What is the best endoscopic treatment for high grade dysplasia in patients with BO?
Patients with high grade dysplasia (whereby the glandular crypts are significantly distorted and may include branching which is not present in LGD) are at highest risk for progression to cancer. Therefore, this epithelium should be eradicated provided the biopsies have been independently reviewed by two expert histopathologists preferably one with special expertise in oesophageal diseases (see also What is the histological definition and grading of dysplasia in patients with BO?). Elimination of metaplastic/dysplastic tissue can be achieved by endoscopic means [ablation/endoscopic mucosal resection (EMR)] or via surgery. Historically, the gold standard for treatment of high grade dysplasia (HGD) and intramucosal cancer was oesophagectomy especially given the risk of a synchronous cancer in the former. Another advantage of oesophagectomy is that the entire segment is removed including occult adenocarcinoma and local lymph nodes although endoscopic surveillance may still be required post-surgery.
Current worldwide practice favours endotherapy (endoscopic mucosal resection or ablation) over surveillance or esophagectomy for HGD/intramucosal cancer though there are no randomised control trials comparing endoscopic treatment versus oesophagectomy. All such patients should be discussed at a multidisciplinary meeting involving the GI pathologist (preferably with an interest in oesophageal diseases), interventional endoscopist, upper GI surgeon and medical oncologist/radiotherapist.
Endoscopic Mucosal Resection (EMR)
EMR is the removal of affected mucosa and submucosa by resection through the middle or deeper part of the submucosa. Unlike other ablative methods, EMR permits histological assessment of the whole lesion permitting definition of lateral extent and depth. EMR is considered appropriate for visible/nodular lesions whereas radio-frequency ablation (RFA) is currently the choice of ablative therapy for flat dysplastic/neoplastic epithelium. All visible nodular visible lesions should undergo EMR. Mucosally confined oesophageal carcinoma has a very low risk of metastatic lymphadenopathy (1-2%) which makes endoscopic resection feasible. If the neoplasia has breached the muscularis mucosae, then by definition the submucosa is involved and lymph node metastases are in the order of 10-20% for sm1/sm2 and up to 55% in sm3 cancers. Oesophagectomy (distal or subtotal) should be considered. Reported complications of EMR include early bleeding (within 12-24 hours), perforation (0.06-5%) and stricture formation particularly after circumferential resection (30-40%) (see also What is the best endoscopic management of early oesophageal adenocarcinoma?).
Endoscopic ablation methods
Ablation can take the form of heat injury [multipolar electrocautery (MPEC), argon plasma coagulation (APC), laser; neodymium-doped yttrium aluminium garnet (Nd-YAG), radio-frequency ablation (RFA), cold injury (cryotherapy) and photochemical injury (PDT). Post ablation/EMR, anti-secretory therapy in the form of PPI’s is prescribed, so the oesophageal mucosa heals with the growth of new squamous epithelium (neo-squamous epithelium).
RFA is currently the choice of ablative therapy for flat dysplastic/neoplastic epithelium. The landmark AIM Dysplasia Trial randomised 127 patients (64 LGD, 63 HGD) in a 2:1 ratio into RFA and endoscopic surveillance or endoscopic surveillance alone. A hundred and seventeen completed a year’s follow-up. At one year, complete eradication of HGD (intention to treat) occurred in 81% of those in the ablation group as compared with 19% in the control group (p<0.001). Moreover, two and three year outcomes of the trial confirmed durability of the treatment effect after allowing for focal touch up RFA. In the HGD group, complete eradication of dysplasia (CE-D) was achieved in 50/54 patients (95%) at two years and 23/24 (96%) at three years.
Reported complications with RFA include transient fever, mild dysphagia, odynophagia, oesophageal stricture (9%) and rarely perforation. Buried metaplasia appears to occur infrequently after RFA. It is therefore a durable, well tolerated and relatively safe procedure and at the very least as efficacious as PDT in the treatment of HGD.
Photodynamic therapy (PDT)
This eradication therapy involves the use of a photosensitising agent delivered either intravenously or orally i.e. porfimer sodium (approved for use in the USA) or 5-aminolevulinic acid (5-ALA, rest of the world) followed 48 hours later by delivery of laser light to the Barrett’s epithelium. Upon contact with laser light, cells containing the photosensitizer form highly reactive oxygen metabolites that destroy tissue.
In a long-term randomised multicentre trial, Overholt et al assessed the safety and efficacy of PDT treatment plus omeprazole compared to omeprazole alone. At five year follow-up, HGD was eradicated in 77% of those treated with PDT and omeprazole versus 37% on proton pump inhibitor (PPI) alone. Cancer progression which was a secondary outcome was lower in the PDT group (15%) as compared with the omeprazole group (29%) [p=0.004].
PDT achieves a relatively uniform depth of ablation and a significantly greater depth of penetration (with tissue necrosis>5mm) as compared with other ablative techniques. In addition, longer segments of tissue can be treated because it is a non-contact ablative technique. Efficacy rates of 57-100% have been achieved with porfimer sodium (deeper tissue penetration than 5-ALA) with mean follow-up intervals of 10-51 months. It has been reported that a third of patients treated with PDT develop oesphageal strictures. Cutaneous phototoxicity is also common, occurring in 30-69% of patients. The drawbacks of PDT are its high cost, complications and limited availability.
Endoscopic spray cryotherapy ablation uses liquid nitrogen (-196◦C, CSA system) (or rapidly expanding carbon dioxide gas (-78◦ C at flow temperature of 6-8L/min, Polar Wand) to produce rapid freezing and slow thawing of a defined volume of tissue causing injury. Non-randomised and uncontrolled studies show success rates comparable to other ablative modalities for the treatment of Barrett’s HGD, with complete eradication of dysplasia seen in 87-96% and complete elimination of intestinal metaplasia in 57-96% of treated patients. In early-stage oesophageal cancer, spray cryotherapy eliminates mucosal cancer in 75% of patients.
Evidence summary and recommendations
|Endoscopic mucosal resection alters histological grade or local T stage in 48% of patients and dramatically reduces oesophagectomy rates by providing safe and effective therapy. EMR has a high success rate (94%) for complete Barrett's excision in short segment Barrett's Oesophagus.||IV|||
|Radiofrequency ablation has been shown to completely eradicate high grade dysplasia in 81% of patients at one year of follow-up as compared to a 19% complete eradication in patients undergoing endoscopic surveillance alone. Further positive outcomes were maintained in those undergoing radiofrequency ablation at two and three-years of follow-up with 95% and 96% complete eradication, respectively.||II||, |
|Endoscopic mucosal resection should be considered for patients with intramucosal adenocarcinoma or high grade dysplasia and visible/nodular lesions.||D|
|Radiofrequency ablation should be considered for patients with high grade dysplasia and flat segments of Barrett's. Radiofrequency ablation may be the preferred treatment strategy over endoscopic mucosal resection for patients with long segments Barrett's Oesophagus or circumferential Barrett's due to a lower rate of stricture formation.||B|
It is advisable to refer patients with Barrett’s Oesophagus and dysplasia or early oesophageal adenocarcinoma to tertiary referral centres for management.
Issues requiring more clinical research study
- What is the long term durability and reduction of risk to progression to oesophageal cancer for patients treated with endoscopic therapy?
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