Esophageal adenocarcinoma is increasing in incidence. The main risk factor is the premalignant condition of Barrett’s esophagus. There is great interest in chemoprevention to prevent or slow malignant transformation. There are many agents proposed as playing a role in chemoprevention; however, none is licensed for this role as yet. Aspirin possesses many favorable qualities for chemoprevention and is the focus of the largest randomized control trial in this field.
Esophageal cancer is continuing to increase at a fast rate with a 40-fold increase in prevalence over the past 40 years. This rise is mainly due to the ongoing increase in incidence of esophageal adenocarcinoma (EAC), the predominant histologic type in the United States and the United Kingdom. Despite improvements in surgical and oncologic treatment, prognosis of those diagnosed with EAC remains poor, with an overall 5-year survival of less than 15%. The main risk factor for EAC is the premalignant condition of Barrett’s esophagus (BE). BE is common, affecting 10% to 15% of those who undergo upper gastrointestinal endoscopy for reflux symptoms. Its incidence is rising. BE is also underdiagnosed; with an autopsy study finding for every known case, 20 remain undiagnosed.
Progression from BE to EAC occurs at a rate of 0.5% to 1% per patient year of follow-up and patients have a 30- to 125-times increased risk of developing EAC compared with the general population. Those most at risk include white men of increasing age; smokers; those with frequent, severe reflux of long duration; and those with low fruit and vegetable intake with a raised body mass index (BMI). Helicobacter cagA strain is thought to be protective. Incidence of EAC is highest in the United Kingdom (5.8 to 8.7 per 100,000), followed by Australia (4.8 per 100,000), Netherlands (4.4 per 100,000), and the United States (3.7 per 100,000). The progression from Barrett to adenocarcinoma occurs via a multistep process through squamous epithelium to columnar-lined epithelium, specialized intestinal metaplasia to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinoma with later invasion and metastasis. This process is thought to develop slowly over several years, which lends BE as a perfect model with which to study chemoprevention. Median time to diagnosis of columnar-lined esophagus from start of symptoms was 2.6 years, to intestinal metaplasia 5.0 years, and to LGD 30 years in a large (1082 patients), multicenter cohort study ; 10% had HGD at 9.6 years and 10% EAC at 13.8 years in the same cohort. The aim of chemoprevention is to prevent or slow the progression along the metaplastic-dysplastic carcinoma spectrum to allow cancers to be prevented or picked up at an earlier stage to allow more effective treatment by earlier intervention.
Paradigm of chemoprevention
EAC is an aggressive disease with poor prognosis, making chemoprevention a desirable prospect. The few treatment options are associated with high mortality and morbidity. Despite an increased understanding of the progression of the disease and advances in surgical techniques, mortality from this condition has changed little. The alternative strategies to preventing or reducing mortality from Barrett associated EAC are not without their controversies. These include screening, surveillance to pick up EAC before symptomatic presentation, lifestyle modifications, treatment of HGD, and identification of biomarkers that predispose individuals to a higher risk of developing EAC ( Fig. 1 ). Surveillance is proposed as cost effective when the incidence of cancer is at least 0.5% to 1%. Less than this is not cost effective; therefore, the rate of malignant transformation is pivotal. If EAC is picked up at a stage when it is confined to the esophagus, there is a 70% 5-year survival. Challenges facing surveillance include low adherence to guidelines and considerable inter- and intraobserver variations between pathologists on the degree of dysplasia present. The authors hope to see downstaging of EAC and not just a longer lead time. This has to be balanced against the morbidity and mortality associated with surveillance. It has been proposed that surveillance combined with chemoprevention is a cost-effective way of preventing EAC. Smoking and raised BMI are associated with an increased risk of developing EAC. Patients with a raised BMI are also more likely to develop BE.
