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The incidence of hepatocellular carcinoma (HCC) has recently increased in the United States. Although imaging plays a major role in HCC screening and staging, the possibility of predicting HCC tumor grade, aggressiveness, angiogenesis and hypoxia with imaging are unmet needs. In addition, new antiangiogenic drugs now available to treat advanced HCC necessitate the use of new imaging criteria beyond size. The investigators would like to develop and validate non-invasive magnetic resonance imaging (MRI) methods based on advanced diffusion-weighted imaging (DWI), MR Elastography, BOLD (blood oxygen level dependent) MRI and perfusion-weighted imaging (PWI, using gadolinium contrast) to be used as non-invasive markers of major histopathologic features of HCC, and to predict and assess early response of HCC to systemic therapy. The investigators also would like to develop quality control tools to improve the quality and decrease variability of quantitative MRI metrics. These techniques combined could represent non-invasive correlates of histologic findings in HCC, could enable individualized therapy, and provide prognosis in patients with HCC.
The incidence of hepatocellular carcinoma (HCC) has recently increased in the US mostly due to an increase in chronic hepatitis C infection. Angiogenesis is critical for the growth and metastatic progression of HCC. With the development of new antiangiogenic drugs such as sorafenib, imaging methods to predict and assess therapeutic response beyond changes in size become critical. However, validated imaging methods to predict and assess early HCC response to targeted agents are lacking.
In this study, the investigators would like to develop quantitative MRI methods interrogating different features of HCC tumor biology and pathology, including tumor cellularity, grade, angiogenesis and hypoxia. The investigators propose a multiparametric approach combining advanced DWI (IVIM: intravoxel incoherent motion diffusion measuring perfusion fraction and true diffusion coefficient), DCE-MRI (dynamic contrast-enhanced MRI, which measures arterial and portal flow, mean transit time, blood volume and distribution volume), and BOLD MRI using oxygen or carbogen challenge. This protocol will be performed in patients with HCC undergoing hepatic resection. Routine and advanced histopathologic methods will be performed (tumor grade, CK19 expression, presence of microvascular invasion, VEGF expression, microvessel density, HIF 1-alpha expression). MRI metrics will be correlated with histopathologic metrics.
The first portion of the proposal involves the development of a QC algorithm assessing MR data quality and test-retest. The investigators will propose solutions to improve data acquisition and processing. The last 2 years of the study will be dedicated to a prospective randomized study comparing Yttrium 90 radioembolization to sorafenib, assessing the role of baseline MRI metrics and early changes (at 2 weeks) in these metrics as markers of tumor response and time to progression in patients with unresectable HCC.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Magnetic Resonance Imaging | Experimental | dynamic contrast-enhanced MRI measuring arterial and portal flow |
|
| Healthy Controls | No Intervention |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Magnetic Resonance Imaging | Device | Magnetic Resonance Imaging is a radiation free non invasive technique using magnetic radiofrequency waves to image the body. In this study, the research team would like to investigate the possibility of providing functional information on aggressiveness, vascularity and oxygen uptake in liver cancer tumors. |
| Measure | Description | Time Frame |
|---|---|---|
| SubStudy 1: Apparent Diffusion Coefficient (ADC) | Tumor diffusion (apparent diffusion coefficient) measured with diffusion-weighted imaging sequence | Day 1 |
| SubStudy 1: Total Tumor Perfusion (Ft) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Day 1 |
| SubStudy 1: Tumor Arterial Perfusion Fraction (ART) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Day 1 |
| SubStudy 1: Tumor Mean Transit Time (MTT) | Tumor mean transit time (MTT) of contrast agent. Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Day 1 |
| SubStudy 1: Tumor Distribution Volume (DV) | Tumor distribution volume (DV) of contrast agent. Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Day 1 |
| SubStudy 1: Oxygen Uptake | Oxygen uptake measured with T2* and T1-weighted imaging | Day 1 |
| SubStudy 1: Percent Change in Oxygen Uptake | Oxygen uptake measured with T2* and T1-weighted imaging. Oxygen uptake (% change pre and post O2 administration) calculated by Liver ΔR2*=100 x (R2* post O2-R2* pre O2)/R2* pre O2. The healthy participants breathed 100% medical O2 through a mask for 10 min., and were imaged before and after O2 administration with the MRI methods that are sensitive to oxygen uptake in tumors. |
