Systematic Review: Potential Preventive Effects of Statins Against Oesophageal Adenocarcinoma

L. Alexandre; A. B. Clark; E. Cheong; M. P. N. Lewis; A. R. Hart

Disclosures

Aliment Pharmacol Ther. 2012;36(4):301-311. 

In This Article

Abstract and Introduction

Abstract

Background The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically in recent decades, and its prognosis remains extremely poor. There is emerging evidence that statins may prevent OAC.
Aim To systematically review both the experimental and epidemiological evidence to determine whether statins reduce the risk of developing OAC.
Methods Relevant laboratory and epidemiological studies were identified by systematically searching the PUBMED and EMBASE electronic databases for data on statins and oesophageal cancer (OC). The evidence was assessed according to the nine Bradford Hill criteria (BHC) of causality. Pooled effect sizes (ES) were calculated for the risk of OC with prior statin use.
Results Many of the BHC were supported including: 'plausible biological mechanisms', 'coherence', 'strong associations', 'consistency', 'biological gradient', 'analogy' and 'temporality'. Three experimental studies reported that statins inhibited proliferation, induced apoptosis and may limit metastatic potential in OAC cell lines. Fixed effects meta-analysis of two prospective studies in Barrett's oesophagus cohorts, involving 1382 participants, showed an ES of 0.53 (95% CI = 0.36–0.78, P = 0.001, I 2 = 0%) for risk of OAC with prior statin use. Meta-analysis of three prospective studies in general population cohorts, involving 35 214 participants, showed an ES of 0.86 (95% CI = 0.78–0.94, P = 0.001, I 2 = 0%) for risk of OC with prior statin use. The most important criterion, 'experiment', is as yet unfulfilled as to date there are no clinical trials which investigate this hypothesis.
Conclusion There is some evidence that statins may protect against the development of OAC, although to be conclusive, data from randomised clinical trials are required.

Introduction

Oesophageal cancer (OC) is an important global healthcare problem and is associated with a poor prognosis. In 2008 worldwide there were approximately 482 000 new cases and 400 000 associated deaths,[1] making OC the fifth and eighth commonest cause of death from cancer in men and women respectively. The incidence of the two main histological subtypes, namely oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC), significantly differs. In recent decades, in western countries, the incidence of OAC has risen dramatically,[2–5] with at least a threefold increase in men and women since the 1970s in England and the US.[6,7] Conversely, in many countries, the incidence of OSCC has declined or remained stable.[2–4,7,8]

Patients with OAC commonly present when the disease is at an advanced stage and palliative therapies are the only treatment option. However, of those suitable for potentially curative treatment, the outcomes are often still poor, with a recurrence rate post-oesophagectomy of 46% within 12 months[9] and a 5-year survival of only 23%.[10] Barrett's oesophagus (BO), the precursor lesion to OAC, is a histologically and endoscopically defined entity affecting the distal oesophagus, where the native stratified squamous epithelium is replaced by metaplastic columnar epithelium.[11] Unfortunately, screening and surveillance of BO has not led to a reduction in mortality from OAC.[12]

Associated risk factors for OAC include BO,[13] increasing age,[14] male gender,[14] Caucasian race,[3] gastro-oesophageal reflux disease,[14–16] obesity,[16,17] tobacco[18] and specific medications which relax the lower oesophageal sphincter.[19–23] Conversely, the use of non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin,[24] are inversely associated. Despite these known associations, the aetiology of OAC is incompletely understood and other factors may be involved. Statins are commonly used to lower serum cholesterol in the primary and secondary prevention of cardiovascular disease, and demonstrate a number of promising anticancer effects. The aim of this systematic review is to assess the current experimental and epidemiological evidence, according to the Bradford Hill criteria (BHC) of causality, as to whether or not statins may reduce the risk of developing OAC, including the carcinogenic progression from BO to OAC. Further work to clarify any existing findings and the need for new studies will be considered. Determining whether statins prevent carcinogenesis is important to establish if they should be included in aetiological models of OAC and if they may have a clinical application for cancer prevention.

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