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Adenocarcinoma of the Esophagus and Cardia: A Review of the Disease and Its Treatment

Department of Cardiothoracic Surgery, The University of Southern California, Keck School of Medicine, 1510 San Pablo Street, Suite 514, Los Angeles, California 90033

Correspondence: Address correspondence and reprint requests to: Steven R. DeMeester, MD; E-mail: sdemeester{at}surgery.usc.edu

	ABSTRACT

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Background: Over the past 50 years there has been a remarkable change in the epidemiology of esophageal cancer. Previously rare, adenocarcinoma of the esophagus and gastroesophageal junction is now the most common esophageal cancer, and in the United States the incidence is increasing faster than that of any other malignancy. Surveillance in patients with Barrett’s esophagus is identifying adenocarcinoma at an earlier, more curable stage in many patients, and at the same time new endoscopic and surgical options are available for the therapy of these localized tumors.

Methods: This article is a review of the epidemiology, diagnosis, staging, and treatment options for esophageal and gastroesophageal junction adenocarcinoma.

Results: The epidemiology, prognosis, patterns of lymphatic metastasis, and survival for esophageal and gastroesophageal junction adenocarcinoma suggest that these tumors are similar. New options for therapy, as well as the results of surgical resection with and without chemoradiotherapy, are reviewed.

Conclusions: Surveillance programs for Barrett’s are identifying patients with early, curable adenocarcinoma of the esophagus or gastroesophageal junction. Therapy for more advanced tumors hinges on local control of the disease and the eradication of systemic metastases.

Key Words: Esophageal adenocarcinoma • Cardia • Review • Treatment • Barrett’s esophagus

	INTRODUCTION

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The first report of an esophageal adenocarcinoma is credited to White in 1898. A review of the literature in 1900 revealed only six cases, and at the time most physicians believed that these represented extension of gastric tumors into the distal esophagus.^1,2 By the 1950s, scattered reports describing adenocarcinoma developing within a columnar-lined esophagus began to appear, and the existence of a primary adenocarcinoma of the esophagus was established. However, throughout the 1950s and 1960s, the most common complications associated with a columnar-lined esophagus were bleeding, ulceration, and stricture formation. In association with the development and widespread use of increasingly more potent acid-suppression medications over the past 30 years, these acid-related complications have become progressively less common. It is interesting to note that during this same time period there has been a striking change in the epidemiology of cancer of the esophagus.

Once a rare tumor, adenocarcinoma of the esophagus is currently the cancer with the fastest increasing incidence in America, and recent data indicate that in the United States since 1975, the rate of increase of adenocarcinoma of the esophagus has outpaced the next closest cancer, melanoma, by nearly three times.^3–5 The current average yearly increase in incidence in the United States exceeds 20%, and among white men, the incidence has increased >800% since the mid 1970s in some areas of the country.^6–8 These are alarming statistics, and this previously uncommon tumor now ranks within the top 15 cancers in US white men.⁶ Similar trends are reported in many European countries, with the highest reported incidence (7 per 100,000) in the United Kingdom.^7,9 By comparison, the average incidence in the United States is 2.5 per 100,000, although in some regions the incidence in white men is as high as 5.3 per 100,000.^7,8,10 The increased incidence is occurring across all age groups but peaks at 70 to 79 years.¹¹ An increasing incidence has also been reported among white women and black males.^4,8 The tremendous increase in the incidence of esophageal adenocarcinoma has led to a complete epidemiological shift such that in the United States and other industrialized countries, adenocarcinoma has replaced squamous cell carcinoma as the most common esophageal malignancy.^5,12 This year there will be approximately 10,000 new cases of esophageal adenocarcinoma in the United States.

Similar to esophageal adenocarcinoma, the incidence of adenocarcinoma of the cardia or gastroesophageal junction (GEJ) has increased significantly since the mid 1970s.¹³ However, the average rate within the United States stabilized after the late 1980s and perhaps is beginning to decline slightly.¹¹ As with adenocarcinoma of the esophagus, the incidence of adenocarcinoma of the GEJ is greatest in white men. Unlike esophageal adenocarcinoma, the incidence of adenocarcinoma of the GEJ does not differ between white and black women and is similar in blacks and Asians. Furthermore, the rate of adenocarcinoma of the GEJ is double the relatively low esophageal adenocarcinoma rate in these groups.^4,8 The overall incidence of adenocarcinoma of the GEJ (3.1 per 100,000) previously exceeded that of esophageal adenocarcinoma in the United States, but the most recent data indicate that the incidence of esophageal adenocarcinoma is now greater than the incidence of adenocarcinoma of the cardia.^5,11

	THE RELATIONSHIP BETWEEN ADENOCARCINOMA OF THE ESOPHAGUS AND THE CARDIA

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Controversy continues regarding the relationship between adenocarcinoma of the esophagus and the GEJ. One problem is that distal esophageal tumors may grow downward and involve the cardia, and, similarly, GEJ tumors will often extend proximally into the distal esophagus. Thus, these tumors frequently overlap, and assigning a given tumor to be either an esophageal adenocarcinoma or a GEJ tumor is problematic. In an attempt to help clarify the classification of these tumors, Siewert et al.¹⁴ divided them into three types based on the estimated anatomical location of the tumor center. Type 1 tumors were classified as true Barrett’s adenocarcinomas of the distal esophagus, and type 3 tumors were labeled subcardial gastric tumors. Type 2 tumors were those centered at the GEJ. However, there does not seem to be appropriate justification for separating GEJ tumors from adenocarcinomas of the distal esophagus, especially from a pathophysiologic standpoint.¹⁵ Instead, a more meaningful classification scheme would group adenocarcinoma of the esophagus and GEJ together and separate these from distal gastric cancers.