| Measure | Description | Time Frame |
|---|---|---|
| SubStudy 2: Total Tumor Perfusion (Ft) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | baseline and 6 weeks after Y90 |
| SubStudy 2: Tumor Arterial Perfusion Fraction (ART) |
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Inclusion Criteria:
Study group
Control group
Exclusion Criteria:
Age less than 18 years
Unable or unwilling to give informed consent
Contra-indications to MRI:
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| Name | Affiliation | Role |
|---|---|---|
| Bachir Taouli, MD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Icahn School of Medicine at Mount Sinai | New York | New York | 11103 | United States |
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Enrollment from June 2013 through February 2018
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| ID | Title | Description |
|---|---|---|
| FG000 | Hepatocellular Carcinoma (HCC) | Participant with hepatocellular carcinoma (HCC) |
| FG001 | Healthy Volunteer | Healthy volunteer participant |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Hepatocellular Carcinoma (HCC) | Participants with hepatocellular carcinoma (HCC) |
| BG001 | Healthy Participant | Healthy control participants |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | SubStudy 1: Apparent Diffusion Coefficient (ADC) | Tumor diffusion (apparent diffusion coefficient) measured with diffusion-weighted imaging sequence | Data analysis only for a subset of patients with HCC undergoing hepatic resection | Posted | Mean | Standard Deviation | 1x10^-3 mm^2/s | Day 1 |
|
6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Participant | Healthy control participants | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mild contrast reaction | General disorders | MedDRA (10.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Bachir Taouli | Icahn School of Medicine at Mount Sinai | 212-824-8475 | bachir.taouli@mountsinai.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 11, 2018 | May 15, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006528 | Carcinoma, Hepatocellular |
| D008113 | Liver Neoplasms |
| D008107 | Liver Diseases |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D008279 | Magnetic Resonance Imaging |
| ID | Term |
|---|---|
| D014054 | Tomography |
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
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|
|
| Day 1, pre-oxygen administration and 10 min. post-oxygen administration |
| SubStudy 2: ADC | Tumor diffusion measured with diffusion-weighted imaging sequence. In diffusion weighted MR imaging (DWI), the signal is proportional to the Brownian motion diffusion of free water protons in tissues. Deposition of collagen in tissue (as in fibrotic disease), or cellularity in tumors act as impediments to free water diffusion. Using different mathematical models, the degree of diffusion can be quantified from the MRI signal, to provide information on diffusion restriction due to disease. From mono exponential fit of diffusion signal, one can obtain the apparent diffusion coefficient (ADC). However, this coefficient reflects free water proton diffusion, as well as transport of water protons in the capillary vessels (capillary perfusion). | baseline and 6 weeks after Y90 |
| SubStudy 2: Diffusion Coefficient D | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the true diffusion coefficient D, reflecting free water proton diffusion. | baseline and 6 weeks after Y90 |
| SubStudy 2: Pseudodiffusion Coefficient D* | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the pseudo-diffusion coefficient D*, affected by free diffusion and capillary perfusion. | baseline and 6 weeks after Y90 |
| SubStudy 2: Perfusion Fraction (PF) | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the perfusion fraction PF, which reflects how much the diffusion-weighted signal is affected by capillary perfusion. PF is a measure of vascularity in the tissue. | baseline and 6 weeks after Y90 |
Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast
| baseline and 6 weeks after Y90 |
| SubStudy 2: Tumor Mean Transit Time (MTT) of Contrast Agent | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | baseline and 6 weeks after Y90 |
| SubStudy 2: Extravascular Extracellular Volume ve | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast. Extravascular extracellular volume fraction ve (%) - represents the portion of tissue occupied by the extravascular extracellular volume (interstitial space), in which MRI contrast agent can distribute. | baseline and 6 weeks after Y90 |
