Chemoprevention of Esophageal Cancer with esomeprazole and aspirin therapy: efficacy and safety in the phase III randomized factorial AspECT Trial


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Janusz Jankowski1,John de Caestecker2,Sharon Love3,Gavin Reilly4,Yeng Ang5,Krish Ragunath6,Art Tucker7,Ian Penman8,Colin Rodgers9,James Neale10,Claire Brooks11,Stephen Attwood12,Danielle Morris13,Rebecca Harrison14,Pradeep Bhandari15,Peter Watson16,Scott Sanders17,Hugh Barr18,Paul Moayyedi19,Aspect Trial Team20
1Royal College of Surgeons Ireland National; Institute for Health and Care Excellence; University Hospitals of Morecambe Bay NHS Trust,2University Hospitals Leicester NHS Trust,3Centre for Statistics in Medicine, University of Oxford; MRC Clinical Trials Unit,4Centre for Statistics in Medicine, University of Oxford,5Wrightington Wigan and Leigh NHS Foundation Trust,6Queen's Medical Centre, University of Nottingham,7Barts Health NHS Trust,8Western General Hospital; Royal Infirmary of Edinburgh,9Antrim Area Hospital,10Torbay and South Devon NHS Foundation Trust,11University of Oxford, Oncology Clinical Trials Office,12Durham University, School of Medicine, Pharmacy and Health,13East and North Hertfordshire NHS Trust,14UHL,15Queen Alexandra Hospital,16Queen's University Belfast Faculty of Medicine Health and Life Sciences,17South Warwickshire NHS Foundation Trust,18Gloucester Royal, Dept of Surgery,19McMaster University Medical Centre,20University of Oxford

Abstract

Background

Esophageal adenocarcinoma(EA) is the sixth most common cause of global cancer death. We rely on endoscopy screening to identify and monitor patients with Barrett’s esophagus(BE) and find neoplastic lesions early enough to manage their EA. This approach has a modest effect on EA supported by low quality evidence. We evaluated efficacy of aspirin and high dose acid suppression in preventing EA in patients with BE.

Method

We recruited patients with ≥ 1cm of BE and no high grade dysplasia (HGD) or EA at baseline in UK and Canadian hospitals.  To conceal allocation, a central trials unit randomized patients using a computer-generated schedule.  Patients were randomized unblinded 1:1:1:1 in a 2X2 factorial design to high dose  (40mg  twice daily) or low dose (20mg once daily)esomeprazole proton pump inhibitor acid suppression (PPI) , alone or combined with low dose aspirin 300mg/day (330mg in Canada).  The primary composite endpoint was time to all-cause mortality or EA or HGD analyzed using accelerated failure time modelling adjusting for minimization factors (age, length of Barrett’s esophagus and presence of intestinal metaplasia).

Results

We recruited 2563 patients with 20,095 years of follow(median: 8.9 years, interquartile range 8.2-9.8). There were 313 events of the composite primary endpoint. High dose PPI was statistically significantly superior to low dose PPI(p=0.037, N=2535, Time Ratio(TR)=1.27, 95% CI=1.01-1.58). Aspirin therapy showed a trend to benefit but was not statistically significant(p=0.068, N=2280, TR=1.24, 95% CI=0.98 – 1.57).  The combination of aspirin with high dose PPI had the strongest effect compared to low dose PPI with no aspirin(TR=1.59, 95% CI=1.14 to 2.23, p=0.007). There were few serious adverse events reported(1.0% of patients), with 99.9% data collected.

Conclusion

This is the largest chemoprevention RCT in patients with BE. We have shown that PPI high dose and aspirin chemoprevention therapy, significantly reduces rates of death, EA or HGD and is safe.