Ignite Creation Date:
2024-05-05 @ 6:59 PM
Last Modification Date:
2024-10-26 @ 9:40 AM
Study NCT ID:
NCT00586404
Status:
TERMINATED
Last Update Posted:
2017-05-30
First Post:
2007-12-21
Brief Title:
The Study of Barretts Esophagus What Are the Factors of Progression
Sponsor:
Midwest Biomedical Research Foundation
Organization:
Midwest Veterans Biomedical Research Foundation
Study Overview
Official Title:
Barretts Esophagus Study BEST Trial - a Multi-Center and Endoscopic Outcomes Project
Status:
TERMINATED
Status Verified Date:
2017-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
lack of enrollment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BEST
Brief Summary:
This trial is a multi-center clinical and endoscopic outcomes project involving a single large database of patients with Barretts Esophagus BE The initial goal of this project is to define the incidence and prevalence of cancer and high-grade dysplasia HGD in patients with BE Thus our hypothesis is that systematic collection of data on the natural history of BE and risk factors for progression of BE will provide useful information to develop a decision model for risk stratification and risk reduction strategies in BE
Detailed Description:
Barretts esophagus BE is defined as a change in the esophageal mucosa from normal squamous epithelium to columnar epithelium with intestinal metaplasia 1 There is compelling evidence that BE is a precursor lesion for adenocarcinoma of the esophagus 2 There is also evidence that the prevalence of BE is much higher than was initially suspected and that the true incidence rate of cancer in patients with BE is much lower than previously estimated Endoscopic surveillance of all patients with BE is not likely to be cost effective or save many lives Therefore it is important to understand which patients with BE are likely to progress to malignancy and equally important to determine which patients are not likely to progressBecause progression is an uncommon event definitive studies of natural history including evaluation of numerous risk factors require large numbers of patients that can only be accomplished in the context of a multicenter study This model will be a useful tool leading to a reduction in overall health care costs
An Opportunity to Generate the Essential Knowledge for Intervention We have established an initial network of investigators interested in the Barretts Esophagus Study a long term longitudinal prospective study and collected preliminary data in patients with BE To date 1376 patients from 4 centers have been entered into a central databank We have presented preliminary data on the incidence and prevalence rates of high-grade dysplasia and cancer at national meetings We now propose the creation of a formal consortium to perform a cohort study with the ultimate primary aim of defining risk factors for the development of high-grade dysplasia and adenocarcinoma in patients with BE Such a multi-center prospective cohort multi-disciplinary approach to BE was endorsed by the NIH PRG on stomach and esophageal cancers May 2002
BACKGROUND CLINICAL SIGNIFICANCE Barretts Esophagus the pre-malignant lesion for esophageal adenocarcinoma - a Condition of Rapidly Increasing Incidence Patients with BE are at an increased risk for the development of esophageal adenocarcinoma and esophagogastric junction adenocarcinoma Adenocarcinoma of the esophagus is believed to arise from BE in a step-wise progression from low-grade dysplasia to high-grade dysplasia finally leading to frank adenocarcinoma 45 The cost effectiveness of surveillance endoscopy in patients with BE is very sensitive to the incidence of cancer 11 The exact incidence of adenocarcinoma in patients with BE is not known and has been reported to vary from 1 in 50 patient-years of follow up to 1 in 285 patient-years of follow up 18-22 The published incidence data from existing cohorts of patients with BE have been influenced by the small number of patients being evaluated short duration of follow-up as well as by the demographics of the population being studied eg older patients male sex To date the maximum number of patients included in a published study determining the incidence of adenocarcinoma has been only 327 patients 2324 The ultimate goal of the proposed study is to establish a large cohort of patients with BE to address issues of incidence progression and risk factors influencing progression Such an approach was recently endorsed by the NIH 2002 PRG on stomach and esophageal cancers
Factors predicting the development of dysplasia and cancer in BE patients are unknown A few possible factors have been associated with esophageal adenocarcinoma but not studied in BE patients These include GERD symptoms obesity diet smoking prior cholecystectomy drugs and H pylori infection negative association 25-36 The presence of hiatal hernia and BE length have been associated with dysplasia and cancer development in BE patients in a preliminary single center study 37 Reflux symptoms have also been reported to be significantly more prevalent among parents and siblings of patients with BE and esophageal adenocarcinoma than spouse control relatives 38 A few uncontrolled reports have provided conflicting results on the role of anti-reflux surgery and the use of acid suppressive medications proton pump inhibitors H2 receptor antagonists and their effect on the neoplastic progression in BE patients 39-43 However all the studies to date in BE patients have been limited by small sample sizes univariate analysis short duration of follow-up lack of adjustment for confounding variables etc In this proposed study risk factors and mechanisms of capturing data at each site and data transfer to the main study database will be discussed and implemented Sample size calculations for appropriate univariate and multiple logistic regression analysis will be performed
Proposed Study will Fill Significant Gaps in Knowledge In the recent NIH PRG on stomach and esophageal cancers May 2002 and a workshop sponsored by the NIH The American Digestive Health Foundation on endoscopic priorities 44 experts in the field acknowledged that there was a need for multi-center longitudinal studies and there were significant gaps in the knowledge base of BE including
1 Risk stratification of cancer risk
2 Appropriate method of surveillance and technique for identifying dysplasia
3 Frequency and benefits of surveillance
4 Optimal management of BE such as acid suppression and endoscopic reversal techniques The ultimate goal of the BE Study is to address issues 1 and 3 ie risk stratification of Barretts patients and by developing a large multi-site database will prepare the way for future studies that can address the other key issues
The information gained will be clinically useful We will define the natural history of progression of BE patients and to determine factors involved in this progression to high-grade dysplasia and cancer The potentially unique answers obtained from the study would have major clinical relevance in
Defining the natural history of dysplasiacancer in BE patients and to identify risk factors involved in progression to dysplasiacancer
Helping clarify what predisposes only a small subset of BE patients to develop dysplasiacancer Rigorous examination of a number of risk factors may define this patient group thereby focusing our limited health care resources to the patient subset at increased risk for the development of dysplasiacancer - reduction in health care costs
Potential to change our current costly clinical practice of endoscopic surveillance of all BE patients by limiting surveillance to the high-risk group - improve clinical decision making
Providing better and accurate information to our BE patients regarding their true risk for dysplasia and cancer
PRELIMINARY STUDIES At this time preliminary data have been collected from the 4 participating centers and merged into one single databank These preliminary results were presented at the plenary sessions 4546 of the American Gastroenterological Association AGA annual meeting in Atlanta GA May 2001 and at the American College of Gastroenterology ACG annual meeting in Las Vegas NV October 2001 indicating a common interest amongst the investigators and capability of working together
Distribution of Degree of Dysplasia From the four participating centers 1376 patients have met the study criteria and had at least one endoscopy with biopsy revealing intestinal metaplasia thus confirming the diagnosis of BE At the initial endoscopy the distribution of dysplasia was as follows
Diagnosis Number of pts Prevalence Low-grade dysplasia LGD 101 73 High-grade dysplasia HGD 42 3 Esophageal adenocarcinoma 91 67 Incidence and progression to low-grade dysplasia high-grade dysplasia and esophageal adenocarcinoma 1376 patients were enrolled in the prevalence phase of the study To date 618 patients 95 Caucasians 14 Females have had follow-up endoscopic procedures to examine the incidence of dysplasiacancer They have been followed for a total of 2546 patient-years mean follow up 412 patient-years range 1-225 yrs Twelve patients developed cancer during follow up for a cancer incidence of 1 in 212 patient-years of follow up or 05 per year The mean time to development of cancer was 53 yrs range 24-112 yrs Of interest 7 of 12 patients had high-grade dysplasia before cancer development while 2 had only low-grade dysplasia 3 developed cancer from BE without dysplasia documented at any point 22 patients developed high-grade dysplasia during follow up for an estimate of high-grade dysplasia incidence of 1 in 116 patient-years of follow up or 09 per year The mean time to high-grade dysplasia development was 38 yrs range 12-79 yrs 11 of 22 patients developed high-grade dysplasia from BE without documented dysplasia whereas the remaining 11 went from low-grade dysplasia to high-grade dysplasia
Risk Factors for BE and adenocarcinoma The epidemiology and natural history of BE has been poorly studied Some factors have been associated with an increased risk for esophageal adenocarcinoma in the general population see Table 1 but risk factors for progression in BE patients are not clear A number of risk factors have been suggested as factors of risk in BE patients including age gender ethnicity GERD symptoms family history of BEcancer alcohol tobacco dietary factors fat intake cereal fiber calcium etc acid suppressive medications biomarkers genetic markers etc Given this long list of possible risk factors we propose to convene a panel of experts in a planning committee to serve as jury in order to determine which of the potential risk factors should be measured in a prospective study and how they should be measured This would narrow and refine the list of risk factors for the prospective study
There are a lot of purported risk factors to be evaluated Thus there is a long list see below of potential factors of risk in patients with BE associated with progression to dysplasia andor cancer
