Barrett's Esophagus: How Should we Manage it?
Barrett's Esophagus: How Should we Manage it?
Endoscopic treatments aim to remove or destroy areas of neoplasia in the oesophagus, either through resection or ablation, and promote regrowth of the normal squamous lining. The goal of ablative techniques is to achieve complete eradication of dysplasia, along with complete eradication of intestinal metaplasia. These minimally invasive treatments can offer treatment without recourse to radical surgery and, thus, can be considered in patients with earlier-stage disease, and those for whom major surgery would be a very high risk.
The BSG guidelines advise the following algorithm (see figure 2) for management of dysplastic Barrett's oesophagus, and this is discussed further below.
(Enlarge Image)
Figure 2.
Algorithm for management of dysplastic Barrett's oesophagus. Adapted from Fitzgerald et al,22 with permission. LGD, low-grade dysplasia; HGD, high-grade dysplasia; OGD, oesophagogastroduodenoscopy; MDT, multidisciplinary team.
In the 2014 BSG guidelines, as shown in figure 3, patients found to have LGD are advised to have 6-monthly oesophagogastroduodenoscopy (OGD) surveillance until biopsy confirms regression to non-dysplastic Barrett's oesophagus on successive OGDs, or progression to HGD occurs. However, a recent RCT from European centres reported a highly significant reduction in progression for patients with LGD treated with radiofrequency ablation (RFA). The rate of progression to HGD or cancer over a 3-year follow-up was 1.5% in the ablation group versus 26.5% in the untreated group (p<0.001), with progression to cancer 1.5% vs 8.8%, respectively (p=0.03).
(Enlarge Image)
Figure 3.
Algorithm for managing HGD and early oesophageal adenocarcinoma. Adapted from Fitzgerald et al,22 with permission. HGD, high-grade dysplasia; OAC, early oesophageal adenocarcinoma; MDT, multidisciplinary team; OGD, oesophagogastroduodenoscopy; RFA, radiofrequency ablation.
It must be noted that the rate of progression in the control arm in this trial (26.5% over 3 years) was much higher than might be expected from the natural history of LGD reported in other studies, with a recent meta-analysis calculating a risk of progression to HGD or cancer of around 1% per year. The use of an expert pathology panel for consensus diagnosis, with a very robust classification as LGD, is likely to have influenced the composition of the group seen in the study by Phoa et al Of 511 patients with an initial diagnosis of LGD screened for entry to the trial, only 247 were confirmed to have LGD after review by the expert panel, and 140 went on to be randomised.
In light of these findings, it seems likely that historical overdiagnosis of LGD has led to an underestimation of the true risk of progression with LGD. This suggests the need for consensus reporting of all Barrett's dysplasia specimens, and the question of whether to offer intervention in the absence of consensus is difficult.
The recently published National Institute for Health and Care Excellence guidelines now support the use of RFA for the ablation of LGD.
The diagnosis of HGD has serious implications for patients. They have a high risk of progression to adenocarcinoma, and also a significant risk that a small focus of cancer may already be present, but not yet detected. For this reason, historically, the treatment of HGD was radical oesophagectomy for those considered fit for surgery. The advent of endotherapy led to great debate over whether these treatments could offer oncologically sound treatment. Although there have not been any randomised trials directly comparing surgery with endotherapies, the growing body of evidence for endotherapies over the past 20 years or so has resolved this debate, and endoscopic resection (ER) is now considered the treatment of choice for patients with macroscopically visible HGD or T1a adenocarcinoma. The management of HGD and early oesophageal cancer is shown in the algorithm in figure 3.
For visible lesions, ER is preferred over ablative therapy alone because it provides the most accurate staging information. Depth of invasion can be accurately assessed: data from stepwise ER of entire Barrett's oesophagus segments have confirmed that the most advanced disease is located in visible lesions. A meta-analysis of studies in which patients have undergone oesophagectomy for HGD found the risk of invasive OAC to be 11% in those with visible lesions, compared to 3% in those with no visible lesion.
There are now numerous ablative techniques for HGD: each of these techniques has its strengths and weaknesses, and some key features are presented in Table 1 below. RCT data are available for some of these modalities, and includes direct comparison of certain techniques. Currently, there is a large-scale trial (Barrett's Radiofrequency Intervention for Dysplasia by Endoscopy, NCT017337) underway aiming to compare outcomes between RFA and argon plasma coagulation. This pilot study has just been closed to recruitment, and initial data will be available soon. On the basis of currently available RCT data, and taking account of the side effect profiles of each treatment, RFA is recommended as the first-line therapy for HGD outside the context of RCTs.
