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Risk of Esophageal Adenocarcinoma After Helicobacter pylori Eradication Treatment
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND & AIMS
Helicobacter pylori infection is associated with a decreased risk of esophageal adenocarcinoma, and the declining prevalence of such infection might contribute to the rising incidence of this tumor. We examined the hypothesis that eradication treatment of Helicobacter pylori increases the risk of esophageal adenocarcinoma.
METHODS
This population-based multinational cohort, entitled the "Nordic Helicobacter Pylori Eradication Project (NordHePEP)", included all adults (≥18 years) receiving Helicobacter pylori eradication treatment from 1995-2018 in any of the five Nordic countries (Denmark, Finland, Iceland, Norway, Sweden) with follow-up throughout 2019. Data came from national registers. We calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) by dividing the cancer incidence in the exposed cohort by that of the entire Nordic background populations of the corresponding age, sex, calendar period, and country. Analyses were stratified by factors associated with esophageal adenocarcinoma, i.e., education, comorbidity, gastroesophageal reflux, and certain medications.
RESULTS
Among 661,987 participants who contributed 5,495,552 person-years after eradication treatment (median follow-up 7.8 years, range 1-24 years), 550 cases of esophageal adenocarcinoma developed. The overall SIR of esophageal adenocarcinoma was not increased (SIR=0.89, 95% CI 0.82-0.97). The SIR did not increase over time after eradication treatment, but rather decreased and was 0.73 (95% CI 0.61-0.86) 11-24 years after treatment. There were no major differences in the stratified analyses. The overall SIR of esophageal squamous cell carcinoma, calculated for comparison, showed no association (SIR=0.99, 95% CI 0.89-1.11).
CONCLUSION
This absence on an increased risk of esophageal adenocarcinoma after eradication treatment of Helicobacter pylori suggests eradication is safe from a cancer perspective.
Additional Info
Disclosure statements are available on the authors' profiles:
Risk of esophageal adenocarcinoma after Helicobacter pylori eradication treatment in a population-based multinational cohort study
Gastroenterology 2024 Mar 19;[EPub Ahead of Print], AK Wiklund, G Santoni, J Yan, C Radkiewicz, S Xie, H Birgisson, E Ness-Jensen, M von Euler-Chelpin, JH Kauppila, J LagergrenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Helicobacter pylori infection and the ensuing gastric inflammatory response are inversely related to both premalignant (Barrett’s esophagus)1 and malignant (adenocarcinoma) lesions in the esophagus.2 Given this organism’s ability to suppress gastric acid production and, thus, conceivably provide a protective effect against esophageal adenocarcinoma, could a strategy to test and treat H pylori for other indications lead to a subsequent increased incidence of this malignancy?
Wiklund et al provide key insights to the potential answer. In their multinational population-based cohort study involving 661,987 patients with a median follow-up duration of 7.8 years after eradication and almost 5.5 million person-years of study, they found an unexpected and intriguing result. Based on a total of 550 cases of esophageal adenocarcinoma, the standardized incidence ratio (SIR) of observed cases among persons receiving anti–H pylori therapy to expected cases (derived from contextualized incidence in the entire Nordic population) was not increased (SIR, 0.89; 95% CI, 0.82–0.97). Moreover, the incidence ratio decreased over time with the strongest decrease seen at the longest interval follow-up duration of 11–24 years after treatment (SIR, 0.73; 95% CI, 0.61–0.86). Subsequent subgroup analyses showed that the SIR increased in two specific categories: patients with gastroesophageal reflux disease (GERD; defined as having heartburn, hiatal hernia, esophagitis, or Barrett’s esophagus) and those with long-term use of proton pump inhibitors. Notably, in these subgroups, the increased SIR was only statistically significant within the 1- to 5-year follow-up cohort, with subsequent groups (eg, 6- to 10- and 11- to 24-year follow-up) showing no statistically significant increase in risk.
An obvious strength of this study is its size in combination with the depth of data obtained (eg, follow-up and contextualized incidence based on calendar period, country, sex, age, and defined risk factors including amount of education, comorbidity, GERD, and medication use). At the same time, these results are limited to Nordic countries, which harbor lower H pylori infection rates. It is also important to note that these results are grounded on an assumption of successful eradication based on prescribed treatment rather than lab-proven eradication. However, even with these limitations, this study provides sufficient data to challenge the hypothesis that H pylori eradication increases risk of esophageal adenocarcinoma over time, suggesting that treatment of H pylori is safe within the context of developing this malignancy. Importantly, it also provides a framework for further studies on this issue, particularly in populations with higher incidences of H pylori infection (eg, Central/South America and Asia) and patients with complications of GERD such as Barrett’s esophagus and chronic PPI use, as well as for defining the importance of strain-specific virulence constituents (eg, cagA-positive H pylori strains).3
References
Prior to the discovery of Helicobacter pylori, upper gastrointestinal diseases were dominated by gastric cancer and peptic ulcer disease. At that time, gastroesophageal reflux disease (GERD) was largely submerged in dyspepsia and “sour stomach.” Cure of H pylori resulted in a return of the regulation of acid secretion to normal. It was postulated that a general improvement in acid secretion and eradication of the H pylori–related immune response would also eliminate hypothesized H pylori–related protections against childhood allergy/asthma, obesity, GERD, Barrett’s esophagus, and esophageal adenocarcinoma. This paper addressed whether eradication of H pylori was associated with an increased risk of esophageal adenocarcinoma.
The study was a retrospective, multinational, population-based Nordic cohort study of all individuals older than 18 years who received H pylori eradication treatment consisting of a minimum 7-day regimen with a proton pump inhibitor plus at least two of the following: amoxicillin, clarithromycin, or metronidazole. The authors followed these patients for a median duration of 7.8 years for the development of esophageal cancer after eradication treatment and examined the standardized incidence ratio (SIR) and 95% confidence intervals (CI) among the exposed cohort compared with the expected number of cases in the general Nordic population. The overall SIR of esophageal adenocarcinoma was not increased after H pylori treatment compared with the general population (SIR, 0.89; 95% CI, 0.82–0.97). This remained true even with stratification for education, Charlson comorbidity index score, and use of nonsteroidal anti-inflammatory drugs and statins. Further, the SIR decreased with longer follow-up durations after eradication (11–24 years: SIR, 0.73; 95% CI, 0.61–0.86). As expected, the SIR was increased in those with GERD (SIR, 1.47; 95% CI, 1.16–1.83) and long-term proton pump inhibitor use (SIR, 1.61; 95% CI, 1.29–2.00).
The concern regarding whether eradication of H pylori infection would increase the incidence of esophageal adenocarcinoma can now be stamped as “disproven.” The postulated benefits attributed to H pylori infection include protection against Barrett’s esophagus, obesity, allergy-related diseases (eg, eosinophilic esophagitis and childhood asthma) and immune-related diseases (eg, inflammatory bowel disease). To date, none of the putative associations has been confirmed. We conclude that one should not defer H pylori eradication treatment because the proven deleterious effects of infection (gastric atrophy, morbid peptic ulcer disease, and gastric cancer) outweigh the potential postulated, and likely false, benefits.