However, none of these are yet adequately validated for clinical use. Identifying those patients most at risk of developing cancer means chemoprevention can be effectively tailored toward those most at need to optimize the risk-benefit ratio and minimize risk of side-effects of chemoprevention to those at lower risk. Biomarkers predicting malignant potential are currently being studied. These include p16, p53, cyclin D1, aneuploidy, tetraploidy, E-cadherin, tumor necrosis factor a (TNF-a), b-catenin, c-Myc, cyclooxygenase 2 (COX-2), and prostaglandin E2 (PGE2).
A good chemoprevention agent needs to be effective at reducing EAC, with an acceptable side-effect profile. It also needs to be cost effective and acceptable to patients taking it. EAC has a low incidence even in patients with BE; therefore, chemoprevention trials need large numbers of patients with long follow-up and a safe medication. The cost-effectiveness of screening and chemoprevention relies on how effective the medication is at preventing progression to cancer. Chemoprevention is more cost effective in high-risk groups, such as those with HGD, even in higher-cost or less-effective interventions. Approaches to chemoprevention include targeting those at high risk or using a safe medication with other recognized health benefits. Compliance is a major issue with chemoprevention. Patients generally feel well. Compliance of taking aspirin (100 mg) on alternate days was 75% at 5 years and 67% at 10 years. A study of 39,876 women showed no protective benefit of aspirin in preventing any cancers. If study subjects fall short of good compliance, the general population may do even less well. A chemopreventive agent that was safe, cheap, effective, and acceptable would have great impact on not only on cancer reduction but also on health economics.
Possible agents
There are no agents licensed currently for chemoprevention in BE. There have been many agents suggested as having a chemopreventive effect ( Fig. 2 ). The medications gaining the most interest have been nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors and aspirin, and proton pump inhibitors (PPIs). Others that have been suggested include statins, green tea, antioxidants, vitamins A and E, curcumin, telomerase inhibitors, folic acid, berries, ornithine decarboxylase, matrix metalloproteinase inhibitors, and anti–vascular endothelial growth factor (VEGF) monoclonal antibodies. The role and research of some of these agents are discussed, with particular focus on NSAIDs and PPIs.
Food Groups
A large prospective cohort study followed 490,802 people for 2,193,751 person years of follow-up. High fruit and vegetable intake was found to reduce the risk of developing esophageal squamous cell carcinoma (hazard ratio [HR] 0.78; 95% CI, [0.57–0.93] but not EAC HR 0.98 [0.9–1.08]), with stronger protective relationship for fruit when analyzed further. There was an inverse relationship between intake of Chenopodiaceae (spinach) and risk of developing EAC (HR 0.66; 95% CI, [0.46–0.95]), with a nonsignificant trend toward cruciferae being protective, suggesting green vegetables containing nutrients, such as isothiocyanates, may be protective. A further, retrospective population-based case-control study was performed by Chen and colleagues. They interviewed 124 EAC patients, 124 distal gastric cancer patients, and 449 controls (or their proxy) about their food intake in the years before diagnosis. They found those with highest intake of vitamin A, β-cryptoxanthin, riboflavin, folate, zinc, fiber, protein, and carbohydrates were associated with a 40% to 50% lower incidence of EAC than those consuming the lowest amounts and found increased risk with those found consuming the most fat. The study was potentially limited by the risk of recall bias. Folate and riboflavin (necessary for DNA metabolism) deficiencies also interfere with DNA repair and methylation.
Antioxidants
Low manganese superoxide dismutase (MnSOD) levels are associated with higher rates of BE and EAC. Supplementation of MnSOD in animal models has been shown to reduce oxidative stress DNA injury and has been proposed for preventing malignant transformation.
Cyclin-Dependent Kinase Inhibitors
Flavopiridol (cyclin-dependent kinase inhibitor) reduced the prevalence of BE and EAC in p27-deficient mice. Down-regulation of cyclin D1 occurred. Limitations of use as a chemopreventive agent include intravenous administration and side-effects, such as diarrhea, asthenia, neutropenia, and clotting problems.
Retinoic Acid
Retinoids have been trialed as a chemopreventive agent; however, the trial was halted due to side-effect of esophaeal ulceration. Dietary deficiency of β-carotene (vitamin A provitamin) is associated with increased risk of EAC in epidemiologic studies. All- trans retinoic acid has been shown to induce apoptosis and increases p53 expression in a metaplastic Barrett cell line. The development of less toxic retinoids may play a future role in chemoprevention.
Telomerase Inhibitors
Telomerase activity has been shown elevated in Barrett adenocarcinoma cell lines. It is thought that Barrett EAC stimulated telomerase, leading to unchecked proliferation. Use of 2,6-bis[3-(N-piperidino)propionamido]anthracene-9,10-dione (PPA), a G-complex intercalating telomerase inhibitor, led to growth arrest, reduced colony number and increased apoptosis and reduction in telomerase activity, raising the possibility of use in chemoprevention.
Lyophilized Black Raspberries
Lyophilized black raspberries have been shown in animal models to reduce cancer development in gastrointestinal tract cancers, and research in vitro has supported this. Kresty and colleagues performed a trial of the use of lyophilized black raspberries daily for 6 months in patients with BE. They measured urinary markers of oxidative stress in these patients and found a marked reduction. Significant weight gain was observed during the study postulated as due to extra calories consumed from the raspberries.
Polyphenols
Polyphenols are found in green tea and berries, among other products. Green tea consumption in Asian studies is linked to a lower rate of several cancers, including colorectal cancer. Polyphenols have been shown to exert a chemopreventive effect in carcinogenic cell line studies. Resveratol is found in grape skin and red wine. It is thought to exert an antioxidant effect. In animal studies, a reduction of intestinal metaplasia and cancer was found, but this did not reach statistical significance.
Proton Pump Inhibitors
In a Minnesota population, 19.8% reported at least weekly reflux symptoms, and prevalence of heartburn was 42%. The most intuitive agents for chemoprevention of EAC seem to be PPIs. These are used to improve gastroesophageal reflux disease symptoms and induce mucosal healing in erosive reflux esophagitis that makes diagnosis of Barrett and dysplasia more difficult. Use of PPIs since their release 20 years ago has rocketed, but the rate of EAC has not been reduced; it has increased exponentially during this time. Those patients with regular heartburn (once a week) had 7.7% increased risk of developing EAC. The longest duration of gastroesophageal reflux (more than 20 years) and more severe symptoms were associated with a 43.3 odds ratio (OR) of developing EAC. The Factors Influencing the Barrett’s Adenocarcinoma Relationship (FINBAR) study found patients with BE 18 times more likely (and those with EAC 3 times more likely) than controls to have severe reflux and reflux of longer duration. Because reflux is associated with increased risk of EAC, it seems logical that by treating reflux the risk of developing cancer also is reduced. It has been shown that even when rendered asymptomatic from gastroesophageal reflux with lansoprazole (15–30 mg), 40% of patients with BE had incomplete acid suppression as judged by 24-hour pH studies. Therefore, if the aim of treatment is effective acid suppression, 24-hour pH studies may be necessary to titrate doses. Barrett mucosa is less sensitive than squamous epithelium. This study demonstrates symptoms guiding reflux treatment are not reliable.
An Australian study of 350 patients with BE, with a mean follow-up of 4.7 years, found use of PPIs reduced progression to LGD and HGD. The investigators found that patients who used PPI therapy had a mean time to diagnosis of LGD of 14.1 years (95% CI, 13.1–15.0); 19% developed LGD during the study, in contrast to those who did not start a PPI on enrollment in a mean time to diagnosis of 8.8 years. Within 3.2 years of enrollment, 50% developed LGD. A delay of 2 years in commencing PPI therapy led to 5.6-times increased risk of LGD, compared with those starting a PPI within a year of commencing surveillance, and to 20.9-times increased risk (2.8–158) of progressing to HGD or EAC compared with those whose PPI therapy was not delayed. A Veterans Affairs study found PPI use reduced the risk of development of EAC or HGD by 61%. Lao-Sireix and colleagues showed that effective acid suppression reduced proliferation in BE but had no effect on expression of COX-2, c-Myc, or apoptosis. Continuous acid suppression is desirable because pulsed therapy has been shown to induce proliferation and lead to dysplasia. Continuous acid suppression leads to differentiation and less risk of dysplasia. PPI use is known to increase gastrin levels and hypergastrinemia has been associated with increased COX-2 expression.
