Intrinsic Dosimetry for Radioembolization Utilizing PET-CT Imaging Data: A Prospective Registry Study
Phase: NA
Conditions: Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Metastatic Extrahepatic Bile Duct Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Stage D Adult Primary Liver Cancer (BCLC), Unspecified Adult Solid Tumor, Protocol Specific
Sponsor: Fox Chase Cancer Center

ERP-RT-060 
 
 
ERP RT-060 - Intrinsic Dosimetry for Radioembolization utilizing PET-CT Imaging Data: A 
Prospective Registry Study. 
 
Principal Investigator: 
 
Joshua E. Meyer, MD 
Dept. of Radiation Oncology 
Fox Chase Cancer Center 
333 Cottman Avenue 
Phone: 215-728-2667 
Fax: 215-214-1629 
joshua.meyer@fccc.edu 
 
Co-Investigators: 
JQ Michael Yu, MD, FRCPC 
Dept. of Diagnostic Imaging 
Fox Chase Cancer Center 
333 Cottman Avenue 
Phone: 215-728-3865 
Fax: 215-728-4755 
michael.yu@fccc.edu 
 
Iavor Veltchev, PhD 
Dept. of Radiation Oncology 
Fox Chase Cancer Center 
333 Cottman Avenue 
 
Phone: 215-214-2854 
Fax: 215-728-4789  
iavor.veltchev@fccc.edu 
 
Mohan Doss, PhD 
Dept. of Diagnostic Imaging 
Fox Chase Cancer Center 
333 Cottman Avenue 
Phone: 215-728-1707 
Fax: 215-728-4755 
mohan.doss@fccc.edu 
 
Statistician: 
Elizabeth Handorf, PhD 
 
Biostatistics and Bioinformatics Facility 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue 
 
Phone: 215-728-4330 
 
Fax: 215-728-2553 
 
Elizabeth.Handorf@fccc.edu 
 
 
 
 
 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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Study Monitor: 
 
 
 
 
 
Beth Adaire-Halenda, CCRP 
 
 
 
 
 
Fox Chase Cancer Center  
 
 
 
 
 
Room P-3002 
 
333 Cottman Avenue 
 
 
 
 
 
Philadelphia, PA 19111 
 
 
 
 
 
Phone: 215-214-3704 
 
 
 
 
 
Fax: 215-214-1511 
 
 
 
 
 
beth.adaire@fccc.edu 
 
 
 
 
Version: 
 
4/10/2013 
Amendment 1  
Version Date: 10/27/2013 
Amendment 2  
Version Date: 01/14/2014 
Amendment 3  
Version Date: 02/27/2014 
Amendment 4  
Version Date: 03/13/2014 
Amendment 5  
Version Date: 09/30/2014 
 
 
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Amendment 5Ver. 9/30/2014 
 

ERP-RT-060 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population: 43 Patients with liver-dominant or liver-only 
metastatic disease from any primary histology or patients 
with primary hepatocellular or biliary cancer. 
ECOG performance status of 0, 1 or 2 
Day of treatment Visit 1(Day 0): 
Radioembolization as per pre-planned prescription 
Post-treatment PET-CT to determine dose from radioembolization 
 
Registration Visit 
Decision made to undergo radioembolization 
Informed Consent 
Verify baseline laboratory and imaging studies 
 (contrast enhanced CT or MRI of the liver) 
Pre-treatment evaluation: 
Staging arteriogram in preparation for radioembolization (coil 
embolization as necessary) 
Injection of Tc-99m labeled macroaggregated albumin (MAA) SPECT 
& Planar imaging of Liver, 3 Phase Liver CT Simulation,  
SPECT scan of Tc-99m MAA 
Day after treatment Visit 2(Day 1) 
Post-treatment PET-CT to assess potential 
migration of spheres from implantation 
(subset of patients) 
Follow Up 
Symptom guided physical exam, Serum Chemistry, CBC with Differential and Platelets, 
ECOG Performance Status, Adverse Event Assessment and Tumor Imaging.  
Follow-up visits will be scheduled at 1 week, 1 month, 3 months, and then every 3 
months for one year, every 6 months for 1 year and then annually for 3 years or death 
whichever comes first. 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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1.0 Introduction 
 
1.1 Abstract 
 
This protocol for human research study is conducted according to US and international 
standards of Good Clinical Practice (International Conference on Harmonization (ICH) 
Guidelines) and applicable government regulations (e.g. Title 45, Part 46 Code of Federal 
Regulations). 
 
