Barrett's Esophagus: How Should we Manage it?
Barrett's Esophagus: How Should we Manage it?
The increased risk of OAC for patients with Barrett's oesophagus is well recognised, and this has led to the introduction of endoscopic surveillance programmes in many countries to achieve early detection of dysplastic or malignant change, and to enable curative intervention. Historically, early detection of cancer before lymphatic spread remains the primary aim of surveillance, but with increasing endoscopic options for early disease, the accurate identification of dysplasia is now critical.
Choosing an appropriate interval for surveillance endoscopy must balance this goal against the costs and acceptability of frequent endoscopy, along with the low annual cancer risk for patients with Barrett's oesophagus, which is below 0.5% for those in surveillance, and evidence from population studies suggest it may be closer to 0.12%–0.16%, overall.
Evidence that endoscopic surveillance for Barrett's oesophagus reduces mortality from OAC continues to be debated. There is evidence for improved outcomes, or earlier stage at diagnosis with surveillance, however, randomised trial data are lacking. Recent population-wide studies in Northern Ireland and The Netherlands have shown improved outcomes from OAC, with participation in surveillance programmes, with this result persisting after adjustment for lead-time and length-time bias. However, other retrospective studies have failed to demonstrate any benefit from surveillance programmes.
Surveillance programmes are expensive, and with uncertain efficacy, the cost-effectiveness of such programmes has been questioned. A large, randomised, controlled trial (RCT) is underway in the UK (Barrett's Oesophagus Surveillance Study) to assess the efficacy and cost-effectiveness of surveillance.
Given these concerns, risk stratification is a key goal of current research to identify those at highest risk of progression, rather than a 'one size fits all' policy that includes those at very low risk of malignancy. The recently updated British Society of Gastroenterology (BSG) guidelines have made several changes in line with this approach. For those with Barrett's oesophagus segment <3 cm, surveillance is now only advocated for those with intestinal metaplasia, and the recommended interval has been extended to 3–5 years. Surveillance every 2–3 years is reserved for those with Barrett's oesophagus segments with a length of 3 cm or greater. The current guidelines on endoscopic surveillance are summarised in figure 1.
(Enlarge Image)
Figure 1.
Guidelines for endoscopic surveillance of Barrett's oesophagus. Adapted from Fitzgerald et al,22 with permission. Note: the interval for repeat oesophagogastroduodenoscopy and biopsy after a finding of gastric metaplasia only, depends on the confidence of the endoscopic and histological findings and the number of biopsies taken. OGD, oesophagogastroduodenoscopy.
Further risk stratification through biomarkers has been a key aim of much recent research. The genetic changes that occur in progression from Barrett's oesophagus to invasive adenocarcinoma have been shown to be protean and complex. A large, genome-wide study of patients with disease across the spectrum from Barrett's oesophagus, dysplasia and adenocarcinoma, identified p53 and SMAD4 as the strongest markers of high-risk disease. As a biomarker, p53 has shown promise, and BSG guidelines advise consideration of its use as an immunostain to identify dysplasia. A preliminary study identified 86% of patients with dysplasia using a non-endoscopic cell collection device. The same genome-wide study showed that SMAD4 was highly specific, occurring only in adenocarcinoma, but since it was found in only 13% of cases it would be a low-sensitivity biomarker.
Even highly effective surveillance can only have a limited outcome on overall survival from OAC, as only a small proportion of patients who develop adenocarcinoma have a previous diagnosis of Barrett's oesophagus. In a large, population-based study in Northern Ireland, only 7.3% of cases with OAC occurred in patients known to have Barrett's oesophagus. Although this may be influenced by successful surveillance programmes, this results largely from the high proportion of patients with undiagnosed Barrett's oesophagus: previous studies have estimated that up to 2% of the population have Barrett's oesophagus, with 80% undiagnosed.
This has led some to consider screening for Barrett's oesophagus: several groups have examined the possibility of screening patients with chronic symptoms of gastro-oesophageal reflux disease (GORD). The prevalence of Barrett's oesophagus in patients with chronic GORD is 5%–15%. A meta-analysis by Taylor and Rubenstein found that while there was a strongly increased risk of long-segment Barrett's oesophagus with GORD symptoms (OR, 4.92, 95% CI 2.01 to 12.0), there was no association between short-segment Barrett's oesophagus and GORD (OR 1.15, 95% CI 0.76 to 1.73).
