VEGF antagonists, it is anticipated that other targeted therapies, such as MEK and met inhibitors, will be evaluated in this disease. Such avenues of exploration, in addition to early diagnosis of and therapy for early-stage disease, are the most likely path toward significant improvements in therapy for esophageal cancer.

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