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Title: The potential role of statins in the treatment and prevention of oesophageal adenocarcinoma
Author: Alexandre, Leo
ISNI:       0000 0004 6423 8480
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2017
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Oesophageal adenocarcinoma (OAC) is an aggressive malignancy with a very poor prognosis overall. Barrett’s oesophagus (BO) is the only known precursor lesion. Emerging preclinical evidence indicates statins, medications commonly used in the primary and secondary prevention of cardiovascular disease, inhibit proliferation, promote apoptosis and limit invasiveness of OAC. Inhibition of the mevalonate pathway depletes downstream products involved in candidate growth-signalling cascades. This research aimed to determine: (1) associations between statin use after diagnosis of oesophageal carcinoma (OC) and mortality outcomes; (2) the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a future phase III randomised controlled trial; and (3) associations between statin use and malignant progression to high-grade dysplasia (HGD)/OAC in BO populations. In a cohort of 4445 patients with OC in a large primary care dataset, the General Practice Research Database, post-diagnostic statin use was associated with significant reductions in OC-specific and all-cause mortality. Significant associations were demonstrated in patients with OAC but not in oesophageal squamous cell carcinoma. A multi-centre, double-blind, parallel group, randomised, placebo-controlled feasibility trial of adjuvant statin therapy recruited patients with operable OAC. In total, 32 patients were randomised (1:1) to simvastatin (40mg) or matched placebo. Treatment started from the date of discharge following surgery and continued for up to one year. The trial estimated recruitment, retention, drug absorption, adherence, safety, quality of life, generalisability, and mortality outcomes. The feasibility of a future phase III trial was demonstrated; and derived feasibility estimates inform its design and conduct. A nested case-control analysis of a cohort with BO registered with the United Kingdom National Barrett’s Oesophagus Registry (UKBOR) demonstrated no significant associations between statin use and malignant progression. Significant dose and duration-response relationships were not demonstrated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available