- Email: [email protected]
Barrett's oesophagus: Treatment with surgery
Accepted Manuscript Barrett’s esophagus: Treatment with Surgery Steven R. DeMeester, MD, Professor of Surgery
PII:
S1521-6918(14)00194-2
DOI:
10.1016/j.bpg.2014.12.004
Reference:
YBEGA 1323
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 30 October 2014 Revised Date:
8 December 2014
Accepted Date: 11 December 2014
Please cite this article as: DeMeester SR, Barrett’s esophagus: Treatment with Surgery, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/j.bpg.2014.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Barrett’s esophagus: Treatment with Surgery
Steven R. DeMeester, MD Professor of Surgery
The University of Southern California [email protected] Office: (323) 442-9066 1
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Abstract:
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Barrett’s esophagus develops as a consequence of gastroesophageal reflux disease and may progress to esophageal adenocarcinoma. Antireflux surgery is an option for patients with reflux disease, but the efficacy and impact on the natural history of disease in patients with Barrett’s esophagus is controversial. This review addresses the existing data on these important issues.
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Keywords: Gastroesophageal reflux disease; Barrett's esophagus; Esophageal adenocarcinoma; Antireflux surgery; Nissen fundoplication
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Conflict of interest statement: None.
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Barrett’s esophagus (BE), defined by the presence of an endoscopically visible segment of columnar-lined esophagus with goblet cells on histology, develops as a consequence of gastroesophageal reflux disease (GERD). Consequently, any patient with Barrett’s has GERD, since reflux is the only known etiology for BE. Accepted therapies for longterm management of GERD include medical therapy, typically with proton pump inhibitors (PPIs), or antireflux surgery, typically with a fundoplication. There is controversy about the goal of therapy in patients with BE. Many physicians focus on relief of symptoms in patients with Barrett’s similar to any patient with reflux disease. This approach is largely based on the belief that no therapy can alter the natural history of BE and that progression, while rare, was inevitable in some patients. While relief of symptoms is an important goal in the treatment of any patient with GERD, in a patient with BE at least some consideration should be given to the impact of therapy on the Barrett’s mucosa. Barrett’s esophagus is a premalignant condition and the precursor to the fastest increasing cancer in the United States, esophageal adenocarcinoma. Recent studies, although controversial, have suggested that treatment with PPIs may reduce the risk of progression in patients with BE.[3] In light of the potential that therapy can in fact alter the natural history of BE, it is worth considering if perhaps therapy beyond relief of symptoms should be the goal in these patients.
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Conceptually there are three ways in which therapy for BE may alter the risk of progression. One mechanism is if the therapy leads to a reduction or more importantly a loss of intestinal metaplasia within the columnar-lined segment. Loss of intestinal metaplasia would imply a significant decrease in the risk of progression since patients with intestinal metaplasia have an increased risk for progression compared to those with a columnar segment without intestinal metaplasia.[4] Further, there is evidence that the risk of progression in BE increases with longer segments of Barrett’s.[5] Therefore, it would appear that a therapy that leads to a shorter length of BE and particularly to loss of intestinal metaplasia would be beneficial in terms of reducing the risk of progression.
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The second mechanism whereby a therapy could alter the risk of progression to adenocarcinoma is if the therapy led to a loss of dysplasia within the Barrett’s mucosa. The reliability of a single pathologist’s assessment of dysplasia, particularly low-grade dysplasia, is problematic, and much of what is called low-grade dysplasia is likely inflammatory changes rather than actual genetic changes within the Barrett’s mucosa. None-the-less, the fact remains that numerous studies have shown that low-grade dysplasia is associated with an increased risk of progression. The most recent and compelling evidence for this comes from a Danish population-based study. In this study the presence of low-grade dysplasia imparted a significant risk of progression, and these biopsies were read by a single pathologist with no secondary confirmation of the findings.[6] Consequently, regression of low-grade dysplasia to no dysplasia should be considered a beneficial change that reduces the risk of cancer in a patient with BE. 3
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The third mechanism by which a therapy could alter the risk of progression is to induce “quiescence” within the Barrett’s mucosa. Patients can live normally with their BE provided it doesn’t progress to cancer, and a therapy that doesn’t lead to a loss of intestinal metaplasia or dysplasia can still be beneficial if the cellular or genetic alterations associated with progression are disrupted or halted. Gastroesophageal reflux causes BE and it is logical that continued irritation and injury to the esophageal mucosa by frequent episodes of reflux can lead to progression of disease. Control of the reflux could induce alterations in the pathways and genes that are upregulated by chronic inflammation and lead to a quiescent Barrett’s mucosa and a lower risk for progression.
Research agenda:
Confirm the importance of intestinal metaplasia as the indicator that a columnarlined esophagus is at risk for progression to esophageal adenocarcinoma.
