Accepted Manuscript Esophageal adenocarcinoma: the influence of medications used to treat comorbidities on cancer prognosis Aaron P. Thrift

PII: DOI: Reference:

S1542-3565(15)00362-6 10.1016/j.cgh.2015.03.028 YJCGH 54235

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 25 March 2015 Please cite this article as: Thrift AP, Esophageal adenocarcinoma: the influence of medications used to treat comorbidities on cancer prognosis, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/ j.cgh.2015.03.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

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Esophageal adenocarcinoma: the influence of medications used to treat comorbidities on cancer prognosis

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Aaron P. Thrift Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine,

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Houston, Texas

Correspondence: Aaron P. Thrift, Ph.D., Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, MS: BCM305, Houston, Texas, 77030-3498. Tel: 713-798-9107;

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Fax: 713-798-3658; E-mail: [email protected]

Conflicts of Interest: No relevant conflicts of interest exist.

Financial support: None.

Figures and Tables: 0.

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Article length (including references): 5,596.

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Abbreviations used in this paper: COX-2, Cyclooxygenase-2; H2RA, histamine receptor antagonist; NSAID, non-steroidal anti-inflammatory drugs PPI, proton-pump inhibitor; SEER,

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Surveillance, Epidemiology and End Results.

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ABSTRACT Esophageal adenocarcinoma has undergone a continuous rise in incidence since the early 1970s and is the fastest rising cancer among white men in the United States. Epidemiological studies have demonstrated that medications commonly used to treat multiple chronic conditions (for

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example, aspirin, non-aspirin non-steroidal anti-inflammatory drugs, and statins) as well as

powerful acid-suppressants such as proton-pump inhibitors are associated with a reduced risk of esophageal adenocarcinoma. The chemopreventive potential of these classes of medications appears to be especially applicable to persons with Barrett’s esophagus, the only known pre-

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malignant condition for esophageal adenocarcinoma. However, it is not known whether these medications also influence cancer recurrence and cancer-specific mortality in persons diagnosed

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with esophageal adenocarcinoma. This is an important question as most patients with esophageal adenocarcinoma suffer from one or more comorbid conditions at the time of their cancer diagnosis, and are receiving medication to treat these conditions. This paper summarizes the evidence on the associations between four commonly used classes of medications and (1) risk of developing esophageal adenocarcinoma and Barrett’s esophagus, and (2) risk of cancer

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recurrence and cancer-specific mortality in patients with esophageal adenocarcinoma.

Keywords: Aspirin; Barrett’s esophagus; Cancer outcomes; Metformin; NSAIDs; Statins;

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Survival.

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Esophageal cancer is the eighth most common malignancy and the sixth leading cause of cancer death in the world.1 A total of 18,170 new cases of esophageal cancer and 15,450 deaths from esophageal cancer were expected to occur in the United States in 2014.2 The two most common histologic types of esophageal cancer are adenocarcinoma and squamous cell carcinoma. The

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epidemiology of the two histologic types is very different. Esophageal adenocarcinoma is now the most common histologic type of esophageal cancer in many Western countries, and is the fastest rising cancer among white men in the United States.3-5 The most recent data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute

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show that the overall annual incidence of esophageal adenocarcinoma in the United States

increased nine-fold (from 0.3 to 2.7 per 100,000) between 1973 and 2011, and 10-fold among

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white men (from 0.6 to 6.0 per 100,000) for the same time period.6 The increase in incidence of esophageal adenocarcinoma is thought to be predominantly due to increases in the prevalence of gastroesophageal reflux disease and obesity,7 combined with declining rates of Helicobacter pylori infection in Western populations. Conversely, the incidence of esophageal squamous cell carcinoma has decreased,3, 5 due to declining rates of cigarette smoking and heavy alcohol consumption in the United States and elsewhere.8

