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ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
Introduction
The ACRIN 6690 trial: “A Prospective, Multicenter Comparison of Multiphase Contrast-Enhanced CT
and Multiphase Contrast-Enhanced MRI for Diagnosis of Hepatocellular Carcinoma and Liver Transplant
Allocation” represents an opportunity for transplant centers to participate in a multicenter study
investigating CT and MRI imaging in the HCC transplant population. The success of this trial will rely
heavily on a site’s multidisciplinary team of radiologists, transplant surgeons, hepatologists and
pathologists and their interaction with the ACRIN 6690 project team to enroll participants and carry out
the protocol’s imaging and correlative pathology examinations.
Specifically, the ACRIN 6690 trial will evaluate multiphase contrast-enhanced CT and MRI to establish
the respective performance characteristics of these modalities to accurately detect, diagnose, and stage
hepatocellular cancer in patients with chronic liver disease. Eligible study participants are patients newly
listed on the United Network for Organ Sharing (UNOS) transplant waiting list with HCC-exception points
(points assigned based on the patient’s liver cancer diagnosis). Participants are required to undergo
multiphasic contrast-enhanced imaging with CT and MRI; within 30 days of the standard of care imaging
trial participants will undergo complementary imaging (if initial diagnosis was made on CT, then MRI or if
initial diagnosis was made on MRI, then CT). Subsequently, participants will undergo imaging with both
modalities scheduled in accordance with the 90-day intervals required for cyclical update of the HCCexception points with UNOS. The additional research imaging exams are included in the case
reimbursement from ACRIN. Should local ablative therapy occur for treatment of one or several liver
cancers, post-ablation imaging will be obtained a month after completion of therapy and then at
aforementioned regular intervals to assess the ability of imaging to detect residual or recurrent disease
after such local ablative therapy.
Enrollment
This study will enroll a total of 440 participants and will be open to all UNOS accredited liver transplant
centers in the United States. The United States is divided currently into 11 transplant regions, which vary
in area and number of organ transplant procedures. ACRIN plans to enlist a sufficient number of centers
from the various regions to accomplish a sample which is representative of the relative distribution of
transplant activity in HCC patients in the US. Historic UNOS data are used for benchmarking to determine
regional accrual quotas.
Participation
ACRIN will review the interest from the regional areas and communicate back to each site if they will be
asked to participate. This protocol specific application (PSA) serves both to facilitate discussion among
site investigators and support staff about the site’s potential to successfully carry out this protocol and to
document the site’s capabilities for review by the ACRIN Institutional Participation Committee.
Case Reimbursement
ACRIN will provide case reimbursement for this trial. This is a per case rate that will be provided based on
accruing a patient to the trial and conducting the serial timepoint imaging per protocol. The
reimbursement will be as follows:

Each case will be reimbursed a “base” case rate of $3,750. This is meant to cover the
complementary baseline imaging, a complementary post ablation image, data management,
pathology and general data support costs.

For each 90-day imaging update timepoint, an additional $1,000 will be issued for the case.
Overall, the per patient case rate is dependent upon how long the patient remains on the waitlist, but all
patients, if maintained on the trial to explant, will receive a minimum of $3,750.
Please complete the following application in electronic format. This will expedite the processing
of the application and help maintain correct information on file.
E-mail completed applications to [email protected]. If you have any questions about the
application, please contact project manager Donna Hartfeil at [email protected] or 215-717-2765.
Thank you for your interest.
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
Name of Site:
Address:
A. Personnel
1. Multidisciplinary Trial Team
Radiologist: The radiologist for the trial will typically be someone from the body imaging group who
normally works with the transplant team and/or is involved in the interdisciplinary tumor
board/transplant committee. This person would support the trial by identifying potential participants,
consenting the patients, and coordinating schedules for imaging. This person will be a critical success
factor for a site’s participant enrollment.
Name of Lead Radiologist Physician (mandatory):
Telephone:
Fax:
E-mail:
Name of Research Nurse/Coordinator Working with Radiology (optional):
(Note: At least one Research Nurse/Coordinator must be identified)
Telephone:
E-mail:
Transplant Surgeon(s): The support of surgeons and their staff to identify potential participants, assist
with the consent process, and coordinate schedules will be a critical success factor for a site’s
participant enrollment.
