Applications of Dual Energy CT for Improving Staging and Monitoring of Therapy Response in Patients With Osseous Metastases From Castrate-resistant Prostate Cancer
Phase: NA
Conditions: Dual Energy CT (DECT), Prostate Cancer
Sponsor: Duke University

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Applications of dual energy CT for improving staging and monitoring of 
therapy response in patients with osseous metastases from castrate-
resistant prostate cancer 
Sponsor: 
PI – Duke Cancer Institute 
Funding Source: 
Society of Abdominal Radiology 
Protocol Source: 
PI - Duke Cancer Institute 
Duke IRB#: 
Pro00078046 
Principal Investigator 
Dr Daniele Marin, M.D.  
Dept of Radiology 
Durham, NC 27710 
Box 3808 Med Ctr 
Durham, NC 27710 
919 684 7366 
Fax 
daniele.marin@duke.edu 
Co-Principal Investigator(s) 
Name, degree 
Email address 
Sub-Investigator(s) 
Dr. Christoph Schabel, MD PhD 
christoph.schabel@duke.edu 
Dr. Bhavik Patel, MD, MBA 
bhavik.patel@duke.edu 
Andrew Armstrong, M.D. 
andrew.armstrong@duke.edu 
Statistician 
Kingshuk Roy Choudhury, 
Ph.D. 
kingshuk@duke.edu 
Lead Study Coordinator 
Name, degree TBS 
Email address 
Regulatory Coordinator 
Steve Shipes, Ph.D. 
steven.shipes@duke.edu 
Data Manager 
Name, degree 
Email address 
Original version: 
Date 10/10/2016 
Amended version 
1: 
Date 
NCT03111914

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Protocol Title:  
Pilot study to assess feasibility of using dual energy CT to improve staging 
and monitoring of therapy response in patients with osseous metastases from 
castrate-resistant prostate cancer. 
Short Title: 
Dual energy CT for improving staging and monitoring of therapy response 
in patients with castrate-resistant prostate cancer. 
Purpose of the Study:  
To evaluate the capabilities of dual energy CT as a more precise and 
accurate tool for staging and monitoring of therapy response in patients with 
osseous metastases from castrate-resistant prostate cancer. 
Our working hypothesis is that, by providing quantitative material-specific 
information of tissue composition, dual energy CT may yield more accurate and 
precise quantitative information for the staging and monitoring of therapy response 
in patients with osseous metastases from castrate-resistant prostate cancer. State 
of the art dual-energy MDCT technology, which is available and routinely utilized 
at Duke University, relies on simultaneous acquisition of two CT datasets at 
different energy levels, without increasing patient radiation exposure. The dual 
energy datasets can be used to calculate conventional CT images, similar to a 
routine single energy CT acquisition, or they can be further processed to extract 
material-specific information. The latter datasets have proven to be beneficial in 
multiple clinical scenarios (2-4).  
Patients with osseous metastases from prostate cancer provide a common 
clinical and diagnostic challenge. Not uncommonly, subclinical metastatic lesions 
may only become detectable at imaging in response to therapy due to increased 
bone deposition during the first three months of post therapy. Commonly used 
imaging tests (such as CT or bone scan) are unable to reliably differentiate this 
phenomenon (also referred to as “flare”) from progressive metastatic osseous 
disease. This diagnostic challenge may have profound negative effects on patient 
management as it will require multiple additional imaging follow-up studies before 
an accurate assessment of tumor response can be formulated with appropriate 
management (Prostate Cancer Clinical Trials Working Group 3 [PCWG3]).  
We postulate that dual energy CT may provide additional critical information 
in this clinical scenario. Specifically, by providing material-specific quantitative 
information on iodine concentration within tissues, dual energy CT may be able to 
distinguish between iodine uptake within viable metastatic osseous disease and 
lack of thereof within treatment-related reactive sclerotic lesions. This 
differentiation may not be possible using conventional attenuation measurements 
with single-energy CT due to the challenging anatomical environment within the 

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vertebral body where sclerotic metastatic tissue coexists with the complex 
structural anatomy of the fine trabecular bone. 
 
