Experts from HKU’s Department of Medicine collaborated with colleagues from the Department of Pharmacology and Pharmacy on research which confirms a long-held suspicion that the long-term use of proton pump inhibitors – medicines that suppress acid production in the stomach – is associated with increased risk of stomach cancer. The Acid Test and 2012. They discovered that 153 (0.24%) of the patients developed stomach cancer with a median follow-up of 7.6 years. During this timeframe, 3,271 (5%) of the patients were treated with PPIs, and they showed a 2.44-fold increase in risk of developing stomach cancer. More frequent use was associated with a higher cancer risk, with daily use linked to a 4.55-fold higher risk than that of a non-user. The effects of PPI use on stomach cancer development in patients who had received HP eradication therapy were compared to non-users, after adjusting for various differences in the baseline characteristics between the two groups. “The studies showed the longer PPIs were used, the greater was the risk of developing stomach cancer, rising to five-fold after more than a year, to more than six-fold after two or more years, and more than eight-fold after three or more years,” said Professor Leung. Professor Leung Wai-keung, Li Shu Fan Medical Foundation Professor in Gastroenterology, and Clinical Professor of the Department of Medicine, said the study focussed on patients being treated for Helicobacter pylori (HP) infection and being prescribed proton pump inhibitors (PPI). HP infection is considered to be the most important risk factor for stomach cancer development, estimated to increase chances of contracting it three-fold. He explained: “Helicobacter pylori is bacteria in the stomach. Its discovery was huge – and Australians Barry Marshall and Robin Warren won the Nobel Prize in Physiology or Medicine in 2005 for making that discovery. Prior to that, it was believed peptic ulcers were caused by stress and bad lifestyle such as sleep deprivation and spicy food. People are infected by HP bacteria as children, but for most it is asymptomatic and they only know about it much later if they develop symptoms such as pain, ulcers, bleeding or stomach cancer.” “We found that the long-term use of PPIs doubled the risk of stomach cancer development even after successful HP eradication. The risk rose in tandem with the dose and duration of PPI treatment.” Proton pump inhibitors are drugs commonly used for dealing with excess stomach acid, and to treat stomach ailments such as peptic ulcer, acid reflux, dyspepsia. They are sold over the counter to the patients directly in the UK and US (though not Hong Kong) and are frequently prescribed. Indeed, while acknowledging that PPI is a potent acid suppressant and an important drug, Professor Leung said it is over-prescribed. “The possible link between PPI usage and cancer has been made before, but what is unique to this study is that it only looks at patients who had been infected with HP and who had received treatment to eradicate it.” “Other studies have looked at general patients,” he added, “but this is a stronger message: Since HP therapy eradicates the infection it has been thought that it is safe to use PPIs, but this research says it is not safe. People have struggled to accept that this is true. We have had a lot of commentary on the paper and people are now beginning to accept that PPIs may have negative effect.” At the same time, Professor Leung emphasised: “This is an observational study and therefore not conclusive regarding causality, so we are not discouraging the use of PPIs completely but recommending that doctors regularly review the indications of a prescribed PPI and use the minimum effective dosage, frequency and duration.” Best evidence now However, he also said that this study, though observational, “may represent the best evidence we can get for now. The next level of research would be a controlled study which randomly assigns patients to either a PPI or placebo and that is unlikely to happen for several reasons; first, ethical, it could put some patients at risk, and second, timing – the study will take many years.” He suggested that H2-receptor antagonist, a less potent acid suppressant may be a safer alternative for the patient. “It is also cheaper so why not use it?” he said. “Some people erroneously believe that the most expensive drug is the best.” The findings, which are attracting a lot of attention, have been published in the latest issue of the prestigious international scientific journal, Gut . They could represent a major step in the prevention of stomach cancer, which is the fifth most common cancer and the third leading cause of cancer-related death in the world. It is particularly prevalent in East Asia, accounting for more than 70 per cent of the cases globally. █ Previous studies have suggested that the risk of gastric cancer development could be reduced by about 40 per cent by elimination of HP, yet a considerable proportion of patients continue to progress to stomach cancer even after successful HP eradication. $60-million question The team was able to look into the link between the two. “The reason we were able to focus on a possible link between the two was that the Department of Pharmacology and Pharmacy alerted us to the fact that they had identified a large cohort of HP patients while doing another study. This gave us the opportunity to ask the $60-million question: does PPI usage effect the development of stomach cancer?” To do so, they studied clinical data on more than 63,000 HP-infected patients who had received HP eradication therapy between 2003 From left: Dr Esther Chan Wai-yin, Associate Professor of Department of Pharmacology and Pharmacy; Professor Leung Wai-keung, Clinical Professor of Department of Medicine; and Dr Michael Cheung Ka-shing, Specialist in Gastroenterology and Hepatology, Department of Medicine. The studies showed the longer PPIs [proton pump inhibitors] were used, the greater was the risk of developing stomach cancer, rising to five-fold after more than a year, to more than six-fold after two or more years, and more than eight-fold after three or more years. Professor Leung Wai-keung 15 | 16 The University of Hong Kong Bulletin | May 2018 Research
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