The first major RCT of RFA randomised 127 patients on a 2:1 allocation to RFA or a sham procedure. Complete eradication of HGD was seen in 81.0% of treated patients versus 19.0% of controls (p<0.001). In a later report on extended follow-up of this group, 96% of those achieving eradication of HGD remained free of HGD at 3-year follow-up. Risk of any disease progression was reduced in the ablation group (3.6% vs 16.3%, p=0.03), as was the risk of cancer (1.2% vs 9.3%, p=0.045).
A meta-analysis of RFA for Barrett's oesophagus calculated pooled estimates for complete eradication of dysplasia of 91% (87%–95%, 95% CI), and complete eradication of intestinal metaplasia 78% (70%–86%, 95% CI). The commonest complication was stricture, which occurred in 5% of patients treated with RFA.
The low risk of nodal metastasis with T1a cancer (0%–10%) has resulted in very good tumour-free and overall survival with ER for T1a cancers in high-volume centres. One recent large series reported tumour-free survival of 93.8% at mean follow-up of 56.6 months. ER for T1b tumours is associated with poorer outcomes, with 5-year tumour-free and overall survival at 60% and 58%, respectively, likely due to increased depth and higher risk of nodal involvement (up to 46%). For upper third tumours of the submucosa (T1bsm1) the risk of lymph node metastasis is relatively low (around 10%), and some series report good outcomes treating T1bsm1 tumours endoscopically. Decision making may be further influenced by pathological indicators of good prognosis, such as clear resection margins, and absence of vascular and lymphatic invasion. The use of ER for T1bsm1 cancer remains debated, however, and the current BSG guidance advises surgery for patients who are fit enough, but that ER should be offered with curative intent in patients who are high-risk surgical candidates (see figure 3).
While ER is effective at removing Barrett's oesophagus-associated intramucosal lesions, these patients have a high rate of metachronous lesions after ER alone, affecting around 15%–20%. The risk of developing further lesions can be reduced significantly with ablative therapy to the remaining Barrett's oesophagus segment. Current guidance advises removal of all visible lesions with ER, followed by ablative therapy (currently, RFA is the preferred method) to all residual areas of Barrett's oesophagus.
Management of Barrett's Oesophagus-associated Neoplasia
Endoscopic treatments aim to remove or destroy areas of neoplasia in the oesophagus, either through resection or ablation, and promote regrowth of the normal squamous lining. The goal of ablative techniques is to achieve complete eradication of dysplasia, along with complete eradication of intestinal metaplasia. These minimally invasive treatments can offer treatment without recourse to radical surgery and, thus, can be considered in patients with earlier-stage disease, and those for whom major surgery would be a very high risk.
The BSG guidelines advise the following algorithm (see figure 2) for management of dysplastic Barrett's oesophagus, and this is discussed further below.
(Enlarge Image)
Figure 2.
Algorithm for management of dysplastic Barrett's oesophagus. Adapted from Fitzgerald et al,22 with permission. LGD, low-grade dysplasia; HGD, high-grade dysplasia; OGD, oesophagogastroduodenoscopy; MDT, multidisciplinary team.
Low-grade Dysplasia
In the 2014 BSG guidelines, as shown in figure 3, patients found to have LGD are advised to have 6-monthly oesophagogastroduodenoscopy (OGD) surveillance until biopsy confirms regression to non-dysplastic Barrett's oesophagus on successive OGDs, or progression to HGD occurs. However, a recent RCT from European centres reported a highly significant reduction in progression for patients with LGD treated with radiofrequency ablation (RFA). The rate of progression to HGD or cancer over a 3-year follow-up was 1.5% in the ablation group versus 26.5% in the untreated group (p<0.001), with progression to cancer 1.5% vs 8.8%, respectively (p=0.03).
(Enlarge Image)
Figure 3.
Algorithm for managing HGD and early oesophageal adenocarcinoma. Adapted from Fitzgerald et al,22 with permission. HGD, high-grade dysplasia; OAC, early oesophageal adenocarcinoma; MDT, multidisciplinary team; OGD, oesophagogastroduodenoscopy; RFA, radiofrequency ablation.
It must be noted that the rate of progression in the control arm in this trial (26.5% over 3 years) was much higher than might be expected from the natural history of LGD reported in other studies, with a recent meta-analysis calculating a risk of progression to HGD or cancer of around 1% per year. The use of an expert pathology panel for consensus diagnosis, with a very robust classification as LGD, is likely to have influenced the composition of the group seen in the study by Phoa et al Of 511 patients with an initial diagnosis of LGD screened for entry to the trial, only 247 were confirmed to have LGD after review by the expert panel, and 140 went on to be randomised.
