Evaluation of Liver Cancer With Magnetic Resonance Imaging (MRI)

Evaluation of HCC Response to Systemic Therapy With Quantitative MRI

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.

Study Overview

• Status: Completed
• Conditions: HCC; Hepatocellular Carcinoma
• Intervention / Treatment: Device: Magnetic Resonance Imaging

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 11103
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Study group

• Patients diagnosed with HCC, who will undergo resection or transplantation within 6 months, as part of routine clinical care and patients diagnosed with unresectable HCC
• 18 years of age and older
• Patient is able to give informed consent for this study

Control group

• Healthy volunteers 18 years of age and older
• Subject is able to give informed consent for this study

Exclusion Criteria:

• Age less than 18 years
• Unable or unwilling to give informed consent

• Contra-indications to MRI:

  1. Electrical implants such as cardiac pacemakers or perfusion pumps
  2. Ferromagnetic implants such as aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants
  3. Ferromagnetic objects such as jewelry or metal clips in clothing
  4. Pregnant subjects
  5. Pre-existing medical conditions including a likelihood of developing seizures or claustrophobic reactions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Healthy Controls
Experimental: Magnetic Resonance Imaging; dynamic contrast-enhanced MRI measuring arterial and portal flow	Device: Magnetic Resonance Imaging; 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.; Other Names: MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.	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

Secondary Outcome Measures

Outcome Measure	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)	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

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): February 2, 2018
• Study Completion (Actual): February 2, 2018

Study Registration Dates

• First Submitted: June 4, 2013
• First Submitted That Met QC Criteria: June 5, 2013
• First Posted (Estimate): June 6, 2013

Study Record Updates

• Last Update Posted (Actual): July 9, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: MRI; magnetic resonance imaging; HCC; hepatocellular carcinoma; liver disease; liver cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma, Hepatocellular
• Other Study ID Numbers: GCO 12-0214