Evaluation of Bone Metastases With Dual Energy Computed Tomography (CT)
Conditions: Malignant Neoplasm, Metastatic Malignant Neoplasm to the Bone
Sponsor: Case Comprehensive Cancer Center

 
 
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CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:  CASE 5Y14 
 
 
STUDY TITLE:   Evaluation of Bone Metastases with Dual Energy CT 
 
PRINCIPAL INVESTIGATORS: 
 
 
 
 
Naveen Subhas MD 
 
Imaging Institute 
Cleveland Clinic 
 
 
 
9500 Euclid Avenue A21  
 
 
 
Cleveland, OH   44195 
 
 
 
 
(216) 445-9464 
 
 
CO- INVESTIGATORS: 
 
 
Namita Gandhi MD 
 
Imaging Institute 
 
Cleveland Clinic 
 
 
 
 
9500 Euclid Avenue L10  
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
(216) 444-3682 
 
 
Shyam Srinivas MD PhD 
 
Imaging Institute 
 
Cleveland Clinic 
 
 
 
 
9500 Euclid Avenue JB3  
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
(216) 444-2665 
 
 
 
Nancy Obuchowski PhD 
 
Quantitative Health Sciences 
 
Cleveland Clinic 
 
 
 
 
9500 Euclid Avenue JJN3-01 
 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
(216) 444-2665 
 
 
Joshua Polster MD 
 
Imaging Institute 
 
Cleveland Clinic 
 
 
 
 
9500 Euclid Avenue A21  
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
(216) 445-2548 

 
 
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G Thomas Budd MD 
 
Solid Tumor Oncology 
 
Cleveland Clinic 
 
9500 Euclid Ave R35 
 
Cleveland, OH 44195 
 
(216) 444-5782 
 
 
  
 
 
STATISTICIAN: 
Nancy Obuchowski, PhD 
 
(216) 445-9549 
 
 
SPONSOR: 
N/A 
 
 
CLINICAL FACILITY: 
Cleveland Clinic  
 
 
 
 
 
 
 
APPROVALS: 
Protocol Review and Monitoring Committee: Pending 
 
 
Cleveland Clinic IRB: Pending 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
Imaging Institute 
 
Cleveland Clinic 
 
 
 
DEPARTMENT HEAD:  
Manuel Cerqueira MD 
 
 
 
Imaging Institute 
 
Cleveland Clinic 
 
 
 
 
9500 Euclid Avenue JB3  
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
(216) 444-2665 

 
 
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Abstract 
 
Computed tomography (CT) scans are routinely used in the evaluation of oncologic 
patients for initial diagnosis and subsequent disease staging.  Detection of bone 
metastasis on standard CT, however, is limited in sensitivity, particularly in case of 
osteolytic intramedullary lesions [1].  Recent studies have shown the ability to detect 
bone marrow edema using CT with the use of a virtual non-calcium (VNC) dual energy 
CT (DECT) technique[2, 3]. Because bone marrow edema is similar in composition to 
intramedullary bone metastases (i.e. both are of soft tissue composition as opposed to 
calcium or fat), VNC DECT may also be helpful in the detection of bone marrow 
metastasis. Cancer patients obtaining a Positron Emission Tomography (PET) CT and a 
separate diagnostic CT scan as part of their routine clinical care will be enrolled into the 
study.   The diagnostic CT scan will be performed on a DECT scanner and the images 
will be reconstructed as SECT images for routine clinical interpretation as well as VNC 
DECT images.  The SECT images alone will be evaluated and scored, and then the VNC 
DECT images will be added to the SECT images for a second evaluation (consecutive 
reading session).  Multiple readers blinded to the PET-CT findings for detection of bony 
metastatic disease will participate. 
  
Primary Aims 
 
1) Compare the accuracy of SECT with VNC DECT to standard SECT alone in the 
detection of metastatic bone lesions using PET-CT as the reference standard. 
 