In light of these findings, it seems likely that historical overdiagnosis of LGD has led to an underestimation of the true risk of progression with LGD. This suggests the need for consensus reporting of all Barrett's dysplasia specimens, and the question of whether to offer intervention in the absence of consensus is difficult.
The recently published National Institute for Health and Care Excellence guidelines now support the use of RFA for the ablation of LGD.
High-grade Dysplasia
The diagnosis of HGD has serious implications for patients. They have a high risk of progression to adenocarcinoma, and also a significant risk that a small focus of cancer may already be present, but not yet detected. For this reason, historically, the treatment of HGD was radical oesophagectomy for those considered fit for surgery. The advent of endotherapy led to great debate over whether these treatments could offer oncologically sound treatment. Although there have not been any randomised trials directly comparing surgery with endotherapies, the growing body of evidence for endotherapies over the past 20 years or so has resolved this debate, and endoscopic resection (ER) is now considered the treatment of choice for patients with macroscopically visible HGD or T1a adenocarcinoma. The management of HGD and early oesophageal cancer is shown in the algorithm in figure 3.
For visible lesions, ER is preferred over ablative therapy alone because it provides the most accurate staging information. Depth of invasion can be accurately assessed: data from stepwise ER of entire Barrett's oesophagus segments have confirmed that the most advanced disease is located in visible lesions. A meta-analysis of studies in which patients have undergone oesophagectomy for HGD found the risk of invasive OAC to be 11% in those with visible lesions, compared to 3% in those with no visible lesion.
There are now numerous ablative techniques for HGD: each of these techniques has its strengths and weaknesses, and some key features are presented in Table 1 below. RCT data are available for some of these modalities, and includes direct comparison of certain techniques. Currently, there is a large-scale trial (Barrett's Radiofrequency Intervention for Dysplasia by Endoscopy, NCT017337) underway aiming to compare outcomes between RFA and argon plasma coagulation. This pilot study has just been closed to recruitment, and initial data will be available soon. On the basis of currently available RCT data, and taking account of the side effect profiles of each treatment, RFA is recommended as the first-line therapy for HGD outside the context of RCTs.
The first major RCT of RFA randomised 127 patients on a 2:1 allocation to RFA or a sham procedure. Complete eradication of HGD was seen in 81.0% of treated patients versus 19.0% of controls (p<0.001). In a later report on extended follow-up of this group, 96% of those achieving eradication of HGD remained free of HGD at 3-year follow-up. Risk of any disease progression was reduced in the ablation group (3.6% vs 16.3%, p=0.03), as was the risk of cancer (1.2% vs 9.3%, p=0.045).
A meta-analysis of RFA for Barrett's oesophagus calculated pooled estimates for complete eradication of dysplasia of 91% (87%–95%, 95% CI), and complete eradication of intestinal metaplasia 78% (70%–86%, 95% CI). The commonest complication was stricture, which occurred in 5% of patients treated with RFA.
Intramucosal Adenocarcinoma
The low risk of nodal metastasis with T1a cancer (0%–10%) has resulted in very good tumour-free and overall survival with ER for T1a cancers in high-volume centres. One recent large series reported tumour-free survival of 93.8% at mean follow-up of 56.6 months. ER for T1b tumours is associated with poorer outcomes, with 5-year tumour-free and overall survival at 60% and 58%, respectively, likely due to increased depth and higher risk of nodal involvement (up to 46%). For upper third tumours of the submucosa (T1bsm1) the risk of lymph node metastasis is relatively low (around 10%), and some series report good outcomes treating T1bsm1 tumours endoscopically. Decision making may be further influenced by pathological indicators of good prognosis, such as clear resection margins, and absence of vascular and lymphatic invasion. The use of ER for T1bsm1 cancer remains debated, however, and the current BSG guidance advises surgery for patients who are fit enough, but that ER should be offered with curative intent in patients who are high-risk surgical candidates (see figure 3).
While ER is effective at removing Barrett's oesophagus-associated intramucosal lesions, these patients have a high rate of metachronous lesions after ER alone, affecting around 15%–20%. The risk of developing further lesions can be reduced significantly with ablative therapy to the remaining Barrett's oesophagus segment. Current guidance advises removal of all visible lesions with ER, followed by ablative therapy (currently, RFA is the preferred method) to all residual areas of Barrett's oesophagus.
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