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Ann Thorac Surg 1998;65:176-181
© 1998 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Prognosis of Adenocarcinoma Arising in Barrett’s Esophagus

Section of Surgical Sciences, Department of Cardiac and Thoracic Surgery, Division of Medical Oncology, Division of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Dr Hoff, Cardiovascular Surgical Associates, 4230 Harding Rd, Suite 501 W, Nashville, TN 37205.

Presented at the Forty-third Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 7–9, 1996.

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background. The rising incidence of adenocarcinoma of the esophagus, as well as its association with Barrett’s esophagus, has been reported previously. We report our experience in treating patients with adenocarcinoma arising in Barrett’s esophagus.

Methods. A retrospective review was performed of 70 consecutive patients with adenocarcinoma of the esophagus treated between November 1988 and April 1996 with preoperative chemoradiation and resection. Demographics, pathologic features, and survival were compared with patients who developed adenocarcinoma of the esophagus without Barrett’s. Statistical analyses was performed using Student’s t test, Fisher’s exact test, and Kaplan-Meier where appropriate.

Results. Thirty-two (46%) patients had adenocarcinoma arising in Barrett’s esophagus. During the last 4 years, 72% (23 of 32) of patients with adenocarcinoma had coexistent Barrett’s. No differences in patients with or without Barrett’s with regard to age, sex, race, tumor location, preoperative chemotherapy, type of operation, or operative stage were observed. Tumors in patients with Barrett’s were larger (p = 0.017), had better differentiation (p = 0.002), and were less likely to have a complete response to preoperative chemoradiation (p = 0.05). Actuarial survival, however, was better in the group with associated Barrett’s esophagus (p = 0.033).

Conclusions. The incidence of adenocarcinoma of the esophagus arising in Barrett’s esophagus appears to be increasing. It may be distinct clinically and biologically from adenocarcinoma of the esophagus that does not develop in association with Barrett’s epithelium. Long-term survival was better in our patients with adenocarcinoma associated with Barrett’s esophagus.

	Introduction

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The rising incidence of adenocarcinoma of the esophagus, as well as its association with Barrett’s esophagus, has been reported previously [1]. In recent years, a growing body of literature, both clinical and experimental, has emerged that parallels this increasingly common clinical problem. Fig 1 shows the number of citations in the English-language literature concerning adenocarcinoma arising in Barrett’s esophagus, and shows a dramatic rise in the number of reports dealing with the clinical problem, as well as those on a molecular or experimental level.

View larger version (32K): [in this window] [in a new window]   Literature citations concerning adenocarcinoma arising in Barrett’s esophagus.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
A retrospective review was performed of consecutive patients with adenocarcinoma of the esophagus treated between November 1988 and April 1996 with preoperative chemoradiation and resection. Demographics, pathologic features, and survival were compared with patients in whom adenocarcinoma of the esophagus developed without Barrett’s esophagus.

Patients were treated using a previously described prospective protocol involving combination chemotherapy with cisplatin, 5-fluorouracil (5-FU), and leucovorin and 3000 cGy of concurrent mediastinal radiotherapy [2][3]. All patients were then reevaluated and appropriate candidates proceeded to surgical resection. Since 1995, we have used a protocol that involves two cycles of preoperative paclitaxel (Taxol) and cisplatin with concurrent radiotherapy, followed by surgical resection. Postoperatively, patients receive two cycles of paclitaxel, 5-fluorouracil, and high-dose leucovorin in an attempt to improve overall response rates.

Statistical analyses was performed using Student’s t test and Fisher’s exact test, with a level of statistical significance set at p = 0.05. Survival data were analyzed using Kaplan-Meier survival analysis.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
Since November 1988, we have treated 70 patients with adenocarcinoma of the esophagus. The mean age was 59 years (range, 31 to 79 years). There were 64 men and 6 women. Sixty-five patients were white, 5 were black.

Dysphagia was a common complaint at presentation, occurring in 86% (60 of 70) patients. Weight loss was noted by 74% of patients (52 of 70), heartburn was present in 39% of patients (27 of 70), and a documented hiatal hernia was present in 17% of patients (12 of 70).

Thirty-two (46%) patients had adenocarcinoma arising in Barrett’s esophagus. During the last 4 years of the study period, 72% (23 of 32) of patients had adenocarcinoma of the esophagus arising in Barrett’s esophagus. Fig 2 shows the rising incidence of adenocarcinoma of the esophagus in our experience, as well as the increasing proportion of those patients in whom adenocarcinoma arises in Barrett’s esophagus.

View larger version (35K): [in this window] [in a new window]   Incidence of adenocarcinoma.

In the 32 patients with adenocarcinoma arising in Barrett’s esophagus, transhiatal esophagectomy was performed in 26 patients, a combined abdominal and thoracic approach was used in 4 patients, 1 patient was not resected because of metastatic disease at exploration, and 1 patient was denied operation because of poor performance status at reevaluation. Of 38 patients whose adenocarcinoma did not arise in Barrett’s, transhiatal esophagectomy was performed in 20 patients, a combined abdominal and thoracic approach was used in 10 patients, and 8 patients did not undergo resection (p = not significant). Of those 8 patients, 3 had metastatic disease at exploration, 2 were denied operation because of poor performance status, 2 patients early in our experience died of toxicity related to chemotherapy before operation, and 1 patient was unresectable because of locally advanced disease.

Tumors in patients with Barrett’s were smaller, as evidenced by a lower preoperative stage (p = 0.017). Of patients with Barrett’s epithelium, 13 had tumors 5 cm in diameter or greater, whereas 18 patients had tumors less than 5 cm in diameter, and 1 patient had high-grade dysplasia only. In the latter patient no tumor was found in the specimen at the time of resection. The preoperative biopsy showed adenocarcinoma and the patient received preoperative chemoradiation. In patients without Barrett’s changes, 27 had tumors larger than 5 cm, whereas 11 patients had tumors smaller than 5 cm.

Tumors arising in Barrett’s epithelium were better differentiated than those that did not arise in Barrett’s. Tumors in Barrett’s were well differentiated in 2 patients, moderately differentiated in 18 patients, and poorly differentiated in 3 patients, whereas those that did not arise in Barrett’s were well differentiated in only 3 patients, moderately differentiated in 8 patients, and poorly differentiated in 13 patients (p = 0.002).

No difference in patients with or without Barrett’s was observed with respect to operative stage (p = not significant). Patients with tumors arising in Barrett’s were less likely to have a complete response to preoperative chemoradiation as evidenced by no detectable tumor in the resected esophagus (4 of 32 [12.5%] versus 10 of 34 [29%]; p = 0.05).

The average hospital stay was 14 days, with hospital stays of less than 1 week common recently. There were no hospital deaths (0% mortality). Anastomotic leak complicated the postoperative course in 3 patients (4%), wound infection in 1 patient (1%), and pneumonia in 4 patients (7%).

Mean follow-up for all patients was 23.1 months. One-year and 5-year survival overall was 74% and 43%, with overall disease-free survival of 74% at 1 year and 42% at 5 years. Median survival for all patients was 30 months.

Actuarial survival was better in the group with associated Barrett’s esophagus (p = 0.033, Fig 3). One-year and 5-year survival for patients with tumors arising in Barrett’s esophagus was 81% and 64%, respectively, whereas it was 70% and 32% for patients whose tumors did not arise in Barrett’s epithelium.

View larger version (15K): [in this window] [in a new window]   Actuarial survival in patients with and without Barrett’s esophagus.

	Comment

Top Abstract Introduction Material and Methods Results Comment References

There has been a recent increase in the number of reports in the medical literature describing the demographics and epidemiology of the development of Barrett’s esophagus and its implications (Fig 1). Recent reports have described an increased prevalence in the last 10 years [3][5][6]. Our data confirm those of Kirby and colleagues [5], who showed a dramatic rise in the incidence of adenocarcinoma of the esophagus, now comprising as much as 75% of all patients with carcinoma of the esophagus. In addition, their experience was that in the last 5 years, more than 50% of cases of adenocarcinoma of the esophagus developed in Barrett’s epithelium, similar to the substantial increase seen in our patients.

The explanation for the recent increase in the prevalence of these two related conditions is not yet known. Evaluation of factors associated with the development of these two conditions may help understand these recent changes. In previous years, when squamous cancer of the esophagus predominated, demographic risk factors such as older age, male sex, black race, smoking, alcohol consumption, and other dietary and nutritional factors were all closely associated with the development of the disease. Recent reports now show that these traditional risk factors are not associated with the development of adenocarcinoma in Barrett’s esophagus. The majority of the literature confirms the general consensus that adenocarcinoma of the esophagus now develops in middle-aged, middle-class, well-nourished white men without a significant smoking or drinking history [7].

It is not lost on investigators that the recent increase in the prevalence of Barrett’s esophagus and adenocarcinoma parallels the explosion in the availability and use of more powerful drugs to treat gastroesophageal reflux and to reduce lower esophageal sphincter pressure [6]. Whether this is a clinical coincidence or linked etiologically has yet to be determined. Several studies have shown the link between gastroesophageal reflux disease (and its sequlae) and ulcer disease with the development of adenocarcinoma of the esophagus [6][8]. In particular there has been much recent interest in the effect of both acid reflux and biliary or pancreaticoduodenal reflux on the development of Barrett’s and adenocarcinoma [9][10][11]. In a clinical study, Champion and associates [9] showed that acid reflux was the primary factor in the development of Barrett’s, with bile reflux perhaps having a synergistic role. Clark and colleagues [10], in a rat model, showed that reflux of gastroduodenal contents into the esophagus induced both Barrett’s changes and neoplasia. They further showed this carcinogenic process is promoted by a diet with a high fat content. In another experimental study, Pera and coworkers [11] reported that pancreatic secretions were particularly important in carcinogenesis. Other investigators have reported their interest at the molecular level in a variety of agents that may have roles in the development of Barrett’s and adenocarcinoma, including p53 mutations, various chromosomal anomalies, and cytokines such as transforming growth factor and epithelial growth factor [12].

