Leo Alexandre

BOB CAT: a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

OBJECTIVES:Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).METHODS:We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.RESULTS:In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.CONCLUSIONS:In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Statin Use Is Associated With Reduced Risk of Histologic Subtypes of Esophageal Cancer: A Nested Case-Control Analysis

BACKGROUND & AIMS Most patients with esophageal adenocarcinoma (EAC) or squamous cell cancer (ESCC) present with advanced, incurable disease. Statins have reported anti-carcinogenic effects and may be chemoprotective. We investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and ESCC) in the UK general population. METHODS We identified all individuals in the UK General Practice Research Database diagnosed with esophageal cancer from 2000 through 2009. Patients were linked to the National Cancer Registry to confirm histologic subtypes. Each patient was matched with up to 4 controls for age, sex, and practice. We performed a nested case-control analysis using conditional logistic regression to estimate the risk of each subtype with regular statin use, adjusted for body mass index, smoking, alcohol intake, and concomitant use of medications. RESULTS In total, 581 participants with EAC, 213 with esophagogastric junctional adenocarcinoma, and 332 with ESCC were matched to 2167, 783, and 1242 controls, respectively. Regular statin use was inversely associated with development of EAC (odds ratio = 0.58; 95% confidence interval: 0.39-0.87) (with significant dose and duration responses) and esophagogastric junctional adenocarcinoma (odds ratio = 0.29; 95% confidence interval: 0.09-0.92) (with high-dose use only). Statin use for 1-4 years was inversely associated with ESCC (odds ratio = 0.51; 95% confidence interval: 0.27-0.98). CONCLUSIONS In a nested case-control analysis of a UK population-based cohort, statin use was inversely associated with histologic subtypes of esophageal cancer. Randomized controlled trials are warranted to determine whether statins have chemopreventive effects in high-risk groups.

Pathophysiological mechanisms linking obesity and esophageal adenocarcinoma

In recent decades there has been a dramatic rise in the incidence of esophageal adenocarcinoma (EAC) in the developed world. Over approximately the same period there has also been an increase in the prevalence of obesity. Obesity, especially visceral obesity, is an important independent risk factor for the development of gastro-esophageal reflux disease, Barretts esophagus and EAC. Although the simplest explanation is that this mediated by the mechanical effects of abdominal obesity promoting gastro-esophageal reflux, the epidemiological data suggest that the EAC-promoting effects are independent of reflux. Several, not mutually exclusive, mechanisms have been implicated, which may have different effects at various points along the reflux-Barretts-cancer pathway. These mechanisms include a reduction in the prevalence of Helicobacter pylori infection enhancing gastric acidity and possibly appetite by increasing gastric ghrelin secretion, induction of both low-grade systemic inflammation by factors secreted by adipose tissue and the metabolic syndrome with insulin-resistance. Obesity is associated with enhanced secretion of leptin and decreased secretion of adiponectin from adipose tissue and both increased leptin and decreased adiponectin have been shown to be independent risk factors for progression to EAC. Leptin and adiponectin have a set of mutually antagonistic actions on Barretts cells which appear to influence the progression of malignant behaviour. At present no drugs are of proven benefit to prevent obesity associated EAC. Roux-en-Y reconstruction is the preferred bariatric surgical option for weight loss in patients with reflux. Statins and aspirin may have chemopreventative effects and are indicated for their circulatory benefits.

Systematic review:potential preventive effects of statins against oesophageal adenocarcinoma

The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically in recent decades, and its prognosis remains extremely poor. There is emerging evidence that statins may prevent OAC.

Association Between Statin Use After Diagnosis of Esophageal Cancer and Survival: A Population-Based Cohort Study

