Tuesday, 13 November 2012

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Benefit of Aspirin as Chemoprevention for Barrett’s May Not Outweigh Risks by Caroline Helwick

San Francisco—There is no evidence that aspirin is beneficial for preventing esophageal adenocarcinoma in people younger than age 55 years. Even for appropriate patients, the benefits emerge only after many years of use and the related risks remain unclear, said Janusz Jankowski, MD, PhD, the Sir James Black professor at the University of Oxford in the United Kingdom.

Dr. Jankowski is chief investigator of AspECT (Aspirin Esomeprazole Chemoprevention Trial), a randomized trial that is currently evaluating the chemopreventive effect of aspirin in patients with Barrett’s esophagus (BE). Some of the controversy may well be resolved by AspECT, which is one of the largest randomized trials involving the upper gastrointestinal (GI) tract ever. Currently, 2,513 patients are being tested to ascertain whether low-dose aspirin versus no aspirin—both in combination with esomeprazole (20 vs. 80 mg)—can reduce cancer risk. Efficacy results are expected in 2019 ( Identifier: NCT00357682).

Dr. Jankowski reviewed the available evidence for aspirin’s effect in preventing esophageal adenocarcinoma in a lecture at the American Society for Clinical Oncology 2012 Gastrointestinal Cancers Symposium.

When compared with other chemopreventive agents like cyclooxygenase (COX) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin has shown the greatest efficacy in reducing the risk for cancer (20%-30%) and cardiovascular events (25%), at by far the lowest cost (approximately $5 per year), although with a slightly higher risk for upper GI bleeding (2.5%-4% per year).

“Compared with traditional NSAIDs and COX inhibitors, aspirin wins hands down for preventing cancer and cardiovascular disease, but GI bleeds are the biggest side effect,” Dr. Jankowski said. “And this GI bleeding profile is only relevant for aspirin taken alone. If you take another NSAID, the risk is additive.”

Although rare, aspirin also has been associated with a risk for macular degeneration.

“We have to consider when we look at randomized data, that aspirin could be preventing some problems but causing others at a very low frequency,” Dr. Jankowski noted.

Preliminary data from the AspECT trial suggest that 5% of individuals are intolerant to aspirin, meaning that one in 20 will discontinue its use due to effects such as GI upset, skin rash or worsening of asthma. And as patients age, the risk for complications gradually increases and could approach 20% by the age of 70, after 20 years of use, Dr. Jankowski said.

“The big challenge is to see if the 20% to 25% of patients who get a cancer prevention benefit are different from the 20% who may get aspirin-induced complications,” Dr. Jankowski said. “Randomized studies are the only way to fully answer the questions related to the risks and benefits of aspirin as chemoprevention.”

An analysis of individual patient data from randomized trials (Rothwell PM et al. Lancet 2011;377:31-41) concluded that taking aspirin daily (=75 mg) reduced deaths due to common cancers, during and after the trials, in 20% to 25% of subjects. The effect was most pronounced for GI tumors; it was apparent after four years and became significant after 10 years.

“One-fifth to one-quarter of patients taking aspirin for cardiac reasons got a secondary benefit in terms of cancer prevention,” Dr. Jankowski observed. “But, based on the data, you may have to take aspirin for at least 10 years, and maybe 20, to get this benefit, so the side-effect frequency needs to be exceptionally low. And as good as aspirin is, the response rate is just 20% and we still don’t know who the responders will be.”

It also is possible that the preventive effect is smaller, he added, based on his reanalysis of the Rothwell data.

“In our hands, we showed that cancer prevention is not 20% to 25%, but more like 7% to 10% (risk ratio [RR] 0.9; 95% confidence interval [CI], 0.87-1.00]),” he said. “This is crucial. We need to understand the real benefit and risks in order to determine the value, especially as primary prevention.”

From cardiology data it is clear that aspirin use affects cardiovascular events only in persons already at high risk (i.e., the secondary prevention population). A recent paper recapitulated this finding in cancer as well as cardiac disease, Dr. Jankowski noted.

In a meta-analysis of randomized controlled trials involving 100,000 participants followed for a period of six years (Seshasai SR et al. Arch Intern Med. 2012;172:209-216), it was found that aspirin treatment reduced total cardiovascular events by a modest 10%, did not prevent cardiovascular deaths and was associated with a 31% increased risk for nontrivial bleeding events. The investigators concluded that routine use of aspirin for primary prevention is not warranted.

“So, should one take low-dose aspirin?” Dr. Jankowski asked. “At this time, the answer is indefatigably ‘No, you should not,’ unless you have secondary risk factors for cardiac or GI conditions.”
The international Consensus Statements for Management of Barrett’s Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process (BADCAT, Gastroenterology, 2012;143:336-346) confirmed Dr. Jankowski’s conclusions. The group’s consensus is that it is not currently known whether aspirin can prevent the progression of BE and that the inherited genetics of BE has not been clarified. These topics should be a research focus, the group stated.

Early data from the AspECT trial, however, have offered encouraging signs that four years of aspirin treatment may be protective.

“There are not enough data to determine if it prevents cancer, but we see new squamous islands appearing where Barrett’s esophagus was,” said Dr. Jankowski.

“We may have a recommendation regarding aspirin use within the next two years,” he added. “Meanwhile, there is no evidence whatsoever, even with risk factors for cancer or cardiac disease, that a person should take aspirin before the age of 55 years. And we don’t think that taking aspirin after the age of 75 makes sense, based on the need to take it for 10 years to achieve a benefit, and because of the high incidence of side effects at this age. Between the ages of 55 and 75, a patient could take aspirin, but there are still risk–benefit issues and we don’t know who will respond. We need to deal with these issues urgently.”

Prateek Sharma, MD, professor of medicine at the University of Kansas School of Medicine, Kansas City, commented on the findings.

“The majority of esophageal adenocarcinomas originate in patients with Barrett’s esophagus. These patients progress to low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma and finally to invasive carcinoma,” he noted. “Currently, we survey patients with Barrett’s esophagus to detect high-grade dysplasia and early cancer, which can then be treated for cure. We could achieve substantial health care savings if we had an agent that would prevent these conditions.

Although observational studies have generated preliminary data on the ability of certain agents such as aspirin, sulindac and DFMO [difluoromethylornithine) to prevent esophageal cancer, their broad clinical applicability is limited due to their toxicity,” he added. “Further research is needed to identify which subset of patients would benefit from chemoprevention and the dose required, duration of treatment and toxicity.”