Possible agents
There are no agents licensed currently for chemoprevention in BE. There have been many agents suggested as having a chemopreventive effect ( Fig. 2 ). The medications gaining the most interest have been nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors and aspirin, and proton pump inhibitors (PPIs). Others that have been suggested include statins, green tea, antioxidants, vitamins A and E, curcumin, telomerase inhibitors, folic acid, berries, ornithine decarboxylase, matrix metalloproteinase inhibitors, and anti–vascular endothelial growth factor (VEGF) monoclonal antibodies. The role and research of some of these agents are discussed, with particular focus on NSAIDs and PPIs.
Food Groups
A large prospective cohort study followed 490,802 people for 2,193,751 person years of follow-up. High fruit and vegetable intake was found to reduce the risk of developing esophageal squamous cell carcinoma (hazard ratio [HR] 0.78; 95% CI, [0.57–0.93] but not EAC HR 0.98 [0.9–1.08]), with stronger protective relationship for fruit when analyzed further. There was an inverse relationship between intake of Chenopodiaceae (spinach) and risk of developing EAC (HR 0.66; 95% CI, [0.46–0.95]), with a nonsignificant trend toward cruciferae being protective, suggesting green vegetables containing nutrients, such as isothiocyanates, may be protective. A further, retrospective population-based case-control study was performed by Chen and colleagues. They interviewed 124 EAC patients, 124 distal gastric cancer patients, and 449 controls (or their proxy) about their food intake in the years before diagnosis. They found those with highest intake of vitamin A, β-cryptoxanthin, riboflavin, folate, zinc, fiber, protein, and carbohydrates were associated with a 40% to 50% lower incidence of EAC than those consuming the lowest amounts and found increased risk with those found consuming the most fat. The study was potentially limited by the risk of recall bias. Folate and riboflavin (necessary for DNA metabolism) deficiencies also interfere with DNA repair and methylation.
Antioxidants
Low manganese superoxide dismutase (MnSOD) levels are associated with higher rates of BE and EAC. Supplementation of MnSOD in animal models has been shown to reduce oxidative stress DNA injury and has been proposed for preventing malignant transformation.
Cyclin-Dependent Kinase Inhibitors
Flavopiridol (cyclin-dependent kinase inhibitor) reduced the prevalence of BE and EAC in p27-deficient mice. Down-regulation of cyclin D1 occurred. Limitations of use as a chemopreventive agent include intravenous administration and side-effects, such as diarrhea, asthenia, neutropenia, and clotting problems.
Retinoic Acid
Retinoids have been trialed as a chemopreventive agent; however, the trial was halted due to side-effect of esophaeal ulceration. Dietary deficiency of β-carotene (vitamin A provitamin) is associated with increased risk of EAC in epidemiologic studies. All- trans retinoic acid has been shown to induce apoptosis and increases p53 expression in a metaplastic Barrett cell line. The development of less toxic retinoids may play a future role in chemoprevention.
Telomerase Inhibitors
Telomerase activity has been shown elevated in Barrett adenocarcinoma cell lines. It is thought that Barrett EAC stimulated telomerase, leading to unchecked proliferation. Use of 2,6-bis[3-(N-piperidino)propionamido]anthracene-9,10-dione (PPA), a G-complex intercalating telomerase inhibitor, led to growth arrest, reduced colony number and increased apoptosis and reduction in telomerase activity, raising the possibility of use in chemoprevention.
Lyophilized Black Raspberries
Lyophilized black raspberries have been shown in animal models to reduce cancer development in gastrointestinal tract cancers, and research in vitro has supported this. Kresty and colleagues performed a trial of the use of lyophilized black raspberries daily for 6 months in patients with BE. They measured urinary markers of oxidative stress in these patients and found a marked reduction. Significant weight gain was observed during the study postulated as due to extra calories consumed from the raspberries.
Polyphenols
Polyphenols are found in green tea and berries, among other products. Green tea consumption in Asian studies is linked to a lower rate of several cancers, including colorectal cancer. Polyphenols have been shown to exert a chemopreventive effect in carcinogenic cell line studies. Resveratol is found in grape skin and red wine. It is thought to exert an antioxidant effect. In animal studies, a reduction of intestinal metaplasia and cancer was found, but this did not reach statistical significance.
Proton Pump Inhibitors
In a Minnesota population, 19.8% reported at least weekly reflux symptoms, and prevalence of heartburn was 42%. The most intuitive agents for chemoprevention of EAC seem to be PPIs. These are used to improve gastroesophageal reflux disease symptoms and induce mucosal healing in erosive reflux esophagitis that makes diagnosis of Barrett and dysplasia more difficult. Use of PPIs since their release 20 years ago has rocketed, but the rate of EAC has not been reduced; it has increased exponentially during this time. Those patients with regular heartburn (once a week) had 7.7% increased risk of developing EAC. The longest duration of gastroesophageal reflux (more than 20 years) and more severe symptoms were associated with a 43.3 odds ratio (OR) of developing EAC. The Factors Influencing the Barrett’s Adenocarcinoma Relationship (FINBAR) study found patients with BE 18 times more likely (and those with EAC 3 times more likely) than controls to have severe reflux and reflux of longer duration. Because reflux is associated with increased risk of EAC, it seems logical that by treating reflux the risk of developing cancer also is reduced. It has been shown that even when rendered asymptomatic from gastroesophageal reflux with lansoprazole (15–30 mg), 40% of patients with BE had incomplete acid suppression as judged by 24-hour pH studies. Therefore, if the aim of treatment is effective acid suppression, 24-hour pH studies may be necessary to titrate doses. Barrett mucosa is less sensitive than squamous epithelium. This study demonstrates symptoms guiding reflux treatment are not reliable.
An Australian study of 350 patients with BE, with a mean follow-up of 4.7 years, found use of PPIs reduced progression to LGD and HGD. The investigators found that patients who used PPI therapy had a mean time to diagnosis of LGD of 14.1 years (95% CI, 13.1–15.0); 19% developed LGD during the study, in contrast to those who did not start a PPI on enrollment in a mean time to diagnosis of 8.8 years. Within 3.2 years of enrollment, 50% developed LGD. A delay of 2 years in commencing PPI therapy led to 5.6-times increased risk of LGD, compared with those starting a PPI within a year of commencing surveillance, and to 20.9-times increased risk (2.8–158) of progressing to HGD or EAC compared with those whose PPI therapy was not delayed. A Veterans Affairs study found PPI use reduced the risk of development of EAC or HGD by 61%. Lao-Sireix and colleagues showed that effective acid suppression reduced proliferation in BE but had no effect on expression of COX-2, c-Myc, or apoptosis. Continuous acid suppression is desirable because pulsed therapy has been shown to induce proliferation and lead to dysplasia. Continuous acid suppression leads to differentiation and less risk of dysplasia. PPI use is known to increase gastrin levels and hypergastrinemia has been associated with increased COX-2 expression.
Related posts:
Barrett’s Esophagus: Clinical Issues
Barrett’s Esophagus Surveillance: When, How Often, Does It Work?
Biology of Barrett’s Esophagus and Esophageal Adenocarcinoma
Cryotherapy for Barrett’s Esophagus: Who, How, and Why?
The Role of Radiofrequency Ablation in the Management of Barrett’s Esophagus
Endotherapy for Barrett’s Esophagus: Which, How, When, and Who?
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