Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Esophageal Neoplasms

Stomach Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Stomach Diseases

Esophageal Cancer

Stomach Cancer

All Drugs and Chemicals

Proton Pump Inhibitors

Enzyme Inhibitors

Long-term use of medications, particularly proton pump inhibitors

Proton pump inhibitor

Jesper Lagergren, MD, PhD

This is a population-based case-control study in all 5 Nordic countries from 1994 onwards. All cases with an esophageal or gastric tumor will be compared with 10 times as many population controls, frequency-matched by age, sex, and calendar year, country. This design offers excellent statistical power, length and completeness of follow-up, quality of data on exposures, outcomes and confounders, and control for confounding.

The project will include a specific study entitled "Long-term medication with proton pump inhibitors and risk of gastric cancer", which is summarized here:

Research question: Medication with proton pump inhibitors (PPI) (e.g., omeprazole and esomeprazole) is one of the most common long-term therapies globally, prompted by its high anti-acidic efficacy and good short-term safety profile. Gastric cancer is the 3rd leading cause of cancer-related mortality globally, responsible for 770,000 deaths each year. There are clear biological mechanisms linking long-term PPI-use with an increased risk of gastric cancer. However, existing research has not been able to provide a definite answer to whether long-term PPI-use is associated with an increased risk of gastric cancer. The reasons are that the literature is hampered by too short follow-up time to assess cancer development, and also insufficient statistical power, lack of population-based design and confounding.

With the availability of nationwide complete medication registries in the Nordic countries, the firsts two starting already in 1994 (Denmark and Finland), we can now, by adding registry data from all Nordic countries together, conduct the first study providing a robust and valid answer to this research question.

Overarching aim This project aims to clarify if (and if so to what extent) long-term PPI-therapy influences the risk of developing gastric adenocarcinoma.

For validation reasons, we will also examine how long-term use of histamine-2-receptor blockers (H2RB) influences the risk of developing gastric adenocarcinoma. These analyses will validate that the findings are specific for PPIs. H2RB are used for the same indications as PPIs, but with a different biological mechanism.

Hypothesis We plan to test the hypothesis that long-term use of PPI (but not H2RB) increases the risk of gastric adenocarcinoma.

Prerequisites

This will be the first project with all prerequisites to provide conclusive answers to the hypotheses above, i.e.:

* Long follow-up (up to 28 years)
* Complete follow-up (by virtue of the nationwide complete Nordic registries)
* Population-based design (which rules out biased selection of cases or controls)
* Superior statistical power (all five Nordic countries participate with nationwide data)
* High-quality data on exposures, outcomes and confounders (thanks to well-maintained and complete nationwide Nordic health data registries)
* Control for confounding factors (available for all participants, both cases and controls)

PROJECT DESCRIPTION

Theory and method

Study design We will conduct a nationwide and population-based multi-national case-control study in the five Nordic countries during the total study period from 1994 through 2022, thus allowing up to 28 years of follow-up. The start of the study period will vary between countries depending on when their national drug registries started, i.e. in 1994 (Denmark), 1994 (Finland), 2002 (Iceland), 2004 (Norway) and 2005 (Sweden).

Participants The study will include all adult residents in Sweden, Denmark, Finland, Iceland and Norway with a first gastric adenocarcinoma diagnosed during the study period according to the national cancer registries. The control participants are selected from the general populations of the five countries and frequency-matched for age, sex, calendar year, and country. The index date for matching is the date of gastric adenocarcinoma diagnosis. For each case of gastric cancer, 10 control participants will be included. Because the controls are matched within each country by age and calendar year, the time-window used to ascertain the exposure will be the same in cases and controls. We will have the same detailed information on all study variables in cases and controls.

Exposure The exposure is long-term PPI-use. Two definitions will be used. The first, high PPI-consumption, is defined as \>180 defined daily doses (DDD) of PPI per year during the time from start of the drug registry or entry in the cohort until the index date. The second definition is cumulative exposure to PPI, defined by the total number of DDDs consumption during the time window of exposure. The DDDs are retrieved from the prescribed drug registries. From a Swedish cohort of 8,276,316 adult individuals of the general population that we use for research purposes, 496,579 (6.0%) were exposed to long-term PPI-use (\>180 DDDs).