Name of Transplant Surgeon (mandatory):
Telephone:
E-mail:
Name of Research Nurse/Coordinator Working with Surgeon (optional):
Telephone:
E-mail:
Name of Additional Physician (optional):
Hepatologist
Telephone:
Surgeon
Medical Oncologist
E-mail:
Name of Research Nurse/Coordinator Working with Physician (optional):
Telephone:
ACRIN 6690 1.16.14
E-mail:
Page 1 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
Of the physicians listed above, please indicate who will serve as the site principal investigator,
or if this role will be shared?
Please also indicate, of the Research Nurse/Coordinator personnel listed above, who will serve
as the lead contact?
B. Site Requirements
1. Pathology
Participants will undergo imaging scheduled in accordance with the 90-day intervals required for
cyclical update of the HCC-exception points with UNOS. The goal is to have imaging data from both
CT and MRI available which is less than 90 days old when transplantation/explantation occurs. Results
from this last imaging time point will be used for direct correlation with explant pathology analysis. The
reference standard for the trial will be the systematic pathologic examination of the liver explant, as
described in Section 9.0 of the protocol. Therefore, it is essential to review the protocol procedures and
information with a pathologist at your center who has an interest in liver pathology and typically works
with the liver transplant team in context with explant pathology examinations and liver biopsies. An
established interdisciplinary working relationship is ideal for this trial and will facilitate data correlation
and exchange.
Please confirm that your site can perform the protocol pathology requirements and provide the name
and contact information of the pathologist who will coordinate the tissue and data review.
Can your site carry out the pathology requirements (section 9.0 of the protocol)?
Yes
No
Name of Pathologist:
Telephone:
E-mail:
Does your site have an IRB-approved pre-existing tissue or serum bank for future review/research?
Yes
No
If yes, approximately how many HCC-MELD patients have pre-existing tissue or serum banked at your
site?
Is the collection of tumor markers, such as (CA 19-9) standard of care at your site?
Yes
No
2. Information Technology Infrastructure
Each participating site is required to submit all acquired CT and MRI images of study participants to the
ACRIN core laboratory. The preferred image transfer method is via TRIAD OA, a software application
that includes a rich client and a site server (DICOM file cache). ACRIN provides support for installation
of the triad APPLICATION on a suitable site computer(s) of choice. Such computer(s), that reside on
the same local area network (LAN) as the acquisition scanner or PACS, can then be set up as a
DICOM destination for the purpose of this study. TRIAD then allows “push”-type transfer of the trial
related studies directly to the ACRIN server. Alternatively, image can be transferred to the ACRIN
central archive by inserting a CD or DVD in the drive of a PC with the TRIAD rich client installed. The
TRIAD software anonymizes, encrypts and applies lossless compression to the images before they are
transferred to the ACRIN image archive in Philadelphia.
ACRIN 6690 1.16.14
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ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
Will your site grant the necessary firewall permissions to transfer electronic
image files from a TRIAD server at your site to ACRIN’s image archive via the
Internet?
If yes, please indicate if your site has a PC available with the following
specifications to support the TRIAD software:
 Operating System Windows XP Pro, Windows 2000 Server SP4 and
above, and Windows 2003 server
 Access to the Internet: Internet Explorer
 A 100 GB hard drive is preferred
 At least 512 GB RAM
 Ability to view PDF documents
 Software utilities required to run image transmission software:
o Windows Installer 3.1
o Microsoft NET framework 2.0
o MDAC Type 2.8
o MS SQL 2005 Express
Yes
No
Yes
No
Please contact the ACRIN TRIAD help desk to arrange the installation of the
TRIAD software prior to first accrual. ([email protected]) or by phone at
215-940-8820)
Other options for image submissions include using a secured file transfer protocol (sFTP) to submit
images to a specified location on the ACRIN server; or submitting images via a CD shipped to the
ACRIN imaging core laboratory. Plain/hard copy films will not be accepted.
If you are unable to support the use of TRIAD at your site, is your site capable of submitting the CT or
MRI images via sFTP or CD/DVD?
Yes
No
C. Imaging Equipment and Scanning Procedures
1. What is your site’s standard of care as far as imaging at your institution for patients with HCCexception points?
CT
MRI (answer # 2)
2. If the standard of care imaging is MRI, does your site use Eovist (Hepatocyte-specific
MR contrast agent) as standard of care for abdominal/liver imaging?
we image all patients with Eovist
we image some patients with Eovist (please provide % estimate:
)
we use Eovist only sporadically or never
2a. If you use Eovist at least some of the time for imaging your liver patients, would you be comfortable
with using a standard extracellular gadolinium chelate that does not have dominant hepatobiliary
excretion rather than Eovist for the trial patients?