 
 
Background & Significance:   
 
Prostate cancer (PCA) is the most frequently diagnosed cancer in North 
America. It is the fourth most common cause of cancer death overall and the third 
most common cause of cancer death in men. In this cancer, bone represents a 
preferential site of metastases, and patients with advanced disease have a very 
high incidence of bone metastases. Autopsy data from prostate cancer patients 
indicate an incidence of secondary bone lesions as high as 65–75%, preceded 
only by multiple myeloma. These bone metastases are typically osteosclerotic (i.e. 
with increased osteoblastic activity), and likely to produce a significant impact on 
patients’ functional status and quality of life, not only related to pain, but also to the 
relevant risk of skeletal-related events that can negatively impact physical well-
being and activities of daily living.  
Castrate-resistant PCA presents a spectrum of disease ranging from rising 
prostate-specific antigen (PSA) levels in the absence of metastases or symptoms 
and despite androgen-deprivation therapy, to metastases and significant 
debilitation from cancer symptoms. Castrate-resistant PCA is usually suspected in 
patients with new symptoms on androgen deprivation therapy, with a rising PSA, 
or with new evidence of disease on bone scans or CT scans. 
Novel hormonal agents such as abiraterone acetate and enzalutamide 
improved survival significantly for patients with metastatic castration-resistant 
prostate cancer. Nevertheless, median survival is limited to 35 months after 
initiation of therapy. Therefore, it is beneficial to have a more accurate diagnostic 
measure to assess time to progression, either for patients to receive optimal 
therapy regimes or for studies to have a more accurate time to progression 
measure (5, 6). For this reason, the PCWG3 defined criteria for progression of the 
disease. The most challenging task is the assessment of bone metastases in the 
early phase of therapy due to common onset of a flare phenomenon. The flare 
phenomenon refers to the increase in radiotracer uptake at previously diagnosed 
or new previously undetected lesions soon after initiating therapy. Increased 
uptake is transient, but variable, lasting between three and six months. It is thought 
that the increase is a response to bone deposition and repair at treated sites. This 
increase in signal makes the distinction between progression of bone lesions or 
increased metastatic spread and successful treatment considerably difficult. In CT 
scans these lesions would appear osteosclerotic and thus could not be 
distinguished between therapy response and progression. For this reason, the 
PCWG3 defined progression as “appearance of at least two new lesions on first 
post-treatment scan, with at least two additional lesions on the next scan (2+2 
rule). If at least two additional new lesions are seen on the next (confirmatory) 
scan, the date of progression is the date of the first post-treatment scan, when the 
first two new lesions were documented.” This implicates that progression needs to 
be dated back and diagnosis of progression is delayed by three months typically. 

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This highlights the critical need to precisely and accurately determine between 
flare and progressive disease after onset of therapy. 
State of the art dual-energy CT enables simultaneous acquisition of two CT 
datasets at different energy levels without exposing patients to additional radiation 
dose. These datasets can be used to reconstruct regular CT images of identical 
image quality compared to conventional single-energy CT or facilitate further 
processing of dual-energy material-specific density images. Preliminary evidence 
suggest that material density images may improve detection of lithic metastatic 
lesions, such as in patients with multiple myeloma (7).However, the diagnostic 
accuracy of material density analysis in patients with sclerotic osseous metastases 
(such as patients with PCA) remains to be investigated. This is a particularly 
challenging task due to bone mineral deposition within primarily osteosclerotic 
metastatic lesions, remodeling of bone due to therapy response, and the complex 
structural anatomy of the trabecular bone within the vertebral bodies. 
Our working hypothesis is that, by providing quantitative material-specific 
information of tissue composition, dual energy CT may yield more accurate and 
precise quantitative information for the staging and monitoring of therapy response 
in patients with osseous metastases from castrate-resistant prostate cancer. 
 
Purpose of this study 
 
Primary Objective: 
 
Demonstrate the feasibility of using dual energy CT to improve staging and 
monitoring of therapy response in patients with osseous metastases from castrate-
resistant prostate cancer, compared to regular single energy CT and technetium 
bone scans. 
 
Secondary Objectives: 
 
Analyze the feasibility to detect bone metastasis at baseline more 
accurately. 
Analyze iodine uptake of soft tissue metastasis more accurately and monitor 
its change during therapy. 
Correlate whether iodine quantification is a viable biomarker for early 
detection (small size) of lymph node metastases. 
 
Exploratory Objective: 
 
 
 
Determine whether dual energy CT is able to have prognostic capabilities 
in terms of therapy response and overall survival. 
 
 
 
Design & Procedures:   

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This is a prospective Health Insurance Portability and Accountability Act-
compliant study for which we are asking for authorization from the Institutional 
Review Board. 
 
Inclusion Criteria: 
1.  Oncology patients with castrate-resistant prostate cancer planned for 
therapy with abiraterone acetate or enzalutamide and prednisolone 
undergoing clinically indicated MDCT of the chest, abdomen and pelvis 
2. > 18 years old 
3. Serum creatinine < 2.0 
4. BMI < 35kg/m^2 
5.  Sign informed consent 
 
Exclusion Criteria: 
 History of anaphylactoid reaction to iodinated contrast material 
 
 
 
All MDCT examinations will be performed using a third-generation dual-
source dual-energy MDCT platform (Somatom Definition FORCE, Siemens 
Healthcare, Forchheim, Germany). Each patient will receive an unenhanced dual 
energy scan followed by a contrast-enhanced dual energy scan as part of clinical 
routine work up (Table 1). The preliminary unenhanced dual energy scan, which is 
currently not part of our routine clinical protocol, will provide necessary information 
for the baseline material density quantitative analysis of the bone marrow. For the 
contrast-enhanced scan, each patient will be scanned in a caudocranial direction 
during the hepatic venous phase 60-70 seconds after the start of contrast medium 
injection. No change in the contrast material injection protocol will be performed 
for this this study. 
Patients will be examined with a dual-energy protocol at baseline (i.e., 
before starting therapy), and during the first and second follow up scans in order 
to differentiate between patients with partial remission, stable, or progressive 
disease. 
 
Table 1. Details of the dual-energy CT scan protocols. 
 
 
kVp 
Pitch 
Effective 
mAs 
mAs 
/ 
rotation 
Relative 
CTDIvol  (%) 
Relative 
DLP (%)* 
1st scan 
Tubes 1 + 2 
120 
1 
200 
200 
100 
100 
 
Tube 1 
100 
1 
 
 
 
 
 
Tube 2 
150 
1 
 
 
 
 
2nd scan 
Tubes 1 + 2 
120 
1 
200 
200 
100 
100 
 
Tube 1 
100 
1 
 
 
 
 
 
Tube 2 
150 
1 
 
 
 
 
 
Images will be reconstructed following conventional protocols and will 
include 5.0 and 0.6 mm slice thickness using filtered back projection (FBP) and 
commercially available iterative reconstruction (advanced modeled iterative 
reconstruction algorithm [ADMIRE]).   

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In addition, we will collect relevant clinical and demographic patient’s 
information, such as prostate cancer related parameters, medical record number, 
age, gender, and body weight, height and body mass index. We will also collect 
information regarding the CT parameters, radiation dose and image quality. 
 
 
For part of this investigation we will use commercially available dual-energy 
CT postprocessing software (SyngoVia VB10, Siemens Helathcare, Forchheim, 
Germany). At the same time, we will also be working in collaboration with Siemens 
Healthcare as part of study Pro00078046. Selected and fully anonymized image 
datasets in dicom format or raw-projection format will be shared with Siemens 
scientists for the purpose of developing postprocessing software which will be used 
in the study. While existing dual-energy CT software can be used to separately 
analize the pre and postcontrast phases, we will work in collaborations with 
Siemens to elaborate strategies and potentially dedicated prototype software 
which will register the image datasets and perform advanced dual-energy CT 
postprocessing.   
 
 
All reconstructed CT datasets will be stored on a dedicated and password-
protected server in the Department of Radiology. The image reconstruction 
process will take place within the radiology department on a radiology owned and 
maintained workstation. 
 
Selection of Subjects:   
 
1. 
Subject Recruitment and Compensation: 
 
Consent Process:   
One hundred and fifty eligible participants will be contacted via mail by their 
attending oncologist (Dr. A. Armstrong) prior to their clinically indicated CT scan. 
The study coordinator will consent eligible participants according to the inclusion 
criteria provided in the Design & Procedure section. If necessary, the participants 
will have no less than 24 hours to consider their participation. Consenting will take 
place in a private room. The prospective participant may have family or a friend 
present during the consent process, if they wish.  At least an hour will be slotted 
for the consent process, but we will not prevent the subject from asking questions 
beyond that time. If the subject wishes to consider the study overnight or longer, 
an additional appointment will be made for the subject to continue the consent 
process. From the time of initial contact until the participant completes the study 
they will have complete freedom to access the coordinator by phone, email or in 
person. Each patient is given the possibility to refrain from the study after the 
baseline scan or the first follow up examination without any disadvantage 
regarding clinical treatment or imaging. 
 
There will be no financial compensation for participation to this study. 

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Subject’s Capacity to Give Legally Effective Consent:  
Subjects without capacity to give consent will not be recruited in this study. 
 
2. 
Study Interventions: 
The diagnostic scan will be preceded by a not clinically indicated non 
enhanced dual energy scan. The overall radiation dose to the patient for the first 
and second acquisition will be twice the radiation dose of a conventional CT of the 
chest, abdomen and pelvis.  
 
 
 
3. 
Risk/Benefit Assessment: 
 
The contrast-enhanced CT scan of the chest, abdomen and pelvis will be 
performed according to the clinical indication of castration-resistant prostate 
cancer, as determined by the referring oncologist. 
This initial diagnostic scan will be preceded by an unenhanced dual energy 
scan, which is currently not part of our routine clinical protocol. This preliminary 
scan will provide the necessary information for the baseline material density 
quantitative analysis of the bone marrow. A second acquisition following 
intravenous contrast medium administration will be performed thereafter. Our 
protocol will result in a twofold increase in overall radiation dose to the patient 
compared to a routine conventional CT of the chest, abdomen and pelvis. This 
protocol will be repeated at baseline, first and second follow up resulting in three 
Informing the patient of the study
No consent for 
CT
No CT
Consent for CT
Indicated CT
Consent for study with additional non-enhanced 
CT
Non-enhanced CT
Clinically indicated and enhanced CT after 
administration of 150ml contrast media
Repetition of non enhanced CT at:
Baseline
First follow up 
after 3 months
Second follow 
up after 6 
months

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additional CT scans in total and a cumulative additional radiation exposure of 
approximately 30mSv. This increase in radiation dose is not outside the standard 
of care as multiphasic MDCT examinations which include pre-, post-contrast 
imaging are routinely performed, even in young patients without cancer, for the 
work-up of indeterminate liver, renal, or adrenal lesions, as well as in patients with 
unexplained hematuria. Of note, many of these multiphasic CT protocols at our 
institution include dual-energy CT as the standard of care. Considering the 
demographic of PCA, we anticipate that most of our patients will consist of older 
age males with decreased life-expectancy. As such, the clinical implications of the 
marginal increase in radiation dose with our dual-energy CT protocol are favored 
to be negligible. Furthermore, some patients might even benefit from additional 
unenhanced CT scans because some secondary findings can be distinguished 
more precisely when additional unenhanced CT information is available. 
 
An additional identifiable risk to the subjects is the unlikely but not 
impossible loss of confidentiality. We have taken all the precaution to minimize this 
risk. Identifiable PHI will remain with their respective CT exam on a radiology 
department server and on PACS.  HIPAA trained Duke personnel will have access 
to these exams, and only HIPAA trained Duke personnel will be involved in the 
study. For each exam, a date, exam protocol type, patient name, and patient ID 
number will be recorded.  Files containing these ID numbers and the dates of the 
exams will be kept by one of the investigators on a password-protected computer. 
 
4. 
Costs to the Subject:  
There will be no cost to the patients entered in the study. 
 
5. 
Data Analysis & Statistical Considerations:   
 
All image data will be processed using either commercially available software 
(SyngoVia VB10) or software prototypes developed for dual-energy CT 
postprocessing. All study data will be analyzed at Duke University. However, to 
further develop software prototypes which will be needed for image registration 
and advanced dual-energy CT postprocessing, we will work in collaboration with 
Siemens scientists as part of project with duke id Pro00078046. This will require 
we share with Siemens sample datasets, which will include DICOM image series 
or raw-projection datasets. In all cases, we will only share fully anonymized data.  
 
To ensure consistency and reproducibility of the data, quantitative measurements 
of iodine uptake will be performed on a dedicated secondary workstation unit 
(Core2 x6800; Intel, Santa Clara, Ca) equipped with a previously validated custom 
Matlab-based software (Matlab, Ver. 2009a, Math-Works, Natick, Ma). Qualitative 
analysis of post-processed datasets will be performed on an offline workstation 
equipped with Osirix (Pixmeo SARL, Bernex, Switzerland). Statistical analysis will 
be performed in collaboration with the department of biomedical statistics. Multi-
parametric regression analysis will identify whether dual energy based, calcium 
corrected iodine maps a valuable biomarker for monitoring and staging of 

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metastatic bone disease in prostate cancer. For the specific objectives of this study 
we intend to perform the following analyses. 
To demonstrate the feasibility to monitor metastatic bone disease in 
castration resistant prostate cancer more accurately than regular single energy 
CT, single phase dual energy CT and technetium bone scans a quantitative 
analysis of iodine uptake will be performed. ROC statistics will be calculated to find 
optimal threshold of this biomarker. Qualitative analysis will be done by multiple 
readers in blinded fashion to determine sensitivity and specificity for distinction 
between disease progression at first follow-up three month after initiation of 
therapy. Findings will be correlated with technetium based bone scans. 
To analyze the feasibility to detect bone metastasis at baseline more 
accurately, unenhanced bone marrow imaging will be calculated and additional 
dual energy based, calcium corrected iodine maps will be used to determine a 
threshold for detection of vital bone metastasis in order to calculate color coded 
bone maps for risk of presence of bone metastases. Qualitative analysis will be 
done by multiple readers in blinded fashion to determine sensitivity and specificity. 
To analyze iodine uptake of soft tissue metastasis more accurately and 
monitor its change during therapy, a ROI based analysis will be performed for 
suspect metastatic lesions at three time points to see effects of therapy and to 
distinguish between partial remission, stable disease and progressive disease. A 
blinded multi reader assessment of iodine maps will be performed to calculate 
sensitivity and specificity for qualitative analysis of dual energy based examination 
compared to single-energy CT.  
As an exploratory objective we want to determine whether dual energy CT 
has prognostic capabilities when assessing bone marrow metastases and soft 
tissue metastasis in terms of therapy response and overall survival. This 
exploratory objective will require long term follow up and access to patient data 
exceeding the time period of the baseline and first two follow up CT examinations. 
Caplan Mayer curves will be drawn and correlated with findings of bone marrow 
analysis. 
 Another exploratory objective is to correlate whether adjusted iodine 
quantification is a viable biomarker for early detection of lymph node metastases, 
which are too small to fulfill RECIST criteria of a metastasis at baseline but will 
become evident on follow up. A ROI analysis will be performed to assess whether 
adjusted iodine uptake might be a viable biomarker for early detection of lymph 
node metastases. 
 
 

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6. 
Data & Safety Monitoring:  
Each CT dataset included in our study will have patient data associated with 
it on PACS and on the radiology department server.  From each dataset, the 
necessary image reconstructions will be made either on a workstation within the 
radiology department by a Duke radiologist. Qualitative scoring of the 
reconstructed images will take place in the radiology department by Duke 
radiologists.  For each exam, a date, exam protocol type, patient name, and patient 
ID number will be recorded.  PHI will be kept on a password-protected computer 
and will be deleted from the data after publication, thus leaving no link to 
identifiable PHI.  
 
7. 
Privacy, Data Storage & Confidentiality:  
Every effort will be made to ensure subjects’ confidentiality. All images 
containing subject PHI will remain on PACS and on the radiology department 
server.  PHI recorded with data will be kept in a file on a password-protected 
computer. Any images used in publications or presentations will have all PHI 
removed.  No identifiable PHI will be released outside of DUHS. There will be 
signed informed consents that will have some PHI on them that will need to be 
kept for at least six years along with the Regulatory Binder with an enrollment log 
in it. 
 
References: 
 
 
1. 
Uhrig M, Simons D, Kachelriess M, et al. Advanced abdominal imaging with dual energy CT is 
feasible without increasing radiation dose. Cancer Imaging. 2016;16(1):15. 
2. 
Agrawal MD, Pinho DF, Kulkarni NM, et al. Oncologic applications of dual-energy CT in the 
abdomen. Radiographics. 2014;34(3):589-612. 
3. 
Walsh SL, Nair A, Hansell DM. Post-processing applications in thoracic computed tomography. 
Clin Radiol. 2013;68(5):433-48. 
4. 
Lestra T, Mule S, Millet I, et al. Applications of dual energy computed tomography in abdominal 
imaging. Diagn Interv Imaging. 2016;97(6):593-603. 
5. 
Evangelista L, Bertoldo F, Boccardo F, et al. Diagnostic imaging to detect and evaluate response to 
therapy in bone metastases from prostate cancer: current modalities and new horizons. Eur J Nucl 
Med Mol Imaging. 2016;43(8):1546-62. 
6. 
Azad GK, Taylor B, Rubello D, et al. Molecular and Functional Imaging of Bone Metastases in 
Breast and Prostate Cancers: An Overview. Clin Nucl Med. 2016;41(1):e44-50. 
7. 
Thomas C, Schabel C, Krauss B, et al. Dual-energy CT: virtual calcium subtraction for assessment 
of bone marrow involvement of the spine in multiple myeloma. AJR Am J Roentgenol. 
2015;204(3):W324-31.