Clinical trial NCT04382911
Conditions: Endometriosis
Sponsor: University of North Carolina, Chapel Hill
Start date: 2020-08-07; Completion date: 2022-07-11
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Purpose: The primary objective is to evaluate the sensitivity and specificity of 18F-fluoroestradiol (FES) PET/MRI for evaluating endometriosis.

Participants: A total of 12 participants will be recruited from individuals with clinically suspected endometriosis who are scheduled for planned operative laparoscopy at the University of North Carolina at Chapel Hill (UNC).

Procedures (methods): This is a prospective, one arm, single center study of 12 subjects with clinically suspected endometriosis to demonstrate FES PET/MR's clinical utility for diagnosis of endometriosis. This study will be an evaluation of the radiotracer, FES, which binds to estrogen receptors and has previously been used to study estrogen receptor expression in tumors, to detect endometriosis. Participants will undergo one FES PET/MR scan within 4 weeks prior to their scheduled surgery. Participants will also complete questionnaires regarding their condition, pain, and quality of life.

Detailed description:
This is a prospective, one arm, single center study of 12 subjects with clinically suspected endometriosis to demonstrate FES PET-MRI's clinical utility for diagnosis of endometriosis. The primary objective is to evaluate the sensitivity and specificity of 18F-fluoroestradiol (FES) PET/MRI for evaluating endometriosis. Secondary objectives include comparing PET to conventional MRI, using histopathology from laparotomy as the gold standard and evaluating association of uptake values (SUV-max) with Endometriosis Health profile -30 (EHP-30) and pain rating scales, controlling for covariates.

Arms: arm 1: All enrolled subjects will receive the tracer and then have a PET/MRI scan.
Interventions: intervention 1: 18F-fluoroestradiol
Intervention descriptions: intervention 1: Patients will receive the FES tracer during a PET/MRI scan

Protocol documents:
Prot_SAP_000.pdf: 
Evaluation of Endometriosis with 18F-fluoroestradiol PET / MRI 
 
 
NCT number NCT04382911 
Document Date August 27, 2020 


FES PET/MRI Endometriosis 
 
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PI: Oldan 
 
UNIVERSITY OF NORTH CAROLINA 
August 27, 2020 
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Evaluation of Endometriosis with 18F-fluoroestradiol PET / MRI  
 
Drug Name(s): 18F-fluoroestradiol (FES) 
Sponsor: The University of North Carolina at Chapel Hill 
Protocol Date: March 12, 2020 
Amendment 1 Date: August 27, 2020 
Amendment 2 Date:  
Amendment 3 Date: 
Amendment 4 Date:  
 
 
 
 
 
 
 
 
Principal Investigator: Jorge Oldan, MD  
Biostatistician: Thad Benefield, MS 
 
Department of Radiology 
Campus Box 7510 
Chapel Hill, NC 27599-7510 
Phone 919-846-7675 
email: oldan@med.unc.edu 
 
 
 


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PROTOCOL TITLE:  
 
Evaluation of Endometriosis with 18F-fluoroestradiol PET / MRI 
Short Title:  
FES PET/MRI of Endometriosis  
 
 
 
Lead Investigator: 
Jorge Oldan, MD 
 University of North Carolina at Chapel Hill 
Protocol Version: 1.2  
Version Date: August 27, 2020 
 
 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
   
Principal Investigator Name:  
 
 
 
 
 
 
 
Principal Investigator Signature:   
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Table of Contents ................................................................................................................... 3 
Abbreviations and Definitions of Terms .............................................................................. 5 
Protocol Synopsis ................................................................................................................... 6 
INCLUSION CRITERIA ....................................................................................................................................... 6 
EXCLUSION CRITERIA ...................................................................................................................................... 7 
1. BACKGROUND AND RATIONALE ........................................................................................................................... 8 
1.1 
INTRODUCTION ................................................................................................................................ 8 
1.2 
EXISTING WORK WITH FES .............................................................................................................. 9 
2. STUDY OBJECTIVES ................................................................................................................................................ 9 
2.1 
PRIMARY OBJECTIVES ..................................................................................................................... 9 
2.2 
SECONDARY OBJECTIVES ................................................................................................................ 9 
3. INVESTIGATIONAL PLAN ..................................................................................................................................... 10 
3.1 
STUDY DESIGN .............................................................................................................................. 10 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SUBJECTS ........................................................ 10 
3.3 
STUDY POPULATION ...................................................................................................................... 10 
3.3.1 
INCLUSION CRITERIA ..................................................................................................................... 10 
3.3.2 
EXCLUSION CRITERIA .................................................................................................................... 10 
4. STUDY PROCEDURES ........................................................................................................................................... 10 
4.1 
SCREENING/BASELINE VISIT PROCEDURES ..................................................................................... 11 
4.2 
RESEARCH IMAGING PROCEDURE .................................................................................................. 11 
4.3 
MEDICAL RECORD ABSTRACTION .................................................................................................. 12 
4.4 
INTERPRETATION ........................................................................................................................... 12 
4.5 
VARIABLES OF INTEREST ............................................................................................................... 12 
5. STATISTICAL CONSIDERATION ............................................................................................................................ 12 
5.1 
PRIMARY ENDPOINT ...................................................................................................................... 12 
5.2 
STATISTICAL METHODS ................................................................................................................. 13 
5.3 
SAMPLE SIZE AND POWER ............................................................................................................. 14 
5.4 
INTERIM ANALYSIS ........................................................................................................................ 14 
6. ADVERSE EVENTS (DRUGS- CONTRAST AGENTS) .............................................................................................. 14 
6.1 DEFINITIONS ............................................................................................................................................ 14 
6.1.1 ADVERSE EVENT (AE) .......................................................................................................................... 14 
6.1.2 SUSPECTED ADVERSE REACTION (SAR) ............................................................................................... 14 
6.1.3 UNEXPECTED AE OR SAR .................................................................................................................... 15 
6.1.4 SERIOUS AE OR SAR ........................................................................................................................... 15 
6.2 DOCUMENTATION OF NON-SERIOUS AES OR SARS ................................................................................... 16 
6.3 SAES OR SERIOUS SARS ....................................................................................................................... 16 
6.3.1 TIMING ................................................................................................................................................. 16 
6.3.2 DOCUMENTATION AND NOTIFICATION .................................................................................................... 16 
6.3.3 REPORTING .......................................................................................................................................... 16 
7. DATA AND SAFETY MONITORING PLAN ............................................................................................................. 17 
7.1 
ADVERSE EVENTS SAFETY ASSESSMENTS ..................................................................................... 17 
8. STUDY MANAGEMENT ........................................................................................................................................ 17 
8.1 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT .................................................... 17 
8.2 
REGISTRATION PROCEDURES ........................................................................................................ 18 


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8.3 
DATA MANAGEMENT AND MONITORING/AUDITING........................................................................... 18 
8.4 
ADHERENCE TO THE PROTOCOL .................................................................................................... 18 
8.5 
EMERGENCY MODIFICATIONS ......................................................................................................... 18 
8.6 
PROTOCOL DEVIATIONS/VIOLATIONS ............................................................................................. 19 
8.7 
AMENDMENTS TO THE PROTOCOL .................................................................................................. 19 
8.8 
RECORD RETENTION ..................................................................................................................... 20 
8.9 
OBLIGATIONS OF INVESTIGATORS .................................................................................................. 20 
8.10 
CONFLICT OF INTEREST ................................................................................................................. 20 
9. PLANS FOR PUBLICATION ................................................................................................................................... 20 
10. REFERENCES ........................................................................................................................................................ 21 
11. APPENDIX............................................................................................................................................................. 23 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
Abbreviation 
Definition 
FES 
Fluoro-Estradiol 
PET 
Positron Emission Tomography 
MRI 
Magnetic Resonance Imaging  
PACS 
Picture Archiving and Communication System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
Study Title 
Evaluation of Endometriosis with 18F-fluoroestradiol PET / 
MRI 
Funder 
The University of North Carolina  
Clinical Phase 
Pilot Study 
Study Rationale 
Current techniques to diagnose endometriosis (apart from 
laparoscopy) lack the necessary sensitivity to detect the 
disease. As endometriosis expresses estrogen receptors, a 
radiotracer that binds to estrogen receptors may be able to 
detect it in a noninvasive fashion. 
Study Objective(s) 
The primary objective is to evaluate the sensitivity and 
specificity of 18F-fluoroestradiol (FES) PET/MR for evaluating 
endometriosis.   Secondary objectives include comparing PET 
to conventional MRI, using histopathology from laparotomy as 
the gold standard and evaluating association of uptake values 
(SUV-max) with EHP-30 and pain rating scales, controlling for 
covariates. 
 
 
Investigational Drug 
 
This study will be an evaluation of the radiotracer, FES, which 
binds to estrogen receptors and has previously been used to 
study estrogen receptor expression in tumors, to detect 
endometriosis.   
Study Design 
 
This is a prospective, one arm, single center study of 12 
subjects with clinically suspected endometriosis to 
demonstrate FES PET-MR’s clinical utility for diagnosis of 
endometriosis.  
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
• Age 18 or older 
• Clinically suspected endometriosis. 
• Scheduled for planned operative laparoscopy with no 
hormone treatment for at least two cycles (Note: if women 
are amenorrhoeic, 56 days will be used as a substitute for 
2 cycles.) 
• Able to provide informed consent 
 


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Exclusion Criteria 
• Male patients 
• Patients under 18 
• Institutionalized subject (prisoner or nursing home 
patient) 
• Patients with known endometrial, breast, or ovarian 
cancer.  
• Pregnant or breast-feeding women 
• Contraindication to MRI (pacemaker, metallic implants, 
metallic fragments or foreign bodies, body piercings 
that are unable to be removed, and certain cardiac 
devices)  Subjects will be screened for any 
contraindications prior to the MRI.   
• Claustrophobia that would prevent subjects from being 
inside the MRI scanner for the duration of the scan.  
Number Of Subjects  
 
A total of 12 participants will be recruited from individuals with 
clinically suspected endometriosis.  
Study Duration 
This study is anticipated to last approximately 1 year.  
Statistical And 
Analytic Plan 
The sensitivity of FES PET /MR is defined as the ability of 
readers (radiologists) to detect endometriosis in patients. 
Diagnostic accuracy will be defined by the histologic presence 
of endometriosis and by symptomatic improvement as defined 
clinically by the referring physician within 3 months of surgery.  
DATA AND SAFETY 
MONITORING PLAN 
The Principal Investigator will provide continuous monitoring 
of patient safety in this trial with periodic reporting to an 
independent Medical Monitor. 
 
