To our knowledge, we report the largest prospective chemoprevention trial in BE patients conducted in North America. Data from this clinical trial provide the first demonstration of a statistically significant effect from the combination of esomeprazole 40 mg bid and aspirin 325 mg qd for 28 days on tissue PGE2 values in participants with BE, as compared to esomeprazole 40 mg bid without active aspirin. Although the lower dose aspirin (81mg qd) + PPI did not significantly alter tissue PGE2 concentration, this finding was likely influenced by our relatively small sample size. Of note, a significant difference relative to the aspirin placebo + PPI group was observed when the percent decrease in PGE2 levels was compared. These results support further evaluation of 325 mg aspirin administered together with twice daily esomeprazole as a potential chemoprevention strategy for BE patients in larger, more definitive phase III trials.
Esophageal adenocarcinoma is a lethal disease with a 5-year survival rate of approximately 17% 6
Survival is stage dependent and early spread prior to the onset of symptoms is characteristic of this tumor. Currently, the best hope for improved survival of patients with esophageal adenocarcinoma is detection of cancer at an early and potentially curable stage. In order to accomplish this, current strategies have focused on identifying more patients at risk, namely those with BE, in conjunction with widespread endoscopic surveillance of patients with known BE. Both strategies, however, are inherently flawed, expensive, and impractical. Furthermore, there are no prospective clinical data to confirm either approach is effective. Although observational studies have demonstrated surveillance to be associated with cancer downstaging with improved 5-year survival, the relevance of these studies is markedly limited by the risk of lead-time bias.17, 18
In this context, alternative intervention strategies, such as chemoprevention, are worthy of consideration, specifically during the early stages of neoplastic transformation.5
It is widely accepted that chronic injury and resulting inflammation play a major role in the development of several cancers, including esophageal adenocarcinoma.9, 19-23
The catalysis of arachidonic acid to PGE2
by COX enzymes is thought to be critically involved in injury- or inflammation-induced esophageal carcinogenesis. Low pH, as well as exposure to caustic bile salts, can induce COX-2 expression in both ex-vivo culture models of BE and in esophageal adenocarcinoma cell lines.24, 25
COX-2 expression increases concomitantly with neoplastic progression in BE, thereby supporting the association of the arachidonic acid pathway with the development of esophageal adenocarcinoma.26
Moreover, higher PGE2
levels have been reported in Barrett’s epithelium compared to normal squamous mucosa.27
induces the proliferation of Barrett’s epithelial cells, while PGE2
inhibition reduces their proliferation.19
In addition, PGE2
is known to diminish tumor surveillance by inhibiting natural killer cell activity.28
Recent animal studies further demonstrate that inhibition of PGE2
production with the use of selective and non-selective COX-2 inhibitors can decrease the rate of esophageal adenocarcinoma development.19
Thus, chronic induction of PGE2
appears to stimulate esophageal carcinogenesis through multiple mechanisms.
A number of candidate chemoprevention agents have been proposed for BE patients including PPIs, selective and non-selective COX inhibitors (including aspirin), lyophilized black raspberries, antioxidants, green tea, retinoids, ursodeoxycholic acid, statins and curcumin.10, 29-31
Most attention has been directed toward the use of aspirin and other NSAIDs, which appear to lower esophageal cancer risk by favorably affecting COX-related pathways that are upregulated by excess exposure to acid and/or bile salts. While observational studies suggest that PPI therapy is associated with a decreased risk for the development of high-grade dysplasia and adenocarcinoma, the chemopreventive potential of PPIs, by suppressing acid and bile salt reflux, appears to be marginal when used as monotherapy.32-34
There are a variety of possible explanations for this marginal effect, including the inability of PPIs to completely eliminate acid/bile salt reflux or activation of gastrin-cholecystekinin (CCK)-COX-2 mediated pro-carcinogenic signaling pathways. It is therefore logical to use a PPI agent in combination with NSAIDS, to determine if the combination more effectively targets intermediate markers of Barrett’s-associated carcinogenesis.
Unfortunately, selective COX-2 inhibitors have been shown to increase the risk of thrombotic cardiovascular events making their widespread use for cancer chemoprevention problematic. An alternate approach is to use aspirin with a PPI, as was performed in our study. Aspirin decreases the risk of thrombotic cardiovascular events and is frequently recommended for patients at increased risk for myocardial infarction. In addition, PPIs may make aspirin a more useful and safer chemopreventive agent by minimizing aspirin-induced mucosal injury. Given the age-related increase in risk for gastrointestinal bleeding associated with NSAID use, this is a real concern for any chemoprevention strategy among BE patients, who tend to be of older age.35
While PPIs, by targeting the root cause of the problem, may prevent chronic esophageal injury and decrease inflammation, aspirin use could control any COX-2 activation that may result from breakthroughs in acid suppression or gastrin activation by PPIs.
Clinical trial data regarding the potential chemopreventive effects of aspirin and other NSAIDs in BE patients are currently limited. One clinical trial examined the effect of celecoxib given for 48 weeks in participants with low-grade and high-grade dysplasia, and found no difference in the proportion of biopsy samples with dysplasia between participants treated with celecoxib compared to placebo.36
Another small crossover study demonstrated that esomeprazole 40 mg twice daily in conjunction with aspirin at a dose of 325 mg daily administered for 10 days resulted in lower esophageal mucosal PGE2
content in BE participants, whereas esomeprazole alone or in combination with rofecoxib did not reduce PGE2
To our knowledge, no additional clinical trial data have yet been reported on the potential effects of different doses of aspirin, in combination with PPI therapy, as a potential esophageal cancer chemopreventive strategy. The rationale for the use of the lower and higher dose of aspirin was to define if the smaller dose of aspirin was equally effective in decreasing tissue PGE2
in Barrett’s patients compared to the higher dose. Another reason to undertake such a dose ranging study is that the higher dose of aspirin in one colon cancer prevention study appeared to be less effective than the lower dose aspirin.37
Strengths of the current study design included the avoidance of recruitment of participants with intestinal metaplasia of the cardia, the requirement for confirmation of intestinal metaplasia with goblet cells, and detailed interview to make sure patients were not unwittingly using aspirin or other NSAIDS prior to randomization. Thus, careful steps were taken to ensure a homogenous group of study participants with histologically-confirmed BE. Although our trial was conducted at multiple, geographically disparate sites, the relatively limited racial/ethnic diversity of our randomized cohort makes it unlikely that ethnopharmacology had any appreciable influence on our findings. While a significant difference was noted in the higher dose aspirin arm vs. the aspirin placebo arm, no such difference could be detected in the lower dose aspirin arm, despite a trend in that direction. The lack of a significant effect in the lower dose aspirin + esomeprazole arm may have been due to a lack of power and not a true lack of efficacy. The inability to achieve the a priori sample size, the lack of a sample size adjustment for the increased variability in PGE2, and the use of planned non-parametric tests (instead of the parametric tests that the sample size was based on) all may have contributed to the study being under-powered to detect a significant effect for the lower dose aspirin + esomeprazole arm. As such, we cannot conclude from our data that a combination of lower dose aspirin + esomeprazole does not provide chemopreventive benefits for BE patients.
There are a number of factors that make BE studies challenging to conduct. Importantly, many patients with BE already take aspirin or NSAIDs, which makes any such longer term clinical trial difficult to perform. Also, PGE2 levels represent a surrogate end point for more direct clinical endpoints, such as progression to high-grade dysplasia and adenocarcinoma. There is no simple study design for assessing these more clinically relevant, yet substantially less common endpoints without considerable resource investment.
Our rational to use PGE2
as a surrogate biomarker of NSAID-related chemoprevention is based upon its direct role in carcinogenesis in Barrett’s mucosa through upregulation of proliferation, resistance to apoptosis, and angiogenesis. Furthermore, PGE2
biosynthesis is a downstream target of several oncogenic signals and it can be downregulated by tumor suppressors.38-40
The findings that carcinogenic bile salts in pH dependent manner upregulate PGE2
biosynthesis along with increased expression of key regulators of PGE2
by DNA damage and by aberrant p53 expression41
further support that the effect of genetic or epigenetic gains or losses that promote neoplasia could be inferred through a mechanistically relevant composite biochemical readout such as PGE2
We believe that data from the current phase II trial provide strong support for a larger, more definitive phase III trial to further clarify the role of aspirin and esomeprazole in esophageal cancer chemoprevention among BE patients. Indeed, our study represents the largest chemoprevention trial in BE to date and has the advantage of examining a geographically diverse patient population. The ongoing multi-center phase III AspECT trial, which is being conducted in the United Kingdom and elsewhere in Europe, is also examining aspirin and esomeprazole as a combination chemopreventive intervention for BE patients,42
with results that should serve to complement these findings.
In conclusion, data from this multi-center, prospective phase II trial demonstrate that twice daily esomeprazole in combination with higher dose (325 mg) daily aspirin therapy can favorably affect tissue PGE2 levels in BE patients. Although the lower dose aspirin (81 mg) was not found to significantly reduce PGE2 levels as compared to esomeprazole alone based on the primary endpoint analysis, data from our secondary analyses suggest that esomeprazole twice per day in combination with 81 mg aspirin per day may also provide some chemopreventive benefits for BE patients. As such, a larger trial is recommended to more fully investigate the aspirin dose effect to see what aspirin dose is optimal. Given the importance of PGE2 and related molecular pathways in Barrett’s-associated carcinogenesis, this dual regimen of aspirin and esomeprazole warrants further evaluation as a novel chemoprevention strategy for an increasingly common disease with potentially devastating clinical outcomes.