Regarding the epidemiology of adenocarcinoma of the esophagus and GEJ, Blot et al.³ wrote, "the patterns...are sufficiently alike to implicate shared risk factors or even a single neoplastic entity." The incidence of both cancers has increased while the incidence of noncardia gastric cancer has decreased in Western countries.¹⁵ Likewise, the risk of both GEJ and esophageal adenocarcinoma is increased in people with symptoms of gastroesophageal reflux and in those with an increased body mass index.^16,17 Although studies at the molecular biological level have produced conflicting results, many have demonstrated the similarity of these tumors.^18–22

Most important, though, is evidence that the likelihood and pattern of lymph node metastases and overall survival are similar in patients with GEJ and esophageal adenocarcinoma.^15,23,24 The most common locations for involved nodes with a tumor in either the distal esophagus or at the GEJ are parahiatal and paraesophageal; thus, with either tumor, these nodes need to be removed as part of a surgical resection of the lesion.²³ Siewert et al.¹⁴ acknowledge this fact as well. Consequently, these tumors should be evaluated and treated similarly and will be considered together for the remainder of this review.

	ETIOLOGY, PATHOPHYSIOLOGY, AND RISK FACTORS

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The specific etiological factor or factors responsible for the dramatic increase in the prevalence of esophageal and GEJ adenocarcinomas are unknown. Many potential risk factors have been evaluated, sometimes with conflicting results (Table 1), but the one indisputable risk factor is increased exposure of the esophagus to refluxed gastric juice.^{16,17,25–40} Lagergren et al.¹⁷ found in a Swedish nationwide case-control study that compared with asymptomatic individuals, people with long-standing severe reflux symptoms were 43 times more likely to develop adenocarcinoma of the esophagus. It has also been demonstrated that in people with reflux, it is intestinal metaplasia of the esophagus, or Barrett’s, that is the major risk factor for cancer.⁴¹ In one study, subjects with Barrett’s were found to have a 30 times increased risk of adenocarcinoma, whereas those with reflux but without Barrett’s had only a modestly increased risk (3.1 times) compared with the general population.⁴¹ The risk of cancer increases slightly with an increasing length of Barrett’s, but it increases significantly with progression of Barrett’s to dysplasia.^26,42,43 Recent epidemiological studies have demonstrated an increase in the prevalence of Barrett’s esophagus and its sequela, esophageal adenocarcinoma, which started in the late 1970s.^5,44 Although it is unlikely that the prevalence of reflux disease in the population has changed dramatically over the last 30 years, it is interesting that during this time period there has been a dramatic increase in the availability and potency of pharmacological gastric acid–suppressing agents. Whether there is an association between pharmacologic manipulation of gastric acidity and the malignant consequences of reflux disease remains to be determined. However, in the study by Lagergren et al., the risk of esophageal adenocarcinoma was increased by a factor of 3 in patients who used medications for reflux.¹⁷

View larger version (120K): [in this window] [in a new window]   FIG. 1. A very small adenocarcinoma is present immediately at the gastroesophageal junction (GEJ). Biopsy samples from adjacent areas at the GEJ show intestinal metaplasia with low- and high-grade dysplasia, demonstrating that intestinal metaplasia of the cardia is a premalignant lesion similar to Barrett’s in some patients.

	DIAGNOSIS AND STAGING

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The diagnosis of esophageal and GEJ cancer is made or confirmed with upper endoscopy and biopsy, and the diagnostic endoscopy itself can provide important information about the likely stage of the tumor. Large, circumferential tumors are almost always transmural, and approximately 80% of transmural tumors are associated with lymph node metastases.²³ In contrast, when a random biopsy sample from an area of Barrett’s esophagus that endoscopically seems like any other area of Barrett’s shows adenocarcinoma, it is unlikely that the tumor has metastasized to lymph nodes. In other words, in the absence of a visible lesion, we have found that a biopsy sample that shows adenocarcinoma in Barrett’s esophagus is associated with lymphatic metastases in only 1 out of 370 lymph nodes examined with both routine histological and immunohistochemical examination.⁷⁴

Pretreatment staging is typically performed with a combination of endoscopic ultrasonography (EUS) and thoracic and abdominal computed tomographic (CT) scanning. The staging accuracy of this combination is 79% for assessing the primary tumor, 82% for assessing lymph node involvement, and only 64% for determining systemic disease.^54,55 Positron emission tomography (PET) with ¹⁸F-fluoro-deoxy-D-glucose scanning improves the diagnostic accuracy for solid-organ systemic metastases, and the new combination, or fusion, CT-PET systems may provide accurate information about regional lymph node involvement as well.⁵⁶ Furthermore, ¹⁸F-fluoro-deoxy-D-glucose PET is increasingly being used to assess response after induction chemoradiotherapy in patients with esophageal cancer.⁵⁷ Perhaps the most accurate staging method short of esophagectomy and lymphadenectomy is EUS with fine-needle aspiration of suspicious lymph nodes or thoracoscopic and laparoscopic lymph node sampling.^56,58 However, a report describing tumor seeding of a port site after laparoscopic staging is worrisome, and EUS with fine-needle aspiration of regional nodes cannot be performed in the area of the primary tumor.⁵⁹ At this time, neither approach to pathologic stage nodal disease has gained widespread enthusiasm outside the setting of a clinical trial.