1 Age 2 Gender 3 Ethnicity 4 Reflux symptoms 5 Smoking 6 Alcohol 7 Dietary fat 8 Dietary fiber vegetables fruits 9 Dietary calcium 10 Obesity 11 Family history of reflux BE or esophageal cancer 12 Use of aspirin non-steroidal anti-inflammatory drugs 13 Use of lower esophageal sphincter relaxing medications 14 Use of acid suppressive medications 15 Cholecystectomy 16 Anti-reflux surgery fundoplication 17 Length of BE 18 Hiatal hernia 19 Helicobacter pylori infection 20 Low-grade dysplasia on biopsy This proposal will make it feasible to narrow on the factors to be studied in the prospective trial
Statistical Analysis Prevalence and incidence rates We expect to increase the baseline-screened population from 1376 to more than 2500 individuals in the final study The number of patients we expect to enroll each year will be calculated and the expected number of new prevalence cases using the 97 prevalence rate with the preliminary study data will be estimated In the preliminary study to date 618 patients have had at least one follow-up visit Including the remaining 700 patients from the preliminary study and assuming a 10 rate for loss to follow up we will have 6100-7450 patient years of follow up The expected number of new incidence cases using the 13 incidence rate with the preliminary study data will be estimated
An Opportunity to Generate the Essential Knowledge for Intervention We have established an initial network of investigators interested in the Barretts Esophagus Study a long term longitudinal prospective study and collected preliminary data in patients with BE To date 1376 patients from 4 centers have been entered into a central databank We have presented preliminary data on the incidence and prevalence rates of high-grade dysplasia and cancer at national meetings We now propose the creation of a formal consortium to perform a cohort study with the ultimate primary aim of defining risk factors for the development of high-grade dysplasia and adenocarcinoma in patients with BE Such a multi-center prospective cohort multi-disciplinary approach to BE was endorsed by the NIH PRG on stomach and esophageal cancers May 2002
BACKGROUND CLINICAL SIGNIFICANCE Barretts Esophagus the pre-malignant lesion for esophageal adenocarcinoma - a Condition of Rapidly Increasing Incidence Patients with BE are at an increased risk for the development of esophageal adenocarcinoma and esophagogastric junction adenocarcinoma Adenocarcinoma of the esophagus is believed to arise from BE in a step-wise progression from low-grade dysplasia to high-grade dysplasia finally leading to frank adenocarcinoma 45 The cost effectiveness of surveillance endoscopy in patients with BE is very sensitive to the incidence of cancer 11 The exact incidence of adenocarcinoma in patients with BE is not known and has been reported to vary from 1 in 50 patient-years of follow up to 1 in 285 patient-years of follow up 18-22 The published incidence data from existing cohorts of patients with BE have been influenced by the small number of patients being evaluated short duration of follow-up as well as by the demographics of the population being studied eg older patients male sex To date the maximum number of patients included in a published study determining the incidence of adenocarcinoma has been only 327 patients 2324 The ultimate goal of the proposed study is to establish a large cohort of patients with BE to address issues of incidence progression and risk factors influencing progression Such an approach was recently endorsed by the NIH 2002 PRG on stomach and esophageal cancers
Factors predicting the development of dysplasia and cancer in BE patients are unknown A few possible factors have been associated with esophageal adenocarcinoma but not studied in BE patients These include GERD symptoms obesity diet smoking prior cholecystectomy drugs and H pylori infection negative association 25-36 The presence of hiatal hernia and BE length have been associated with dysplasia and cancer development in BE patients in a preliminary single center study 37 Reflux symptoms have also been reported to be significantly more prevalent among parents and siblings of patients with BE and esophageal adenocarcinoma than spouse control relatives 38 A few uncontrolled reports have provided conflicting results on the role of anti-reflux surgery and the use of acid suppressive medications proton pump inhibitors H2 receptor antagonists and their effect on the neoplastic progression in BE patients 39-43 However all the studies to date in BE patients have been limited by small sample sizes univariate analysis short duration of follow-up lack of adjustment for confounding variables etc In this proposed study risk factors and mechanisms of capturing data at each site and data transfer to the main study database will be discussed and implemented Sample size calculations for appropriate univariate and multiple logistic regression analysis will be performed
Proposed Study will Fill Significant Gaps in Knowledge In the recent NIH PRG on stomach and esophageal cancers May 2002 and a workshop sponsored by the NIH The American Digestive Health Foundation on endoscopic priorities 44 experts in the field acknowledged that there was a need for multi-center longitudinal studies and there were significant gaps in the knowledge base of BE including
1 Risk stratification of cancer risk
2 Appropriate method of surveillance and technique for identifying dysplasia
3 Frequency and benefits of surveillance
4 Optimal management of BE such as acid suppression and endoscopic reversal techniques The ultimate goal of the BE Study is to address issues 1 and 3 ie risk stratification of Barretts patients and by developing a large multi-site database will prepare the way for future studies that can address the other key issues