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There are three ways a therapy might alter the risk of progression in patients with Barrett’s esophagus: 1. The therapy leads to a reduction or loss of intestinal metaplasia 2. The therapy leads to a loss of dysplasia 3. The therapy induces quiescence in the Barrett’s mucosa and stops progression to cancer
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An important question is whether there is evidence that antireflux surgery can alter the risk of Barrett’s progression by one of more of these three proposed mechanisms. An effective Nissen fundoplication has been shown to stop abnormal reflux of gastric juice into the esophagus and cure or eliminate GERD. It not only normalizes esophageal acid exposure, but stops reflux of bile and weakly acidic material into the esophagus as well.[1] Prevention of reflux by a fundoplication alleviates symptoms but in addition has been shown to promote changes that could be considered beneficial for preventing progression of BE on to adenocarcinoma. First, antireflux sugery has been shown in several studies to lead to regression in the length of BE.[1, 7] More importantly, 4
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antireflux surgery has been shown to lead to a complete loss of intestinal metaplasia in some patients with BE. The likelihood of loss of intestinal metaplasia is related to the length of BE, with shorter segments more likely to regress. In studies from our institution intestinal metaplasia of the cardia, sometimes called ultra-short BE, was shown to regress to no intestinal metaplasia in 73% of patients after a fundoplication, while short or long-segments of BE regressed to no intestinal metaplasia in 14% of patients.[8] [9] In a series by Low 10/14 patients (71%) with BE showed regression of the length with 2 patients (14%) showing complete loss of intestinal metaplasia. Both of these patients had short-segment BE.[10] Similarly, Oelschlager reported complete loss of intestinal metaplasia after antireflux surgery in 30 of 54 patients (55%) with short-segment BE but in none of 36 patients with long-segment BE.[11] In perhaps the largest series of carefully followed patients with short-segment BE treated with laparoscopic Nissen fundoplication, Csendes reported loss of intestinal metaplasia in 61% of patients at mean of 49 months.[12] Lastly, in a systematic review published in 2007 Chang reported a 17% overall rate of complete loss of intestinal metaplasia after antireflux surgery in patients with BE.[7]
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Antireflux surgery has also been shown to induce regression of low-grade dysplasia.[1, 7] At our center we observed regression of low-grade to no dysplasia in 7 of 16 patients (44%) after a fundoplication.[9] In the series by Oelschlager low-grade or indefinite dysplasia regressed to no dysplasia or no intestinal metaplasia in 8 of 15 patients (53%).[11] In the systematic review by Chang antireflux surgery was associated with a 57% overall rate of regression of low-grade dysplasia. Most regression was to nondysplastic BE, but in 4% regression was to no intestinal metaplasia.[7] Although it could be argued that the diagnosis of low-grade dysplasia was not confirmed by a second pathologist and often represented inflammation rather than true low-grade dysplasia, even unconfirmed low-grade dysplasia is associated with an increased risk for progression, and regression should be considered a beneficial change for patients with BE. Further, there is evidence that antireflux surgery can alter gene expression in patients with GERD. COX-2 gene expression has been shown to increase progressively during each step of the carcinogenic process from BE to esophageal adenocarcinoma.[13] Following antireflux surgery gene expression levels of both COX2 and interleukin-8 have been shown to normalize, providing a genetic mechanism whereby true low-grade dysplasia could revert to non-dysplastic BE.[14, 15] Lastly, antireflux surgery has also been shown to reduce the risk of Barrett’s progression. In a longitudinal prospective series of patients followed closely with endoscopic surveillance for a non-intestinalized columnar-lined esophagus, Oberg reported that compared to patients on medical therapy those that had an antireflux operation were 10.3 times less likely to develop intestinal metaplasia.[16] If no intestinal metaplasia develops in these patients they are at a reduced risk for developing 5
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esophageal adenocarcinoma.[17] In patients with BE several series have shown absent or rare progression to high-grade dysplasia or adenocarcinoma after antireflux surgery.[9, 10, 18] In the systematic review by Chang progression of any type was seen in only 4.2% of patients after antireflux surgery.[7] Compared to medical therapy a number of studies have shown a reduced risk of progression in patients treated with a fundoplication.[1] In a carefully followed group of patients in Sweden Oberg found the risk of developing low-grade dysplasia in patients on medical therapy for non-dysplastic BE was increased 2.3 times compared to those that had been treated with a fundoplication. Further, no patient in that series progressed to high-grade dysplasia or adenocarcinoma after fundoplication. This was a highly statistically significant difference compared to the frequency of progression to high-grade dysplasia or adenocarcinoma in medically treated patients.[19] To date there is only one randomized trial that reports the risk of BE progression in medically and surgically treated patients. This trial from Spain reported by Parrilla consisted of 101 patients with BE randomized to undergo medical treatment (n=58) or antireflux surgery (n=43). At a median follow-up of 6 years patients with a functioning fundoplication were significantly less likely to have progressed to dysplasia compared to the medical treatment group.[20] In a subsequent analysis the authors reported that expression of Ki-67 and p53 remained stable over time in the group that had antireflux surgery but increased progressively and significantly in the medical therapy group.[21] These findings support the concept that antireflux surgery can induce a quiescent state in the Barrett’s mucosa that may equate to a reduced likelihood of progression. Further support for this concept is evidence that patients that progress after antireflux surgery usually do so within the first 5 years of surgery, suggesting that progression in these patients occurred as a consequence of genetic alterations already in place at the time of surgery.[22] In contrast, progression after 5 years is uncommon, and likely related to break-down of the fundoplication. If the fundoplication had no impact on the natural history of the disease one would expect cancers to occur regularly throughout the follow-up period rather than be clustered within the first couple of years.
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Research agenda:
Compare the frequency of regression and progression in carefully matched patients with Barrett’s esophagus on medical therapy and after antireflux surgery.
Practice points: -
Antireflux surgery alters the natural history of Barrett’s esophagus by promoting loss of intestinal metaplasia, regression of low-grade dysplasia, and reduction of progression to high-grade dysplasia and esophageal adenocarcinoma. 6
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Some of the most widely quoted population-based studies on gastroesophageal reflux, esophageal adenocarcinoma and antireflux surgery are from Lagergren and colleagues at the Karolinska institute in Sweden. In 1999 they reported that the risk of adenocarcinoma of the esophagus was almost 8 times higher in people with weekly heartburn and regurgitation compared to those without these symptoms.[23] Further, they found that the frequency and duration of symptoms was directly related to the risk of adenocarcinoma. They went on to report in 2001 that there was no evidence of a protective effect of antireflux surgery against esophageal adenocarcinoma because the cancer risk remained elevated even 10 or more years after surgery. However, they conceded that they “may have overlooked a small long-term protective effect of surgery since the excess risk of cancer remained stable after surgery but increased substantially with time among reflux patients who did not have surgery”.[24] In a subsequent study published in 2007 the authors evaluated the cancer risk in relation to the functioning of the fundoplication. They found that patients who developed esophageal adenocarcinoma after antireflux surgery were significantly more likely to have persistent or recurrent reflux.[25] In 2010 the authors used the Swedish Inpatient Register and the Swedish Cancer Registry to show that the risk of esophageal adenocarcinoma was increased 12-fold after antireflux surgery compared to the risk in the general population of Sweden.[26]
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These findings must be evaluated in light of the shortcomings and limitations of the databases used for these studies. First, a critical limitation is that the prevalence of Barrett’s esophagus was unknown since it was not recorded in the database. Barrett’s esophagus is the single most significant risk factor for esophageal adenocarcinoma and it is virtually a certainty that the prevalence of Barrett’s was different in the antireflux surgery group, the medically treated group, and the general population in Sweden.[27] The inability to match cases and controls for the prevalence of Barrett’s in studies on esophageal adenocarcinoma is like trying to study ovarian cancer without knowing the prevalence of women in the case and control groups. It is an insurmountable problem for interpretation of the findings in the series of studies by Lagergren and colleagues.
