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hemoprevention in Barrett’ssophagus: Are We There Yet, Aree There Yet . . .?

Doc, What Can I Do to Decrease MyRisk of Dying from Cancer?

This is perhaps the most commonly asked ques-tion from patients after they receive a Barrett’s

sophagus diagnosis, and one of the most challenging tonswer. Chemoprevention, the use of pharmacologic agentsr supplements to modify cancer risk, is an area of intense

nterest given the relative ease of administration. If effective,hemoprevention could be doubly appealing: it could bothiminish cancer risk and decrease (or eliminate) the need for

nvasive, costly endoscopic procedures used for surveillancend treatment of Barrett’s esophagus or dysplasia.

What Information Does the CurrentStudy Provide?The current study by Nguyen et al1 updates the group’s

rior Veterans’ Affairs (VA) epidemiologic study of chemopre-ention with more subjects, additional follow-up time for pro-on pump inhibitors (PPI), and new data for aspirin/nonsteroi-al anti-inflammatory drugs and statins.2

The main findings of interest include the inverse associa-ions found for PPIs and aspirin/nonsteroidal anti-inflamma-ory drugs. The incidence rate ratio for high-grade dysplasia orsophageal adenocarcinoma among persons with at least onePI prescription compared with nonusers was remarkably low

incidence rate ratio, 0.42; 95% confidence interval, 0.21– 0.82);ata confined to the 13 patients with esophageal adenocarci-oma showed an even stronger reduction in risk (incidence rateatio, 0.33; 95% confidence interval, 0.11– 0.98).

The data for aspirin/nonsteroidal anti-inflammatory drugs alsohowed an inverse association. Although this finding is intriguing,t is difficult to interpret, given this medication class is widelyvailable over the counter and the data set only evaluated prescrip-ion use. No associations were found for statin use.

The current study had many strengths including the exten-ive experience of the investigator group in the field of Barrett’ssophagus; a considerable number of patients (given the rarityf esophageal adenocarcinoma) who developed either cancer13 patients) or high-grade dysplasia (an additional 17 uniqueatients); its use of pharmacy records for much of the time

nterval (which show the medications actually dispensed); aanual record review to confirm the Barrett’s esophagus diag-

oses; the requirement for at least 2 endoscopies (ensuring thentire study population had at least some follow-up evalua-ion); and the uniform collection of data by a single endoscopistnd pathologist. This combination of strengths is difficult toeplicate in many settings.

There were several unavoidable weaknesses of the study thatimited the ability to make firm conclusions. One was durationf follow-up evaluation: despite a long follow-up interval1982–2004), the duration of follow-up evaluation for individ-

al patients was relatively short for chemoprevention agents f

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mean, 2.8 years for statins to 5.1 years for PPIs). Also, theample size limited the power of the study and restricted thebility to conduct detailed analyses of dose and duration. In-tead, the primary exposure definition was a single medicationrescription. This is an inherent difficulty of doing research onatients with Barrett’s esophagus, for which relatively few pa-ients are followed up at any given center and few of thoseatients progress on to cancer or dysplasia. Finally, an un-nown number of veterans had dual insurance or otherwiseeceived medical care outside of the VA system. If either medi-ations were received or a cancer diagnosis was made outsidehe VA, these events would not have been reported in theatabase.

Is There Biological Evidence toSupport the Observed InverseAssociations?The idea that acid inhibition could decrease the risk of

arrett’s esophagus progressing to cancer is highly intuitive: wenow that gastroesophageal reflux disease (GERD) can causesophagitis, and that chronic inflammation in other organs (eg,he lung and colon) is associated with an increased risk ofeoplasia. Thus, it makes sense that reducing esophagitis byecreasing acid reflux may decrease the risk of Barrett’s esoph-gus progressing to esophageal adenocarcinoma.