The comparison exposure is long-term use of an H2RB (\>180 DDDs), measured using the same two definitions described for PPI, i.e., high H2RB consumption and cumulative exposure. DDDs for H2RB are also retrieved from the prescribed drug registries.

Outcome The study outcome will be gastric adenocarcinoma. Adenocarcinoma represents \>95% of all gastric malignancies. We will not assess rare histologies of gastric malignancy because these have different aetiology, including the potential association with PPI-use. We will also conduct separately sub-analyses of cardia adenocarcinoma and non-cardia adenocarcinoma.

Confounders A confounder is by definition associated with both the exposure and the outcome (and is not in the causal pathway between these).29 The main risk factor for gastric adenocarcinoma is 1) Helicobacter pylori-infection, but also other less strong risk factors might also have some confounding effects in this project, i.e., 2) age (as for most cancer types), 3) sex (a majority of patients with gastric adenocarcinoma are men), 4) calendar year (there have been changes in diagnostic ability of gastric adenocarcinoma), 5) country (there are some variations in incidence rates of gastric adenocarcinoma between the Nordic countries), 6) comorbidity (some severe diseases included in the Charlson comorbidity index might increase the risk of gastric adenocarcinoma), 7) long-term medication with aspirin or non-steroidal anti-inflammatory drugs (such medication may decrease the risk of gastric adenocarcinoma) and 8) long-term medication with statins (could also decrease this risk).

All these 8 variables will be controlled for. Age, sex, calendar year, and country will be controlled for by matching. Helicobacter pylori, comorbidity, long-term medication (\>180 defined DDDs per year) with aspirin or non-steroidal anti-inflammatory drugs and statins will be adjusted for using multivariable logistic regression. Regarding Helicobacter pylori, we will use treatment of this infection as a marker of infection, which is the most complete and valid way to assess presence of this infection in the dataset. For comorbidity we will use the most recent version of the well-validated Charlson comorbidity index.30 We have excellent data of both medication variables from the drug registries.

Data sources For each participant, both cases and all controls, we will collect data from the following nationwide registries in all five countries: 1) Prescribed drug registries, 2) cancer registries, 3) patient registries, 4) cause of death registries and 5) registries of the total population. This will allow data on demographic characteristics (age, sex, calendar year, country), use of all relevant medications (including PPI, H2RB, Helicobacter pylori treatment, aspirin or non-steroidal anti-inflammatory drugs and statins with substance, brand name, ATC-code, formulation, package size, amount, dosage and dates for prescription and dispensation), comorbidity (all diagnoses and surgical procedures), and mortality.

Project organisation

Research team Ten people are directly involved in this project. The project originates and is organised from our research group at Karolinska Institutet (KI). The local team includes 7 people: The chief investigator Jesper Lagergren (main applicant), the biostatistician Giola Santoni, the statistician Jacinth Yan, the postdoctoral researcher Cecilia Radkiewicz, the PhD candidate we hope to recruit, and the administrator Giulia Marras. In addition, we have representatives of each of the four non-Swedish countries included in the project, i.e., associate professor My von Euler-Chelpin (Denmark), professor Joonas Kauppila (Finland), associate professor Helgi Birgisson (Iceland) and associate professor Eivind Ness-Jensen (Norway).

The main roles of these team members are outlined here:

1. Jesper Lagergren will lead the work and the team conducting the work, be responsible for the progress of the project, and be supervisor of the postdoc and PhD candidate.
2. Giola Santoni will guide and supervise in the data complex data management and statistical analyses and co-supervise the PhD candidate.
3. Jacinth Yan will conduct complex data management and analyses.
4. Cecilia Radkiewicz will help with the planning and co-supervise the PhD candidate.
5. The PhD candidate will draft the detailed study protocol, do data management and statistical analyses with support of Giola Santoni, and draft the paper.
6. My von Euler-Chelpin is responsible for the Danish data collection.
7. Joonas Kauppila is responsible for the Finnish data collection.
8. Helgi Birgisson is responsible for the Icelandic data collection.
9. Eivind Ness-Jensen is responsible for the Norwegian data collection.
10. Giulia Marras will help organise the collaboration and administer the project.

