Conditions: Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 114
Healthy volunteers: no

Brief summary:
This clinical trial studies the use of sodium fluorine-18 (18F-NaF) plus fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/ whole body magnetic resonance imaging (WBMRI) to detect skeletal metastases in patients with stage III-IV breast cancer or stage II-IV prostate cancer.

Detailed description:
Eligible participants had previously received a bone scan using the radiolabel 99mTc-methyl diphosphonate (t99-MDP) as part of their regular medical care.

18F-NaF and 18F-FDG are radioactive substances (radiolabels) that are absorbed by cancerous cells and allow for the cancer to be found using diagnostic procedures such as positron emission tomography (PET)/ whole body magnetic resonance imaging (WBMRI). PET/WBMRI is a combination procedure that combines the detailed PET images of areas inside the body from PET with the WBMRI scans, and may help find and diagnose skeletal metastases in patients with breast or prostate cancer. It is not yet known whether 18F-NaF/18F-FDG PET/WBMRI is better than standard imaging methods in detecting skeletal metastases.

Eligible participants diagnosed with breast/prostate cancers and who have had 99mTc MDP bone scanning as part of their routine care are recruited and enrolled. Participants then receive an 18F-NaF/18F-FDG positron emission tomography (PET)/ WBMRI combination scan.

The PET/MRI scans will be interpreted by 2 American Board Nuclear Medicine (ABNM)-certified physicians and 2 American Board of Radiology (ABR)-certified radiologists, all with significant clinical experience, who are blinded to the subjects' medical history and the results of other imaging modalities.

The scans will be analyzed and compared against each other, with a consensus read will be obtained for each scan. Characterization of lesions as true-positive, true-negative, false-positive or false-negative will be done through a combination of clinical follow-up, imaging follow-up and/or histopathology findings. An overall diagnosis based on each scan will be determined on a 5-point scale (1=benign, 2=likely benign, 3=uncertain, 4=likely malignant, 5=malignant) to conduct a receiver operating characteristic (ROC) analysis.

If the diagnosis is positive for metastases on any of the scans, the investigator will identify the number of lesions and locations of positivity, and record this information.

Clinical is obtained at about 12 months after the initial scans.

Arms:
arm 1: Preliminary pilot assessment to confirm feasibility \& improved diagnostic accuracy of the combined 18F-NaF CT \& 18F-FDG PET scan procedures, as compared to the regular medical care procedure, 99mTc MDP bone scans. arm 2: Assessment to define the accuracy of the combined 18F-NaF CT \& 18F-FDG PET/CT scan procedures compared to 99mTc MDP bone scan. arm 3: Assessment to define the utility of 18F-NaF \& 18F-FDG as the radiolabels in a single combined PET / WB-MRI procedure.

Interventions: intervention 1: Bone scan intervention 2: 99mTc-methyl diphosphonate intervention 3: Positron Emission Tomography (PET) scan intervention 4: 18F-Fludeoxyglucose (18F-FDG) intervention 5: Computed Tomography (CT) scan intervention 6: 18F-Sodium Fluoride (18F-NaF) intervention 7: Whole Body Magnetic Resonance Imaging (WB-MRI) scan intervention 8: Gadopentetate dimeglumine intervention 9: Gadofosveset intervention 10: Gadobutrol
Intervention descriptions: intervention 1: Scan to diagnose a number of bone conditions including cancer or metastasis intervention 2: Radiolabel for bone scan procedures intervention 3: Scan to detect gamma rays emitted by a positron-emitting radioligand such as 18F intervention 4: Radiolabel for positron emission tomography scan procedures intervention 5: Scan to detect \& analyze X-rays intervention 6: Radiolabel for CT and PET scans, \& as a contrast agent for MRI scans. intervention 7: Whole Body Magnetic Resonance Imaging (WB-MRI) scan: Scan that uses strong magnetic fields \& radio waves to generate images of the organs in the body. intervention 8: A gadolinium-based contrast agent for MRI intervention 9: A gadolinium-based contrast agent for MRI intervention 10: A gadolinium-based contrast agent for MRI

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
Version 9  
Date: June 28, 2017 
BONE0001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Combined 18F NaF/18F FDG PET/MRI for Detection of Skeletal Metastases 
 
 
Principal Investigator: 
 
Andrei Iagaru, MD 
Co-Chief, Division of Nuclear Medicine and Molecular Imaging 
Associate Professor of Radiology - Nuclear Medicine 
300 Pasteur Drive, Room H-2230 
Stanford, CA 94305 
Phone: 650 725 4711 
Fax: 650 498 5047 
Email: aiagaru@stanford.edu 
 
Co-investigators: 
 
Guido Davidzon, MD 
Clinical Assistant Professor, Radiology-Nuclear Medicine 
 
Andreas Loening, MD, PhD 
Assistant Professor of Radiology 
 
Shreyas Vasanawala, MD, PhD 
Chief of MRI 
Associate Professor of Radiology 
 
Biostatistician: 
Alex McMillan, PhD 
 
 
Version # 9 (June 28, 2017) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 6 
1. OBJECTIVES ........................................................................................................................ 7 
1.1. PRIMARY OBJECTIVE ......................................................................................................... 7 
1.2. SECONDARY OBJECTIVES ................................................................................................... 7 
2. BACKGROUND .................................................................................................................... 7 
2.1 CLINICALTRIALS.GOV COMPLIANCE .................................................................................... 7 
2.2 RATIONALE ......................................................................................................................... 7 
2.3 PRELIMINARY RESULTS ....................................................................................................... 7 
2.4 STUDY DESIGN ................................................................................................................... 9 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 10 
3.1 INCLUSION CRITERIA ........................................................................................................ 10 
3.2 EXCLUSION CRITERIA ....................................................................................................... 10 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 10 
3.4 STUDY TIMELINE .............................................................................................................. 10 
4. STUDY AGENT INFORMATION .................................................................................... 10 
4.1 STUDY AGENT .................................................................................................................. 10 
4.2 AVAILABILITY .................................................................................................................. 11 
4.3 AGENT ORDERING ............................................................................................................ 11 
4.4 AGENT ACCOUNTABILITY ................................................................................................. 11 
5. IMAGING SPECIFICS ....................................................................................................... 11 
5.1 MODALITY OR MODALITIES TO BE USED ........................................................................... 11 
5.2 DETAILS OF IMAGING (I.E. DYNAMIC, STATIC, NUMBER OF SCANS, ETC.) ........................... 11 
5.3 DETAILS OF PROCESSING/ANALYSIS .................................................................................. 11 
6. STUDY PROCEDURES & DETAIL ................................................................................. 12 
6.1 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 12 
6.2 ALTERNATIVES ................................................................................................................. 12 
7. STUDY CALENDAR .......................................................................................................... 12 
8. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 12 
8.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 12 
8.2 ADVERSE EVENT REPORTING............................................................................................ 13 
9. REGULATORY CONSIDERATIONS ............................................................................. 14 
9.1 INSTITUTIONAL REVIEW OF PROTOCOL ............................................................................. 14 
9.2 DATA MANAGEMENT PLAN .............................................................................................. 14 
10. STATISTICAL CONSIDERATIONS ............................................................................. 14 
10.1 POPULATIONS ................................................................................................................. 14 
10.2 KEY VARIABLES ............................................................................................................. 15 
10.3 ENDPOINTS ..................................................................................................................... 15 
10.4 PLAN OF ANALYSIS ......................................................................................................... 15 


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10.5 SAMPLE SIZE ................................................................................................................... 15 
10.6 INTERIM ANALYSES ........................................................................................................ 15 
10.7 CRITERIA FOR FUTURE STUDIES ...................................................................................... 15 
10.8 ACCRUAL ESTIMATES ...................................................................................................... 15 
11. APPENDIX ......................................................................................................................... 17 
12. REFERENCES ................................................................................................................... 19 
 


 
 
 
Version 9  
Date: June 28, 2017 
BONE0001 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
In the table below summarize the basic aspects of this research. This is to be used as a quick 
reference guide. Remove any section that is not relevant to the research.  
 
 
TITLE 
Combined 18F NaF/18F FDG PET/MRI for 
Detection of Skeletal Metastases 
INDICATION 
Breast cancer, lung cancer, prostate cancer 
INVESTIGATIONAL 
PRODUCT 
OR 
PROCEDURE 
18F NaF/18F FDG PET/MRI 
PRIMARY OBJECTIVE 
Testing the hypothesis that the new simultaneous 
combined 18F NaF/18F FDG PET/MRI provide 
improved diagnostic accuracy over 99mTc MDP 
bone scanning 
SECONDARY OBJECTIVE 
 
Evaluating the combined 18F NaF/18F FDG 
PET/MRI as a reliable bone scanning 
modality 
 
Evaluating the performance and reliability of 
the proposed WBMRI sequences 
TREATMENT SUMMARY 
No treatment 
SAMPLE SIZE  
170 participants: 10 from the pilot phase, 30 
from PET/CT vs. WBMRI, 80 from first version 
of combined 18F NaF/18F FDG PET/MRI and 50 
from second version of combined 18F NaF/18F 
FDG PET/MRI 
STATISTICAL CONSIDERATIONS 
 
Per patient: concordance in cases, 
concordance in controls, sensitivity, 
specificity, positive predicted value, 
negative predictive value 
 
Per lesion: distribution of lesions seen on 
each modality  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 months follow-up 
18F NaF/18F FDG PET/WBMRI 
Eligible participant diagnosed with breast/prostate cancers and had 99mTc MDP bone scanning 
SCHEMA 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Include additional abbreviations as needed.  Remove any unnecessary abbreviations. 
 
MDP 
Methylene diphosphonate 
FDG 
Fluorodeoxyglucose 
IRB 
Institutional Review Board 
IV 
Intravenous 
PET/MRI 
Positron emission tomography – magnetic resonance 
imaging 
SPECT/CT 
Single photon emission computed tomography – 
computed tomography 
RECIST 
Response evaluation criteria in solid tumors 
EORTC 
European organization for research and therapy in 
cancer 
ROC 
Receiver-Operative-Characteristic 
SUV 
Standard Uptake Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
Testing the hypothesis that the combined 18F NaF/18F FDG PET/MRI, either alone or in 
combination, provide improved diagnostic accuracy over 99mTc MDP bone scanning 
 
1.2. 
Secondary Objectives 
 
• 
Evaluating the combined 18F NaF/18F FDG PET/MRI as a reliable bone scanning 
modality 
• 
Evaluating the performance and reliability of the proposed WBMRI sequences: 
IDEAL and eDWI 
            • 
Evaluating a fast MRI protocol (2:30 min/bed) 
 
 
2. 
BACKGROUND 
 
2.1 
Clinicaltrials.gov compliance 
The FDA has approved all imaging scanners. This study has been registered on 
clinicaltrials.gov (NCT00375830). 
 
2.2 
Rationale 
 
 
Fluorine-18 Fluorodeoxyglucose (18F FDG) PET/CT is established as a powerful imaging 
tool for cancer detection and monitoring response to therapy. However, not all cancers 
are identified reliably due to variable rates of glucose metabolism. Whole-body MRI 
(WBMRI) emerges currently as an excellent modality for morphological characterization 
of soft tissue and skeletal lesions. Sodium Fluorine-18 (18F NaF) was used in the 1970’s 
for bone scanning and can be used as a skeletal tracer in current PET/CT scanners. The 
direct comparison of combined 18F NaF/18F FDG PET/CT and WBMRI for skeletal 
metastases detection was not attempted to date. However, such an approach has the 
potential to improve cancer diagnosis, staging, prognosis, and therapy monitoring. The 
combination of these technologies may also allow for improved screening or earlier 
cancer detection. Expanding on our prospective data from a preliminary pilot phase trial 
(10 subjects) comparing WBMRI, separate 18F NaF PET/CT and separate 18F FDG 
PET/CT, as well as on the pilot trial (56 participants at Stanford) of the combined 18F 
NaF/18F FDG PET/CT, we will now attempt a prospective study comparing these 
imaging modalities against themselves and against conventional 99mTc MDP bone 
scintigraphy. 
2.3 
Preliminary results 
To date we have prospectively evaluated in a pilot phase trial (Sep 2007 – Oct 2008) 10 
patients with cancer diagnosis, referred for 99mTc MDP bone scanning. There were 5 men 
and 5 women, 47 - 81 year-old (average: 61.5 ± 12), recruited for further imaging with 
18F NaF PET/CT, 18F FDG PET/CT and WBMRI. All 4 scans were performed within 1 
month for each participant. Lesions detected with each test were tabulated and results 
were compared. The image quality and evaluation of extent of disease was superior by 
18F NaF PET/CT over 99mTc-MDP scintigraphy in all patients with skeletal lesions and 


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over 18F FDG PET/CT in 3 of the patients with skeletal metastases. 18F NaF PET/CT 
showed osseous metastases where 18F FDG PET/CT was negative in another 3 
participants.  Extra-skeletal metastases were identified by 18F FDG PET/CT in 6 
participants. WBMRI with the combination of IDEAL, STIR and DWI pulse sequences 
showed less lesions than 18F NaF PET/CT in 5 patients, same number of lesions in 2 
patients and more lesions in 1 patient. When compared to 18F FDG, WBMRI showed 
fewer lesions in 3 patients and same lesions in 6 patients. Our pilot phase prospective trial 
demonstrated superior image quality and evaluation of skeletal disease extent with 18F 
NaF PET/CT over 99mTc-MDP scintigraphy and 18F FDG PET/CT, as well as the 
feasibility of multi-sequence WBMRI. In addition, 18F FDG PET/CT provided valuable 
soft tissue information that can change disease management. Further evaluation of these 
findings using the recently introduced PET/MRI scanners is warranted.  
 
In another prospective trial we demonstrated the non-inferiority of the combined 18F 
NaF/18F FDG PET/CT when compared to separate 18F NaF PET/CT and 18F FDG 
PET/CT scans for evaluation of cancer patients. This strategy of combining 2 PET 
radiopharmaceuticals in a single scan opens the possibility for improved patient care and 
reduction in healthcare costs due to a reduction in the number of scans being conducted. 
 
In another 30 patients we have shown superior evaluation of skeletal disease extent with 
the combined 18F NaF/18F FDG PET/CT and the WBMRI compared to 99mTc-MDP 
scintigraphy. Further, PET/CT and WBMRI detected extra-skeletal disease that may 
change the management of these patients. A combination of 18F NaF/18F FDG PET and 
WBMRI may provide the most accurate staging of patients with breast and prostate 
cancers.  
 
The recent introduction of hybrid PET/MRI scanners in clinical practice showed 
promising initial results for several clinical scenarios. More than a decade ago, 
multimodality imaging was introduced into clinical routine with the development of the 
PET/CT. Since then, PET/CT has been widely accepted in clinical imaging and has 
emerged as one of the main cancer imaging modalities. With the recent development of 
combined PET/MRI systems for clinical use, a promising new hybrid imaging modality 
is now becoming increasingly available. The combination of functional information 
delivered by PET with the morphologic and functional imaging of MR imaging (e.g., 
diffusion-weighted imaging, dynamic contrast-enhanced MR imaging and MR 
spectroscopy) offers exciting possibilities for clinical applications as well as basic 
research. However, the differences between CT and MR imaging are fundamental. This 
also leads to distinct differences between PET/CT and PET/MRI not only regarding 
image interpretation but also concerning data acquisition, data processing and image 
reconstruction. PET/MRI is expected to show advantages over PET/CT in clinical 
applications in which MRI is known to be superior to CT due to its high intrinsic soft 
tissue contrast. Two of these clinical indications are breast and prostate cancers. 
 
80 subjects were enrolled to compare 18F NaF/18F FDG PET/MRI and the   
to 99mTc-MDP scintigraphy. Our results indicate that the ability of 18F NaF/18F FDG 
PET/MRI to identify more skeletal lesions than 99mTc-MDP BS, and to additionally 


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identify extra-skeletal disease, represents a beneficial alternative to the single modalities 
performed separately. 18F NaF/18F FDG PET/MRI is a promising approach for evaluation 
of skeletal and extra-skeletal lesions in a selected population of breast and prostate cancer 
patients. However, the current duration of exam (4 min/bed) is too long for some of the 
elderly patients. Therefore, we are now shortening the WBMRI protocol from 4 min/bed 
to 2:30 min/bed, reducing the total time from approximately 45 min/scan to 20-25 
min/scan. We plan to enroll and have funding 50 additional subjects (25/year) to further 
evaluate the combined 18F NaF/18F FDG PET/MRI as a reliable bone scanning modality. 
 
2.4 
Study Design 
We intend to perform a prospective trial to determine the role of the combined 18F 
NaF/18F FDG PET/MRI in the evaluation of skeletal metastases in patients with breast 
and prostate cancers. This study will be a comparative study that will investigate different 
types of bone scanning techniques. Patients will undergo preliminary evaluations to 
ensure eligibility, receive and sign informed consent, be enrolled in the trial, and then 
undergo the combined 18F NaF/18F FDG PET/MRI. Patients will be followed clinically 
by 12-months post scan evaluation.  
 
Patients who present to the Nuclear Medicine and Molecular Imaging Clinic for a 99mTc 
MDP bone scan as part of their routine disease work-up/standard of care will be asked to 
participate in this study. If agreeable, written informed consent will be obtained by a 
member of the research team after explaining the risks, benefits, and procedures of the 
study. We will follow Stanford guidelines for screening patients for renal function prior 
to PETMRI if they are getting contrast. All scans will be performed within a 1-month 
timeframe. Blind interpretation of the combined 18F NaF/18F FDG PET/MRI will be 
performed by Nuclear Medicine and Radiology readers. A direct comparison for each 
detected lesion will be performed among the imaging modalities. 
 
We will attempt to recruit patients who are referred for a 99mTc MDP bone scan for 
detection of skeletal metastases. In a typical year, approximately 3,500 99mTc bone scans 
are performed in our Clinic, 90% (3,150) of them with referral for osseous metastases 
identification. We plan to recruit 40 patients per year for 2 consecutive years. Cancers 
with highest potential to metastasize to the skeleton (breast and prostate cancers) will be 
considered.  
 
All age ranges of adult population (>18-year-old) will be recruited. Both men and women 
will be recruited. All ethnic background will be recruited. No healthy volunteers will be 
recruited. Pregnant women will be excluded because of the risk posed by unnecessary 
radiation to the fetus. Patients with metallic implants (prosthesis, ICD, pacemakers) will 
be excluded since these are contraindications for MRI. 
 
The subjects will be paid $150 to participate in this protocol. No costs will be charged to 
the subjects. 
 


