Proton pump inhibitors and upper gastrointestinal cancers

Abstract

Proton pump inhibitors (PPIs) were introduced in the 1980s. They are now one of the most commonly prescribed drugs in general practice. They are cost-effective when used correctly; however, PPIs are often used beyond accepted clinical indications. Recent published studies performed outside the UK have suggested that adverse effects are associated with long-term use of PPIs; in particular, an increased risk of gastric cancer. This article will aim to systematically assess the evidence and discuss its application to our clinical practice.

The GP curriculum and proton pump inhibitors in upper gastrointestinal cancers

Clinical module 2.01: The GP consultation in practice requires GPs to:

Understand the principles of evidence-based practice and how you can apply these principles, given the condition of the patient and the healthcare system

Clinical module 3.12: Digestive health requires GPs to:

Understand the epidemiology of gastrointestinal symptoms and disorders in primary care, and the evidence on the risks for cancer and other serious diseases

Use an evidence-based approach to management and prescribing for common symptoms such as dyspepsia

Modify the form of modalities of treatment to cater for patient’s gastrointestinal function and preferences

Understanding the basics

Proton pump inhibitors and the role of gastrin

Proton pump inhibitors (PPIs) act by blocking the H, K-ATPase channel of the gastric parietal cells, which are responsible for acid transport. Gastrin is an important digestive hormone that is released by G cells in the antrum, stimulating gastric acid secretion. Hypergastrinemia refers to abnormal levels of gastrin, which can be due to several disease states including Zollinger Ellison syndrome and Helicobacter pylori infection. Acid suppression therapy causes an increase in gastrin production through negative feedback. Gastrin may be involved in the neoplastic process, due to induced hypergastrinemia, gastric atrophy and bacterial overgrowth in the stomach. The true implications of hypergastrinemia are still being evaluated and is an area attracting research interest (Dacha et al., 2015).

The PPIs licensed in the UK include lansoprazole, omeprazole, pantoprazole, rabeprazole and esomeprazole. The National Institute for Health and Care Excellence (NICE) does not suggest that any single PPI is superior to any of the others.

The economic impact of PPIs is significant. Over £100 000 000 is spent annually on PPIs in England. If prescribing was reduced by one third, this would save the NHS £35 000 000 over 12 months.

The clinical indications for PPIs include oesophagitis, peptic ulcer disease, Barrett’s oesophagus, non-steroidal anti-inflammatory drugs (NSAIDs), steroid gastroprotection, Zollinger Ellison syndrome, and the treatment of H.pylori infection.

PPIs are often well tolerated; the common side effects include abdominal pain, constipation, diarrhoea, dizziness, rash, and headaches. However, recently there has been a move to increase awareness of the adverse effects of long-term use of PPIs.

PPIs significantly reduce acid secretion and work to heal ulceration and promote healing. However, data suggests long-term acid suppression can lead to gastric atrophy, atrophic gastritis, and intestinal metaplasia. These conditions can all increase the risk of gastric cancers (Kuipers, 2006).

PPIs and their role in gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GORD) is defined as a chronic condition caused by reflux of gastric contents into the oesophagus, or in some cases affecting the oropharynx or respiratory tract. Symptoms include those typical of ‘dyspepsia’ such as upper abdominal pain, nausea or vomiting, heartburn, and acid reflux, lasting more than 4 weeks.

GORD can be classified into endoscopy positive (findings of oesophagitis or erosions) or endoscopy negative (reflux symptoms with normal endoscopy findings). Approximately a quarter of patients with GORD will develop Barrett’s oesophagus, and between 1 and 10% of this subgroup will go on to develop oesophageal adenocarcinoma over the next one to two decades.

Eighty-per cent of people with GORD will experience reoccurrence of their symptoms. That said, it is essential to offer patients strategies to self-manage. Initial management should address modifiable risk factors and lifestyle advice prior to initiation of pharmacological treatment. More specific advice is outlined in Box 1.

