Aspirin Plus PPI Prevents Esophageal Cancer

But Risks May Loom

Nick Mulcahy

June 05, 2018

CHICAGO — Combined use of aspirin and a high-dose proton pump inhibitor (PPI) protects against the development of esophageal cancer in people who are at elevated risk for the malignancy, according to the results of a major phase 3 chemoprevention trial from the United Kingdom, the Aspirin and Esomeprazole Chemoprevention in Barrett's Metaplasia (AspECT) trial.

Dr Janusz Jankowski

However, as the trial continues, there are looming risks from the ongoing use of aspirin in aging study participants. These risks may negate the survival benefit that has been demonstrated in the trial, principal investigator Janusz Jankowski, MD, of the Royal College of Surgeons, Ireland, told Medscape Medical News.

The magnitude of the overall benefits seen in the trial were "surprising" and were greater than expected, said Jankowski while discussing the results with reporters during a press conference here at the American Society of Clinical Oncology (ASCO) 2018 annual meeting.

Before enrollment, 2563 of the study patients already had Barrett's esophagus, which increases the risk for esophageal cancer and is predominantly caused by acid reflux.

Notably, the study participants were already taking a PPI (esomeprazole [multiple brands]) for Barrett's when they were recruited into the trial during otherwise routine physician office visits at 85 centers in the United Kingdom.

The trial, which began in 2003, uses a 2x2 randomized design to assign participants to one of four study groups:

  • High-dose esomeprazole (80 mg daily)

  • High-dose esomeprazole with low-dose aspirin (300 mg daily)

  • Low-dose esomeprazole (40 mg daily)

  • Low-dose esomeprazole with low-dose aspirin

A placebo control was not used because it was considered unethical to withhold a PPI in the trial, Jankowski explained. Aspirin was included for its anti-inflammatory effect.

The primary endpoint was a composite of three events (and the related time to their occurrence): death from any cause; diagnosis of esophageal adenocarcinoma or diagnosis of high-grade dysplasia; a high-risk precancerous condition.

The composite endpoint was necessary because only 2% to 3% of patients with Barrett's esophagus subsequently develop esophageal cancer, said Jankowski.

The median follow-up was 8.9 years. The investigators report that there was a 27% delay in the time to the composite endpoint with high-dose vs low-dose esomeprazole (P = .037).

The investigators also report that there was no significant difference for the composite endpoint between aspirin vs no aspirin, said Jankowski. However, when the investigators censored some patients for use of other nonsteroidal anti-inflammatory drugs outside the protocol, there appeared to be some benefit. "The benefit from aspirin seems borderline," he summarized.

Jankowski also provided 8-year survival rates: 90% vs 87% for high- vs low-dose esomeprazole, a 3% absolute difference (P = .0459). However, this survival benefit was not seen until the seventh year of taking the daily chemoprevention.

Low-dose aspirin with high-dose PPI was "by far the most effective" combination and was "very significant" in its effect, Jankowski told the audience at the meeting, but he did not provide the specific values (owing to an agreement with a publisher). Also, he reported that there were 313 composite events but did not specify them as to type and treatment.

At 9 years, "it looks like there is a benefit of the high-dose proton pump inhibitor," summarized Jankowski.

The analysis adjusted for patients' ages and duration of Barrett's esophagus.

Dr Andrew Epstein

Commenting on the new results, Andrew Epstein, MD, an ASCO expert from Memorial Sloan Cancer Center in New York City, agreed with the investigators that "patients with Barrett's esophagus should speak with their physicians" about taking the combination therapy to delay the events studied in the trial. However, he emphasized that this recommendation does not apply to patients with gastroesophageal reflux disease.

However, ASCO seemed to have some differences with the claims from the investigators, as the headline of their press release on the trial called the benefits from aspirin and esomeprazole "moderate."

Meeting discussant Zev Wainberg, MD, of the University of California, Los Angeles, congratulated the investigators on "an incredible effort" and agreed that chemoprevention must be explored as rates of esophageal cancer climb globally. "Should we do this?" he asked the audience about the aspirin and esomeprazole combination. "We need to see more of these data," he answered emphatically.

Will Aspirin's Side Effects Show Up?

Investigator Jankowski said the rate of serious adverse events (1%) in the trial so far is "exceptionally low, which is very important in prevention [trials]," because the whole point is to improve health.

However, Jankowski is also concerned that trouble may be brewing.

"The big issue here is the lack of serious side effects," he said. "I have been telling people for the last 20 years: you know what, we don't want to kill people with low-dose aspirin."

Aspirin side-effect rates increase "exponentially" after age 65 among regular users, he said. At enrollment, the average age of the study population was about 50 years. Now, with a median follow-up of 9 years, some patients are approaching age 65, observed Jankowski.

Then Jankowski made a related point about efficacy: "Over the next 5 to 10 years, will the aspirin users in the trial get a bigger benefit? The answer is probably yes," he said. But, as time goes on, there is also an increased risk for aspirin-related death from complications such as gastrointestinal bleeding and stroke, he explained.

The risk/benefit math may not add up favorably. "We are probably buying an extra 2 to 3 years in someone's lifespan [for the people who benefit from chemoprevention that includes aspirin]. So, if you kill even a few people prematurely — with 20 to 30 life-years lost [per person] — the whole balance is completely negated."

Jankowski is acutely aware of the possible risks. At various times with potential enrollees in his clinic, Jankowski emphasized aspirin's risks when explaining the trial, telling them, as an analogy: "If I came up with a surgical treatment and there is a 1 in 100 chance you might die from this intervention in the next 10 years, would you want this intervention?"

"I think the aspirin rate [of death from long-term use] might be higher — so we have got to get this in context," he said.

Aspirin's risks are also a concern to another expert, Jeffrey Meyerhardt, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. Further, he questioned the definition of low-dose aspirin in the trial (ie, 300 mg/day). "We usually think of low-dose as 80 mg/day. I think of 300 mg/day as a standard dose," he said.

This is one of the largest studies to date that shows that "reducing the acid [with a PPI] helps with Barrett's esophagus," he said.

I think these results are a good justification to put people on a higher dose [of PPI]. Dr Jeffrey Meyerhardt

One of the important — and perhaps practice-changing — findings from the study is that it indicates that a higher-dose PPI is preferable to the lower, standard dose for Barrett's esophagus, Meyerhardt said. "I think these results are a good justification to put people on a higher dose [of PPI]," he told Medscape Medical News.

A recently published observational study from Sweden indicated that there was actually an increased risk for esophageal cancer with use of PPIs, as reported by Medscape Medical News.

Meyerhardt also commented on that trial. "The greatest cancer risk was seen with short-term PPI use," he pointed out. In patients who received PPIs for 5 years or longer, the association was not significant. "This seems to be the reverse of what you would observe if PPIs cause esophageal cancer," he told Medscape Medical News at the time.

The study received funding from Cancer Research UK and AstraZeneca. Dr Jankowski reports financial ties to industry, including AstraZeneca and Teueda.

American Society of Clinical Oncology (ASCO) 2018. Abstract LBA4008, presented June 4, 2018.

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