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3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
• 
Patient is ≥ 18 years old at the time of the drug administration  
• 
Patient provides written informed consent 
• 
Patient is diagnosed with ≥ stage 3 breast cancer or ≥ stage 2 prostate cancer 
(and/or PSA >10 micrograms/L), including patient with recurrent breast or 
prostate cancer 
•  
Patient is scheduled to undergo a conventional bone scan 
• 
Patient is capable of complying with study procedures 
• 
Patient is able to remain still for duration of imaging procedure (about one hour)  
 
3.2 
Exclusion Criteria 
• 
Patient is < 18 years old at the time of the drug administration 
•  
Patient is participating in other research protocols at the time of the NaF/FDG 
PETMRI scan 
• 
Patient is pregnant or nursing 
• 
Metallic implants (contraindicated for MRI) 
• 
Renal function impairment preventing administration of MRI contrast 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 
study specific procedure. The participant must receive a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in 
the medical record or research file.  
 
3.4 
Study Timeline 
Primary Completion: 
It will take 2 years for the study to reach “Primary Completion” from once the study 
opens to accrual of the additional 50 participants.  
 
Study Completion: 
It will take 3 years for the study to reach “Study Completion” from once the study opens 
to accrual. 
 
4. 
STUDY AGENT INFORMATION 
4.1 
Study Agent  
- Radiopharmaceutical: combination of 18F NaF/18F FDG 
- Dose: 18F NaF = 1 mCi; 18F FDG = 4 mCi 
 


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4.2 
Availability 
Molecular Imaging Program at Stanford 
Lucas Cyclotron Radiochemistry Facility  
1201 Welch Road, Room PS049 
Stanford, CA 94305-5484  
 
4.3 
Agent Ordering 
Ordered in Radiology Information System (RIS) 
 
4.4 
Agent Accountability 
RIS is password protected and part of the electronic medical records. 
 
5. 
IMAGING SPECIFICS  
5.1 
Modality or Modalities to be used 
PET/MRI 
5.2 
Details of Imaging (i.e. dynamic, static, number of scans, etc.) 
Whole-body (head to toes) PET/MRI images will be obtained using a GE SIGNA scanner 
(GE Healthcare). The PET emission scan is corrected using segmented attenuation data 
of the MRI scan. The PET images are reconstructed with a standard iterative algorithm 
(OSEM, two iterative steps, 28 subsets) using GE software release 5.0. All images are 
reformatted into axial, coronal, and sagittal views and viewed with the software provided 
by the manufacturer (AW, GE Medical Systems). 
 
PET/MRI images will be acquired in 3D mode at 45-60 minutes after injection of 4 mCi 
of 18F FDG and 1 mCi of 18F NaF, using 7-10 bed positions, 2:30 minutes/bed.  
 
5.3 
Details of processing/analysis 
The PET/MRI scans will be interpreted by 2 ABNM certified Nuclear Medicine 
physicians (Andrei Iagaru, Guido Davidzon) and 2 ABR certified Radiologists (Andreas 
Loening, Shreyas Vasanawala) with significant clinical experience, blinded to the 
subjects’ medical history and the results of other imaging modalities. The outcomes of 
the imaging methods will be analyzed and compared against each other. Consensus read 
will be obtained for each scan. Characterization of lesions as true positive, true negative, 
false positive or false negative will be done through a combination of clinical follow up, 
imaging follow-up and/or histopathology findings (when possible). For purposes of this 
study, the investigators will document an overall diagnosis of the findings for each scan 
on a 5 point scale to permit a receiver operating characteristic (ROC) analysis (1=benign, 
2=likely benign, 3=uncertain, 4=likely malignant, 5=malignant).  If the diagnosis is 
positive for metastases on any of the scans, the investigator will identify the number of 
lesions and locations of positivity, and record this information. 
 


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6. 
STUDY PROCEDURES & DETAIL 
6.1 
Criteria for Removal from Study 
The Protocol Director may withdraw subjects from the study for one or more of the 
following reasons: failure to follow the instructions of the Protocol Director and/or study 
staff; determination that continuing the participation could be harmful to the subject; the 
study is cancelled or other administrative reasons. 
 
6.2 
Alternatives 
The alternative is to not participate in the study.  
 
7. 
STUDY CALENDAR 
 
   
Pre-Study 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
12 Months 
 
Imaging scans done within 1 month of each other 
 
 
-------------------> 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Post-Scan Follow up 
 
 
 
 
 
X 


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8. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
8.1 
Potential Adverse Events 
Risks associated with Participation  
 
The administration of the radioactive substance will feel like a slight pinprick if given by 
intravenous injection. Patients who are claustrophobic may feel some anxiety while 
positioned in the scanner. Also, some patients find it uncomfortable to hold one position 
for more than a few minutes. The subjects will not feel anything related to the 
radioactivity of the substance in their body. Because the radioactivity is very short-lived, 
the radiation exposure is low. The substance amount is so small that it does not affect the 
normal processes of the body.  
 