A second major limitation is that the comparison groups were not matched for gender or severity of reflux disease. It is also a virtual certainty that the patients that had antireflux surgery were more commonly men with the most severe gastroesophageal reflux disease.[27] Since this is the group of patients most at risk to develop Barrett’s esophagus, there can be little doubt that the antireflux surgery group was stacked with patients with Barrett’s esophagus compared to the general population and to medically treated patients. With this in mind it is easy to understand why in 2001 the authors 7
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noted that the antireflux group had “an excess risk” of cancer compared to the patients with reflux that were treated medically.[24] Importantly, they noted that the risk of cancer was stable over time in patients that had antireflux surgery, suggesting the natural history was altered in these patients. In contrast, the cancer risk increased over time in the patients with reflux who did not have a fundoplication, no doubt related to disease progression, development of Barrett’s esophagus and ultimately esophageal adenocarcinoma in some of these medically treated patients.
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In addition to database limitations that prohibited a fair analysis of whether an antireflux operation altered the risk of adenocarcinoma, Lagergren and colleagues reached several flawed conclusions in the analysis of their findings. Their conclusion that there was no evidence of a protective effect of antireflux surgery for esophageal adenocarcinoma was misguided. A major basis for this conclusion was from their studies showing that compared to the corresponding Swedish population the cancer risk remained elevated in patients after antireflux surgery.[24, 26] The problem with these studies and the authors’ conclusion is that the comparison group should not be the general population of Sweden. Instead, the incidence of cancer in patients after antireflux surgery should be compared to the incidence in a matched population of patients with GERD and BE treated medically. An analogy would be to look at the risk of myocardial infarction in patients with heart disease on statins and compare it to the risk in the general population. Undoubtedly the risk of myocardial infarction would be elevated in the statin group since this is the group with heart disease. To conclude that statins are not effective since there are more myocardial infarctions in the group taking them compared to the general population would be inappropriate. Similarly, Lagergren and colleague’s conclusions about antireflux surgery and cancer risk are inappropriate. There is no therapy that prevents disease 100% of the time, and that is not the standard that is applied to medical or surgical interventions. Instead, the standard for acceptance of efficacy of a medical or surgical therapy is that it reduces the risk compared to an alternative (or no) therapy. Antireflux surgery won’t prevent all esophageal adenocarcinomas from developing in patients with BE, but that is not the standard it needs to achieve. Another flaw in the logic that an antireflux operation is not protective against the development of adenocarcinoma comes from the two studies by Lagergren and colleagues that show that recurrent or persistent reflux after a fundoplication was associated with an increased risk for esophageal adenocarcinoma. If a fundoplication does not alter the natural history of BE then the function or non-function of the fundoplication would be irrelevant in terms of cancer risk.[25, 28] If a non-functioning fundoplication is associated with an increased cancer risk, then by deduction a functioning fundoplication must decrease this risk.
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A thoughtful reanalysis of the series of studies by Lagergren should lead to the following conclusions. Esophageal adenocarcinoma develops from gastroesophageal reflux disease, and more severe reflux is associated with an increased risk for progression to cancer. After fundoplication the risk of cancer was stable, but the cancer risk increased over time in those with reflux not treated by a fundoplication. Failure of the fundoplication led to an increased risk of cancer, similar to patients with reflux without a fundoplication. Thus, the studies by Lagergren are in fact some of the most powerful studies ever published showing that antireflux surgery does in fact decrease the risk of esophageal adenocarcinoma. One message is clear to those of us who are surgeons performing antireflux surgery in patients with BE, it is of no benefit if the fundoplication breaks down and reflux recurs. The onus is upon us to select appropriate patients, do it well and make it last.
Practice points:
Barrett’s esophagus represents end-stage reflux disease, and these patients are more difficult to treat both medically and with antireflux surgery. Surgeons must pay attention to secure repair of the crura since large hiatal hernias are common in these patients, and a shortened esophagus should be addressed with a Collis gastroplasty to reduce tension on the repair.
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Barrett’s esophagus represents long-standing reflux disease since it is estimated to take 5 or more years for BE to develop.[1] Longer segments of BE are associated with more physiologic abnormalities including larger hiatal hernias and worse LES function.[2] These anatomic and functional abnormalities make successful treatment of patients with long-segment Barrett’s more difficult with either PPIs or antireflux surgery. The frequency of a recurrent hiatal hernia or failure of the fundoplication is increased in BE patients compared to those with less severe reflux disease.[9] Consequently, particular attention must be paid to securely closing the crura and addressing tension in these patients to minimize the risk of recurrent GERD. When a short esophagus is encountered a Collis gastroplasty should be considered. Every effort must be made to prevent failure of the fundoplication given the evidence that a failed fundoplication is a risk factor for progression to adenocarcinoma in patients with Barrett’s esophagus.