However, these symptoms are common among the general population, with around 20% having symptoms up to once a week, and around 6% of the population over the age of 45 years experiencing chronic symptoms. To screen all these individuals with endoscopy would require huge resources: estimates from the USA suggest that 6.6 million individuals would require endoscopy, with 1 OAC detected for every 1320 procedures. It must also be noted that 40% of patients with OAC (and 71% of patients with junctional adenocarcinoma of the cardia) do not report any GORD symptoms.
Consequently, endoscopic screening in an unselected population with GORD is not currently recommended either in the USA or the UK. However, in the presence of multiple risk factors (chronic GORD plus 3 of the following: male, aged over 50 years, Caucasian, obese), the BSG guidelines advise consideration of screening, with a lower threshold for those with a first-degree relative with Barrett's oesophagus, or OAC.
An alternative approach to screening is to use less invasive techniques to reduce the cost and/or morbidity. Studies assessing capsule endoscopy to identify Barrett's oesophagus have shown a relatively low sensitivity at 60%–78%. Others have used ultrathin transnasal endoscopes in patients with GORD or known Barrett's oesophagus, and demonstrated results very similar to conventional endoscopy.
A further possibility currently being trialled is a swallowed cytology collection device (Cytosponge). The device is contained within a small capsule which is attached to a length of string: patients swallow the capsule, the gelatine capsule then dissolves in the acidic gastric secretions to reveal the collection device (analogous to a cytology brush), which is then withdrawn through the oesophagus using the string, collecting cells as it passes.
Accurate biomarkers of Barrett's oesophagus are required due to the mixed cell population collected by the device, with a previous study suggesting the most promising molecular marker using immunohistochemistry is Trefoil Factor 3 (TFF3). Furthermore, the acceptability of the device has been demonstrated in a primary care setting.
The Barrett's oEsophagus Screening Trial (BEST2, ISRCTN 12730505) is a case-controlled study which aims to identify the sensitivity and specificity of the Cytosponge, and whether biomarkers can be used to risk-stratify patients when compared with the grade of dysplasia found at endoscopy and biopsy. Other outcomes include the safety profile of the device, along with the feasibility of high-throughput processing if the device were to be used for population-based screening.
To date, none of these technologies have entered routine clinical practice, but further trial results are awaited, and the prospect of screening could radically alter surveillance for Barrett's oesophagus and, potentially, lead on to a significant reduction in deaths from OAC.
There is increasing evidence for the use of certain drugs as chemoprevention for patients with Barrett's oesophagus. A number of cohort studies have shown a significantly reduced risk of progression to high-grade dysplasia (HGD) or OAC for patients taking proton pump inhibitors (PPI) versus no therapy, or on histamine-2 receptor antagonists (H2RA). However, data from RCTs are still awaited, and the BSG guidelines advise that 'there is not yet sufficient evidence to advocate acid suppression drugs as chemopreventive agents'.
Evidence for a protective effect from non-steroidal anti-inflammatory drugs (NSAID) comes from large meta-analyses of patients taking aspirin as primary or secondary prevention for cardiovascular disease. In the largest of these, incorporating data from 23 535 patients, those followed-up for 10–20 years after starting aspirin, and having taken aspirin daily for 5 years or more, had a significant reduction in risk of OAC, HR 0.36 (95% CI 0.18 to 0.71).
Once again, there are no data from randomised trials, and given the risks of NSAIDs, such as gastrointestinal bleeding and cerebral haemorrhage, this will be crucial in informing management decisions for patients with Barrett's oesophagus.
Aspirin and Esomeprazole for Chemoprevention in Barrett's metaplasia is a large, multicentre RCT (NCT00357682) which aims to address the lack of randomised data, and evaluate the risks and benefits of both PPIs and NSAIDs as chemoprevention in Barrett's oesophagus. The trial has four arms, with patients randomised to low-dose or high-dose PPI (esomeprazole)± aspirin.
There is some evidence from observational studies for a protective effect from statins against oesophageal cancer. A recent meta-analysis reviewed the effects of statins in a patient with Barrett's oesophagus, including 11 observational studies with a total of 1999 patients, and found an OR for progressing to OAC was 0.57 (95%CI 0.43 to 0.75) for those on a statin.
While the absence of randomised data limits current recommendations for chemoprevention, this paradigm may become a key component in the management of Barrett's oesophagus in future.