The average effective patient dose from whole-body 18F-FDG PET examinations is about 
25 mSv independent of the acquisition protocol preferred (Brix G, Lechel U, Glatting G, 
Ziegler SI, Munzing W, Muller SP, Beyer T.Radiation exposure of patients undergoing 
whole-body dual-modality 18F-FDG PET/CT examinations. J Nucl Med. 2005 
Apr;46(4):608-13). The bladder wall receives an average of 440 mrad/mCi (s.e. 76) in ten 
subjects who voided at 2 hr after administration of tracer. If these subjects had voided at 
1 hr, the bladder-wall dose would have been reduced to 220 mrad/mCi. The brain 
received an average of 81 mrad/mCi in eight subjects. The doses to other organs, 
calculated from published dog biodistribution data, are between 50 and 85 mrad/mCi 
except for spleen and heart, which both received 160 mrad/mCi (Jones SC, Alavi A, 
Christman D, Montanez I, Wolf AP, Reivich M. The radiation dosimetry of 2 [F-
18]fluoro-2-deoxy-D-glucose in man. J Nucl Med. 1982 Jul;23(7):613-7). 
 
Fluorine ions are a normal body constituent. The amount of fluorine ions in Sodium 
Fluoride F 18 Injection at the indicated dose has minimal effect on normal human 
physiology. When F-18 injection was approved for marketing in 1972, no adverse 
reactions were noted in over 400 patient studies reported in the medical literature. In a 
1999 review of the published literature, publicly available reference sources and adverse 
drug reaction reporting systems indicated that adverse reactions have not been reported 
for F-18 injection. Fluorine-18 ions decay with a physical half-life of 109.7 minutes.  
Ninety-seven percent (97%) of the decay results in emission of a positron with a 
maximum energy of 0.635 MeV, and 3% of the decay results in electron capture with 
subsequent emission of characteristic X-rays of oxygen.  The bone and bone marrow are 
considered the target and critical organs. These estimates were calculated based on 
human data and using the data published by the International Commission on 
Radiological Protection for Sodium Fluoride F-18 injection. 
 
Side effects of the MRI contrast agent injection include mild headache, nausea and local 
pain. Rarely (less than 1% of the time) low blood pressure and lightheadedness occurs. 
This can be treated immediately with intravenous fluids. Very rarely (less than one in one 
thousand), patients are allergic to the contrast agent. These effects are most commonly 
hives and itchy eyes, but more severe reactions have been seen which result in shortness 
of breath. 


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8.2 
Adverse Event Reporting 
We do not anticipate hazardous situations for the subjects as a result of this protocol. 
However, procedures will be in place for verification of correct radiopharmaceutical dose 
and route of administration (i.e., each dose will be double checked for dosimetry and 
quality by a researcher and technologist). The study Principal Investigator (PI) or his 
designee will report unanticipated AEs related to the Stanford CCTO Safety Coordinator 
within 10 working days of becoming aware of the event (5 days if the event is life-
threatening or resulted in death) using the Adverse Events Communication Form. If the 
principal investigator determines the unanticipated adverse device effect presents an 
unreasonable risk to subjects, the study will be terminated as soon as possible, but no 
later than 5 working days after the PI makes the determination and no later than 15 
working days after first receiving notification of the effect. 
 
9. 
REGULATORY CONSIDERATIONS 
9.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) were reviewed and 
approved by the Stanford IRB.  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol 
Director will disseminate the protocol amendment information to all participating 
investigators. 
 
9.2 
Data Management Plan 
Study data, patients' medical records, and eCRFs will be monitored in accordance with 
Stanford standard operating procedures (SOPs), and the respective national or regulatory 
government regulations. The investigator will be responsible for monitoring the safety of 
subjects who have enrolled in the study. The Stanford Data Safety Monitoring Committee 
(DSMC) will also monitor the study annually. The Stanford Cancer Institute Data and 
Safety Monitoring Committee (DSMC) will audit study related activities at least annually 
in accordance with the DSMC SOP to determine whether the study has been conducted 
in accordance with the protocol, local standard operating procedures, FDA regulations, 
and Good Clinical Practice (GCP).  This may include review of regulatory binders, case 
report forms, eligibility checklists, and source documents.  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the 
research to ensure the protection of human subjects.  Results of DSMC audits will be 
communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as needed.   
 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Populations 
Patients with ≥ stage 3 breast cancer or ≥ stage 2 prostate cancer (and/or PSA >10 
micrograms/L), including patients with recurrent breast or prostate cancer will be 
enrolled. The analysis subset will consist of patients with an interpretable 99mTc MDP 


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bone scan, 18F NaF/18F FDG PET/MRI evaluations, and a known clinical bone lesion 
evaluation at 12 months. 
10.2 
Key Variables   
Diagnostic bone metastases status using 99mTc MDP bone scan, 18F NaF/18F FDG 
PET/MRI, bone metastases status at 12 months (all binary) 
10.3 
Endpoints 
Primary: concordance between 99mTc MDP bone scan and 18F NaF/18F FDG PET/MRI, 
as the proportion of patients where the modalities agree. 
Secondary:  
 
Per patient: concordance in cases, concordance in controls, sensitivity, specificity, 
positive predicted value, negative predictive value 
 
Per lesion: distribution of lesions seen on each modality  
 
Proportion of diagnostic quality scans using the faster protocol compared to first 
cohort of 80 participants 
10.4 
Plan of Analysis 
The principal analysis will aggregate patients from the two groups and will be conducted 
on a per-patient basis. We will calculate the concordance between the modalities across 
outcomes (combining cases and controls) and evaluate the results by calculating the 
kappa coefficient. Secondary endpoints will be calculated, both as aggregates of the three 
diseases and separately by disease. Sensitivities and other summaries will only be 
calculated if they involve a denominator of at least 10.  
10.5 
Sample Size 
A key parameter in determining the sample size for a study of the sensitivity and 
specificity of a new diagnostic modality relative to a standard modality is the degree of 
concordance of the modalities, or roughly speaking, the degree to which the modalities 
are correlated. The higher the concordance, the smaller the sample size required. For 
example, if current modalities for bone metastases detection (99mTc MDP bone scan) have 
a sensitivity of 80%, then the number of cases needed to demonstrate a 10% margin of 
superiority ranges from 83 to 284.  Details are given in the Appendix  
10.6 
Interim Analyses 
No interim analyses are planned. 
10.7 
Criteria for Future Studies 
The accrual will continue until reaching the sample size required for statistical analysis, 
as described above, given the results from the previous 30 patients. The combined 
PET/MRI scanners are an ideal tool to evaluate this hypothesis. 
10.8 
Accrual estimates 
 
 
 
We will attempt to recruit patients who are referred for a 99mTc MDP bone scan for 


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Page 16 of 20
detection of skeletal metastases. In a typical year, approximately 3,500 99mTc bone scans 
are performed in our clinic, 90% (3,150) of them with referral for osseous metastases 
identification. We plan to recruit 40 patients per year. Cancers with highest potential to 
metastasize to the skeleton (breast and prostate cancers) will be considered.


 
 
 
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11. 
APPENDIX 
The sample size follows Connett et al 1 . We replace the nomenclature of “Control” by “Old 
modality” and “Case” by “New Modality”.  The numbers A, B,C D are the true probabilities 
summing to 1 as shown in the table:  
 
 
Old Modality 
 
New 
Modality 
Positive 
Negative  
Positive 
A 
B 
Se.New 
Negative C 
D 
 
 
Se.Old 
 
1 
 
A convenient parametrization consists of 
 The proportion discordant 
C
B
K


 
 the sensitivity of the old modality Se.Old=A+C,  
 the target improvement in sensitivity 



C
B
C
A
B
A







  
Connett et al adopt the parameterization: 
 Odds ratio 
C
B


 
 Proportion positive under old but negative under new 









K
K
C
P01
 
With this parametrization the sample size is given by 






01
2
2
01
2
1
1
1
1
P
P
z
z
n













 
The Connett parameters can be derived thus: 

2
/
01


K
P
 and 








K
K
 
 

 
 
To illustrate, we set the sensitivity of the old modality to 0.8, Delta to 0.1, If we set the 
discordance close to its minimum value 0.11 we get the following table: 
 
 
Old Modality 
 
New 
Modality 
Positive 
Negative 
 
Positive 
0.795 
0.105 
0.900 
Negative 
0.005 
0.095 
0.100 
 
0.800 
0.200 
1.000 
 
With resulting OR=21, P01=0.005.  With these parameters Connett's formula give N=84. 
                                                 
1 
Connett, J. E., Smith, J. A., & McHugh, R. B. (1987). Sample size and power for pair-matched case- 
control studies. Statistics in Medicine, 6, 53-59. 
 


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Page 18 of 20
If we set the discordance to 0.3 (maximum attainable with the other constraints) we get the table 
 
Old Modality 
 
New 
Modality 
Positive 
Negative 
 
Positive 
0.700 
0.200 
0.900 
Negative 
0.100 
0.000 
0.100 
 
0.800 
0.200 
1.000 
With resulting OR=2 P01=0.1, and the Connett formula gives a sample size of 233 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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12. 
REFERENCES 
 
1. Feldman F, van Heertum R, Manos C. 18FDG PET scanning of benign and malignant 
musculoskeletal lesions. Skeletal Radiol. 2003 Apr;32(4):201-8.  
2. Uematsu T, Yuen S, Yukisawa S, Aramaki T, Morimoto N, Endo M, Furukawa H, Uchida Y, 
Watanabe J. Comparison of FDG PET and SPECT for detection of bone metastases in breast 
cancer. AJR Am J Roentgenol. 2005 Apr;184(4):1266-73.  
3. Nakai T, Okuyama C, Kubota T, Yamada K, Ushijima Y, Taniike K, Suzuki T, Nishimura T. 
Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast 
cancer. Eur J Nucl Med Mol Imaging. 2005 Aug 20 
4. Jadvar H, Pinski JK, Conti PS. FDG PET in suspected recurrent and metastatic prostate 
cancer. Oncol Rep. 2003 Sep-Oct;10(5):1485-8.  
5. Jadvar H, Conti PS. Diagnostic utility of FDG PET in multiple myeloma. Skeletal Radiol. 
2002 Dec;31(12):690-4. 
6. Fogelman I, Cook G, Israel O, Van der Wall H. Positron emission tomography and bone 
metastases. Semin Nucl Med. 2005 Apr;35(2):135-42 
7. Jadvar H, Gamie S, Ramanna L, Conti PS. Musculoskeletal system. Semin Nucl Med. 2004 
Oct;34(4):254-61.  
8. Peterson JJ, Kransdorf MJ, O'Connor MI. Diagnosis of occult bone metastases: positron 
emission tomography. Clin Orthop Relat Res. 2003 Oct;(415 Suppl):S120-8. 
9. Bohdiewicz PJ, Wong CY, Kondas D, Gaskill M, Dworkin HJ. High predictive value of F-18 
FDG PET patterns of the spine for metastases or benign lesions with good agreement 
between readers. Clin Nucl Med. 2003 Dec;28(12):966-70. 
10. Lauenstein TC, Goehde SC, Herborn CU, Goyen M, Oberhoff C, Debatin JF, Ruehm SG, 
Barkhausen J. Whole-body MR imaging: evaluation of patients for metastases. Radiology. 
2004 Oct;233(1):139-48.  
11. Schmidt GP, Baur-Melnyk A, Tiling R, Hahn K, Reiser MF, Schoenberg SO. Comparison of 
high resolution whole-body MRI using parallel imaging and PET-CT. First experiences with 
a 32-channel MRI system. Radiologe. 2004 Sep;44(9):889-98. 
12. Chan Y, Chan K, Lam W, Metreweli C. Comparison of whole body MRI and radioisotope 
bone scintigram for skeletal metastases detection. Chin Med J (Engl). 1997 Jun;110(6):485-9.  
13. Nakanishi K, Kobayashi M, Takahashi S, Nakata S, Kyakuno M, Nakaguchi K, Nakamura H. 
Whole body MRI for detecting metastatic bone tumor: comparison with bone scintigrams. 
Magn Reson Med Sci. 2005;4(1):11-7.  
14. Ghanem N, Uhl M, Brink I, Schafer O, Kelly T, Moser E, Langer M. Diagnostic value of 
MRI in comparison to scintigraphy, PET, MS-CT and PET/CT for the detection of 
metastases of bone. Eur J Radiol. 2005 Jul;55(1):41-55.  
 
 
 
 
 
 
 
 
 


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Page 20 of 20
STANFORD UNIVERSITY   Participant Eligibility Checklist 
Version 9: 28 June 2017 
Protocol Director: 
Andrei Iagaru, M.D.                                 eProtocol: 3778 
Protocol Title: Combined 18F NaF/18F FDG PET/MRI for Detection of Skeletal Metastases  
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation 
1. Patient is > 18 years old at the time of the drug administration 
 
 
 
 
2. 
Patient provides written informed consent 
 
 
 
 
3. 
Patient is diagnosed with > stage 3 breast cancer or > stage 2 
prostate cancer (and/or PSA >10 micrograms/L), including patient 
with recurrent breast or prostate cancer 
 
 
 
 
4. 
Patient is scheduled to undergo a conventional bone scan 
 
 
 
 
5. 
Patient is capable of complying with study procedures 
 
 
 
 
6. 
Patient is able to remain still for duration of imaging procedure 
(about one hour) 
 
 
 
 
 
Exclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation 
1. Patient is < 18 years old at the time of the drug administration 
 
 
 
 
2. Patient is participating in other research protocols at the time of the 
NaF/FDG PETMRI scan 
 
 
 
 
3. 
Patient is pregnant or nursing 
 
 
 
 
4. 
Metallic implants (contraindicated for MRI) 
 
 
 
 
5. 
History of renal insufficiency 
 
 
 
 
*All subject files must include supporting documentation to confirm subject eligibility.  The method of confirmation can 
include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record 
review.   
Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for participation in the 
study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford IRB, and 
has finalized financial and contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.   
Signature: 
Date: 
Printed Name: 
 
Signature: 
Date: 
Printed Name: 
 
Signature: 
Date: 
Printed Name: