This first study on the topic indicates that discontinuing long-term PPI therapy is associated with a decreased risk of gastric adenocarcinoma and oesophageal adenocarcinoma, and not of oesophageal squamous cell carcinoma.

Strengths of the study include the population-based design and large sample size, where virtually all long-term users of prescribed and dispensed PPIs in Sweden were included, which counteracted selection bias and improved statistical power. Defining drug use as dispensations from a registry rather than by questionnaire had the advantages of prospective data collection, thus avoiding misclassification due to issues of recalling, and actual dispensing (and paying for) the prescribed medication, which reduced non-compliance. The use of nationwide complete registries ensured long and complete follow-up for all endpoints. Including oesophageal squamous cell carcinoma as a control outcome with no association with PPI use facilitated the interpretation, and the lack of association between discontinuation of long-term PPI use and this cancer supported the validity of the findings for gastric and oesophageal adenocarcinoma.

Using PPI as a time-varying covariate and the use of 1 year latency minimized the risk of immortal time and latency bias [17]. Causality can rarely be claimed in observational studies examining the effect of PPI on oesophageal and gastric adenocarcinoma, but several measures were attempted to avoid bias from confounding and other sources. First, only long-term users of PPI were included in the cohort, thus avoiding short-term users. Second, contrasting studies assessing the influence of PPI use on the risk of developing these tumors, the results were adjusted for NSAID, aspirin, and statin therapy. This could otherwise be a major concern because these medications are often prescribed alongside long-term PPI therapy and may decrease the risks of these tumors, which was the case of NSAID/aspirin in this study [19, 20]. Third, the adjustment for the key confounding variables age, sex, Charlson Comorbidity Index, obesity, diabetes and hyperlipidaemia, tobacco smoking, Barrett’s esophagus, anti-reflux surgery, or Helicobacter pylori eradication therapy ensured that virtually all known confounders were accounted for.

Other weaknesses of the study include the inability to accurately examine duration and cumulative dosage of PPI use, given the methodological pitfalls and the risk of introducing immortal time using this approach in cohort studies [21]. The inability to assess over-the-counter prescriptions of PPIs should not be a major problem in this study, because PPIs are available over-the-counter only at low doses (< 1 DDD), small packages (maximum 28 tablets), and at a significantly higher cost compared to prescribed PPIs in Sweden. Thus, the vast majority of patients on long-term PPI therapy have prescriptions. Nevertheless, it is not possible to exclude that some participants classified as discontinuers in fact were on small amounts of PPI bought without prescription. We also acknowledge that a supposed higher volume of endoscopies among patients remaining on PPI may lead to earlier detection of oesophageal and gastric cancer, which could lead to a slight overestimation of the incidence among these patients compared to those who stopped using PPI.

The decreased risk of gastric adenocarcinoma following discontinuation of long-term PPI use was hypothesized and also observed in the main analysis. Among the exclusion variables, the main risk factor for gastric adenocarcinoma is Helicobacter pylori infection, while smoking is a weak risk factor, and Barrett’s esophagus and anti-reflux surgery are not associated with this tumor. Helicobacter pylori or its treatment is not an indication for long-term PPI use and should therefore not be a major confounder for the association between PPI discontinuation and risk of gastric adenocarcinoma, although some patients with gastroduodenal ulcers may be prescribed PPI indefinitely. Nevertheless, after excluding participants with Helicobacter pylori eradication therapy and tobacco smoking-related disorders in a sensitivity analysis, the association was attenuated to null for gastric adenocarcinoma. Although this sensitivity analysis had low power, the association should be interpreted with some caution.

Several previous studies have indicated a strong association between PPI use and gastric adenocarcinoma. In this study, we found an incidence of gastric adenocarcinoma in patients remaining PPI in parity with the incidence in the Swedish general population (of which approximately 6% use PPI), but the risk was slightly lower in patients discontinuing PPI [22]. A meta-analysis of observational studies found that long-term PPI therapy was associated with a 43% increased risk of gastric cancer (odds ratio 1.43, 95% CI 1.23–1.66) [4]. Two more recent and large cohort studies have provided further evidence of an increased risk of gastric cancer among long-term users of PPIs. A cohort study from Hong Kong among 63,397 Helicobacter pylori-eradicated participants, found that long-term use of PPIs was associated with an over twofold increased risk of gastric cancer (hazard ratio 2.44, 95% CI 1.42–4.20) [23]. A Swedish cohort study identified a threefold increased risk of gastric cancer among 797,067 individuals on maintenance PPI therapy compared to the corresponding general population (standardized incidence ratio 3.38, 95% CI 3.23–3.53), and the association remained in participants who used PPIs for indications without any association with gastric cancer, e.g., GERD (standardized incidence ratio 3.04, 95% CI 2.80–3.31) [24]. The lower effect sizes observed in the present study compared to studies assessing the association between PPI use and gastric and oesophageal adenocarcinoma may indicate better control of methodological issues such as confounding and time-related biases in this study.

