Abstract
Background: Proton pump inhibitors (PPIs) are widely prescribed for gastric acid-related conditions, but concerns have emerged regarding their long-term safety, particularly their potential association with gastrointestinal (GI) cancer. While previous studies have focused on selected GI cancer sites, none have examined the impact of PPI dose and duration across the entire GI tract. This doctoral research addressed this gap by investigating the association between the site of GI cancer and prior history of PPI dispensing in New Zealand from 2009 to 2019.
Method: This retrospective population-based study utilised three national datasets: the New Zealand Cancer Registry (NZCR), Mortality Collection (MORT), and Pharmaceutical Collection (Pharms). Individuals diagnosed with GI cancers (ICD-10-AM codes C15–C26) between the 1st of January 2009 and the 31st of December 2019 were identified from the NZCR. Demographic and mortality (all-cause and GI cancer-specific causes) data were summarised. Age-standardised incidence and mortality rates were calculated by sex, ethnicity, and New Zealand deprivation index (NZDep index). The PPI dispensing history for each individual prior to GI cancer diagnosis was obtained from the Pharms database. PPI exposure variables, dispensing duration, cumulative defined daily dose (DDD), and normative dose, were analysed among those with continuous PPI dispensing, excluding the intermittent PPI group. Multinomial logistic regression was used to assess the association between prior history of PPI dispensing and the site of GI cancer. Models were adjusted for age, sex, ethnicity, NZDep index, and follow-up time. Adjusted odds ratios were calculated to estimate the odds of being diagnosed with each GI cancer site, relative to colorectal cancer, among individuals with prior PPI exposure compared to those without.
Results: Between 2009 and 2019, 55,611 individuals were diagnosed with GI cancer in New Zealand, with 56.8% dying during the study period. Over two-thirds were aged ≥65 years at diagnosis, and mortality was higher in males. Māori and Pacific peoples had the highest percentage of all-cause and GI cancer-specific mortality (Māori: all-cause: 64.9%; GI cancer-specific: 56.2%; Pacific peoples: all-cause: 59.4% and GI cancer-specific: 52.9%). Age-standardised analysis showed a rise in the small intestinal cancer incidence rate (3% annually in males, 4% in females), while the overall GI cancer mortality rate declined in both sexes (p<0.05). Colorectal cancer was the most frequently diagnosed GI cancer and the leading cause of GI cancer-related mortality in New Zealand, with Europeans showing the highest incidence and mortality rates. Māori and Pacific populations had the highest incidence and mortality rates for stomach and liver/gallbladder/biliary tract cancers. The GI cancer burden was greatest in the most deprived populations.
Among those with GI cancer, 59.0% had a history of prior PPI dispensing. Of these, 85.5% had been continuously dispensed PPIs over the study period, with more than half receiving them for over one year, and 30.5% dispensed high daily doses (≥1.50 DDD/day). Compared to the non-PPI group, the PPI group had higher odds of being diagnosed with cancers at sites above the colorectum, including the oesophagus, stomach, small intestine, liver/biliary tract/gallbladder, pancreas, and ill-defined organs, relative to colorectal cancer. Among these, the strongest associations were observed for cancers at the oesophagus, stomach, and small intestine. In contrast, no association was identified for cancers occurring below the colorectum. These associations were dose- and duration-dependent, and sensitivity analyses excluding the intermittent PPI group supported the findings.
Conclusion: This study offers the first nationwide analysis of PPI exposure across all GI cancer sites. The results show that many individuals had been dispensed PPIs for extended periods prior to their initial GI cancer diagnosis. Stronger associations with PPI exposure were observed for cancers located above the colorectum, particularly oesophageal, stomach, and small intestinal cancers, highlighting clear site-specific variations in GI cancer diagnoses between the PPI and non-PPI groups. The site-specific nature of these findings is consistent with the pharmacological action of PPIs, which primarily act on the upper GI tract, thereby supporting the biological plausibility of a site-dependent adverse effect.
These findings highlight the need for greater awareness among both clinicians and patients about the potential impact of long-term PPI use on cancer diagnoses across GI sites, to support more cautious and informed prescribing. Clinicians should ensure that PPI prescriptions are regularly reviewed and limited to the lowest effective dose and shortest appropriate duration. The study also reveals ethnic and socioeconomic disparities in GI cancer in New Zealand, underlining the importance of ongoing public health efforts and equitable access to preventive care across all communities.