American Joint Committee on Cancer Staging System for Esophageal Cancer
In the current American Joint Committee on Cancer (AJCC) staging system for esophageal carcinoma, the T designator is divided into T1 to T4 according to the depth of tumor penetration into the wall of the esophagus. A T1 tumor is defined as penetration up to but not through the submucosa, a T2 tumor has penetration into but not through the muscularis propria, and a T3 tumor is a transmural tumor with growth into the periesophageal tissues. If the tumor invades an adjacent structure, such as the aorta or spine, it is classified as T4. However, data from several centers suggest that the muscularis mucosa, which separates the mucosa from the submucosa, is an important anatomical boundary and that the likelihood of lymph node metastases increases significantly once tumors invade deeper than the muscularis mucosa.^53,60 Furthermore, the likelihood of lymph node metastases increases progressively with the depth of tumor penetration into the wall of the esophagus (Table 2).^{23,53,61–63}

Given the significant flaws in the current AJCC staging system, accurate comparison of outcomes after therapy for esophageal carcinoma is difficult. It may be less of an issue after neoadjuvant therapy, where the presence or absence of residual disease seems to be the most important prognostic factor, although even that is not known with certainty. However, the inadequacies of the staging system have been well detailed in several reports, and it is hoped that critically needed refinements will be forthcoming in the next revision.^61,63,66

Molecular Staging of Barrett’s and Esophageal Cancer
Recently it has been demonstrated that the presence of methylated adenomatous polyposis coli gene DNA in the serum of patients with esophageal adenocarcinoma correlated with a more advanced disease stage and worse survival.⁶⁷ It has also been shown that patients with a mutation in the p53 gene have a worse prognosis than similarly staged patients without a mutated p53 gene.^20,68 Furthermore, a panel of tumor markers can provide prognostic information after resection, and molecular markers have been used to predict the response to chemotherapy in patients with esophageal cancer.^69–71 Gradually the cellular alterations necessary for malignant development, growth, and metastatic potential are becoming better understood, and over the next decade, biologic and molecular staging of cancers will become increasingly important, as will markers that predict the response to therapy and the likelihood of metastases or recurrence.

Biology of Esophageal Adenocarcinoma
The frequently advanced nature of esophageal adenocarcinoma at presentation and reports that indicate a high incidence of bone marrow micrometastases have led many physicians to consider this a systemic disease at the time of diagnosis.^72,73 However, clinical experience does not support this concept. For example, metastases of any type are extremely rare in patients with intramucosal tumors, and nearly all patients are cured by resection alone.^53,75 Further, the high cure rate in patients with limited lymph node metastases after en-bloc resection suggests that, similar to other cancers, esophageal adenocarcinoma starts locally and progresses in a stepwise fashion to nodal and systemic disease.⁶³

	TREATMENT

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Treatment options for esophageal or GEJ adenocarcinoma include endoscopic ablation or mucosal resection, esophagectomy, definitive chemoradiotherapy, neoadjuvant or adjuvant therapy in combination with esophagectomy, and palliative procedures that use stents or laser or photodynamic therapy (PDT). Critical factors that influence the plan for therapy should include the stage of the tumor, the overall health of the patient, and the goal of therapy.

Surgical Resection for Esophageal Cancer
To date, no therapy has been proven superior to esophagectomy for both cure and palliation of patients with localized esophageal cancer. The primary goal of surgery is complete (R0) resection of the tumor and surrounding lymph nodes to maximize the opportunity for cure and minimize the incidence of local recurrence. Repeatedly it has been confirmed that complete surgical resection is the most important prerequisite for long-term survival in patients with localized esophageal cancer.^{14,23,66,76–79} However, accomplishing this goal is easier for intramucosal tumors than it is for transmural tumors. Consequently, the surgical approach and extent of resection should be modified according to the extent of disease present in each patient. There are currently four main surgical options: vagal-sparing esophagectomy without lymphadenectomy, en-bloc esophagectomy with thoracic and abdominal lymphadenectomy, transhiatal resection, or a minimally invasive esophagectomy (laparoscopic only or a combined thoracoscopic and laparoscopic approach). Although few centers offer all four surgical options, each option likely has a place in the appropriate patient, and each offers potential advantages.

