The effect of medications which cause inflammation of the gastro-oesophageal tract on cancer risk: A nested case-control study of routine Scottish data

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In this study of oesophageal and gastric cancer cases and controls in a community-based population, we found little evidence of an association between gastro-oesophageal cancer risk and the use of bisphosphonates, tetracyclines or spironolactone. Although there was some evidence that bisphosphonates increased the risk of oesophageal cancer, there was no obvious dose-response relationship and these increases were largely offset by a reduction in gastric cancer risk.

Strengths and limitations

The main strength of our study lies in the high-quality and nationally representative data on which it is based.³⁶  It is the first study to investigate the effect of tetracycline and spironolactone on gastro-oesophageal cancer risk and has found no evidence of an increased incidence, which is important and reassuring given the large numbers of patients who use these medications often for prolonged periods of time. We used prescribing data collected as part of routine clinical care, in many cases, several years before the onset of oesophageal or gastric cancer which accurately reflects GP prescribing practices and negates the risk of recall bias.  Although a weakness of this approach is that we do not know if patients used their prescribed medications, the main conclusions were similar when restricting our analysis to patients who received multiple repeat prescriptions  (>12) where non-compliance is likely to be less of an issue. Additionally, GP records do not contain data on over-the-counter medications which may have impaired our ability to accurately adjust for aspirin use (due to exposure misclassification).

Our study is observational and hence open to confounding; although we have controlled for several of the key determinants of cancer risk through the matched design and analysis (e.g. age, comorbidities and general practice) some other risk factors, including ethnicity and nutrition, were not available. This could be a particular concern in the bisphosphonate analysis, as patients with osteoporosis may be more likely to report upper gastrointestinal disorders, even prior to bisphosphonate initiation.³⁷ Our analysis is based on GP diagnosed cancer.  Although a recent CPRD study found that over 95% of gastro-oesophageal cancers are captured within GP records³⁸, a higher proportion of oesophageal cancers were recorded in the Scottish Cancer Registry³⁹ than the PCCIUR data, which could suggest some misclassification of cancer site in our study. This potential issue would not affect our primary analysis which combined oesophageal and gastric cancers. Finally, histological data were not available to allow a separate analysis of squamous cell carcinoma and adenocarcinoma, the two most common forms of oesophageal cancer.

Comparisons with other research

To our knowledge, this is the first study to investigate the impact of tetracyclines and spironolactone use on gastro-oesophageal cancer risk.

Several studies have previously examined the effect of bisphosphonates on gastro-oesophageal cancer risk. In agreement with our findings, two UK-based studies which combined the oesophageal and gastric cancer sites together in a single analysis found no significant association^{40, 41} with bisphosphonate use, while another Danish study reported a 37% decrease in risk.⁴² Although a recent meta-analysis reported no significant association between bisphosphonate use and oesophageal cancer risk²⁴, several individual studies have observed an association. For example, one UK-based study reported a 30% increased risk of oesophageal cancer among bisphosphonate users, which was similar to the 34% effect size estimated in our study.^{43, 44} Our finding of reduced gastric cancer incidence among bisphosphonate users was replicated by several other studies^43-45, including one which found a 39% reduction in the risk of gastric cancer⁴², although a recent meta-analysis reported no overall effect.²⁴ Several studies investigating the effect of bisphosphonate use on cancer incidence, separately for both the oesophageal and gastric sites, reported a similar pattern to our study (i.e. increased risk of oesophageal cancer which was largely offset by a decreased risk of gastric cancer).^43-45

Implications

Bisphosphonate, tetracycline and spironolactone are widely used and effective treatments for a range of indications including osteoporosis, infections/acne/rosacea and hypertension/cardiac failure respectively. Our study suggests that any inflammation caused by these medications does not substantially increase the risk of gastro-oesophageal cancer, and GPs or patients should not be unduly concerned about cancer risk when prescribing or taking these treatments.

It is unclear why bisphosphonate users had an increased risk of oesophageal cancer in our study. Firstly, these results could represent a true causal association; bisphosphonates are well known to cause dyspepsia and other inflammatory changes (e.g. oesophagitis, mucosal abnormalities)⁴⁶ which could form an important part of the upper-gastrointestinal cancer pathway.³⁰ Perhaps more likely, particularly given our concurrent finding of lower gastric cancer risk among bisphosphonate users, is that these associations are at least partly driven by a form of ascertainment bias. One Danish study reported that, due to higher rates of gastrointestinal side effects, patients receiving bisphosphonates were more than twice as likely to undergo upper endoscopy (4.1% vs. 1.7%).⁴² This could lead to earlier detection of oesophageal cancer and more accurate classification of some oesophageal tumours proximal to the oesophagogastric junction in bisphosphonate users, which would have otherwise been incorrectly recorded as gastric in origin.⁴²