Comparison of Yttrium-90 Absorbed Doses Using PET/CT Versus PET/MR Imaging in Patients Undergoing Selective Internal Radiation Therapy for Hepatic Malignancies
Phase: NA
Conditions: Hepatic Malignancies
Sponsor: Case Comprehensive Cancer Center

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STUDY NUMBER:  CASE 13219  
ClinicalTrials.gov NCT #:  
Protocol Date: 11.04.2019 (Revised 1.16.2020 and 2.4.2020) 
STUDY TITLE:  Comparison of yttrium-90 absorbed doses using PET/CT versus 
PET/MR imaging in patients undergoing selective internal radiation therapy for hepatic 
malignancies  
PRINCIPAL INVESTIGATOR: 
Ram Gurajala, M.D.  
Interventional Radiology, Imaging Institute 
Cleveland Clinic 
9500 Euclid Avenue, 
 
Cleveland, OH 44195 
 
SPONSOR:  
Case Comprehensive Cancer Center 
SUPPORT/FUNDING: 
Siemens Medical Solutions 
NCT04332419

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Title: Comparison of yttrium-90 absorbed doses using PET/CT versus PET/MR imaging 
in patients undergoing selective internal radiation therapy for hepatic malignancies  
 
 
Principal Investigator: Ram Gurajala, M.D. 
 
 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE: 
 
 
_______________________________________ 
 
Date: 2/4/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
11/4/2019 
 
Initial IRB approval reviewed on 11/26/19 
1/16/2020 
 
Revised protocol (version 1) for Initial IRB approval 
2/4/2020 
 
Revised protocol (version 2) for Initial IRB approval 
6/10/21 
 
Revised protocol (version 3) Dosimetry and volumetry results from an 
earlier pilot series of 8 cases (IRB#17-823 Effect of PET/MR 
Attenuation correction in Y90 dosimetry analysis compared to 
PET/CT); will be compared to verify their consistency and evaluate the 
validity of using them interchangeably and will be included in the 
statistical analysis 
 
 
 
 

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PROTOCOL SUMMARY 
 
12 consecutive cases undergoing yttrium-90 radioembolization (Y-90 RE) for hepatic 
malignancies at our institute are consented to participate at this trial. Within 6 hours after 
the procedure, the patients undergo PET/CT and PET/MR imaging (less than 1 hour apart) 
for evaluation of the treatment and software-assisted measurement of yttrium-90 absorbed 
doses in the tumor and surrounding liver tissue. Dosimetry data acquired from the two 
imaging modalities from these cases, in addition to the post-Y90 RE dosimetry and 
volumetry results from an earlier pilot series of 8 cases (IRB#17-823 Effect of PET/MR 
Attenuation correction in Y90 dosimetry analysis compared to PET/CT; similar protocol 
design), will be compared to each other to verify their consistency and evaluate the validity 
of using them interchangeably. 
 
 
ABBREVIATIONS  
 
 
 
 
CT 
Computed Tomography  
DSMP 
Data and Safety Monitoring Plan 
GCP 
Good Clinical Practice 
HIPAA Health Information Portability and Accountability Act   
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
PET 
Positron Emission Tomography 
RDC 
Reproducibility Coefficient 
RE 
Radioembolization 
SD 
Standard Deviation 
SIRT 
Selective Internal Radiation Therapy  
SPECT Single Photon Emission Computed Tomography 

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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Selective Internal Radiation Therapy 
1.2 
Post Y-90 Radioembolization Imaging 
1.3  
Rationale of Study 
 
2.0 
OBJECTIVE 
2.1  
Primary Objective 
2.2 
Secondary Objective 
 
3.0 
STUDY DESIGN 
3.1 
Number of Subjects 
3.2 
Study Protocol 
3.3 
Expected Duration of Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
6.0 
POTENTIAL RISKS 
6.1 
Adverse effects 
6.2 
Data and Safety Monitoring Plan (DSMP) 
 
7.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
7.1 
Data Reporting 
7.2 
Regulatory Considerations  
7.2.1 Written Informed consent 
7.2.2 Subject Data Protection 
7.2.3 Retention of records 
7.2.4 Audits and inspections  
 
REFERENCES 
 
  
 
 
 
 
 
 
 
 
 

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1.0 INTRODUCTION 
 
1.1 Selective Internal Radiation Therapy 
The liver is one of the most common sites for metastatic diseases. Moreover, primary 
cancers in the liver are a major global matter of concern, with incidence rates that have 
increased substantially within the past two decades [1]. Selective internal radiation 
therapy (SIRT) with yttrium (Y)-90 is a well-established modality for palliative 
treatment of primary and metastatic liver malignancies and constitutes delivery of 
radioactive-emitting embolic microspheres through selection of arteries that directly 
feed the tumor. Radioembolization (RE) through this method achieves prolonged 
patient survival with limited systemic adverse effects and acceptable safety profile [2, 
3]. 
1.2 Post Y-90 Radioembolization Imaging 
Various imaging modalities including single-photon emission computed tomography 
(SPECT) and positron emission tomography (PET), in combination with computed 
tomography (CT) or magnetic resonance imaging (MRI), are incorporated as part of  
standard patient care after Y-90 RE to evaluate the distribution of radionuclide particles 
within the liver (and elsewhere in the body) and to calculate the radionuclide absorbed 
doses in the tumors, which in turn would permit optimal planning for continuation of 
patient’s care [4]. Accurate tumor Y-90 dosimetry is crucial for determination of the 
treatment efficacy and prediction of the response to therapy. In comparison to SPECT, 
post-Y-90 RE imaging with PET/CT has been proven to serve as a favorable modality 
for this purpose as it delivers better spatial resolution and higher precision in 
quantifying tumor absorbed doses. These advantages improve Y-90 RE treatment 
planning by generating more pertinent dose-response and dose-toxicity data [5]. Hence, 
Y-90 PET/CT has become the modality of choice for post-Y-90 RE imaging in many 
centers across the US including our institute. Y-90 PET/MR is another imaging 
modality that may be performed after SIRT with Y-90 and confers superior soft tissue 
contrast and determination of the liver/tumor contours, compared to Y-90 PET/CT 
imaging [6]. For this reason, post-Y-90 RE PET/MR is frequently performed at our 
institute, encompassing over 200 cases since 2016. Despite this, Y-90 PET/CT still 
provides a better quantification of PET images, due to the better attenuation correction, 
and remains as the gold standard method [6]. This necessitates assessment of the 
validity of dosimetry results acquired by Y-90 PET/MR, in comparison to PET/CT 
imaging.  
1.3 Rationale of Study 
In a prior pilot study to compare post-Y-90 RE dosimetry results between PET/CT and 
PET/MR imaging, the current investigators observed significant inconsistencies 

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between the two modalities; in other words, tumor absorbed doses were on average 
36% (SD = 43%) lower in PET/MR-based calculations than in PET/CT [7]. This 
resulted in PET/MR software upgrades which predominantly included a few 
improvements in the attenuation correction as well as the respiratory motion correction 
methods. In order to validate these PET/MR-based dosimetry upgrades, this protocol 
was designed including another pilot trial of 8 cases, to compare Y-90 dosimetry data 
between PET/CT and PET/MR. Given the promising results of the second pilot trial 
(IRB#17-823 Effect of PET/MR Attenuation correction in Y90 dosimetry analysis 
compared to PET/CT), the investigators are proposing this study (with similar design) 
to extend their research on more cases. 
 
2.0 OBJECTIVE 
2.1 Primary Objective 
To assess the agreement between post-Y-90 RE absorbed doses (Gy) in the liver tumor 
tissues based on PET/CT versus PET/MR imaging. This objective would permit the 
comparison of Y-90 tumor absorbed doses, acquired from PET/MR, with the current 
standard of care PET/CT imaging to verify the data consistency and to validate its 
application for the prediction of tumor response to treatment. The endpoint for this 
objective would be the measurement of the reproducibility coefficient (RDC) between 
the two imaging modalities for post-Y-90 RE absorbed doses (Gy) in the liver tumor 
tissues (please see the Study Design for further details). 
2.2 Secondary Objective 
To assess the agreement between post-Y-90 RE absorbed doses (Gy) in the background 
liver tissues (surrounding tumors), based on PET/CT versus PET/MR imaging. This 
objective would permit the comparison of Y-90 background liver absorbed doses, 
acquired from PET/MR, with the current standard of care PET/CT imaging to verify the 
data consistency and to validate its application for the prediction of dose toxicity. The 
endpoint for this objective would be the measurement of the RDC between the two 
imaging modalities for post-Y-90 RE absorbed doses (Gy) in the background liver 
tissues (please see the Study Design for further details). 
 
3.0 STUDY DESIGN 
3.1 Number of Subjects 
Upon IRB approval and patient’s informed consent, 12 new consecutive cases will be 
enrolled in the study. The sample size calculation (n = 12) is based on the fact that the 

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RDC should be < 5% for clinical use. The following table summarizes the estimated 
upper 95% confidence bound for the RDC as a function of the unknown RDC.  Based 
on this table and our expectation that our new technique will have an excellent 
reproducibility with PET, a sample size of 12 will provide sufficient precision to 
determine if the RDC with our new technique is near 5%. 
Estimated Upper 95% Confidence Bound for RDC 
 
Magnitude of RDC 
# Cases 
RDC=2% 
RDC=3% 
RDC=4% 
RDC=5% 
10 
3.2 
4.8 
6.4 
8.0 
12 
3.0 
4.5 
6.1 
7.6 
15 
2.9 
4.3 
5.7 
7.2 
 
 
3.2 Study Protocol 
 
The study protocol is outlined in the diagram below. Upon the patient’s informed 
consent and eligibility approval (according to the inclusion/exclusion criteria below) 
for participation in the trial, they undergo PET/CT (standard imaging) and PET/MR 
(additional imaging), within 6 hours after SIRT with Y-90 for palliative treatment of 
the liver malignancy. Patients will be randomized to receive either of the imaging 
modalities first, based on the availability of the imaging device, and less than 1 hour 
apart. This limited time threshold allows to ignore the trivial amounts of β− decay in 
radionuclide emission that happens after trans-arterial delivery of Y-90 microspheres 
into the liver, with regards to its half-life of ~64 hours. Upon acquirement and 
construction of PET/CT and PET/MR images, a software (MIM SurePlan LiverY90) 
would be utilized for semi-automatic determination of the liver/tumor contours and 
calculation of the Y-90 absorbed doses (Gy) in the regions of interest (including within 
tumor and background liver outlines) using the Local Deposition Method.  
 
Dosimetry/volumetry data from the two modalities from these cases, in addition to the 
results from the pilot cases (IRB#17-823 Effect of PET/MR Attenuation correction in 
Y90 dosimetry analysis compared to PET/CT ; similar protocol design), will be 
compared using the Bland Altman method to assess the pattern of differences between 
dosimetry values and to measure the reproducibility of the methods [8]. The RDC is 
the minimum difference between the two measurements that can be considered a true 
difference, with 95% confidence.  It will be calculated as 2.77 times the within-subject 
SD (wSD), where wSD is the square root of the mean variance across the N subjects, 
and the variance for each subject is calculated from their two dosimetry values [9,10]. 
In addition, the reproducibility coefficient will also be expressed as a percentage of a 
subject’s PET/CT value of dose, using the within-subject coefficient of variation 

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(wCV) instead of wSD. An upper 95% confidence bound for the RDC will be 
constructed using a chi square statistic as the pivotal statistic, as follows: 
2.77 × √𝑁 ×  %𝑤𝐶𝑉2/𝜒𝑀,𝛼
2
, where 𝜒𝑀,𝛼
2
 is the 𝛼th percentile of the chi square 
distribution with N degrees of freedom. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3 Expected Duration of Subject Participation 
The study involves one-time PET/MR imaging in addition to the standard PET/CT 
imaging, both performed on the same day of the treatment procedure (Y-90 RE). Upon 
completion of the imaging procedures, the patient’s involvement in the study would be 
completed. The researchers, however, will need to access the patient’s medical records 
to record basic medical information including the patient demographics, diagnosis, and 
treatment and to analyze the imaging data and dosimetry. 
 
4.0 SUBJECT SELECTION 
4.1 Inclusion Criteria 
A) The patient has a liver malignancy and is scheduled for SIRT with Y-90; AND 
B) The patient is an adult (18 years or above), self-competent, and able to provide 
informed consent to participate in the study 
4.2 Exclusion Criteria 
Patient's consent & 
eligibility approval
Y-90 RE
PET/CT followed by 
PET/MR (within 1h)
Image analysis & 
Y-90 dosimetry
PET/MR followed by 
PET/CT (within 1h)

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A) The patient loses competence, has a condition that questions their ability to provide 
informed consent independently (e.g. cannot communicate in English), or withdraws 
consent to participate within any time in the study period; OR 
B) The patient is not eligible to undergo MRI due to the presence of metal devices or 
implants in their body; OR 
C) Both imaging modalities cannot take place within 6 hours after Y-90 RE; OR 
D) Both imaging modalities cannot take place within 1 hour apart from each other 
4.3 Inclusion of Women and Minorities 
Adult patients who are able to communicate in English efficiently may participate 
in the study, regardless of their gender, age, race, or ethnic origin. 
 
5.0 REGISTRATION 
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 
6.0 POTENTIAL RISKS 
6.1 Adverse effects 
 
The additional PET/MR imaging in this study does not involve any extra radiation to 
the patient, besides what one would receive as part of the standard protocol during Y-
90 RE and PET/CT imaging. There are no known biological risks associated with 
PET/MRI.  A PET/MRI procedure may cause possible anxiety in some individuals, due 
to the confined space of the testing area resulting in feelings of claustrophobia and the 
loud banging made by the machine. The patients retain the right to withdraw from 
participating in the study in such conditions. 
Since the MRI is a powerful magnet, patients cannot be scanned if they have certain 
metal devices in their body.  There is also a risk of injury if metal is brought into the 
imaging room, which may be pulled into the magnet.  Patients will be asked to remove 
any magnetic objects from their clothes and body in order to prevent any injuries.  A 
safety zone is established around the MR scanner to prevent objects containing iron 
from coming into contact with the scanner. 
6.2 Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center 
Data and Safety Monitoring Plan in accordance with NCI guidelines.  

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7.0 RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
7.1 Data Reporting  
The OnCore™ Database would be utilized, as required by the Case Comprehensive 
Cancer Center, in order to provide data collection for both accrual entry and trial 
data management. OnCore™ is a Clinical Trials Management System housed on 
secure servers maintained at Case Western Reserve University. Access to data 
through OnCore™ is restricted by user accounts and assigned roles. Once logged 
into the OnCore™ system with a user ID and password. OnCore™ defines roles 
for each user which limits access to appropriate data. User information and 
password can be obtained by contacting the OnCore™ Administrator at OnCore-
registration@case.edu. 
OnCore™ is designed with the capability for study setup, activation, tracking, 
reporting, data monitoring and review, and eligibility verification. This study 
would utilize electronic Case Report Form completion in the OnCore™ database. 
A calendar of events and required forms are available in OnCore™. 
7.2 Regulatory Considerations 
 
The study would be conducted in compliance with the IRB-approved protocol, HIPAA 
and ICH guidelines, as well as all applicable federal (including 21 CFR parts 56 & 50), 
state and local regulations. 
7.2.1 Written Informed consent 
Provision of written informed consent would be obtained prior to any study-related 
procedures. The Principal Investigator would ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects would 
also be notified that they are free to discontinue from the study at any time. The subject 
would be given the opportunity to ask questions and be allowed time to consider the 
information provided. 
The original, signed written Informed Consent Form would be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of 
the signed written Informed Consent Form would be given to the subject. Additionally, 
documentation of the consenting process would be located in the research chart. 
7.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), all study subjects would sign an authorization to release medical information 
to the sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review 

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Board access to subject’s medical information that includes all hospital records relevant 
to the study, including subjects’ medical history.  
7.2.3 Retention of records 
The Principal Investigator of the Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events and all IRB correspondence for as long 
as needed to comply with local, national and international regulations. No records 
would be destroyed until the Principal Investigator confirms destruction is permitted.  
7.2.4 Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent 
Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to 
perform audits or inspections, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonization 
(ICH), and any applicable regulatory requirements. For multi-center studies, 
participating sites must inform the sponsor-investigator of pending audits.  
 
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