Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use

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Abstract

Proton-Pump Inhibitors (PPIs) are commonly prescribed in the general population and in cancer patients. A supposed role in the prevention of gastric mucosal damage apparently justify their use in patients undergoing cytotoxic chemotherapy, steroids and radiotherapy on the gastro-duodenal region. They are frequently given also to patients admitted to Intensive Care Units, for the prevention of stress-related gastric ulcers. The evidence about these use of gastroprotection is reviewed. In the majority of the cases the prescription of PPIs is not justified. In two circumstances (chemotherapy and stress-related gastric disease) randomized studies have shown a protective action of PPIs although this effect did not translate into the reduction of serious clinical consequences. PPIs are not free of toxic effects that are acknowledged by an expanding literature. Also the interaction with anticancer drugs is a potential source of unwanted consequences.

Introduction

Gastric mucosal damage is a frequent event in the natural history of cancer. Gastroprotection is widely prescribed due to pre-existing or associated conditions. Moreover, cancer patients are frequently exposed to gastric-damaging drugs and potentially riskful clinical conditions. Chemotherapy, steroids, non-steroidal anti-inflammatory agents (NSAID) can have a role in inducing or worsening gastric damage. While the treatment of several diseases, namely peptic ulcer, Helicobacter pylori (HP) gastric damage, Zollinger-Ellison Syndrome and gastroesophageal reflux disease, is established, prevention of gastrointestinal (GI) bleeding, although it gained widespread success, is more debatable. Recognized indications are prolonged NSAID and aspirin (ASA) treatment when associated with other risk factors, such as anticoagulant or steroid concomitant administration and elderly age (Lanza et al., 2009).

Gastroprotection can be achieved using several drugs, although Proton Pump Inhibitors (PPIs) are the most effective agents and have gained a predominant place in drug prescription for both treatment of gastric acid-related disorders and prevention of mucosal damage.

PPIs are irreversible inhibitors of the hydrogen/potassium adenosine triphosphatase (ATPase) system of the gastric parietal cells and achieve a reduction of gastric acid secretion by up to 99%. These drugs have a plasma half-life of 60–90 min, although the covalent binding with ATPase determines a long-lasting inhibition of acid production (24 h). PPIs are the most prescribed drugs in the world. They fall only behind the statins in total spending worldwide, estimated at over US$ 11 billion annually in the USA (Lodato et al., 2016). The prevalence of patients receiving PPIs in the Italian adult population was 22% and up to 55% in people older than 75 in 2014. In the inpatient setting more than 50% of the patients are taking PPIs (Lodato et al., 2016). Expenses for this class of agents are higher than that of anticancer monoclonal antibodies and target agents (Rapporto OSMED, 2014). Gastroprotection is one of the most frequent medical practice at risk of inappropriateness, because it is subject to frequent over-prescription (Heidelbaugh et al., 2012, Forgacs and Loganayagam, 2008, Heidelbaugh et al., 2010). A study conducted in an Ann Arbor, MI Veterans’ Administration hospital determined that, out of 946 patients, only 35% were prescribed PPIs for a documented disease, while 36% had no evident indication (Heidelbaugh et al., 2012). In another study conducted on 168,727 adult ambulatory patients approximately 39% received PPIs without any evidence-based indication (Jacobson et al., 2003).

Data available from the Veteran Affairs health care systems suggest that 20–33% of cancer patients currently take acid-reducing agents, with higher frequency in gastrointestinal cancers (35–50%). Of these the large majority are PPIs (Smelick et al., 2013).

Cancer patients are subject to specific risk factors for gastric damage: chemotherapy, radiation therapy (RT) and steroids. Stress gastric ulcers (SGU) are a further clinical condition that frequently involves cancer patients undergoing critical events (sepsis, cancer-related organ failure). In the review we will summarize the available literature and discuss the use of gastroprotective agents in cancer patients, with particular emphasis on PPIs.

Section snippets

Chemotherapy-induced gastric damage

Chemotherapy (CT) is a well-known inducer of mucosal damage. Historical experience has demonstrated that gastric damage is a frequent occurrence (Sartori et al., 1991). Mucosal gastric damage can present with endoscopical features of diffuse gastritis, erosions or ulcers. Erosions should be distinguished from ulcers: the first are more superficial and do not pass through the muscular layer, leading to lower risk of bleeding and not resulting in perforation. While erosions are frequently

Interaction between PPIs and radiotherapy

About a half of cancer patients will need RT during the course of their disease (Borras et al., 2016). In recent years, modern technologies allowed for a consistent increase in the therapeutic index of RT treatments, increasing tumor control probability and decreasing the toxicity profile at the same time (Franco et al., 2013). Moreover, a better supportive global care of the patients increased tolerance to combination therapies (Numico et al., 2015). Finally, a deeper understanding of

Stress gastric ulcers in cancer patients

Stress gastric ulcers are a common event in Intensive Care Units (ICU). Their frequency is proportional to the time of stay and up to 90% of the patients have been shown to have endoscopically detectable mucosal erosions and sub-epithelial hemorrhage within 24 h of admission (Eddleston et al., 1994). Splanchnic hypoperfusion, reperfusion injury, and increased systemic release of pro-inflammatory cytokines are the main mechanisms that mediate gastrointestinal mucosal vulnerability and ulceration.

Steroids and gastroprophylaxis

Steroids are frequently prescribed to cancer patients. They are given at a moderately high dose for repeated short periods (two to three days) as antiemetic prophylaxis in chemotherapy with high and moderate emetic potential (Roila et al., 2010) and are widely used in premedications (especially in the use of monoclonal antibodies). They are used at the same or higher doses in patients with symptoms of cranial hypertension related to brain or spinal metastases (Bradley and Mehta, 2004) and

Toxicity of PPI in cancer patients

In the last four decades, PPIs have been among the most widely prescribed medications; their large use was linked to the belief of few adverse events, generally of little or no clinical relevance.

More recently some observation studies supported evidence of several side effects. As known, the value of such studies is limited by patient selection and other possible biases (due to patient characteristics and contemporary use of other drugs) but the amount of literature data greatly grew in the

Interaction of PPI with oral anticancer agents

Drug interaction is an increasing concern in cancer patients, being extremely common and quite underestimated (van Leeuwen et al., 2013). The expanding role of anticancer oral drugs is posing the problem of bioavailability and of interaction with food and other drugs. The brisk and long standing increase of gastric pH induced by PPIs could have an impact on GI absorption and significantly modify circulating levels of active metabolites. The solubility of many oral anticancer drugs is

Summary and conclusions

PPIs are one of the most prescribed drugs in the world and account for great global spending. In cancer patients they are frequently used either for treatment or prophylaxis of concomitant conditions. In the majority of the cases, however, the prescription of PPIs is not justified by the evidence of a clinical positive impact. In two circumstances, chemotherapy and stress-related gastric disease, prospective studies have shown a protective action of PPIs. However this effect did not translate

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