Contrary to concerns that the use of proton pump inhibitors (PPI) may mask symptoms of gastric cancer and hence delay detection, the commonly used medication instead shows a link to an earlier stage of diagnosis and decreased risk for mortality.

“This study did not find any support for the hypothesis that PPI use within 2 years prior to the diagnosis of gastric non-cardia adenocarcinoma delays the diagnosis, which may result in poor oncological outcomes,” reported the authors of research published in the American Journal of Gastroenterology.

“Instead, PPI use was associated with a decreased risk of disease-specific and all-cause 5-year mortality and a decreased risk of presenting with advanced tumor stage at the time of diagnosis,” they wrote.

Representing the fifth most common cause of cancer-related deaths, gastric cancer has a notably high mortality rate, with a key contributing factor including common diagnosis at a later stage, when the disease has advanced.

Some studies have suggested that PPI may also play a role by suppressing the symptoms of gastric cancer, and thereby delaying detection, during treatment for gastric and duodenal ulcers or other gastrointestinal symptoms.

However, in a recent prior study, the authors of the current study reported finding no link between long-term PPI use and gastric cancer in a Nordic population that included 17,232 cases of gastric non-cardia adenocarcinoma.

For the current follow-up cohort study, the researchers, first author Onyinyechi Duru, of Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, and colleagues evaluated data on 21,433 patients with gastric non-cardia adenocarcinoma from five Nordic nations.

Of the patients, 11,697 (54.6%) were non-PPI users in the 2 years prior to their gastric cancer diagnosis, while the remaining 9736 (46.4%) had used PPI, with 26% assessed as light users, defined as having a daily dose of 31-180 mg, and 19.4% assessed as heavy users, defined as a daily dose ≥ 180 mg.

For the primary outcome of 5-year disease-specific mortality, those with heavy as well as light PPI exposure had a lower risk for 5-year disease-specific mortality than non-PPI users (adjusted hazard ratio [HR], 0.90 and 0.87, respectively).

Nearly identical results were observed in the risk for 5-year all-cause mortality, with a decreased risk among heavy PPI users (adjusted HR, 0.89) and light PPI users (adjusted HR, 0.87) vs non-PPI users.

Of note, in both outcomes, the reduced risk for 5-year mortality was confined to the period within 1 year of diagnosis and not observed between 1 and 5 years after diagnosis.

Further analysis showed that heavy PPI use as well as light PPI use were associated with a significantly lower risk of presenting with metastatic disease, with an adjusted odds ratio (OR) of about 0.70 for each, and in a subgroup of patients with localized disease, similar reductions were also observed in terms of the risk for advanced tumor stage (adjusted OR, 0.71) compared with non-PPI users.

Mechanisms?

In speculating on how PPI use could provide the benefits observed, the authors noted possible biological as well as medical management reasons.

“It has been suggested that PPIs may have an antitumor effect on gastric cancer cells mediated via the STAT3/SHP-1 signaling transduction pathway,” they noted.

Such an antitumor effect could explain the presentation of a more localized disease among PPI users, despite the risk of having delayed diagnoses due to symptom masking, implying “a more indolent and less aggressive cancer biology” resulting from PPI use.

Conversely, non-PPI users had a higher likelihood of presenting with metastatic disease, despite sometimes having no or few symptoms from the underlying gastric adenocarcinoma.

Regarding a potential role of medical management, the authors noted that PPI users in the present study had more serious comorbidities, which would have led to more interactions with healthcare providers and chances to be referred to endoscopy.

That theory is supported by a higher percentage of heavy PPI users (86.3%) and light PPI users (83.9%) receiving gastroscopies in the study compared with non-PPI users (78.7%).

Direct Endoscopy Still Essential

Overall, despite the favorable outcomes observed with PPI, the authors underscored the importance of endoscopy when symptoms suggestive of gastric cancer are present.

“It must be stressed that the results of this study must not be used as an argument for recommending PPI use instead of direct endoscopy for patients with symptoms suggestive of gastric cancer,” they wrote.

“Any delays in the diagnosis of this aggressive tumor might indeed lead to worse oncological outcomes.”

Senior author Jesper Lagergren, MD, PhD, of the Karolinska Institutet, told Medscape Medical News that the observation of potential benefits of PPI in gastric cancer “was not what we hypothesized, so not what we expected.”

“But it was still not a major surprise because PPI users had more contacts with healthcare and therefore a higher chance of earlier tumor detection,” he added.

The study’s bottom line ultimately is that “using PPI does not seem to reduce the survival in patients who develop a gastric cancer,” he said.

Further commenting to Medscape Medical News on the findings, Douglas R. Morgan, MD, MPH, director of the Division of Gastroenterology and Hepatology at The University of Alabama at Birmingham, noted that more broadly, “the association between long-term PPI use and gastric cancer incidence and outcomes remains controversial.”

He added that recent research and meta-analyses have suggested that previous gastric cancer incidence studies linking PPI to gastric cancer may indeed have limitations of bias and confounding.

However, “importantly, the [new results] contrast with a growing body of literature that suggests that PPI use after diagnosis and during treatment may negatively affect outcomes,” Morgan noted.

“Overall, the absolute excess risk of gastric cancer risk with PPI use is limited and may be primarily observed in high gastric cancer incidence populations, such as East Asia, after H pylori eradication,” he said.

Therefore, “the [new] findings suggest that in a low incidence region, PPI use may not mask early cancer-related symptoms to delay diagnosis and/or that PPI use may be an indicator of consistent healthcare contact.”

Lagergren had no disclosures to report. Morgan’s disclosures included receiving grant and/or research support from American Molecular Laboratories; Freenome; the National Cancer Institute; Panbela Therapeutics, Inc.; and Thorne Research.