A final concept to consider is whether early control of gastroesophageal reflux can prevent the development of Barrett’s esophagus. In the PRO-GERD series of studies 2721 GERD patients were followed for 5 years and 9.7% progressed to BE. The risk was related to the severity of reflux disease, and in those with Los Angeles grade C/D esophagitis 19.7% of patients developed BE compared to 12.1% in patients with Los 9
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Angeles grade A/B esophagitis.[29] It is interesting to speculate that perhaps early intervention in some of these patients with an antireflux operation or the new LINX sphincter augmentation device might reduce the increasing burden of Barrett’s esophagus and esophageal adenocarcinoma. Following the old adage that an ounce of prevention is worth a pound of cure, these possibilities deserve further exploration in future trails and retrospective reviews of surgically treated patients who had erosive esophagitis before their fundoplication.
Research agenda:
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Patients at risk for disease progression on medical therapy should be offered antireflux surgery in an effort to alter the natural history of the disease. Trials evaluating progressive disease in those on medical therapy or after antireflux surgery are warranted given the significant risk of Barrett’s in patients with advance erosive esophagitis on endoscopy.
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In conclusion, an appropriate question to ask is does antireflux surgery reduce the risk of esophageal adenocarcinoma compared to alternative therapies in patients with a similar severity of reflux disease and prevalence of Barrett’s esophagus? This question has not been answered definitively, but findings from the series of papers by Lagergren and colleagues in combination with studies showing loss of intestinal metaplasia, regression of dysplasia, reduced progression to high-grade dysplasia or adenocarcinoma and normalization or stabilization of genes associated with Barrett’s progression all point in the same direction, that antireflux surgery impacts the natural history of reflux disease and BE. Consequently, in all likelihood the above question should be answered affirmatively. Further, future studies should focus on early surgical intervention in patients at risk for disease progression in an effort to prevent the development of Barrett’s esophagus and ultimately adenocarcinoma.
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References:
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1. DeMeester SR, DeMeester TR. Columnar Mucosa and Intestinal Metaplasia of the Esophagus: Fifty Years of Controversy. Annals of Surgery 2000; 231: 303-321. 2. Oberg S, DeMeester TR, Peters JH et al. The extent of Barrett's esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure. Journal of Thoracic & Cardiovascular Surgery 1999; 117: 572-580. 3. Singh S, Garg SK, Singh PP et al. Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis. Gut 2014; 63: 1229-1237. 4. Bhat S, Coleman HG, Yousef F et al. Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study.[Erratum appears in J Natl Cancer Inst. 2013 Apr 17;105(8):581]. Journal of the National Cancer Institute 2011; 103: 1049-1057. 5. Anaparthy R, Gaddam S, Kanakadandi V et al. Association between length of Barrett's esophagus and risk of high-grade dysplasia or adenocarcinoma in patients without dysplasia. Clinical Gastroenterology & Hepatology 2013; 11: 1430-1436. 6. Hvid-Jensen F, Pedersen L, Drewes AM et al. Incidence of adenocarcinoma among patients with Barrett's esophagus. New England Journal of Medicine 2011; 365: 1375-1383. 7. Chang EY, Morris CD, Seltman AK et al. The effect of antireflux surgery on esophageal carcinogenesis in patients with barrett esophagus: a systematic review. Annals of Surgery 2007; 246: 11-21. 8. DeMeester SR, Campos GM, DeMeester TR et al. The impact of an antireflux procedure on intestinal metaplasia of the cardia. Annals of Surgery 1998; 228: 547-556. 9. Hofstetter WL, Peters JH, DeMeester TR et al. Long-term outcome of antireflux surgery in patients with Barrett's esophagus. Annals of Surgery 2001; 234: 532-538; discussion 538-539. 10. Low DE, Levine DS, Dail DH, Kozarek RA. Histological and anatomic changes in Barrett's esophagus after antireflux surgery. American Journal of Gastroenterology. 1999; 94: 80-85. 11. Oelschlager BK, Barreca M, Chang L et al. Clinical and pathologic response of Barrett's esophagus to laparoscopic antireflux surgery. Annals of Surgery 2003; 238: 458-464; discussion 464-456. 12. Csendes A, Braghetto I, Burdiles P et al. Late results of the surgical treatment of 125 patients with short-segment Barrett esophagus. Archives of Surgery 2009; 144: 921-927. 13. Kuramochi H, Vallbohmer D, Uchida K et al. Quantitative, tissue-specific analysis of cyclooxygenase gene expression in the pathogenesis of Barrett's adenocarcinoma. Journal of Gastrointestinal Surgery 2004; 8: 1007-1016; discussion 1016-1007. 14. Vallbohmer D, DeMeester SR, Oh DS et al. Antireflux surgery normalizes cyclooxygenase-2 expression in squamous epithelium of the distal esophagus. American Journal of Gastroenterology 2006; 101: 1458-1466. 15. Oh DS, DeMeester SR, Vallbohmer D et al. Reduction of interleukin 8 gene expression in reflux esophagitis and Barrett's esophagus with antireflux surgery. Archives of Surgery 2007; 142: 554-559; discussion 559-560. 11
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16. Oberg S, Johansson J, Wenner J et al. Endoscopic surveillance of columnarlined esophagus: frequency of intestinal metaplasia detection and impact of antireflux surgery. Annals of Surgery 2001; 234: 619-626. 17. Spechler SJ, Souza RF. Barrett's esophagus. New England Journal of Medicine 2014; 371: 836-845. 18. McDonald ML, Trastek VF, Allen MS et al. Barretts's esophagus: does an antireflux procedure reduce the need for endoscopic surveillance?. Journal of Thoracic & Cardiovascular Surgery 1996; 111: 1135-1138; discussion 1139-1140. 19. Oberg S, Wenner J, Johansson J et al. Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma. Annals of Surgery 2005; 242: 49-54. 20. Parrilla P, Martinez de Haro LF, Ortiz A et al. Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett's esophagus.[see comment]. Annals of Surgery 2003; 237: 291-298. 21. Martinez de Haro LF, Ortiz A, Parrilla P et al. Long-term follow-up of malignancy biomarkers in patients with Barrett's esophagus undergoing medical or surgical treatment. Annals of Surgery 2012; 255: 916-921. 22. DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus: fifty years of controversy. Annals of Surgery 2000; 231: 303-321. 23. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.[see comment]. New England Journal of Medicine 1999; 340: 825-831. 24. Ye W, Chow WH, Lagergren J et al. Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery. Gastroenterology 2001; 121: 1286-1293. 25. Lagergren J, Viklund P. Is esophageal adenocarcinoma occurring late after antireflux surgery due to persistent postoperative reflux?[see comment]. World Journal of Surgery 2007; 31: 465-469. 26. Lagergren J, Ye W, Lagergren P, Lu Y. The risk of esophageal adenocarcinoma after antireflux surgery. Gastroenterology 2010; 138: 1297-1301. 27. DeMeester SR. Antireflux surgery and the risk of esophageal adenocarcinoma: an antithetical view of the data from sweden. Annals of Surgery 2013; 257: 583-585. 28. Attwood SEA, Lundell L, Ell C et al. Standardization of surgical technique in antireflux surgery: the LOTUS Trial experience. World Journal of Surgery 2008; 32: 995998. 29. Malfertheiner P, Nocon M, Vieth M et al. Evolution of gastro-oesophageal reflux disease over 5 years under routine medical care--the ProGERD study. Alimentary Pharmacology & Therapeutics 2012; 35: 154-164. 30. Nocon M, Labenz J, Jaspersen D et al. Long-term treatment of patients with gastro-oesophageal reflux disease in routine care - results from the ProGERD study. Alimentary Pharmacology & Therapeutics 2007; 25: 715-722.
