What endoscopic surveillance protocol should be followed for patients with BO and high grade dysplasia?

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What endoscopic surveillance protocol should be followed for patients with BO and high grade dysplasia?

Introduction

High Grade Dysplasia (HGD) or early neoplasia (defined here as intramucosal cancer - IMC) in Barrett’s Oesophagus (BO) has traditionally led to consideration of oesophagectomy. In recent years, endoscopic therapy has become an effective alternative in treating these conditions[1][2] (see also What is the best endoscopic treatment for high grade dysplasia in patients with BO? and What is the best endoscopic management of early oesophageal adenocarcinoma?). The most recent international guidelines now recommend endoscopic intervention once HGD or IMC is diagnosed, although surgery can still be considered in young and fit patients or in the presence of extensive dysplasia.[3][4] As far as we know, surveillance for IMC has not been suggested. Surveillance in the setting of HGD used to be a reasonable alternative to oesophagectomy before the advent of effective endoscopic therapy, as not all cases of HGD progress to invasive cancer, and such patients might be spared the risks of major surgery. However, with safe endoscopic therapy now available it is less clear if or when surveillance is still reasonable in patients with HGD (for endoscopic surveillance after endoscopic treatment for BO neoplasia, see After successful endoscopic treatment for BO neoplasia, how frequently should patients undergo endoscopy?).

If contemplating endoscopic surveillance for HGD rather than intervention, the following issues should be considered: How accurately can invasive cancer be excluded with endoscopic surveillance?; what is the risk of progression from HGD to invasive cancer?; and what other clinical factors might shift the balance between the risk of complications of endoscopic therapy and the risk of missing a potentially advanced cancer on surveillance.

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Risk of undiagnosed cancer

The accuracy of a pre-operative diagnosis of HGD is imperfect and the concern over undiagnosed invasive malignancy has traditionally been an argument for intervention. The reported rates of unsuspected cancer found at surgery in patients with a preoperative diagnosis of HGD vary greatly, mostly between 7%[5] and 36%.[6][7] The need for careful inspection with high resolution endoscopes and sampling according to rigorous biopsy protocols has been recognised. Narrow band imaging (NBI) has been widely studied in the assessment of Barrett’s epithelium, and there are some data that suggest that it may be superior to white light endoscopy (WLE) for the detection of dysplasia in Barrett’s.[8][9] In a more recent prospective study it was shown that, in expert hands, high resolution WLE was sufficient to detect all areas of IMC, while the accuracy for detecting HGD was improved with additional NBI examination.[10]

In summary, the risk of undiagnosed cancer is difficult to determine. More recent studies appear to be more accurate in determining the degree of dysplasia, presumably due to improved visualisation with high resolution endoscopy.

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Risk of progression from HGD to cancer

Progression from HGD to invasive cancer is common, albeit not universal. A meta-analysis published in 2008 sought to determine the cancer incidence in patients with HGD in BO who underwent endoscopic surveillance. Four studies and 236 patients were included, with follow-up totalling 1241 patient-years. Sixty-nine cancers developed, resulting in a weighted incidence rate of 6.6 per 100 patient years.[11] A more recent retrospective population-based study from the Netherlands identified a cohort of 326 patients who underwent endoscopic surveillance after diagnosis of HGD in BO. After excluding prevalent cancers (diagnosed within the first six months after diagnosis of HGD), the rate of progression to cancer was 14.4 per 100 patient years.[12] Some of the risk factors identified included older age and multifocal (rather than unifocal) HGD. All of the findings in this study were taken from a pathology database and no endoscopic and only limited clinical data were available, raising the possibility of confounding by indication. Despite this, these findings support the notion that the risk of progression to cancer is substantial. Risk factors for progression to cancer previously identified have again included multifocal (rather than unifocal) HGD,[8] and nodular (rather than flat) disease.[13][14]

In summary, the risk of progression is at least 6.6% per year, with some data pointing to much higher rates.

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In what situations may surveillance be reasonable?

