What is the best endoscopic treatment for high grade dysplasia in patients with BO?

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What is the best endoscopic treatment for high grade dysplasia in patients with BO?

Introduction

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.[1]

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.

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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.[2] 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.[3][4][5][6][7][8] Reported complications of EMR include early bleeding (within 12-24 hours), perforation (0.06-5%) and stricture formation particularly after circumferential resection (30-40%)[9] (see also What is the best endoscopic management of early oesophageal adenocarcinoma?).

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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).

Radio-frequency ablation

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.[10] 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.[11] 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.[12] Buried metaplasia appears to occur infrequently after RFA.[10] 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.[13]

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].[14]

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.[15] 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.[16] It has been reported that a third of patients treated with PDT develop oesphageal strictures.[17] Cutaneous phototoxicity is also common, occurring in 30-69% of patients.[18][17] The drawbacks of PDT are its high cost, complications and limited availability.

Cryotherapy

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.[19][20] In early-stage oesophageal cancer, spray cryotherapy eliminates mucosal cancer in 75% of patients.[21]

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Evidence summary and recommendations

Evidence summary Level References
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 [22]
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 [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
Endoscopic mucosal resection should be considered for patients with intramucosal adenocarcinoma or high grade dysplasia and visible/nodular lesions.
D
Evidence-based recommendationQuestion mark transparent.png Grade
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


Practice pointQuestion mark transparent.png

It is advisable to refer patients with Barrett’s Oesophagus and dysplasia or early oesophageal adenocarcinoma to tertiary referral centres for management.

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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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References

  1. Dresner SM, Griffin SM, Wayman J, Bennett MK, Hayes N, Raimes SA. Human model of duodenogastro-oesophageal reflux in the development of Barrett's metaplasia. Br J Surg 2003 Sep;90(9):1120-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12945080.
  2. Dunbar KB, Spechler SJ. The risk of lymph-node metastases in patients with high-grade dysplasia or intramucosal carcinoma in Barrett's esophagus: a systematic review. Am J Gastroenterol 2012 Jun;107(6):850-62; quiz 863 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22488081.
  3. Leers JM, DeMeester SR, Oezcelik A, Klipfel N, Ayazi S, Abate E, et al. The prevalence of lymph node metastases in patients with T1 esophageal adenocarcinoma a retrospective review of esophagectomy specimens. Ann Surg 2011 Feb;253(2):271-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21119508.
  4. Badreddine RJ, Prasad GA, Lewis JT, Lutzke LS, Borkenhagen LS, Dunagan KT, et al. Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma. Clin Gastroenterol Hepatol 2010 Mar;8(3):248-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19948247.
  5. Bollschweiler E, Baldus SE, Schröder W, Prenzel K, Gutschow C, Schneider PM, et al. High rate of lymph-node metastasis in submucosal esophageal squamous-cell carcinomas and adenocarcinomas. Endoscopy 2006 Feb;38(2):149-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16479422.
  6. Westerterp M, Koppert LB, Buskens CJ, Tilanus HW, ten Kate FJ, Bergman JJ, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005 May;446(5):497-504 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15838647.
  7. Liu L, Hofstetter WL, Rashid A, Swisher SG, Correa AM, Ajani JA, et al. Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma. Am J Surg Pathol 2005 Aug;29(8):1079-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16006804.
  8. Ancona E, Rampado S, Cassaro M, Battaglia G, Ruol A, Castoro C, et al. Prediction of lymph node status in superficial esophageal carcinoma. Ann Surg Oncol 2008 Nov;15(11):3278-88 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18726651.
  9. Peters FP, Kara MA, Rosmolen WD, ten Kate FJ, Krishnadath KK, van Lanschot JJ, et al. Stepwise radical endoscopic resection is effective for complete removal of Barrett's esophagus with early neoplasia: a prospective study. Am J Gastroenterol 2006 Jul;101(7):1449-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16863545.
  10. 10.0 10.1 10.2 Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 2009 May 28;360(22):2277-88 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19474425.
  11. 11.0 11.1 Shaheen NJ, Overholt BF, Sampliner RE, Wolfsen HC, Wang KK, Fleischer DE, et al. Durability of radiofrequency ablation in Barrett's esophagus with dysplasia. Gastroenterology 2011 Aug;141(2):460-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21679712.
  12. Pouw RE, Wirths K, Eisendrath P, Sondermeijer CM, Ten Kate FJ, Fockens P, et al. Efficacy of radiofrequency ablation combined with endoscopic resection for barrett's esophagus with early neoplasia. Clin Gastroenterol Hepatol 2010 Jan;8(1):23-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19602454.
  13. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ, American Gastroenterological Association. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology 2011 Mar;140(3):1084-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21376940.
  14. Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, et al. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia. Gastrointest Endosc 2007 Sep;66(3):460-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17643436.
  15. Tokar JL, Haluszka O, Weinberg DS. Endoscopic therapy of dysplasia and early-stage cancers of the esophagus. Semin Radiat Oncol 2007 Jan;17(1):10-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17185193.
  16. Vij R, Triadafilopoulos G, Owens DK, Kunz P, Sanders GD. Cost-effectiveness of photodynamic therapy for high-grade dysplasia in Barrett's esophagus. Gastrointest Endosc 2004 Nov;60(5):739-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15557950.
  17. 17.0 17.1 Overholt BF, Lightdale CJ, Wang KK, Canto MI, Burdick S, Haggitt RC, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005 Oct;62(4):488-98 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16185958.
  18. Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett's dysplasia or cancer. Aliment Pharmacol Ther 2004 Nov 15;20(10):1125-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15569115.
  19. Shaheen NJ, Greenwald BD, Peery AF, Dumot JA, Nishioka NS, Wolfsen HC, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 2010 Apr;71(4):680-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20363409.
  20. Greenwald BD, Dumot JA, Horwhat JD, Lightdale CJ, Abrams JA. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus. Dis Esophagus 2010 Jan;23(1):13-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19515183.
  21. Greenwald BD, Dumot JA, Abrams JA, Lightdale CJ, David DS, Nishioka NS, et al. Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy. Gastrointest Endosc 2010 Apr;71(4):686-93 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20363410.
  22. Moss A, Bourke MJ, Hourigan LF, Gupta S, Williams SJ, Tran K, et al. Endoscopic resection for Barrett's high-grade dysplasia and early esophageal adenocarcinoma: an essential staging procedure with long-term therapeutic benefit. Am J Gastroenterol 2010 Jun;105(6):1276-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20179694.

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Appendices


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