Esophageal Cancer, Precancerous Condition
Conditions
Keywords
esophageal cancer, Barrett's esophagus
Brief summary
RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of esomeprazole and aspirin may prevent esophageal cancer in patients with Barrett's metaplasia. It is not yet known whether esomeprazole is more effective with or without aspirin in preventing esophageal cancer in patients with Barrett's metaplasia. PURPOSE: This randomized phase III trial is studying esomeprazole with or without aspirin to compare how well they work in preventing esophageal cancer in patients with Barrett's metaplasia.
Detailed description
PRIMARY OBJECTIVES * To assess whether intervention with aspirin results in a decreased rate of all causes of mortality or conversion rate from Barrett's metaplasia to adenocarcinoma or high grade dysplasia. * To assess whether high dose PPI (protein pump inhibitor) therapy results in a decreased rate of all causes of mortality or conversion rate from Barrett's metaplasia to adenocarcinoma or high grade dysplasia. SECONDARY OBJECTIVES * To assess whether intervention with aspirin results in decreased high-grade dysplasia, in decreased all cause mortality, in decreased oesophageal cancer incidence and in decreased cause-specific mortality when each is considered separately * To assess whether intervention with high dose PPI results in decreased high-grade dysplasia, in decreased all cause mortality, in decreased oesophageal cancer incidence and in decreased cause-specific mortality when each is considered separately * To assess whether there are clinical and molecular risk factors which can be identified in BM (Barrett's Metaplasia) for the development of BA. * To assess the cost effectiveness of aspirin and/or PPI treatment in the prevention of BA. * To assess whether intervention with PPI and/or aspirin induces changes in the expression of molecular markers for BA. * To investigate new genes important in the progression of BA, as a unique tissue bank will be available with a complete endoscopic, histological, physiology and pharmaceutical history. * To assess inherited genetic factors for predisposition to oesophagitis above BM, BM, LGD HGD and BA. * To assess what the biological risk factors are for cardiac disease and aspirin resistance. * To assess gender differences in outcomes. Cancer Research UK approved the study in 2003 for a 10 year period to run from 1st January 2005 to 31st December 2014. Funding is renewable annually and is dependent on a satisfactory review by an independent committee. An application for a funding extension was made to CRUK 18 months before the end of the grant and the funding was extended to 31Aug2018. A total of 2557 patients have been accrued for this study in the UK.
Interventions
DRUGEsomeprazole
20mg per day
DRUGAspirin
300mg per day
Sponsors
AstraZeneca
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged ≥18 years. 2. Circumferential Barrett's metaplasia of at least 1cm in length (≥C1M1) or a tongue of Barrett's metaplasia of at least 2cm in length (≥C0M2) (irrespective of the presence now or historically of histologically proven intestinal metaplasia). 3. Able to give written informed consent. 4. WHO performance status of 0 or 1 i.e. fully active and self-caring.
Exclusion criteria
1. High grade dysplasia or carcinoma at enrolment. 2. Medical conditions which would make completing endoscopies or completing the trial difficult including: 1. Frequent transient ischaemic attacks (3 or more) or severe cerebral vascular accident in the previous 6 months\* 2. Severe respiratory disease with arterial oxygen saturation less 90% at rest 3. Severe ischaemic heart disease (exercise tolerance less than 100 yards or life expectancy \< 4 years) or myocardial infarction in the previous 3 months 4. Severe inflammatory bowel disease requiring at least one hospital admission of 5 days in the last year or bowels open \> 6 times/day \* Patients answering yes to criterion a. were eligible for the PPI-only (non-aspirin) arms of the trial 3. Continuous/frequent non-steroidal anti-inflammatory drug use or COX-2 inhibitors (more than 60 days per year in total). 4. Patients with absolute contraindications to PPIs, aspirin or their excipients i.e. allergies, ulcers, renal impairment or use of oral anticoagulants. 5. Pregnant or lactating women will not undergo endoscopy and may be given dispensation to stop drug therapy for a year. This should be discussed with the Trial Office. If a patient was suitable for inclusion but later becomes unsuitable this should be discussed with the Trial Office before they are withdrawn. Only in exceptional circumstances should patients not be followed up i.e. withdrawal of consent or current life threatening disease with poor outcome and therefore unable to tolerate endoscopy. In these circumstances patients should be followed up in outpatient clinics.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia | Events are assessed from the date of randomisation to the end of study which can be patient withdrawal, loss to follow up or study end (8 years or 10 years from randomisation, depending on consent) | Death is recorded on a continuous basis through reporting from trial sites. Oesophageal adenocarcinoma is recorded through endoscopies taken every two years or ad-hoc at clinician decision High Grade Dysplasia is recorded through endoscopies taken every two years or ad-hoc at clinician decision |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cause Mortality | Through study completion, an average of 8.9 years. | Accelerated Failure Time (AFT) analysis comparing time to all cause mortality in low dose PPI (20mg) patients to high dose PPI (80mg) patients and in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group. |
| Adenocarcinoma Oesophageal Cancer | Assessed every 2 years through study completion, an average of 8.9 years | Number of aspirin and non-aspirin patients and low dose PPI and high dose PPI patients with adenocarcinoma oesophageal cancer |
| High Grade Dysplasia | High Grade Dysplasia is assessed every two years through study completion, an average of 8.9 years. | Diagnosis of high grade dysplasia is compared in aspirin and non-aspirin trial patients, and in high dose PPI and low dose PPI patients. |
Participant flow
Recruitment details
2557 eligible participants were recruited across from 4th March 2005 to 25th February 2009. There were 84 centres across England, Scotland, Wales, and Northern Ireland, and one in McMaster Health Sciences Centre, Hamilton, ON, Canada.
Participants by arm
| Arm | Count |
|---|---|
| Arm A 20mg Esomeprazole
Esomeprazole: 20mg per day | 699 |
| Arm B 80mg Esomeprazole
Esomeprazole: 80mg per day | 698 |
| Arm C 20mg Esomeprazole + 300mg Aspirin
Esomeprazole: 20mg per day
Aspirin: 300mg per day | 566 |
| Arm D 80mg Esomeprazole + 300mg Aspirin
Esomeprazole: 80mg per day
Aspirin: 300mg per day | 572 |
| Total | 2,535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 24 | 32 | 22 | 27 |
| Overall Study | Did not receive allocated Treatment | 10 | 9 | 9 | 10 |
| Overall Study | Lost to Follow-up | 39 | 33 | 26 | 35 |
| Overall Study | Other reason | 157 | 130 | 114 | 99 |
| Overall Study | Patient decision | 73 | 80 | 51 | 59 |
| Overall Study | Physician Decision | 32 | 20 | 24 | 30 |
| Overall Study | Withdrew consent | 6 | 6 | 5 | 5 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Arm D | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 204 Participants | 204 Participants | 137 Participants | 154 Participants | 699 Participants |
| Age, Categorical Between 18 and 65 years | 495 Participants | 494 Participants | 429 Participants | 418 Participants | 1836 Participants |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 135 Participants | 136 Participants | 118 Participants | 124 Participants | 513 Participants |
| Sex: Female, Male Male | 564 Participants | 562 Participants | 448 Participants | 448 Participants | 2022 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 73 / 1,138 | 90 / 1,142 | 105 / 1,265 | 79 / 1,270 |
| other Total, other adverse events | 0 / 1,138 | 0 / 1,142 | 0 / 1,265 | 0 / 1,270 |
| serious Total, serious adverse events | 340 / 1,138 | 378 / 1,142 | 359 / 1,265 | 359 / 1,270 |
Outcome results
Primary
First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia
Death is recorded on a continuous basis through reporting from trial sites. Oesophageal adenocarcinoma is recorded through endoscopies taken every two years or ad-hoc at clinician decision High Grade Dysplasia is recorded through endoscopies taken every two years or ad-hoc at clinician decision
Time frame: Events are assessed from the date of randomisation to the end of study which can be patient withdrawal, loss to follow up or study end (8 years or 10 years from randomisation, depending on consent)
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia | 127 Participants |
| No Aspirin | First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia | 154 Participants |
| Low Dose PPI | First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia | 174 Participants |
| High Dose PPI | First Event of Death, Oesophageal Adenocarcinoma, High Grade Dysplasia | 139 Participants |
Comparison: Accelerated Failure Time (AFT) analysis comparing time to primary event in low dose PPI (20mg) patients to high dose PPI (80mg) patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.p-value: 0.06895% CI: [0.98, 1.57]Accelerated Failure Time
Comparison: Accelerated Failure Time (AFT) analysis comparing time to primary event in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and PPI randomisation group.p-value: 0.03795% CI: [1.01, 1.58]Accelerated Failure Time
Secondary
Adenocarcinoma Oesophageal Cancer
Number of aspirin and non-aspirin patients and low dose PPI and high dose PPI patients with adenocarcinoma oesophageal cancer
Time frame: Assessed every 2 years through study completion, an average of 8.9 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | Adenocarcinoma Oesophageal Cancer | 35 Participants |
| No Aspirin | Adenocarcinoma Oesophageal Cancer | 35 Participants |
| Low Dose PPI | Adenocarcinoma Oesophageal Cancer | 41 Participants |
| High Dose PPI | Adenocarcinoma Oesophageal Cancer | 40 Participants |
Comparison: There are 81 diagnoses in the PPI dose comparison with adenocarcinoma oesophageal cancer as the endpoint. Median follow-up is 8.7 years IQR: (8.1 , 9.9)p-value: 0.86495% CI: [0.67, 1.61]Accelerated Failure Time
Comparison: There are 70 diagnoses of adenocarcinoma in the aspirin comparison. Median follow-up is 8.8 years, IQR: (8.1 , 10), Range: (0 , 11.5)p-value: 0.92195% CI: [0.64, 1.64]Accelerated Failure Time
Secondary
All Cause Mortality
Accelerated Failure Time (AFT) analysis comparing time to all cause mortality in low dose PPI (20mg) patients to high dose PPI (80mg) patients and in aspirin patients to non-aspirin patients. Included in AFT model are stratification factors (Barrett's length, age group and presence of baseline intestinal metaplasia) and aspirin randomisation group.
Time frame: Through study completion, an average of 8.9 years.
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | All Cause Mortality | 73 Participants |
| No Aspirin | All Cause Mortality | 90 Participants |
| Low Dose PPI | All Cause Mortality | 105 Participants |
| High Dose PPI | All Cause Mortality | 79 Participants |
Comparison: All recordings of death, regardless of the cause are used in this analysis and both PPI groups are compared.p-value: 0.03995% CI: [1.01, 1.82]Accelerated Failure Time
Comparison: There are 163 deaths in the aspirin comparison with all-cause mortality as the endpoint. Median follow-up is 8.9 years IQR: (8.2 , 10.0) Range: (0 , 11.5)p-value: 0.15995% CI: [0.92, 1.7]Accelerated Failure Time
Secondary
High Grade Dysplasia
Diagnosis of high grade dysplasia is compared in aspirin and non-aspirin trial patients, and in high dose PPI and low dose PPI patients.
Time frame: High Grade Dysplasia is assessed every two years through study completion, an average of 8.9 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | High Grade Dysplasia | 37 Participants |
| No Aspirin | High Grade Dysplasia | 55 Participants |
| Low Dose PPI | High Grade Dysplasia | 59 Participants |
| High Dose PPI | High Grade Dysplasia | 44 Participants |
Comparison: There are 103 such diagnoses in the PPI dose comparison. Median follow-up is 8.7 years IQR: (8.1 , 9.9) Range: (0 , 11.48)p-value: 0.11995% CI: [0.92, 2.02]Accelerated Failure Time
Comparison: There are a total of 92 conversions to HGD in the aspirin comparison. Median follow-up is 8.8 years IQR (8.1 , 10.0) Range (0 , 11.5)p-value: 0.05395% CI: [1, 2.29]Accelerated Failure Time