However, the biological data supporting a chemopreventiveffect of acid suppression are conflicting. Some studies showcid suppression decreases markers of proliferation in Barrett’ssophagus.3,4 In contrast, other in vitro studies suggest thatntermittent acid exposure or a predominance of bile in theefluxate (such as what might occur in someone on PPIs) maye more likely to induce proneoplastic changes than continu-us acid exposure alone. In a laboratory model, brief exposuref Barrett’s esophagus cells to bile salts, in the absence of acid,

ed to increased proliferation; however, a combination of bilealts and acid together inhibited cell proliferation.5 Another initro study also showed that acid exposure resulted in antipro-iferative effects in nonneoplastic Barrett’s epithelial cells, lead-ng the investigators to speculate that antisecretory medicationsn dosages higher than those required to heal esophagitis orelieve GERD symptoms could be detrimental.6

Are the Inverse AssociationsConsistent With Other Studies?A recent Australian study of 502 cancer-free Barrett’s

sophagus patients reported that those not on PPIs at the timef Barrett’s esophagus diagnosis were 3.4 times more likely toave higher-risk endoscopic macroscopic markers (eg, ulcer-tion, nodularity, or stricture) or low-grade dysplasia than pa-ients who were on a PPI at the time of diagnosis.7 No differenceas seen in high-grade dysplasia or cancer rates between PPIsers and nonusers. The same group previously reported thatatients who delayed starting PPIs by 2 years or more afterarrett’s esophagus diagnosis had a higher risk of high-gradeysplasia or cancer compared with patients who started shortlyfter their diagnosis.8

In contrast, surgical antireflux procedures, the most potent

orm of antireflux therapy, have not been shown convincingly

NICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:1266–1268

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December 2009 CHEMOPREVENTION IN BARRETT’S 1267

o decrease cancer risk compared with medical therapy, despiteultiple studies with more than 4000 years of patient fol-

ow-up evaluation.9,10 This was not, however, a comparison witho therapy.

Could the Results Be Caused by Biasor Confounding?The primary limitation of the current study was one

hat hampers all epidemiology studies: confounding or thenability to control for other factors that may alter the chancef either the exposure (the medications of interest) or theutcome (dysplasia and esophageal adenocarcinoma). For ex-mple, the investigators did not have access to informationelated to socioeconomic status, tobacco and alcohol use, Hel-cobacter pylori status, dietary intake, and other factors that maye associated with both the exposure and the outcome andherefore could confound the results.

For all of the published studies, is it acid suppression itselfhat is decreasing risk? Or could it just be that patients withymptomatic GERD are both more likely to be treated with aciduppression and less likely to have early neoplastic changes?

Interestingly, only 67% of patients with Barrett’s esophagusn the current study received at least one PPI prescription. Thiss substantially lower than what was reported by some membersf the same research group in a study of 7732 veterans witharrett’s esophagus in which 91.5% of patients filled at least onePI prescription in the first year after diagnosis.11

Why did the current study report a lower proportion ofreated patients in a comparable veterans population? If ahysician recommended a PPI, we might expect at least onerescription to be dispensed even if a patient were intolerant oroncompliant. Why were some patients not treated, even at anxperienced center where each patient received at least 2 endos-opies separated by at least 6 months? Possibilities includehysician-determined factors (eg, no treatment because thereas no evidence of GERD symptoms or esophagitis), patient-etermined factors (eg, did not want medications), and poten-ial biases (eg, patient received medications outside the VAystem). Future studies elucidating why some people are treatednd others are not would provide key insights into whether aciduppression itself influences cancer risk or whether confound-ng factors might explain the differences seen. That a singlerescription is associated inversely with disease risk raises thepecter of confounding.

The importance of confounding as a potential cause of thetudy’s findings cannot be underestimated. A well-known ex-mple is a large study that suggested a link between coffeeonsumption and pancreatic cancer.12 The study showed atrong association (odds ratio, 2.7; 95% confidence interval,.6 – 4.7 for �3 cups/d), evidence of a dose effect (more riskith greater coffee consumption), and the investigators ad-

usted for many potential confounders that had been measuredarefully through in-person interviews. However, the coffee-ancer association subsequently was discredited by other stud-es. The associations observed were believed to have resultedrom biased controls, other gastrointestinal patients withoutancer; these patients likely had a lower-than-expected coffeeonsumption for various reasons associated with their gastro-ntestinal ailments.13–16 The lesson from such studies is clear: ifarge epidemiologic studies with detailed data on confounders

annot fully statistically adjust for potential biases, we must be a

oubly cautious in reaching treatment decisions when usingmaller data sets with little information on confounders.