 
 


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1. BACKGROUND AND RATIONALE 
 
1.1 
Introduction 
Endometriosis is a major cause of infertility and pain for many women of childbearing 
age. Estimates of the frequency of endometriosis in infertile women range from 20-50%, 
with an estimated overall prevalence of 0.8-6% in the female population. 1   
Imaging is often used for evaluation of endometriosis. Endometriosis is divided by 
location into ovarian, peritoneal, and deep; ovarian endometriosis is located in the ovary 
(often known as endometrioma), peritoneal endometriosis is in the peritoneum 
penetrating less than 5 mm, and a deep infiltrating endometriotic (DIE) lesion penetrates 
into the retroperitoneal space or pelvic organ walls to at least 5 mm, affecting 4-37% of 
women with endometriosis. Transvaginal ultrasound is usually the first-line imaging 
modality used, with MRI as a second line to look for deep implants.2 In general, these 
are both quite effective, with transvaginal ultrasound being effective for genital DIE and 
MRI for the diagnosis of pelvic genital and extragenital DIE; however, even MRI can 
have difficulty distinguishing between surgical scar and active lesions if the patient has 
been previously operated, and questions still remain about its efficacy in evaluating 
nerves and bowel.3   
While DIE is often amenable to detection by conventional methods, more superficial 
lesions, even those with extensive coverage of the pelvic endometrium, are frequently 
invisible to currently-used imaging techniques.4 The lack of non-surgical diagnostic or 
even screening tests is one factor leading to the average five to nine-year delay 
between symptom onset and diagnosis.5,6 The ability to detect earlier-stage 
endometriosis could play a key role in preventing unnecessary surgery on the one hand 
and prevention of progression on the other.7 The overlap in symptoms between 
endometriosis and other causes of chronic pelvic pain also makes recurrence difficult to 
assess, leading to potentially preventable repeat surgery.7 Finally, without non-surgical 
diagnostic techniques, innovations in medical therapy are very difficult to develop. 
These factors have led to an international consensus that non-invasive diagnostic 
testing is a key research priority for the field.7  
One potential option for imaging endometriosis is a radiotracer, 16α-[18F]fluoro-17β-
estradiol or more commonly 18F-fluoroestradiol (FES). This involves an estradiol 
molecule which has been labeled with a radioactive fluorine atom, which binds to 
estrogen receptors and can be detected by positron emission tomography (PET). The 
tracer correlates with receptor expression in biopsy material8,9, and can be administered 
with minimal (<50 micrograms) estrogenic material10 and doses similar to those in other 
nuclear medicine studies.11–13 This tracer has already been demonstrated for use with 
estrogen-receptor positive breast, endometrial, and ovarian cancers, correlating with 
expression in tumors, response to endocrine therapy, assessment of tumor burden and 
heterogeneity of disease, and pharmacodynamics.14 Other applications have included 
differentiating endometrial hyperplasia from endometrial cancer and differentiating 


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benign uterine leiomyomas from malignant uterine sarcomas.14 Given that 
endometriosis contains estrogen receptors, we hope to use FES to identify 
endometriosis using non-invasive imaging approaches.  
 
1.2 
Existing work with FES 
Current use of FES: At the present time, FES has only been used to find endometriosis 
in one study of 4 patients with extragenital endometriosis, specifically of the deep 
infiltrating variety. This study showed multiple lesions detectable on FES-PET that were 
not detectable on MRI; of the 9 lesions found by histology, 4 were found by MRI, 8 by 
FES-PET, and the histology agreed with PET in all cases.3 There was also a limited 
relationship between SUVmax and chronic pelvic pain.3 Furthermore, this study was 
performed using PET/CT, which increases the radiation exposure to patients relative to 
PET/MR.  
Our innovation: Previous work with FES has involved breast cancer or other 
malignancies which express estrogen receptors, such as endometrial cancer. We are 
hoping to build on prior work by Cosma et al.3 which shows that endometriosis, which 
also displays endometrial receptors, can be detected by FES-PET.  
 
In addition, we will utilize PET/MR rather than PET/CT, to allow us to avoid the 
radiation dose associated with the CT. This is particularly important in women of 
childbearing age. In addition, the superior soft tissue contrast of MRI vis-à-vis CT can 
help to localize lesions in the pelvis. Furthermore, we will utilize novel MR imaging 
approaches to potentially enhance the sensitivity of MR-only studies to endometriosis. 
Utilizing PET/MR will also improve the co-registration for the development of MR based 
approaches. If endometriosis could be reliably detected through noninvasive imaging, 
infertility patients who did not display FES uptake, particularly those with prior surgical 
history who might be difficult to stage using MRI, could avoid the expense and pain of 
exploratory laparotomy. 
2. STUDY OBJECTIVES 
The aim of this study is to demonstrate FES PET/MR’s clinical utility for diagnosis of 
endometriosis.   
2.1 
Primary Objectives 
Aim 1: The primary objective is to evaluate the sensitivity and specificity of FES 
PET/MR for evaluating endometriosis.   
2.2 
Secondary Objectives 
Aim 2: To compare PET to conventional MRI, using histopathology from laparotomy as 
the gold standard.  
Aim 3: To evaluate the association of uptake values (SUV-max) with EHP-30 and pain 
rating scales, controlling for BMI, race, age, and physician. 


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3. INVESTIGATIONAL PLAN  
3.1 
Study Design 
This is a prospective, one arm, single center study of 12 subjects with clinically 
suspected endometriosis to demonstrate PET-MR’s clinical utility for diagnosis of 
endometriosis.  
3.2 
Study Duration, Enrollment and Number of Subjects 
We will include a total of 12 participants in this trial. These subjects will be followed for 
up to 3 months after initial imaging with PET-MR.  
3.3 
Study Population 
3.3.1 Inclusion Criteria 
• Age 18 or older 
• Female of childbearing age 
• Clinically suspected (symptomatic) endometriosis. 
• Scheduled for planned operative laparoscopy with no hormone treatment for at 
least two cycles (Note: if women are amenorrhoeic, 56 days will be used as a 
substitute for 2 cycles.) 
• Able to provide informed consent 
 
3.3.2 Exclusion Criteria 
• Male 
• Institutionalized subject (prisoner or nursing home patient) 
• Known history of breast, ovarian or endometrial cancer. 
• Pregnant or breast-feeding women 
• Contraindication to MRI (pacemaker, metallic implants, metallic fragments or 
foreign bodies, body piercings that are unable to be removed, and certain cardiac 
devices)  Subjects will be screened for any contraindications prior to the MRI.   
• Claustrophobia that would prevent subjects from being inside the MRI scanner 
for the duration of the scan.   
 
4. STUDY PROCEDURES 
Patients with suspected (but not confirmed) endometriosis and suspicion of extragenital 
DIE who are scheduled for planned operative laparoscopy with no hormone treatment 
for at least two cycles will be recruited from the Minimally Invasive Gynecological 
Surgery  Clinic (Director, E. Carey, Co-I) at UNC. If women are amenorrhoeic, 56 days 
will be used as a substitute for 2 cycles. The Endometriosis Health Profile-30 (EHP-30), 
a quality of life questionnaire used in women with endometriosis, a pain numeric rating 
scale, and information about the last menstrual period will be obtained. Patients will 
undergo FES PET/MR within 4 weeks prior to surgery. Prior to surgery, suspected 
areas of endometriosis will be identified on imaging. These imaging findings will then be 


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compared to surgical findings and histopathology from exploratory laparotomy. Surgical 
documentation of endometriosis location will rely on published, consensus staging 
methods.15,16 Surgeons will not see the results from the FES-PET/MRI prior to surgery. 
The results of FES-PET MRI will not be used to guide surgery. The surgeons will be 
performing exploratory laparoscopy as per standard of care. 
4.1 
Screening/Baseline Visit procedures 
A total of 12 participants will be enrolled to this study. The study subjects will be 
consecutively recruited from individuals that have clinically suspected endometriosis 
and have planned exploratory laparoscopy. Eligible patients will be identified by 
research staff review in coordination with the UNC MIGS group. 
Once a patient has been referred, the patient will be approached by a coordinator from 
Radiology to assess interest in participation.   
All eligible participants who agree to participate in the study will be asked to come to 
their scheduled appointment thirty minutes early to complete the informed consent 
process.   
Review of the consent will take place in the privacy of an exam room, or when possible, 
a sample consent form will be sent to the patient via email prior to the patient’s visit to 
allow for ample review.   
Patients will complete the EHP-30 and pain scale questionnaire.  In addition, patients 
will be asked the date of their last menstrual period.  These questionnaires may be 
completed in person, via the phone, or via REDCap, whichever is preferred by the 
participant.   
4.2 
Research Imaging Procedure 
Participants who consent for the study will be escorted by the research coordinator to 
the dedicated study room for the imaging exam. For our female patients who are of child 
bearing age, a pregnancy test will be performed prior to the administration of the 
radiotracer. 
The subject will have the PET-MR scan performed in a similar manner to a conventional 
clinical PET-MR scans. The imaging agent will be injected approximately one hour prior 
to imaging after dosimetry and radiotracer has been verified per protocol. The research 
technologist will assist in positioning the patient in the PET-MR unit. Once positioned, 
the total scan time is approximately 1 hour. The length of time for the positioning and 
examination of a subject’s pelvis may vary but it is expected that the entire visit will take 
about 150 minutes. We will not utilize gadolinium contrast agent for this study.  
We have extensive experience in the synthesis of radiotracers at the UNC Biomedical 
Research Imaging Center (BRIC), with dedicated radiochemists and radiopharmacists. 
We thus expect to be able to synthesize the radiotracer without much difficulty, as there 
is an established IND available for cross-filing on the NCI website 17, which contains a 


