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© 2004 Oxford University Press
CORRESPONDENCE |
Re: Cost-Effectiveness of Aspirin Chemoprevention for Barrett's Esophagus
Affiliations of authors: Digestive Diseases Centre, Departments of Genetics and Molecular Medicine, University of Leicester, Leicester, UK (JJ); GI Unit, McMaster University, Hamilton, Ontario, Canada (PM)
Correspondence to: J. A. Z. Jankowski, MD, PhD, FRCP, Level 4, Windsor Building, Departments of Genetics and Molecular Medicine, Medical School and University Hospitals Trust, Royal Infirmary, LE1 5WW, Leicester, UK (e-mail: j.jankowski{at}le.ac.uk)
We write in regard to the article by Hur et al. (1) that appeared in the Journal. This article highlighted the value of aspirin for chemoprevention of Barrett's esophagus. We believe that this article is extremely timely. We are now addressing this same point in one of the largest randomized controlled trials in clinical gastroenterology that will involve 5000 male patients aged between 40 and 75 years with long-segment Barrett's metaplasia of the esophagus and have a 2-by-2 intervention trial factorial design (Fig. 1). This trial has been reviewed and funded by external grant authorities in the United Kingdom (namely Cancer Research UK, Medical Research Council, National Cancer Research Institute, and the University Hospitals of Leicester) and has been rated as a high-priority study. The agents tested are a high-dose proton pump inhibitor (PPI) and a low-dose PPI. In addition, half of these patients will receive either low-dose aspirin or no aspirin. The trial is named the Aspirin Esomeprazole Chemoprevention Trial (ASPECT; http://www.digestivediseases.org). The follow-up will be at least 8 years long, with 2 years of initial recruitment, for a total of 10 years. Patients will receive endoscopy and biopsy examinations every 2 years. The primary end point is all-cause mortality. We suspect that low-dose aspirin therapy will benefit people with Barrett's metaplasia because this group has a higher-than-average incidence of ischemic heart disease and cardiac death, with 42% dying of vascular-related disease compared with 32% in a sex- and age-matched population in the United Kingdom. In addition, we will investigate the effects of aspirin and the PPIs on the rate of progression of benign Barrett's esophagus to invasive cancer.
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This trial is important for several reasons. First, the long-term follow-up should rovide information about the natural history of Barrett's esophagus, which is presently unclear. Second, results of the trial should indicate whether commonly used acid suppressor agents are harmful or beneficial and, if so, in what doses. Third, the results should identify potential risks or benefits of using aspirin in combination with a PPI in the group of dyspeptic patients with regard to cancer risk and cardiovascular risk.
The trial will take place predominantly in the United Kingdom because we have the world's highest incidence of esophageal adenocarcinoma (the cancer most closely related to Barrett's esophagus) and the highest progression rate from Barrett's metaplasia to cancer, which is twice that in North America (2). In addition, there will also be U.S. experts advising us as well as the possibility of contemporaneous study sites being set up by U.S. and Canadian collaborators.
We would like to open a debate about the value of surveillance, even in stratified groups with Barrett's esophagus, compared with the value of chemoprevention in a wider reflux population in North America. In North America, the current practice of frequent endoscopic surveillance captures at best 10% of individuals with Barrett's esophagus, leaving 90% of patients unprotected. We believe that, with the increasing incidence of esophageal cancer, surveillance has failed to make a large meaningful impact in cancer prevention. Advocates for intensive surveillance correctly point to the better staging and, hence, prognosis of surveillance-detected cancers, but cost-effectiveness models have indicated that frequent surveillance in populations, such as that in North America, is currently not a cost-effective use of health resources.
Until now, many other clinicians have accepted the futility of surveillance, and they have responded with two arguments—namely, "it is better to do something rather than nothing" and "the patients want us to do something." Now there is a clear choice, and we believe that the results of our trial may indicate that our chemoprevention will be more useful and beneficial to patients with Barrett's esophagus and long-standing reflux disease. In fact, observational studies, both case–control and cohort, have provided evidence of benefit from such interventions, indicating that the use of aspirin and PPIs will treat the symptoms and have a reasonable chance of chemoprevention in 30%–50% of patients (3). The cost of these chemopreventive treatments is low, with low-dose aspirin being $4–$6 per year and generic PPI therapy being about $214 per year. In addition, 85% of patients with Barrett's esophagus in the United Kingdom are now on some sort of PPI drug at various doses anyway. Our optimism is shared by patients and clinicians alike, 93% and 82%, respectively, saying that they would prefer chemoprevention to regular endoscopic surveillance if offered. There is a third group of clinicians who believe that there is already overwhelming evidence to advise widespread use of aspirin as a chemotherapeutic agent regardless of its complications, but this belief is premature because aspirin resistance is now a described phenomenon in 10%–25% of people (4).
Although we are upbeat about the scientific rationale for this trial, we are also eager to get hard evidence that aspirin therapy does work from our prospective long-term study. For now, we aim to combine chemoprevention with regular endoscopic surveillance so that we can also acquire tissue samples. Consequently, we aim to address the following additional translational questions that will be vital to further studies. What are the biomarkers for cancer progression? What are the biomarkers for chemoprevention resistance (hence generating new targets for additional therapy)? Finally, what are the host susceptibility factors for Barrett's esophagus and its cancer?
In conclusion, can we proclaim "surveillance is dead, long live chemoprevention"? Perhaps not yet. However, we expect chemoprevention to become the initial and primary intervention, with surveillance as the safety net.
NOTES
Dr. Jankowski is a consultant for several companies, including Astra-Zeneca and Johnson & Johnson. The authors of this paper submit it for all the members of ASPECT, the Aspirin Esomeprazole Chemoprevention Trial, University of Leicester Digestive Diseases Centre.
REFERENCES
1 Hur C, Nishioka NS, Gazelle GS. Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus. J Natl Cancer Inst2004;96:316–25.
2 Jankowski JA, Provenzale D, Moayyedi P. Esophageal adenocarcinoma arising from Barrett's metaplasia has regional variations in the West. Gastroenterology2002;122:588–90.[Medline]
3 Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology2003;124: 47–56.[CrossRef][ISI][Medline]
4 Hankey GJ, Eikelboom JW. Aspirin resistance. BMJ2004;328:477–9.
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J Natl Cancer Inst 2004 96: 887.
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