Management of Non-dysplastic Barrett's Oesophagus
Surveillance
The increased risk of OAC for patients with Barrett's oesophagus is well recognised, and this has led to the introduction of endoscopic surveillance programmes in many countries to achieve early detection of dysplastic or malignant change, and to enable curative intervention. Historically, early detection of cancer before lymphatic spread remains the primary aim of surveillance, but with increasing endoscopic options for early disease, the accurate identification of dysplasia is now critical.
Choosing an appropriate interval for surveillance endoscopy must balance this goal against the costs and acceptability of frequent endoscopy, along with the low annual cancer risk for patients with Barrett's oesophagus, which is below 0.5% for those in surveillance, and evidence from population studies suggest it may be closer to 0.12%–0.16%, overall.
Evidence that endoscopic surveillance for Barrett's oesophagus reduces mortality from OAC continues to be debated. There is evidence for improved outcomes, or earlier stage at diagnosis with surveillance, however, randomised trial data are lacking. Recent population-wide studies in Northern Ireland and The Netherlands have shown improved outcomes from OAC, with participation in surveillance programmes, with this result persisting after adjustment for lead-time and length-time bias. However, other retrospective studies have failed to demonstrate any benefit from surveillance programmes.
Surveillance programmes are expensive, and with uncertain efficacy, the cost-effectiveness of such programmes has been questioned. A large, randomised, controlled trial (RCT) is underway in the UK (Barrett's Oesophagus Surveillance Study) to assess the efficacy and cost-effectiveness of surveillance.
Given these concerns, risk stratification is a key goal of current research to identify those at highest risk of progression, rather than a 'one size fits all' policy that includes those at very low risk of malignancy. The recently updated British Society of Gastroenterology (BSG) guidelines have made several changes in line with this approach. For those with Barrett's oesophagus segment <3 cm, surveillance is now only advocated for those with intestinal metaplasia, and the recommended interval has been extended to 3–5 years. Surveillance every 2–3 years is reserved for those with Barrett's oesophagus segments with a length of 3 cm or greater. The current guidelines on endoscopic surveillance are summarised in figure 1.
(Enlarge Image)
Figure 1.
Guidelines for endoscopic surveillance of Barrett's oesophagus. Adapted from Fitzgerald et al,22 with permission. Note: the interval for repeat oesophagogastroduodenoscopy and biopsy after a finding of gastric metaplasia only, depends on the confidence of the endoscopic and histological findings and the number of biopsies taken. OGD, oesophagogastroduodenoscopy.
Further risk stratification through biomarkers has been a key aim of much recent research. The genetic changes that occur in progression from Barrett's oesophagus to invasive adenocarcinoma have been shown to be protean and complex. A large, genome-wide study of patients with disease across the spectrum from Barrett's oesophagus, dysplasia and adenocarcinoma, identified p53 and SMAD4 as the strongest markers of high-risk disease. As a biomarker, p53 has shown promise, and BSG guidelines advise consideration of its use as an immunostain to identify dysplasia. A preliminary study identified 86% of patients with dysplasia using a non-endoscopic cell collection device. The same genome-wide study showed that SMAD4 was highly specific, occurring only in adenocarcinoma, but since it was found in only 13% of cases it would be a low-sensitivity biomarker.
Screening
Even highly effective surveillance can only have a limited outcome on overall survival from OAC, as only a small proportion of patients who develop adenocarcinoma have a previous diagnosis of Barrett's oesophagus. In a large, population-based study in Northern Ireland, only 7.3% of cases with OAC occurred in patients known to have Barrett's oesophagus. Although this may be influenced by successful surveillance programmes, this results largely from the high proportion of patients with undiagnosed Barrett's oesophagus: previous studies have estimated that up to 2% of the population have Barrett's oesophagus, with 80% undiagnosed.
This has led some to consider screening for Barrett's oesophagus: several groups have examined the possibility of screening patients with chronic symptoms of gastro-oesophageal reflux disease (GORD). The prevalence of Barrett's oesophagus in patients with chronic GORD is 5%–15%. A meta-analysis by Taylor and Rubenstein found that while there was a strongly increased risk of long-segment Barrett's oesophagus with GORD symptoms (OR, 4.92, 95% CI 2.01 to 12.0), there was no association between short-segment Barrett's oesophagus and GORD (OR 1.15, 95% CI 0.76 to 1.73).
