Statins Are Associated With Reduced Risk of Esophageal Cancer, Particularly in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis

doi:10.1016/j.cgh.2012.12.036

Clinical Gastroenterology and Hepatology

Volume 11, Issue 6, June 2013, Pages 620-629

https://doi.org/10.1016/j.cgh.2012.12.036 Get rights and content

Background & Aims

The incidence of esophageal cancer is increasing in the United States, especially among patients with Barrett's esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer.

Methods

We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients.

Results

A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60–0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45–0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389.

Conclusions

Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE.

Section snippets

Methods

This systematic review was conducted following guidance provided by the Cochrane Handbook²⁰ and Kanwal and White²¹ and is reported according to the Meta-analysis of Observational Studies in Epidemiology guidelines.²² The process followed a priori established protocol.

Search Results

Of a total 2336 unique studies identified using our search criteria, 13 studies fulfilled our inclusion criteria and were included in the meta-analysis (7 case-control, 5 cohort, and 1 post hoc analysis of 22 RCTs),3, 15, 16, 17, 18, 19, 24, 34, 35, 36, 37, 38, 39, 40, 41 of which 3 had been published only in the abstract form.34, 37, 39 Figure 1 summarizes the process of study identification, inclusion, and exclusion. These cumulatively reported 9285 cases of EC in 1,132,969 patients, who were

Discussion

The identification of potential agents for chemoprevention in EC is highly desirable. Aspirin, NSAIDs, and PPIs may have potential chemopreventive effects in patients with BE but they are not without significant side effects.46, 47 In this comprehensive meta-analysis of all published studies in more than 1.13 million patients with 9285 cases of EC, we found that use of statins is associated with a 28% reduction in the risk of EC, after adjusting for confounding variables, although there was

Conclusions

In summary, a meta-analysis of all studies suggests that statin use is associated with a reduced risk of EC, with greater and most consistent benefit on the risk of EAC in patients with known BE. Longer duration of statin use, in combination with aspirin/NSAIDs, may provide greater protective effect. Given the high mortality rates after a diagnosis of EC, these results support chemoprevention trials evaluating statins in populations at high risk of developing EAC.

Acknowledgment

The authors sincerely thank Dr Andrew Hart for sharing additional information from their original study for the purposes of this meta-analysis.

References (54)

D.A. Corley et al.
Surveillance and survival in Barrett's adenocarcinomas: a population-based study
Gastroenterology
(2002)
J. Kuoppala et al.
Statins and cancer: a systematic review and meta-analysis
Eur J Cancer
(2008)
S. Singh et al.
Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis
Gastroenterology
(2013)
M.R. Sadaria et al.
Statin therapy attenuates growth and malignant potential of human esophageal adenocarcinoma cells
J Thorac Cardiovasc Surg
(2011)
D.M. Nguyen et al.
Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus
Gastroenterology
(2010)
F. Kastelein et al.
Nonsteroidal anti-inflammatory drugs and statins have chemopreventative effects in patients with Barrett's esophagus
Gastroenterology
(2011)
F. Kanwal et al.
“Systematic Reviews and Meta-analyses” in clinical gastroenterology and hepatology
Clin Gastroenterol Hepatol
(2012)
R. DerSimonian et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986)
S.G. Thompson et al.
Can meta-analyses be trusted?
Lancet
(1991)
G.H. Guyatt et al.
GRADE guidelines: 7. Rating the quality of evidence-inconsistency
J Clin Epidemiol
(2011)

P.J. Easterbrook et al.

Publication bias in clinical research

Lancet

(1991)

M. Sikkema et al.

Risk of esophageal adenocarcinoma and mortality in patients with Barrett's esophagus: a systematic review and meta-analysis

Clin Gastroenterol Hepatol

(2010)

C. Marelli et al.

Statins and risk of cancer: a retrospective cohort analysis of 45,857 matched pairs from an electronic medical records database of 11 million adult Americans

J Am Coll Cardiol

(2011)

H.Y. Bhutta et al.

Mo1542 do statins prevent the histological subtypes of esophageal cancer?Prospective data from the UK General Practice Research Database (GPRD)

Gastroenterology

(2012)

D.M. Nguyen et al.

Medication usage and the risk of neoplasia in patients with Barrett's esophagus

Clin Gastroenterol Hepatol

(2009)

D.A. Corley et al.

Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis

Gastroenterology

(2003)

A.R. Patrick et al.

The association between statin use and outcomes potentially attributable to an unhealthy lifestyle in older adults

Value Health

(2011)

A. Jemal et al.

Global cancer statistics

CA Cancer J Clin

(2011)

C. Bosetti et al.

Trends in oesophageal cancer incidence and mortality in Europe

Int J Cancer

(2008)

M.B. Cook et al.

Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005

Br J Cancer

(2009)

P. Sharma

Clinical practiceBarrett's esophagus

N Engl J Med

(2009)

J.M. Inadomi et al.

Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis

Ann Intern Med

(2003)

S. Bonovas et al.

Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials

J Clin Oncol

(2006)

M.F. Demierre et al.

Statins and cancer prevention

Nat Rev Cancer

(2005)

O.O. Ogunwobi et al.

Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells

Am J Gastroenterol

(2008)

P.C. Konturek et al.

Inhibition of Barret's adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins

J Physiol Pharmacol

(2007)

F. Ye et al.

Suppression of esophageal cancer cell growth using curcumin, (-)-epigallocatechin-3-gallate and lovastatin

World J Gastroenterol

(2012)

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Citation Excerpt :
A systematic review and meta-analysis by Thomas et al. evaluated statin use and the development of esophageal cancer, concluding that statins were associated with a significantly lower incidence of EAC in both the general population and in patients with Barrett's esophagus.24 Likewise, a meta-analysis by Singh et al. found that statins reduced the risk of EAC in patients with Barrett's.25 On evaluation of statin therapy in patients with esophageal cancer, statins were associated with a significant increase in survival for patients with either adenocarcinoma or squamous cell cancer.26
Esophageal adenocarcinoma (EAC) is a lethal malignancy with poor prognosis. Pharmacologic inhibitors of inflammation, such as statins, have been shown to decrease the risk of development and progression of esophageal cancer, but the mechanism of this protection is unclear. The objective of this study was to elucidate the effect of statins on toll-like receptor 4-mediated–proliferation of human EAC cells and identify the mechanism responsible for these observed effects.
Human EAC cells (OE33 and FLO1) were treated with simvastatin or atorvastatin for increasing doses and time periods. Toll-like receptor 4 (TLR4) expression was assessed. Cells were pretreated with statin followed by lipopolysaccharide (LPS). Cell proliferation and expression of signaling proteins were evaluated. FLO1 cells were injected into the flank of nude mice. Mice received intraperitoneal injections of simvastatin, atorvastatin, or control solution and tumor volume was measured.
OE33 and FLO1 cells demonstrated decreased TLR4 expression after treatment with simvastatin or atorvastatin for 8 h (P < 0.05). LPS increased proliferation, whereas pretreatment with statin abolished this response (P < 0.05). Statins decreased expression and activation of LPS-induced signaling proteins, including MyD88, TRAF6, Akt, and NF-κB (P < 0.05). Mice receiving daily statin injections demonstrated smaller tumors than control mice (P < 0.001 at day 33).
Treatment of EAC cells with simvastatin or atorvastatin decreases TLR4-mediated proliferation and in vivo tumor growth. Decreased TLR4 expression and subsequent reduction in MyD88-dependent signaling could be a mechanism by which statins act to reduce tumor growth rates.
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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (RC4DK090413) and the American College of Gastroenterology.

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Original articleSystematic review and meta-analysesStatins Are Associated With Reduced Risk of Esophageal Cancer, Particularly in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis

Background & Aims

Methods

Results

Conclusions

Section snippets

Methods

Search Results

Discussion

Conclusions

Acknowledgment

Gastroenterology

Eur J Cancer

Gastroenterology

J Thorac Cardiovasc Surg

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Control Clin Trials

Lancet

J Clin Epidemiol

Lancet

Clin Gastroenterol Hepatol

J Am Coll Cardiol

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Value Health

Global cancer statistics

CA Cancer J Clin

Trends in oesophageal cancer incidence and mortality in Europe

Int J Cancer

Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005

Br J Cancer

Clinical practiceBarrett's esophagus

N Engl J Med

Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis

Ann Intern Med

Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials

J Clin Oncol

Statins and cancer prevention

Nat Rev Cancer

Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells

Am J Gastroenterol

Inhibition of Barret's adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins

J Physiol Pharmacol

Suppression of esophageal cancer cell growth using curcumin, (-)-epigallocatechin-3-gallate and lovastatin

World J Gastroenterol

Original article
Systematic review and meta-analyses
Statins Are Associated With Reduced Risk of Esophageal Cancer, Particularly in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis