Where is the Truth When It Comes to Cancer Risk in Barrett's Esophagus?

GASTROENTEROLOGY 2012;142:1245–1254

SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor

John Y. Kao, MD, University of Michigan Medical School Associate Section Editor STAFF OF CONTRIBUTORS Nuzhat A. Ahmad, Philadelphia, PA Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Lin Chang, Los Angeles, CA Tsutomu Chiba, Kyoto, Japan Massimo Colombo, Milan, Italy B. Joseph Elmunzer, Ann Arbor, MI Alex Ford, Leeds, United Kingdom

Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, Stanford, CA Colin W. Howden, Chicago, IL W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Josep M. Llovet, New York, NY Julian Panes, Barcelona, Spain Joel Rubenstein, Ann Arbor, MI

WHERE IS THE TRUTH WHEN IT COMES TO CANCER RISK IN BARRETT’S ESOPHAGUS? Hvid-Jensen F, Pedersen L, Drewes AM, et al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med 2011;365:1375–1383. Despite surveillance programs for patients with Barrett’s esophagus (BE), the incidence of esophageal adenocarcinoma (EAC) is increasing in Western countries and 95% of cases of EAC still present de novo (Gastroenterology 2002;122:633– 640; Cancer Epidemiol Biomarkers Prev 2010;19:1468 –1470). Furthermore, surveillance algorithms based on multiple random biopsies and the histopathologic detection of dysplasia are imperfect. Overall, this has put the usefulness of surveillance programs into question. Over the last 25 years the reported annual incidence of EAC in BE has varied significantly (Gut 2011 Nov 23 [Epub ahead of print]), with 2 recent meta-analyses, published in 2008 and 2010, calculating a pooled incidence rate of 0.53% and 0.65% per year, respectively (Clin Gastroenterol Hepatol 2010;8:235–244; Am J Epidemiol 2008;168: 237–249). To further evaluate this issue, Hvid-Jensen and collaborators conducted a cohort study within the whole Danish population of 5.4 million individuals (N Engl J Med 2011;365:1375–1383). Denmark has a tax-supported health system that is very well-suited to this kind of study, because each citizen is assigned a civil number at birth or immigration that appears in all medical documentation and registries. The authors searched the Danish Pathology Registry for individuals with evidence of intestinal metaplasia (IM) in esophageal biopsies, which they used as the diagnostic hallmark of BE. Between 1992 and 2009, 11,028 patients received this histologic diagnosis. From the Danish Cancer Registry, 2602 cases of inci-

Sameer Saini, Ann Arbor, MI Shiv K. Sarin, New Delhi, India Shamita B. Shah, Stanford, CA Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Michael L. Volk, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Kenneth K. Wang, Rochester, MN Alastair J. M. Watson, Norwich, UK

dent EAC were found in the same period. The authors then linked the 2 registers and found that only 7.6% of EAC cases (n ⫽ 197) had a previous diagnosis of BE. These represented the incident cases of EAC in BE. When corrected for the median follow-up time of 5.2 years, the incidence rate of EAC in BE was 0.29% per year. However, 66.5% of these cases occurred within 1 year from the diagnosis of BE and were therefore interpreted as prevalent cases. Hence, when the authors considered only the 66 cases occurring ⱖ1 year after the index endoscopy, the incidence rate was 0.12% per year. The authors also looked at the progression to highgrade dysplasia in their cohort and found an incidence rate after the first year of follow-up of 0.19% per year, which resulted in a combined incidence rate of highgrade dysplasia/EAC of 0.26% per year. In addition, the authors found that low-grade dysplasia (LGD) was a risk factor for progression to cancer. Patients with LGD were found to be about 5 times more likely to develop cancer (relative risk, 4.8; 95% confidence interval, 2.6 – 8.8), independent of whether the LGD diagnosis was made at the index endoscopy or anytime during the surveillance. In patients with LGD at the index endoscopy, the incidence rate of EAC was 0.51% per year and the combined incidence rate of high-grade dysplasia/ EAC was 1.27% per year. Other factors found to be associated with the risk of progression were male gender and age ⬎70 years. There were no data on Barrett’s segment length. The authors concluded that the incidence rate of EAC in BE is significantly lower than previously reported, but consistent with a recent population study on the Northern Irish cohort (J Natl Cancer Inst 2011;103:1049 –1057). Comment. This study has several strengths. It is a population study. It is the largest retrospective cohort published thus far and it has a long period of overall follow-up (67,105 person-years). However, there are important aspects of the

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methodology and the interpretation of the results that need to be considered before drawing conclusions about the implications for clinical practice. The identification of BE cases in this paper is based on pathological codes for IM in esophageal biopsies. It is well accepted that the diagnosis of BE should rely on the correlation between endoscopic and pathologic findings (Gastroenterology 2011;140:e18 –52). In 2006, the International Working Group for the Classification of Oesophagitis developed well-defined guidelines for the endoscopic diagnosis of BE (the Prague classification; Gastroenterology 2006;131:1392–1399). The aim of the Prague classification was to improve agreement for the identification of endoscopic landmarks at the gastroesophageal junction and better direct tissue sampling. In the absence of endoscopic–pathologic correlation, the authors cannot exclude the possibility that cases of cardia IM or ultrashort BE have been included in their cohort. The proportion of patients falling into these categories and those with very short tongues cannot be estimated from the data provided. IM has been found in as many as 18% of patients with an endoscopically normal gastroesophageal junction (Lancet 1994;344:1533–1536), and this seems to be a different condition from esophageal IM, in that it correlates more frequently with Helicobacter pylori infection and can occur independently from gastroesophageal reflux disease (Lancet 1994;344:1533–1536; Hepatogastroenterology 2002;49:1153–1156). More importantly, IM at the gastroesophageal junction has a distinct demographic and clinical profile from BE, with an equal prevalence in males and females, a high incidence in African Americans (who have a lower risk to develop BE), and a 4.5-fold lower rate of dysplasia compared with long segments of BE (Gastroenterology 1999;116:277–285). If it is not feasible to analyze the endoscopic records, it would be interesting to know what proportion of the Barrett’s cohort in the Danish study had ⬎1 set of biopsies taken, because these are more likely to represent individuals with a clinically relevant diagnosis of BE. It is germane to compare the Danish results with 2 recently published studies: A meta-analysis that pooled published data on ⬎11,000 patients with esophageal IM and found an annual incidence of EAC of 0.33% per year (Gut 2011 Nov 23 [Epub ahead of print]), and another population study from the Northern Ireland cohort which showed an incidence rate of cancer of the esophagus and cardia of 0.27% in patients with endoscopic evidence of columnar lined esophagus and histologically confirmed IM (J Natl Cancer Inst 2011;103:1049 –1057). It is interesting that these 2 studies, both with a long follow-up of approximately 59,000 person-years, show a comparable cancer incidence rate, which is 2-fold lower than previous meta-analyses (Clin Gastroenterol Hepatol 2010;8:235–244; Am J Epidemiol 2008;168:237–249). It should also be noted that, when Hvid-Jensen et al refer to the Northern Ireland study, they quote an incidence rate of 0.13%. In fact, this is the progression rate of patients with columnar lined esophagus both with and without IM,

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which is by definition a different cohort of subjects from the one included in their own study. Hence, this reinforces the concept that the definition and classification of BE can greatly influence the estimate of the cancer risk. The authors conclude that their findings shed doubts on the value of surveillance of patients with nondysplastic BE. However, it is important to note that a large proportion of their EAC (66.5%) occurred within a year from the diagnosis of BE, which highlights the inadequacy of the current practice of surveillance in routine clinical practice. The currently accepted biopsy protocol (Seattle protocol), which includes 4-quadrant biopsies every 1–2 cm (Gastroenterology 2011;140:e18 –52), samples ⬍5% of the BE epithelium; therefore, sampling error is inevitable (Am J Gastroenterol 2007;102:1154 –1161). Furthermore, as many as 90% of endoscopists do not adhere to this biopsy protocol (Am J Gastroenterol 2008;103:1079 –1089) and, even when dysplasia is found, its diagnosis is very subjective (Gastroenterology 2011;141:1179 –1186). As a medical community, we need to determine how we best address the shortcomings of surveillance and identify the BE patients who are most likely to benefit from surveillance. Most of the cases of EAC present de novo in patients without previous evidence of BE. Indeed, the authors found that BE-associated EACs account for only 7.6% of all the incident cases during the study period. For a more realistic estimation, it would be interesting to know what proportion of the 2405 de novo incident cases arose on a background of undiagnosed BE. There is evidence that the vast majority of EAC cases do arise from this metaplastic condition (Surg Endosc 2002;16:671– 673), and, hence, to reduce population mortality from EAC, we need to focus on identifying the at-risk group. Endoscopic screening is clearly fraught with logistical and cost considerations, but there are emerging nonendoscopic technologies such as the Cytosponge and associated TFF3 biomarker (BMJ 2010;341:c4372); additionally, serum biomarkers may be available in the future (Cancer Epidemiol Biomarkers Prev 2007;16:2649 –2655). In summary, we welcome the efforts to assemble large, retrospective, population-based datasets to understand the cancer risk in BE because these studies may help to identify patients who will be best served by surveillance programs. Optimally, future studies will combine clinical, endoscopic, and histologic data to better understand risks for a given individual, although the logistical hurdles of performing this type of prospective study are substantial; huge numbers of patients would need to be followed for many years. Overall, the recent studies (Gut 2011 Nov 23 [Epub ahead of print]; J Natl Cancer Inst 2011;103:1049 – 1057) suggest that the risk of progression to EAC is lower than we previously thought (around 0.30% per annum), indicating that intensive surveillance of certain low-risk categories of patients may not be justified. The future, but not futuristic, scenario needs to be one in which endoscopists are free to focus on the subgroups of individuals at highest risk rather than being burdened by large endoscopic surveillance clinics for individuals

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highly unlikely to develop cancer. To accomplish this, we need to develop a nonendoscopic screening test to diagnose and risk stratify BE in the population at risk and develop more sophisticated endoscopic evaluations, incorporating advanced imaging techniques and biomarkers that can accurately determine those that need intervention. EAC is a devastating disease and our current approaches for disease prevention seem to be flawed. MASSIMILIANO DI PIETRO MRC Cancer Cell Unit Hutchison/MRC Research Centre MARIA O’DONOVAN Department of Histopathology Cambridge University Hospitals REBECCA C. FITZGERALD MRC Cancer Cell Unit Hutchison/MRC Research Centre Cambridge, United Kingdom

A MINDFUL WAY THROUGH IBS: REDUCING ABDOMINAL PAIN AND IMPROVING QUALITY OF LIFE Gaylord SA, Palsson OS, Garland EL, et al. Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial. Am J Gastroenterol 2011;106:1678 –1688. Irritable bowel syndrome (IBS) is a common, gastrointestinal (GI) disorder, which affects nearly 5%–11% of the population (Gut 2007;56:1770 –1798). Although the pathophysiology of IBS is not well understood, it is generally accepted that altered brain– gut interactions play a role; therefore, both peripherally and centrally acting therapies are used to treat IBS. With regard to the latter, both psychotropic agents and psychological and behavioral approaches have shown efficacy in reducing IBS symptoms (Gut 2009;58:367–378). Nonpharmacologic, central-acting therapies such as cognitive– behavioral therapy (CBT), hypnosis, and comprehensive stress management improve global symptoms of IBS (Gut 2009;58:367–378). These behavioral therapies aim to reduce over-reactivity to stressors and maladaptive psychological coping behaviors (eg, avoidance, isolation, intrusive thoughts, rumination; Gastroenterol Clin North Am 2011;40:183–206). In general, these treatments are more commonly used in patients with moderateto-severe IBS symptoms; those refractory to medical therapy; and concurrent symptoms of generalized anxiety disorder, depression, or other psychiatric disorders (Gastroenterology 2002;123:2108 –2131). A central-acting therapy of recent interest for the treatment of IBS is mindfulness meditation. Mindfulness meditation is defined as a “nonjudgmental acceptance and interested awareness of moment-to-moment experience of sensations, perceptions, emotions, and other forms of mental activity” (J Altern Complement

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Med 2002;8:719 –730). Others define mindfulness meditation as paying attention to experiences occurring at the present moment in a nonjudgmental manner (Gen Hosp Psychiatr 1995;17:192–200; Gastroenterol Hepatol 2008;5:624 – 636). In a recent study by Gaylord et al (Am J Gastroenterol 2011;106:1678 –1688), a randomized, controlled, 8-week treatment trial was conducted to determine efficacy of mindfulness in women with IBS immediately after and 3 months after this treatment. Their primary hypothesis was that mindfulness meditation would improve IBS symptom severity as measured by the IBS symptom severity score (IBS-SSS; Aliment Pharmacol Ther 1997;11:395– 402) compared with a social support intervention. Secondary outcomes included disease-specific quality of life (QOL; Dig Dis Sci 1998;43:400 – 411), general psychological distress (Brief Symptom Inventory-18; Administration, scoring, and procedures manual. Minneapolis: National Computer Systems; 2000), and symptom-specific anxiety (Visceral Sensitivity Index; Aliment Pharmacol Ther 2004;20:89 –97). Women with IBS who met Rome II diagnostic criteria for IBS (Gut 1999;45[Suppl 2]:II43– 47) were enrolled in the study. Inclusion criteria were a diagnosis of IBS by a physician or using Rome II criteria; female gender; age between 18 and 75 years; ability to understand English; and willingness to document bowel symptoms and medication use regularly, complete assessments, and attend weekly structured sessions. The study design was comprised of two 8-week parallel treatment arms, mindfulness meditation, and a social support intervention. Both treatment arms consisted of a 2-hour session per week for 8 weeks and a half-day retreat. The meditation intervention program was led by experienced mindfulness instructors and based on Kabat-Zinn’s and Santorelli’s mindfulness stress reduction program (Adv Mind Body Med 2005; 21:22–27). One of the mindfulness group interventions was the use of the “body scan,” in which patients focused their attention on various parts of the body to perceive sensations (ie, muscle tension). In addition, the mindfulness group was instructed to practice meditation, mindful yoga, coping strategies for IBS symptoms and perceptions, minimize catastrophizing, and read assignments from books such as Full Catastrophe Living (New York: Delacorte Press; 1990), and IBS for Dummies (Hoboken, NJ: Wiley; 2005). Catastrophizing in pain has been defined as a “tendency to focus on and exaggerate the threat value of painful stimuli and negatively evaluate one’s ability to deal with pain” (Psychosom Med 2004;66 435– 441). The social support group was taught by masters-level social workers. This intervention consisted of weekly open-group discussions on predesignated topics and patients’ related experiences and weekly reading and homework assignments from the book, IBS for Dummies (Hoboken, NJ: Wiley; 2005). At the beginning, end, and 3 months after the treatment intervention, IBS-SSS (Aliment Pharmacol Ther