The results of this study indicate that use of H2 blockers and PPIs are both markers of an increased risk of oesophageal and gastric adenocarcinoma. However, the increased risk of oesophageal adenocarcinoma and gastric non‐cardia adenocarcinoma among persons on long term gastric acid suppressive drugs were highly driven by the indications of acid suppressing treatment. Thus the observed associations could be entirely due to the underlying indication being an independent risk factor of the specified cancer rather than to a harmful effect of the agents per se.
Some methodological considerations should be highlighted. Advantages of our design include the prospectively collected exposure and comorbidity data and the comparatively large sample size. Prospective recording ensures that the information is not affected by the occurrence of cancer. This provides exposure information free of recall bias among both cases and controls, a major concern in case control studies that are inherently dependent on retrospective exposure data collected by personal interviews or in patient administered questionnaires after the cancer diagnosis has been confirmed. The large sample size reduces chance errors and provides an opportunity to study subgroups of interest. Nevertheless, statistical power was limited in some of our subanalyses, in particular when examining associations with gastric cardia adenocarcinoma. The recordings in the database are based on the GPs' routine medical care with a certain amount of missing values and misclassification. Such missing data could be differential (that is, differ between cases and controls) regarding some potential confounders. However, we found that missing values were evenly distributed between cases and controls. Furthermore, missing values were included in the analyses as a separate category of each exposure variable, and this category was not associated with any extreme estimate of risk (data not shown). Any remaining exposure misclassification should be non‐differential and could, at the most, slightly dilute the risk estimates.
Another potential source of error is case ascertainment and tumour classification. Validation studies of the GPRD have found that over 90% of all referrals are entered into the GP's computer with a diagnosis code that truly reflects the specialist's diagnosis.31
Furthermore, our manual review of all computer detected cases together with review of additional information provided by the GPs in a large sample of cases should have acted against major tumour misclassification. Notwithstanding, there remained a considerable number of missing histology classifications in oesophageal cancer and missing subsite classifications in gastric cancer. However, patients with unknown histology or unknown subsite were not found to be associated with any extreme relative risk estimates, indicating that they represent a proportional mix of the categorised oesophageal histology and gastric subsite, respectively.
Another source of error was that the GPRD does not contain adequate information regarding some potential risk factors, including dietary habits, socioeconomic factors, or heredity. However, it is unlikely that any of these factors could explain our results as they will most likely be equally distributed between users and non‐users of acid suppressing drugs. If this is true, they would not act as confounding variables in our study. Also, no information on Helicobacter pylori
status was available. On the other hand, we had access to data regarding several other and possibly more important variables, including clinical upper gastrointestinal disorders. Another limitation is that the computerised database started in the late 1980s and therefore lacks information before that period. The average treatment duration among users of three years and more was 1838 days (that is, slightly more than five years) and only two patients had a registered duration of 10 years or longer. Thus we did not have sufficient recorded information on the risk associated with very long durations (for example, greater than five years). Finally, we were unable to capture exposure to over the counter acid suppressing drugs but the impact of this possible error has been reported to be negligible, especially when the exposure of interest is long term use.34
In line with most previous findings, our results confirm that gastro‐oesophageal reflux symptoms, hiatal hernia, and oesophagitis increase the risk of adenocarcinoma of the oesophagus, and to a lesser degree of the gastric cardia.7,8,9,11,35
Hopes have been raised that reduction of gastric acid in the oesophagus, either by antireflux surgical procedure or pharmacological treatment, could reduce the risk of developing oesophageal adenocarcinoma. To date, no strong evidence of a protective effect of antireflux surgery10
or antireflux pharmacotherapy7,8,9
against oesophageal adenocarcinoma can be found however, and our study does not provide any evidence in favour of a protective effect. Our finding of increased risks of oesophageal adenocarcinoma among long term users of acid suppressing drugs is in agreement with the literature, although to our knowledge no previous prospective study has examined the association between use of PPIs and risk of oesophageal and gastric adenocarcinoma. The association was limited to current long term users, which should take care of protopathic bias (that is, an as yet undiagnosed cancer prompting the need for acid suppression).