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full set of manufacturing and QC documents. A manufacturing IND has already been 
obtained.  
4.3 
Follow-Up Phone Call 
Patients will be called 3 to 4 weeks following the FES PET scan to determine the last 
menstrual period following the scan.   
4.4 
Medical Record Abstraction 
Participants’ medical record will be reviewed for up to 3 months following their initial 
research imaging to meet the primary aim. The operative surgeon will be asked to fill 
out a specific post-operative form defining the areas in which they identified visible 
endometriosis within the pelvis.  
4.5 
Interpretation 
Upon completion of all study image data collection, a reader study will be performed 
with a fellowship-trained abdominal radiologist and nuclear radiologist (separate 
individuals). The abdominal and nuclear reads will be performed separately, without 
discussion between radiologists. MR information will be used for anatomic localization 
of the PET scan, as is commonly performed. Differences between the two will then be 
discussed in the eventual publication. All images will be reconstructed using standard 
algorithms, and nuclear medicine studies presented on MIM workstations for nuclear 
medicine viewing, with PACS viewing software with conventional zoom/pan/window and 
level tools. Locations of endometriosis will be recorded with the same classification 
system as the surgical system. This research classification will be made by radiologists 
who are blinded to the surgical findings of endometriosis. 
4.6 
Variables of Interest 
Primary Variables of Interest: 
• Presence of endometriosis based on imaging (true/false) 
• Localization of endometriosis (American Society for Reproductive Medicine 
Revised Classification of Endometriosis 1997 and World Endometriosis 
Foundation System)15  
• Standardized Uptake values (positive real number) 
• EHP-30 value (integer) 
• Pain rating (integer) 
5. STATISTICAL CONSIDERATION    
5.1 
Primary Endpoint 
The sensitivity of FES PET /MR is defined as the ability of readers (radiologists) to 
detect endometriosis in patients. Diagnostic accuracy will be defined by the histologic 
presence of endometriosis and by symptomatic improvement as defined surgically by 
the referring physician within 3 months of surgery.  


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5.2 
Statistical Methods 
Subjects will be recruited until 12 subjects complete the research imaging. For subjects 
that are enrolled and do not complete the research PET/MR, they will be considered a 
screen fail and replaced.  Two radiologists, a nuclear radiologist and an abdominal 
radiologist, will be recruited to conduct the reader study.  Both the radiologists and 
surgeons will utilize the Revised Endometriosis Classification System.  
Sensitivity and specificity of 18F-fluoroestradiol (FES) PET/MR for evaluating 
endometriosis will be computed by comparing imaging against surgical findings and 
histopathology in order to answer Aim 1.  We will compute point estimates, along with 
95% confidence intervals and precision estimates that may be used to plan future 
studies. 
We will address Aim 2 in the following fashion.  After imaging, we will compare the PET 
results against conventional MRI, using histopathology obtained at exploratory 
laparotomy as the gold standard. We will do this in 2 phases, first, at the patient level, 
and then, as an ancillary analysis, at the endometriotic implant site level. For each 
phase, we will report sensitivity, specificity, and accuracy of the PET results, along with 
associated 95% confidence intervals. We will also report sensitivity, specificity, and 
accuracy, along with associated 95% confidence intervals, using conventional MRI. We 
will use McNemar’s test, constructing the 2x2 table among all patients with a surgical 
diagnosis of positive to compare sensitivity for PET versus conventional MRI. Similarly, 
we will use McNemar’s test among all patients with a surgical diagnosis of negative to 
compare specificity for PET versus conventional MRI.  P-values <0.05 for the 
comparison of sensitivity and specificity will be construed as evidence that 
sensitivity/specificity differ between PET and conventional MRI.  P-values >0.05 will be 
considered inconclusive.    
To evaluate Aim 3, whether uptake values are associated with EHP-30 and pain rating 
scales, we will implement a random effects linear regression model, modeling SUV-max 
as a function of EHP-30 and the pain rating, while controlling for patient-level covariates 
(BMI, race, age). We will include physician as a random effect to account for physician-
level correlation. P-values <0.05 for the EHP-30 and pain rating parameter estimates 
will be taken as evidence of association with uptake values.  P-values >0.05 will be 
considered inconclusive.    
As a sensitivity analysis for Aim 3, we will compute Cook’s distance (D) for all 
observations, remove observations where D >1, and recalculate the above specified 
model, comparing model conclusions to the original analysis.    
Budgetary constraints limit sample size for this study. For Aim 2 and Aim 3, precision of 
estimators will be low, power levels of tests will be low, and confidence intervals will be 
wide. However, study results are expected to be useful in a grant proposal for a future 
study.    
   


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5.3 
Sample Size Rationale 
With 12 patients, we will have 80% power at alpha=.05 to detect an odds ratio of 21.91 
for comparing sensitivities between PET/MRI versus conventional MRI. The detectable 
OR will be >10000000 for comparing specificities between PET/MRI versus 
conventional MRI. 
Given our analysis strategy, McNemar’s test, the following information was needed for 
the power calculation for detecting differences in sensitivity between 2 modalities:   the 
total number of patients and the anticipated proportion of discordant pairs.   We used 12 
for the number of patients due to budget constraints for the pilot study.  The proportion 
of discordant pairs is the percentage of test results that do not agree between PET/MRI 
and conventional MRI.  We estimated this to be 55% based on published studies about 
MRI and the Cosmal et al. study. From this, we estimated an odds ratio of 21.91. Power 
calculations are made using GPower, version 3.1.9.2. 
 
5.4 
Interim Analysis 
Interim analyses will not be conducted. 
6. ADVERSE EVENTS (DRUGS- CONTRAST AGENTS) 
6.1 Definitions  
6.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a drug) in 
a patient or clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product. 
Hospitalization for elective surgery or routine clinical procedures that are not the result 
of an AE (e.g., surgical insertion of central line) need not be considered AEs and should 
not be recorded as an AE.  Disease progression should not be recorded as an AE, 
unless it is attributable by the investigator to the study therapy. 
6.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.   
Causality assessment to a study drug is a medical judgment made in consideration of 
the following factors: temporal relationship of the AE to study drug exposure, known 
mechanism of action or side effect profile of study treatment, other recent or 


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concomitant drug exposures, normal clinical course of the disease under investigation, 
and any other underlying or concurrent medical conditions.  Other factors to consider in 
considering drug as the cause of the AE: 
Single occurrence of an uncommon event known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
One or more occurrences of an event not commonly associated with drug exposure, but 
otherwise uncommon in the population (e.g., tendon rupture); often more than once 
occurrence from one or multiple studies would be needed before the sponsor- 
investigator could determine that there is reasonable possibility that the drug caused the 
event.   
An aggregate analysis of specific events observed in a clinical trial that indicates the 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group 
6.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure (IB) for 
an unapproved investigational product or package insert/summary of product 
characteristics for an approved product).  Unexpected also refers to AEs or SARs that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.   
6.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of the sponsor- investigator, it results 
in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from the event 
as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization; 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition.  For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an important 
medical event. 


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Pregnancy that occurs during the study must also be reported as an SAE. 
6.2 Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study treatment 
and continue through the 30-day follow-up period after treatment is discontinued.   
Collected information should be recorded in the Case Report Forms (CRF) for that 
patient.  Please include a description of the event, its severity or toxicity grade, onset 
and resolved dates (if applicable), and the relationship to the study drug. Documentation 
should occur at least monthly.  
6.3 SAEs or Serious SARs  
6.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs caused by 
a protocol-mandated intervention will be collected (e.g. SAEs related to invasive 
procedures such as biopsies, medication washout.  
For any other experience or condition that meets the definition of an SAE or a serious 
SAR, recording of the event must begin from day 1 of study treatment and continue 
through the 30 day follow-up period after treatment is discontinued.   
6.3.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded within 24 hours of learning of 
its occurrence.  
6.3.3 Reporting  
IRB Reporting Requirements: 
The UNC-IRB will be notified of all SAEs that qualify as an Unanticipated Problem as 
per the UNC IRB Policies using the IRB’s web-based reporting system within 7 days of 
the Investigator becoming aware of the problem.   
Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on study 
should be recorded as SAEs.  The patient is to be discontinued immediately from the 
study. The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and 
must document the outcome of the pregnancy (either normal or abnormal outcome). If 
the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE.   
Funding Source (e.g. Manufacturer) Reporting Requirements: 


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If an investigator deems that an event is both a serious SAR AND unexpected, it must 
also (in addition to REDCap) be recorded on the MedWatch Form 3500A as per 21 CFR 
312.32. The MedWatch 3500a form can be accessed at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
(Please be sure and access form 3500a, and not form 3500). The Sponsor-investigator 
of the study will make the final determination regarding FDA submission. 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA. 
 
7. Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in this trial 
with periodic reporting to an independent Medical Monitor. The medical monitor will 
review any reported Unanticipated Adverse Drug Effects after patients 5 and 10. 
Meetings/teleconferences will be held at a frequency dependent on study accrual, and 
in consultation with the study Biostatistician.  These meetings will include the 
investigators and any other relevant personnel the principal investigators may deem 
appropriate.  At these meetings, the research team will discuss all issues relevant to 
study progress, including enrollment, safety, regulatory, data collection, etc. 
The team will produce summaries or minutes of these meetings. These summaries will 
be available for inspection when requested by any of the regulatory bodies charged with 
the safety of human subjects and the integrity of data including, but not limited to, the 
oversight (Office of Human Research Ethics (OHRE) Biomedical IRB, the Scientific 
Review Committee (SRC), the Office of Clinical Trials (OCT), or the North Carolina 
TraCS Institute Data and Safety Monitoring Board (DSMB).   
The PI will be responsible for submitting the following information for review by the 
independent medical monitor: 1) safety and accrual data including the number of study 
participants imaged; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response data; 
and 4) summaries of team meetings that have occurred since the last report.  Findings 
of the medical monitor review will be disseminated by memo.  
7.1 
Adverse Events Safety Assessments 
A licensed provider will observe subject vitals following the administration of the 
radiotracer on through the completion of the imagining scan. Study personnel will 
contact subjects 1 day (+3 days window) after to inquire about delayed onset 
complications. The subjects will also be given a phone number that they can call to 
reach a nurse if they believe they have developed a complication of the procedure. 
8. STUDY MANAGEMENT 
8.1 
Institutional Review Board (IRB) Approval and Consent 


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It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the consent 
form, assent form, and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.  
For patients under the age of 18, appropriate assent must be obtained in addition to 
parental permission prior to participation in the study.   
8.2 
Registration Procedures 
Study participants will be registered into CRMS, a web based clinical research platform 
by one of the Study Coordinators. 
8.3 
Data Management and Monitoring/Auditing 
The FES PET-MR scan that is obtained of all eligible enrolled subjects will be de-
identified for inclusion in the appropriate readers study.  Copies of the clinical report 
forms as well as the de-identified images described in the preceding will be submitted 
for each case to the Study Coordinators for maintaining the study record and entering 
data in preparation for the reader study. 
The online REDCap software system provided by UNC’s TraCS Institute will be used to 
collect and store research data. Information regarding why a data value is missing will 
be documented in the study database. 
Coded copies of subject study images will be received at the time of the scan and will 
be stored in the participant file in a locked file cabinet. 
8.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   
8.5 
Emergency Modifications 


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UNC investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior UNC’s IRB/IEC 
approval/favorable opinion.   
For any such emergency modification implemented, an IRB modification form must be 
completed by UNC Research Personnel within five (5) business days of making the 
change.   
8.6 
Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an IRB 
approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• Did not result from willful or knowing misconduct on the part of the investigator(s).  
An unplanned protocol variance is considered a violation if the variance meets any of 
the following criteria:  
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious or continuing noncompliance with federal regulations, State 
laws, or University policies. 
If a deviation or violation occurs please follow the guidelines below: 
Protocol Deviations: UNC personnel will record the deviation and report to any data 
and safety monitoring committee in accordance with their policies.  Deviations should be 
summarized and reported to the IRB according to the UNC IRB reporting requirements. 
Protocol Violations: Violations should be reported by UNC personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
Unanticipated Problems: 
Any events that meet the criteria for “Unanticipated Problems” as defined by UNC’s IRB 
must be reported by the study team using the IRB’s web-based reporting system.   
8.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator at UNC.  It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required.   


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The written amendment, and if required the amended consent form, must be sent to 
UNC’s IRB for approval prior to implementation.  
8.8 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
8.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the 
treatment of all study participants.  The Principal Investigator must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
8.10 Conflict of Interest 
Any investigator who has a conflict of interest (COI) with this study as defined by the 
policies of the University of North Carolina will have the conflict reviewed by a properly 
constituted Conflict of Interest Review Committee with a committee-sanctioned conflict 
management plan that has been reviewed and approved by the IRB prior to 
participation in this study.  All University of North Carolina investigators will follow the 
University conflict of interest policy. 
9. PLANS FOR PUBLICATION 
Study results will be submitted to a peer-reviewed journal for publication. This study will 
also be listed on Clinicaltrials.gov and study results will be posted in accordance with 
appropriate regulations and ICJME requirements.  
Neither the complete nor any part of the results of the study carried out under this 
protocol will be published or passed on to any third party without the consent of the 
study sponsor-investigator. Any investigator involved with this study will be obligated to 


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provide the sponsor-investigator with complete results and all data derived from the 
study. 
10. REFERENCES  
 
1Vander Borght M, Wyns C. Fertility and infertility: Definition and epidemiology. Clin 
Biochem 2018;62:2–10. https://doi.org/10.1016/j.clinbiochem.2018.03.012. 
 
2 Exacoustos C, Manganaro L, Zupi E. Imaging for the evaluation of endometriosis and 
adenomyosis. Best Pract Res Clin Obstet Gynaecol 2014;28:655–81. 
https://doi.org/10.1016/j.bpobgyn.2014.04.010. 
 
3 Cosma S, Salgarello M, Ceccaroni M, Gorgoni G, Riboni F, La Paglia E, et al. 
Accuracy of a new diagnostic tool in deep infiltrating endometriosis: Positron emission 
tomography-computed tomography with 16α-[18F]fluoro-17β-estradiol. J Obstet 
Gynaecol Res 2016;42:1724–33. https://doi.org/10.1111/jog.13117 
 
4Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol 
2018;131:557–71. https://doi.org/10.1097/AOG.0000000000002469. 
 
5Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, et al. The social and 
psychological impact of endometriosis on women’s lives: a critical narrative review. Hum 
Reprod Update 2013;19:625–39. https://doi.org/10.1093/humupd/dmt027. 
 
6Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco 
Nardone C, et al. Impact of endometriosis on quality of life and work productivity: a 
multicenter study across ten countries. Fertil Steril 2011;96:366-373.e8. 
https://doi.org/10.1016/j.fertnstert.2011.05.090. 
 
7Rogers PAW, Adamson GD, Al-Jefout M, Becker CM, D’Hooghe TM, Dunselman GAJ, 
et al. Research Priorities for Endometriosis. Reprod Sci Thousand Oaks Calif 
2017;24:202–26. https://doi.org/10.1177/1933719116654991. 
 
8Yager JD, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev 
Pharmacol Toxicol 1996;36:203–32. 
https://doi.org/10.1146/annurev.pa.36.040196.001223. 
 
9International Agency for Research on Cancer. IARC Monographs on the Evaluation of 
Carcinogenic Risks to Humans, Volume 21: Sex Hormones (II). 
http://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-
Identification-Of-Carcinogenic-Hazards-To-Humans/Sex-Hormones-II--1979. 
Accessed August 27, 2019.  
 
10Highman B, Roth SI, Greenman DL. Osseous changes and osteosacomas in mice 
continuously fed diets containing diethylstilbestrol or 17 beta-estradiol. J Natl Cancer 
Inst 1981;67:653–62. 


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11Mejia AA, Nakamura T, Masatoshi I, Hatazawa J, Masaki M, Watanuki S. Estimation 
of absorbed doses in humans due to intravenous administration of fluorine-18 
fluorodeoxyglucose in PET studies. J Nucl Med Off Publ Soc Nucl Med 1991;32:699 
706. 
 
12Blau M, Wicks R, Thomas SR, Lathrop KA. Radiation absorbed dose from albumin 
microspheres labeled with technetium-99m. Task Group of the Medical Internal 
Radiation Dose Committee. The Society of Nuclear Medicine. J Nucl Med Off Publ Soc 
Nucl Med 1982;23:915–7. 
 
13Wackers FJ, Berman DS, Maddahi J, Watson DD, Beller GA, Strauss HW, et al. 
Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, 
safety, and preliminary comparison to thallium-201 for myocardial perfusion imaging. J 
Nucl Med Off Publ Soc Nucl Med 1989;30:301–11. 
 
14Liao GJ, Clark AS, Schubert EK, Mankoff DA. 18F-Fluoroestradiol PET: Current 
Status and Potential Future Clinical Applications. J Nucl Med Off Publ Soc Nucl Med 
2016;57:1269–75. https://doi.org/10.2967/jnumed.116.175596. 
 
15Revised American Society for Reproductive Medicine classification of endometriosis: 
1996. Fertil Steril 1997;67:817–21. 
 
16Johnson NP, Hummelshoj L, Adamson GD, Keckstein J, Taylor HS, Abrao MS, et al. 
World Endometriosis Society consensus on the classification of endometriosis. Hum 
Reprod Oxf Engl 2017;32:315–24. https://doi.org/10.1093/humrep/dew293. 
 
17 National Cancer Institute, Division of Cancer Treatment and Diagnosis. Investigator's 
Brochure for [18F]-Fluoroestradiol. 
https://imaging.cancer.gov/programs_resources/cancer-tracer-synthesis-
resources/docs/fes_ib_pdf.pdf. Accessed August 27, 2019. 
 
 


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11. APPENDIX 
Appendix A: FES 
Most of this information is taken directly from the NCI Investigator’s Brochure. 
11.1 Chemical name 
16α-[18F]-fluoro-17β-estradiol (FES) 
 
11.2 Pharmacology and toxicology 
16α-[18F]-fluoro-17β-estradiol (FES) is a radiopharmaceutical designed 
for imaging estradiol binding to estrogen receptors (ERs) in vivo. Its molecular 
weight is 290.4 Daltons. FES has chemical properties very similar to estradiol. 
The relative binding affinity (RBA, FES/estradiol) for the estrogen receptor is 0.81. 
The metabolism of FES and estradiol are similar2, 3 with elimination primarily by 
conjugation in the liver, followed by renal clearance of the glucuronide. 
Measurements of the relative binding affinity for the blood transport protein, sex 
hormone binding globulin (SHBG)4, was 10% relative to estradiol5. An average of 
45% of circulating FES is bound to SHBG, similar to estradiol6. In the sections 
that follow, the pharmacology and toxicity of estradiol in addition to FES is 
reviewed. 
FES is produced with a specific activity greater than 170 Ci/mmol and the 
injected mass dose is less than or equal to 5 μg (17 nmole). The requirement for 
high specific activity, low mass dose, assures that only a small fraction of the 
estrogen receptors (ER) are occupied during a PET imaging study. If the receptor 
approaches saturation, then FES uptake would no longer reflects receptor 
concentration. A 5-μg dose is far below any known toxicity for fluoroestradiol or 
other ER ligands. 
The pharmacology of FES is best understood by analogy to estradiol. 
Estradiol is a naturally occurring steroid that comes from two sources: (1) 
synthesis in the ovary in pre-menopausal women and (2) conversion from 
adrenal steroids, largely through aromatization (and aromatase enzymes)7, 8 in a 
variety of tissues, most notably fat, breast tissue, and breast cancers. Pre-
menopausal levels of estradiol vary widely depending upon the phase of the 
menstrual cycle, reaching levels as high as 500 pg/ml  (1.7 nM) mid-cycle. In 
post-menopausal women, and in men, levels are generally less than 30 pg/ml 
(0.1 nM). 
Estradiol is very lipophilic and is generally present in slightly higher 
concentration in tissues with higher fat content. Circulating estradiol is largely 
protein bound with high affinity but low capacity to SHBG and with low affinity but 
high capacity to albumin6, 9. Much of circulating estradiol is bound to SHBG and 
the remainder is bound to albumin6. FES is an estrogen analog used as a 
diagnostic agent to image regional estradiol binding to ER and is closely related 
to estradiol1. Estradiol exerts its physiologic effect by binding to ER, a nuclear 


