What is the best endoscopic management of early oesophageal adenocarcinoma?
Early oesophageal adenocarcinoma (EOA) comprises the histological tumour classification of T1a (invasion into the mucosa) and T1b (invasion into submucosa but not muscularis propria). The depth of invasion can be further stratified based on which mucosal (m1-m3) or submucosal (sm1-sm3) layer is involved (see also What are the histological features of early adenocarcinoma of the oesophagus?). EOA represents 6-12% of patients presenting with oesophageal adenocarcinoma. The risk of lymph node involvement with T1a and T1b EOA is 1.3-2.5% and 12-31% respectively. Unlike locally advanced or node-involving disease, EOA can often be cured with surgical or endoscopic approaches. Compared to oesophagectomy, endoscopic treatment is less morbid, less expensive and organ preserving. Over the past 10 years endoscopic treatment has been increasingly used for EOA. In general endoscopic treatment methods can be divided into tissue resection and tissue ablation. Tissue resection methods are endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Tissue ablation comprises radiofrequency ablation (RFA), argon plasma coagulation (APC), photodynamic therapy (PDT) or cryotherapy. There are no randomised control trials that compare the efficacy of any endoscopic therapy to oesophagectomy for EOA. Careful interrogation of all Barrett’s mucosa is recommended as a longer inspection time leads to a higher likelihood of detecting suspicious lesions. There may be a spatial predisposition for HGD and EOA to be located between the 12 o’clock and 3 o’clock arc. Several studies have found advanced histology to be within this region in over 50% of cases. Confirmation of the histology by an experienced gastrointestinal pathologist is recommended prior to further therapy.
Endoscopic resection enables accurate histological T staging, particularly the depth of invasion. It is considered the most accurate means of T staging for EOA and can alter pre-resection histological grade. Endoscopic ultrasound is no longer considered useful EOA staging and is generally not employed. All visible abnormalities within the Barrett’s segment should be described based on the revised Paris classification of superficial neoplastic lesions in the gastrointestinal tract (e.g. Paris 0-Is or 0-IIc, see Figure 1) and resected to establish a complete histological staging and potential cure.
Figure 1. Schematic representation of the Paris classification for mucosal neoplasia. Lesion morphology assists with evaluating the risk of invasive disease and guides the approach to endoscopic resection. AMN are broadly divided into protruded, flat elevated, and flat morphologies. Protruded lesions rise > 2.5 mm above the surrounding mu cosa and include pedunculated (0-Ip), subpedunculated (0-Isp), and sessile (0-Is) types. Flat elevated lesions (0–IIa) rise < 2.5 mm above the surrounding mucosa, and features such as central depression (0–IIa + c) or a broad based nodule (0–IIa + Is) are described. Flat lesions include 0–IIb (barely perceptible elevation), 0–IIc (depressed), and 0–III (excavated) types. Source from Holt, Bronte A.,Bourke, Michael J. - Clinical Gastroenterology and Hepatology - Volume 10, Issue 9, 969-979 © 2012 AGA Institute
Provided the histology is favourable (T1a, size <2cm, well differentiated, no lymphovascular invasion, clear resection margins), further endoscopic treatment for the remaining Barrett’s can be planned. Options include close endoscopic surveillance, complete Barrett’s excision or complete Barrett’s ablation. In those who are medically fit some form of endoscopic treatment of the residual Barrett’s segment is generally advocated due to the risk of metachronous neoplasia. This is believed to be approximately 20-30% in the next five years. Endoscopic resection may not be possible in cases of refractory oesophageal stricture. Following endoscopic resection of EOA and complete elimination of the residual Barrett’s segment patients require regular surveillance to exclude recurrent or metachronous Barrett’s metaplasia or neoplasia. Endoscopic resection of EOA should be performed in referral centres that have integrated expertise in endoscopy, imaging, surgery, and histopathology.
