Aspirin and NSAIDs; benefits and harms for the gut.

Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett's oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose.

Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence.

Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world's first proven chemopreventive agent is currently unknown but the evidence looks hopeful.

The evidence base of proton pump inhibitor chemopreventative agents in Barrett's esophagus--the good, the bad, and the flawed!

Gastric acid is believed to be an important etiological factor in the pathogenesis of Barrett's esophagus. Pulsatile acid exposure increases cell proliferation in ex vivo Barrrett's tissue and normalization of esophageal pH reverses this. Proton pump inhibitors (PPIs) are the mainstay of therapy in Barrett's esophagus, and have numerous beneficial effects including symptom control, reduction of inflammation, and promotion of the development of squamous islands. However, PPI therapy causes hypergastrinemia and has not prevented recent increase in the incidences of esophageal cancer. Additionally, evidence presented here by Feagins et al. suggests that acid exposure has a p53-mediated, antiproliferative effect on a nondysplastic Barrett's epithelial cell line, an effect that acid suppression might abrogate. These complex pH, inflammation, and growth factor biological interactions can be most reliably tested in large clinical trials with hard end points like cancer conversion or all causes of mortality. Combining the anti-inflammatory effects of acid suppression with aspirin, a nonsteroidal anti-inflammatory agent, is the subject of the AspECT clinical trial, and this may be the future of chemoprevention in Barrett's.

Acid suppression and chemoprevention in Barrett's oesophagus.

Barrett's oesophagus is a pre-malignant condition affecting 1% of the population in the West. Even though most patients with Barrett's will not develop oesophageal cancer, the incidence of adenocarcinoma is 0.45-1%, conferring a 40-fold increased risk compared with the general population. The risk rises to 40-50% within 5 years for those with high grade dysplasia. Currently, the only strategies available to diminish adenocarcinoma rates are surveillance endoscopy, endoscopic thermal or photodynamic ablation or tissue resection. The latter options are reserved for those who already have dysplasia. 10-50% of patients undergoing oesophagectomy for high grade dysplasia have been shown to have adenocarcinoma. Therefore approaches are needed to be that either remove or prevent stimuli propelling patients down the dysplasia-adenocarcinoma pathway. Both gastric acid and bile acids have been reported as potential insults involved in the pathogenesis of Barrett's oesophagus. This is thought to be mediated by a range of molecules including cyclo-oxygenase-2, c-myc and mitogen-activated protein kinase signalling. Proton pump inhibitors not only suppress acid but also bile reflux, although symptom control is a poor guide as to adequacy of acid suppression. There is some evidence that proton pump inhibitors cause partial regression in Barrett's oesophagus length, although the data is contradictory. Proton pump inhibitors have also been shown to increase cell differentiation and apoptosis, reduce proliferation and COX-2 levels, with the supposition that this may diminish cancer risk. However this role in decreasing cancer risk has not yet been evaluated. The use of NSAIDS and aspirin, most likely via inhibition of COX-2 and other inflammatory pathways, is associated with a reduction of adenocarcinoma rates. Both PPIs and NSAIDs/Aspirin may therefore be potential chemopreventative agents but further studies are required to appraise their use.