However, these symptoms are common among the general population, with around 20% having symptoms up to once a week, and around 6% of the population over the age of 45 years experiencing chronic symptoms. To screen all these individuals with endoscopy would require huge resources: estimates from the USA suggest that 6.6 million individuals would require endoscopy, with 1 OAC detected for every 1320 procedures. It must also be noted that 40% of patients with OAC (and 71% of patients with junctional adenocarcinoma of the cardia) do not report any GORD symptoms.
Consequently, endoscopic screening in an unselected population with GORD is not currently recommended either in the USA or the UK. However, in the presence of multiple risk factors (chronic GORD plus 3 of the following: male, aged over 50 years, Caucasian, obese), the BSG guidelines advise consideration of screening, with a lower threshold for those with a first-degree relative with Barrett's oesophagus, or OAC.
An alternative approach to screening is to use less invasive techniques to reduce the cost and/or morbidity. Studies assessing capsule endoscopy to identify Barrett's oesophagus have shown a relatively low sensitivity at 60%–78%. Others have used ultrathin transnasal endoscopes in patients with GORD or known Barrett's oesophagus, and demonstrated results very similar to conventional endoscopy.
A further possibility currently being trialled is a swallowed cytology collection device (Cytosponge). The device is contained within a small capsule which is attached to a length of string: patients swallow the capsule, the gelatine capsule then dissolves in the acidic gastric secretions to reveal the collection device (analogous to a cytology brush), which is then withdrawn through the oesophagus using the string, collecting cells as it passes.
Accurate biomarkers of Barrett's oesophagus are required due to the mixed cell population collected by the device, with a previous study suggesting the most promising molecular marker using immunohistochemistry is Trefoil Factor 3 (TFF3). Furthermore, the acceptability of the device has been demonstrated in a primary care setting.
The Barrett's oEsophagus Screening Trial (BEST2, ISRCTN 12730505) is a case-controlled study which aims to identify the sensitivity and specificity of the Cytosponge, and whether biomarkers can be used to risk-stratify patients when compared with the grade of dysplasia found at endoscopy and biopsy. Other outcomes include the safety profile of the device, along with the feasibility of high-throughput processing if the device were to be used for population-based screening.
To date, none of these technologies have entered routine clinical practice, but further trial results are awaited, and the prospect of screening could radically alter surveillance for Barrett's oesophagus and, potentially, lead on to a significant reduction in deaths from OAC.
Chemoprevention
There is increasing evidence for the use of certain drugs as chemoprevention for patients with Barrett's oesophagus. A number of cohort studies have shown a significantly reduced risk of progression to high-grade dysplasia (HGD) or OAC for patients taking proton pump inhibitors (PPI) versus no therapy, or on histamine-2 receptor antagonists (H2RA). However, data from RCTs are still awaited, and the BSG guidelines advise that 'there is not yet sufficient evidence to advocate acid suppression drugs as chemopreventive agents'.
Evidence for a protective effect from non-steroidal anti-inflammatory drugs (NSAID) comes from large meta-analyses of patients taking aspirin as primary or secondary prevention for cardiovascular disease. In the largest of these, incorporating data from 23 535 patients, those followed-up for 10–20 years after starting aspirin, and having taken aspirin daily for 5 years or more, had a significant reduction in risk of OAC, HR 0.36 (95% CI 0.18 to 0.71).
Once again, there are no data from randomised trials, and given the risks of NSAIDs, such as gastrointestinal bleeding and cerebral haemorrhage, this will be crucial in informing management decisions for patients with Barrett's oesophagus.
Aspirin and Esomeprazole for Chemoprevention in Barrett's metaplasia is a large, multicentre RCT (NCT00357682) which aims to address the lack of randomised data, and evaluate the risks and benefits of both PPIs and NSAIDs as chemoprevention in Barrett's oesophagus. The trial has four arms, with patients randomised to low-dose or high-dose PPI (esomeprazole)± aspirin.
There is some evidence from observational studies for a protective effect from statins against oesophageal cancer. A recent meta-analysis reviewed the effects of statins in a patient with Barrett's oesophagus, including 11 observational studies with a total of 1999 patients, and found an OR for progressing to OAC was 0.57 (95%CI 0.43 to 0.75) for those on a statin.
While the absence of randomised data limits current recommendations for chemoprevention, this paradigm may become a key component in the management of Barrett's oesophagus in future.
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