Is There Any Harm to Using TheseMedications?A crucial question when deciding on chemoprevention

s the downside to taking the medication. For example, a cost-ffectiveness model of selective cyclo-oxygenase inhibitors sug-ested that even if they were effective at decreasing the risk ofeoplastic progression in Barrett’s esophagus, any benefitsould be outweighed by increased deaths from myocardial in-arctions. In contrast, if a potential chemopreventive agent werenexpensive, had few known side effects, and might work, someatients may hedge their bets and take the medication untilore definitive studies came along.Unfortunately, there is an emerging body of evidence sug-

esting that acid-suppression medications are not without risk,nd that effects may be dose related. For example, PPI use haseen found to be associated with a small but significant in-reased risk of Clostridium difficile infections,17 food-borne bac-erial infections,18 and pulmonary infections. Recent studieslso have suggested a possible small increase in the risk of hipractures in patients taking acid-suppressing medications.19 –21

Are There Other Reasons to Use TheseMedications?For many patients with Barrett’s esophagus, there are

ther clear indications for using the medications studied; thus,hether the patient should be on the agent is a no-brainer.otent acid suppression, such as with a PPI, is necessary to healnd maintain healing of esophagitis. Patients with GERDymptoms also have a clear indication for acid suppression.hese patients should be on a PPI in a dose sufficient to heal

heir esophagitis or adequately treat their GERD symptoms.ut not all patients with Barrett’s esophagus have GERD. The

reatment of patients who lack both esophagitis and GERD isess clear; some patients with Barrett’s esophagus may not havehronic GERD. Other causes for Barrett’s esophagus may in-lude a remote episode of non-GERD vomiting-induced esoph-gitis, radiation injury, or other pathways. Such patients, whoack ongoing pathologic reflux, would be unlikely to benefitrom pharmacologic acid inhibitors, even if they were effectivet decreasing cancer risk in GERD patients.

Similarly, many patients with Barrett’s esophagus have an-ther indication for antiplatelet agents (ie, aspirin). The Unitedtates Preventive Services Task Force recommends the use ofspirin for men ages 45 to 79 years when the potential benefitf a reduction in myocardial infarctions outweighs the poten-ial harm owing to an increase in gastrointestinal hemorrhage.isk calculators are available on the Internet (eg, http://www.

raminghamheartstudy.org), and many, if not most, Barrett’ssophagus patients likely qualify for aspirin therapy.

Balancing the Potential Benefits andRisks: What Do We Say to Patients?Chemoprevention is an exciting but unproven method

or decreasing cancer risk in patients with Barrett’s esophagus.he limitations of epidemiologic data underscore the need for

cautious approach, particularly for agents that may have some

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1268 DOUGLAS A. CORLEY CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 12

isk and for a condition in which the overall likelihood of dyingrom esophageal adenocarcinoma is low.22

Evidence to date supports the following:

1. Use of pharmacologic acid suppression to eradicateesophagitis and relieve GERD symptoms in symptomaticpatients.

2. The use of aspirin in patients with other indications forantiplatelet therapy, which likely include a substantialportion of patients with Barrett’s esophagus. It is un-known if the cardioprotective dose also may be a che-mopreventive dose.

At this time there is insufficient evidence to support theollowing:

1. Routine use of high-dose PPI therapy beyond thatneeded for symptom relief and mucosal healing.

2. Use of invasive tests (such as pH probes) to monitor thedegree of acid suppression in persons who have com-plete mucosal healing and minimal symptoms.

3. Routine use of aspirin in persons not at increased risk forcardiovascular disease.

Finally, randomized controlled trials, such as the Aspirinsomeprazole Chemoprevention Trial, will provide a more de-nitive assessment of the effects of acid-suppressing medica-ions and aspirin as chemoprevention agents in Barrett’s esoph-gus.

DOUGLAS A. CORLEY, MD, PHDDivision of Gastroenterology

Kaiser PermanenteSan Francisco, California

Division of ResearchKaiser Permanente

Oakland, California

References

1. Nguyen DM, El-Serag HB, Henderson L, et al. Medication usageand the risk of neoplasia in patients with Barrett’s esophagus.Clin Gastroenterol Hepatol 2009;7:1299–1304.

2. El-Serag HB, Aguirre TV, Davis S, et al. Proton pump inhibitors areassociated with reduced incidence of dysplasia in Barrett’sesophagus. Am J Gastroenterol 2004;99:1877–1883.

3. Lao-Soirée P, Roy A, Worrall C, et al. Effect of acid suppression onmolecular predictors for esophageal cancer. Cancer EpidemiolBiomarkers Prev 2006;15:288–293.

4. Leedham S, Jankowski J. The evidence base of proton pumpinhibitor chemopreventative agents in Barrett’s esophagus—thegood, the bad, and the flawed! Am J Gastroenterol 2007;102:21–23.

5. Kaur BS, Ouatu-Lascar R, Omary MB, et al. Bile salts induce orblunt cell proliferation in Barrett’s esophagus in an acid-depen-dent fashion. Am J Physiol Gastrointest Liver Physiol 2000;278:G1000–G1009.

6. Feagins LA, Zhang HY, Hormi-Carver K, et al. Acid has antiprolif-erative effects in nonneoplastic Barrett’s epithelial cells. Am J

Gastroenterol 2007;102:10–20.

7. Hillman LC, Chiragakis L, Shadbolt B, et al. Effect of proton pumpinhibitors on markers of risk for high-grade dysplasia and oesoph-ageal cancer in Barrett’s oesophagus. Aliment Pharmacol Ther2008;27:321–326.

8. Hillman LC, Chiragakis L, Shadbolt B, et al. Proton-pump inhibitortherapy and the development of dysplasia in patients with Bar-rett’s oesophagus. Med J Aust 2004;180:387–391.

9. Corey KE, Schmitz SM, Shaheen NJ. Does a surgical antirefluxprocedure decrease the incidence of esophageal adenocarcinomain Barrett’s esophagus? A meta-analysis. Am J Gastroenterol 2003;98:2390–2394.

0. Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medicaland surgical therapies for gastroesophageal reflux disease: fol-low-up of a randomized controlled trial. JAMA 2001;285:2331–2338.

1. El-Serag HB, Wieman M, Richardson P. The use of acid-decreas-ing medication in veteran patients with gastro-oesophageal refluxdisorder with and without Barrett’s oesophagus. Aliment Pharma-col Ther 2008;27:1293–1299.

2. MacMahon B, Yen S, Trichopoulos D, et al. Coffee and cancer ofthe pancreas. N Engl J Med 1981;304:630–633.

3. Clavel F, Benhamou E, Tarayre M, et al. More on coffee andpancreatic cancer. N Engl J Med 1987;316:483–484.

4. Goldstein HR. No association found between coffee and cancerof the pancreas. N Engl J Med 1982;306:997.

5. Hsieh CC, MacMahon B, Yen S, et al. Coffee and pancreaticcancer (chapter 2). N Engl J Med 1986;315:587–589.

6. Michaud DS, Giovannucci E, Willett WC, et al. Coffee and alcoholconsumption and the risk of pancreatic cancer in two prospectiveUnited States cohorts. Cancer Epidemiol Biomarkers Prev 2001;10:429–437.

7. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppres-sive agents and the risk of community-acquired Clostridium diffi-cile-associated disease. JAMA 2005;294:2989–2995.

8. Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppress-ing drugs and the risk of bacterial gastroenteritis. Clin Gastroen-terol Hepatol 2007;5:1418–1423.

9. Corley D, Kubo A, Zhao W. Proton pump inhibitors, H2 antago-nists, and risk of hip fracture: a large population-based study.Gastroenterology 2009;136(Suppl 1):A70.

0. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pumpinhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319–326.

1. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pumpinhibitor therapy and risk of hip fracture. JAMA 2006;296:2947–2953.

2. Anderson LA, Murray LJ, Murphy SJ, et al. Mortality in Barrett’soesophagus: results from a population based study. Gut 2003;52:1081–1084.

onflicts of interestThe author discloses the following: Dr Corley receives research

unding from Wyeth Pharmaceuticals.

undingSupported by the United States National Institutes of Health (RO1

K63616). The study sponsor reviewed the protocol, but did notarticipate in the collection, analysis, or interpretation of the data.

doi:10.1016/j.cgh.2009.09.003