Vagal-Sparing Esophagectomy
The technique for a vagal-sparing esophagectomy was described in the 1980s by Akiyama et al.,⁸⁰ from Japan. We have adopted this technique, and to date 36 patients with either high-grade dysplasia (n = 16) or intramucosal cancer (n = 20) are alive and disease free at a median of 22 months after a vagal-sparing resection. In a subset of these patients, we have confirmed vagal integrity and found a significant reduction in the prevalence of dumping and diarrhea compared with patients who had a standard esophagectomy with vagotomy.⁸¹ The vagal-sparing procedure is applicable only to patients with intramucosal tumors, because no lymphadenectomy is performed. In patients with a visible lesion, it is critical to confirm that the tumor is confined to the mucosa, because submucosal invasion imparts a significant risk of lymph node metastases and precludes a vagal-sparing approach. It has been demonstrated that EUS, even with high-frequency 20-MHz probes, is unable to accurately distinguish mucosal from submucosal invasion.⁸² Consequently, we are now using endoscopic mucosal resection (EMR) to definitively stage the depth of invasion of small (1.5 cm) tumors and to determine the appropriateness of a vagal-sparing esophagectomy.⁸³

En-Bloc Esophagectomy
To clearly define what can be accomplished with surgery alone for esophageal adenocarcinoma, we evaluated the outcome of 100 consecutive en-bloc esophagectomies.⁶³ The overall survival was 52% at 5 years and was 94%, 80%, 77%, 24%, and 29% in patients with AJCC stage I, IIa, IIb, III, and IV tumors, respectively. During detailed follow-up (median, 40 months), 69% of patients remained free of disease. Systemic disease developed in 31% of patients, but locoregional recurrence occurred in only one patient (1%). Similar excellent local control and survival rates with en-bloc resection have been reported by Altorki and Skinner.⁷⁶ These data serve to refute the nihilistic attitude that esophageal cancer is systemic and incurable at the time of diagnosis, and the low incidence of local recurrence after en-bloc resection stands in stark contrast to the 20% to 40% incidence of local recurrence after transhiatal resections.^84,85 Because local recurrence after esophagectomy typically results in rapid death from cancer, local control remains one of the primary goals of therapy for this disease.^85,86 Currently, an en-bloc resection is recommended for all patients with limited nodal disease (5 nodes on EUS) and good cardio-pulmonary status without significant medical comorbidities.

Transhiatal Versus En-Bloc Resection
Debate continues regarding whether the approach and extent of lymphadenectomy alter the survival for surgically treated esophageal adenocarcinoma. Increasingly, there is evidence that it does. In a randomized prospective trial, Hulscher et al.⁸⁷ reported improved survival in the group that had an en-bloc resection compared with a transhiatal group; however, the numbers were insufficient to reach statistical significance. In an analysis of the results for therapy of distal esophageal or GEJ adenocarcinoma in a well-defined and stable Finnish population, Sihvo et al.⁸⁸ found that patients who had an en-bloc resection with two-field lymphadenectomy had a significantly improved survival compared with patients who had a less extensive resection (Fig. 2). It is interesting to note that the 5-year survival after en-bloc resection was 50%, which is nearly identical to the 5-year survival reported after en-bloc resection in other series. ^63,76 Similarly, the 23% 5-year survival after non–en-bloc resection is similar to what has been reported in numerous series of transhiatal resections with or without neoadjuvant therapy.⁸⁹

View larger version (15K): [in this window] [in a new window]   FIG. 2. Kaplan-Meier survival curve showing significantly improved 5-year survival for patients who underwent en-bloc esophagectomy (solid line) versus other less extensive forms of esophagectomy (dashed line) for adenocarcinoma of the esophagus or gastroesophageal junction in Finland (from Sihvo et al.,88 with permission).

View larger version (21K): [in this window] [in a new window]   FIG. 3. Kaplan-Meier plots showing survival in patients with T3N1 adenocarcinoma of the esophagus or gastroesophageal junction treated by en-bloc or transhiatal resection alone without neoadjuvant therapy. Patients with advanced age or medical comorbidities were selected for transhiatal resection. All patients were followed up for a minimum of 5 years, and all deaths were due to cancer (noncancer deaths were excluded in each group to eliminate potential physiologic differences, such as age and comorbidities, that could lead to a different risk of death). Survival after en-bloc resection was significantly improved compared with survival after transhiatal resection in patients with one to eight metastatic lymph nodes (modified from Johansson et al.90). pos, positive.

Volume and Outcome Relationship for Esophagectomy
In addition to offering the chance for cure, esophageal resection and reconstruction with a gastric pull-up or colon interposition provides prompt and effective palliation for esophageal cancer.⁹² However, esophageal surgery is complex, and these procedures are best performed in high-volume centers by surgeons who see this disease frequently.^93,94 Mortality rates in experienced centers are generally <5%, whereas centers with limited experience and low-volume surgeons have mortality rates that approach 20%.⁹⁵ The presence of medical comorbidities also increases operative risk, but age itself is not an important factor.^96,97

Postesophagectomy Morbidity and Quality of Life
Esophagectomy with reconstruction is an enormous procedure and is associated with significant postoperative morbidity in many patients. Some of the most troubling early symptoms that patients experience, as reported by a patient who underwent esophagectomy for cancer at age 40, are nausea and gastric retention, dumping, diarrhea, and dysphagia related to anastomotic stricture.⁹⁸ As a consequence of these difficulties, as well as recovering from the discomfort of the operation and the slow process of regaining stamina and energy, quality of life decreases significantly during the first 6 weeks after esophagectomy and takes 6 to 9 months to return to preoperative values.⁹⁹ Quality of life has been found to be similar whether patients have a transhiatal or a transthoracic resection.¹⁰⁰ Long-term functional outcome after esophagectomy was reported by Headrick et al.¹⁰¹ from the Mayo Clinic. At a median of 5.3 years after surgery, 7 (13%) of 48 patients were entirely asymptomatic, 15% had dumping, 38% had some degree of dysphagia, and 68% had gastroesophageal reflux symptoms. Despite these difficulties, Short Form-36 quality-of-life scores were better than the national norm for role-physical and role-emotional, although the health perception score was lower. Social function scores improved with increasing time after operation but were adversely affected by the occurrence of an anastomotic leak.¹⁰¹

Follow-up information similar to this, along with data on quality of life after esophagectomy, is becoming increasingly more important because Barrett’s surveillance programs are leading to the identification of earlier-stage tumors that are often curable. Consequently, surgeons need to place a major emphasis on the evaluation of outcome and be willing to modify their procedures to reduce the long-term morbidity of esophageal resection and reconstruction in these patients, who are likely to live for many years after surgery. ENorts at vagal nerve preservation, minimally invasive esophagectomy, and reducing the incidence of anastomotic stricture and leak are all warranted to reduce morbidity and improve quality of life after esophagectomy.

Route of Reconstruction and Choice of Graft
In most circumstances, the posterior mediastinal route is chosen for reconstruction. The posterior mediastinum is typically a more direct and, thus, shorter route for reconstruction and has been shown to have a lower perioperative morbidity rate and to lead to better graft emptying than the substernal route.¹⁰² If a substernal route is used, it is important to recognize that the thoracic inlet can impair bolus passage into the graft, and at our center we routinely excise the medial portions of the left clavicle and first rib as well as the left half of the manubrium to prevent this problem.

The most widely used esophageal replacement graft is the tubularized stomach. Colon interposition or small intestine grafts are less frequently used alternatives. There are advantages and disadvantages with each graft, but the familiarity, reliable vascular supply, and single anastomosis required with a gastric pull-up make it the first choice for most esophageal surgeons. When the stomach is not available or if for oncological reasons the stomach is unsuitable, a colon interposition based on the ascending branch of the left colic artery is an excellent option for reliable reconstruction. The requirement for three anastomoses, the added time for mobilization, and the potential for redundancy are clear disadvantages for colon interposition, but there are also advantages, including a reduced incidence of anastomotic leak and stricture compared with gastric pull-up.^103,104 Most esophagectomies involve division of the vagus nerves, and, thus, a pyloroplasty is typically included with the procedure. Although narrow gastric tubes can empty satisfactorily without a pyloroplasty, some have found that the ischemia and anastomotic leak rates are unacceptably high with narrow gastric tubes.⁹¹ Some centers, particularly in Europe, omit a pyloroplasty and report no significant problems with delayed graft emptying or regurgitation and aspiration events.^105,106 However, a meta-analysis concluded that pyloric drainage procedures reduce the occurrence of early postoperative gastric outlet obstruction after esophagectomy, and in our experience, a pyloroplasty is beneficial.¹⁰⁷ Currently, we use a simple and quick technique that eliminates the risk of leakage. Through a gastrotomy along the lesser curve in an area that will be excised with tubularization of the stomach, we pass a 21-mm circular stapler and excise a portion of the anterior pyloric channel. This technique has been in use for >2 years at out institution and has been very effective (unpublished data).

Most esophageal surgeons prefer a cervical esophagogastric anastomosis, and although the anastomotic leak rate is higher with this technique, the consequences of a leak are less significant than those of a leak from an intrathoracic anastomosis.^108–110 The functional outcome of a high intrathoracic and a cervical anastomosis are similar, but the lower the anastomosis, the greater the risk for significant reflux, particularly if it is placed below the level of the azygos vein. Reflux of gastric juice occurs commonly after esophagectomy and gastric pull-up because the lower esophageal sphincter has been excised, and patients should be advised to eat several hours before lying down at night and to sleep with the head of the bed elevated.¹¹¹ Despite these precautions, it has been demonstrated that reflux-induced injury occurs to the esophageal squamous mucosa proximal to the anastomosis, and 50% of patients have been found to have cardiac columnar metaplasia proximal to the anastomosis on postoperative endoscopy. Of concern, goblet cells indicative of recurrent Barrett’s esophagus can be found in as many as one half of these patients.^112,113

Limited Resection and Ablation Techniques
PDT has been used to successfully ablate both Barrett’s and foci of adenocarcinoma in some patients.^114,115 However, several problems limit the utility of PDT in this setting. First, the depth of injury with PDT is variable and imprecise, and because PDT destroys the tissue, there is no specimen and, thus, no way to ensure that all of the cancer has been eradicated. Furthermore, lymph node metastases, if present, will be untreated.⁷⁵ A second issue is that PDT rarely eradicates all the Barrett’s mucosa, and despite phenotypical downstaging, the underlying genetic abnormalities may persist, and these patients remain at significant risk for recurrent or persistent dysplasia and adenocarcinoma.¹¹⁶ This concern has been borne out in an analysis of patients treated with PDT published by Overholt et al.¹¹⁷ In 89 patients with high-grade dysplasia or early cancer, PDT eliminated the Barrett’s in only 46 (52%). High-grade dysplasia persisted in 7%, cancer developed in 3.4%, and 14% of patients died at a mean follow-up of approximately 50 months. Another problem with PDT is that it leads to the development of fibrotic esophageal strictures in >30% of patients.¹¹⁴ Finally, in a cost-analysis model, PDT was shown to be more expensive than esophagectomy.¹¹⁸ Consequently, there is little to support the routine use of PDT for patients with dysplastic Barrett’s or adenocarcinoma.

A potentially useful therapy for early esophageal cancer is EMR. With this technique, a 1-to 1.5-cm disk of mucosa is excised, and the tissue can be pathologically reviewed to confirm the adequacy of resection. The cleavage plane is between the submucosa and the muscularis propria; thus, the depth of invasion of early tumors can be precisely determined to stage the lesion and allow planning of the type of esophagectomy (vagal-sparing vs. lymph node–removing procedure).⁸³ EMR can also be used as therapy for esophageal cancer, and in a series from Japan, the survival after EMR in patients with early squamous tumors was similar to that after esophagectomy.¹¹⁹ However, squamous cancer differs from Barrett’s-associated adenocarcinoma in that many patients with an early esophageal adenocarcinoma have adjacent areas of Barrett’s, and as long as residual Barrett’s remains, these patients are at risk for further cancer development. This concern is illustrated in a series of patients treated for early adenocarcinoma with EMR alone in Germany. Long-segment Barrett’s was present in 60% of the patients, and 17% had failed PDT. During a mean follow-up of 12 months, 17% of patients developed recurrent or metachronous adenocarcinoma.¹²⁰ Similarly, in our series assessing the accuracy of EMR for staging early adenocarcinoma, two patients had an additional, undetected adenocarcinoma in the resected esophagus despite the absence of any tumor at the EMR site and numerous prior endoscopies with biopsies. Both patients had long-segment Barrett’s with multifocal high-grade dysplasia.⁸³ In an effort to reduce the likelihood of recurrence, PDT has been added to EMR in patients with intramucosal adenocarcinoma and Barrett’s.¹²¹ Longer follow-up is necessary to assess the outcome with this technique and compare its results with those of esophagectomy before it is widely applied.

Neoadjuvant Therapy Followed by Surgical Resection
Poor survival with surgery alone in patients with large tumors and advanced local disease has prompted investigation into the use of neoadjuvant chemotherapy or chemoradiotherapy in addition to surgery.

Neoadjuvant Chemotherapy
Seven published randomized prospective trials have compared neoadjuvant chemotherapy followed by surgery with surgery alone (Table 4).^79,122–127 Only one trial, the medical research council trial from England, found a survival advantage associated with the use of neoadjuvant chemotherapy. However, several details of the trial are worth reviewing. There were 802 patients enrolled in this trial. Preoperative staging consisted of chest radiograph and liver scan by ultrasound or CT. Complete (R0) surgical resection was accomplished in only 54% of the surgery-alone group, and although it was significantly increased in the neoadjuvant chemotherapy group (60%), it remained poor. Furthermore, in the surgery-alone arm, 32% of patients had residual disease at the margins of the specimen, and an astounding 17% left the operating room without a resection. This is markedly different from common clinical practice in most US centers, where routine staging includes CT and often PET scan and EUS. Consequently, the validity and relevance of this study in the United States are unclear.

Neoadjuvant Chemoradiotherapy
Three of the most commonly used drugs to treat esophageal cancer (cisplatin, 5-fluorouracil, and mitomycin) also enhance radiation effects. To take advantage of these radiosensitizing benefits, several clinical trials have been conducted in which radiation and chemotherapy are given before resection. To date, seven randomized prospective trials^{78,79,84,133–136} have been reported, and of these, only the trial by Walsh et al.¹³⁶ found a survival benefit with neoadjuvant chemoradiotherapy. The other six trials, including the final analysis of the University of Michigan (Urba et al.⁸⁴) trial, found that neoadjuvant chemoradiotherapy offered no survival benefit compared with surgery alone (Table 5).

View larger version (21K): [in this window] [in a new window]   FIG. 4. Kaplan-Meier plot of survival for patients according to the intention-to-treat analysis from the Walsh trial modified by plotting median and 1-, 2-, and 3-year survival from data published in the text of the article (multimodal group: 16 months and 52, 37, and 32 months, respectively; surgery-alone group: 11 months and 44, 26, and 6 months, respectively).136 It is interesting to note that the discrepancy in the data between the article and the Kaplan-Meier graphs is only for the multimodal group (dashed line) and is present in both the intention-to-treat and the treatment-actually-received graphs (only the intention-to-treat graph is shown). With the log-rank method of statistical analysis, it is unlikely that the correct curve for the multimodal arm is significantly different from the surgery-alone curve.