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Age, sex and ethnicity/race are predictors of cancer risk. Esophageal adenocarcinoma is rare in persons under the age of 50 years. Based on SEER data, esophageal adenocarcinoma incidence increases with age and peak incidence is seen in the seventh decade of life (median age at diagnosis is 67 years).9 A remarkable feature of esophageal adenocarcinoma is the sex ratio,

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with eight-fold higher incidence observed in white men compared with white women.10 This marked male predominance has remained fairly constant over time.5 Esophageal adenocarcinoma is especially rare in non-white ethnic/racial groups; however, the incidence of esophageal

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adenocarcinoma has also increased in these minority populations in the United States.10 Esophageal adenocarcinoma is an aggressive and invasive cancer and patients with

esophageal adenocarcinoma have poor clinical outcomes. Unfortunately, curative treatment is applied to a relatively small proportion of patients with esophageal adenocarcinoma who get diagnosed at an early stage and, overall, patients with esophageal adenocarcinoma have survival rates that are among the lowest for all cancers, similar to cancers of the liver, lung and pancreas. Five-year survival is less than 40% for localized and remains less than 5% for distant disease.11 In all groups of patients however, there are notable long-term survivors, even among those 3

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treated with palliative therapy. There is evidence that environmental factors (for example, smoking, alcohol, diet or use of medications such as aspirin and statins) influence tumor aggressiveness, recurrence and survival in breast, prostate and colon cancers but there is little

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direct evidence as to whether the same is true for patients with esophageal adenocarcinoma.

Barrett’s esophagus

Barrett’s esophagus is the only known premalignant condition for esophageal adenocarcinoma,12 and is present in approximately 10% of patients with frequent gastroesophageal reflux disease

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symptoms and 1% to 2% of the general adult population.13, 14 Like esophageal adenocarcinoma, the incidence of Barrett’s esophagus has increased in many Western populations.13 Persons with Barrett’s esophagus have 30- to 40-fold higher risk of esophageal adenocarcinoma than the

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general population.15, 16 Consequently, persons with Barrett’s esophagus are often entered into a program of periodic endoscopic biopsy surveillance with the aim of reducing morbidity and mortality associated with esophageal adenocarcinoma. However, approximately 95% of patients with Barrett’s esophagus will never progress to esophageal adenocarcinoma and data are conflicting on whether or not these patients benefit from long-term surveillance.17-21

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Furthermore, only approximately 5% of patients with esophageal adenocarcinoma have a diagnosis of Barrett’s esophagus prior to their cancer diagnosis; however, it is worth noting that most of this evidence comes from relatively old data.20, 22-25

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Cancer chemoprevention

Cancer chemoprevention aims to use chemical agents to block, reverse, or delay the development

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of invasive cancer. There is strong evidence of a chemopreventive effect for aspirin or nonaspirin non-steroidal anti-inflammatory drugs (NSAIDs) on risk of cancer, particularly for the association between aspirin use and lower risk of colorectal cancer.26 As such, these medications have been recommended for chemoprevention of cancer in persons considered at high-risk.27 Cyclooxygenase-2 (COX-2) is an inflammation-associated enzyme and the majority of NSAIDs inhibit cancer cell growth through the inhibition of COX-2 expression and thus endogenous prostaglandin synthesis.28, 29 COX-2 expression levels increase along the esophageal inflammation-metaplasia-dysplasia-carcinoma sequence and may be a target for chemoprevention in esophageal adenocarcinoma.30-36 A pooled analysis of individual-level 4

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participant data from five population-based case-control studies and one cohort study in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON; http://beacon.tlvnet.net) found 32% lower risk of esophageal adenocarcinoma associated with any NSAID use (OR=0.68, 95%CI 0.56-0.83); the magnitude of the inverse association was similar for aspirin (OR=0.77,

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95%CI 0.60-0.97) and non-aspirin NSAID (OR=0.81, 95%CI 0.67-0.96) users (versus non-users of these classes of medication).37 Similar associations were reported in an earlier meta-analysis of nine case-control studies and one cohort study (vs. non-users: any aspirin use, OR=0.64,