Yes
No
ACRIN 6690 1.16.14
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ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
3. CT and MRI Scanner Information
Please provide the following information for all CT and MRI scanners to be used in this study.
Type of
Scanner
Manufacturer
CT
MRI
CT
MRI
CT
MRI
CT
MRI
CT
MRI
CT
MRI
Model/ Magnet
Strength
Is the scanner ACR
accredited?
If you answer No for
any scanner, please
read the note below.
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Accreditation expiration
date(s)
Note: If the site does not have American College of Radiology (ACR) CT or MR accreditation, a CT or
MR QCQC Questionnaire must be submitted with the Protocol Specific Application. The CT or MR QC
questionnaire can be found at www.acrin.org/6690_protocol.aspx (click on the “protocol application and
activation materials” link) and is also included at the end of this application.
ACRIN 6690 1.16.14
Page 4 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
The following are the minimum technical specifications for multiphasic contrastenhanced CT of the liver
Feature
Specification
Scanner type
Detector type
Multidetector row scanner
Minimum of 8 detector rows
Reconstructed slice
thickness
Minimum of 5 mm
reconstructed slice thickness
Injector
Power Injector, preferably
dual chamber injector with
saline flush
No less than 3mL/sec
of contrast, better 4–6 mL/sec
with at least 300 mg I /mL or
higher concentration, for dose
of 1.5 mL/kg body weight
1) Late arterial phase
1) Artery fully enhanced, beginning
contrast enhancement of portal vein
2) Portal venous phase
2) Portal vein enhanced, peak liver
parenchymal enhancement, beginning
contrast enhancement of hepatic veins
3) Delayed phase
3) Variable appearance, >120 sec
after initial injection of contrast
Bolus tracking or timing
bolus recommended for
accurate timing
Contrast injection rate
Mandatory dynamic
phases on contrastenhanced MDCT
(comments describe
typical hallmark image
features)
Dynamic phases
(timing)
Comment
Need to be able to image entire liver
during brief late arterial phase time
window
Thinner slices are preferable,
especially if multiplanar
reconstructions are performed
Bolus tracking desirable
Is your site able to perform the CT scan acquisition parameters described in Section
10.0 of the protocol and noted above?
ACRIN 6690 1.16.14
Yes
Page 5 of 9
No
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
The following are the minimum technical specifications for multiphase contrastenhanced MRI of the liver
Feature
Specification
Comment
Scanner type
1.5 T or greater main magnetic field
strength
Phased array multichannel torso coil
Low field magnets not suitable
Coil type
Gradient type
Injector
Contrast injection rate
Minimum sequences
Mandatory dynamic
phases on contrast
enhanced MRI
(comments describe
typical hallmark image
features)
Dynamic phases
(timing)
ACRIN 6690 1.16.14
Current generation high speed
gradients (providing sufficient
coverage)
Dual chamber power injector
recommended
2–3 mL/sec of extracellular
gadolinium chelate that does not have
dominant hepatobiliary excretion
Pre-contrast and dynamic postextracellular-gadolinium T1-weighted
gradient echo sequence (3D
preferable), T2 (with and without FAT
SAT), T1w in and out of phase
imaging
1) Late arterial phase
Unless patient-related factors
precludes use (e.g., body
habitus)
Bolus tracking desirable
Preferably resulting in
vendor-recommended total
dose
1) Artery fully enhanced,
beginning contrast
enhancement of portal vein
2) Portal venous phase
2) Portal vein enhanced, peak
liver parenchymal
enhancement, beginning
contrast enhancement of
hepatic veins
3) Delayed phase
3) Variable appearance, > 120
sec after initial injection of
contrast
The use of a bolus tracking method for
timing contrast arrival for late arterial
phase imaging is preferable. Portal
venous phase (35–55 sec after
initiation of late arterial phase scan ),
delayed phase (120–180sec after
initial contrast injection)
Page 6 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
Is your site able to perform the MRI scan acquisition parameters described in
Section 10.0 of the protocol and noted above?
Yes
No
4. CT or MRI Scanner Qualification (Trial Specific)
ACRIN qualification of the CT and MRI scanner to be used on this study is also required prior to
enrollment of study participants. This is separate from the ACR accreditation requirement noted above.