The development of radioembolization with microspheres represents a significant 
advance in the treatment of patients with metastatic disease to the liver. [1,2] This 
technique uses semi-empirical formulas for dose calculation that rely on body surface 
area or crude volumes as the determinants of dose. Moreover, dose is assumed to be 
uniformly distributed throughout the treated volume. Although the efficacy of treatment 
and limited side effects are evidence of high intratumoral doses with minimal radiation to 
normal liver, there have been few attempts to quantify the actual doses delivered. 
Knowledge of these doses may allow more accurate determination of the effect of dose 
on response, improved algorithms for prescription of the safest and most effective dose 
for each patient, and safer integration of additional treatment to the area with either 
microspheres or external beam radiation. Therefore, we are proposing a new technique to 
better characterize the dose deposition of radioactive microspheres. The research plan 
will be based on the recent publication of positron emission from Yttrium 90 (Y-90), 
which can be utilized to image sphere distribution on a positron emission tomography 
(PET) scanner, without the administration of additional radiolabeled tracer. Three 
dimensional dose distributions will be generated and fused onto the CT data of patients to 
display doses to tumors and normal tissues.  
 
1.2 Background 
 
The current methodology for determining the prescribed dose for patients to be treated 
with radiolabeled microspheres likely leads to suboptimal treatment of hepatic 
malignancies, with most patients being either overtreated or undertreated. The 
development of a novel technique for defining actual dose delivered will better define the 
activity required to achieve specific doses, and begin to support the transition from a 
model of dose prescription based primarily on body surface area to one that predicts the 
dose to both tumor and normal tissues.  
 
The current formulae for determining the prescribed activity to patients to be treated with 
radiolabeled microspheres are crude and do not take into account significant variations in 
tumor size, shape, or location. There are two radiolabeled microsphere products currently 
available for treating patients with liver tumors (metastatic or primary): SIR-Spheres 
(Sirtex Medical, North Sydney, Australia) and Therasphere (Nordion, Ottawa, Canada). 
The formula most commonly used for SIR-Spheres is largely driven by body surface 
area:  
 
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Amendment 5Ver. 9/30/2014 
 

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A [GBq] = BSA – 0.2 + (TV/TLV) 
 
where A = activity, GBq = Gigabecquerels (units), BSA = body surface area, TV = tumor 
volume, and TLV = total liver volume. This may be multiplied by the lobe factor 
(fraction of the total liver volume being treated) for patients in whom whole liver 
treatment is not being pursued. The formula used for calculation of activity in 
Therasphere administration is:  
 
A [GBq] = (D [Gy] x m [kg])/49.38 
 
where D is the desired dose in Gy, m is the tumor mass in kg. Dose is set to a nominal 
100-120 Gy, based on an expected uniform distribution of microspheres over the treated 
region. However, there is no data available to date that would definitely confirm this. 
Moreover, this should not be expected to be true. This is due to the existence of 
hypervascular malignancy with blood supply derived from the hepatic arterial system and 
normal tissue deriving its blood supply from the portal vein–all within the treated 
volume. 
 
Neither one of these formulas, nor any others in routine use, takes into account the 
differences in expected dose based upon the size, shape, and location of tumors. In fact, 
the prescription is simply the total activity to be administered, without any calculation of 
the dose to be delivered from this activity. Additionally, there is almost no calculation of 
expected normal tissue doses, with the exception of the use of Tc-99m macro-aggregated 
albumin (MAA) in order to quantify the lung shunt at the time of angiography prior to 
treatment. These limitations in the current prescription methodology hamper the ability to 
move this treatment technique forward, because without doses to both normal tissues and 
tumors it is not possible to ascribe better responses or increased side effects to the doses 
received. Therefore, in the ten years since this treatment has become available, there has 
been little or minimal advancement in the treatment technique. 
 
The emission of positrons from Y-90 has recently been used to generate positron 
emission tomographs of radiolabeled microsphere distribution [3]. A similar technique 
has been used to measure the absorbed dose in an anatomical phantom – a laboratory 
stand-in for a patient – after treatment with SIR-spheres [4]. However, to our knowledge 
this technique has not been routinely performed in patients.  
 
With the availability of a new technique to quantify the dose to tumors and normal 
tissues, it will be possible to correlate response and toxicity with actual dose delivered. A 
second potential application will be the correlation of the activity on the MAA scan with 
the actual dose deposition. It will be valuable to determine whether the MAA scan is a 
reliable predictor of dose distribution. With this relationship better defined, we may be 
able to escalate the dose delivered in many patients in order to improve the control rates 
and decrease doses in patients who are expected to have higher doses to normal tissues.  
 
1.2.1 Preliminary Data 
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Amendment 5Ver. 9/30/2014 
 

ERP-RT-060 
The 3D dose absorbed in a patient is calculated by convolving the activity distribution 
A(x, y, z) with the dose kernel for Y-90 source, according to the following expression.  
 