Neoadjuvant Chemoradiotherapy Followed by Surgery: Critical Appraisal
A review of the trials allows several comparisons to be made and a few conclusions to be reached. At the outset is important to recognize that all of the trials suffer from a relatively low power to detect small differences between groups given the small sample size in each trial. Furthermore, variations in the chemotherapy and radiation protocols also confound attempts at a meta-analysis. Despite these issues, it is interesting to note that the 3-year survival in the multimodal groups was similar in both the Walsh and Urba trials (32% and 30%, respectively). However, there was a substantial difference in 3-year survival in the surgery-alone groups (6% vs. 16%, respectively). Consequently, the different outcomes in the Walsh and Urba trials were largely a consequence of the difference in survival in the surgery-alone groups. The 6% 3-year survival in the Walsh trial is less than one half of the average survival for surgery alone in the other 5 randomized studies (17%) and, indeed, is one of the worst surgical survivals ever reported for this disease. This certainly gives credence to concerns about the lack of adequate systemic staging and the substandard surgical resections in that trial.

A second conclusion is that neoadjuvant chemoradiotherapy did not reduce the incidence of systemic recurrence. This is in keeping with O’Sullivan and associates’ report⁷² that neoadjuvant chemoradiotherapy does not reduce the prevalence of bone marrow micrometastases. Instead, the major effect of neoadjuvant chemoradiotherapy seems to be better locoregional disease control—in effect compensating for inadequate surgical resections. Two clear messages from these trials are that to affect survival in patients with locally advanced esophageal cancer, surgeons need to minimize the incidence of local recurrence by performing an adequate resection, and oncologists need to reduce the incidence of systemic failure with more effective chemotherapy.

It has been proposed that improved local control might be obtained with higher doses of preoperative radiation. However, even the high doses of radiation used for definitive treatment of esophageal cancer do not reliably eliminate locoregional disease.^138,139 In addition, the rates of infection, anastomotic breakdown, adult respiratory distress syndrome, long-term respirator use, and mortality are all greater in patients receiving neoadjuvant chemoradiotherapy with large doses (>45 Gy) or high-fractionation schedules (>200 cGy/day) of radiation.^78,140,141

A last conclusion from the trials is that if there is one glimmer of hope with neoadjuvant chemoradiotherapy, it is in the approximately 20% of patients who have a complete pathologic response and demonstrate excellent survival compared with those with residual disease in the resected specimen (64% vs. 19% at 3 years, respectively, in the Urba trial). A note of caution, though, is that only the clinical stage of the disease was known in these patients before therapy. Jiao et al.¹⁴² have demonstrated with minimally invasive pathologic staging that only patients without lymph node metastases were likely to have a significant treatment response. Obviously, patients with limited disease, especially those with N0 disease, are also the ones who do well with resection alone. It is the patients with extensive disease and multiple involved lymph nodes who are most in need of an improvement in survival with neoadjuvant therapy, and unfortunately it seems that these are the very patients least likely to achieve a complete pathologic response. Furthermore, there is increasing evidence that patients who do not achieve a complete pathologic response not only derive no benefit from the neoadjuvant therapy, but in fact may have worse survival than those who undergo resection alone.¹⁴³ Thus, until complete pathologic response rates improve or until we are able to accurately identify those patients most likely to achieve a complete response before initiation of therapy, a generic recommendation for neoadjuvant chemoradiotherapy in patients with esophageal adenocarcinoma is unwarranted.

Adjuvant Therapy
Only a few randomized trials have compared surgery alone with surgery with adjuvant chemotherapy, radiotherapy, or chemoradiotherapy, and none has found any difference in survival.^144–148 However, adjuvant therapy has not been targeted specifically to those patients at highest risk of recurrence. When this approach is taken, there is retrospective evidence that adjuvant therapy can improve survival and prolong the time to recurrence.^149,150

Definitive Chemoradiotherapy Without Surgery
Radiotherapy alone for esophageal cancer has a very poor track record, with trials suggesting a median survival of 6 months, and rare cures.^151–153 Furthermore, less than one half of treated patients experience long-term palliation of their dysphagia.¹³⁸ Thus, radiation is rarely used alone. However, even combination chemoradiotherapy has been plagued by an unacceptably high (50%–65%) rate of persistent or recurrent local disease.^139,154,155 Furthermore, on multivariate analysis, definitive chemoradiotherapy or radiotherapy alone resulted in the worst cause-specific survival for patients with esophageal cancer (compared with groups that included surgical resection).¹⁵⁶ Despite these data, there is a disturbing trend to treat patients with definitive chemoradiotherapy and save surgery for salvage in those whose disease recurs without evidence of systemic disease. Even more worrisome, extrapolating from the trials of neoadjuvant chemoradiotherapy in which only patients who had a complete pathologic response have an improvement in survival, some physicians have begun to question the role for surgical resection after neoadjuvant therapy. This seems illogical given what is known about the results for definitive chemoradiotherapy, our current inability to determine those patients who have had a complete pathologic response without esophagectomy, and the fact that residual disease is present in most (75%–80%) patients after neoadjuvant therapy. Rather than question the role of surgery, a careful analysis of the data leads one to question the role of chemoradiotherapy for localized esophageal cancer.