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receptor. ER is selectively expressed in a variety of tissues, most notably the 
breast, uterus, ovaries, bone, and pituitary. 
Ovarian synthesis of estradiol is a key component of female endocrine 
function in a complex feedback loop with the pituitary. Estradiol also promotes 
new bone formation and is important in maintaining bone mineral density, 
especially in women. Estrogens affect the cardiovascular system, largely through 
their beneficial effect on serum lipids. In the breast, estradiol promotes ductal 
epithelial cell proliferation and is a key component stimulating lactation. 
Estrogens are established growth factors for endometrial and many breast 
cancers. Approximately 60% of breast cancers express ER, and estradiol and 
other estrogens provide a key stimulus for tumor growth and an opportunity for 
endocrine-based therapy. This last effect is the impetus for developing a 
diagnostic agent for imaging ER expression in breast cancer patients that led to 
our investigation of FES for use in PET diagnostic imaging10. 
FES metabolism has also been studied in humans. Metabolite analysis of 
blood and urine was performed in patients undergoing [18F]FES PET studies2. 
Results were similar to rat data, showing that FES is rapidly metabolized to polar 
species, with less than 20% of blood radioactivity in the form of [18F]FES by 60 
minutes after injection. There is also net clearance of both FES and labeled 
metabolites from the blood via hepatic uptake, biliary excretion, and urinary 
excretion of polar conjugates. By 120 minutes after injection, circulating FES is 
less than 5% of peak values, and the total of FES and labeled metabolites is less 
than 40% of the peak. Clearance rates of intravenous FES and intravenous 
estradiol are similar; for both compounds circulating levels have decreased to 
less than 5% of peak levels by 60 minutes after injection. Analysis of metabolites 
excreted in the urine sampled 90 – 120 minutes after injection has been done 
using glucuronidases to dissociate the glucuronide conjugates and acid 
hydrolysis to break the sulfate conjugation bond. These experiments recovered 
mostly [18F]FES, with a small percentage of a more polar substance not identified 
in the studies2. These results suggest that, on the time scale of PET imaging, 
FES is metabolized primarily to non-oxidized conjugated FES.  
In summary, FES biochemistry, ER binding affinity, and metabolism are 
very similar to estradiol, suggesting that data on estradiol biochemistry and 
pharmacology are applicable to FES. Any differences between results for FES 
and estradiol appear to arise from the fact that only short-term (1 – 2 hours), 
transient kinetics and metabolism of the radiolabeled [18F]FES are relevant to its 
use in PET. Studies of estradiol physiology suggest that exposures of several 
hours to days are needed to elucidate physiologic effects and thus longer-term, 
equilibrium kinetics and metabolism are most relevant. Because of the 18F half-
life limitation, oxidation plays only a minor role in [18F]FES metabolism and liver 
conjugation is responsible for enterohepatic circulation and prompt excretion in 
urine over the life of 18F.  


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Biodistribution studies in humans further support the concept that FES 
metabolism is similar to that of estradiol. The liver rapidly takes up FES with 
subsequent excretion into bile2, 11 . From sequential images of the biodistribution 
of FES using PET, it was shown that FES passed into the bile and moved 
through the small intestine11. Very little, if any, radioactivity was seen in the large 
intestine, suggesting highly efficient enterohepatic circulation, similar to that of 
estradiol. Similar results were found using 16-α-radioiodo-17-β-estradiol in a 
swine model 12. 
11.3 Toxicity of FES in humans 
Estradiol is a naturally occurring substance with biochemical and 
pharmacologic properties nearly identical to FES. It is important to interpret 
toxicity data for FES relative to reported toxicity for estradiol in the context of the 
intended use of FES as a single-dose-administration agent for diagnostic 
imaging. In this setting, FES reaches physiologic levels (i.e., greater than post-
menopausal levels) only on a transient basis. This must be viewed in the context 
of many years of exposure to physiologic levels of estradiol in most women. 
[18F]FES could potentially exert toxic effects through one of three mechanisms: 
(1) radiation exposure to tissues from the radioactive label11, (2) physiologic 
actions mediated through the ER, and (3) directly toxic or mutagenic effects of 
FES metabolites. Radiation exposure from [18F]FES at activity doses used in 
PET (6 mCi, typical) is low, and is comparable to other nuclear medicine 
procedures11. Radiation exposure is discussed in detail in Section 10.4. With 
respect to the other two mechanisms of toxicity, FES injected as a bolus for PET 
imaging transiently reaches physiologic concentrations, but returns to sub-
physiologic levels within an hour after injection. As such, toxic effects due to 
actions mediated through the ER and directly toxic effects of metabolites will be 
far less than those of natural ER ligands.  
Given the biochemical and pharmacologic similarity between FES and 
estradiol, the low mass administered and short-term exposure to FES resulting 
from PET studies, the estradiol toxicity literature serves as an appropriate gauge 
for any potential toxicity of FES. 
11.4 Dosimetry 
The uptake of [18F]FES in normal human tissues has been measured and 
used to estimate the radiation absorbed dose associated with the imaging 
procedure. Dosimetry studies were performed at the University of Washington 
and have been peer-reviewed and published in the Journal of Nuclear 
Medicine11. For more details, the reader is referred to the investigator’s brochure 
at NCI. 
Table 1. Human dosimetry estimates 
(source: investigator’s brochure) 


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Organ  
Mean 
mrad/mC
i  
Mean 
mGy/MBq  
SD* 
mGy/MBq  
25% 
mGy/MBq  
75% 
mGy/MBq  
Adrenals  
85  
0.023  
0.003  
0.021  
0.025  
Brain  
36  
0.010  
0.001  
0.009  
0.010  
Breasts  
32  
0.009  
0.002  
0.008  
0.010  
Gall Bladder Wall  
379  
0.102  
0.041  
0.075  
0.134  
Lower Large Intestine  
45  
0.012  
0.001  
0.011  
0.013  
Small Intestine  
99  
0.027  
0.015  
0.017  
0.038  
Stomach  
50  
0.014  
0.001  
0.013  
0.014  
Upper Large Intestine  
110  
0.030  
0.016  
0.019  
0.042  
Heart Wall  
96  
0.026  
0.004  
0.024  
0.029  
Kidney  
128  
0.035  
0.004  
0.032  
0.038  
Liver  
466  
0.126  
0.030  
0.105  
0.149  
Lungs  
61  
0.017  
0.002  
0.015  
0.018  
Muscle  
79  
0.021  
0.001  
0.021  
0.022  
Ovaries  
66  
0.018  
0.002  
0.016  
0.019  
Pancreas  
84  
0.023  
0.002  
0.021  
0.024  
Red Marrow  
48  
0.013  
0.002  
0.012  
0.014  
Bone Surface  
53  
0.014  
0.001  
0.014  
0.015  
Skin  
18  
0.005  
0.000  
0.005  
0.005  
Spleen  
54  
0.015  
0.003  
0.012  
0.017  
Testes  
44  
0.012  
0.001  
0.011  
0.012  
Thymus  
50  
0.014  
0.001  
0.013  
0.014  
Thyroid  
45  
0.012  
0.001  
0.012  
0.013  
Urinary Bladder Wall  
186  
0.050  
0.020  
0.036  
0.066  
Uterus  
145  
0.039  
0.013  
0.031  
0.049  
Lens  
33  
0.009  
0.000  
0.009  
0.009  
*SD = Standard Deviation 
Effective Dose Equivalent = 0.022 mSv/MBq (0.004 SD). For a 6 mCi (222 MBq) 
dose, this would be about 4.8 mSv. 
11.5 Previous FES human imaging studies 
Early studies established a correlation between FES uptake and in vitro 
assay of ER expression13 and documented the biodistribution and radiation 
dosimetry of FES11. Several studies documented the metabolism, clearance, and 
serum protein binding of FES in humans5, 11. Other studies demonstrated 
heterogeneous uptake of FES in advanced breast cancer as a reflection of 
heterogeneous ER expression14, 15. One paper measured FES uptake in 
meningiomas16 Finally, other studies have measured FES uptake in patients 
treated with hormonal therapy17, 18, 19. The general conclusion from the studies 
summarized above is that [18F]FES PET images identified estrogen receptor 