Qualification for this trial will include the submission of anonymized, retrospective, multiphase MR and CT
liver images from patients with cirrhosis and HCC at each site. Each site interested in participation in this
trial must submit anonymized DICOM images of three complete exams of each modality, multiphasic
contrast-enhanced CT and MRI, of (non-protocol) patients with HCC obtained during the previous 12
months on the scanners intended for use in the trial. The CT and MRI data need not have been obtained
in the same patient. The images will be reviewed centrally for technical adequacy (timing of contrast
enhancement relative to image acquisition, biologic motion, MRI artifacts, etc). Feedback will be provided
back to the sites.
The application and instructions are available on the ACRIN 6690 protocol-specific Web page (click on the
“Imaging Materials” section) at www.acrin.org/6690_protocol.aspx.
D. Participant Recruitment
ACRIN will work closely with the participating sites to support participant enrollment. Accrual
success will significantly depend upon well planned coordination and effective communication
among the transplant team, imaging personnel and the study participant.
This study will enroll a total of 440 participants and will be open to all UNOS accredited liver transplant
centers in the United States. The United States is divided currently into 11 transplant regions, which vary
in area and number of organ transplant procedures. This study will not enroll equal numbers from all
regions but rather, the quota of participants recruited from a particular UNOS region will be kept
proportional to the overall contribution of the region to the national total of patients transplanted with
HCC-exception points. Historic UNOS data are used to determine the regional quotas.
1. Accrual Support Personnel
Please identify the person(s) at your site who will lead the development and implementation of the
site accrual plan:
Telephone:
ACRIN 6690 1.16.14
Fax:
E-mail:
Page 7 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
2. Does your site regularly hold interdisciplinary liver tumor conferences?
Yes
No
If yes, who participates regularly (check all that apply):
transplant surgeons
hepatologists
pathologists
non-transplant surgeons
radiologists
all of the above
3. Historical HCC Patient Treatment Information:
a) Please provide the number of patients transplanted with HCC-exception
points at your center in 2013:
b) What is the standard of care as far as treatment at your institution for
patients with HCC exception points and maintaining their status on the waitlist:
1) we treat all patients while on the waitlist with some form of local
ablative therapy.
2) we treat some of our patients with local ablative therapy
(please provide %
)
3) we never/hardly ever treat patients with local ablative therapy.
c) To the best of your knowledge, has the frequency of local ablative therapy
changed in 2013?
1) Yes, increased
2) Yes, decreased
3) No change
ACRIN 6690 1.16.14
Page 8 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
4. Historical Data for Recruitment Summary
Provide the percentage breakdown of the minority population and gender served at your site during
January 1st to December 31st, 2009.
Note: This data should be specific to the HCC-exception point population on the transplant list in 2009.
Race
%
Asian
Ethnicity
%
Hispanic or Latino
Black or African American
Non-Hispanic or Latino
White
American Indian or Alaskan
Native
Native Hawaiian or other
Pacific Islander
Gender
%
Male
Female
Pathologist Support Letter
Please include a support letter from the Pathologist who will be supporting the tissue review and image
correlation at your site. A template letter from the site principal investigator to the pathologist is attached
for your convenience.
ACRIN Protocol Principal Investigator Attestation
I,
(name of protocol principal investigator*) have reviewed and agree
with the information contained in this application and approve of its review by the ACRIN Institutional
Participants Committee.
Application Submission Information
Please e-mail the completed application, including support letter, to [email protected]
ACRIN 6690 1.16.14
Page 9 of 9
ACRIN 6690 Protocol-Specific Application
A Prospective, Multicenter Comparison of Multiphase Contrast
Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis
of Hepatocellular Carcinoma and Liver Transplant Allocation
ACRIN 6690 Pathologist Support Letter
Dear Enter Name of your site Pathologist,
Thank you for your willingness to serve as the supporting pathologist for ACRIN 6690 trial: A Prospective,
Multicenter Comparison of Multiphase Contrast Enhanced CT and Multiphase Contrast-Enhanced MRI for
Diagnosis of Hepatocellular Carcinoma and Liver Transplant Allocation
As the pathologist, your support is essential to the study’s success. Remuneration for your assistance in
carrying out the activities described below has been factored into to the trial’s case reimbursement
calculation and I would be pleased to discuss specific arrangements with you.
Upon receipt of an explant liver, you or a designee familiar will need to check with the transplant team
and/or ACRIN 6690 trial study coordinator to see whether the patient is enrolled in the trial so that the
explant workup can be performed according to the specifications of this trial protocol. Alternatively, the
study coordinator and I will work to inform you of when the study participant went to transplant.