12
PII:
S1521-6918(14)00194-2
DOI:
10.1016/j.bpg.2014.12.004
Reference:
YBEGA 1323
To appear in:
Best Practice & Research Clinical Gastroenterology
Received Date: 30 October 2014 Revised Date:
8 December 2014
Accepted Date: 11 December 2014
Please cite this article as: DeMeester SR, Barrett’s esophagus: Treatment with Surgery, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/j.bpg.2014.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Barrett’s esophagus: Treatment with Surgery
Steven R. DeMeester, MD Professor of Surgery
The University of Southern California [email protected] Office: (323) 442-9066 1
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Abstract:
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Barrett’s esophagus develops as a consequence of gastroesophageal reflux disease and may progress to esophageal adenocarcinoma. Antireflux surgery is an option for patients with reflux disease, but the efficacy and impact on the natural history of disease in patients with Barrett’s esophagus is controversial. This review addresses the existing data on these important issues.
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Keywords: Gastroesophageal reflux disease; Barrett's esophagus; Esophageal adenocarcinoma; Antireflux surgery; Nissen fundoplication
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Conflict of interest statement: None.
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Barrett’s esophagus (BE), defined by the presence of an endoscopically visible segment of columnar-lined esophagus with goblet cells on histology, develops as a consequence of gastroesophageal reflux disease (GERD). Consequently, any patient with Barrett’s has GERD, since reflux is the only known etiology for BE. Accepted therapies for longterm management of GERD include medical therapy, typically with proton pump inhibitors (PPIs), or antireflux surgery, typically with a fundoplication. There is controversy about the goal of therapy in patients with BE. Many physicians focus on relief of symptoms in patients with Barrett’s similar to any patient with reflux disease. This approach is largely based on the belief that no therapy can alter the natural history of BE and that progression, while rare, was inevitable in some patients. While relief of symptoms is an important goal in the treatment of any patient with GERD, in a patient with BE at least some consideration should be given to the impact of therapy on the Barrett’s mucosa. Barrett’s esophagus is a premalignant condition and the precursor to the fastest increasing cancer in the United States, esophageal adenocarcinoma. Recent studies, although controversial, have suggested that treatment with PPIs may reduce the risk of progression in patients with BE.[3] In light of the potential that therapy can in fact alter the natural history of BE, it is worth considering if perhaps therapy beyond relief of symptoms should be the goal in these patients.
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Conceptually there are three ways in which therapy for BE may alter the risk of progression. One mechanism is if the therapy leads to a reduction or more importantly a loss of intestinal metaplasia within the columnar-lined segment. Loss of intestinal metaplasia would imply a significant decrease in the risk of progression since patients with intestinal metaplasia have an increased risk for progression compared to those with a columnar segment without intestinal metaplasia.[4] Further, there is evidence that the risk of progression in BE increases with longer segments of Barrett’s.[5] Therefore, it would appear that a therapy that leads to a shorter length of BE and particularly to loss of intestinal metaplasia would be beneficial in terms of reducing the risk of progression.
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The second mechanism whereby a therapy could alter the risk of progression to adenocarcinoma is if the therapy led to a loss of dysplasia within the Barrett’s mucosa. The reliability of a single pathologist’s assessment of dysplasia, particularly low-grade dysplasia, is problematic, and much of what is called low-grade dysplasia is likely inflammatory changes rather than actual genetic changes within the Barrett’s mucosa. None-the-less, the fact remains that numerous studies have shown that low-grade dysplasia is associated with an increased risk of progression. The most recent and compelling evidence for this comes from a Danish population-based study. In this study the presence of low-grade dysplasia imparted a significant risk of progression, and these biopsies were read by a single pathologist with no secondary confirmation of the findings.[6] Consequently, regression of low-grade dysplasia to no dysplasia should be considered a beneficial change that reduces the risk of cancer in a patient with BE. 3
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The third mechanism by which a therapy could alter the risk of progression is to induce “quiescence” within the Barrett’s mucosa. Patients can live normally with their BE provided it doesn’t progress to cancer, and a therapy that doesn’t lead to a loss of intestinal metaplasia or dysplasia can still be beneficial if the cellular or genetic alterations associated with progression are disrupted or halted. Gastroesophageal reflux causes BE and it is logical that continued irritation and injury to the esophageal mucosa by frequent episodes of reflux can lead to progression of disease. Control of the reflux could induce alterations in the pathways and genes that are upregulated by chronic inflammation and lead to a quiescent Barrett’s mucosa and a lower risk for progression.