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positive tissue that was heterogeneously distributed within human tumors. These 
data may be helpful in identifying patients who will benefit from endocrine therapy 
for their cancer and predict the likelihood of response to specific treatment 
hormonal regimens.  
In a paper published in 2010, Tsujikawa et al20 reported on the correlation 
between the uptake of 16α-[18F]fluoro-17β-estradiol (FES) and expression of 
estrogen receptors, as well as other related immunohistochemistry markers. 
Nineteen patients with endometrioid adenocarcinoma underwent preoperative 
PET studies with FES and FDG. Standardized uptake values (SUVs) for each 
tracer and the regional FDG to FES SUV ratio were calculated using images after 
coregistration. FES uptake showed a significantly positive correlation with 
expression of estrogen receptor α (ERα). The FDG to FES ratio showed a 
significantly negative correlation with expression of ERα and progesterone 
receptor B (PR-B). The FES uptake and FDG to FES ratio did not correlate with 
expression of ERβ, Ki-67 or glucose transporter 1 (GLUT1). FDG uptake was not 
correlated with any of the immunohistochemical scores. The PR-B score was 
strongly correlated with the ERα score. Well-differentiated carcinoma (grade 1) 
showed a significantly higher FES uptake and significantly lower FDG to FES 
ratio than moderately or poorly differentiated carcinoma (grade 2 – 3). None of 
the PET parameters were significantly different between advanced-stage 
carcinoma (≥ stage IB) and early-stage carcinoma (IA) based on the Féderation 
International de Gynécologie et d’Obstétrique (FIGO) staging classification. 
Differentiation grade was the most closely correlated parameter to FES uptake 
and FDG to FES ratio by multivariate analyses. The authors concluded FES PET 
combined with FDG would be useful for non-invasive evaluation of ERα 
distribution, as well as ERα function, which reflects differentiation grade in 
endometrial carcinoma20.  
In a study of 16 female healthy volunteers published in 2007, Tsuchida et 
al21 administered a single dose of FES to investigate the relationship between 
endometrial and myometrial FES uptake and menstrual phase or endogenous 
estrogen level. 
Endometrial SUV was significantly higher in the proliferative phase than in 
the secretory phase (6.03 ± 1.05 vs. 3.9 ± 1.29, P = .022). In contrast, there was 
no significant difference in myometrial SUV when the proliferative and secretory 
phases were compared (P = .23). Further, there was no correlation between SUV 
and endogenous estrogen level in the proliferative phase. The authors concluded 
that the change of ER concentration relative to menstrual cycle as characterized 
by FES PET was consistent with those from previous reports that used an 
immunohistochemical technique. These data suggest that FES PET is a feasible, 
noninvasive method for characterizing changes in ER concentration21.  
In a study published in 2008 by Tsujikawa et al22 FES and FDG PET studies were 
performed in 38 patients with benign and malignant uterine tumors to compare 
differences in tracer accumulation. Regional values of tracer uptake were 


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evaluated by using standardized uptake value (SUV). Patients with endometrial 
carcinoma showed significantly greater mean SUV for FDG (9.6 ± 3.3) than for 
FES (3.8 ± 1.8) (P < .005). Patients with endometrial hyperplasia showed 
significantly higher mean SUV for FES  (7.0 ± 2.9) than for FDG (1.7 ± 0.3) (P < 
.05). Patients with leiomyoma showed significantly higher mean SUV for FES 
(4.2 ± 2.4) than for FDG (2.2 ± 1.1) (P < .005), and patients with sarcoma 
showed opposite tendencies for tracer accumulation. Tracer uptake in patients 
with endometrial carcinoma was significantly higher for FDG (P < .001) and 
significantly lower for FES (P < .05) when compared with values in patients with 
endometrial hyperplasia. On the other hand, patients with sarcoma showed a 
significantly higher uptake for FDG (P < .005) and a significantly lower uptake for 
FES (P < .05) compared with patients with leiomyoma. The authors concluded 
that ER expression and glucose metabolism of uterine tumors measured by 
using PET showed opposite tendencies, and that PET studies utilizing both FES 
and FDG could provide pathophysiologic information for the differential diagnosis 
of uterine tumors. These results demonstrate the potential predictive capability of 
FES PET22.  
In another study by Peterson et al published in 200823, [18F]fluoroestradiol 
uptake was compared with ER expression assayed in vitro by 
immunohistochemistry (IHC) with both qualitative and semiquantitative 
measures. Seventeen patients with primary or metastatic breast cancer were 
studied with dynamic [18F]FES PET; cancer tissue samples, collected close to the 
time of imaging, were assayed for ER expression by IHC. For each tumor, 
partial-volume-corrected measures of [18F]FES uptake were compared with ER 
expression measured by three different ER scoring methods: qualitative scoring 
(0 – 31), the Allred score (0 – 10), and a computerized IHC index. The authors 
noted that there was excellent agreement (r2 = 0.99) between observers using 
IHC as well as the different methods of measuring ER content (P < 0.001), and 
they concluded that there is good agreement between [18F]FES PET and ER 
expression measured by IHC, and that [18F]FES imaging may be a useful tool for 
aiding in the assessment of ER status, especially in patients with multiple tumors 
or for tumors that are difficult to biopsy23. 
In a study by Dehdashti et al published in 200924, 51 post-menopausal 
women with advanced estrogen receptor positive breast cancer were studied. 
Patients underwent FES PET and FDG PET at baseline and repeat FDG PET 
after 30 mg estradiol. Tracer uptake was measured as the standardized uptake 
value (SUV). Patients were subsequently treated with either an aromatase 
inhibitor or fulvestrant. PET results were correlated with responsiveness to 
endocrine therapy. Per study criteria, 17 patients responded and 34 patients did 
not respond to endocrine therapy. Four responders and one non-responder had 
a clinical flare reaction, while only the responders demonstrated metabolic flare. 
After estradiol challenge, a significantly higher mean (± SD) percent change in 
SUV for FDG was noted in responders (20.9 ± 24.2) compared with non-


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responders (-4.3 ± 11.0, P < 0.0001). On FES PET, a higher tumor SUV was 
noted in responders (3.5 ± 2.5) compared with non-responders (2.1 ± 1.8, P = 
0.0049). There was significantly longer overall survival in patients with metabolic 
flare than in those without flare regardless of type of endocrine therapy (P = 
0.0062). The authors concluded that baseline tumor FES uptake and metabolic 
flare after an estradiol challenge are both predictive of responsiveness to 
endocrine therapy in ER+ breast cancer24.  
In a study by Kumar et al published in 200725 an improved automated 
radiosynthesis methodology for [18F]FES was developed. Stability studies of the 
resulting injectable form were performed up to 24 hours after dose formulation 
under normal storage conditions. A comparison of FES versus FDG PET imaging 
was then conducted in ER+ breast cancer patients. The results of the improved 
synthesis methodology were favorable and the subsequent PET imaging 
suggested specificity of FES for ER+ tumors versus FDG25.  
In a 2008 paper Tsujikawa et al26 reported two postmenopausal patients under 
suspicion of endometrial carcinoma on the basis of cytology and/or magnetic 
resonance imaging (MRI), who were on tamoxifen treatment since undergoing 
surgery for breast cancer. Pelvic MRI suggested endometrial carcinomas, 
whereas FDG and FES-PET showed no abnormal tracer accumulation. A 
postoperative histopathologic examination revealed that the lesions were 
endometrial hyperplasias with no malignant findings. They concluded that FES 
PET enabled them to evaluate endometrial ER expression noninvasively. The 
evaluation of ER expression using FES PET requires careful attention regarding 
the influence of hormonal therapy because tamoxifen greatly affects FES 
accumulation of even endometrial hyperplasia, which should be an FES-avid 
lesion26.  
Another study published by Tsujikawa et al in 200927 investigated whether 
[18F]FES and [18F]FDG PET reflect clinic-pathologic features in patients with 
endometrial tumors27. A total of 22 patients with endometrial adenocarcinoma 
and nine with endometrial hyperplasia underwent [18F]FES PET for estrogen 
receptor imaging and [18F]FDG PET. The diagnostic accuracy of MRI findings for 
clinical staging was also compared. They found that although the SUV for 
[18F]FDG was significantly lower in endometrial hyperplasia than in carcinoma, a 
statistically significant difference between high-risk and low-risk carcinoma was 
observed only in SUV for [18F]FES. High-risk carcinoma showed a significantly 
greater [18F]FDG to [18F]FES ratio (3.6 ± 2.1) than did low-risk carcinoma (1.3 ± 
0.5, P < 0.01) and hyperplasia (0.360.1, P < 0.005). Low-risk carcinoma showed 
a significantly higher [18F]FDG to [18F]FES ratio than hyperplasia (P < 0.0001). In 
receiver operating-characteristic (ROC) analysis, the most accurate diagnostic 
PET parameter for predicting high-risk and low-risk carcinoma was the [18F]FDG 
to [18F]FES ratio. The optimal [18F]FDG/[18F]FES cutoff value of 2.0, determined 
by ROC analysis, revealed 73% sensitivity, 100% specificity, and 86% accuracy, 
which was better than the 77% accuracy for MRI. The [18F]FDG to [18F]FES ratio 


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of 0.5 yielded a correct diagnosis for carcinoma from hyperplasia with 100% 
accuracy. They concluded that endometrial carcinoma reduces estrogen 
dependency with accelerated glucose metabolism as it progresses to a higher 
stage or grade, that the [18F]FDG to [18F]FES ratio reflects tumor aggressiveness, 
and that this index will be useful for making noninvasive diagnoses and deciding 
the appropriate therapeutic strategy for patients with endometrial carcinoma27. 
11.6 Reported adverse events and potential risks 
Approximately 1500 subjects are represented in the published studies. 
Other than infrequent transient intravenous site discomfort and an “alcohol taste”, 
there have been no adverse events related to [18F]FES administration.  
Although lab values have not been routinely measured pre- and post-FES PET 
scans as part of the PET procedure, many patients at the University of 
Washington have undergone serial measurements of renal and liver function, 
differential blood counts and assay of electrolytes as part of their clinical 
management. To estimate toxicity risk, 109 consecutive patients who underwent 
FES PET scans between 2002 and 2005 were examined. Of these 109, 30 
patients had hematology and serum chemistry values measured both before FES 
PET scanning (median 16 days prior) and within 21 days after the infusion of 
[18F]FES (median 10.5 days post scan).  
Measurements of renal and liver function (serum creatinine, SGOT, 
SGPT, and alkaline phosphatase) showed no clinically significant changes pre- 
versus post-FES infusion in this group of patients. Three patients had elevated 
alkaline phosphatase prior to FES infusion, due to extensive bony metastatic 
disease, and these patients continued to have elevated levels post FES infusion 
with no clinically significant change. Differential blood counts (platelet counts, 
WBC, neutrophils, hemoglobin, and hematocrit) were examined. These showed a 
number of patients with abnormal blood values prior to FES PET scanning; 
however, this was expected in a heavily pre-treated population undergoing 
salvation therapy for metastatic breast cancer. There were no clinically significant 
changes in blood counts seen post-[18F]FES infusion compared with the 
preimaging values. 
11.7 FES Administered Dose 
The [18F]fluoroestradiol is a sterile, IV injectable solution with a volume of 
≤ 20 ml containing 0.15 M phosphate buffered saline: < 15% ethanol (v:v). The 
injected dose of [18F]FES is generally 6 mCi (185 MBq) with an allowable range 
of 3 to 6 mCi of [18F]fluoroestradiol. The drug product solution is stored at room 
temperature in a gray butyl septum sealed, sterile, pyrogen-free glass vial with an 
expiration time of 8 hours. The mass of injected drug is ≤ 5 μg (≤ 17 nmol) of 
FES. 
11.8 Agent Availability 
[18F]FLT will be provided by the Biomedical Research Imaging 
Radiopharmaceutical Core under an IND held by the Cancer Imaging Program 
(CIP)/NCI.  


