Gastric Adenocarcinoma, Gastric Cancer, Gastric Neoplasms
Conditions
Keywords
Diagnostic, Diagnosis, HDGC, SRCC, Confocal Endoscopic Microscopy (CEM)
Brief summary
Background: Some people have a mutation in the cadherin-1 gene (CDH1) gene that is known to lead to stomach cancer. They are advised to get regular endoscopies with biopsies even if their stomach appears normal. The endoscopy method currently used is called the 'Cambridge Method.' Researchers want to test a new method called the 'Bethesda Protocol.' Objective: To compare the Cambridge Method and Bethesda Protocol and find out which is more efficient in catching early signs of cancer. Eligibility: Adults age 18 and older who have a mutation in the CDH1 gene. Design: Participants will be screened with a review of their medical history, medical records, and physical status. Participants will be put into group 1 (Bethesda Protocol) or group 2 (Cambridge Method). Participants will have a physical exam. They will have endoscopy. For this, they will be put under general anesthesia. They will wear compression cuffs around their legs to prevent blood clots. A lighted tube will be inserted into their mouth and go down to their stomach. For group 1 participants, 88 pieces of tissue will be taken from 22 areas of their stomach. For group 2 participants, 30 pieces of tissue will be taken from 6 areas of their stomach. Then group 2 will be injected with a contrast dye. A microscope will be inserted, and more samples will be taken. About 14 days later, participants will have a follow-up visit or phone call. They may give stool samples every 3 to 6 months for 12 months for research purposes. Participants may have another endoscopy 6-18 months later.
Detailed description
Background: Hereditary Diffuse Gastric Cancer (HDGC) is most often attributed to inactivating germline mutations in the E-cadherin (CDH1) tumor suppressor gene. Mutation carriers have a 24-70% lifetime risk of developing gastric adenocarcinoma. International consensus guidelines recommend endoscopic screening and surveillance of CDH1 mutation carriers who decline risk-reducing total gastrectomy (TG). However, this approach lacks sufficient sensitivity for detection of occult, intramucosal foci of signet ring cancer cells (SRCC), which are pathognomonic of HDGC. Our team has established a systematic endoscopic screening protocol (Bethesda protocol) that demonstrates a higher rate of SRCC detection compared to historic controls using the currently recommended Cambridge method. Objective: Determine if Bethesda protocol provides improved sensitivity for detection of early-stage gastric cancer in CDH1 germline mutation carriers compared to the Cambridge method. Eligibility: Subjects with pathogenic or likely pathogenic CDH1 germline mutation. Age \>=18 years. Physiologically able to undergo upper endoscopy Design: Phase II randomized study to compare Bethesda protocol and Cambridge method for detection of intramucosal SRCC in asymptomatic CDH1 mutation carriers undergoing endoscopic screening or surveillance.
Interventions
DEVICECellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes
Participants of both study arms will undergo confocal endomicroscopy of the gastric mucosa until sufficient data for statistically accurate and reliable application of machine learning (i.e., computer models), currently believed to total the first 50 enrolled participants.
DEVICEOlympus Graphics Interchange Format (GIF) 190 endoscope
Participants will undergo white light endoscopy. The mucosa of the stomach may be thoroughly washed before examination, as medically indicated, and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Nontargeted biopsies will be obtained as indicated per the assigned Arm.
PROCEDUREGastric mucosal biopsy
As clinically indicated.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: * An individual who harbors a pathogenic, or likely pathogenic, cadherin-1 gene (CDH1) germline variant. Note: individuals with CDH1 variant classified as any of the following are not eligible: * variant of uncertain significance * benign * likely benign. * Age greater than or equal to 18 years. * Physiologically able to undergo upper endoscopy. * Ability of subject to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Any clinical contraindication (e.g., known bleeding disorder, thrombocytopenia) to endoscopic biopsy. * Unstable angina or recent (within 3 months) myocardial infarction. * Any clinical contraindication to general anesthesia. Re-Enrollment: INCLUSION CRITERIA: * Subject must have previously been enrolled on the study and must have undergone endoscopy. Note: Subject may re-enroll only once after initial endoscopy performed * Subject must have clinical need for a repeat endoscopy * Prior on-protocol endoscopy must have occurred at least 6 months (+/- 2 weeks) and no greater than 18 months (+/- 4 weeks)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Improved Sensitivity for Detection of Early-stage Gastric Cancer in CDH1 Germline Mutation Carriers Compared to the Cambridge Method | 14 days | Among participants who undergo gastrectomy, in each of the two arms, the fraction of participants who had signet ring cell carcinoma (SRCCs) previously identified by endoscopic biopsy out of those who had SRCCs detected on final pathologic analysis of gastrectomy explants will be used to determine the difference between 30% sensitivity in the Cambridge method and 60% sensitivity in the Bethesda protocol of each arm on a Fisher's exact test with a 0.05 two-sided significance level and reported with a 95% confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Had Signet Ring Cell Carcinoma (SRCC) Identified on Final Pathology But Were Negative for SRCC on Esophagogastroduodenoscopy (EGD) | 14 days | False negative rate of SRCC detection in participants who undergo risk-reducing total gastrectomy using the Bethesda protocol and Cambridge method. The differences in fractions will be compared using a two-tailed Fisher's exact test and reported with a 95% confidence interval. |
| Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method | 14 days | The difference in fractions of participants with signet ring cell carcinoma (SRCCs) crude cancer detection rates found on endoscopy by the Bethesda protocol and the Cambridge method determined by the power to detect a difference with a two-sided 0.05 significance level between 15% and 30% crude cancer detection rates and reported with a 95% confidence interval. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | From the start of endoscopy through 14 days following study interventions, an average of 2 weeks | Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy Bethesda protocol (investigational) with confocal endomicroscopy in assigned participants
Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes: Participants of both study arms will undergo confocal endomicroscopy of the gastric mucosa until sufficient data for statistically accurate and reliable application of machine learning (i.e., computer models), currently believed to total the first 50 enrolled participants.
