What is the appropriate management of low grade dysplasia in patients with BO?
What is the appropriate management of low grade dysplasia in patients with BO?
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.
Low grade dysplasia (LGD) has long been regarded as a condition associated with only a modest increase in the risk of oesophageal adenocarcinoma development, compared to non-dysplastic Barrett’s. Published guidelines recommend increased frequency of surveillance. Until recently there has been no strong evidence to indicate that ablation therapy reduces neoplasia development in LGD. However, recent European studies have suggested that when individuals have confirmed low grade dysplasia that is agreed on by expert pathologists, the risk of progression to neoplasia is higher than previously thought. This information, combined with more robust evidence regarding the efficacy of radiofrequency ablation (RFA) have led to increased use of ablation therapy for LGD. A recent randomised controlled trial supports this approach.
The decision to advise intensified surveillance or endoscopic ablation for LGD needs to take into account the features of the Barrett’s segment and histology as well as patient age, fitness and preference.
No strong evidence exists for surgical antireflux procedures or chemoprevention as interventions for LGD.
Management strategies for low grade dysplasia in Barrett’s Oesophagus
Diagnosis of LGD
The histological diagnosis of LGD is subject to poor inter-observer agreement between pathologists (see also What is the histological definition and grading of dysplasia in patients with BO?). When the diagnosis of LGD is confirmed by two or more pathologists, the incidence of progression is substantially higher than when pathologists disagree on the diagnosis. Therefore, confirmation of the diagnosis of LGD by a second pathologist, ideally an expert gastrointestinal pathologist, is essential in estimating the risk of progression and deciding on management.
Surveillance for LGD and risk of progression to HGD and cancer
Continued surveillance but at shorter intervals of 6-12 months has been the standard of care for LGD in Barrett’s (see also How Frequently Should Patients with Barrett’s Oesophagus Undergo Endoscopy?). However, recent studies have suggested a rate of progression higher than previously estimated, leading some experts to advocate ablation for LGD.
a. Progression of LGD to cancer
The reported incidence of cancer arising in patients with LGD has varied greatly from no greater than in non-dysplastic Barrett’s to much higher rates. A systematic review was conducted in 2009 assessing the rate of progression to cancer of LGD, high grade dysplasia (HGD) and non-dysplastic Barrett’s Oesophagus. The weighted average incidence rate for progression to cancer from LGD was 17/1000 patient years. This compared with 6/1000 patient years for non-dysplastic Barrett’s and 66/1000 patient years for HGD.
b. Progression to HGD or cancer
Three recent European studies have evaluated the incidence of progression from LGD to either HGD or cancer and found surprisingly high progression rates. A German study derived from community based practices demonstrated 19% progression over two years. A Dutch study of 147 individuals diagnosed with LGD from non-university hospitals found that when the slides were reviewed by two expert pathologists, only 15% (22) were still considered LGD, with 85% downstaged to non-dysplastic or indefinite. Among those considered to have true LGD, 85% were found to have cancer (two patients) or HGD (six patients) over 109 months follow-up (progression rate 13.4% per year). The same researchers along with other European groups performed a RCT of RFA versus surveillance and found progression to HGD or cancer in 26.5% of the surveillance group at three years.
c. Endoscopic surveillance of LGD and detection of HGD and cancer
The purpose of surveillance in LGD is to detect HGD and cancer in order to intervene with endoscopic ablation or surgery. High definition endoscopes with narrow band imaging can be used in expert centres to detect visible mucosal abnormalities in most individuals with HGD or cancer. In a study of 50 consecutive patients referred to an expert tertiary referral centre for assessment of dysplastic BO, all patients with HGD or cancers were found to have endoscopically visible lesions, with no additional cancers or patients with HGD found on 4 quadrant biopsies every 1cm from flat mucosa. Many of these individuals had only LGD as their worst prior pathology. This raises the possibility that some individuals in other studies considered to have progression from LGD to HGD or cancer may have had potentially visible lesions that were missed on initial assessment. In individuals found to have confirmed LGD, very careful endoscopic assessment is mandatory and referral to an expert centre should be considered. (see also What are the endoscopic features of neoplasia (dysplasia and early cancer) within a BO segment?).
The principle of ablation therapies is that neosquamous mucosa will replace the ablated area provided effective antireflux treatment is provided. There is a large literature on several forms of ablation for dysplastic Barrett’s Oesophagus: argon plasma coagulation (APC), photodynamic therapy (PDT), radiofrequency ablation (RFA), multipolar electrocautery (MPEC), Nd-YAG laser and cryotherapy. Most of these studies are uncontrolled case series. A systematic review of rates of progression to adenocarcinoma after ablation therapy with any of the modalities above, found a significantly reduced cancer incidence rate of 1.6/1000 patient years after ablation for LGD compared to 17/1000 patient years derived from surveillance studies.
Randomised controlled studies of RFA and PDT compared to surveillance have included significant numbers of individuals with LGD, but the number of cancers developing in LGD patients has been small, making it difficult to draw conclusions regarding efficacy for LGD. The randomised studies are described in more detail below.
a. Photodynamic therapy
Although six RCT’s of PDT for Barrett’s have been performed, only one of these provides useful data regarding individuals with LGD. Ackroyd et al. performed a RCT of PDT versus surveillance in 36 individuals with LGD. Sixteen out of eighteen in the treatment group showed a reduction in the area of Barrett’s of median 30% compared to 2/16 in the placebo group. There was regression of LGD to non-dysplastic Barrett’s in all 18 subjects treated with PDT compared to 4/16 in the placebo group (p<0.001). There were no cases of progression in either group. This study used the oral photosensitiser aminolevulinic acid, which is less likely to cause strictures than intravenous sensitising agents. No dysphagia or strictures were reported. Despite this positive study, PDT is currently not widely used, probably because the delivery system is somewhat more complex that other forms of ablation and the perceived risk of strictures. PDT has not been directly compared with RFA.
b. Radiofrequency ablation
- i. Shaheen et al performed a multicentre, randomised, sham-controlled trial (AIM dysplasia trial) of RFA using the Barrx Halo system, initially with the Halo 360 balloon device and subsequently with the Halo 90 focal ablation device until all visible Barrett’s was ablated. 127 subjects were enrolled, including 64 with LGD who were randomised in 2:1 ratio to RFA or sham procedure. The primary outcome measures were complete eradication of dysplasia (CRD) and intestinal metaplasia (CRIM) and were reported at 12 months to be 90% and 80% respectively in the RFA-treated LGD patients compared to 2% and 23% respectively in the control group. Progression from LGD to HGD occurred in 5% of the treatment group and 14% of the sham group at 12 months, but no cancers occurred. Strictures occurred in 6% of RFA-treated individuals.
- ii. RFA was also compared to surveillance in a European multicentre RCT involving only subjects with LGD. One hundred and thirty six subjects were randomised 1:1 to RFA or surveillance. The follow-up period was three years, at which point progression to cancer was reported in 8.8% of controls versus 1.5% in RFA treated subjects (p=0.03). 26.5% of control patients had progressed to HGD or cancer compared to 1.5% in the RFA group. Although this data appears compelling, the progression rate in the control group is high and occurred within 12 months of randomisation in many cases, suggesting prevalent lesions may have been missed at initial assessment. The pathological criteria for LGD were very stringent, potentially leading to exclusion of some individuals who may have been considered to have LGD by some pathologists. Corroborating evidence is needed to confirm the generalisability of these findings and also to determine whether particular subgroups with LGD are at higher risk than others.
- iii. Durability of RFA. Shaheen et al reported on two and three year follow-up data from subjects who took part in the AIM dysplasia trial described above. Among LGD patients, 51/52 (98%) had eradication of dysplasia and intestinal metaplasia at two years. However, three subjects with initial LGD progressed to HGD despite RFA, but were successfully treated with RFA and /or EMR. Another patient progressed from LGD to adenocarcinoma that was successfully treated with EMR. These data demonstrate that ongoing careful surveillance is needed even after apparently successful ablation for LGD. Shaheen reported that 5.1% of RFA treated subjects had subsquamous intestinal metaplasia, compared 40% of controls, though the significance of this finding remains uncertain. Much longer term data are still needed to determine the longterm efficacy of RFA.
c. Economic analyses of radiofrequency ablation for LGD
A cost effectiveness analysis compared different strategies for managing LGD: A. surveillance six monthly for the first year after diagnosis then annually; RFA if HGD developed and oesophagectomy for cancer; B. RFA when LGD diagnosed then surveillance annually once eradicated. Although option A was less costly, there was considered to be an improved outcome in terms of quality-adjusted life years (QALY) using option B, with an incremental cost effectiveness ratio (ICER) of US$18,231 per QALY, which is considered cost-effective. Option B remained cost-effective across a range of values for the relevant variables, such as risk of progression, efficacy, cost and durability of RFA, and quality of life after surgery. The major shortcoming of this model is that all cancer was treated with oesophagectomy and the potential to successfully treat many early cancers with endoscopic mucosal resection was not considered.
Conventional antireflux surgery and also biliary diversion procedures have been studied in case series and have shown apparent regression of LGD in small numbers of patients. However, these series are uncontrolled and do not provide strong evidence of efficacy..
There are no randomised trials that have specifically addressed the question of whether acid suppression with proton pump inhibitors reduces progression rate of dysplasia. Pharmacological therapy (chemoprevention) with celecoxib 200mg for 48 weeks for dysplastic Barrett’s has been studied in a randomised, placebo-controlled study. This study included 64 individuals with LGD, but did not show any benefit in rates of regression or progression of dysplasia. Chemoprevention with aspirin is being studied, but there is no evidence at this stage to indicate an overall benefit in LGD.
There are several areas of uncertainty relating to the LGD. Recent evidence suggests that when LGD is confirmed by agreement of at least two pathologists, there is a much higher incidence of progression to HGD or cancer than previously demonstrated. However, this information needs to confirmed by other researchers and the reason for the differences from other estimates still needs to be clarified. RCT’s support the use of ablation with both PDT and RFA for LGD. For RFA, reduced progression to HGD and cancer has been demonstrated following RFA. On the other hand, ablation therapy is expensive, often uncomfortable and inconvenient for the patient and the long term efficacy of ablation is not known. Given that most individuals with LGD will probably not progress, the option of intensified surveillance continues to be a valid approach, though surveillance must be performed in a rigorous manner and referral to an expert centre should be considered. The decision to advise intensified surveillance or endoscopic ablation for LGD needs to take into account the features of the Barrett’s segment and histology as well as patient age, fitness and preference. Where LGD is confirmed by two pathologists and is present on repeat endoscopies, ablation should be considered, especially in a relatively young and fit patient. RFA is the form of ablation with the strongest evidence.
Evidence summary and recommendations
|The histological diagnosis of LGD is subject to poor inter-observer agreement between pathologists. Confirmation of LGD by agreement between at least two pathologists predicts a higher risk of progression to HGD or cancer.||III-2|||
|The average incidence rate for progression to cancer from LGD is 17/1000 patient years, which is approximately three times the risk for non-dysplastic Barrett’s, though there is a broad range of progression rates reported from individual studies.||III-2, IV||, |
|In individuals with confirmed LGD, more advanced lesions may be visualised by rigorous high definition endoscopy performed in an expert centre.||III-1|||
|Endoscopic ablation of with a range of methods is associated with lower rates of progression to cancer.||IV|||
|RFA is the form of ablation with the strongest evidence for benefit in confirmed LGD, with an RCT demonstrating reduced progression to cancer or HGD.
There is no evidence to indicate that ablation for confirmed LGD results in reduced mortality compared to surveillance.
|The diagnosis of low grade dysplasia should be confirmed by a second pathologist, ideally an expert gastrointestinal pathologist.||C|
|In patients with confirmed low grade dysplasia, it is advised to perform rigorous high definition endoscopy or refer to an expert centre for assessment.||C|
Issues requiring more clinical research study
- Are the high rates of progression of low grade dysplasia (LGD) shown in recent European studies replicated in studies from other regions?
- Exploration of potential reasons for high rates of progression – are prevalent lesions missed on initial endoscopy in studies from community centres?
- What are the long-term outcomes after ablation for Barrett’s with LGD? Is there significant risk of recurrent dysplasia and neoplasia from recurrent intestinal metplasia and buried Barrett’s? How do the long-term outcomes compare with surveillance for LGD?
- Is it possible to identify a subgroup of LGD patients at higher or lower risk of progression?
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