How frequently should patients with BO undergo endoscopy?
How frequently should patients with BO undergo endoscopy?
The management of patients diagnosed with Barrett’s oesophagus with low grade dysplasia (LGD) is currently uncertain, as there is considerable debate about the risks of progression to high grade dysplasia (HGD) or cancer in this group. Population-based studies which have followed Barrett’s oesophagus patients diagnosed with LGD in the community have reported rates of progression to cancer of ~0.5% p.a. (Hvid-Jensen et al 2011). In contrast, studies undertaken in academic centres in which diagnoses of LGD are made only after review by expert gastrointestinal pathologists report rates of progression as high as 13% p.a. (Curvers et al 2010). Importantly, in those studies, about 85% of patients diagnosed originally with LGD were down-staged to non-dysplastic Barrett’s oesophagus upon expert review. In the group of down-staged patients, the rate of progression was ~0.5% p.a – about the same as the rate observed in the community-based studies. These apparently conflicting data have implications for how LGD is diagnosed, how patients are managed and frequency of surveillance.
Endoscopic surveillance in patients with Barrett’s Oesophagus (BO) is the current standard of practice. The aim of surveillance is to effectively detect Barrett’s dysplasia and early cancer that can be curatively treated with the least invasive modality, thereby improving survival and reducing death from oesophageal adenocarcinoma. The decision to commence an endoscopic surveillance programme is based on multiple factors including age, co-morbidities and the patient’s wishes and ability to adhere to the recommended surveillance schedule.
What is the evidence that endoscopic surveillance is effective?
Although endoscopic surveillance is the current standard of practice, there is no direct evidence based on randomised controlled trials for its effectiveness. There is indirect evidence based on earlier stage and improved survival in those patients with oesophageal adenocarcinoma detected in a surveillance program, although these retrospective studies are subject to potential lead and length time bias. A recent case-control study has shown that endoscopic surveillance of Barrett’s Oesophagus patients was not associated with a substantially decreased risk of death from oesophageal adenocarcinoma, although a small to moderate benefit could not be excluded.
What is the evidence for frequency of endoscopic surveillance?
There are no prospective studies comparing the effectiveness of differing frequencies of endoscopic surveillance. A prospective UK cohort study found no relationship between the frequency of detection of dysplasia and frequency of endoscopic surveillance in patients with non dysplastic Barrett’s Oesophagus. In those with low grade dysplasia, more frequent (< three monthly) endoscopic surveillance was associated with an increased detection of high-grade dysplasia and adenocarcinoma. However those patients, who underwent endoscopy more frequently than third monthly, were also more likely to have oesophageal strictures and ulcers, both of which are associated with advanced lesions. 40% of adenocarcinomas diagnosed in the overall cohort were diagnosed at endoscopies done for symptoms rather than at the time of a scheduled surveillance procedure. This study was limited by no standardisation of endoscopic and biopsy protocol with low adherence to Seattle biopsy protocol and wide variation in endoscopic surveillance in low grade dysplasia.
What is the evidence for basing endoscopic frequency on previous endoscopic and histological findings?
Current international guidelines use the presence or absence of dysplasia on previous protocol biopsies to determine the frequency of endoscopic surveillance. There has been no prospective study comparing the effectiveness of differing frequencies of endoscopic surveillance based on these factors. Indirect evidence comes from studies that have shown a previous history of any grade of dysplasia, low grade dysplasia and high grade dysplasia, aneuploidy and increased 4N (tetraploidy) are associated with an increased risk of progression to high grade dysplasia and adenocarcinoma. The British Society of Gastroenterology guidelines also use the presence or absence of intestinal metaplasia and segment length to determine the frequency of endoscopic surveillance. Again this is based on indirect evidence of a higher risk of progression to adenocarcinoma in those with intestinal metaplasia compared to those without and in those with longer Barrett’s segment length.
What non-patient factors influence current endoscopic surveillance practice?
A number of studies in countries outside Australia have surveyed practitioners regarding their endoscopic surveillance practice. 50-60% of practitioners reported adhering to endoscopic frequency and biopsy guidelines. Factors that influenced adherence to guidelines included younger practitioner age, practice in an academic centre, belief in the efficacy of Barrett’s surveillance and medico-legal considerations.
A US cross-sectional study found that 65% of patients with non-dysplastic Barrett’s Oesophagus had endoscopic over-surveillance. Patient related factors, including numeracy skills and patient perception of cancer risk were not associated with over-surveillance, suggesting that non-patient factors may influence the frequency of endoscopic surveillance.
An Australian study found that dissemination of guidelines to endoscopists had little effect on adherence to endoscopic frequency and biopsy guidelines. However, introduction of a Barrett’s Oesophagus surveillance officer led to a marked sustained improvement in adherence to endoscopic frequency (17% to 92%) and biopsy protocols (45% to 83%).
In an attempt to overcome the lack of high quality clinical evidence, mathematical modelling studies have examined the cost-effectiveness of varying endoscopic surveillance strategies, including different endoscopic frequencies. These studies have significant limitations including predating the use of endoscopic treatment for high grade dysplasia and early adenocarcinoma, inconsistent methods and delivery of surveillance and variable data regarding the incidence of progression of BO to high-grade dysplasia and carcinoma. A large systematic review with economic modelling concluded that there was insufficient evidence available to assess the clinical effectiveness of endoscopic surveillance of Barrett’s Oesophagus (see also Is surveillance cost-effective for follow-up of patients with BO?).
Transient low grade dysplasia results in a substantial increase in endoscopic workload (28-61% of endoscopies) and costs ($509,549 over 10 years in a cohort of 95 patients) in a Barrett’s surveillance programs. The authors recommended returning to a non-dysplastic surveillance program after two endoscopies that showed no dysplasia.
Current recommendations of other international guidelines
Currently, both the British Society of Gastroenterology (BSG) and American Gastroenterological Association (AGA) have published guidelines for endoscopic surveillance of BO.  The guidelines differ in the criteria for the diagnosis of BO with both requiring a columnar lined oesophagus (CLO) but the AGA also requiring intestinal metaplasia to be present in biopsies from the CLO. This Australian guideline uses the AGA criteria for a diagnosis of BO (see also What is the endoscopic definition of BO and how is it described? and What is the histological definition of BO?). Both guidelines use the grade of dysplasia found at endoscopy to determine the timing of the subsequent surveillance endoscopy. These recommendations are based on the evidence of an increased risk of oesophageal adenocarcinoma with increasing degrees of dysplasia. In those with no dysplasia, the BSG guidelines also take into account the absence of intestinal metaplasia and short-segment (<3cm) length, both of which appear to be associated with a decreased risk of malignant progression (see also Are there groups of patients with BO that can be discharged from surveillance?). Both guidelines recommend biopsies of any visible lesion or mucosal irregularity and quadrantic biopsies. The BSG guidelines recommend quadrantic biopsies every 2 cm in all surveillance endoscopies. The AGA guidelines recommend Seattle protocol biopsies with quadrantic biopsies every 2 cm unless there is suspected or known dysplasia where every 1 cm is recommended. These biopsy protocols have been shown to increase the detection of advanced (high grade and early adenocarcinoma) lesions. However, there is low adherence to the protocols resulting in lower detection rates of dysplasia.
Recommendations for frequency of endoscopic BO surveillance
The recommendations of this Australian guideline for frequency of surveillance of BO are shown in Tables 1-4. For a diagnosis of BO, the guidelines require both a CLO and the presence of intestinal metaplasia in biopsies from the CLO. Recommendations for CLO without intestinal metaplasia are discussed below. After careful and meticulous examination of the Barrett's segment for any lesion or visible abnormality, Seattle protocol biopsies from the CLO are recommended at the time of endoscopic surveillance. In this protocol biopsies are taken of any mucosal irregularity (labelled separately) and quadrantic biopsies every 2cm unless known or suspected dysplasia then quadrantic biopsies every 1cm. The presence of dysplasia (indefinite, low and high grade) should be confirmed by a second pathologist, ideally an expert gastrointestinal pathologist (see also What is the histological definition and grading of dysplasia in patients with BO? and What is the appropriate management of low grade dysplasia in patients with BO?).
The management of patients diagnosed with BO with low grade dysplasia is currently uncertain, as there is considerable debate about the risks of progression to high grade dysplasia or cancer in this group. This has implications for how low grade dysplasia is diagnosed and how patients with low grade dysplasia are managed (see also What is the histological definition and grading of dysplasia in patients with BO? and What is the appropriate management of low grade dysplasia in patients with BO?).
Decisions regarding the frequency of endoscopy and management of patients with BO also need to take into consideration clinical judgement and individual patient circumstances including:
a) The presence of concurrent erosive oesophagitis within the BO segment (see also What is the optimal tissue sampling at endoscopy for diagnosis of BO?).
b) The presence of a lesion or visible abnormality within the BO segment at endoscopy (see also What are the endoscopic features of neoplasia (dysplasia and early cancer) within a BO segment? and What is the best endoscopic management of early oesophageal adenocarcinoma?).
Table 1-4: Recommended frequency of endoscopic surveillance of patients with Barrett’s Oesophagus
| BO SURVEILLANCE PROTOCOL
NO DYSPLASIA ON ENDOSCOPIC ASSESSMENT AND SEATTLE PROTOCOL BIOPSY*
|Short (<3cm) segment||Long (≥ 3cm) segment|
|Repeat endoscopy in 3-5 years.||Repeat endoscopy in 2-3 years.|
|*Note: If there has been previous low grade dysplasia, see low grade dysplasia protocol.|
|BO SURVEILLANCE PROTOCOL
INDEFINITE FOR DYSPLASIA ON BIOPSY
|The changes of indefinite for dysplasia on biopsy should be confirmed by a second pathologist, ideally an expert gastrointestinal pathologist. If indefinite for dysplasia is confirmed, then the following endoscopic surveillance is recommended:|
|Repeat endoscopy in 6 months with Seattle protocol biopsies for suspected dysplasia (biopsy of any mucosal irregularity and quadrantic biopsies every 1cm) on maximal acid suppression.|
|If repeat shows no dysplasia then follow as per non-dysplastic protocol.|
|If repeat shows low grade or high grade dysplasia or adenocarcinoma then follow as per protocols for these respective conditions.|
|If repeat again shows confirmed indefinite for dysplasia, then repeat endoscopy in 6 months with Seattle protocol biopsies for suspected dysplasia (biopsy of any mucosal irregularity and quadrantic biopsies every 1cm).|
|BO SURVEILLANCE PROTOCOL
LOW GRADE DYSPLASIA ON BIOPSY
|The changes of low grade dysplasia on biopsy should be confirmed by a second pathologist, ideally an expert gastrointestinal pathologist. If low grade dysplasia is confirmed, then the following endoscopic surveillance is recommended:|
|Repeat endoscopy every 6 months with Seattle protocol biopsies for dysplasia (biopsy of any mucosal irregularity and quadrantic biopsies every 1cm). If two consecutive 6 monthly endoscopies with Seattle dysplasia biopsy protocol show no dysplasia, then consider reverting to a less frequent follow up schedule.|
|BO SURVEILLANCE PROTOCOL
HIGH GRADE DYSPLASIA OR ADENOCARCINOMA ON BIOPSY
|Referral to a referral centre that has integrated expertise in endoscopy, imaging, surgery and histopathology.|
Endoscopic surveillance in patients with CLO without intestinal metaplasia
In some patients, despite Seattle protocol biopsies from a CLO, there will be no intestinal metaplasia or dysplasia within the biopsies from the CLO. In these patients, if there is evidence of a long (≥ 3cm) segment of CLO, it is recommended that they continue endoscopic surveillance as per the protocol for long segment BO (i.e. every 2-3 years). If there is 1-<3cm of CLO without intestinal metaplasia or dysplasia, a repeat endoscopy in 3-5 years is suggested with consideration of discharge from endoscopic surveillance if the repeat endoscopy with Seattle protocol biopsies again shows no intestinal metaplasia or dysplasia within the CLO. In patients with CLO less than 1cm without intestinal metaplasia or dysplasia on biopsies from the CLO, no endoscopic surveillance is suggested. If dysplasia is found in any biopsies from a CLO without intestinal metaplasia, then recommendations are as per the protocols for BO with dysplasia.
Evidence summary and recommendations
In the absence of any randomised trial evidence, the frequency of surveillance endoscopy in Barrett’s Oesophagus can be guided by currently available practice guidelines.
A diagnosis of dysplasia (indefinite, low and high grade) should be confirmed by a second pathologist, ideally an expert gastrointestinal pathologist.
It is recommended that oesophageal biopsies at the time of endoscopic surveillance of Barrett’s Oesophagus be taken according to the Seattle protocol.
Issues requiring more clinical research study
- Is endoscopic surveillance in Barrett’s Oesophagus effective?
- What factors are associated with an increased risk of progression in Barrett’s Oesophagus?
- Does integration of these risk factors into endoscopic surveillance protocols improve their effectiveness?
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