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Esophageal Cancer Prevented By Proton Pump Inhibitor Plus Aspirin

Goodwin, Peter M.

doi: 10.1097/01.COT.0000546186.31507.03
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CHICAGO—A 25 percent risk reduction for esophageal adenocarcinoma (EA) was found to be associated with a long-term chemoprevention regimen consisting of daily high doses of a proton pump inhibitor (PPI) plus aspirin in the phase III randomized ASPECT multicenter study from the U.K. reported at the 2018 ASCO Annual Meeting (Abstract LBA4008).

The trial investigated high- or low-dose daily esomeprazole together with or without aspirin in a cohort of 2,563 patients who had Barrett's esophagus (BE) and were therefore at high risk of EA.

“Although we focused this study on people with Barrett's esophagus, we believe that any person with heartburn may want to consider taking high-dose proton pump inhibitors and aspirin after speaking with their doctor,” said lead study author Janusz Jankowski, MD, PhD, Deputy Vice Chancellor of the Royal College of Surgeons, Ireland, and Consultant Clinical Adviser with the National Institute for Health and Care Excellence (NICE), U.K. But he warned that patients should not self-medicate since the benefits so far had been confirmed only in the specific subset of patients who had BE.

Jankowski said he hoped that NICE and national bodies in other countries would consider the study findings when developing guidelines for preventing esophageal cancer.

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Study Results

The ASPECT study randomized patients who had more than 1 cm of BE to two different doses of esomeprazole: 40 mg twice daily (high-dose PPI), or 20 mg once daily (low-dose PPI). In addition, all patients were randomized either to receive aspirin at 300 mg per day (330 mg in Canada) or take only the PPI with aspirin.

Jankowski said that because only a few percent of patients had been expected to develop EA or high-grade dysplasia—despite the increased risk posed by BE—they had used a composite primary endpoint of time to all-cause mortality, which included other more common causes of death such as obesity, bronchopneumonia, and heart disease in addition to cancer. This endpoint had been analyzed by using “accelerated failure time modeling” adjusting for factors such as age, linear extent of BE, and the presence of intestinal metaplasia.

After a median of 8.9 years per patient and a total of 20,095 patient-years of follow up, there were 313 endpoint events among 2,535 patients. High-dose PPI was found to be statistically significantly superior to low-dose PPI (p=0.037). The researchers reported that, while aspirin therapy showed a “trend” to benefit, this had not been statistically significant. The strongest preventative effect was found in patients who were treated with the combination of aspirin together with high-dose PPI compared with those who had low-dose PPI and no aspirin (p=0.007).

Less than 1 percent of patients reported serious adverse events. At an ASCO press briefing, Jankowski said this was important since the regimen had been used as a candidate for chemoprevention, so it had been necessary to confirm it added no significant additional toxicity.

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Evidence

Jankowski told Oncology Times that, while the evidence for an association of aspirin with prevention of gastrointestinal cancers had emerged since the late 1980s, the theory that PPIs might have had anti-cancer properties had not previously been validated and there had been no consensus on the net benefit or otherwise of these agents for health beyond the advantage of acid inhibition.

There had been a theoretical view however that acid reduction itself could help avoid cancer by reducing DNA change. “If you look at pathophysiological process: We can't reverse the Barrett's unless you ablate it (and the evidence for that is very weak), so the next best thing is to deal with the abnormal physiology which is to reduce the acid reflux,” he noted.

When Jankowski was asked for his take on the clinical implications of the data, he said the findings had produced a statistically significant result. “High-dose proton pump inhibitor [therapy] was more effective at decreasing the mortality of patients with Barrett's esophagus.”

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Aspirin Plus Non-Steroidals?

Jankowski had an interesting comment on the role of aspirin. “We showed that aspirin—in the primary endpoint—wasn't significant on its own. However, when we censored for co-use of non-steroidal drugs—which was a protocol violation—then aspirin became significant. So it appears that the effect of aspirin with non-steroidals was a confounding factor, meaning that non-steroidals may very well have had some sort of anti-inflammatory effect [like] aspirin.”

He warned that since they only had just 9 years of median experience, additional longer-term data were lacking. Even so, clear numbers had emerged. “[With] proton pump inhibitors, the number needed to treat was 1 in 34 and for aspirin it's 1 in 43: so you have to treat a lot of patients to get a statistical benefit,” he stated.

When he was asked for his cautious recommendation for using aspirin plus PPI as chemoprevention in patients with BE, he began by emphasizing the need for longer follow-up to see if the benefit so far would be maintained and to check for long-term adverse events and side effects and assess the optimum duration of therapy. He was also awaiting feedback from regulatory authorities in different countries.

But Jankowski emphasized his message for patients. “You should not be self-medicating. What we have looked at here is the ‘sweet spot’ of getting the risk/benefit ratio right in a highly selected group of patients who were very tightly controlled and monitored.” He warned that if patients self-medicated, this risk/benefit ratio could easily go “the wrong way.”

When he was asked whether these new data had given a reassuring message about the long-term use of PPIs, he was cautious. “We don't know about the longer term. What we have to be very careful of is that this is one snapshot in time and we need to follow up with this group for another 5 or 10 years. And hopefully we can [then] give an answer.”

At the ASCO press briefing held to discuss the ASPECT data, Andrew Epstein, MD, Hospice and Palliative Instructor in Medicine and Assistant Attending Physician at Memorial Sloan Kettering Cancer Center and Assistant Professor of Medicine at Weill Cornell Medical College, New York City, said the risk of esophageal cancer weighed on patients with BE.

“This low-cost, over-the-counter regimen seems to be a win-win, delaying or preventing cancers and with little to no side effects,” he commented. “It's an approach that people with Barrett's should consider and discuss with their doctors.”

Peter M. Goodwin is a contributing writer.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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