Data storage and management Because Danish law does not allow their data to leave the country, data will be stored at a safe server at the governmental agency Statistics Denmark, and managed by remote access. Giola Santoni is responsible for the data management and statistical analyses.

Main applicant The main applicant, Jesper Lagergren, will spend approximately 10% of his work-time for this specific project. He is the chief investigator of this multi-national project.

DATA ANALYSIS AND STATISTICS

Design This will be a population-based case-control study with prospectively collected data on all variables for all cases and controls in the five Nordic countries. The data collection is prospective, which avoids recall bias and selection bias. For each case of gastric adenocarcinoma, 10 control participants from the general populations will be recruited. The control participants will be frequency-matched to the cases regarding age, sex, calendar year and country of residence. The additional possible confounders, i.e., Helicobacter pylori, comorbidity and medication with aspirin or non-steroidal anti-inflammatory drugs as well as statins will be adjusted for by modelling.

Statistical analysis Conditional logistic regression will be used to estimate the relative risk of gastric adenocarcinoma comparing long-term PPI-users with non-users, providing odds ratios with 95% confidence intervals. Three models will be applied: 1) A crude model where only the matching variables are controlled for; 2) an adjusted model additionally adjusted for Helicobacter pylori, comorbidity and medication with aspirin or non-steroidal anti-inflammatory drugs as well as statins, and 3) a model with multivariable adjustment for all 8 confounders listed under 'Confounders' above, which will guarantee that these variables are completely adjusted for. We will also do stratified analyses for each of these 8 confounders. In addition, we will assess whether increased length of PPI-use (\>10 years) among long-term users is associated with higher risk estimates, which would argue in favour of causality. Except for conventional confounding, confounding by indication (particularly protopathic bias) is a special threat to the validity of many pharmaco-epidemiological studies. However, long-term PPI-use is not an indication for gastric adenocarcinoma. Thus, this should not be a problem in the present project.

Statistical power One of the advantages of the project is the excellent statistical power, which is due to inclusion of cases from five entire countries, long and complete follow-up and relatively high prevalence of long-term PPI-users. In order to further optimise the power, we include 10 controls per case, after which further controls will not improve power.31 The main analysis will include all approximately 47,000 cases and 470,000 controls, and sub-analyses of non-cardia adenocarcinoma will include 35,300 cases and 353,000 controls, while the sub-analysis of cardia adenocarcinoma will include 11,700 cases and 117,000 controls. The exposure prevalence of long-term PPI-use is 6% (and 2% for H2RB use). The main analysis has 100% power to verity an odds ratio already of 1.10, and we expect a much stronger association. For the analysis of cardia adenocarcinoma, the study has 94% power to verify an odds ratio of 1.15.

Nordic Gastric and Esophageal Tumor Study

This requires approvals from all institutions delivering the data.

Risk of developing gastric adenocarcinoma using logistic regression providing odds ratios

Risk of developing esophageal cancer using logistic regression providing odds ratios

University of Copenhagen

University of Oulu

Norwegian University of Science and Technology

Reykjavik University

Karolinska Institutet

Professor of Surgery

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Diabetes Mellitus

Metabolic Diseases

Glucose Metabolism Disorders

Endocrine System Diseases

The exposure is diabetes morbidity present at study entery

The exposure is diabetes incidence during study follow up

Rachel Dankner, MD MPH

This is a large nationwide population study, with 10 year follow-up, of the effect of diabetes, metabolic control and a large number of glucose-lowering medications, on total and site-specific cancer incidence and survival.

The study is based on electronic medical records from the largest Israeli health maintenance organization in Israel, Clalit Health Services. 2,301,990 insurees age 21 years old or above at study entry, January 2002 will be included. Four study groups will be established according to the prevalence of diabetes and/or cancer on that date: neither diabetes nor cancer; prevalent diabetes but not cancer; prevalent cancer but not diabetes; both diabetes and cancer prevalence. Subjects free of diabetes at study entry will be followed for diabetes incidence, and all four groups will be followed until December 2012 for study outcomes. The cohort data file will be linked to the Israel National Cancer Registry for cancer morbidity.