95%CI 0.52-0.79; any non-aspirin NSAID use, OR=0.65, 95%CI 0.50-0.85).38 Aspirin and non-

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aspirin NSAIDs appear to have their greatest effect in preventing progression from Barrett’s esophagus to esophageal adenocarcinoma and/or high-grade dysplasia. While observational data are somewhat conflicting (e.g., aspirin and non-aspirin NSAIDs may also prevent the

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development of Barrett’s esophagus in the first place39-43), results from two prospective cohort studies among patients with Barrett’s esophagus suggest up to 70% lower risk of neoplastic progression associated with any use of NSAIDs.44, 45 However, clinical trial data are limited. One randomized trial found no effect of celecoxib treatment on risk of progression (defined as a change from baseline in the proportion of biopsy samples diagnosed with dysplasia or cancer) in

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patients with Barrett’s esophagus.46 They also found no effect of celecoxib treatment on any esophageal adenocarcinoma-associated biomarkers. In another clinical trial, patients taking short-term daily aspirin therapy (325 mg) together with twice daily esomeprazole had reduced production of prostaglandin E2 in Barrett’s esophagus tissue; however, the study was not

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designed to assess hard clinical endpoints (e.g., esophageal adenocarcinoma and/or high-grade dysplasia).47 The ongoing AspECT trial could provide more definitive evidence.48 This large

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multicenter phase III randomized trial aims to evaluate the effect of long-term esomeprazole with or without aspirin therapy on neoplastic progression among patients with Barrett’s esophagus. Statins or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are

one of the most commonly used drugs in the United States.49 In addition to their role in heart disease prevention, it is proposed that statins may decrease a person’s risk of developing cancer. By inhibiting HMG-CoA reductase, statins lower intracellular levels of mevalonate and its downstream products which are important in cellular homeostasis, cell signaling, protein synthesis, and cell cycle development.50 Results from mechanistic studies of cancer cell lines demonstrate the pro-apoptotic, anti-proliferative, and anti-invasive potential of statins.50 In 5

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Barrett’s esophagus and esophageal adenocarcinoma cell lines, statins decrease cell proliferation and stimulate apoptosis.51, 52 Few studies have examined the association between the use of statins and the risk of esophageal adenocarcinoma. In their case-control study comparing esophageal adenocarcinoma patients with hospital-based controls, Beales et al. found 48% lower

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risk of esophageal adenocarcinoma associated with any statin use (OR=0.52, 95%CI 0.27-

0.92).53 Likewise, a nested case-control study within the UK General Practice Research Database reported an odds ratio of 0.58 (95%CI 0.39-0.87) associated with regular statin use, and risk decreased linearly with increasing duration of use (P for trend=0.005).54 While results are

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somewhat conflicting, perhaps reflecting issues of study design, there is increasing evidence that statin use may not only prevent progression from Barrett’s esophagus to esophageal adenocarcinoma,45, 55-58 but may also reduce a person’s risk of developing Barrett’s esophagus in

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the first place.41, 59 Importantly, the magnitude of the inverse association with statin use is especially strong among those also using NSAIDs.45, 53, 55, 56

Proton-pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs) have the ability to decrease gastric acid and bile production and are the most commonly used medications in the management of gastroesophageal reflux disease. It has been shown that bile acids promote

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COX-2 expression in the esophagus.32, 60 Thus, by reducing the amount of bile and stomach acid than refluxes into the lower esophagus, it is hypothesized that PPIs and H2RAs subsequently promote healing of the mucosal barrier in persons with gastroesophageal reflux disease and Barrett’s esophagus. The concomitant anti-inflammatory properties of PPIs may also contribute

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to their chemopreventive potential for esophageal adenocarcinoma.61 Well-conducted epidemiological studies of the association between acid-suppressant therapy and risk of