Olympus Graphics Interchange Format (GIF) 190 endoscope: Participants will undergo white light endoscopy. The mucosa of the stomach may be thoroughly washed before examination, as medically indicated, and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Nontargeted biopsies will be obtained as indicated per the assigned Arm. | 98 |
| 2/ Arm 2: Cambridge Method (Control) With Confocal Endomicroscopy Cambridge method (control) with confocal endomicroscopy in assigned participants
Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes: Participants of both study arms will undergo confocal endomicroscopy of the gastric mucosa until sufficient data for statistically accurate and reliable application of machine learning (i.e., computer models), currently believed to total the first 50 enrolled participants.
Olympus Graphics Interchange Format (GIF) 190 endoscope: Participants will undergo white light endoscopy. The mucosa of the stomach may be thoroughly washed before examination, as medically indicated, and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Nontargeted biopsies will be obtained as indicated per the assigned Arm. | 97 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cancelled appointment | 1 | 0 |
| Overall Study | cancelled - food in stomach | 2 | 0 |
| Overall Study | Study closed per PI decision prior to scheduled intervention | 5 | 5 |
| Overall Study | Taken off study due to principal investigator (PI) discretion. | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy | 2/ Arm 2: Cambridge Method (Control) With Confocal Endomicroscopy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 17 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 80 Participants | 165 Participants |
| Age, Continuous | 44.46 years STANDARD_DEVIATION 15.89 | 49.84 years STANDARD_DEVIATION 13.6 | 47.13 years STANDARD_DEVIATION 15.04 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Ethnicity: Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 91 Participants | 92 Participants | 183 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Race: Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 88 Participants | 90 Participants | 178 Participants |
| Region of Enrollment United States | 98 participants | 97 participants | 195 participants |
| Sex: Female, Male Female | 56 Participants | 53 Participants | 109 Participants |
| Sex: Female, Male Male | 42 Participants | 44 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 97 |
| other Total, other adverse events | 4 / 98 | 0 / 97 |
| serious Total, serious adverse events | 0 / 98 | 0 / 97 |
Outcome results
Primary
Proportion of Participants With Improved Sensitivity for Detection of Early-stage Gastric Cancer in CDH1 Germline Mutation Carriers Compared to the Cambridge Method
Among participants who undergo gastrectomy, in each of the two arms, the fraction of participants who had signet ring cell carcinoma (SRCCs) previously identified by endoscopic biopsy out of those who had SRCCs detected on final pathologic analysis of gastrectomy explants will be used to determine the difference between 30% sensitivity in the Cambridge method and 60% sensitivity in the Bethesda protocol of each arm on a Fisher's exact test with a 0.05 two-sided significance level and reported with a 95% confidence interval.
Time frame: 14 days
Population: No participants underwent total gastrectomy in Arm 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy | Proportion of Participants With Improved Sensitivity for Detection of Early-stage Gastric Cancer in CDH1 Germline Mutation Carriers Compared to the Cambridge Method | 1 proportion of participants |
Secondary
Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method
The difference in fractions of participants with signet ring cell carcinoma (SRCCs) crude cancer detection rates found on endoscopy by the Bethesda protocol and the Cambridge method determined by the power to detect a difference with a two-sided 0.05 significance level between 15% and 30% crude cancer detection rates and reported with a 95% confidence interval.
Time frame: 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy | Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method | 0.31 proportion of participants |
| 2/ Arm 2: Cambridge Method (Control) With Confocal Endomicroscopy | Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method | 0.20 proportion of participants |
Secondary
Proportion of Participants Who Had Signet Ring Cell Carcinoma (SRCC) Identified on Final Pathology But Were Negative for SRCC on Esophagogastroduodenoscopy (EGD)
False negative rate of SRCC detection in participants who undergo risk-reducing total gastrectomy using the Bethesda protocol and Cambridge method. The differences in fractions will be compared using a two-tailed Fisher's exact test and reported with a 95% confidence interval.
Time frame: 14 days
Population: No participants underwent total gastrectomy in Arm 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy | Proportion of Participants Who Had Signet Ring Cell Carcinoma (SRCC) Identified on Final Pathology But Were Negative for SRCC on Esophagogastroduodenoscopy (EGD) | 0.5 proportion of participants |
Other Pre-specified
Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence.
Time frame: From the start of endoscopy through 14 days following study interventions, an average of 2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (Investigational) With Confocal Endomicroscopy | Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 4 Participants |
| 2/ Arm 2: Cambridge Method (Control) With Confocal Endomicroscopy | Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 0 Participants |