Stage-Specific Therapy for Esophageal Carcinoma
Although much is uncertain about the ideal therapy for patients with esophageal cancer, there are two ends of the spectrum about which very clear statements can be made. The first is that for early disease, particularly high-grade dysplasia, resection alone is all that is necessary for cure of the patient.¹⁰¹ Thus, this is the ideal stage for intervention from a survival standpoint. Once an intramucosal tumor is present, survival cannot be assured, although resection alone should produce cure in most patients given our current understanding of the likelihood of metastases with this stage of the disease. Many of these nearly microscopic tumors are found only upon review of the esophagectomy specimen.⁷⁴ Thus, in patients with high-grade dysplasia with or without a known focus of intramucosal adenocarcinoma, surgical resection alone is the most appropriate therapy. However, because the likelihood of cure and long-term survival is high, the issue of quality of life is critical. Concerns regarding quality of life after esophagectomy have driven alternative therapies for these early stages of disease, including PDT and EMR, despite the inability of these therapies to match the cure rate of esophagectomy.¹²⁰ These same concerns led us to develop the vagal-sparing procedure for these patients. This method of esophagectomy is readily performed laparoscopically and minimizes the morbidity of traditional esophagectomy with vagal nerve disruption while preserving the curative benefits of complete removal of the diseased esophagus. The other end of the spectrum is in patients with evidence of systemic metastatic disease on staging studies. These patients are not candidates for primary surgical resection and are best treated with chemotherapy with or without added radiotherapy. Palliation of dysphagia can be accomplished with a stent or other endoscopic therapies as necessary.

The difficulty comes in determining the best therapy for patients with tumor stages between these two ends of the spectrum. After carefully evaluating outcome with en-bloc surgical resection alone in 100 consecutive patients with adenocarcinoma of the esophagus, we know that 80% of patients with five or more involved lymph nodes on pathologic analysis of the resected specimen will develop systemic disease. Thus, these patients are candidates for preoperative (neoadjuvant) therapy, postoperative (adjuvant) therapy, or both. Our experience with chemosensitivity-directed adjuvant chemotherapy after en-bloc resection, although encouraging, is too premature to know whether the results will be superior to those with neoadjuvant therapy in these patients. However, for young, fit patients with limited nodal disease (fewer than 5 nodes by EUS), our current preference is primary en-bloc resection with chemosensitivity-directed adjuvant chemotherapy after they recover from their resection. This concept is based on data from our center that median survival in patients with five or more involved lymph nodes is 23% when they are treated with en-bloc resection alone and on data that only approximately 15% of these patients can expect a complete pathologic response with neoadjuvant chemoradiotherapy.^56,58,63 Once molecular markers are developed that enable identification of patients who are likely to achieve a complete pathologic response with neoadjuvant therapy, then selection of this group of patients for neoadjuvant therapy would be warranted. Until that time, patients with intermediate-stage tumors such as these may be those best suited for clinical trials with new neoadjuvant therapy protocols. Ideally, surgeons should focus on the goal of complete resection and minimization of local recurrence in all these patients, whether or not they undergo neoadjuvant therapy, because these are the primary goals of surgery for this disease.

Palliation for Esophageal Carcinoma
Surgical resection and esophageal replacement using the stomach or colon remains the standard for both curative treatment and palliation of patients with esophageal cancer. However, in patients with systemic metastases or unresectable local disease, esophageal bypass procedures are associated with a high mortality and short postoperative survival and, with rare exceptions, are no longer performed. Instead, palliation for these patients is best obtained with the use of coated self-expanding metal stents or, in some cases, PDT or laser therapy. Advancements in technology have revolutionized both the ease of placement and the safety of esophageal stents, and they can also be used to seal a perforation associated with dilation of an advanced cancer or a tracheal-esophageal fistula.

	NEW HORIZONS IN THE TREATMENT OF ESOPHAGEAL CANCER

TOP ABSTRACT INTRODUCTION THE RELATIONSHIP BETWEEN... ETIOLOGY, PATHOPHYSIOLOGY, AND... DIAGNOSIS AND STAGING TREATMENT NEW HORIZONS IN THE... REFERENCES

 
Significant strides continue to be made in the treatment of patients with cancer, and one area certain to play an increasingly important role is chemosensitivity testing. A better understanding of the molecular effect of chemotherapeutic agents, as well as new methods for rapid, reliable, and less labor-intensive analysis of the genes involved, has opened the door to testing for responsiveness to a steadily expanding list of chemotherapy agents.^157–160 Other treatment strategies that may play a role include the use of angiogenesis inhibitors and immunotherapy.^161,162 It is also likely that in the near future, panels of genes that are capable of predicting a high likelihood of response to therapy will be identified and that individualization of therapy for patients with esophageal adenocarcinoma will become a reality. However, at this time, early detection (while the tumor is still intramucosal) and complete surgical resection are the surest ways to cure esophageal cancer, and thus surveillance endoscopy for patients with Barrett’s esophagus and perhaps endoscopic or PillCam¹⁶³ screening of patients with reflux symptoms may be the most useful current strategies.

Received for publication December 29, 2004. Accepted for publication July 20, 2005.

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TOP ABSTRACT INTRODUCTION THE RELATIONSHIP BETWEEN... ETIOLOGY, PATHOPHYSIOLOGY, AND... DIAGNOSIS AND STAGING TREATMENT NEW HORIZONS IN THE... REFERENCES

 

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