Certain pathologic settings unique to the development of adenocarcinoma in Barrett’s have been the subject of recent investigations [13][14][15][16]. Paraf and colleagues [13] showed that depth of tumor invasion and regional lymph node status were independent predictors of improved survival. Lieberman and coworkers [14] showed similar results but failed to demonstrate the presence of Barrett’s as a predictor of improved survival, in contrast to our data. It is of interest in both of these studies that patients were treated with resection alone, as opposed to the neoadjuvant chemoradiation employed in our study. Iftikhar and colleagues [15] showed that the length of columnar lined esophagus greater than 8 cm was a significant risk factor for the development of dysplasia and subsequent carcinoma. In a smaller study Cameron and associates [16] showed that adenocarcinoma was associated with short and long segments of Barrett’s esophagus and suggested that larger cancers overgrow and conceal underlying metaplastic epithelium.

Despite the increasingly certain relationship of gastroesophageal reflux and Barrett’s epithelium in the development of adenocarcinoma, controversy exists as to the role of endoscopic surveillance in the management of patients with high-grade dysplasia and no frank carcinoma. To this point it is not clear that a schedule of routine endoscopy with biopsy is cost effective or efficacious in the diagnosis of carcinoma in its early, treatable stages. Peters and coworkers [17] showed patients referred from surveillance programs had better outcomes and earlier stage tumors. In light of this, they recommended resection for high-grade dysplasia alone. We concur with this strategy, and we have recently performed transhiatal esophagectomy in 3 patients who have developed high-grade dysplasia in Barrett’s epithelium. Rice and colleagues [18] showed that 38% of patients resected for high-grade dysplasia had invasive intramucosal carcinoma at resection. Pera and associates [19] showed 50% of their patients with high-grade dysplasia had occult carcinoma at resection and these patients had a 67% overall 5-year survival. Endoscopic strategies may improve our ability to diagnose early adenocarcinoma [20]. The exact role of vital-dye staining and endoscopic ultrasound remain to be elucidated, but endoscopic ultrasound is now used in all our patients for staging before treatment.

We favor multimodality treatment of all esophageal cancers. It is our contention that in most if not all patients with invasive carcinoma of the esophagus, the lymphatic drainage contributes to the fact that the disease is micrometastatic at the time of diagnosis. The best approach, therefore, to improve long-term survival in these patients is a multidisciplinary one allowing preoperative radiosensitizing chemotherapy with concurrent mediastinal irradiation. This may downstage the disease and improve local control at the time of resection, as well as providing treatment of micrometastatic disease at a time when tumor bulk is lowest. Resection may have the added benefit of removing chemotherapeutically resistant cell lines. This approach also has the benefit of providing significant symptomatic relief to those patients who present with significant obstructive symptoms who may already have suffered weight loss, allowing them to swallow better and improve their nutritional status, thereby lowering operative risk and improving short-term outcome.

Naunheim and colleagues [21] published their results with a similar multimodality approach, showing long-term actual survival of 25% of patients who came to resection. Rusch and coworkers [22] advocate a similar multidisciplinary treatment plan for patients with high-grade dysplasia or early carcinoma. Lerut and coworkers [23] described an astonishing 5-year survival rate of 85% in patients without nodal metastases and 38% in patients with nodal metastases in their patients who underwent multimodality treatment. Wolfe and colleagues [24] describe encouraging results with this preoperative neoadjuvant protocol, showing 55% 5-year survival in patients with adenocarcinoma and Barrett’s. Walsh and colleagues [25] reported a prospective, randomized trial comparing esophagectomy alone with combined chemotherapy, radiotherapy, and esophagectomy. Survival in patients who underwent multimodality treatment was superior to esophagectomy alone in patients with resectable adenocarcinoma of the esophagus.

New therapeutic strategies have been proposed that may ultimately show promise in improving survival in these patients. These include profound acid suppression, laser ablation of Barrett’s epithelium, and photodynamic therapy.

In conclusion, the incidence of adenocarcinoma of the esophagus arising in Barrett’s esophagus appears to be increasing. It may be distinct clinically and biologically from adenocarcinoma of the esophagus that does not develop in association with Barrett’s epithelium. Long-term survival appears to be better in patients with adenocarcinoma associated with Barrett’s esophagus when treated with a multimodality approach.

	References

Top Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Steven J. Hoff John L. Sawyers James R. Stewart Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hoff, S. J. Articles by Stewart, J. R. Search for Related Content PubMed PubMed Citation Articles by Hoff, S. J. Articles by Stewart, J. R.