Box 1.

Management of reflux disease.

• Avoid and address factors associated with dyspepsia (coffee, chocolate, alcohol, spicy foods, fatty foods, stress, obesity)

• Smoking cessation

• Eat smaller more frequent meals

• Consider eating a last meal 3 to 4 hours before bedtime or raising the end of the bed

• Consider reducing or stopping medications that may be exacerbating symptoms (calcium channel blockers, alpha blockers, bisphosphonates, corticosteroids, nitrates, theophyllines, antidepressants)

• Suspend NSAIDs or aspirin where possible (risk outweighs benefits)

• Testing for H.pylori (ensure 2-week washout period after using PPI)

• Take PPIs 15–30 minutes before the first meal of the day

• When prescribing PPIs, aim for the shortest duration and the lowest dose

• Consider rebound hypersecretion syndrome when discontinuing PPIs, you may advise 2–4 weeks of alginate or antacid therapy to prevent rebound symptoms

Adapted from NICE (2014).

In dyspepsia, a 4-week trial of PPI is recommended. In GORD a 4-week trial is appropriate, but if there is proven oesophagitis on endoscopy, an 8-week trial is recommended. A Histamine Receptor Antagonist (H2RA) such as ranitidine may be offered if the response to PPI is inadequate.

In those with alarm symptoms, do not initiate PPIs; rather refer for urgent endoscopy as per your local protocol. For those on pre-existing treatment, there is no proven guidance on cessation of PPIs or a defined ‘washout period’ prior to endoscopy. Alarm symptoms include dysphagia, bleeding, recurrent vomiting and unintentional weight loss. Those on long-term use of PPIs should be offered annual reviews and encouraged to step down or stop treatment when appropriate. If symptoms are non-responsive to treatment or persistent this may need referral to a gastroenterologist.

Possible adverse effects of long-term use of PPIs

Long-term use of PPIs has been suggested to be linked with the adverse effects listed in Box 2; although meta-analysis evidence is limited for all the effects, the absolute risks are small. Many of these effects are only associations with more research needed due to lack of causal links. There would need to be much clearer advice in order for this work to lead to change in clinical practice, therefore the studies should be interpreted with caution.

Box 2.

The potential risks of PPIs.

• Infections: Clostridium difficile infection and pneumonia

• Increased risk of bone fractures

• Increased mortality in the elderly

• Acute intersitial nephritis

• Hypomagnaesemia

• Vitamin B12 deficiency

• Rebound acid hypersecretion syndrome

• Dementia

PPIs and anti-platelet agents

PPIs have also been highlighted as impacting the effectiveness of clopidogrel, through influencing platelet activation and thus increasing the risk of adverse cardiovascular events. In 2014, the Medicines and Healthcare Regulatory Agency (MHRA) recommended lansoprazole as the PPI of choice in patients on clopidogrel. Omeprazole and Esomeprazole should be avoided unless benefits outweigh risk.

There is no evidence to suggest stopping PPI use in those on aspirin, but PPIs may interfere with aspirin’s ability to interact with platelets as suggested by a Danish cohort study of people who had experienced a myocardial infarction.

Upper gastrointestinal cancers

Upper gastrointestinal cancers include oesophago-gastric cancers and primary hepatic, pancreatic and biliary cancers. Approximately 20 000 new cases of upper gastrointestinal cancers are diagnosed each year in the UK. Incidence rates in England are higher in more deprived areas. The survival rates are poor for all. Early stages of illness are often undetected, as patients are usually asymptomatic. Upper gastrointestinal cancers are more likely to be diagnosed in late stages, when options for treatment may purely be palliative. Early diagnosis can lead to improved survival rates.

Gastric cancers in particular are the fifth commonest cancer in the world, but 17th most common in the UK, accounting for only 2% of all new cancers. Approximately 7-in-10 cases are detected at late stages in the UK (Cancer Research UK, 2015).

There are numerous risk factors that increase risk of developing upper gastrointestinal cancers. These include: age, gender, ethnicity, lower socio-economic status, diet, smoking, excessive alcohol intake, and family history (see Table 1). Geographically speaking, gastric cancers are more common in Japan, China, Southern/Eastern Europe, and South/Central America.

Table 1.

Risk factors of gastric cancer.

Known Risk Factors	Possible Risk Factors
H.pylori infection	Salt and salty foods
Smoking	Alcohol
Family history of stomach cancer	Obesity
Inherited genetic conditions	GORD
Previous gastric surgery	Occupational exposure: lead, asbestos
Epstein–Barr virus	Cystic fibrosis
Exposure to ionising radiation
Working in rubber industry
Type A blood
Smoked, cured and processed meats

Reproduced with permission from the Canadian Cancer Society (2019).

H.pylori infection and gastric cancer

Prevalence of H.pylori is decreasing in the developed world with improved sanitation and eradication therapy (Table 2). H.pylori is predominantly linked with non-cardia gastric cancers.

Table 2.

Global prevalence of H.pylori infection.

Geographical region	Prevalence (%)
Latin America/Caribbean	60.2
Western Asia	54.3
Europe	39.8
North America	26.6

Source: Coronel-Castillo et al. (2018).

People with gastric cancer have a higher rate of H.pylori infection. A randomised control trial performed endoscopies on 231 patients diagnosed as H.pylori positive, having GORD, and who had been treated with omeprazole maintenance therapy for over a year. Many H.pylori positive patients were found to have pangastritis. Treatment of H.pylori was shown to reduce gastric mucosal inflammation and atrophy. Current guidelines advise eradication of H.pylori prior to commencing long-term use of PPIs. However, there is no data that suggests that H.pylori eradication can prevent gastric cancer in those using PPIs in the long term (Malfertheiner et al., 2016).

Long-term inflammation can lead to chronic atrophic gastritis and pre-malignant changes to the mucosa. H.pylori causes mucosa-associated lymphoid tissue (MALT) lymphoma. MALT is also associated with cancer. Previous studies have shown treatment of H.pylori infection reduces the risk of gastric cancer by up to 47% (Lee et al., 2016).

Does long-term use of PPIs increase the risk of upper gastrointestinal cancers: What does the evidence say?

There are suggestions that PPIs may have an effect on the incidence of gastric cancer. With the decline in the incidence of gastric cancer over the last 50 years, and with PPIs only being available from the 1980s, this goes against the above argument.

As gastric cancer is a rare disease, very few randomised control trials (RCTs) have been performed. There are two RCTs that look at precancerous lesions and PPIs (Eslami, 2013; Song, 2014). Follow up took place over 36 months and no association between PPIs and gastrointestinal cancer was found.

A systematic review of observational studies illustrated a link between gastric cancer and PPIs. However, when duration was considered, the risk was only increased in those taking PPIs for more than 3 years. No statistically significant increase in gastric cancer risk was seen in those taking PPIs for less than a year (Tran-Duy et al., 2016).

There are several confounding factors that can be minimised in studies, but not eradicated. These include indication for PPI, H.pylori status, role of other medications/risk factors (e.g. aspirin), and early cancer symptoms that may also warrant prescription of a PPI.

Another study has suggested acid suppression therapy could lead to delays in the detection of gastric and oesophageal adenocarcinoma on endoscopy in approximately one third of patients. This was defined by the use of H2RA or PPIs for 6 months prior to initial endoscopy. The use of acid suppressants may mask lesions such as ulcerations that are thus not detected initially or shown as minor benign changes. On follow up endoscopy some were found to have malignant changes. It is not clear whether at the time of initial endoscopy these patients had gastric cancer. Anti-acid suppressant therapy can create overgrowth of normal mucosa at ulcer edges or areas of malignant tissue. Therefore, when red flag symptoms are present prompt recognition and referral is suggested with prescription of PPIs to be considered on an individual basis (Bramble et al., 2000).

The study performed by Cheung et al. (2018)

In 2017, a large retrospective cohort study took place involving the University of Hong Kong and Queen Mary’s Hospital in Hong Kong. The study aimed to investigate the risk of upper gastrointestinal cancers in those treated for H.pylori infection and subsequently on long-term use of PPIs. A separate cohort of PPI users without a history of H.pylori infection was also recruited for comparison.

Subjects were adults from a Hong Kong hospital database. Three groups of patients were excluded: patients who developed gastric cancer within 12 months, those taking PPIs or H2RA within 6 months of gastric cancer diagnosis and those who failed to complete eradication therapy. Following exclusion, 63 397 patients were followed up for a median of 7.6 years. The median time from H.pylori therapy to stomach cancer development was 4.9 years and 153 (0.24%) went on to develop gastric cancer.

The study found a 2.4-fold increase in the risk of gastric cancer in those on long-term use of PPIs despite successful H.pylori eradication therapy (95% confidence interval (CI) 1.42 to 4.20). The majority of cancers were non-cardia (i.e. not occurring in the body or antrum of the stomach). This risk was not observed in H2RA users. A time-dependent response was reported with increasing duration and daily use (95% CI 1.23 to 20.61 for >1 year) and a further increased risk observed at 2 and 3 years.

As with any study, limitations can be identified. We know gastric cancer is more common in the Hong Kong population, compared with the UK where incidence has fallen by almost 50% in the last two decades. It may be related to increased intake of foods retaining salt or processed meats. Other risk factors such as smoking and alcohol intake were often unavailable on the hospital database. Family history could also not be taken into account.

The British Society of Gastroenterology (BSG) published a statement in February 2018 after the publication of the study by Cheung et al (2018). They highlighted that those in the PPI group were 10 years older than those not taking PPIs. The median age of gastric cancer diagnosis in this study was 71.4 years. Most cases of gastric cancer in the UK are found in the cardia of the stomach, in contrast with the findings in the above study. Gastric cancer associated with H.pylori is often seen in the lower body or antrum of the stomach (non-cardia). H.pylori is also less common in the UK. The increased prescribing of PPIs over the last two decades and a falling incidence of gastric cancers weakens the case for a causative association between PPI use and gastric cancer. The BSG conclude that:

there is not enough evidence at the moment to advise against the use of PPIs first line for short term use. Prolonged use should be accompanied with an explanation of the evidence for possible risks (BSG position statement).

Applications to clinical practice

Current research evidence suggests that we have a responsibility as clinicians to explain the risks of long-term use of PPIs to patients, to clearly define clinical indications and to offer regular review. The available data suggests that the duration of use may increase gastric cancer risk. If long-term use of PPIs is required, testing and eradication of H.pylori is recommended. With a growing elderly population in everyday general practice, it is vital to consider implications of polypharmacy.

It is not clear how the Cheung et al. (2018) study directly relates to our population. Defining the onset of cancerous or pre-cancerous changes is difficult, and there are several risk factors evident from worldwide data. Further prospective studies are needed to take into account confounding factors and minimise bias.

Despite growing research awareness of the potential adverse effects of PPIs, further research is needed to inform changes in current clinical practice.

KEY POINTS

20 years of experience with PPIs indicates adverse effects, but more research is needed

PPIs should not be withheld when clinically indicated

Caution is advised in the elderly, in Clostridium difficile infection and patients with bone fractures

Recent observational studies suggest an increased risk of gastric cancer with long-term use of PPIs, but without evidence for direct causation

Clinicians have a responsibility to document indications when prescribing, offer structured medication reviews, and consider stepping down therapy when possible, consistent with NICE guidance

Patients should be counselled on the risk and benefits of long-term use of PPIs

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