What are the risk factors for progression from non-dysplastic BO to high-grade dysplasia or adenocarcinoma?

From Cancer Guidelines Wiki

What are the risk factors for progression from non-dysplastic BO to high-grade dysplasia or adenocarcinoma?

Introduction

Many observational studies have attempted to define the rate of progression from non-dysplastic Barrett’s Oesophagus to states of low- or high-grade dysplasia, or adenocarcinoma. There is emerging consensus from large-scale, population-based cohort studies and meta-analyses that the rate of progression to cancer among patients with non-dysplastic Barrett’s Oesophagus is in the range of 1 to 5 per 1000 per year (i.e. 0.1% to 0.5%).[1][2] A subset of studies has further attempted to identify those factors which modify the rate of progression to dysplasia or cancer. The quality of these ‘modifying factor studies’ has been uneven, with the majority of studies suffering from one or more of the following limitations: small sample sizes and low statistical power; retrospective exposure assessment; high rates of loss to follow-up; selection bias (single institution referral centres); inadequate confounder control. To date, no randomised controlled trials have been published which have tested whether any factors modify the rate of progression to cancer, although at least one is in the field.[3] These elements of study quality must be borne in mind when assessing the evidence base. Wherever possible, estimates from higher quality studies have been used in the summaries below.

Back to top

Patient factors associated with rate of progression from BO to high-grade dysplasia or adenocarcinoma

Some studies[4][5][6] but not all[7][8] report significantly increased rates of progression with increasing age. There is consistent evidence that the rates of progression to cancer are significantly higher in men than women, with most estimates converging on two-fold higher rates among men.[6][8][9] Rates of progression appear to be about two-fold higher among ever smokers than never smokers.[6][10] A number of studies have assessed whether progression rates are modified by measures of obesity with no evidence of an effect. One study has assessed biochemical analytes, and reported significantly higher rates of progression to cancer among those with higher HOMA scores and higher leptin levels.[11]

Back to top

Endoscopic factors associated with rate of progression from non-dysplastic BO to high-grade dysplasia or adenocarcinoma

Longer segments of columnar mucosa in Barrett’s Oesophagus have been consistently associated with higher rates of progression to cancer.[7][9][10][12][13][14][15][16] Endoscopic features that have been associated with significantly increased rates of progression in some studies include the presence of nodules,[13][15] ulceration[17] and strictures.[8][17] Such areas of abnormality are likely to harbour high-grade dysplasia or adenocarcinoma, and as such require further investigation (see also What are the endoscopic features of neoplasia (dysplasia and early cancer) within a BO segment?)

Back to top

Histologic factors associated with rate of progression from non-dysplastic BO to high-grade dysplasia or adenocarcinoma

For non-dysplastic Barrett’s Oesophagus, there are no histological features that have been reliably associated with risk of progression. Markers of cellular atypia such as aneuploidy appear to confer higher risks of progression to cancer,[18] although these are frequently associated with dysplasia.

Back to top

Pharmacologic factors associated with rate of progression from non-dysplastic BO to high-grade dysplasia or adenocarcinoma

There is evidence from observational studies that several classes of medications significantly reduce the rate of progression to cancer among patients with Barrett’s Oesophagus, including non-steroidal anti-inflammatory drugs (NSAIDs),[12][19][20] proton-pump inhibitors (acid suppressant medications)[19][21][22] and statins (HMG co-A reductase inhibitors which act to lower serum cholesterol).[12][23][24] However, it is important to note that no randomised trials have yet reported on these associations, although at least one such trial is currently underway.[25]

Back to top

Evidence summary and recommendations

Evidence summary Level References
Factors that have been associated with an increased rate of progression from non-dysplastic BO to high-grade dyplasia or adenocarcinoma in observational studies include those relating to the patient (age, sex, smoking), endoscopic appearance (greater segment length), and histology (aneuploidy). III-2 [9], [10], [17], [18], [26]
There is observational evidence that regular users of proton-pump inhibitors, non-steroidal anti-inflammatory drugs, and statins, may have lower rates of progression from BO to neoplasia. These findings await confirmation from randomised controlled trials. II, III-2, III-3 [12], [19], [22], [23], [24]
Evidence-based recommendationQuestion mark transparent.png Grade
A clinical assessment of a patient’s future risk of high-grade dysplasia or adenocarcinoma in the setting of non-dysplastic Barrett’s Oesophagus should consider their:
  • Age
  • Sex
  • Smoking history
  • Endoscopic findings
C


Back to top

Issues requiring more clinical research study

  • Do medications reduce the rate of progression to cancer? Is chemoprevention possible?
  • Are there any dietary factors that reduce the rate of progression from BO to cancer?
  • Does obesity modify the rate of progression to cancer?

