Elsevier

The Lancet Oncology

Volume 6, Issue 12, December 2005, Pages 945-952
The Lancet Oncology

Fast track ā€” Articles
Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study

https://doi.org/10.1016/S1470-2045(05)70431-9Get rights and content

Summary

Background

Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) probably decrease the risk of colorectal neoplasia; however their effect on development of oesophageal adenocarcinoma is less clear. We aimed to assess the role of NSAID in the development of oesophageal adenocarcinoma and precursor lesions in people with Barrett's oesophagusā€”a metaplastic disorder that confers a high risk of oesophageal adenocarcinoma.

Methods

We did a prospective study of the relation between duration, frequency, and recency of NSAID use and the risk of oesophageal adenocarcinoma, aneuploidy, and tetraploidy in a cohort of 350 people with Barrett's oesophagus followed for 20ā€ˆ770 person-months. We used proportional-hazards regression to calculate hazard ratios (HR) adjusted for age, sex, cigarette use, and anthropometric measurements.

Findings

Median follow-up was 65Ā·5 months (range 3Ā·1ā€“106Ā·9). Compared with never users, HR for oesophageal adenocarcinoma (n=37 cases) in current NSAID users was 0Ā·32 (95% CI 0Ā·14ā€“0Ā·76), and in former users was 0Ā·70 (0Ā·31ā€“1Ā·58). 5-year cumulative incidence of oesophageal adenocarcinoma was 14Ā·3% (95% CI 9Ā·3ā€“21Ā·6) for never users, 9Ā·7% (4Ā·5ā€“20Ā·5) for former users, and 6Ā·6% (3Ā·1ā€“13Ā·6) for current NSAID users. When changes in NSAID use during follow up were taken into account, the associations were strengthened: HR for oesophageal adenocarcinoma for current users at baseline or afterwards was 0Ā·20 (95% CI 0Ā·10ā€“0Ā·41) compared with never users. Compared with never users, current NSAID users (at baseline and follow-up) had less aneuploidy (n=35 cases; 0Ā·25 [0Ā·12ā€“0Ā·54]) and tetraploidy (n=45 cases; 0Ā·44 [0Ā·22ā€“0Ā·87]).

Interpretation

NSAID use might be an effective chemopreventive strategy, reducing the risk of neoplastic progression in Barrett's oesophagus.

Introduction

The incidence of oesophageal adenocarcinoma has risen substantially in the USA, western Europe, Australia, and in other developed countries over the past 30 years, with little sign of abating.1, 2 Incidence is highest in white men, and is about eight times greater than that for white women and five times greater than that for black men, although substantial increases have been recorded for every group.2, 3, 4 In the USA, oesophageal adenocarcinoma became the most common histological type of oesophageal cancer in the late 1990s. Although the cause of oesophageal adenocarcinoma and the underlying reasons for the rapid increase in incidence are not understood fully, the rise in obesity in many developed countries is thought to have a substantial role.5 Mortality remains high for those diagnosed with oesophageal adenocarcinoma, and most survive for less than 1 year after diagnosis.6

Most oesophageal adenocarcinomas arise in a specialised intestinal metaplastic epithelium as a result of goblet-cell metaplasia, a disorder called Barrett's oesophagus, which develops in about 10% of people with chronic gastro-oesophageal reflux disease.7, 8, 9 Every year, about 0Ā·5ā€“1Ā·0% of individuals with Barrett's oesophagus develop oesophageal adenocarcinoma; aneuploidy, tetraploidy, and loss of heterozygosity at chromosome 17p, with or without high-grade dysplasia, identify those at particularly high risk.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 However, little is known about why in some people the oesophageal epithelium undergoes malignant transformation, whereas in others it remains in a fairly benign state indefinitely.25

Observational studies26, 27, 28 in human beings and mechanistic studies in animals27 suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAID) prevent development of colorectal cancer and premalignant adenomatous polyps. Clinical trials29, 30, 31, 32 of aspirin for prevention of recurrent adenomas or colon cancer generally support this notion, although findings have been inconsistent. By contrast, the role of NSAID in lowering the risk of oesophageal cancer risk has not been addressed thoroughly, although several studies of human beings33, 34, 35, 36, 37 and animals38, 39 suggest a protective effect. An inexpensive, widely available, and fairly safe means of preventing neoplastic progression in people at high risk of oesophageal cancer would have substantial benefits in terms of public health and economics.40, 41, 42, 43

We aimed to assess the role of NSAID in the development of oesophageal adenocarcinoma and precursor lesions in a cohort of people with Barrett's oesophagus. By use of prospective, longitudinal observational data, we analysed the association between NSAID intake and incidence of oesophageal adenocarcinoma, aneuploidy, and tetraploidy.

Section snippets

Study participants

We analysed participants in the Seattle Barrett's oesophagus projectā€”a dynamic cohort study that began in 1983. Every participant in this continuing programme of cancer surveillance has periodic endoscopy and multiple biopsies at every endoscopy according to a standard protocol.24, 44 From February, 1995, the study was expanded to include an extensive personal interview about medical history, diet, history of use of certain prescription and over-the-counter drugs, and anthropometric

Results

350 people were eligible for analyses. Of these, 105 (30%) were ongoing participants who had been under surveillance for a median of 62Ā·4 months (range 2Ā·4ā€“148Ā·8), and 245 (70%) were newly diagnosed with Barrett's oesophagus at baseline. The median number of follow-up visits was five (1ā€“20) for 61 (17%) people with high-grade dysplasia at baseline, with a median time between visits of 6Ā·0 months (0Ā·7ā€“32Ā·2), and three visits (1ā€“15) for those without high-grade dysplasia at baseline, with a

Discussion

We have shown that people who took aspirin or other NSAID regularly had a substantially lower incidence of oesophageal adenocarcinoma, aneuploidy, and to a lesser extent, tetraploidy, compared with those who did not take such drugs regularly. These findings persisted after adjustment for major risk factors for oesophageal adenocarcinoma, including age, sex, education, cigarette use, ratio of waist to hip, and body-mass index. We found that risk did not vary with these factors. Furthermore, risk

Glossary

Aneuploidy
A population of cells with abnormal DNA content, separated from the diploid peak, and representing more than 2Ā·5% of cells.
Tetraploidy
A population of cells increased beyond the normal level present during stage G2 of the cell cycle (>6%) and with DNA content between 3Ā·85 and 4Ā·10N inclusive.

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