Hypothesis 
 
The addition of VNC DECT to SECT will be more accurate in the detection of metastatic 
bone marrow lesions compared to SECT alone. 
 
Introduction 
 
Significance and Rationale 
 
Bone is the most common site of metastatic disease.[4]  Nearly 300,000 US adults are 
estimated to be living with metastatic bone disease.[5]  Nearly two thirds of bone 
metastases occur in patients with breast, prostate, and lung cancer.[5]  Bone metastases 
can present as predominantly sclerotic, lytic or mixed sclerotic and lytic lesions.   
 
CT is the primary imaging modality utilized for the detection and staging of metastatic 
cancer because of its ability to evaluate a wide range of tissues in a short time and 
availability in many locations.   The sensitivity of CT in detection of bone metastases is, 
however, limited with a recent meta-analysis reporting a pooled sensitivity of 73% 
compared to PET (pooled sensitivity 90%) and MRI (pooled sensitivity 90%)[1].   
Detection of osteolytic lesions that are intra-medullary without cortical or soft tissue 
involvement is especially challenging on CT. These lesions most frequently occur in 

 
 
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patients with breast and lung cancer as well as patients with multiple myeloma and 
lymphoma.  The primary difficulty of identifying intramedullary bone marrow lesions 
with conventional CT is the ability to visually discriminate the lesion which is of soft 
tissue composition through the trabecular bone which is composed of calcium.  DECT 
with the use of a virtual non-calcium technique provides the ability to remove calcium 
and thereby the trabecular bone from the image and at least theoretically improve 
visualization of the underlying marrow elements composed of soft tissue and fat.   
 
 
Although DECT has been available for several decades, it has not been widely used in 
clinical practice because of technical limitations and radiation dose concerns.[6] Recent 
second generation of DECT scanners from several vendors now have addressed many of 
the prior limitations allowing DECT scans to be performed with dose and image quality 
comparable to SECT scans.[7-9]  Schenzle et al. showed that there is no significant 
difference in image noise for chest CT using DECT compared to SECT when performed 
with the same dose and the contrast to noise ratio can be doubled with optimized DECT 
protocols.[7]  They concluded that CT can be routinely performed in dual energy mode 
without additional dose or compromises in image quality.  Similarly, Purysko et al. 
showed that by adjusting the tube current (mA) at the scanner console to match the 
radiation output (CTDIvol) from a single energy CT (SECT), DECT of the abdomen can 
be performed without radiation dose penalty to patients. Using this technique in a cohort 
of patients undergoing single energy (SECT) and dual energy CT (DECT) in different 
occasions, DECT exams achieved similar image quality with similar or lower radiation 
dose compared to SECT. [10] The advantage of DECT is ability to separate tissues by 
material composition rather than simply by attenuation as in SECT.  This is possible 
because change in attenuation of different materials between the two energies is related to 
the individual properties of the material (primarily its atomic number).  As a general rule 
of thumb, as the difference in atomic numbers between the materials increases, the ability 
to separate the materials improves.  DECT using this technique is currently being used in 
routine clinical practice in a number of applications such as multiphasic vascular, liver 
and kidney studies.[11, 12]  For intramedullary bone, this same technique is modified to 
separate or “decompose” each voxel into fat, soft tissue (hematopoietic marrow), and 
calcium (trabecular bone).   After the voxel is decomposed into those 3 materials, the 
calcium can be subtracted from the voxel creating a “virtual non-calcium” (VNC) image 
and removing the trabecular bone from the medullary space.[2]  
 
 
Relevant literatures 
 
There have been no studies to date showing the benefit of VNC DECT for the evaluation 
of bone metastases.  Recent studies have, however, demonstrated the ability to visualize 
bone marrow edema with CT by using a VNC post processing technique of a DECT scan 
without increased radiation dose.[2, 3, 13]  Pache et al. showed that VNC DECT can be 
used to identify bone marrow edema in the knee in a study of 21 patients with acute knee 
trauma.[2]  The same group also showed that the detectability of the bone marrow edema 
is no different when using a dose equivalent to SECT and concluded that DECT can 

 
 
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provide additional information compared to SECT without additional radiation dose.[3]  
More recently, Bierry et al. showed that bone marrow edema in vertebral compression 
fractures can be accurately detected using VNC DECT.[13] Our hypothesis is that the 
same principle which allows visualization of bone marrow edema should also allow 
visualization of bone marrow metastases using a VNC technique with subtraction of 
trabecular bone.  Preliminary work performed by one of the investigators (JP) has 
demonstrated the ability to identify bone marrow metastasis using a trabecular bone 
subtraction algorithm with SECT. 
 
Methods 
 
Data Collection 
 
A subset of cancer patients being imaged with PET/CT for diagnosis and/or staging of 
disease at our institution also undergo a diagnostic CT scan as part of the clinical workup 
at the same time or within a short period of time.  This subset of patients will be divided 
into 2 cohorts: patients with bone metastases on PET/CT and patients without bone 
metastases on PET/CT.  30 patients with bone metastases and 15 patients without bone 
metastases will be enrolled into the study.  To be included in the study, the time between 
the diagnostic CT and PET/CT will be no more than 30 days with no intervening 
treatment to ensure that any differences found between the exams are related to imaging 
technique and not a change in disease.  Minors (age < 18 years) will be excluded from the 
study.  In order to maximize recruitment and generalizability of study results, all cancer 
types and both newly diagnosed and previously treated patients will be included.  
However, the vast majority of the patients that are imaged with PETCT and diagnostic 
CT are lymphoma patients. 
 
All study patients will undergo a dose-matched DECT (140 kVp and 100 kVp) scan 
instead of a standard 120 kVp SECT for their diagnostic CT All scans will be performed 
on a single second-generation DECT scanner (Somatom Definition Flash, Siemens, 
Forchheim, Germany).  A dual energy CT protocol using 140 kVp with Sn filter for the 
high energy beam (tube B) and 100 kVp for the low energy beam (tube A) will be 
performed with ~1.3 (tube A/tube B) ratio of tube currents. Multiplanar reformations will 
be done in 1mm – 3mm thick slices using a soft reconstruction kernel.    To ensure that 
the radiation dose of the DECT will be no higher than the standard SECT protocols 
(Appendix 1), the CT dose index (CTDIvol) which measures the radiation output of the 
CT tube will be calculated for the SECT scan in each patient and the DECT tube currents 
will be adjusted to match this CTDvol.  CT scans will be performed as routine diagnostic 
scans with administration of intravenous contrast and with or without oral contrast 
depending on the clinical indication.  Established institutional guidelines will be followed 
for the administration of intravenous and oral contrast. (Appendix 2 and Appendix 3)    . 
Linearly mixed images from the DECT will serve as the SECT equivalent images for 
clinical interpretation.  These images are generated by combining the data from both 
energies (in other words, all the radiation dose will be used to generate these images).  
Post processed VNC DECT images will also be generated.  8 readers will evaluate the 
anonymized images in a single reading session.  The SECT equivalent images will first 

 
 
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be interpreted alone; then the SECT equivalent images along with the VNC DECT 
images will be interpreted. The order of cases will be randomized and different for each 
reader.  All of the following bony structures when visible will be evaluated: scapula, 
clavicle, thoracic vertebra, lumbar vertebra, ribs, sacrum, right and left pelvis (ilium, 
ischium and pubic bones) and right and left proximal femurs for the presence of 
metastatic lesions.  For each location, the readers will mark the presence or absence of 
lesions, the number of lesions and their confidence in the presence of one or more lesions 
in that particular anatomic location.  Confidence will be scored on a 0-100 scale allowing 
a direct correspondence to the degree of confidence from 0% to 100% for the presence of 
a lesion.  The default score will be zero, i.e. no confidence in the presence of a lesion at a 
particular location.  PETCT images will be evaluated by two readers in consensus to 
determine the presence of metastatic bone lesions in each anatomic location.  The 
evaluating criteria will be the same as in routine clinical practice (i.e. all lesions must 
have visibly increased FDG uptake compared to the surrounding background 
(SUVlesion/SUVbackground ≥ 20%)). 
 
Data Analysis 
Each patient will be evaluated and scored at approximately 46 separate locations (12 
pairs of ribs, 12 thoracic vertebra, 5 lumbar vertebra, sacrum, right and left hemipelvis, 
and right and left scapula). For each location, the readers will mark the presence or 
absence of lesions, the number of lesions and their confidence in the presence of one or 
more lesions in that particular anatomic location (using a 0-100 point confidence scale). 
Each location will be correlated with PETCT which will serve as the reference standard.  
Previous studies have shown PET to be the most accurate imaging technique to detect 
bone metastases and superior to nuclear medicine bone scintigraphy.[1]  PET is still an 
imperfect gold standard.  Unfortunately, only histopathology of each lesion would serve 
as a better gold standard which would not be feasible or ethical. Accuracy will be 
measured using nonparametric estimates of the area under the receiver operating 
characteristic (ROC) curve using methods for clustered data (i.e. multiple locations per 
patient) [14].  ROC area estimates will be constructed for each reader for both SECT 
alone and DECT as an adjunct to SECT.  For each reader, the ROC areas of SECT and 
DECT plus SECT will be compared using a Wald test [14]; a significance level of 0.05 
will be used. 
 
ANOVA methods for multiple-reader ROC studies will be used to test the null hypothesis 
that the readers’ mean ROC area with DECT as an adjunct to SECT is the same as the 
readers’ mean ROC area with SECT alone [15].  A significance level of 0.05 will be 
used.  A 95% confidence interval for the difference in ROC areas will be constructed. 
Sample Size Considerations 
Methods for determining sample size for multi-reader CAD studies was used [16]. The 
following assumptions were made for sample size calculation: 
1. Based on previous work by Yang et al [1], we expect readers to have a high ROC 
area with SECT.  Thus, we used an estimate of 0.90 as the ROC area with SECT. 
2. We expect that DECT will increase readers’ sensitivity by 0.10 or more, with 
little to no effect on specificity.  Thus, we assumed that the ROC area with DECT 
will be 0.05 greater than with SECT alone. 

 
 
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Patients with metastatic disease will have, on average, 2 lesions [1],  
 
 
The formula for determining sample size for MRMC studies [17] is: 
 
 
Power = 1 – F(fc; 1, df1,                                                          [1] 
 
where F(fc; 1, df1, ) is the distribution function of the test statistic F under the alternative 
hypothesis and fc = F-1(1-; 1, df1), where df1 is (J-1) and  
 
 = [J ((QT-HH)+0.05)2] / [2{b2(1-rb) + 2[(1-r1)+(J-1)(r2-r3)]}]  
         
is the noncentrality parameter of the noncentral F distribution, J is the total number of 
readers in the study, b2 is the variability between readers, rb is the correlation between 
accuracies when the same readers evaluate subjects using different tests, 2 is the 
variability due to different subject samples, r1 is the correlation between accuracies when 
the same subjects are evaluated by the same reader using different tests, r2 is the 
correlation between accuracies when the same subjects are evaluated by different readers 
using the same tests, and r3 is the correlation between accuracies when the same subjects 
are evaluated by different readers using different tests.  We used estimates of b2, rb, r1, 
r2, and r3 from prior studies [16].  Note that 2 is a function of the effective sample size, 
which we estimate as: # patients x 46 locations / design effect, where the design effect is 
1+(s-1)r [16], where s=46 locations and r is the correlation between locations which we 
assume to be 0.5 for locations with mets and 0.2 for locations without mets [16].   
From equation 1, we estimate that a study with 8 readers and 30 patients with 
bone metastases and 15 patients without metastatic disease will provide 84% power to 
detect a difference in ROC area of 0.05 or larger.   
   
 
 
Informed Consent 
A waiver of informed consent is being requested as participation in this study involves no 
more than minimal risk to the patient.  DECT is FDA approved and used in routine 
clinical practice at many centers including the Cleveland Clinic for other purposes such 
as vascular imaging.  Patients participating in this study will not receive additional CT 
scans or radiation.  Dose and image quality of the scans will be equivalent to standard 
SECT scans.  All the imaging studies that will be evaluated as part of this protocol will be 
obtained as a part of the routine clinical care of the patient.  Eligible patients will be 
provided an information sheet (Appendix 4) explaining the study prior to their CT scans 
and participation in the study will be voluntary.  Since all patients will undergo PETCT 
which will serve as the truth for the presence or absence of bone marrow metastasis, 
DECT will never by definition reveal lesions not detected by PETCT and any advantage 
of DECT over SECT in the detection of bone metastases will not directly benefit patients 
in the study.  
 
To increase recruitment of patients with bone metastases, we would like to add an 
additional procedure as an amendment to the protocol.  Patients of study co-investigators 
or licensed independent practitioners working with the co-investigators, with known bone 

 
 
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metastases who will be getting a routine clinical CT scan, will be asked to participate in 
the study by the ordering clinician.  Patients will be provided with the patient information 
sheet (Appendix 4).  If they volunteer to participate in the study, the clinical CT scan will 
be performed using a dual energy technique as stated in the protocol.   In these patients, 
follow-up CT scans performed as part of routine clinical care will be used to confirm the 
presence or absence of any additional lesions detected using the dual energy CT 
technique.  As before, enrolled patients will not receive any additional CT scans or any 
additional radiation exposure by participating in this study. 
 
Confidentiality Assurances 
Images will be anonymized and all patient identifiers will be removed. A subset of the 
deidentified images will be sent to Siemens Healthcare in Germany for dual energy 
reconstruction (please see HIPAA deidentification application, Appendix 5).  The images 
will be sent either electronically using secure file exchange server and/or physically on 
DVD. The reconstructed images will be sent back to CCF for analysis.   All patient 
information will be kept in a spreadsheet on a password-protected folder on the CCF 
network. Only authorized study staff will have access to this spreadsheet. 
 
REFERENCES 
 
1. 
Yang, H.L., et al., Diagnosis of bone metastases: a meta-analysis comparing 
(1)(8)FDG PET, CT, MRI and bone scintigraphy. Eur Radiol. 21(12): p. 2604-17. 
2. 
Pache, G., et al., Dual-energy CT virtual noncalcium technique: detecting 
posttraumatic bone marrow lesions--feasibility study. Radiology. 256(2): p. 617-
24. 
3. 
Pache, G., et al., Dose reduction does not affect detection of bone marrow lesions 
with dual-energy CT virtual noncalcium technique. Acad Radiol. 19(12): p. 1539-
45. 
4. 
Roodman, G.D., Mechanisms of bone metastasis. N Engl J Med, 2004. 350(16): p. 
1655-64. 
5. 
Li, S., et al., Estimated number of prevalent cases of metastatic bone disease in 
the US adult population. Clin Epidemiol, 2012. 4: p. 87-93. 
6. 
Henzler, T., et al., Dual-energy CT: radiation dose aspects. AJR Am J 
Roentgenol, 2012. 199(5 Suppl): p. S16-25. 
7. 
Schenzle, J.C., et al., Dual energy CT of the chest: how about the dose? Invest 
Radiol, 2010. 45(6): p. 347-53. 
8. 
Toepker, M., et al., Virtual non-contrast in second-generation, dual-energy 
computed tomography: reliability of attenuation values. Eur J Radiol, 2012. 
81(3): p. e398-405. 
9. 
Kaufmann, S., et al., Tin-filter enhanced dual-energy-CT: image quality and 
accuracy of CT numbers in virtual noncontrast imaging. Acad Radiol, 2013. 
20(5): p. 596-603. 
10. 
Purysko A, B.M., Herts BR, Primak AE, Obuchowski NA, Remer EM, Binu J, 
Aucejo F, Comparison of Dose from Single Energy and Dual Energy Multi-
detector Computed Tomography Examinations in the Same Patient Screened for 
Hepatocellular Carcinoma. Abstract Radiologic Society North America, 2013. 

 
 
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11. 
Heye, T., et al., Dual-energy CT applications in the abdomen. AJR Am J 
Roentgenol, 2012. 199(5 Suppl): p. S64-70. 
12. 
Flors, L., et al., Endoleak detection after endovascular repair of thoracic aortic 
aneurysm using dual-source dual-energy CT: suitable scanning protocols and 
potential radiation dose reduction. AJR Am J Roentgenol, 2013. 200(2): p. 451-
60. 
13. 
Bierry, G., et al., Dual-energy CT in vertebral compression fractures: 
performance of visual and quantitative analysis for bone marrow edema 
demonstration with comparison to MRI. Skeletal Radiol, 2014. 
14. 
Obuchowski NA.  Nonparametric Analysis of Clustered ROC Curve Data.  
Biometrics, 1997; 53:170-180. 
15. 
Obuchowski NA and Rockette HE.  Hypothesis Testing of the Diagnostic 
Accuracy for Multiple Diagnostic Tests:  An ANOVA Approach with Dependent 
Observations.  Communications in Statistics:  Simulation and Computation, 1995; 
24:285-308. 
16. 
Obuchowski N, Hillis S.  Sample size tables for computer-aided detection 
studies.   American Journal of Roentgenology 2011; 197: 821-8.  
  
17. Zhou XH, Obuchowski NA, McClish D. Statistical Methods in Diagnostic Medicine. 
Wiley and Sons, 2nd edition, 2011.   
 
 
 

 
 
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APPENDIX 1 
 
 
 

 
 
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APPENDIX 2 
 
 

 
 
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APPENDIX 3 
 

 
 
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APPENDIX 4 
RESEARCH STUDY EXPLANATION FOR PATIENTS 
Evaluation of bone metastasis with dual energy CT 
 
The Cleveland Clinic Imaging Institute is conducting a research study to determine if a 
dual energy CT can find cancer in bones better than a single energy CT.   You are being 
asked to participate in this research because your physician has ordered a diagnostic CT.  
Currently both dual and single energy CTs are used to obtain diagnostic CTs.  If you 
agree to participate in this research, you will undergo your diagnostic CT using the dual 
energy CT.  Dual energy CT uses two x-ray beams at different strengths to create the 
images instead of using a single x-ray beam as is done in single energy CT.   
 
Participation in the research will not result in additional scans or radiation to you.  The 
scanner will look the same and feel the same as a standard CT (see picture below).  The 
scan will take the same time as a single energy CT scan.  The clinical findings from the 
dual energy CT will be reported to your physician and recorded in your medical record.  
Your care will not change as a result of participating in this study.   
 
For research purposes, the dual energy CT will also create an additional set of images that 
will be used for further analysis.  This analysis will have no impact on your clinical care. 
Your scan and medical information will be kept in a confidential manner by the research 
team.  You will experience no direct benefit but knowledge gained from the study will 
increase our understanding and may benefit future patients. 
 
Your participation is voluntary and your decision will not impact your CT appointment or 
current clinical care.  If you have questions about the research, please tell the radiation 
technologist and they will have a member of the research team meet with you. 
 
Please indicate your decision of whether to participate or not participate in the research to 
the radiation technologist.  
 
Naveen Subhas MD 
Principal Investigator 
 
 
 
 
 
 

 
 
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APPENDIX 5