The guidelines of the US-based Society of Thoracic Surgeons, published in 2009, state that surveillance may be considered for patients with flat and unifocal HGD, due to their relatively low rate of progression.[15] As mentioned above, the more recent guidelines by gastroenterological societies differ on this.[3][4] The risk of serious complications with endoscopic therapy is very low,[1] and we need to consider the situations when one would not intervene with endoscopic therapy once HGD is diagnosed. For instance, there may be situations where safe endoscopic treatment is unable to be delivered, due to anatomical reasons like oesophageal strictures or diverticula, or due to systemic issues like chemotherapy or inability to safely stop antithrombotic therapy. Thus there may be instances where either the only therapeutic option is surgery, or where the timing of endoscopic therapy is best delayed to increase the safety of the procedure. The balance between risk of intervention and risk of being on surveillance may shift in these certain circumstances, and surveillance may be preferable.

Some authors have reported apparent regression of dysplasia[14] although it is impossible to exclude sampling error, histologic misclassification, or removal of a single focus of HGD with the biopsy forceps, and therefore it is unclear whether HGD can truly regress. Nevertheless, in cases of a single finding of unifocal HGD that cannot be reproduced on subsequent endoscopies, especially in an elderly or frail person, it could be argued that surveillance may be reasonable due to a lower risk of progression.[14]

Therefore, surveillance for HGD is not advisable except for uncommon instances where surgical treatment may be the only therapeutic option; where endoscopic therapy has to be delayed in order to optimise other clinical conditions; or possibly where HGD cannot be seen on subsequent examinations in elderly or frail patients.

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What surveillance protocol should be followed for HGD?

Evidence on how best to perform surveillance for HGD is scant. The endoscopic surveillance protocol used by the authors of one of the largest prospective study on surveillance in HGD called for three-monthly endoscopies in the first year.[14] If no HGD was found on two consecutive endoscopies in the first year, then the frequency of endoscopy was decreased to six-monthly for the second year. After the second year, repeat at yearly intervals was implemented if no HGD was found. Persistent HGD was managed on an individual basis, with ongoing three-monthly endoscopies, or lesser frequency as per patient wishes or comorbidities. The biopsy protocol described targeted biopsies for visible lesions plus quadrantic biopsies every 2cm.

The AGA guidelines recommend three-monthly endoscopy with quadrantic biopsies every 1cm plus targeted biopsies of visible lesions, while the British guidelines do not make any recommendations.[3][4] An expert consensus statement, formed by a large number of expert participants in a Delphi process and published in 2012, recommended quadrantic biopsies every 1-2cm plus targeted biopsies, for surveillance of HGD.[16] One study directly assessed the yield of quadrantic biopsies taken at 2cm intervals compared with biopsies taken every 1cm, in the setting of known HGD. Biopsies taken every 1cm led to a significantly higher cancer detection rate.[17]

In summary, the biopsy protocol for endoscopic surveillance for HGD should be three-monthly endoscopy with high resolution WLE, with optional additional examination with virtual chromoendoscopy such as NBI. Targeted biopsies of visible lesions plus quadrantic biopsies taken every 1cm throughout the segment of Barrett’s mucosa should be taken.

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Summary

The role of surveillance in the setting of HGD has shifted with the advent of effective endoscopic therapy. Since the risk of progression from HGD to cancer is substantial and the risk of complications with endoscopic therapy is low, endoscopic intervention is indicated in most instances of HGD, with surveillance reserved for uncommon situations where endoscopic therapy is either not feasible or has to be delayed; or possibly, in older or frail patients, where persistence of HGD cannot be confirmed.

If surveillance is performed for HGD, endoscopy using high resolution endoscopes with targeted and random quadrantic biopsies every 1cm throughout the Barrett’s segment should be performed. No comparative data on different intervals between endoscopic surveillance is available and no evidence-based recommendations can be made regarding this, but expert consensus is that it should be performed every three months.

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Evidence summary and recommendations

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Surveillance is generally not indicated for patients with high grade dysplasia, and therapeutic intervention must be considered instead.