Request Support
1. Become familiar with the study protocol.
a. Identify and sample all OPTN Class 4 and 5 lesions described on the most recent CT and
MRI imaging and obtain 1:1 macroscopic and histopathologic correlation; summary report
forms of most recent CT and MRI performed in the participant will be provided to you.
b. Identify and sample all other suspicious focal liver lesions and report/record those which
turn out to be OPTN Class 5 lesions but were not recorded as such (false negative
imaging findings);
c. Report pathologic staging on a per patient basis based on the requirements noted
Section 9.0 of the protocol;
d. Provide macroscopic images of all relevant nodules for correlative purposes;
e. Provide systematic digital macroscopic images of each side of all gross specimen liver
slabs/sections. Indicate on slabs where sampling took place.
2. Educate other pathologists and staff in the pathology department about the trial.
3. Report any problems related to the process or image correlation to me.
4. Help to ensure timely evaluation of explant livers and corresponding CT/MRI images. The trial team
strongly encourages the physical presence of a body imaging expert at the time of correlation of
explant liver workup by the pathologist to facilitate lesion identification for histologic sampling.
Your support in this trial is greatly appreciated. The Trial Central pathologist, Michael Nalesnik, MD will be
available for questions and clarification throughout the trial as needed.
Please sign and return this letter as acknowledgment of the requested support.
We look forward to collaborating with you on this trial.
Sincerely,
Enter name of site protocol PI here
Enter name of institution here
Referring Pathologist’s Acknowledgement.
I have reviewed the responsibilities described above and agree to participate as a member of the site
protocol team.
Pathologist signature (electronic signature is acceptable):
Date:
CT Scanner Quality Control Questionnaire
The following information is required for sites applying to participate in an ACRIN trial involving
CT imaging that do NOT have CT accreditation either by the American College of Radiology (ACR)
or the Intersocietal Commission for the Accreditation of Computed Tomography Laboratories
(ICACTL).
Medical Physicist: Identify the medical physicist who oversees the quality control program and attach
CV:
Equipment Quality Control Program
Does your institution have a Quality Control program that at a minimum reviews the image quality criteria
itemized in the box below?
Yes
No
For the scanner(s) to be used in the protocol, please record whether the physicist performs an
annual evaluation of the following:
Yes
(If no, record frequency)
Alignment light accuracy*
Alignment of table to gantry
Table/gantry tilt
Slice localization from scanned projection
radiograph (localization image)
Table incrementation accuracy
Slice thickness*
Image quality
(High-contrast (spatial) resolution, low-contrast resolution,
image uniformity, noise, artifact evaluation)
CT number accuracy and linearity *
Display devices *
(Video display, hard-copy display)
Dosimetry
(Computed tomography dosimetry index (CTDI), patient
radiation dose for representative examinations)
Safety evaluation
(Visual inspection, audible/visual signals, posting
requirements and scattered radiation measurements)
*Please provide the name and contact information of an on-site technologist who will conduct routine
quality control inspections for these areas:
Name, title, and contact information of individual completing this questionnaire:
Date:
Version Date: 2-2-11
CT QC Program Questionnaire
MRI Scanner Quality Control Questionnaire
The following information is required for sites applying to participate in an ACRIN protocol
involving MRI that do NOT have American College of Radiology (ACR) MRI accreditation.
MRI Equipment Quality Control
Please record the name and title of the individual(s) responsible for overseeing the quality control for the
scanners to be used in the protocol:
Does facility have regularly scheduled preventive maintenance checks performed and documented by a
qualified service engineer on a regular basis?
Yes
No
Does facility maintain documentation of services performed to correct any system deficiencies?
Yes
No
Please complete the following regarding MR equipment performance checks for the scanner(s) to be
used in the protocol:
Checked Annually by Medical Physicist?
No
Yes
(If no, provide frequency of inspection)
Magnetic Field Homogeneity
Slice Position Accuracy
Slice Thickness Accuracy
Radiofrequency Coil Checks
Soft-Copy Displays (Monitors)
Checked Weekly by Technologist?
No
Yes
(If no, provide frequency of inspection)
Center frequency
Table Positioning
Setup and Scanning
Geometric Accuracy
High-Contrast Resolution
Low-Contrast Resolution
Artifact Analysis
Film Quality Control
Visual Checklist
Name, title, and contact information of individual completing this questionnaire:
Date:
Version Date: 2-2-11
MRI QC Program Questionnaire