ACRIN Protocol-Specific Application s1

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 HCC- exception 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 Surgeon Medical Oncologist Telephone: E-mail:

Name of Research Nurse/Coordinator Working with Physician (optional): Telephone: E-mail:

ACRIN 6690 1.16.14 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 Page 2 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

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 Yes No 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: Yes No o Windows Installer 3.1 o Microsoft NET framework 2.0 o MDAC Type 2.8 o MS SQL 2005 Express

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 HCC- exception 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

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 Is the scanner ACR Scanner accredited? Model/ Magnet Accreditation expiration Manufacturer If you answer No for Strength date(s) any scanner, please read the note below. CT Yes No MRI CT Yes No MRI CT Yes No MRI CT Yes No MRI CT Yes No MRI CT Yes No MRI 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.

The following are the minimum technical specifications for multiphasic contrast- enhanced CT of the liver

Feature Specification Comment Scanner type Multidetector row scanner Detector type Minimum of 8 detector rows Need to be able to image entire liver during brief late arterial phase time window Reconstructed slice Minimum of 5 mm Thinner slices are preferable, thickness reconstructed slice thickness especially if multiplanar reconstructions are performed Injector Power Injector, preferably Bolus tracking desirable dual chamber injector with saline flush Contrast injection rate 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 Mandatory dynamic 1) Late arterial phase 1) Artery fully enhanced, beginning phases on contrast- contrast enhancement of portal vein enhanced MDCT 2) Portal venous phase 2) Portal vein enhanced, peak liver (comments describe parenchymal enhancement, beginning typical hallmark image contrast enhancement of hepatic veins features) 3) Delayed phase 3) Variable appearance, >120 sec after initial injection of contrast Dynamic phases Bolus tracking or timing (timing) bolus recommended for accurate timing

Is your site able to perform the CT scan acquisition parameters described in Section 10.0 of the protocol and noted above? Yes No

ACRIN 6690 1.16.14 Page 5 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 multiphase contrast- enhanced MRI of the liver

Feature Specification Comment Scanner type 1.5 T or greater main magnetic field Low field magnets not suitable strength Coil type Phased array multichannel torso coil Unless patient-related factors precludes use (e.g., body habitus) Gradient type Current generation high speed gradients (providing sufficient coverage) Injector Dual chamber power injector Bolus tracking desirable recommended Contrast injection rate 2–3 mL/sec of extracellular Preferably resulting in gadolinium chelate that does not have vendor-recommended total dominant hepatobiliary excretion dose Minimum sequences Pre-contrast and dynamic post- extracellular-gadolinium T1-weighted gradient echo sequence (3D preferable), T2 (with and without FAT SAT), T1w in and out of phase imaging Mandatory dynamic 1) Late arterial phase 1) Artery fully enhanced, phases on contrast beginning contrast enhanced MRI enhancement of portal vein (comments describe typical hallmark image 2) Portal venous phase 2) Portal vein enhanced, peak features) liver parenchymal enhancement, beginning contrast enhancement of hepatic veins

3) Delayed phase 3) Variable appearance, > 120 sec after initial injection of contrast Dynamic phases The use of a bolus tracking method for (timing) 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)

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: Fax: E-mail:

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 % Ethnicity %

Asian Hispanic or Latino

Black or African American Non-Hispanic or Latino

American Indian or Alaskan

Native

Native Hawaiian or other

Pacific Islander

Gender %

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:

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:

Version Date: 2-2-11 MRI QC Program Questionnaire