Long-term PPI Use and Increased Esophageal CA Risk

Kristin Jenkins

March 05, 2018

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.

However, investigations into whether PPIs may be causally related have not provided any evidence to support this, he pointed out.

In fact, observational studies have shown an inverse relationship between the two, with lower rates of EAC seen in patients receiving PPIs. This evidence prompted prospective controlled studies evaluating the EAC risk reduction for patients with Barrett's esophagus as well as several cohort observational studies, Johnson noted.

Ultimately, evidence from these investigations led the American Gastroenterological Association to recommend that PPIs be given to all patients with Barrett's esophagus regardless of heartburn symptoms, stating that PPIs also had a chemoprevention role.

Johnson noted that "well-recognized significant risks for both SCC and EAC, including smoking, alcohol, and obesity, are strikingly absent from this analysis." In addition, "the lack of logistic regression analysis to account for stratification bias is unfortunate and undermines the conclusions."

The fact that the study didn't demonstrate an increased risk for cancer over time suggests a lead time bias in which PPI therapy was initiated in response to symptoms of esophageal cancer, Johnson said. "Well-done analyses of this type of potential risk would exclude these early cases for at least 6 months to avoid protopathic bias."

Jeffrey Meyerhardt, MD, a medical oncologist at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, agreed. Even though the study authors "made efforts to try and tease this up, the strongest associations were still observed in patients taking PPIs for acid reflux, which could be an early sign of esophageal cancer."

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

Meyerhardt said that patients who require long-term PPI therapy should be screened with upper endoscopy at least once. "That is standard in guidelines but often not done."

Study Should Not Change Practice

Scott Gabbard, MD, a gastroenterologist at the Cleveland Clinic, Ohio, also warned that findings from this cohort study must be interpreted with caution. Like Johnson, he advised against clinicians making any practice changes, pointing out that maintenance PPI therapy is generally recommended in patients with Barrett's esophagus. In one meta-analysis, PPI therapy decreased the risk for adenocarcinoma and high-grade dysplasia by 71% in  patients with Barrett's esophagus, he noted.

"I would not let one cohort study change my practice," Gabbard told Medscape Medical News. "This study demonstrates an association, not a cause and effect. I would be very careful not to state that PPIs cause esophageal cancer based on these data."

Gabbard said he encourages once-daily PPI therapy in his own patients with Barrett's esophagus. In patients with GERD who don't have Barrett's esophagus, he prescribes the lowest effective dose of PPI.

"I would be most interested in [the outcomes for] patients with Barrett's esophagus who did and did not take maintenance PPI," Gabbard said. This wasn't reported in the current study, he pointed out. "That said, we need more well-done studies to answer these questions fully."

Both Johnson and Gabbard said they would encourage practitioners to follow published guidelines for prescribing PPIs.

In its guideline for the diagnosis and management of Barrett's esophagus, the American College of Gastroenterology recommends maintenance PPI therapy for patients with GERD who continue to have symptoms after PPI therapy is discontinued.

The guidelines also recommend long-term PPI therapy for patients with complications, such as erosive esophagitis and Barrett's esophagus. It is advised that PPI maintenance therapy be administered in the lowest effective dose, including on-demand or intermittent therapy.

This study was supported by the Karolinska Institutet, the Swedish Research Council, and the Swedish Cancer Society.  Brusselaers and study coauthors and Gabbard have disclosed no relevant financial relationships. Johnson has or has had financial ties to Pfizer Inc, which makes a PPI; Epigenomics; WebMD; CRH Medical; and Medtronic. Meyerhardt reports relationships with Chugai Pharma, Ignyta, and Roche/Genentech. 

Cancer Epidemiol. Published online February 22, 2018. Abstract

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