Long-term PPI Use and Increased Esophageal Cancer Risk

This article was posted on MedScape on Monday, March 5, 2018 and is written by Kristin Jenkins.

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“Long-term maintenance therapy with proton-pump inhibitors (PPIs) was shown to be  associated with an increased risk for esophageal cancer, even in patients taking PPIs for indications not previously associated with this cancer risk, according to results from a new study from Sweden.

The authors call for “a more restrictive attitude towards maintenance use of PPIs.”

However, this “surprising” observation comes from a single cohort study that lacks the evidence to demonstrate a causal relationship, warn experts approached for comment. They say that clinicians shouldn’t stop prescribing PPIs as recommended by current guidelines.

The new study was published online February 22 in Cancer Epidemiology by a team led by Nele Brusselaers, MD, PhD, associate professor of clinical epidemiology at the Karolinska Institutet and the Karolinska University Hospital in Stockholm.

In the study, data from four national registers in Sweden were used to identify 796,492 patients without a history of cancer who were exposed to maintenance PPI therapy between 2005 and 2014. Most were female (58.5%), and 34.0% were age 70 years or older.

The indications for PPI use included maintenance therapy with aspirin (34.8%), nonsteroidal anti-inflammatory drugs (NSAIDs) (30.4%), gastroesophageal reflux disease (GERD) (25.3%), gastroduodenitis (13.2%), and peptic ulcer disease (10.0%). Less than 10% of participants were taking PPIs for other indications.

The team compared this cohort of nearly 800,000 patients taking PPIs to adults in the general population matched for sex and age over the same period.

They found that the overall standardized incidence ratio (SIR) for esophageal adenocarcinoma (EAC) in PPI users was 3.93, and the overall SIR for esophageal squamous cell carcinoma (SCC) was 2.77.

The study also showed that in patients without GERD who were taking PPI maintenance therapy with NSAIDs or aspirin, the SIR for EAC was 2.74 and 2.06, respectively.

To evaluate confounding by indication, stratified analyses were performed for each indication not associated with an increased risk for EAC. This separate analysis was one of the study’s chief strengths because it minimized the risk for confounding by indication that has limited previous research, Brusselaers and colleagues say. However, they were unable to identify the indication for PPI therapy in 25% of the cohort.

Increase in Cancer Not Seen With H2-Antagonists

A comparative analysis in 20,177 patients taking only histamine-2 receptor (H2) antagonists (such as ranitidine) found no increased risk for EAC (SIR, 0.39) or SCC (SIR, 0.50).

This finding “lends support to the hypothesis that this association may be due to PPI medication per se, and not related to other factors that predispose to using anti-acidic medications,” the study authors say.
“To assess generalizability and validity of these results, further investigations in other settings with other distributions of risk factors for oesophageal cancer is necessary,” they write. “Yet, we believe that a more restrictive attitude towards maintenance use of PPIs may be indicated…. Long term use of PPIs should be addressed with caution.”

Assuming that 10.7% of Swedish adults are taking PPI maintenance therapy, 5.4% of all esophageal cancer cases seen in that country’s population during the study period could be conservatively estimated to be attributable to PPI use, they suggest. The population of Sweden was 9.03 million in 2005 and had increased to 9.519 million by 2012.

This is not the first time that long-term PPI therapy has been implicated in increased cancer risk. Most recently, Medscape Medical News reported a Hong Kong study showing that long-term PPI therapy doubled gastric cancer risk after Helicobacter pylori eradication.

Dramatic Increase in Esophageal Cancer

When approached for comment, David A Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said this study “potentially does more harm than good.” A discussion with patients about whether PPI therapy is necessary “is always appropriate,” but clinicians shouldn’t stop prescribing PPIs as recommended, he emphasized.

“These findings are surprising because of the lack of evidence that goes with this observation. The allegation of harm should always start with a hypothesis as to why a reported association may be causal. None is suggested in this report,” Johnson told Medscape Medical News.

Since the introduction of PPIs, the incidence of SCC of the esophagus has increased dramatically, Johnson acknowledged. The incidence of EAC in industrialized countries has also increased.”


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Story Source:

“Long-term PPI Use and Increased Esophageal CA Risk” – MedScape – Mar 05, 2018.

Cancer Epidemiol. Published online February 22, 2018. Abstract

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