Three case control studies7,9,28
and one cohort study22
have shown that treatment with H2
blockers is associated with an increased risk of oesophageal adenocarcinoma. However, after adjustment for GORD, no increased risk remained in the study by Chow and colleagues.7
A potential limitation of some of these studies was their inability to adjust for confounding by indication (that is, the inability to distinguish the effect of H2
blockers on cancer risk from the effect of the conditions for which they were prescribed). The fact that gastro‐oesophageal reflux is the strongest independent risk factor of oesophageal adenocarcinoma8
and at the same time one of the most common indications for long term acid suppression, could fully explain the reported associations. Indeed, we had access to valid prospectively recorded information on the indication for acid suppression, giving us the possibility of assessing separately different indications for long term use of H2
blockers and PPIs. Our findings clearly indicated that the increased risk of oesophageal adenocarcinoma was much more dependent on the specific indication for acid suppressing treatment rather than on the treatment per se.
We found that a history of gastric ulcer was associated with an increased risk of gastric adenocarcinoma but not with adenocarcinoma of the oesophagus, results in line with previous findings.12,14,15,16,17,18
The relation found between duodenal ulcer and gastric adenocarcinoma is, however, in conflict with previous findings14,15,17
: this could be due to the limited number of cases or some misclassification of ulcer site. Peptic ulcer is also a common reason for using acid suppressive drugs. Concerns have been raised that reduction of gastric acidity could increase the risk of gastric cancer,21,23,24
possibly along the carcinogenic sequence suggested by Correa,36
(that is, via inducing atrophic gastritis19
and intestinal metaplasia to dysplasia and carcinoma). Acid suppression has been shown to increase the rate of progression of H pylori
gastritis to multifocal atrophic gastritis,19
and to induce hypergastrinaemia, which has trophic effects on gastric mucosa.20,23,37
Clinical studies evaluating the effects of long term use of acid suppressive therapy have, however, reported lack of progressive changes (that is, dysplasia and neoplasia) in the gastric mucosal histology.38,39
Several observational studies have addressed the risk of gastric cancer among users of H2
and found a positive association which, however, was compelled within the first years of use, arguing against a causal association. We found that users of both H2
blockers and PPIs were at an increased risk of gastric adenocarcinoma. When combining the use of either H2
blockers or PPIs, the risk estimates of gastric cardia adenocarcinoma were mainly limited to short term users while the risk of gastric non‐cardia adenocarcinoma remained elevated for long term users also, arguing against protopathic bias as an explanation for the latter relationship.
Our review revealed that the treatment indication of peptic ulcer disease was clearly associated with an increased risk of gastric non‐cardia adenocarcinoma among long term users of acid suppressing drugs. Furthermore, peptic ulcer disease constituted 55% (11/20) of all long term indications for acid suppression among patients that subsequently developed gastric non‐cardia adenocarcinoma, while the corresponding percentage was 22% (76/343) among controls. As shown in table 5, numbers were too small to validly report the association by ulcer site. Patients treated long term with acid suppressing drugs for other reasons (that is, gastro‐oesophageal reflux or dyspeptic symptoms) were not associated with an increased risk of gastric non‐cardia adenocarcinoma. There are, in theory, two different explanations for the relationship: (1) confounding by indication (that is, acid suppressing drugs were prescribed mainly to treat risk factors for gastric non‐cardia adenocarcinoma, for example, gastric ulcer), and (2) acid suppressing drugs are harmful and lead to an increased risk of gastric non‐cardia adenocarcinoma, but mainly confined to patients treated for peptic ulcer disease. Our study could not prove which explanation was true even though confounding by indication seems the most plausible.
In conclusion, this large population based observational study revealed that long term use of gastric acid suppressing drugs is a marker of an increased risk of adenocarcinoma of the oesophagus, gastric cardia, and non‐cardia. However, the association with these three types of upper gastrointestinal adenocarcinoma were strongly dependent on specific treatment indications that at the same time are known major risk factors for the respective adenocarcinoma. Even though we cannot with certainty exclude the possibility that very long treatment durations with these drugs could increase per se the risk of one of these adenocarcinomas, our results are most compatible with the hypothesis that confounding by indication is the “mechanism” responsible for the observed associations.