Endoscopic Mucosal Resection (EMR)
The commonly utilised techniques for EMR include multi-band mucosectomy (MBM) and the cap based lift, suck and cut approach. In randomised control trials comparing these two modalities, procedure time and cost were lower with the MBM technique without a significant difference in primary efficacy, complications or maximum thickness of specimens. In the largest series of EMR of T1a adenocarcinoma followed by APC of the remaining Barrett’s segment, involving 1000 patients with median follow up exceeding 4.5 years, the long term complete remission rate was 94%, recurrence of high-grade dysplasia or adenocarcinoma was 14.5% and five year overall survival 92%. There were only two EOA related deaths. The rate of treatment failure was 4.2% and major complications occurred in 1.5%. In other series with shorter follow up complete remission from cancer was achieved in 96-99% with recurrence rates of 2-11%. Without adjuvant therapy of the remaining Barrett’s segment the rate of metachronous lesions exceeds 20%. Subsequent stepwise resection or radiofrequency ablation reduces this risk significantly. The rates of oesophageal stricture are proportional to resection extent. While symptomatic stricture rates approach 13%-20% for focal resections and can exceed 50% in <5cm circumferential Barrett’s excision, endoscopic management of strictures is effective in most cases. There is a low risk of significant complications, which include perforation and bleeding. Although in most instances these are endoscopically manageable, EMR should be carried out in a centre with multidisciplinary support encompassing advanced surgical, medical and radiological care.
Endoscopic Submucosal Dissection
ESD allows en-bloc resection of the relevant pathology which is favourable from an oncological perspective. In a Japanese series of ESD for EOA the endoscopic and pathologic (R0) en-bloc resection rates were 100% and 85%, respectively. Metachronous lesions were found in 4%. Significant bleeding occurred in 4% and this was managed endoscopically in all cases. Stenosis occurred in 15%. In a European series of 30 patients undergoing ESD of EOA or HGD followed by RFA in those with residual Barrett’s mucosa, the en bloc and R0 resection rate was 90% and 39%, respectively. Minor bleeding occurred in 7%. At median follow up of 17 months 96% were free from neoplasia. In a small series of ESD for T1 GOJ adenocarcinoma the rate of curative resection was 72-79% with no local or distant recurrence at median follow up of three years. Both EMR and ESD require advanced skills and tertiary level support, however, ESD requires mandatory overnight admission, is more resource and time consuming.
ESD versus EMR
In a pooled analysis of a systematic review of endoscopic treatment of all types of oesophageal T1 cancers there were no significant differences between EMR and ESD in procedural complications, patients undergoing surgery, positive specimen margins, lymph node positivity, local recurrence and metachronous cancer development. ESD had significantly lower resection pieces and lower local recurrence rates. In a subanalysis of a meta-analysis comprising non-randomised trials of ESD vs EMR for superficial neoplasms of the gastrointestinal tract, ESD had higher en-bloc and curative resection rates. Operative time, bleeding and perforation rates were higher in the ESD group for all gastrointestinal lesions, however, no sub-analysis of oesophageal lesions was performed for these parameters. The low R0 resection rate of lateral margins, requirement for specialised expertise and increased procedure time of ESD favours EMR as the mainstay of endoscopic resection of EOA. However, focal lesions with a strong suspicion of submucosal invasion or those >2cm should be considered for en-bloc ESD to help with accurate histological staging and a possible organ sparing curative resection.
RFA has no role in the treatment of proven, suspected or possible EOA. All visible abnormalities within a given Barrett’s segment must be removed by EMR before RFA is considered. It is used to treat flat dysplasia or residual non-dysplastic Barrett’s mucosa after focal EMR of a visible abnormality. In a multicentre randomised trial of focal EMR followed by RFA of the residual segment versus stepwise complete resection in Barrett’s segments ≤ M5 with HGD and T1a/T1sm1, the rates of remission from neoplasia at median follow up of 24 months were comparably high at 95% and 100%, respectively. There was a significantly increased rate of stenosis in the stepwise resection arm of 88% compared to 14%. In a large systemic review of RFA in dysplastic Barrett’s Oesophagus medium term follow-up showed a durable response to treatment. However, buried metaplasia has been reported within neosquamous epithelium biopsy specimens and this may predispose to the development of subneosquamous cancer. Adenocarcinoma has been reported following RFA. Thus, following RFA of dysplastic Barrett’s Oesophagus caution is recommended. After clearance of neoplasia, dysplasia and Barrett’s mucosa is achieved, six-monthly endoscopic surveillance for one year followed by annual surveillance is advised.
This treatment has no role as a primary therapy of EOA, however, may be an option in patients that are failing or refusing to have conventional treatment. In a retrospective multicentre series of localised EOA in patients failing or unsuitable for conventional therapies the complete intraluminal response to spray cryotherapy was 72% in patients with T1 lesions at 10 month follow up.
Argon Plasma Coagulation
Like other ablative strategies, argon plasma coagulation (APC) has no role for the treatment of visible or suspected EOA. It can be used as an adjunctive to complete endoscopic Barrett’s resection or destruction of small islands that are not feasible for resection. In the largest series of EMR for T1a EOA APC was used as adjuvant therapy for the remaining Barrett’s segment with encouraging long-term results.
Photodynamic Therapy (PDT) has largely been replaced by other ablative modalities. It has no role in primary therapy of EOA. In a retrospective review of 24 patients with T1 EOA, EMR with PDT resulted in a neoplasia remission rate of 83% at 12 months.
T1a versus T1b approach
T1a EOA can be effectively managed with endoscopic resection. Patients should be counselled about the benefits of organ preservation, reduced morbidity and mortality compared to surgery. They also need to be informed of the minor risk of untreated lymph node spread and the need for ongoing endoscopic surveillance. Due to the high risk of lymph node involvement, surgically fit patients with T1b EOA should be offered oesophagectomy as a potentially curative treatment. Selected T1b lesions can be endoscopically resected with the understanding that there is a higher risk of lymph node metastasis. It may be considered in patients not willing or unfit to undergo surgery. Treatment decisions should be made in the context of a multidisciplinary management team comprising endoscopists, surgeons, oncologists, histopathologists and radiologists. In a retrospective review comparing surgery and endoscopic therapy with adjuvant ablation or chemoradiotherapy in 68 T1b patients there was no significant difference in survival at median follow up of 40 months. In a retrospective series of 21 patients with SM1 disease treated with endoscopic resection, complete remission from cancer was achieved in 95% of patients, however recurrent or metachronous carcinoma was found in 28% at median follow up 62 months. The calculated five-year survival was 66% and no Barrett’s cancer related deaths occurred. In addition to endoscopic therapy for EOA, adjuvant chemoradiotherapy appears a logical treatment option. However, there is no data to support this approach.
Recurrence has been described in 6-30% of patients undergoing endoscopic therapy for EOA. Risk factors include larger lesion diameter, long-segment disease, piecemeal removal of the lesion, failure to perform adjunctive ablative therapy, presence of multifocal neoplasia, and an elapsed time of more than 10 months prior to achieving complete remission. In most cases, recurrences can be successfully managed endoscopically. The gastro-oesophageal junction (GOJ) appears to be a common site of neoplasia recurrence and should be assessed in follow up very carefully.
Evidence summary and recommendations
|Endoscopic resection is the most accurate T staging modality for early adenocarcinoma.||IV||, |
|All lesions and visible abnormalities should be staged by focal endoscopic resection.||D|
| Endoscopic mucosal resection is effective and safe for T1a early oesophageal adenocarcinoma when performed in experienced centres.
Selected patients with T1b early oesophageal adenocarcinoma may benefit from endoscopic resection if oesophagectomy is not indicated.
|II, III-2, IV||, , , , |
Patients with T1a on endoscopic work-up should be offered endoscopic resection as a less morbid and potentially equally effective treatment option in comparison to oesophagectomy.
Selected patients with T1b early oesophageal adenocarcinoma may be offered endoscopic resection if oesophagectomy is not indicated.
|Endoscopic submucosal dissection does not offer a significant advantage over endoscopic mucosal resection for most early oesophageal adenocarcinoma.||III-2, IV||, , , |
|If endoscopic resection of early oesophageal adenocarincoma is planned, endoscopic mucosal resection is appropriate in most cases.||C|
|Following resection of early oesophageal adenocarcinoma the remaining untreated Barrett’s mucosa remains at significant risk for metachronous neoplastic disease.||III-2, IV||, , , |
Following resection of early oesophageal adenocarcinoma the remaining Barrett’s mucosa should be eradicated.
Following resection of early oesophageal adenocarcinoma, Barrett’s eradication options include complete Barrett’s endoscopic resection, radiofrequency ablation, cryotherapy and argon plasma coagulation.
Following resection of early oesophageal adenocarcinoma the patient should undergo regular and careful surveillance examinations.
|Ablative therapies such as RFA, cryotherapy, APC and PDT have no role as primary therapy for early oesophageal adenocarcinoma.||II, III-2, IV||, , |
|Ablative therapies should not be used as primary endoscopic therapy for early oesophageal adenocarcinoma.||C|
Endoscopic resection of early oesophageal adenocarcinoma should be performed in referral centres that have integrated expertise in endoscopy, imaging, surgery, and histopathology.
Careful and dedicated interrogation of all Barrett’s mucosa is advised.
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