Research agenda:
Confirm the importance of intestinal metaplasia as the indicator that a columnarlined esophagus is at risk for progression to esophageal adenocarcinoma.
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There are three ways a therapy might alter the risk of progression in patients with Barrett’s esophagus: 1. The therapy leads to a reduction or loss of intestinal metaplasia 2. The therapy leads to a loss of dysplasia 3. The therapy induces quiescence in the Barrett’s mucosa and stops progression to cancer
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An important question is whether there is evidence that antireflux surgery can alter the risk of Barrett’s progression by one of more of these three proposed mechanisms. An effective Nissen fundoplication has been shown to stop abnormal reflux of gastric juice into the esophagus and cure or eliminate GERD. It not only normalizes esophageal acid exposure, but stops reflux of bile and weakly acidic material into the esophagus as well.[1] Prevention of reflux by a fundoplication alleviates symptoms but in addition has been shown to promote changes that could be considered beneficial for preventing progression of BE on to adenocarcinoma. First, antireflux sugery has been shown in several studies to lead to regression in the length of BE.[1, 7] More importantly, 4
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antireflux surgery has been shown to lead to a complete loss of intestinal metaplasia in some patients with BE. The likelihood of loss of intestinal metaplasia is related to the length of BE, with shorter segments more likely to regress. In studies from our institution intestinal metaplasia of the cardia, sometimes called ultra-short BE, was shown to regress to no intestinal metaplasia in 73% of patients after a fundoplication, while short or long-segments of BE regressed to no intestinal metaplasia in 14% of patients.[8] [9] In a series by Low 10/14 patients (71%) with BE showed regression of the length with 2 patients (14%) showing complete loss of intestinal metaplasia. Both of these patients had short-segment BE.[10] Similarly, Oelschlager reported complete loss of intestinal metaplasia after antireflux surgery in 30 of 54 patients (55%) with short-segment BE but in none of 36 patients with long-segment BE.[11] In perhaps the largest series of carefully followed patients with short-segment BE treated with laparoscopic Nissen fundoplication, Csendes reported loss of intestinal metaplasia in 61% of patients at mean of 49 months.[12] Lastly, in a systematic review published in 2007 Chang reported a 17% overall rate of complete loss of intestinal metaplasia after antireflux surgery in patients with BE.[7]
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Antireflux surgery has also been shown to induce regression of low-grade dysplasia.[1, 7] At our center we observed regression of low-grade to no dysplasia in 7 of 16 patients (44%) after a fundoplication.[9] In the series by Oelschlager low-grade or indefinite dysplasia regressed to no dysplasia or no intestinal metaplasia in 8 of 15 patients (53%).[11] In the systematic review by Chang antireflux surgery was associated with a 57% overall rate of regression of low-grade dysplasia. Most regression was to nondysplastic BE, but in 4% regression was to no intestinal metaplasia.[7] Although it could be argued that the diagnosis of low-grade dysplasia was not confirmed by a second pathologist and often represented inflammation rather than true low-grade dysplasia, even unconfirmed low-grade dysplasia is associated with an increased risk for progression, and regression should be considered a beneficial change for patients with BE. Further, there is evidence that antireflux surgery can alter gene expression in patients with GERD. COX-2 gene expression has been shown to increase progressively during each step of the carcinogenic process from BE to esophageal adenocarcinoma.[13] Following antireflux surgery gene expression levels of both COX2 and interleukin-8 have been shown to normalize, providing a genetic mechanism whereby true low-grade dysplasia could revert to non-dysplastic BE.[14, 15] Lastly, antireflux surgery has also been shown to reduce the risk of Barrett’s progression. In a longitudinal prospective series of patients followed closely with endoscopic surveillance for a non-intestinalized columnar-lined esophagus, Oberg reported that compared to patients on medical therapy those that had an antireflux operation were 10.3 times less likely to develop intestinal metaplasia.[16] If no intestinal metaplasia develops in these patients they are at a reduced risk for developing 5
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esophageal adenocarcinoma.[17] In patients with BE several series have shown absent or rare progression to high-grade dysplasia or adenocarcinoma after antireflux surgery.[9, 10, 18] In the systematic review by Chang progression of any type was seen in only 4.2% of patients after antireflux surgery.[7] Compared to medical therapy a number of studies have shown a reduced risk of progression in patients treated with a fundoplication.[1] In a carefully followed group of patients in Sweden Oberg found the risk of developing low-grade dysplasia in patients on medical therapy for non-dysplastic BE was increased 2.3 times compared to those that had been treated with a fundoplication. Further, no patient in that series progressed to high-grade dysplasia or adenocarcinoma after fundoplication. This was a highly statistically significant difference compared to the frequency of progression to high-grade dysplasia or adenocarcinoma in medically treated patients.[19] To date there is only one randomized trial that reports the risk of BE progression in medically and surgically treated patients. This trial from Spain reported by Parrilla consisted of 101 patients with BE randomized to undergo medical treatment (n=58) or antireflux surgery (n=43). At a median follow-up of 6 years patients with a functioning fundoplication were significantly less likely to have progressed to dysplasia compared to the medical treatment group.[20] In a subsequent analysis the authors reported that expression of Ki-67 and p53 remained stable over time in the group that had antireflux surgery but increased progressively and significantly in the medical therapy group.[21] These findings support the concept that antireflux surgery can induce a quiescent state in the Barrett’s mucosa that may equate to a reduced likelihood of progression. Further support for this concept is evidence that patients that progress after antireflux surgery usually do so within the first 5 years of surgery, suggesting that progression in these patients occurred as a consequence of genetic alterations already in place at the time of surgery.[22] In contrast, progression after 5 years is uncommon, and likely related to break-down of the fundoplication. If the fundoplication had no impact on the natural history of the disease one would expect cancers to occur regularly throughout the follow-up period rather than be clustered within the first couple of years.
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Compare the frequency of regression and progression in carefully matched patients with Barrett’s esophagus on medical therapy and after antireflux surgery.
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Antireflux surgery alters the natural history of Barrett’s esophagus by promoting loss of intestinal metaplasia, regression of low-grade dysplasia, and reduction of progression to high-grade dysplasia and esophageal adenocarcinoma. 6
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Some of the most widely quoted population-based studies on gastroesophageal reflux, esophageal adenocarcinoma and antireflux surgery are from Lagergren and colleagues at the Karolinska institute in Sweden. In 1999 they reported that the risk of adenocarcinoma of the esophagus was almost 8 times higher in people with weekly heartburn and regurgitation compared to those without these symptoms.[23] Further, they found that the frequency and duration of symptoms was directly related to the risk of adenocarcinoma. They went on to report in 2001 that there was no evidence of a protective effect of antireflux surgery against esophageal adenocarcinoma because the cancer risk remained elevated even 10 or more years after surgery. However, they conceded that they “may have overlooked a small long-term protective effect of surgery since the excess risk of cancer remained stable after surgery but increased substantially with time among reflux patients who did not have surgery”.[24] In a subsequent study published in 2007 the authors evaluated the cancer risk in relation to the functioning of the fundoplication. They found that patients who developed esophageal adenocarcinoma after antireflux surgery were significantly more likely to have persistent or recurrent reflux.[25] In 2010 the authors used the Swedish Inpatient Register and the Swedish Cancer Registry to show that the risk of esophageal adenocarcinoma was increased 12-fold after antireflux surgery compared to the risk in the general population of Sweden.[26]
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These findings must be evaluated in light of the shortcomings and limitations of the databases used for these studies. First, a critical limitation is that the prevalence of Barrett’s esophagus was unknown since it was not recorded in the database. Barrett’s esophagus is the single most significant risk factor for esophageal adenocarcinoma and it is virtually a certainty that the prevalence of Barrett’s was different in the antireflux surgery group, the medically treated group, and the general population in Sweden.[27] The inability to match cases and controls for the prevalence of Barrett’s in studies on esophageal adenocarcinoma is like trying to study ovarian cancer without knowing the prevalence of women in the case and control groups. It is an insurmountable problem for interpretation of the findings in the series of studies by Lagergren and colleagues.
A second major limitation is that the comparison groups were not matched for gender or severity of reflux disease. It is also a virtual certainty that the patients that had antireflux surgery were more commonly men with the most severe gastroesophageal reflux disease.[27] Since this is the group of patients most at risk to develop Barrett’s esophagus, there can be little doubt that the antireflux surgery group was stacked with patients with Barrett’s esophagus compared to the general population and to medically treated patients. With this in mind it is easy to understand why in 2001 the authors 7
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noted that the antireflux group had “an excess risk” of cancer compared to the patients with reflux that were treated medically.[24] Importantly, they noted that the risk of cancer was stable over time in patients that had antireflux surgery, suggesting the natural history was altered in these patients. In contrast, the cancer risk increased over time in the patients with reflux who did not have a fundoplication, no doubt related to disease progression, development of Barrett’s esophagus and ultimately esophageal adenocarcinoma in some of these medically treated patients.
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In addition to database limitations that prohibited a fair analysis of whether an antireflux operation altered the risk of adenocarcinoma, Lagergren and colleagues reached several flawed conclusions in the analysis of their findings. Their conclusion that there was no evidence of a protective effect of antireflux surgery for esophageal adenocarcinoma was misguided. A major basis for this conclusion was from their studies showing that compared to the corresponding Swedish population the cancer risk remained elevated in patients after antireflux surgery.[24, 26] The problem with these studies and the authors’ conclusion is that the comparison group should not be the general population of Sweden. Instead, the incidence of cancer in patients after antireflux surgery should be compared to the incidence in a matched population of patients with GERD and BE treated medically. An analogy would be to look at the risk of myocardial infarction in patients with heart disease on statins and compare it to the risk in the general population. Undoubtedly the risk of myocardial infarction would be elevated in the statin group since this is the group with heart disease. To conclude that statins are not effective since there are more myocardial infarctions in the group taking them compared to the general population would be inappropriate. Similarly, Lagergren and colleague’s conclusions about antireflux surgery and cancer risk are inappropriate. There is no therapy that prevents disease 100% of the time, and that is not the standard that is applied to medical or surgical interventions. Instead, the standard for acceptance of efficacy of a medical or surgical therapy is that it reduces the risk compared to an alternative (or no) therapy. Antireflux surgery won’t prevent all esophageal adenocarcinomas from developing in patients with BE, but that is not the standard it needs to achieve. Another flaw in the logic that an antireflux operation is not protective against the development of adenocarcinoma comes from the two studies by Lagergren and colleagues that show that recurrent or persistent reflux after a fundoplication was associated with an increased risk for esophageal adenocarcinoma. If a fundoplication does not alter the natural history of BE then the function or non-function of the fundoplication would be irrelevant in terms of cancer risk.[25, 28] If a non-functioning fundoplication is associated with an increased cancer risk, then by deduction a functioning fundoplication must decrease this risk.
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A thoughtful reanalysis of the series of studies by Lagergren should lead to the following conclusions. Esophageal adenocarcinoma develops from gastroesophageal reflux disease, and more severe reflux is associated with an increased risk for progression to cancer. After fundoplication the risk of cancer was stable, but the cancer risk increased over time in those with reflux not treated by a fundoplication. Failure of the fundoplication led to an increased risk of cancer, similar to patients with reflux without a fundoplication. Thus, the studies by Lagergren are in fact some of the most powerful studies ever published showing that antireflux surgery does in fact decrease the risk of esophageal adenocarcinoma. One message is clear to those of us who are surgeons performing antireflux surgery in patients with BE, it is of no benefit if the fundoplication breaks down and reflux recurs. The onus is upon us to select appropriate patients, do it well and make it last.
Practice points:
Barrett’s esophagus represents end-stage reflux disease, and these patients are more difficult to treat both medically and with antireflux surgery. Surgeons must pay attention to secure repair of the crura since large hiatal hernias are common in these patients, and a shortened esophagus should be addressed with a Collis gastroplasty to reduce tension on the repair.
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Barrett’s esophagus represents long-standing reflux disease since it is estimated to take 5 or more years for BE to develop.[1] Longer segments of BE are associated with more physiologic abnormalities including larger hiatal hernias and worse LES function.[2] These anatomic and functional abnormalities make successful treatment of patients with long-segment Barrett’s more difficult with either PPIs or antireflux surgery. The frequency of a recurrent hiatal hernia or failure of the fundoplication is increased in BE patients compared to those with less severe reflux disease.[9] Consequently, particular attention must be paid to securely closing the crura and addressing tension in these patients to minimize the risk of recurrent GERD. When a short esophagus is encountered a Collis gastroplasty should be considered. Every effort must be made to prevent failure of the fundoplication given the evidence that a failed fundoplication is a risk factor for progression to adenocarcinoma in patients with Barrett’s esophagus.
A final concept to consider is whether early control of gastroesophageal reflux can prevent the development of Barrett’s esophagus. In the PRO-GERD series of studies 2721 GERD patients were followed for 5 years and 9.7% progressed to BE. The risk was related to the severity of reflux disease, and in those with Los Angeles grade C/D esophagitis 19.7% of patients developed BE compared to 12.1% in patients with Los 9
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Angeles grade A/B esophagitis.[29] It is interesting to speculate that perhaps early intervention in some of these patients with an antireflux operation or the new LINX sphincter augmentation device might reduce the increasing burden of Barrett’s esophagus and esophageal adenocarcinoma. Following the old adage that an ounce of prevention is worth a pound of cure, these possibilities deserve further exploration in future trails and retrospective reviews of surgically treated patients who had erosive esophagitis before their fundoplication.
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Patients at risk for disease progression on medical therapy should be offered antireflux surgery in an effort to alter the natural history of the disease. Trials evaluating progressive disease in those on medical therapy or after antireflux surgery are warranted given the significant risk of Barrett’s in patients with advance erosive esophagitis on endoscopy.
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In conclusion, an appropriate question to ask is does antireflux surgery reduce the risk of esophageal adenocarcinoma compared to alternative therapies in patients with a similar severity of reflux disease and prevalence of Barrett’s esophagus? This question has not been answered definitively, but findings from the series of papers by Lagergren and colleagues in combination with studies showing loss of intestinal metaplasia, regression of dysplasia, reduced progression to high-grade dysplasia or adenocarcinoma and normalization or stabilization of genes associated with Barrett’s progression all point in the same direction, that antireflux surgery impacts the natural history of reflux disease and BE. Consequently, in all likelihood the above question should be answered affirmatively. Further, future studies should focus on early surgical intervention in patients at risk for disease progression in an effort to prevent the development of Barrett’s esophagus and ultimately adenocarcinoma.
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References:
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16. Oberg S, Johansson J, Wenner J et al. Endoscopic surveillance of columnarlined esophagus: frequency of intestinal metaplasia detection and impact of antireflux surgery. Annals of Surgery 2001; 234: 619-626. 17. Spechler SJ, Souza RF. Barrett's esophagus. New England Journal of Medicine 2014; 371: 836-845. 18. McDonald ML, Trastek VF, Allen MS et al. Barretts's esophagus: does an antireflux procedure reduce the need for endoscopic surveillance?. Journal of Thoracic & Cardiovascular Surgery 1996; 111: 1135-1138; discussion 1139-1140. 19. Oberg S, Wenner J, Johansson J et al. Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma. Annals of Surgery 2005; 242: 49-54. 20. Parrilla P, Martinez de Haro LF, Ortiz A et al. Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett's esophagus.[see comment]. Annals of Surgery 2003; 237: 291-298. 21. Martinez de Haro LF, Ortiz A, Parrilla P et al. Long-term follow-up of malignancy biomarkers in patients with Barrett's esophagus undergoing medical or surgical treatment. Annals of Surgery 2012; 255: 916-921. 22. DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus: fifty years of controversy. Annals of Surgery 2000; 231: 303-321. 23. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.[see comment]. New England Journal of Medicine 1999; 340: 825-831. 24. Ye W, Chow WH, Lagergren J et al. Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery. Gastroenterology 2001; 121: 1286-1293. 25. Lagergren J, Viklund P. Is esophageal adenocarcinoma occurring late after antireflux surgery due to persistent postoperative reflux?[see comment]. World Journal of Surgery 2007; 31: 465-469. 26. Lagergren J, Ye W, Lagergren P, Lu Y. The risk of esophageal adenocarcinoma after antireflux surgery. Gastroenterology 2010; 138: 1297-1301. 27. DeMeester SR. Antireflux surgery and the risk of esophageal adenocarcinoma: an antithetical view of the data from sweden. Annals of Surgery 2013; 257: 583-585. 28. Attwood SEA, Lundell L, Ell C et al. Standardization of surgical technique in antireflux surgery: the LOTUS Trial experience. World Journal of Surgery 2008; 32: 995998. 29. Malfertheiner P, Nocon M, Vieth M et al. Evolution of gastro-oesophageal reflux disease over 5 years under routine medical care--the ProGERD study. Alimentary Pharmacology & Therapeutics 2012; 35: 154-164. 30. Nocon M, Labenz J, Jaspersen D et al. Long-term treatment of patients with gastro-oesophageal reflux disease in routine care - results from the ProGERD study. Alimentary Pharmacology & Therapeutics 2007; 25: 715-722.
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