Long-term PPI Use Tied to Doubled Risk for Gastric Cancer

Megan Brooks

October 31, 2017

UPDATED NOVEMBER 1 //  Use of a proton-pump inhibitor (PPI) after Helicobacter pylori eradication more than doubles the risk for gastric cancer, according to a population-based study from Hong Kong.

The "clear dose-response and time-response" trend in PPI use and gastric cancer risk observed suggests the need for "caution when prescribing long-term PPIs to these patients even after successful eradication of H. pylori," write Wai Keung Leung, MBChB, MD, from Queen Mary Hospital, Hong Kong, and colleagues.

The study was published online October 31 in Gut.

The researchers point out, however, that this was an observational study, which can't prove cause and effect.

The new results also conflict with a recently published, US Food and Drug Administration–mandated follow-up study conducted with pantoprazole, said David A. Johnson, MD, chief of gastroenterology at Eastern Virginia Medical School in Norfolk (Aliment Pharmacol Ther. 2016;43:73-82).

"No increased risk [for gastric cancer] was observed with prolonged PPI exposure," he said.

Dr Johnson, who was asked for comment, also stated that the study has a "geographic bias" because it is from Hong Kong and "specific risks for gastric cancer are well recognized in Asian patients."

In the new study, Dr Leung and colleagues partly focused on H pylori infection and its relationship with gastric cancer.

H pylori eradication has been shown to reduce the risk for gastric cancer by 33% to 47%, but many patients develop gastric cancer even after eradication of H pylori. PPI therapy, "although generally considered safe," is associated with worsening gastric atrophy, particularly in H pylori–infected patients, the researchers point out. A recent meta-analysis found a 43% increased risk for gastric cancer among long-term PPI users, but it is was unable to adjust for H pylori, the major confounding factor.

Using a territory-wide health database in Hong Kong, Dr Leung and colleagues compared the risk for gastric cancer in PPI users and histamine-2 receptor antagonist (H2RA) users among 63,397 adults successfully treated with a 7-day course of triple therapy to eradicate H pylori between 2003 and 2012. 

"PPIs are much more potent than H2RA in terms of gastric acid suppression, and previous studies did not reveal any association between gastric cancer development and H2RA. Hence, H2RA was selected as a negative control exposure in our study," the researchers explain.

During a median follow-up of 7.6 years, 153 (0.24%) people developed gastric cancer after H pylori eradication therapy, mostly in noncardia regions (62%). None of the patients with gastric cancer tested positive for H pylori at diagnosis, but all had long-standing gastritis. The median age at cancer diagnosis was 71.4 years, and the median time from H pylori eradication to gastric cancer was 4.9 years.

After propensity score adjustment, people taking PPIs at least weekly had a greater than twofold increased risk for gastric cancer development (hazard ratio [HR], 2.44; 95% confidence interval [CI], 1.42 - 4.20). The propensity score–adjusted absolute risk difference between PPI use and non-PPI use was 4.29 excess gastric cancer cases per 10,000 person-years.

H2RA users had no increased risk (HR, 0.72; 95% CI, 0.48 - 1.07), which "further supports the specific role of PPIs on gastric cancer development," the researchers say.

After stratification by tumor site, PPI use was only significantly associated with an increased risk for noncardia gastric cancer (HR, 2.59; 95% CI, 1.42 - 4.72) but not cardia cancer (HR, 1.97; 95% CI, 0.57 - 6.82); "although this result should be interpreted with caution as this subgroup analysis has a relatively small number of cardia cancers," the researchers say.

Gastric cancer risk increased with longer duration of PPI use. The HR was 5.04 (95% CI, 1.23 - 20.61) for 1 year of use or longer, 6.65 (95% CI, 1.62 - 27.26) for 2 years of use or longer, and 8.34 (95% CI, 2.02 - 34.41) for 3 years use or longer.

More frequent use was also associated with greater risk. When compared with the reference group (less than weekly use), gastric cancer risk progressively increased with more frequent PPI use. The HR was 2.43 (95% CI, 1.37 - 4.31) for weekly to less than daily use, increasing to 4.55 (95% CI, 1.12 - 18.52) for daily PPI use.

The results remained significant by various sensitivity analyses.

A strength of the study is its use of data from a large population-based database with complete information on subsequent diagnoses and drug prescriptions, which minimizes selection, information, and recall biases, the researchers say. Use of strict exclusion criteria as well as propensity score adjustment to control for potential confounders and restricting the sample to patients with successful H pylori eradication are other strengths.

In terms of study weaknesses, the researchers  lacked information on some risk factors, such as diet, family history, and socioeconomic status.  And despite the large sample of more than 63,000 H pylori–infected patients, the small number of gastric cancer cases did not allow for any "meaningful evaluation of the dosage effect and role of different PPIs," the researchers say. 

The team also notes that PPIs users may have a higher chance of undergoing endoscopy than non-PPI users, leading to discovery of more gastric cancers due to surveillance bias.

Dr Johnson said there was another study weakness: "Important" demographic variables that are risk factors for gastric cancer — such as  smoking, alcohol use, obesity, diet, and family history — are not accounted for.  

He also made a general observation about PPI-related research: "Most studies showed that any potential effects of PPIs tend to disappear with time and that the most likely explanation for the effects is confounding by indication rather than causality."

Despite these limitations, Dr Leung and colleagues write that, to their knowledge, "this is the first study to demonstrate that long-term PPIs use, even after H. pylori eradication therapy, is still associated with an increased risk of gastric cancer. This is likely related to the profound acid suppression of PPIs that worsens atrophic gastritis, particularly in those patients with established gastric atrophy as a result of chronic H. pylori-induced inflammation."

EDITOR'S NOTE: The story has been updated to included comments from an expert not involved with the study.

The study had no specific funding. Dr Leung has received honorarium for attending advisory board meetings of Takeda and Abbott Laboratories. Dr Johnson has or has had financial ties to Pfizer Inc, which makes a PPI; Epigenomics; WebMD; CRH Medical; and Medtronic.

Gut. Published online October 31, 2017. Abstract

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