| Substudy 2: Tumor Stiffness | measured with magnetic resonance elastography | baseline and 6 weeks after Y90 |
| Tumor Response | Tumor response to treatment is evaluated clinically by radiologists according to RECIST and modified RECIST criteria, by which the diameter of the tumor portion that enhances (lights up on imaging) after administration of gadolinium contrast agent is measured before and after treatment. The response is not reported as diameter or diameter difference in mm, but rather as a qualitative variable: complete response, partial response, stable disease and progressive disease. Complete response means no enhancing tumor regions after treatment (i.e. complete tumor necrosis, no more vascular regions of the tumor that take up contrast), partial response is a decrease in the diameter of the enhancing region, stable disease is unchanged diameter, and progressive disease is an increase in the diameter of the enhancing region after treatment. | 6 weeks and 6-12 months |
| Physician Decision |
|
| Withdrawal by Subject |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| SubStudy 1: Age | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls. | Median | Full Range | years |
|
| SubStudy 1: Sex | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls. | Count of Participants | Participants |
|
| SubStudy 1: Ethnicity | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls. | Count of Participants | Participants |
|
| SubStudy 1: Race | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls. | Count of Participants | Participants |
|
| SubStudy 2: Age | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Median | Full Range | years |
|
| SubStudy 2: Sex | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Count of Participants | Participants |
|
| SubStudy 2: Ethnicity | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Count of Participants | Participants |
|
| SubStudy 2: Race | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Count of Participants | Participants |
|
| Units | Counts |
|---|
| Participants |
|
|
| Primary | SubStudy 1: Total Tumor Perfusion (Ft) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data analysis only for a subset of patients with HCC undergoing hepatic resection | Posted | Mean | Standard Deviation | ml/min/100g | Day 1 |
|
|
|
| Primary | SubStudy 1: Tumor Arterial Perfusion Fraction (ART) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data analysis only for a subset of patients with HCC undergoing hepatic resection | Posted | Mean | Standard Deviation | percent of perfusion | Day 1 |
|
|
|
| Primary | SubStudy 1: Tumor Mean Transit Time (MTT) | Tumor mean transit time (MTT) of contrast agent. Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data analysis only for a subset of patients with HCC undergoing hepatic resection | Posted | Mean | Standard Deviation | sec | Day 1 |
|
|
|
| Primary | SubStudy 1: Tumor Distribution Volume (DV) | Tumor distribution volume (DV) of contrast agent. Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data analysis only for a subset of patients with HCC undergoing hepatic resection | Posted | Mean | Standard Deviation | percent | Day 1 |
|
|
|
| Primary | SubStudy 1: Oxygen Uptake | Oxygen uptake measured with T2* and T1-weighted imaging | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls. Oxygen uptake for HCCs is reported in patients, and oxygen uptake for the liver is reported in volunteers. R1 measurements method in the volunteers proved unreliable - therefore no data available for T1/R1 in the healthy participant arm. | Posted | Mean | Standard Deviation | s-1 | Day 1 |
|
|
|
| Primary | SubStudy 1: Percent Change in Oxygen Uptake | Oxygen uptake measured with T2* and T1-weighted imaging. Oxygen uptake (% change pre and post O2 administration) calculated by Liver ΔR2*=100 x (R2* post O2-R2* pre O2)/R2* pre O2. The healthy participants breathed 100% medical O2 through a mask for 10 min., and were imaged before and after O2 administration with the MRI methods that are sensitive to oxygen uptake in tumors. | Healthy Participants only | Posted | Mean | Standard Deviation | percent of oxygen uptake | Day 1, pre-oxygen administration and 10 min. post-oxygen administration |
|
|
|
| Primary | SubStudy 2: ADC | Tumor diffusion measured with diffusion-weighted imaging sequence. In diffusion weighted MR imaging (DWI), the signal is proportional to the Brownian motion diffusion of free water protons in tissues. Deposition of collagen in tissue (as in fibrotic disease), or cellularity in tumors act as impediments to free water diffusion. Using different mathematical models, the degree of diffusion can be quantified from the MRI signal, to provide information on diffusion restriction due to disease. From mono exponential fit of diffusion signal, one can obtain the apparent diffusion coefficient (ADC). However, this coefficient reflects free water proton diffusion, as well as transport of water protons in the capillary vessels (capillary perfusion). | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | 1x10^-3 mm^2/s | baseline and 6 weeks after Y90 |