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11.9 References 
1 Vallabhajosula S. 18F-labeled positron emission tomographic radiopharmaceuticals in 
oncology: An overview of radiochemistry and mechanisms of tumor localization. Semin 
Nucl Med. 2007; 37:400-419.  
2 Mankoff DA, Tewson TJ, Eary JF. Analysis of blood clearance and labeled metabolites 
for the estrogen receptor tracer, [F-18]-16α-fluoroestradiol (FES). Nucl Med Biol. 1997; 
24:341-348.  
3 Bolt HM. Metabolism of estrogens—natural and synthetic. Pharmacol Ther. 1979; 
4(1):155-181.  
4 Pomper MG, VanBrocklin H, Thieme AM, et al. 11 β-methoxy-, 11 β-ethyl- and 17 α-
ethynyl-substituted 16 α-fluoroestradiols: Receptor-based imaging agents with 
enhanced uptake efficiency and selectivity. J Med Chem. 1990; 33:3143-3155.  
5 Tewson TJ, Mankoff DA, Peterson LM, Woo I, Petra P. The interactions of 16α-[F18]-
fluoroestradiol (FES) with sex steroid binding protein (SBP). Nucl Med Biol. 1999; 
26:905-913.  
6 Pan CC, Woolever CA, Bhavnani, BR. Transport of equine estrogens: Binding of 
conjugated and unconjugated equine estrogens with human serum proteins. J Clin 
Endocrinol Metab. 1985; 61(3):499-507. 
7 Kuerer HM, Buzdar AU, Singletary SE. Biologic basis and evolving role of aromatase 
inhibitors in the management of invasive carcinoma of the breast. J Surg Oncol. 2001; 
77(2):139-147.  
8 Reed MJ, Purohit A. Aromatase regulation and breast cancer. Clin Endocrinol (Oxf). 
2001; 54:563-571, 2001.  
9 Petra P. The plasma sex steroid binding protein (SBP or SBHG). A critical review of 
recent developments on the structure, molecular biology and function. J Steroid 
Biochem Molec Biol. 1991; 40:735-753.  
10 Riggs BL, Hartmann LC. Selective estrogen-receptor modulators — mechanisms of 
action and application to clinical practice. N Engl J Med. 2003; 348(12):618-629. 
11 Mankoff DA, Peterson LM, Tewson TJ, et al. [18F]fluoroestradiol radiation dosimetry in 
human PET studies. J Nucl Med. 2001; 42(4):679-684. 
12 Scharl A, Beckman MW, Artwohl JE, Kullander S, Holt JA. Rapid liver metabolism, 
urinary and biliary excretion, and enterohepatic circulation of 16 alpha-radioiodio17beta-
estradiol. Int J Radiat Oncol Biol Phys. 1991; 21:1235-1240. 


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13 Mintun MA, Welch MJ, Siegel BA, et al. Breast cancer: PET imaging of estrogen 
receptors. Radiology. 1988; 169:45-48. 
14 Dehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA. 
Positron emission tomographic assessment of "metabolic flare" to predict response of 
metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med. 1999; 21:51-56. 
15 Dehdashti F, Mortimer JE, Siegel BA, et al. Positron tomographic assessment of 
estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor 
assays. J Nucl Med. 1995; 36(10):1766-1774.  
16 Moresco RM, Scheithauer BW, Lucignani G, et al. Oestrogen receptors in 
meningiomas: a correlative PET and immunohistochemical study. Nucl Med Commun. 
1997; 18:606-615.  
17 Mortimer JE, Dehdashti F, Siegel BA, Katzenellenbogen JA, Fracasso P, Welch MJ. 
Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16α[18F]fluoro-
17β-estradiol in breast cancer: correlation with estrogen receptor status and response to 
systemic therapy. Clin Cancer Res. 1996; 2:933-939.  
18 McGuire AH, Dehdashti F, Siegel BA, et al. Positron tomographic assessment of 16α-
[18F] fluoro-17β-estradiol uptake in metastatic breast carcinoma. J Nucl Med. 1991; 
32(8):1526-1531. 
19 Linden HM, Stekhova SA, Link JM, et al. Quantitative fluoroestradiol positron 
emission tomography imaging predicts response to endocrine treatment in breast 
cancer. J Clin Oncol. 2006; 24(18):2793-2799. 
20 Tsujikawa T, Yoshida Y, Kiyono Y, et al. Functional oestrogen receptor α imaging in 
endometrial carcinoma using 16α-[18F]fluoro-17β-oestradiol PET. Eur J Nucl Med Mol 
Imaging. 2010;38:37-45. 
21 Tsuchida T, Okazawa H, Mori T, et al. In vivo imaging of estrogen receptor 
concentration in the endometrium and myometrium using FES PET— influence of 
menstrual cycle and endogenous estrogen level. Nucl Med Biol. 2007;34(2):205-210. 
22 Tsujikawa T, Yoshida Y, Mori T, et al. Uterine Tumors: pathophysiologic Imaging with 
16α-[18F]fluoro-17β-estradiol and 18F Fluorodeoxyglucose PET-Initial Experience. 
Radiology. 2008; 248(2)599-605. 
23 Peterson LM, Mankoff DA, Lawton T, et al. Quantitative imaging of estrogen receptor 
expression in breast cancer with PET and 18F-fluorostradiol. J Nucl Med. 2008; 
49(3):367-374. 
24 Dehdashti F, Mortimer JE, Trinkaus K, et al. PET-based estradiol challenge as a 
predictive biomarker of response to endocrine therapy in women with estrogen-
receptor-positive breast cancer. Breast Can Res Treat. 2009; 113:509-517. 


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25 Kumar P, Mercer J, Doerkson C, Tonkin K, McEwan AJB. Clinical production, stability 
studies and PET imaging with 16-α-[18F]fluoroestradiol ([18F]FES) in ER positive breast 
cancer patients. J Pharm Pharmaceut Sci. 2007; 10(2): 256s-265s. 
26 Tsujikawa T, Okazawa H, Yoshida Y, et al. Distinctive FDG and FES accumulation 
pattern of two tamoxifen-treated patients with endometrial hyperplasia. Ann Nucl Med. 
2008; 22:73-77. 
27 Tsujikawa T, Okazawa H, Yoshida Y, et al. Functional images reflect aggressiveness 
of endometrial carcinoma: estrogen receptor expression combined with 18F-FDG PET. J 
Nucl Med 2009; 50(10):1598-1604. 

ICF_001.pdf: 
 
Study Title: Evaluation of Endometriosis With 18F-fluoroestradiol PET 
/ MRI 
 
 
 
NCT number NCT04382911 
Document Date 03/15/2021 
 


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University of North Carolina at Chapel Hill 
Consent to Participate in a Research Study 
Adult Participants  
 
Consent Form Version Date: March 15, 2021 
IRB Study # 20-0328 
Title of Study: Evaluation of Endometriosis with 18F-fluoroestradiol PET / MRI  
Principal Investigator: Jorge Oldan 
Principal Investigator Department: Radiology - Nuclear Medicine 
Principal Investigator Phone number: (919) 966-9676 
Principal Investigator Email Address: jorge_oldan@med.unc.edu  
Study Contact Telephone Number: (919) 843-3670;  (919) 843-9463; (919) 966-4997 
Study Contact Email: markeela_lipscomb@med.unc.edu; desma_jones@med.unc.edu; 
terry_hartman@med.unc.edu  
 
CONCISE SUMMARY 
 
The purpose of this research study is to test if a new imaging drug, called F-18 Fluoroestradiol 
(FES), is useful for detecting and diagnosing endometriosis. This investigational drug is used 
with a PET/MRI scan. We will perform FES-PET imaging to compare results with your 
laparoscopic surgery results.   
 
You are being asked to take part in this research study because you are scheduled to have a 
laparoscopy at UNC to determine if you have endometriosis.  
 
If you decide to participate in this research study, you will undergo one (1) scan with the imaging 
drug, and you will complete questionnaires related to your condition, pain, and quality of life. 
We will collect information related to your health for up to 3 months after your research scan. 
Possible risks associated with FES are swelling and redness at the site of the medication 
injection, change in taste, and possible allergic reaction. You may experience anxiety and 
claustrophobia from being in the scanner. You will also be exposed to some radiation from the 
injection of FES during the study and should not participate if you are pregnant or breastfeeding  
With any study, there is a small risk of breach of confidentiality. 
 
There are no direct benefits to you from participating in this study. 
 
If you are interested in learning more about this study, please continue reading below. 
 
What are some general things you should know about research studies? 
You are being asked to take part in a research study.  To join the study is voluntary. 


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You may choose not to participate, or you may withdraw your consent to be in the study, for any 
reason, without penalty. 
 
Research studies are designed to obtain new knowledge. This new information may help people 
in the future.   You may not receive any direct benefit from being in the research study. There 
also may be risks to being in research studies. Deciding not to be in the study or leaving the 
study before it is done will not affect your relationship with the researcher, your health care 
provider, or the University of North Carolina-Chapel Hill. If you are a patient with an illness, 
you do not have to be in the research study in order to receive health care. 
 