  
 
where λ is the decay constant of Y-90 isotope and K is the dose kernel. The activity 
distribution in the equation above is due to electrons emitted by the source, but the 
measured PET scan data is the activity distribution due to emitted positrons. As a result, 
one can rewrite the above equation in the following from, 
 
 
  
where Ap is the measured activity due to positrons and γis the conversion factor. Since 
the PET scanner’s resolution is not sufficient to resolve individual spheres, the dose 
kernel is calculated for a volume element of the size equal to that of the PET scanner’s 
voxel size, which is 0.4 x 0.4 x 0.3 cm. The whole volume of the voxel is assumed to be 
filled with tissue, with uniformly distributed electron sources in it that emit electrons with 
energy spectrum corresponding to that of beta electrons of Y-90 [5]. The Fluka Monte 
Carlo code was used to calculate the voxel dose kernel (VDK) in tissue. All pertinent 
interactions were turned on during the simulations and up to 109 histories were simulated 
to reduce the uncertainties.  
 
Care has to be taken in order to properly process the measured activity Ap (activity due to 
positrons). Current Siemens PET/CT scanners do not provide an option for specifying 
imaging-related parameters for Y-90 isotope. Therefore Y-86 template was used in our 
image acquisition procedure, which has its own tracer parameters that are different from 
those of Y-90. However, the Y-86 template can be used during image acquisition as long 
as one experimentally determines the calibration factor γ for Y-90 microspheres using the 
same PET scanner that is used for the subsequent in-patient dose reconstruction (one 
must use the same imaging template for determining the calibration factor as well as for 
patient scanning). It is interesting to note that in this case the herein defined calibration 
factor γ is the ratio between the branching ratios of Y-90 and Y-86. 
 
The calibration factor γ for the Siemens Biograph 16 slice PET/CT scanner available at 
our center was determined by injecting 740 MBq of 90Y-chloride into a 1 L water bag. 
Subsequently, the ”hot” water bag was scanned together with a ”cold” identical size 
water bag using the PET scanner (to account for the scanner’s noise). After the scan, the 
activity in the “cold” water bag was subtracted from the activity value of the bag 
containing 90Y-chloride. The corrected measured activity was divided by the known total 
activity at the time of scanning to determine the calibration factor (an average value for 
the calibration factor was obtained out of seven measurements) that will be used in dose 
calculations of every patient treated with microspheres. 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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Figures 1 and 2 show the calculated isodose distribution as well as the dose volume 
histogram of one of the patients recently treated by Y-90 microspheres. 
 
 
 
 
 
2.0 Objectives  
 
 
 
2.1 Primary Objective 
 
  
• To determine the relationship between radiation dose to 70% of the tumor volume 
as determined by post-treatment PET-CT and local control at 6 months. 
 
 
2.2 Secondary Objectives  
 
 
• To evaluate the ability of PET-CT to reproducibly determine dose to tumor, 
normal liver, and other surrounding organs 
 
• To determine the stability of microsphere location by examining the changes in 
dose in a subset of patients with PET-CT scans performed on Day 0 and Day 1 
 
• To determine the relationship of dose predicted by Tc-99m labeled Macro-
aggregated albumin (MAA) imaged using SPECT versus post-treatment dosimetry 
 
• To determine the effect of dose delivered on local control and normal tissue 
complications 
 
• To measure the perfusion of the tumor for correlation with dose deposition, based 
on arterial phase CT measurements 
 
• 
To evaluate overall survival for 5 years after Visit 1, Day 0. 
Fig. 1: Reconstructed in-patient dose distribution superimposed 
on patient’s axial CT data. The red, green and blue contours 
designate the tumor, liver and right kidney, respectively. 
Fig 2: Dose volume histogram for tumor, liver, right kidney 
and gallbladder. The numbers indicate the percent line of the 
maximum dose, 134.7 Gy. 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

ERP-RT-060 
 
3.0 Study Plan  
 
 
This study will be a single arm registry study to evaluate the dose received by ability of PET-CT 
to determine dose delivered via radioembolization to the liver for metastatic disease. Patients will 
be staged and treated in the standard fashion, but will undergo a number of imaging studies in 
order to better analyze the dose of radiotherapy delivered. These imaging studies include a Tc-
99m MAA SPECT scan (carrying no additional radiation exposure) as well as 1-2 PET-CT scans 
(a limited radiation exposure is necessary with each scan). 
 
This is a prospective single-arm registry study being performed in order to validate a novel 
method of determining dose deposition from radioembolization by performing post-treatment 
PET-CT scan. Forty three patients will be enrolled over an expected recruitment time of 1.5 to 2 
years. We will utilize these data to investigate the relationship between dose delivered to targets 
and local control. A subset of patients will undergo a second PET-CT with contrast CT on Day 0, 
and another subset of patient will have a second PET-CT on Day 1. All other procedures will be 
consistent with the standard of care. Details of the PET-CT procedure can be found in Appendix 
II.  
 
4.0 Patient Selection Inclusion & Exclusion 
 
4.1 Inclusion Criteria  
 
4.1.1 Patients must be at least 18 years of age. 
 
4.1.2 Patients must have liver-dominant or liver-only metastatic disease from any 
primary histology. Patients with primary hepatocellular or biliary cancer are 
also eligible. 
 