The information gained will be clinically useful We will define the natural history of progression of BE patients and to determine factors involved in this progression to high-grade dysplasia and cancer The potentially unique answers obtained from the study would have major clinical relevance in
Defining the natural history of dysplasiacancer in BE patients and to identify risk factors involved in progression to dysplasiacancer
Helping clarify what predisposes only a small subset of BE patients to develop dysplasiacancer Rigorous examination of a number of risk factors may define this patient group thereby focusing our limited health care resources to the patient subset at increased risk for the development of dysplasiacancer - reduction in health care costs
Potential to change our current costly clinical practice of endoscopic surveillance of all BE patients by limiting surveillance to the high-risk group - improve clinical decision making
Providing better and accurate information to our BE patients regarding their true risk for dysplasia and cancer
PRELIMINARY STUDIES At this time preliminary data have been collected from the 4 participating centers and merged into one single databank These preliminary results were presented at the plenary sessions 4546 of the American Gastroenterological Association AGA annual meeting in Atlanta GA May 2001 and at the American College of Gastroenterology ACG annual meeting in Las Vegas NV October 2001 indicating a common interest amongst the investigators and capability of working together
Distribution of Degree of Dysplasia From the four participating centers 1376 patients have met the study criteria and had at least one endoscopy with biopsy revealing intestinal metaplasia thus confirming the diagnosis of BE At the initial endoscopy the distribution of dysplasia was as follows
Diagnosis Number of pts Prevalence Low-grade dysplasia LGD 101 73 High-grade dysplasia HGD 42 3 Esophageal adenocarcinoma 91 67 Incidence and progression to low-grade dysplasia high-grade dysplasia and esophageal adenocarcinoma 1376 patients were enrolled in the prevalence phase of the study To date 618 patients 95 Caucasians 14 Females have had follow-up endoscopic procedures to examine the incidence of dysplasiacancer They have been followed for a total of 2546 patient-years mean follow up 412 patient-years range 1-225 yrs Twelve patients developed cancer during follow up for a cancer incidence of 1 in 212 patient-years of follow up or 05 per year The mean time to development of cancer was 53 yrs range 24-112 yrs Of interest 7 of 12 patients had high-grade dysplasia before cancer development while 2 had only low-grade dysplasia 3 developed cancer from BE without dysplasia documented at any point 22 patients developed high-grade dysplasia during follow up for an estimate of high-grade dysplasia incidence of 1 in 116 patient-years of follow up or 09 per year The mean time to high-grade dysplasia development was 38 yrs range 12-79 yrs 11 of 22 patients developed high-grade dysplasia from BE without documented dysplasia whereas the remaining 11 went from low-grade dysplasia to high-grade dysplasia
Risk Factors for BE and adenocarcinoma The epidemiology and natural history of BE has been poorly studied Some factors have been associated with an increased risk for esophageal adenocarcinoma in the general population see Table 1 but risk factors for progression in BE patients are not clear A number of risk factors have been suggested as factors of risk in BE patients including age gender ethnicity GERD symptoms family history of BEcancer alcohol tobacco dietary factors fat intake cereal fiber calcium etc acid suppressive medications biomarkers genetic markers etc Given this long list of possible risk factors we propose to convene a panel of experts in a planning committee to serve as jury in order to determine which of the potential risk factors should be measured in a prospective study and how they should be measured This would narrow and refine the list of risk factors for the prospective study
There are a lot of purported risk factors to be evaluated Thus there is a long list see below of potential factors of risk in patients with BE associated with progression to dysplasia andor cancer
1 Age 2 Gender 3 Ethnicity 4 Reflux symptoms 5 Smoking 6 Alcohol 7 Dietary fat 8 Dietary fiber vegetables fruits 9 Dietary calcium 10 Obesity 11 Family history of reflux BE or esophageal cancer 12 Use of aspirin non-steroidal anti-inflammatory drugs 13 Use of lower esophageal sphincter relaxing medications 14 Use of acid suppressive medications 15 Cholecystectomy 16 Anti-reflux surgery fundoplication 17 Length of BE 18 Hiatal hernia 19 Helicobacter pylori infection 20 Low-grade dysplasia on biopsy This proposal will make it feasible to narrow on the factors to be studied in the prospective trial
Statistical Analysis Prevalence and incidence rates We expect to increase the baseline-screened population from 1376 to more than 2500 individuals in the final study The number of patients we expect to enroll each year will be calculated and the expected number of new prevalence cases using the 97 prevalence rate with the preliminary study data will be estimated In the preliminary study to date 618 patients have had at least one follow-up visit Including the remaining 700 patients from the preliminary study and assuming a 10 rate for loss to follow up we will have 6100-7450 patient years of follow up The expected number of new incidence cases using the 13 incidence rate with the preliminary study data will be estimated
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None