Some mechanisms can explain a potentially decreased risk of gastric adenocarcinoma after discontinuation of long-term PPI therapy. First, discontinuation can normalize the elevated gastrin levels associated with long-term PPI use [25, 26], which in turn can counteract parietal cell hyperplasia and polyposis [27, 28]. Second, atrophic gastritis caused by Helicobacter pylori can progress in PPI users and promote carcinogenesis, which could be counteracted by PPI discontinuation [29,30,31]. This mechanism is supported by the lack of association between PPI discontinuation and gastric adenocarcinoma when participants with a history of Helicobacter pylori were excluded in the present study. While Helicobacter pylori eradication therapy decreases the risk of gastric adenocarcinoma, it should be noted that atrophic gastritis represents a late stage and may still progress to intestinal metaplasia following eradication therapy [32, 33].

Similar to the results of gastric adenocarcinoma, the risk of oesophageal adenocarcinoma was decreased in this study. However, the study population represented a group at clearly higher risk of oesophageal adenocarcinoma compared to the corresponding Swedish general population [22], likely due to a higher prevalence of gastroesophageal reflux disease. While the incidence was higher in patients remaining on PPI, both women and men discounting PPI retained an increased risk of oesophageal adenocarcinoma compared to the general Swedish population. Decreased point estimates in the sensitivity analysis and almost all subgroups of participants further support the finding that the risk of oesophageal adenocarcinoma is decreased after stopping long-term PPI therapy. The literature examining the role of PPI use in the etiology of oesophageal adenocarcinoma has provided conflicting results. Three large observational studies have suggested increased risks of oesophageal adenocarcinoma among long-term PPI users but the results have been met with skepticism because of the risk of confounding by indication [6, 8, 34]. In patients with Barrett’s esophagus, a randomized clinical trial (AspECT) with low statistical power found no difference in risk of oesophageal adenocarcinoma comparing high-dose with low-dose PPI [35], and a meta-analysis indicated a decreased risk of oesophageal adenocarcinoma among PPI users [36]. A biological mechanism that can explain the finding of a risk reduction of oesophageal adenocarcinoma after discontinuation of PPI therapy is normalization of the elevated gastrin levels associated with long-term PPI use [25, 26]. Gastrin upregulates oesophageal expression of the pro-inflammatory enzyme COX-2, which is considered a promotor of oesophageal adenocarcinoma development. Thus, normalized gastrin levels may counteract COX-2 activity and decrease oesophageal adenocarcinoma risk, explaining why PPI discontinuation could prevent this tumor [37,38,39].

Other substances present in the refluxate among patients with GERD, particularly bile acids, have been proposed as causative of oesophageal adenocarcinoma. Biliary reflux may be a cause of refractory GERD not responding well to PPI therapy, and most patients with GERD also have pathologically increased biliary reflux [40]. These acids may contribute to oesophageal adenocarcinoma development by inducing oesophageal squamous cells to differentiate to intestinal-like cells and promoting inflammation through activation of nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) [40, 41]. Animal models have demonstrated that oesophageal exposure to reflux of bile acids results in Barrett’s esophagus and subsequent adenocarcinoma [42, 43]. Gastric juices have been shown to be even dose-dependently protective against oesophageal adenocarcinoma in rats with biliary reflux [43]. Consequently, some of the increased risk of oesophageal adenocarcinoma in patients continuing PPI may be attributed to increased toxicity of bile acids in the absence of gastric acid.

The possible risk reduction of oesophageal and gastric adenocarcinoma in individuals discontinuing long-term PPI observed in this study are not indiscriminately generalized to all patients on long-term PPI therapy. PPIs are well tolerated by most patients and usually offer effective symptom relief for GERD and is essential in the prevention of upper gastrointestinal bleeding among patients on anticoagulants. In these settings, the benefits of long-term PPI will outweigh any increase in relative risk of gastric and oesophageal adenocarcinoma. Nevertheless, this study may still have clinical implications for many individuals. Long-term PPI therapy is exceedingly common and has further increased in recent years, and is often used for off-label indications [2]. The findings from this study should encourage physicians to consider stopping long-term PPI therapy in the absence of a clear indication for its use. Yet, given that this is the first study directly assessing how discontinuation of PPI use influences cancer risk, the findings need to be confirmed in future research.

In conclusion, this large population-based cohort study indicates that discontinuation of long-term PPI therapy is associated with a decreased risk of both gastric adenocarcinoma and oesophageal adenocarcinoma, although residual confounding cannot be excluded. In the absence of a clear indication for long-term PPI therapy, the need for PPI therapy should be reconsidered to avoid unnecessary cases of gastric and oesophageal adenocarcinoma.