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esophageal adenocarcinoma are few and the interpretation of the results from these studies are limited by small numbers of events, limited adjustment for possible confounders and issues of selection bias.57, 62-66 However, a recently published meta-analysis of five cohort studies found 67% lower risk of progression to esophageal adenocarcinoma and/or high-grade dysplasia in patients with Barrett’s esophagus that had a history of PPI use (OR=0.33, 95%CI 0.19-0.58; with low between-study heterogeneity, I2=10%); there were too few studies of H2RAs to evaluate its role in esophageal neoplastic progression.67 Obesity, especially visceral abdominal obesity, is associated with increased risks of Barrett’s esophagus and neoplastic progression in patients with Barrett’s esophagus.68-70 6

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Additionally, a meta-analysis of three case-control studies found that persons with diabetes had two-fold increased risk for esophageal adenocarcinoma (summary RR=2.12, 95%CI 1.01-4.46); with moderate between-study heterogeneity, I2=60%).71 It has been suggested that obesity may promote esophageal adenocarcinoma (as well as other obesity-related cancers) via activation of

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the insulin/insulin-like growth factor (IGF) pathway.72 Metformin, one of the most commonly used drugs to treat diabetes mellitus, lowers serum insulin levels. It activates AMP-activated protein kinase, which has downstream effects of reduced cellular proliferation and protein

synthesis.73 Overall, it is still too early to know whether metformin may be used to prevent

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cancer. For esophageal adenocarcinoma, a recent study found no support for metformin as a

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chemopreventive agent for neoplastic progression in patients with Barrett’s esophagus.74

Cancer outcomes

While treatment effectiveness has improved modestly over recent years, median survival for patients with esophageal adenocarcinoma remains less than 12 months.75 There is a need to investigate options for those with cancer, that is, are there factors that contribute to better outcomes after diagnosis? At the time of their diagnosis, persons with cancer are frequently

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laden with multiple comorbid conditions such as cardiovascular disease, diabetes, and hypertension. As such, these patients have a history of frequent prescription and over-the-counter medication use to manage these co-morbid conditions and to improve their overall quality of life. There is a growing body of evidence to suggest that commonly used medications may prevent

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cancer recurrence and reduce cancer-specific mortality (i.e., have therapeutic benefit), while use of some commonly used medications adversely affect cancer outcomes. A better understanding

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of the effects of current and future use of these and other medications on cancer outcomes is important for successful management of all co-existing comorbid conditions while not adversely influencing the patient’s risk of cancer recurrence and cancer-specific mortality. There is an increasing literature supporting the association between aspirin and reduced

risk of cancer recurrence and mortality. Colorectal cancer is well characterized in this regard, with the majority of studies conducted among prospective cohorts of patients diagnosed with colorectal cancer reporting lower colorectal cancer-specific mortality among users of any aspirin or non-aspirin NSAIDs.76-82 Specifically, post-diagnosis use of aspirin or non-aspirin NSAIDs is associated with statistically significant lower colorectal cancer-specific mortality,76, 80, 82 with 7

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stronger effects observed among patients overexpressing COX-277 or with mutations in PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene).81 Post-diagnosis use of aspirin or non-aspirin NSAIDs may reduce risk of recurrence and/or cancer-specific mortality in patients with breast83-90 and prostate91-96 cancers; however, the

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results are somewhat conflicting and additional studies examining these associations across the different molecular subtypes of breast and prostate cancers may help clarify the role of these medications in patient outcomes. For esophageal cancer, the data are limited. Two studies,

following cancer patients recruited initially as cases in case-control studies aimed to identify

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esophageal cancer risk factors, found no association between per-diagnosis aspirin or non-aspirin NSAID use and all-cause mortality.97, 98 However, these studies may suffer from bias (selection,

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survival and information), examined crude self-reported measures and were limited to prediagnosis use.

There has been interest for several years in the potential role of statins in modifying outcomes (recurrence and mortality) in cancer patients. These studies have been generally well designed and used data from automated pharmacy and/or medical records rather than relying on self-reported use. While the results from these studies have been conflicting, especially for

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cancer-specific associations, a large population-based study among cancer patients in the entire Danish population (n=295,925 patients with cancer, with n=162,067 cancer-specific deaths) found that statin users were 15% less likely to die that non-users (HR=0.85, 95%CI 0.82-0.87). The risk estimates varied by individual cancers, but statin use was associated with lower

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mortality for 13 cancers.99 Hazard ratios varied from 0.68 for Pharynx (95%CI 0.55-0.85) and Larynx (95%CI 0.49-0.93) cancers to 0.91 for pancreatic cancer (95%CI 0.81-0.99). When they

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examined 4,398 esophageal cancer patients (with n=3,328 esophageal cancer-specific deaths), there was a statistically significant inverse relationship between statin use and esophageal-cancer specific mortality (HR=0.81, 95%CI 0.69-0.95).99 This study used data from a single time point pre-diagnosis and did not examine post-diagnosis statin use. No study has specifically addressed this relationship among patients with esophageal adenocarcinoma. Likewise, it is unknown whether clinical use of PPIs and H2RAs for preventing acid reflux may reduce cancer recurrence and cancer-specific mortality in patients with esophageal adenocarcinoma. Acid reflux symptoms are also an independent risk factor for squamous cell cancers of the head and neck, and once diagnosed, patients are commonly treated with these 8

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acid-suppressants as part of their cancer treatment (e.g., for the management of acid reflux and to prevent complications from conventional therapies related to acid reflux). A recently published study in patients with head and neck squamous cell cancers demonstrated a protective effect for PPIs and H2RAs.100 If these acid suppressants were shown to be associated with better outcomes

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in patients with esophageal adenocarcinoma then elucidation of their biological effects on tumor progression could lead to new strategies for cancer prevention and treatment.

There is some evidence that metformin use may lower risk of cancer recurrence and cancer-specific mortality; however, associations vary across cancer sites.101-109 The inconsistent

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findings across studies may be due to their retrospective design, inappropriate comparators or the use of exposure data from sources such as medical records and automated pharmacy databases.

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Data are scarce for esophageal adenocarcinoma. In a retrospective study of patients with esophageal adenocarcinoma, metformin use was associated with a dose-dependent increased response to treatment (chemotherapy).110 Metformin has also been shown to inhibit the growth of three esophageal cancer cell lines in vitro.111

Conclusions

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The data presented above from well-conducted observational studies lends support to the role of chemoprophylaxis with NSAIDs, statins and/or PPIs in patients with Barrett’s esophagus (and/or gastroesophageal reflux disease to prevent Barrett’s esophagus). Furthermore, clinical trial evidence is somewhat suggestive of a chemopreventive role for PPIs combined with high-dose

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aspirin (using surrogate endpoints). However, no data are available from large randomized trials with definitive endpoints, and clinical practice guidelines do not endorse the use of PPIs and/or aspirin or non-aspirin NSAIDs solely for secondary prevention of esophageal adenocarcinoma in

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the absence of other indiciations.112 Until such time that evidence is available from wellconducted randomized trials, it is unlikely that these guidelines will change. As only 5% of persons with esophageal adenocarcinoma are diagnosed as a result of screening and surveillance for Barrett’s esophagus,113 it is also important to note that these chemopreventive strategies would be limited to the small fraction of cases that have been identified as having Barrett’s esophagus. A growing body of evidence suggests that these same medications (along with other medications used to treat diabetes or hypertension) may improve outcomes in patients following 9

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their cancer diagnosis. However, there have been no large studies that have both the power and access to detailed patient data to systematically evaluate the association between medication use (both pre- and post-diagnosis) and recurrence and mortality in patients with esophageal adenocarcinoma. New large observational studies, with careful consideration for methodological

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shortcomings like confounding in these studies, are needed to address this important knowledge

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gap, followed by clinical trials to confirm the results in these observational studies.

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Esophageal Adenocarcinoma: The Influence of Medications Used to Treat Comorbidities on Cancer Prognosis.

Esophageal adenocarcinoma has undergone a continuous rise in incidence since the early 1970s and is the fastest rising cancer among white men in the U...
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