Back to top

References

  1. Hvid-Jensen F, Pedersen L, Drewes AM, Sørensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N Engl J Med 2011 Oct 13;365(15):1375-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21995385.
  2. Yousef F, Cardwell C, Cantwell MM, Galway K, Johnston BT, Murray L. The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: a systematic review and meta-analysis. Am J Epidemiol 2008 Aug 1;168(3):237-49 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18550563.
  3. Jankowski J, Barr H. Improving surveillance for Barrett's oesophagus: AspECT and BOSS trials provide an evidence base. BMJ 2006 Jun 24;332(7556):1512 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16793832.
  4. Gatenby PA, Caygill CP, Ramus JR, Charlett A, Watson A. Barrett's columnar-lined oesophagus: demographic and lifestyle associations and adenocarcinoma risk. Dig Dis Sci 2008 May;53(5):1175-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17939050.
  5. 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.
  6. 6.0 6.1 6.2 Hardikar S, Onstad L, Blount PL, Odze RD, Reid BJ, Vaughan TL. The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett's esophagus. PLoS One 2013;8(1):e52192 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23300966.
  7. 7.0 7.1 Anaparthy R, Gaddam S, Kanakadandi V, Alsop BR, Gupta N, Higbee AD, et al. Association Between Length of Barrett's Esophagus and Risk of High-Grade Dysplasia or Adenocarcinoma in Patients Without Dysplasia. Clin Gastroenterol Hepatol 2013 May 21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23707463.
  8. 8.0 8.1 8.2 Bani-Hani KE, Bani-Hani BK, Martin IG. Characteristics of patients with columnar-lined Barrett's esophagus and risk factors for progression to esophageal adenocarcinoma. World J Gastroenterol 2005 Nov 21;11(43):6807-14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16425388.
  9. 9.0 9.1 9.2 Bhat S, Coleman HG, Yousef F, Johnston BT, McManus DT, Gavin AT, et al. Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. J Natl Cancer Inst 2011 Jul 6;103(13):1049-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21680910.
  10. 10.0 10.1 10.2 Coleman HG, Bhat S, Johnston BT, McManus D, Gavin AT, Murray LJ. Tobacco smoking increases the risk of high-grade dysplasia and cancer among patients with Barrett's esophagus. Gastroenterology 2012 Feb;142(2):233-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22062359.
  11. Duggan C, Onstad L, Hardikar S, Blount PL, Reid BJ, Vaughan TL. Association between markers of obesity and progression from Barrett's esophagus to esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2013 Aug 1;11(8):934-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23466711.
  12. 12.0 12.1 12.2 12.3 Kastelein F, Spaander MC, Biermann K, Steyerberg EW, Kuipers EJ, Bruno MJ, et al. Nonsteroidal anti-inflammatory drugs and statins have chemopreventative effects in patients with Barrett's esophagus. Gastroenterology 2011 Dec;141(6):2000-8; quiz e13-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21878200.
  13. 13.0 13.1 Rugge M, Zaninotto G, Parente P, Zanatta L, Cavallin F, Germanà B, et al. Barrett's esophagus and adenocarcinoma risk: the experience of the North-Eastern Italian Registry (EBRA). Ann Surg 2012 Nov;256(5):788-94; discussion 794-5. doi: 10.1097/SLA.0b013e3182737a7e. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23095623.
  14. Rudolph RE, Vaughan TL, Storer BE, Haggitt RC, Rabinovitch PS, Levine DS, et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 2000 Apr 18;132(8):612-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10766679.
  15. 15.0 15.1 Sikkema M, de Jonge PJ, Steyerberg EW, Kuipers EJ. Risk of esophageal adenocarcinoma and mortality in patients with Barrett's esophagus: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2010 Mar;8(3):235-44; quiz e32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19850156.
  16. Thomas T, Abrams KR, De Caestecker JS, Robinson RJ. Meta analysis: Cancer risk in Barrett's oesophagus. Aliment Pharmacol Ther 2007 Dec;26(11-12):1465-77 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17900269.
  17. 17.0 17.1 17.2 Coleman HG, Bhat SK, Murray LJ, McManus DT, O'Neill OM, Gavin AT, et al. Symptoms and Endoscopic Features at Barrett's Esophagus Diagnosis: Implications for Neoplastic Progression Risk. Am J Gastroenterol 2014 Mar 4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24589668.
  18. 18.0 18.1 Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000 Jul;95(7):1669-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10925966.
  19. 19.0 19.1 19.2 Nguyen DM, El-Serag HB, Henderson L, Stein D, Bhattacharyya A, Sampliner RE. Medication usage and the risk of neoplasia in patients with Barrett's esophagus. Clin Gastroenterol Hepatol 2009 Dec;7(12):1299-304 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19523538.
  20. Vaughan TL, Dong LM, Blount PL, Ayub K, Odze RD, Sanchez CA, et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncol 2005 Dec;6(12):945-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16321762.
  21. Kastelein F, Spaander MC, Steyerberg EW, Biermann K, Valkhoff VE, Kuipers EJ et al. Proton Pump Inhibitors Reduce the Risk of Neoplastic Progression in Patients with Barrett's Esophagus. Clin Gastroenterol Hepatol 2012 Nov 27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23200977.
  22. 22.0 22.1 Singh S, Garg SK, Singh PP, Iyer PG, El-Serag HB. Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis. Gut 2013 Nov 12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24221456.
  23. 23.0 23.1 Kantor ED, Onstad L, Blount PL, Reid BJ, Vaughan TL. Use of statin medications and risk of esophageal adenocarcinoma in persons with Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 2012 Mar;21(3):456-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22241250.
  24. 24.0 24.1 Singh S, Singh AG, Singh PP, Murad MH, Iyer PG. Statins Are Associated with Reduced Risk of Esophageal Cancer, Particularly in Patients with Barrett's Esophagus: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2013 Jan 25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23357487.
  25. Jankowski J, Moayyedi P. Re: Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus. J Natl Cancer Inst 2004 Jun 2;96(11):885-7; author reply 887 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15173278.
  26. de Jonge PJ, van Blankenstein M, Looman CW, Casparie MK, Meijer GA, Kuipers EJ. Risk of malignant progression in patients with Barrett's oesophagus: a Dutch nationwide cohort study. Gut 2010 Aug;59(8):1030-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20639249.

Back to top

Appendices


Back to top