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Targeted biopsies of visible lesions plus quadrantic biopsies every 1cm throughout the segment of Barrett’s mucosa should be taken.


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High resolution endoscopes should be used, with optional use of virtual chromoendoscopy such as narrow band imaging (NBI).


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If endoscopic surveillance is performed, intervals of three months may be appropriate.

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References

  1. 1.0 1.1 Chennat J, Konda VJ, Ross AS, de Tejada AH, Noffsinger A, Hart J, et al. Complete Barrett's eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma--an American single-center experience. Am J Gastroenterol 2009 Nov;104(11):2684-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19690526.
  2. Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Ragunath K, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA 2014 Mar 26;311(12):1209-17 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24668102.
  3. 3.0 3.1 3.2 Fitzgerald RC, di Pietro M, Ragunath K, Ang Y, Kang JY, Watson P, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut 2014 Jan;63(1):7-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24165758.
  4. 4.0 4.1 4.2 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.
  5. Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus. Gastroenterology 1993 Jul;105(1):40-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8514061.
  6. Falk GW, Rice TW, Goldblum JR, Richter JE. Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 1999 Feb;49(2):170-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9925694.
  7. Kariv R, Plesec TP, Goldblum JR, Bronner M, Oldenburgh M, Rice TW, et al. The Seattle protocol does not more reliably predict the detection of cancer at the time of esophagectomy than a less intensive surveillance protocol. Clin Gastroenterol Hepatol 2009 Jun;7(6):653-8; quiz 606 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19264576.
  8. 8.0 8.1 Wolfsen HC, Crook JE, Krishna M, Achem SR, Devault KR, Bouras EP, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett's Esophagus. Gastroenterology 2008 Jul;135(1):24-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18442484.
  9. Singh R, Karageorgiou H, Owen V, Garsed K, Fortun PJ, Fogden E, et al. Comparison of high-resolution magnification narrow-band imaging and white-light endoscopy in the prediction of histology in Barrett's oesophagus. Scand J Gastroenterol 2009;44(1):85-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18821132.
  10. Jayasekera C, Taylor AC, Desmond PV, Macrae F, Williams R. Added value of narrow band imaging and confocal laser endomicroscopy in detecting Barrett's esophagus neoplasia. Endoscopy 2012 Dec;44(12):1089-95 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23188660.
  11. Rastogi A, Puli S, El-Serag HB, Bansal A, Wani S, Sharma P. Incidence of esophageal adenocarcinoma in patients with Barrett's esophagus and high-grade dysplasia: a meta-analysis. Gastrointest Endosc 2008 Mar 1;67(3):394-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18045592.
  12. Verbeek RE, van Oijen MG, ten Kate FJ, Vleggaar FP, Schipper ME, Casparie MK, et al. Surveillance and follow-up strategies in patients with high-grade dysplasia in Barrett's esophagus: a Dutch population-based study. Am J Gastroenterol 2012 Apr 1;107(4):534-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22270082.
  13. Buttar NS, Wang KK, Sebo TJ, Riehle DM, Krishnadath KK, Lutzke LS, et al. Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma. Gastroenterology 2001 Jun 1 [cited 32202 Jan 1];120(7):1630-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11375945.
  14. 14.0 14.1 14.2 14.3 Schnell TG, Sontag SJ, Chejfec G, Aranha G, Metz A, O'Connell S, et al. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology 2001 Jun;120(7):1607-19 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11375943.
  15. Fernando HC, Murthy SC, Hofstetter W, Shrager JB, Bridges C, Mitchell JD, et al. The Society of Thoracic Surgeons practice guideline series: guidelines for the management of Barrett's esophagus with high-grade dysplasia. Ann Thorac Surg 2009 Jun;87(6):1993-2002 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19463651.
  16. Bennett C, Vakil N, Bergman J, Harrison R, Odze R, Vieth M, et al. Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012 Aug 1;143(2):336-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22537613.
  17. Reid BJ, Blount PL, Feng Z, Levine DS. Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia. Am J Gastroenterol 2000 Nov;95(11):3089-96 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11095322.

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Appendices


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