|
|
|
| Primary | SubStudy 2: Diffusion Coefficient D | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the true diffusion coefficient D, reflecting free water proton diffusion. | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | 1x10^-3 mm^2/s | baseline and 6 weeks after Y90 |
|
|
|
| Primary | SubStudy 2: Pseudodiffusion Coefficient D* | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the pseudo-diffusion coefficient D*, affected by free diffusion and capillary perfusion. | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | 1x10^-3 mm^2/s | baseline and 6 weeks after Y90 |
|
|
|
| Primary | SubStudy 2: Perfusion Fraction (PF) | Tumor diffusion measured with diffusion-weighted imaging sequence. To separate the diffusion effect from capillary perfusion, a bi-exponential model is used, which provides 3 coefficients: one is the perfusion fraction PF, which reflects how much the diffusion-weighted signal is affected by capillary perfusion. PF is a measure of vascularity in the tissue. | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | 1x10^-3 mm^2/s | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | SubStudy 2: Total Tumor Perfusion (Ft) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | ml/min/100g tissue | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | SubStudy 2: Tumor Arterial Perfusion Fraction (ART) | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | percent of perfusion | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | SubStudy 2: Tumor Mean Transit Time (MTT) of Contrast Agent | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | sec | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | SubStudy 2: Extravascular Extracellular Volume ve | Perfusion/flow measured with dynamic contrast-enhanced imaging using gadolinium contrast. Extravascular extracellular volume fraction ve (%) - represents the portion of tissue occupied by the extravascular extracellular volume (interstitial space), in which MRI contrast agent can distribute. | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | Posted | Mean | Standard Deviation | percent of perfusion | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | Substudy 2: Tumor Stiffness | measured with magnetic resonance elastography | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization. Excluded: 3 treated with other therapies, 2 deceased before 6 weeks follow-up. | Posted | Mean | Standard Deviation | kilo Pascals (kPa) | baseline and 6 weeks after Y90 |
|
|
|
| Secondary | Tumor Response | Tumor response to treatment is evaluated clinically by radiologists according to RECIST and modified RECIST criteria, by which the diameter of the tumor portion that enhances (lights up on imaging) after administration of gadolinium contrast agent is measured before and after treatment. The response is not reported as diameter or diameter difference in mm, but rather as a qualitative variable: complete response, partial response, stable disease and progressive disease. Complete response means no enhancing tumor regions after treatment (i.e. complete tumor necrosis, no more vascular regions of the tumor that take up contrast), partial response is a decrease in the diameter of the enhancing region, stable disease is unchanged diameter, and progressive disease is an increase in the diameter of the enhancing region after treatment. | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization. | Posted | Number | lesions | 6 weeks and 6-12 months | lesions | lesions |
|
|
|
| 8 |
| 0 |
| 8 |
| 1 |
| 8 |
| EG001 | SubStudy 1 | Data analysis only for a subset of patients with HCC undergoing hepatic resection compared to healthy controls | 2 | 32 | 0 | 32 | 3 | 32 |
| EG002 | SubStudy 2 | Data results only for patients with unresectable HCC treated with Yttrium 90 radioembolization | 6 | 24 | 0 | 24 | 0 | 24 |
| Unable to tolerate carbogen | Product Issues | MedDRA (10.0) | Non-systematic Assessment |
|
| Left eye pain | Eye disorders | MedDRA (10.0) | Non-systematic Assessment |
|
Not provided
Not provided
| D009369 | Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| R2* post O2 |
|
|
| ΔR2*=R2* post O2-R2* pre O2 |
|
|
| R1(=1/T1) pre oxygen (O2) administration |
|
|
| R1 post O2 |
|
|
| ΔR1=R1 post O2-R1 pre O2 |
|
|
| 6 weeks post y90 |
|
|
| 6 weeks post y90 |
|
|
| 6 weeks post y90 |
|
|
| 6 weeks post y90 |
|
|
| 6 weeks post y90 |
|
|
| Complete Response |
|