4.1.3  Patients must be clinical candidates for radioembolization with either SIR-
spheres or Therasphere due to metastatic or primary malignancies of the liver. 
 
4.1.4  Women of child bearing potential must have a negative serum pregnancy test 
no more than 72 hours prior to registration. 
 
4.1.5 ECOG performance status (PS) of 0, 1 or 2. 
 
4.1.6  Ability to understand and willingness to sign a written informed consent and 
HIPAA authorization for release of medical information. 
 
4.1.7 Complete Blood Count (CBC), Chemistry Panel (CMP) and Coagulation 
Panel (PT, & INR) no greater than 4 weeks prior to registration.  
 
4.1.8 Diagnostic imaging of the abdomen utilizing either CT with contrast, MRI, or 
PET/CT no greater than 6 weeks prior to registration.   
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

ERP-RT-060 
4.2 Exclusion Criteria   
 
4.2.1  Patients not undergoing radioembolization to the liver 
 
4.2.2  Women of childbearing potential (WOCBP) and men who refuse to comply 
with appropriate contraception as described in section 4.4 below. 
 
4.2.2  Women who are either pregnant or breast feeding. Refer to section 4.4 for 
further detail. 
 
4.3 Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for 
this study.   
 
4.4 Pregnancy 
The effects of this clinical trial on the developing human fetus are unknown.  For this 
reason and because radiation as well as other non-therapeutic agents used in this trial 
are known to be teratogenic, women of child-bearing potential (WOCBP) and men 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of treatment, and for at least 
3 months after the last radiographic evaluation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she must inform her treating 
physician immediately. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  In additional, men enrolled on this study should understand the risks to 
any sexual partner of childbearing potential. 
 
All WOCBP must have a negative pregnancy test no more than 72 hours prior to 
registration. If the pregnancy test is positive, the patient must not receive the visit 1 
scan and must not be enrolled in the study. 
 
WOCBP is defined as follows: Any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma follicle-
stimulating hormone (FSH) level > 35 mIU/ml).  Even women who are using oral, implanted, or 
injectable contraceptive hormones or mechanical products (diaphragm, condoms, spermicides) to 
prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), are 
considered to be WOCBP.  
 
4.5 Patient Registration Procedure 
 
Patients will be consented at the time when the decision to pursue radioembolization 
is made.  No protocol-specific workup will take place prior to obtaining informed 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

ERP-RT-060 
consent. However, at this time it will be determined that the patient has had a 
complete staging workup within the last 4 weeks including:  
 
• Diagnostic imaging of the abdomen utilizing either CT with contrast, 
MRI, or PET/CT 
• Complete metabolic panel (CMP) 
• Complete blood count (CBC) 
• Coagulation studies (PT, INR) 
 
Eligible patients will be entered on study centrally by the Fox Chase Cancer Center 
QA Coordinator or their designee.  Following registration, participants must begin 
protocol related treatments and evaluations within 14 days of registration. If a 
participant does not receive protocol therapy following registration, the participant 
will be recorded as withdrawn from study and will be replaced.  The QA Coordinator 
must be notified of cancellations and withdraws as soon as possible.  
 
Participants may be registered from 9:00 am to 5:00 pm excluding holidays and weekends by 
calling the QA Coordinator at 215-728-4770.  The site’s investigator or designee will then fax 
the completed registration form, entire, complete and signed informed consent document and 
HIPAA authorization documents and the completed eligibility checklist to 215-214-1511.  The 
QA Coordinator or designee will notify the site’s investigator or their designee by email when 
participant registration is confirmed and the sequence number has been assigned.  Participants 
must be registered and have received a sequence number assigned by the QA Coordinator prior 
to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted. 
 
5.0 Study Procedures 
 
Pretreatment Visit 
A 3 Phase Liver CT simulation must be performed before Visit 1, Day 0 (The treatment 
Initiation Day). This simulation may occur before or after the staging angiogram, coil 
embolization, Tc-99m MAA injection, and planar and SPECT imaging of the participant’s liver. 
 
Visit 1 (Day 0) 
Visit 1 will take place after the pretreatment visits, and will be referred to as Day 0, the day of 
radioembolization. Visit 1 will include the following procedures: 
• 
Radioembolization as per standard clinical protocol 
• 
PET-CT performed just after the radioembolization in order to measure Yttrium-90 
activity for in-patient dose reconstruction 
• 
Subset of patients will get contrast CT 
 
Visit 2(Day 1) 
Visit 2 will take place on Day 1, and will be pursued in only a subset of patients. This will 
include only a PET-CT for the purposes of determining the stability of microsphere 
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Amendment 5Ver. 9/30/2014 
 

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placement. The Visit 2, Day 1 PET-CT should be scheduled 24 hours +/- 3 hours after 
the Visit 1, Day 0 post-treatment PET-CT. 
 
Follow-up Visits 
Participants will be followed for 5 years or until death, whichever comes first. Follow-up visits 
will be scheduled at 1 week, 1 month, 3 months, and then every 3 months for one year, every 6 
months for 1 year and then annually for 3 years or death whichever comes first 
 
Additional Radioembolization Treatments 
 
As a part of standard of care, many patients will require a second radioembolization.  
 
Patients requiring a second radioembolization  treatment will be scanned additionally at Visit 1 
(Day 0) and Visit 2 (Day 1) after the second treatment.  
 
Visit 2 of the second radioembolization will take place on Day 1, and will be pursued in only a 
subset of patients. This will include only a PET-CT for the purposes of determining the stability 
of microsphere placement. The Visit 2, Day 1 PET-CT should be scheduled 24 hours +/- 3 hours 
after the Visit 1, Day 0 post-treatment PET-CT.  
 
In these cases the 1 month follow up visit may be conducted on the day of the second treatment.  
  
 Follow up visits may be conducted by any investigator and will include the following studies: 
• CBC and CMP will be drawn at each follow-up visit 
• Beginning at the 3-month visit, each visit should be accompanied by tumor imaging to 
evaluate local control.  The modality of tumor imaging will be at the discretion of the 
investigator, but it is encouraged to use the same modality consistently over time.  
 
 
 
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Amendment 5Ver. 9/30/2014 
 

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6.0 Study Calendar 
 
 
 
Registration 
Visit 
Pre treatment 
Visit(s) 
Visit 1 / 
Day 0 
Visit 2/ 
Day 1 
Follow up 
Informed consent & HIPAAA 
X 
 
  
  
  
Medical history 
X 
 
  
  
  
Symptom Guided Physical examG 
X 
 
 
 
X 
ECOG Performance Status 
X 
 
 
 
X 
CBC w/diff, pltsB 
X 
 
 
 
X 
Serum chemistryB 
X 
 
 
 
X 
EKG (as indicated) 
X 
 
  
  
  
β-HCG 
XE 
 
  
  
  
Coagulation StudiesB 
X 
X 
  
  
  
3 Phase Liver CT Simulation 
 
X 
  
  
  
Staging Angiogram 
 
X 
  
  
  
Coil Embolization 
 
X 
  
  
  
Tc-99m (approx 5mCi) MAA Injection 
 
X 
  
  
  
Planar and SPECT Imaging of Liver 
 
X 
 
 
 
Adverse Event Assessment 
 
 
X 
X 
XH 
PET-CTC,D 
 
 
X 
X 
 
Tumor ImagingF 
X 
 
 
 
XI 
A: Must be completed less than 28 days prior to registration and prior to any protocol specific tests or procedures.  
B: CBC and CMP will be drawn at each follow-up visit, Coagulation studies include PT and INR. Coagulation studies must be 
performed for eligibility however results will not exclude patient participation.  
C:Visit 1, Day 0 post treatment PET CT and contrast CT for subset of participants, Day 1 PET CT. 
D:24 hours +/- 3 hours  after Day 0 
E: See Section 4.4 for more information – Must be negative within 72 hours of first treatment related procedure or scan 
F: Repeat imaging is encouraged to be the same modality (PET-CT, MRI, or contrast CT) as that in baseline study. 
G: Physical exam with investigator where he/she reviews symptoms with the participant and addresses any issues that are identified by 
the participant. This is not the same as a complete physical exam, intentionally. 
H: Record only AE’s possibly, probably, or definitely related to the visit 2 / day 1 PET/CT scan. Possibly, probably or definitely related  
AE’s must be followed until resolution or 30 days after visit 2.  
I: Follow up tumor imaging begins with the month 3 follow up visit.  
 
 
 
 
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Amendment 5Ver. 9/30/2014 
 

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7.0  Adverse Events  
 
For purposes of this clinical trial record only AE’s possibly, probably, or definitely related to the 
visit 1 and visit 2 PET/CT scans. Possibly, probably or definitely related AE’s must be followed 
until resolution or 30 days after visit 2 whichever comes first. 
 
 
7.1 Standard Definitions of Adverse Events (AE) and Serious Adverse Events (SAE) 
 
7.1.1 Adverse Events (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure (NCI CTEP 
Guidelines March 28, 2011) 
 
7.1.2 Serious Adverse Event (SAE) is an AE that is fatal or life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization (for > 
24 hours), persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or is a congenital anomaly/ birth defect, 
or results in any important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above outcomes.  A “life-
threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor. 
 
7.1.3 Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific 
toxicity tables provided in the protocol define severity.  If not included in CTCAE 
v.4.0, severity is expressed in numerical grade using the following definitions: 
 
1. Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2. Grade 2: Moderate-minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL. 
3. Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. Grade 5: Death related to AE 
 
7.1.4 Attribution/Relationship to study drug  
 
1. Definite – clearly related 
2. Probable – likely related 
3. Possible – may be related 
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4. Unlikely – doubtfully related 
5. Unrelated – clearly not related 
 
 
7.1.5 Expectedness  
 
An Expected Adverse Event is one where the specificity or severity is 
 
consistent with the current information available from the resources. 
 