We will compare, after adjustment, all and site-specific cancer rates between individuals with and without diabetes; and investigate if metabolic control, as indicated by HbA1c and blood glucose levels, is related to cancer risk. Using time-dependent Cox proportionate hazard models, we will then evaluate differences in outcomes that associate with the use of one or a combination of glucose-lowering treatments, while stratifying by those who were already diagnosed with diabetes at study entry, and those diagnosed during follow-up. Data for a large number of potential confounding variables, including BMI, plasma glucose, HbA1c, hormone replacement therapy and comorbidities will help mitigate allocation bias. The accessibility and uniformity of the healthcare provided by Clalit Health Services, as well as data on cancer screening tests, will minimize the risk of surveillance bias.

The study was based on electronic records from the largest health maintenance organization in Israel, Clalit Health Services, which insures and provides healthcare to 55% (3.9 million) of the nation's population. All persons between 21 and 90 years and registered with Clalit on January 1, 2002 (the date of study entry), without a previous history of cancer, were included in a closed cohort that was followed until December 31 2012.

All individuals were followed for cancer incidence, which was ascertained by record linkage to the Israel National Cancer Registry, established in 1960. The registry has benefited since 1982 from a national law mandating registration of cancer, and has greater than 95% coverage of solid tumors, and approximately 85% coverage of hematologic cancers \[34\].

Definitions of diabetes: Incident diabetes was defined as fulfillment of at least one of the following six criteria during 2002-12: (1) diabetes recorded in the Clalit Chronic Disease Registry; (2) a physician's diagnosis of diabetes, and one plasma glucose test \> 125 mg/dL within 12 months; (3) one HbA1c measurement \> 6.5%; (4) 2-hour plasma glucose level during an oral glucose tolerance test ≥ 200 mg/dL; (5) 3 or more purchases of glucose-lowering medication within 12 months; (6) 2 plasma glucose measurements \> 125 mg/dL within 12 months. The date of the earliest defining criterion was considered the date of diagnosis.

Prevalent diabetes was defined as being recorded with diabetes in the Clalit Chronic Disease Registry on study entry, or fulfilling criterion #5 above (information on medication use was available from 1998) before study entry.

Types of cancer: The following cancers were investigated: liver (ICD-O-3 codes C22.0 and C22.1), pancreas (C25.0-C25.9), gallbladder (C23.9-C24.9), endometrium (C54.0-C54.9, C55.9), stomach (C16.0-C16.9), kidney (C64.9, C65.9, C66.9., C68.0-C68.9), benign brain and central nervous system (C70.0-C72.9 with behavior code 0), malignant brain (C70.0-C72.9 with behavior code 3), multiple myeloma (C42.1 with relevant morphology codes), colorectum (C18.0-C21.8), non-Hodgkin lymphoma (C02.4, C09.8. C09.9, C11.1, C14.2, C37.9, C42.2, C77 and all other sites for extra-nodal Non Hodgkin's lymphoma), lung (all: C34.0-C34.9), adenocarcinoma, squamous cell), leukemia (C42.0, C42.1, C42.2 with relevant morphology codes), ovary (C56.9), bladder (C67.0-C67.9), breast (C50.0-C50.9), thyroid (C73.9) and prostate (C61.9). Apart from benign brain tumors, all cancers included in the analysis were coded as invasive (behavior code = 3).

Diabetes, Glucose Control, Glucose Lowering Medications, and Cancer Risk: A 10-year Population-based Historical Cohort

The population will be followed historically for a period of up to 11 years whichever came first, cancer incidence, mortality, age 90, or end of follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nordic Gastric and Esophageal Tumor Study	NCT05688761	Cancer of Stoma... Cancer of the E... Drug Use	Proton pump inh...	18 Years -	Karolinska Institutet
Diabetes, Glucose Control, Glucose Lowering Medications, and Cancer Risk: A 10-year Population-based Historical Cohort	NCT02072902	Diabetes Cancer		21 Years - 90 Years	Sheba Medical Center
Nordic Gastric and Esophageal Tumor Study	NCT05688761	Cancer of Stoma... Cancer of the E... Drug Use	Proton pump inh...	18 Years -	Karolinska Institutet

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Spots Global Cancer Trial Database for medications

Every month we try and update this database with for medications cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for medications cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.