BACKGROUND & AIMS Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), commonly prescribed in the primary and secondary prevention of cardiovascular disease, promote apoptosis and limit proliferation of esophageal cancer cell lines. We investigated whether statin use after a diagnosis of esophageal cancer is associated with reduced esophageal cancer-specific and all-cause mortality. METHODS We identified a cohort of 4445 men and women in the United Kingdom diagnosed with esophageal cancer from January 2000 through November 2009 using the General Practice Research Database. The National Cancer Registry and Office of National Statistics datasets established the histologic subtype and cancer-specific mortality, respectively. Cox proportional hazard regression analysis with time-dependent exposures estimated the association between statin use after diagnosis and esophageal cancer-specific and all-cause mortality. RESULTS The median survival time of the entire cohort was 9.2 months (interquartile range [IQR], 3.7-23.2 mo). Among subjects who used statins after a diagnosis of esophageal cancer, the median survival time was 14.9 months (IQR, 7.1-52.3 mo) compared with 8.1 months for nonusers (IQR, 3.3-20 mo). In the entire cohort, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86) and all-cause mortality (HR, 0.67; 95% CI, 0.58-0.77). In patients with esophageal adenocarcinoma, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (HR, 0.61; 95% CI 0.38-0.96) and all-cause mortality (HR, 0.63; 95% 0.43-0.92). This effect was not observed in patients with esophageal squamous cell carcinoma. There was no evidence for effect modification of these associations with statin use before the cancer diagnosis. CONCLUSIONS In a large population-based cohort, statin use after a diagnosis of esophageal adenocarcinoma, but not esophageal squamous cell carcinoma, was associated with reduced esophageal cancer-specific and all-cause mortality.

Meta-analysis: risk of esophageal adenocarcinoma with medications which relax the lower esophageal sphincter.

Reasons for the rising annual incidence of esophageal adenocarcinoma (EAC) remain uncertain. Previous studies have given conflicting results, but some have suggested that drugs which relax the lower esophageal sphincter (LES) may increase the risk of EAC. This study is to determine systematically the risk of EAC associated with individual medications which relax the LES and compare risks with esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Relevant published studies were identified by systematic searching PubMed for case-control studies reporting on risk of EAC, ESCC or GCA with use of medications known to reduce LES pressure. Pooled odds ratios (ORs) were calculated for each malignancy. Data were analyzed from four case-control studies involving 9,412 participants. EAC was significantly associated with theophylline use (OR 1.55, 95% confidence interval [CI] 1.05-2.28; P= 0.03, I(2) = 0%) and anticholinergic medications (OR 1.66, 95% CI 1.13-2.44; P= 0.01, I(2) = 84%). This effect was not observed in cases of ESCC or GCA. Other drug groups including calcium channel modulators and nitrates did not increase the risk of EAC. An inverse relationship was observed between ESCC and nitrates and between GCA and benzodiazepines. The lack of increased EAC risk with many commonly used medications is reassuring. However, a significant correlation was found between EAC and the use of anticholinergics and theophyllines. This may reflect common causality between obstructive lung disease and EAC, and further studies to explore these relationships are warranted.

Strategy for prevention of cancers of the esophagus

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux–inflammation models for Barretts esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine‐based combinations; the molecular derangements that promote neoplastic transformation; the role of COX‐2 inhibitors, proton pump inhibitors, and phase II trials in Barretts adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barretts adenocarcinoma.

PWE-109 A feasibility study of adjuvant statin therapy in the prevention of post-operative recurrence of oesophageal adenocarcinoma (the stat-roc feasibility study)

Introduction Preclinical studies have demonstrated statins inhibit proliferation, promote apoptosis and limit invasiveness of oesophageal adenocarcinoma (OAC) cell lines. Observational research has demonstrated significant improvements in mortality associated with statin use after diagnosis of OAC. We aimed to determine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III randomised controlled trial. Method For this multi-centre, double-blind, parallel group, randomised, placebo-controlled trial, eligible patients were adults with OAC or Siewert type I/II adenocarcinoma due surgery. Participants were recruited from four UK centres and randomly assigned (1:1) to simvastatin 40 mg or matching placebo by block randomisation, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Treatment started from the date of discharge following surgery and continued for up to one year. Feasibility assessments of recruitment, retention, drug absorption, adherence, safety, quality of life, generalisability, all-cause and disease-free survival were made. Trial registration: ISRCTN98060456. Results Between 23rd November 2014 and 22nd July 2016, 120 patients were assessed for eligibility, of which 32 (26.7%) were randomised. Of patients meeting eligibility criteria, 59.3% (32/54) were randomised. Patients allocated to simvastatin had significantly lower LDL cholesterol levels by three months (adjusted mean difference, −0.83 mmol/L, 95% CI −1.4 to −0.22, p=0.009). Median medication adherence for the preceding three months of follow-up at 3, 6, 9 and 12 months, respectively, was 83%, 94%, 99%, and 94%, with no significant differences in adherence between treatment groups. In total, 87.5% in the simvastatin group and 92.9% in the placebo group (p=0.626) experienced at least one adverse event. Completion of quality of life data was high (98.3% of questionnaire items) with no clinically significant differences observed between treatment groups. Cardiovascular disease (p=0.003), diabetes (p=0.003) and aspirin use (p=0.01) were more prevalent in the non-randomised group compared with the randomised group. There were no significant differences between groups for overall (p=0.716) or disease-free survival (p=0.807). Conclusion This RCT supports the feasibility of assessing adjuvant statin therapy in a future phase III trial in patients with operable OAC. Disclosure of Interest None Declared

Erratum: Addendum: BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia (The American journal of gastroenterology (2015) 110 5 (662-682))

Bennett, Cathy, Moayyedi, Paul, Corley, Douglas A, DeCaestecker, John, Falck-Ytter, Yngve, Falk, Gary, Vakil, Nimish, Sanders, Scott, Vieth, Michael, Inadomi, John, Aldulaimi, David, Ho, Khek-Yu, Odze, Robert, Meltzer, Stephen J, Quigley, Eamonn, Gittens, Stuart, Watson, Peter, Zaninotto, Giovanni, Iyer, Prasad G, Alexandre, Leo, Ang, Yeng, Callaghan, James, Harrison, Rebecca, Singh, Rajvinder, Bhandari, Pradeep, Bisschops, Raf, Geramizadeh, Bita, Kaye, Philip, Krishnadath, Sheila, Fennerty, M Brian, Manner, Hendrik, Nason, Katie S, Pech, Oliver, Konda, Vani, Ragunath, Krish, Rahman, Imdadur, Romero, Yvonne, Sampliner, Richard, Siersema, Peter D, Tack, Jan, Tham, Tony C K, Trudgill, Nigel, Weinberg, David S, Wang, Jean, Wang, Kenneth, Wong, Jennie Y Y, Attwood, Stephen, Malfertheiner, Peter, MacDonald, David, Barr, Hugh, Ferguson, Mark K and Jankowski, Janusz

Mo1542 Do Statins Prevent the Histological Subtypes of Esophageal Cancer? Prospective Data From the UK General Practice Research Database (GPRD)

Introduction The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically in the Western world and is associated with a poor prognosis. Statins show anti-cancer properties in experimental work with OAC cell lines for example reduced cell proliferation, increased apoptosis. This study aimed to investigate if statins are negatively associated with the development of two different histological subtypes of oesophageal cancer, OAC and oesophageal squamous cell cancer (OSCC), in a prospective cohort study. Methods The cohort was over 4 million people in the General Practice Research Database (GPRD), a UK database of 488 nationwide general practices. Information is recorded on medication use prior to development of other illnesses, including cancers. Statin use was defined as a prescription for a minimum of 10 months preceding diagnosis of oesophageal cancer. Approximately half the GP practices in the GPRD are linked to the NHS cancer registry, allowing identification and sub-classification of histologically confirmed cases of OAC and OSCC. Each case was matched with four controls and conditional logistic regression estimated the OR plus 95% CIs for the development of each type of cancer, adjusted for diabetes, BMI, smoking, aspirin, PPIs and drugs that relax the lower oesophageal sphincter. Results 581 histologically confirmed cases of OAC (77.8% men, mean age 70.7 years, SD=11.4) and 332 cases of OSCC (38.6% men, 71.9 years, SD=12.3) were identified between 2000 and 2008. The median length of statin use in cases and controls prior to diagnosis or index date was 3.9 years (IQR 2.3–6.1 years). Analysis by histological subtype showed an inverse association for OAC (OR 0.61, 95% CI 0.39 to 0.94) and for OSCC (OR 0.41, 95% CI 0.21 to 0.80). Categorisation into lipophilic and hydrophilic statins demonstrated significant inverse associations for only lipophilic statins for both OAC (OR 0.60, 95% CI 0.38 to 0.95) and OSCC (OR 0.46, 95% CI 0.23 to 0.91). There was a dose-response effect for statins and both OAC and OSCC (p Conclusion The data supports lipophilic statins having a protective effect against the development of both OAC and OSCC, with evidence of a dose-response trend. Confirmation in other populations is required. Detailed statin use, according to class and dose, should be measured in future aetiological studies of both OAC and OSCC. The information supports assessment of these drugs in chemoprevention of OAC in the general population and those with Barrett9s oesophagus in clinical trials. Competing interests None declared.