An Unexpected Adverse Event is one where the nature, severity, or frequency of 
the event is related to participation in the research is not consistent with either: 
 
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the protocol-
related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts: or 
 
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the 
subjects(s) predisposing risk factor profile for the adverse event. 
 
(OHRP Guidance on reviewing unanticipated problems 2007) 
7.2  Recording and Reporting Responsibilities of the participating investigative sites 
and the sponsor 
 
7.2.1 Participating investigative site recording responsibilities: 
 
These are the directions to be utilized by the site’s investigator (sub-investigator) 
and/or study team at the participating site. 
 
1. Upon identification of an AE or SAE, that is possibly, probably or 
definitely related to the investigational PET CT scans performed, the site 
investigator will utilize the above definitions to properly classify the 
event.  Each category listed above must be recorded for each event. 
 
2. Any AE or SAE that is possibly, probably or definitely related to the 
investigational PET CT scans performed ,will be recorded in the “AE case 
report forms” (CRF) and in progress reports with details about the grade 
and attribution of each episode, action taken with respect to the study 
drug, and the patient’s outcome will be recorded in the CRF.  All events 
that are possibly, probably or definitely related to the investigational PET 
CT scans performed,will be recorded on case report forms for the duration 
of the study until they resolve. 
 
3. All SAEs that are possibly, probably or definitely related to the 
investigational PET CT scans performed, will be recorded on the FDA 
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MedWatch form 3500a or other sponsor-provided SAE report form. After 
submitting the initial report it may be necessary to submit follow up 
reports to the Study Monitor, Sponsor and /or the FDA should the event 
require further investigation. 
 
 
 
7.2.2 Investigative site reporting responsibilities: 
 
1. The investigator/ site is responsible to report all SAEs that are possibly, 
probably or definitely related to the investigational PET CT scans 
performed, to the Study Monitor within 24 hours of becoming aware of 
the event.   
2. Each investigator is responsible to report all AEs/SAEs that are possibly, 
probably or definitely related to the investigational PET CT scans 
performed; to their local IRB following guidelines set by that IRB.  Fox 
Chase Cancer Center Quality Assurance (QA) reserves the right to request 
an event be reported to the IRB at their discretion.  Copies of events 
reviewed by the IRB must be sent via fax to the Regulatory Coordinator at 
(215) 728-2914. 
3. Any investigator who is in doubt of whether a particular AE needs to be 
reported is directed to call the Study Monitor for confirmation from the PI. 
4. If the results of an investigator or QA investigation show an adverse event 
not initially determined to be reportable is so reportable, the investigator 
will report the event following the above guidelines based on the date the 
determination is made. 
5. Copies of all related correspondence and reporting documents must be 
submitted to the Regulatory Coordinator by the study monitor and will be 
maintained in a regulatory file. 
 
The participating site should report events to: 
 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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Beth Adaire-Halenda, CCRP 
Study Monitor 
Fox Chase Cancer Center 
Clinical Trials Operations 
333 Cottman Avenue 
Philadelphia, PA 19111 
Telephone 215-214-3704 
Fax  215-214-1511 
beth.adaire@fccc.edu 
 
 
 
7.2.2.1 Pregnancy  
 
All WOCBP should be instructed to contact the Investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the Investigator 
must immediately notify the Fox Chase Cancer Center Study Monitor who will notify the 
Study PI (Joshua Meyer, MD). 
 
 
7.2.3 ERP Reporting Responsibilities: 
 
 
These are the reporting instructions for the study sponsor. 
 
 
1. Adverse events which meet all of the following criteria must be reported 
to all participating institutions for IRB submission within 2 weeks of 
notification of the event.   
i. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
ii. Possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the 
research); and 
iii. Serious (refer to above definition) or otherwise one that suggests that 
the research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized. 
2. If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the 
form of an amendment from the CTO for each site’s IRB of record along with 
the report of the adverse event.   
3. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at CTO. 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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4. SAEs that are related, unexpected, fatal, or life-threatening  are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information.  Further information on the timing of submissions are as directed 
by FDA guidelines  (http://www.fda.gov/medwatch/index.html).  Serious, 
unexpected events that suggest significant clinical risk will be submitted to 
within 15 calendar days after initial receipt of this information. 
 
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178 
http://www.fda.gov/medwatch/report.htm 
 
Mandatory Drug Reporting: 
Central Document Room  
Center for Drug Evaluation and Research  
Food and Drug Administration  
12229 Wilkins Avenue  
Rockville, MD 20852  
Office of Post-Marketing Drug Risk Assessment (HFD 730)  
Center for Drug Evaluation and Research  
Food and Drug Administration  
5600 Fishers Lane  
Rockville, MD 20857  
(301) 827-3169 for any further questions regarding where to send 
drug mandatory reporting forms  
 
8.0 Statistical Considerations 
 
In this study, we will evaluate the dosages received by tumors and surrounding tissue using 
PET-CT data.  The primary objective is to determine the relationship between radiation dose 
to 70% of the tumor volume and local control at 6 months.  We will conduct this analysis at 
the tumor level, as different tumors may receive different doses of radiation, and may have 
different progression statuses at 6 months.  We will use standard summary measures such as 
means, medians, ranges, and standard deviations to characterize the dosages received by 
tumor and other tissue.  We will use percentages and frequency tables to evaluate other 
characteristics such at tumor histology, number of liver tumors per patient, and volume of 
liver tumors. 
We will determine the relationship between radiation dose and local control at 6 months 
using regression models with Generalized Estimating Equations (GEE) to account for within-
patient correlation. We will use logistic regression to adjust for potentially confounding 
factors such as tumor volume, primary histology, and SIR-Spheres versus Therasphere 
intervention.  We will also determine the relationship between radiation dose to healthy 
tissue, and side effects such as fatigue, nausea, pain and elevated liver function tests.  Each 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
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side effect will be characterized as present or absent, and we will test the relationship 
between radiation dose to the relevant type of healthy tissue and each side effect.  For 
example, we will look at the relationship between dose to the normal liver and elevation of 
liver function tests. 
 
In further secondary analyses, we will explore the relationship between the distribution of 
activity measured by PET-CT, and the distribution predicted by T-99m labeled MAA.  This 
can be translated into predicted dose. We will calculate differences between PET-CT and 
MAA doses, and present the data graphically.  We will use the method proposed by Bland & 
Altman (2007) to assess the agreement between the two methods.  Finally, in a subset of 
patients, we will explore the change in dose measured by PET-CT scan between day 0 and 
day 1.  The dose at day 1 will be adjusted to account for the decay of the yittrium-90 using 
A=A0e-(0.693t/T1/2).  Observed changes in dose may be due to microsphere migration, and 
our main interest is to look for a systematic change in dose received based on this migration. 
 
Sample size considerations 
We will power our study to detect a 10 Gy difference in mean radiation doses between 
tumors with local control and 6 months vs those which progressed.  Based on preliminary 
data, we expect that the standard deviation of doses will be 12Gy, and that approximately 
60% of tumors will retain local control at 6 months.  We will use a two-sided test with type I 
error of 0.05.  In preliminary data, within-patient correlation was 0.6-0.7, and we saw an 
average of 2 tumors per patient.  We therefore will enroll 43 patients in this study to have 
approximately 80% power to detect a difference of 10 Gy.   
 
It is anticipated that 10 patients will be recruited for Day 1 PET-CT studies. This number of 
patients would be expected to detect a difference in the range of 12-20 Gy (Day 0 –  
Decay-adjusted day 1).  Although we may not get a significant result, the point estimates 
may give an indication of whether the microspheres are moving. This level of certainty is felt 
to be appropriate for an exploratory aim.  
 
9.0 Administrative   
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
9.1 Data Reporting 
The FCCC Study Monitor will request case report form submission upon resolution 
of outstanding queries.  Participating sites are responsible to respond to queries 
prior to the next scheduled monitoring visit.  Participating sites are responsible for 
submitting case report forms to the QA Specialist / Study Monitor within two weeks 
of request. 
 
The QA Coordinator is responsible for compiling and submitting data to the study 
PI and statistician on an ongoing basis for monitoring as described in the data safety 
monitoring plan and reporting to the Extramural Data and Safety Monitoring 
Committee. 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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All patient information will be stored on an electronic Microsoft Office Excel 
Spreadsheet on a drive accessible only to the study team members for the purpose 
of entering, reviewing and analyzing data.  Any paper records, such as case report 
files, produced will be stored in locked file cabinets with limited access.  
 
The CTO Regulatory Coordinator is responsible for distributing and tracking 
review of all IND Action Letters, Safety Reports, study specific Serious Adverse 
Events 
 
9.2 Retention of Records   
Time points for the retention of records are described in detail in the contract 
between the grantor and the CTO and passed on to the participating site.  Please 
refer to the study specific terms for specific time points.  In all cases the QA 
Specialist / Study Monitor must be notified of any plans to move records to an 
offsite location prior to doing so. 
 
9.3 Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or 
the patient’s legally authorized representative, before his or her participation in the 
study.  The case history for each patient shall document that informed consent was 
obtained prior to participation in the study.  A copy of the informed consent 
documents must be provided to the patient or the patient’s legally authorized 
representative.  If applicable, they will be provided in a certified translation of the 
local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical 
record with a copy in the study file. 
 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014 
 

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10.0 References 
 
1. Sato KT, Lewandowski RJ, Mulcahy MF, et al. “Unresectable Chemorefractory Liver 
Metastases: Radioembolization with 90Y Microspheres – Safety, Efficacy, and Survival.” 
Radiology, 2008; 247:507-515. 
2. Ahmadzadehfar H, Birsack HJ, Ezziddin S, et al. “Radioembolization of Liver Tumors 
with Yttrium-90 Microspheres.” Sem Nucl Med, 2010; 40:105-121.  
3. Gates VL, Esmail AAH, Marshall K, et al. “Internal Pair Production of 90Y Permits 
Hepatic Localization of Microspheres Using Routine PET: Proof of Concept.” J Nucl 
Med 2011; 52:72-6. 
4. Lhommel R, van Elmbt L, Goffette P, et al. “Feasibility of 90Y TOF PET-based 
dosimetry in liver metastasis therapy using SIR-Spheres.” Eur J Nucl Med Mol Imaging 
2010; 37:1654-62. 
5. Cross W, Ing H, Freedman N, “A short atlas of beta-ray spectra” Phys. Med. Biol. 1983; 
28; 1251-1260. 
6. Siegel R, DeSantis C, Virgo K, et al. “Cancer Treatment and Survivorship Statistics, 
2012.” CA Cancer J Clin 2012; 62:220-241. 
 
 
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APPENDIX I 
 
Tc-99m MAA scan protocol 
 
Purpose: 
To assess arterial perfusion of the liver and the fraction of 
radiopharmaceutical tracer that will pass through the liver and lodge in the 
lungs. 
 
Agent: 
Technitium-99m labelled MAA (Macro-aggregated Albumin) 
 
Dose: 
150- 200 MBq 
 
Equipment: 
Any large FOV gamma camera 
 
Administration: 
The patient needs to have a trans-femoral catheter placed in the hepatic 
artery. The Technitium-99 labelled MAA is injected through the catheter 
into the hepatic artery by a qualified physician. 
 
Imaging: 
The patient is positioned supine under the gamma camera and the images 
recorded. 
Analogue: 
• 
Anterior and posterior images of abdomen and thorax.  
Measure 700k -1000k cts for abdomen and equivalent time 
for thorax. 
• 
Right lateral Abdo - same time acquisition as for Anterior. 
Digital: 
 
• 
4 frames; 300”/ frame. 64 x 64 matrix Word mode. 
• 
Image anterior and posterior abdomen 
• 
Image anterior and posterior thorax 
 
Analysis: 
Draw ROI around whole of liver and whole of lung fields. Calculate G 
mean for liver region and lung region. 
 
Calculate Lung/liver ratio 
 
Interpretation:If lung/liver ratio is >10% then there is need for dose reduction of SIR-Spheres 
 
 
 
 
 
 
 
 
 
SPECT protocol: 
 
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SPECT acquisition: 360 arc, using a body-contoured elliptic orbit, optimally obtaining 
120 (minimum of 60) projections at 15–25 s per projection (every 
3–6_angle), depending on the number of projections and sensitivity of the 
detector. The SPECT acquisition takes, on average, approximately 25 min. 
The images are acquired into a 128 x128 (16-bit) matrix, corrected for 
attenuation, and reconstructed using a 2-dimensional orderedsubset 
expectation maximization iterative technique (at least 10 subsets and 2 
iterations are typical, but the number may vary according to the 
manufacturer). 
 
Processing: 
A 3-dimensional postprocessing filter, which should be specified in detail 
by the manufacturer (e.g., the Hanning postprocessing filter with a cutoff 
frequency of 0.85 cycles/cm) is typically applied to the SPECT dataset. 
APPENDIX II 
 
PET/CT scan protocol 
 
Purpose: To assess the treatment dose distribution, and potential calculation of dosimetry 
of Y-90 Sir-Spheres and/or Theraspheres. 
 
 
Instrumentation: PET/CT scanner (Siemens Biograph 16 in Fox Chase Cancer Center) 
 
 
Postherapy Imaging: Within 5 hours after the administration of Sirsphere and/or 
Theraspheres, a PET/CT scan will be performed covering the liver area in order to verify 
localization of the Sirsphere/Therasphere in the targeted tumor.  A proof of concept for 
such a technique has been reported (3).   
 
 
Parameters: The patient will be positioned on the PET/CT scanner with arms raised up, 
and a localization scout scan will be performed in the abdominal region.  A two-bed 
PET/CT acquisition will be set up centered on the liver.  A low dose CT scan will be 
performed followed by a 10 minute per bed PET acquisition. The PET data will be 
reconstructed using manufacturer recommended procedure, and the data will be analyzed 
to determine the hepatic localization of microspheres.  
 
 
For Subset of patients: Diagnostic (intravenous contrast) CT should be performed 
immediately after the PET scan without moving the participant, using portovenous phase 
for optimal visualization of the liver. The volume of IV contrast is per institution 
standard. 
 
 
 
Copyright © 2014 Fox Chase Cancer Center® Extramural Research Program. All rights reserved. 
Amendment 5Ver. 9/30/2014