Details about this study are discussed below.  It is important that you understand this information 
so that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the researchers named above, or 
staff members who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study? 
The purpose of this research study is to evaluate the usefulness of the investigational radiotracer 
FES with PET/MRI in detecting and diagnosing endometriosis. 
 
You are being asked to take part in this research study because you are scheduled to have a 
laparoscopy at UNC to determine if you have endometriosis. 
Are there any reasons you should not be in this study? 
You should not be in this study if you are: 
• male 
• less than 18 years old  
• institutionalized (prisoner or nursing home patient)  
• have a known history of breast, ovarian, or endometrial cancer 
• pregnant or breast feeding 
• unable to have an MRI scan for any reason 
How many people will take part in this study? 
Approximately 12 people at this institution will take part in this study. 
 
How long will your part in this study last? 
Your participation in this study will last a total of 3 months. You will have one study visit and 
we will review your medical record for up to 3 months following your research scan. 
What will happen if you take part in the study? 
1. One study visit that will last up to 2.5 hours. This visit will involve: 
• pregnancy test, if applicable 
• questionnaires related to your symptoms, pain, and quality of life.  You may choose not 
to answer a question for any reason. 
• study drug (FES) administration through an IV (needle placed in your arm) 
• one PET/MRI scan 


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2. One follow-up phone call the day after your study visit to check on you. 
 
3. We will collect study-related health information from your medical records for 3 months 
following your visit.  
 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge.  You will not benefit 
personally from being in this research study. 
 
What are the possible risks or discomforts involved from being in this study? 
 
PET/MRI scan  
Likely and mild:  
• Anxiety/stress  
• Claustrophobia  
• Discomfort from lying still for imaging (typically about 60 minutes).  
 
IV Needle Placement 
Likely and mild:  
• Discomfort from the IV and injection of FES into the vein  
Infrequent and mild:  
• Swelling 
• Bleeding  
• Infection  
• Bruising 
 
Injection of 18F-FES  
Infrequent and mild:  
• Swelling and redness at the site of medication injection  
• Temporary change in taste or smell (i.e a metallic taste or smell) during the injection of 
FES. Normally goes away within a few minutes of injection.  
Rare and Severe:  
• Rare possibility of an allergic-type or other adverse reaction to the radioactive labeled 
tracer FES  
 
A licensed provider will observe you and take your vital signs (blood pressure, pulse) 
following the administration of FES on through the completion of the imaging. You will also 
be contacted by study personnel a day after you receive FES to inquire about any delayed 
onset complications. 
 
Radiation Exposure  
Unknown risk and severity:  
• Risk of radiation exposure to an unborn child. Women of childbearing age will undergo 
pregnancy testing prior to FES PET. Pregnant women will be excluded from the study. 


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Pregnancy tests will be done on all females who might be able to get pregnant at the start of 
the study. Pregnancy tests are not 100% accurate in detecting very early pregnancy and we 
strongly advised the use of barrier contraception or to practice abstinence in the timeframe 
prior to the study procedure. 
 
Pregnancy tests will be paid for by the study.  
 
Risks associated with radiation exposure: 
This research study involves exposure to radiation from one FES PET/MRI scan. Please note that 
this radiation exposure is not necessary for your medical care and is for research purposes only. 
 
The average person in the United States receives a radiation exposure of 0.3 rem (or 300 mrem) 
per year from natural background sources, such as from the sun, outer space, and from 
radioactive materials that are found naturally in the earth’s air and soil. The dose that you will 
receive from participation in this research study is about 0.5 rem, a little more than the amount 
you receive from these natural sources in 1.7 years. 
 
The amount of radiation you will receive in this study has a minimal risk and is below the dose 
guideline established by The University of North Carolina Radiation Safety Committee for 
research subjects. While this level may be considered to have minimal risk for an adult, there are 
no robust human data to identify a safe level of exposure for an early embryo. 
 
Confidentiality 
There is a minimal risk of breach of patient confidentiality. To minimize this risk, you will be 
given a unique subject ID that will be used for all your data and you will not be identified 
directly. 
 
There may be uncommon or previously unknown risks. You should report any problems to the 
researcher. 
 
What are the risks to a pregnancy or to a nursing child? 
We do not know the effect of the study drug on babies before they are born, or on nursing 
children.  Many drugs can get into the mother's milk. You should not breast feed your child 
while taking the study drug. 
 
If you are a woman and you are planning to get pregnant, you should not be in the study. If you 
become pregnant during the study you should notify the researcher right away.  
What if we learn about new findings or information during the study?  
You will be given any new information gained during the course of the study that might affect 
your willingness to continue your participation.  
 
The imaging we are using in this research study is not the same quality as imaging that you may 
have as part of your health care. The images will not be reviewed by a doctor who normally 
reads such images (such as a radiologist). As a result, you may not be informed of any 
unexpected findings. The results will not be placed in your medical record.  Occasionally the 
technologist or principal investigator may notice something abnormal on the imaging.  If this 


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does occur, the images will be reviewed by a qualified doctor to determine if there is anything of 
clinical importance. If something is found to be important then you, and/or your primary care 
provider will be notified.  Any further follow up and costs associated with the incidental finding 
will be your responsibility. There may be benefits to learning such results (such as early 
detection and treatment of a medical condition), but there are risks as well (such as problems 
with getting insurance or a job, or feeling worried about a finding for which no treatment is 
required or appropriate). 
 
Do you wish to be informed in case of clinical/relevant unexpected findings?  Please initial in the 
box below if you do not wish to be notified of clinical/relevant unexpected findings.  If you do 
not initial in the box, you will be notified of any findings. 
  
______ I do not wish to be notified. 
 
How will information about you be protected? 
All of your research records will be stored using a unique ID number only. Research records will 
be kept in a locked file cabinet within a locked office suite at UNC. Only research team members 
will have access to individually identifiable data. Research data will be collected using a 
password protected HIPAA compliant electronic data capture system only accessible by the 
research team. Extracted research data will be de-identified and coded with a unique ID number. 
The linkage file will be destroyed at the conclusion of the study and once the final manuscript is 
published. 
Participants will not be identified in any report or publication about this study.  We may use de-
identified data from this study in future research without additional consent. 
Although every effort will be made to keep research records private, there may be times when 
federal or state law requires the disclosure of such records, including personal information.  This 
is very unlikely, but if disclosure is ever required, UNC-Chapel Hill will take steps allowable by 
law to protect the privacy of personal information.  In some cases, your information in this 
research study could be reviewed by representatives of the University, research sponsors, or 
government agencies (for example, the FDA) for purposes such as quality control or safety. 
 
What is a Certificate of Confidentiality?  
This research is covered by a Certificate of Confidentiality. With this Certificate, the researchers 
may not disclose or use information, documents or biospecimens that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings in the 
United States, for example, if there is a court subpoena, unless you have consented for this use. 
 
The Certificate cannot be used to refuse a request for information from personnel of a federal or 
state agency that is sponsoring the study for auditing or evaluation purposes or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law, such as mandatory reporting requirements for child abuse or neglect, disabled 


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adult abuse or neglect, communicable diseases, injuries caused by suspected criminal violence, 
cancer diagnosis or benign brain or central nervous system tumors or other mandatory reporting 
requirement under applicable law. The Certificate of Confidentiality will not be used if 
disclosure is for other scientific research, as allowed by federal regulations protecting research 
subjects or for any purpose you have consented to in this informed consent document. 
 
You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
 
By signing this informed consent document, you agree that some of the information generated by 
participating in this study and/or a copy of the consent form may be included in your medical 
record and that this information may be viewed by other physicians or caregivers who provide 
healthcare services to you. This will allow the doctors caring for you to know what study 
medications or tests you may be receiving as a part of the study and know how to take care of 
you if you have other health problems or needs during the study. Additionally, the information 
may be shared with your medical insurance plan if the research services provided are billed to 
your insurance. 
 
You will be asked to sign a separate form ("HIPAA Authorization") to allow researchers to 
review your medical records. 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  If you are hurt, become 
sick, or develop a reaction from something that was done as part of this study, the researcher will 
help you get medical care, but the University of North Carolina at Chapel Hill has not set aside 
funds to pay you for any such injuries, illnesses or reactions, or for the related medical care.  Any 
costs for medical expenses will be billed to you or your insurance company.  You may be 
responsible for any co-payments and your insurance may not cover the costs of study related 
injuries. 
If you think you have been injured from taking part in this study, call the Principal Investigator at 
the phone number provided on this consent form.  They will let you know what you should do.  
By signing this form, you do not give up your right to seek payment or other rights if you are 
harmed as a result of being in this study. 
 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty.  The investigators also have the 
right to stop your participation at any time. This could be because you have had an unexpected 
reaction, or have failed to follow instructions, or because the entire study has been stopped. 
 
If you withdraw or are withdrawn from this study all data collected up until the point of 
withdrawal will be retained, however no additional information will be collected unless you 
provide additional written permission for further data collection at the time of your withdrawal  


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Will you receive anything for being in this study? 
You will be receiving a $175 Visa gift card and parking vouchers for taking part in this study. 
Any payment provided for participation in this study may be subject to applicable tax 
withholding obligations. 
 
Will it cost you anything to be in this study? 
It will not cost you anything to be in this study.  
 
What if you have questions about this study? 
You have the right to ask, and have answered, any questions you may have about this research. If 
you have questions about the study (including payments), complaints, concerns, or if a research-
related injury occurs, you should contact the researchers listed on the first page of this form. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights 
and welfare.  If you have questions or concerns about your rights as a research subject, or if you 
would like to obtain information or offer input, you may contact the Institutional Review Board 
at 919-966-3113 or by email to IRB_subjects@unc.edu. 
 
Participant’s Agreement: 
 
I have read the information provided above.  I have asked all the questions I have at this time.  I 
voluntarily agree to participate in this research study. 
 
______________________________________________________ 
Signature of Research Participant 
 
____________________ 
Date 
 
______________________________________________________ 
Printed Name of Research Participant 
  
 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
 
____________________ 
Date 


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______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent