Clinical trial NCT02424955
Conditions: Liver Cancer Liver Tumor Hepatocellular Carcinoma Liver Carcinoma
Keywords: Liver cancer Hepatocellular Carcinoma Liver imaging Stereotactic Ablative Radiotherapy SABR
Sponsor: Stanford University
Start date: 2014-11-18; Completion date: 2022-06-30
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to prospectively analyze the value of 3D ultrasound perfusion imaging for treatment planning, the prediction of therapy success, and to monitor the treatment response in patients with a primary or metastatic liver tumor undergoing radiation treatment.

Detailed description:
Primary Objective:

The primary objectives of this prospective pilot study is to:

1. determine the feasibility and reproducibility of 3D contrast enhanced ultrasound imaging in liver cancer patients undergoing Stereotactic Ablative Radiotherapy and
2. evaluate whether there are treatment induced early changes in imaging metrics derived from 3D contrast enhanced ultrasound. This study will provide valuable insight as to the potential of baseline and/or early post-treatment 3D ultrasound perfusion characteristics (measurements of blood-flow) of primary and metastatic liver tumors to predict tumor response to Stereotactic Ablative Radiotherapy. The investigators' underlying goal is to assess whether early perfusion changes at 1-7 days after SABR initiation can be used as a non-invasive early biomarker for treatment response assessment.

Secondary Objectives:

Evaluate the feasibility of contrast-enhanced ultrasound-to-CT fusion by assisting three-dimensional (3D) perfusion ultrasound (US) imaging with optical and electromagnetic tracking of the ultrasound probe on patients with liver cancer that will undergo CT for treatment planning and/or response evaluation.

Arms: arm 1: undergo 3D ultrasound perfusion imaging with perflutren
Interventions: intervention 1: perflutren lipid microspheres intervention 2: 3D ultrasound
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_001.pdf: 
Feasibility of 3D Perfusion Ultrasound for Liver Cancer SABR Planning and 
Response Evaluation 
Study Protocol and Statistical Analysis Plan 
NCT02424955 
August 29, 2019 


 
 
 
 
 
 
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Feasibility of 3D perfusion ultrasound for liver 
cancer SABR planning and response evaluation 
 
eProtocol # IRB-30071 | OnCore # HEP-0048 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
 
Protocol Director  
Daniel T. Chang, MD 
875 Blake Wilbur Drive 
Stanford, CA 94305 
  
Tel: 
 
 
 
Co-Investigator 
Dimitre Hristov, PhD 
Assistant Professor of Radiology 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
Tel:  
 
Fax: 
 
dimitre.hristov@stanford.edu 
 
 
Co-Investigator 
Aya Kamaya, MD 
300 Pasteur Drive 
 
Stanford, CA 94305 
Tel: 
 
  
 
 
Biostatistician 
  
Radiation Oncology 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
                    
 
               
  
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator 
 
Clinical Research Coordinator 
2589 Samaritan Drive 
San Jose, CA 95124 
 
 
 
Study Coordinator 
 
Clinical Research Coordinator 
800 Welch Road, 
 
Palo Alto, CA 94304 
 
                                
 
 
Instructor, Radiology 
Ahmed El Kaffas, PhD 
300 Pasteur Dr 
Stanford, CA 94305 
elkaffas@stanford.edu  
 
Postdoctoral Fellow 
Huaijun Wang, PhD 
Radiology 
300 Pasteur Drive 
Stanford, CA 94305 
  
 
Postdoctoral Fellow 
Amir Pirmoazen, MD 
Radiology 
300 Pasteur Drive 
Stanford, CA 94305 
  
 
Visiting Instructor 
Isabelle Durot, MD 
300 Pasteur Dr 
Stanford, CA 94305 
  
 


 
TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ........................................................................................................................ 4 
SCHEMA .................................................................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 6 
1 
OBJECTIVES .................................................................................................................................. 7 
1.1 
PRIMARY OBJECTIVE .................................................................................................................... 7 
1.2 
SECONDARY OBJECTIVES ............................................................................................................. 7 
2 
BACKGROUND ................................................................................................................................. 7 
2.1 
STUDY DISEASE ........................................................................................................................... 7 
2.2 
STUDY AGENT/DEVICE/PROCEDURE ............................................................................................ 7 
2.3 
RATIONALE .................................................................................................................................. 8 
2.4 
STUDY DESIGN ............................................................................................................................. 9 
2.5 
CORRELATIVE STUDIES BACKGROUND ...................................................................................... 10 
3 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ............................................. 10 
3.1 
INCLUSION CRITERIA .................................................................................................................. 10 
3.2 
EXCLUSION CRITERIA ................................................................................................................ 11 
3.3 
INFORMED CONSENT PROCESS ................................................................................................... 11 
3.4 
RANDOMIZATION PROCEDURES .................................................................................................. 11 
4 
TREATMENT PLAN ....................................................................................................................... 12 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................... 13 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................................... 13 
5 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ..................................... 13 
5.1 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ........................................................................ 13 
5.2 
AVAILABILITY ............................................................................................................................ 15 
5.3 
AGENT ORDERING ...................................................................................................................... 15 
5.4 
AGENT ACCOUNTABILITY .......................................................................................................... 15 
6 
DOSE MODIFICATIONS ................................................................................................................ 15 
7 
ADVERSE EVENTS AND REPORTING PROCEDURES ............................................................... 15 
7.1 
POTENTIAL ADVERSE EVENTS .................................................................................................... 15 
7.2 
ADVERSE EVENT REPORTING ..................................................................................................... 16 
8 
CORRELATIVE/SPECIAL STUDIES ....................................................................................... 19 
8.1 
LABORATORY CORRELATIVE STUDIES ....................................................................................... 19 
9 
STUDY CALENDAR .................................................................................................................... 20 
10 
MEASUREMENTS ....................................................................................................................... 21 
10.1 
PRIMARY AND SECONDARY OUTCOME MEASURES ................................................................. 21 
10.2 
SECONDARY OUTCOME .......................................................................................................... 22 
11 
REGULATORY CONSIDERATIONS ........................................................................................... 22 
11.1 
DATA AND SAFETY MONITORING PLAN ................................................................................. 22 
11.2 
DATA MANAGEMENT PLAN .................................................................................................... 22 


 
 
 
 
 
 
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12 
STATISTICAL CONSIDERATIONS ............................................................................................ 22 
12.1 
STATISTICAL DESIGN .............................................................................................................. 22 
12.2 
OUTCOME MEASUREMENTS: .................................................................................................. 23 
12.3 
ANALYSIS PLAN: ..................................................................................................................... 23 
12.4 
SAMPLE SIZE .......................................................................................................................... 24 
12.5 
SAMPLE SIZE JUSTIFICATION ................................................................................................... 24 
13 REFERENCES ............................................................................................................................... 24 
14 APPENDICES ................................................................................................................................ 26 
14.1 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST .......................................................... 26 
15 SUPPORTING DOCUMENTATION* ....................................................................................... 27 
14.2 APPENDIX B .................................................................................................................................. 28 
14.3 APPENDIX C .................................................................................................................................. 29 
 
 
 


 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
 
TITLE 
Feasibility of 3D perfusion ultrasound 
for liver cancer SABR planning and 
response evaluation 
STUDY PHASE 
Pilot 
INDICATION 
Evaluation of primary and/or metastatic 
liver tumor perfusion characteristics 
before and after Stereotactic Ablative 
Radiotherapy (SABR). 
INVESTIGATIONAL AGENTS 
Definity® Contrast Agent (perflutren lipid 
microspheres) for Ultrasound of the Liver. 
PRIMARY OBJECTIVE(S) 
The primary objectives of this pilot study 
is to (1) determine the feasibility and 
reproducibility of 3D contrast enhanced 
ultrasound imaging in liver patients 
undergoing Stereotactic Ablative 
Radiotherapy and (2) evaluate whether 
there are treatment induced early 
changes in imaging metrics derived from 
3D contrast enhanced ultrasound. This 
study will provide valuable insight as to 
the potential of baseline and/or early 
post-treatment 3D ultrasound perfusion 
characteristics (measurements of blood-
flow) of primary and metastatic liver 
tumors to predict tumor response to 
treatment.  
TREATMENT SUMMARY 
The study does not modify existing 
standard of care treatment. It only adds 
baseline and early contrast-enhanced 
ultrasound imaging with the DEFINITY® 
ultrasound contrast agent. DEFINITY® 
Vial (Perflutren Lipid Microsphere) for 
Injectable Suspension is Lantheus Medical 
Imaging Inc.’s non-blood based 
ultrasound contrast agent approved by 
the United States Food and Drug 
Administration (FDA). DEFINITY® is the 
first approved ultrasound contrast agent 
in the U.S. that offers flexible dosing and 
administration through IV bolus injection 
and continuous IV infusion. 
SAMPLE SIZE  
20 
STATISTICAL CONSIDERATIONS 
 


 
 
 
 
 
 
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SCHEMA
The following 3D Definity-enhanced ultrasound procedure will be performed at three patient 
visits: once prior to radiotherapy after the simulation CT scan, once at 0-7 days after the first 
fraction of radiotherapy treatment, and once in 2-4 months following the start of 
radiotherapy.  
i.v. infusion of
1.3 mL Definity diluted in 50 mL 
saline, with injection rate up to 10 
ml/min
Ultrasound: 
(a) ~ 2 min to reach steady state,
(b) disruption replenishment measurement,  
(c) ~ 2 min to steady state 
(d) disruption replenishment measurement,  
(e) ~ 2 min to steady state.
Overall exam time including setup and B-mode 
anatomical imaging ~30 min


 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
BID 
Twice daily 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report/Record form 
CR 
Complete response 
CT 
Computed Tomography 
DCE 
Dynamic Contrast Enhanced 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
Federal Drug Administration 
ECOG 
Eastern Cooperative Group Performance Status 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HTN 
Hypertensions 
IND 
Investigational New Drug application 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
MR 
Magnetic Resonance 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RCC 
Renal Cell Carcinoma 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SOP 
Standard Operating Procedure 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
US 
Ultrasonography, Ultrasound 
WBC 
 
White blood cell 
3D 
 
Three Dimensional  
4D 
Four Dimensional 
 
 


 
 
 
 
 
 
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1 
OBJECTIVES 
 
1.1 Primary Objective 
 
 
The primary objectives of this prospective pilot study is to (1) determine the feasibility 
and reproducibility of 3D contrast enhanced ultrasound imaging in liver cancer patients 
undergoing Stereotactic Ablative Radiotherapy and (2) evaluate whether there are 
treatment induced early changes in imaging metrics derived from 3D contrast enhanced 
ultrasound. This study will provide valuable insight as to the potential of baseline and/or 
early post-treatment 3D ultrasound perfusion characteristics (measurements of blood-
flow) of primary and metastatic liver tumors to predict tumor response to Stereotactic 
Ablative Radiotherapy. Our underlying goal is to assess whether early perfusion changes 
at 0-7 days after SABR initiation can be used as a non-invasive early biomarker for 
treatment response assessment.  
 
1.2 Secondary Objectives  
 
Evaluate the feasibility of contrast-enhanced ultrasound-to-CT fusion by assisting three-
dimensional (3D) perfusion ultrasound (US) imaging with optical and electromagnetic tracking 
of the ultrasound probe on patients with liver cancer that will undergo CT for treatment 
planning and/or response evaluation. 
 
2 
BACKGROUND 
 
2.1 Study Disease 
 
Vascular damage and response have been implicated in the response to radiotherapy at 
ablative doses. Perfusion MR, CT, SPECT, and PET can be used to detect therapy-induced 
changes in tumor vascularity. However, radiation exposure from multiple exams 
(CT/PET/SPECT), restrictions on the use of contrast in patients with renal insufficiency 
(MR/CT), limited access (MR/SPECT/PET), and elevated cost render these modalities less 
practical for frequent routine imaging. Two-dimensional (2D) contrast-enhanced 
perfusion ultrasound (US) of injected microbubbbles, is non-ionizing, accessible, and 
relatively inexpensive but fundamentally limited in quantification by the three-
dimensional (3D) heterogeneity of tumor perfusion and the 3D nature of tumor motion.  
 
These fundamental limitations of 2D US imaging have been recently overcome by the 
development of novel real-time 3D US transducers that make 3D dynamic US perfusion 
imaging in patients possible. Our goal is to assess the utility of 3D US perfusion for liver 
SABR planning and response evaluation.   
 
2.2 Study Agent/Device/Procedure 
 
    DEFINITY® is comprised of lipid-coated microspheres filled with octafluoropropane gas. 
DEFNITY® does not contain any human or animal materials. The microspheres contained 
in DEFINITY® have a mean diameter of 1.1 to 3.3 microns (in vitro measurements). The 


 
 
 
 
 
 
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microspheres are stable and small enough to pass through the pulmonary capillaries. The 
microbubbles are eliminated via the breath. 
 
    For cardiac application, after activation of DEFINITY® and intravenous injection, the 
physical acoustic properties of activated DEFINITY® provide contrast enhancement of the 
endocardial borders during echocardiography. The perflutren lipid microspheres exhibit 
lower acoustic impedance than blood and enhance the intrinsic backscatter of blood (21). 
 
In this study it is hoped that perfusion characteristics of the lesion will predict whether a 
patient will respond to therapy. 
 
For clinicaltrials.gov compliance 
This is an FDA approved drug for use in patients with suboptimal echocardiograms to 
opacify the left ventricular chamber and to improve the delineation of the left ventricular 
endocardial border. 
 
This investigation is proposed to be conducted under IND exemption per 21CFR§312.2(b) 
and IRB approval. 
 
2.3 Rationale 
Medical imaging plays a prominent role in the clinical evaluation of cancer therapies. The 
Response Evaluation Criteria in Solid Tumors (RECIST) to evaluate anatomic response to 
treatment were developed to standardize tumor measurements in routine clinical care and 
in clinical trials (1). With the use of RECIST, patients are classified to either respond, 
stabilize, or progress, depending on treatment-induced changes in tumor size measured on 
computed tomographic (CT) scans or magnetic resonance (MR) images. However, cancers 
treated with the new generation of targeted therapies (e.g., such as anti-angiogenic agents) 
often show little change in size during the 1st months of therapy despite substantial clinical 
benefit. Radiologic criteria that additionally take into account functional changes in the 
enhancement of lesions on contrast material–enhanced CT scans (3,4) or dynamic contrast-
enhanced (DCE) MR images (5) have helped to identify patients who went on to show 
clinical benefit as early as 9 weeks into treatment (6).  
DCE ultrasonography (US) can be used to quantify microbubble enhancement and can be 
used to assess functional change in response to antiangiogenic treatment of patients with 
metastatic RCC. The advantage of DCE US are the lack of ionizing radiation (as compared to 
CT) and the relatively low costs and availability (compared to MRI). Furthermore, US 
contrast agents are not nephrotoxic and, therefore, can be injected with renal insufficiency. 
Recent research showed feasibility of two-dimensional (2D) DCE US in patients. Lamuraglia 
et al (7) described DCE US criteria to classify the response to sorafenib (Nexavar; Bayer, 
West Haven, Conn). Correlations between changes in DCE US parameters, during the first 2 
weeks of treatment with sorafenib, and overall survival have also been reported (8), while 
revascularization of tumors following the cessation of treatment with bevacizumab 
(Avastin; Hoffmann-La Roche, Basel, Switzerland) has been characterized by using a DCE 
US–derived perfusion index, which correlates with histologic findings in a murine tumor 
model (9). Other preclinical studies of antiangiogenic treatments have demonstrated 
correlations between DCE US and DC CT measurements (10) and among DCE US, DCE MR 


 
 
 
 
 
 
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imaging, 
and 
fluorine 
18 
fluorodeoxyglucose 
positron 
emission 
tomographic 
measurements (11). 
Dynamic contrast-enhanced ultrasonography (DCE-US) is a technique that can be used to 
detect microvessels and quantitatively assess solid tumor perfusion using raw linear data 
(15). It involves Doppler ultrasound after injection with a contrast agent, which enhances 
the vessel signal (16, 17). Doppler ultrasonography can accurately detect and characterize 
blood flow in vessels with a diameter as low as 100 μm (14). Doppler signals provide 
functional information on neovascularity by indicating the maximal velocity in tumor 
supply vessels (16). The addition of perfusion software and microbubble contrast agents 
has further improved the technique, enabling the visualization of vessels with a diameter as 
small as 40 μm (17). To date, DCE-US has been used in a number of clinical trials with 
receptor tyrosine kinase inhibitors. These studies have indicated that DCE-US parameters 
may be correlated with tumor responses, for example in RCC with sorafenib (18, 19) or in 
gastrointestinal stromal tumors (GIST) treated by imatinib (20).  
 
Dynamic US can be used to quantify dynamic changes in tumor vascularity as early as 3 days 
after bevacizumab administration in patients with HCC. These early changes in tumor 
perfusion may be predictive of tumor response at 2 months, progression-free survival, and 
overall survival, and they may be potential surrogate measures of the effectiveness of 
antiangiogenic therapy in patients with HCC (13). 
 
However, a major limitation of current perfusion US studies is that all imaging is performed 
in a limited two-dimensional (2D) field-of-view which cannot capture the heterogeneity of 
tumor perfusion throughput its volume. Recent animal studies have shown that a 2D 
sampling of tumor perfusion may be highly biased by the position of the US transducer 
placement over the tumor and that entire-tumor three-dimensional (3D) imaging 
approaches are of paramount importance to translate non-invasive perfusion US into a 
clinical applications (12).  
 
Through our research collaboration with Philips, we have acquired a new FDA approved 3D 
US transducer that allows 3D DCE-US perfusion imaging of an extended field-of-view. This 
allows for the first time to quantify tumor perfusion of the entire volumetric extent of a liver 
metastasis and will likely substantially improve reliability and accuracy of US perfusion 
imaging in the clinical arena. 
 
In this pilot study, we will assess performance of 3D US perfusion imaging in patients with 
liver tumors undergoing SABR to evaluate the feasibility of performing 3D perfusion CEUS 
in this patient population and understand whether early changes in perfusion parameters 
are introduced as a result of the SABR treatment.  
 
2.4 Study Design 
 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
This is a pilot, single-center study in subjects with liver tumors. The primary objectives of this 
prospective pilot study is to (1) determine the feasibility and reproducibility of 3D contrast 


  
 
 
 
 
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enhanced ultrasound imaging in liver cancer patients undergoing Stereotactic Ablative 
Radiotherapy and (2) evaluate whether there are treatment induced early changes in imaging 
metrics derived from 3D contrast enhanced ultrasound. This study will provide valuable insight 
as to the potential of baseline and/or early post-treatment 3D ultrasound perfusion 
characteristics (measurements of blood-flow) of primary and metastatic liver tumors to predict 
tumor response to Stereotactic Ablative Radiotherapy.  
 
The target lesion will be located at the simulation CT scan for treatment planning.  Prior to 
Definity® administration, gray scale and Doppler (color or power imaging) ultrasound 
investigations of the target lesion will be performed using commercially available ultrasound 
equipment and standard techniques (B-mode or Harmonic imaging) to study the anatomy of the 
target lesion and surrounding parenchyma. 
 
Immediately after the unenhanced ultrasound evaluation, contrast-enhanced ultrasound will be 
performed, according to the procedures described to study the lesion vascularity in comparison 
to the surrounding parenchyma. Definity® will be administered intravenously through a central 
line or in a peripheral vein.  
 
Unenhanced ultrasound and Definity®-enhanced ultrasound images will be recorded and stored 
anonymously. 
 
The primary analysis will be based on comparison of the readout (perfusion parameters of the 
lesion) at baseline, at 0-7 days after the first fraction of radiotherapy treatment, 2-4 months 
following the start of radiotherapy, and the clinical outcome of the patient, including findings on 
routine CT and PET-CT imaging.  
 
This is a Single Group, Open Label Study designed to evaluate to evaluate as a primary outcome 
feasibility and efficacy.  
 
2.5 Correlative Studies Background 
Correlative studies background is not provided, as there are no correlative studies 
planned. 
 
3 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
All patients consulted for Stereotactic Ablative Radiotherapy (SABR) treatment of primary or 
metastatic liver tumors will be considered for this study. 
 
3.1 Inclusion Criteria 
 
3.1.1 Ability to understand and willingness to sign the written informed consent document 
 
3.1.2 Patient with primary liver tumor or metastasis scheduled for Stereotactic Ablative 
Radiotherapy (SABR) 
 
3.1.3 Patient is at least 18 years of age. No gender/race-ethnic restrictions. 
 


  
 
 
 
 
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3.1.4 Performance status (ECOG) between 0-3 
 
3.1.5 History and Physical done within  4 weeks of enrollment. 
 
3.2 Exclusion Criteria 
 
3.2.1 Patient has previously been enrolled in and completed this study. 
 
3.2.2 Known right to left cardiac shunt, bidirectional or transient. 
 
3.2.3 Patient has any medical condition or other circumstances which would significantly 
decrease the chances of obtaining reliable data, achieving study objectives, or completing 
the study and/or post-dose follow-up examinations. 
 
3.2.4 History of hypersensitivity to perflutren 
 
3.2.5 History of pulmonary hypertension 
 
3.2.6 Patients who are pregnant or are trying to become pregnant  
 
3.3 Informed Consent Process 
 
All participants will be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants will 
sign an IRB approved informed consent prior to participation in any study specific procedure. 
The participant will receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document will be retained in the medical record or research file.  
 
3.4 Randomization Procedures 
 
This is an open label study. 
3.5 Study Timeline 
Definity®-enhanced ultrasound at baseline will be completed prior to delivery of SABR 
treatment. The patient will then be re-scanned 0-7 days post their first fraction of radiation 
treatment. An additional US scan will be performed 2-4 months (when patient comes to 
routine follow-up CT and PET-CT imaging). 
 
Primary Completion: 
 
The expected study completion timeline is within 24 months from when the study 
opens. 
 
Study Completion: 
 


  
 
 
 
 
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The expected study completion timeline is within 24 months and 1 day from when the 
study opens. 
 
4 
TREATMENT PLAN 
 
Pregnancy Test  
 
If the subject is female and of child-bearing potential, exclude the possibility of pregnancy by:  
• testing serum βHCG or urine pregnancy test prior to the start of Definity® administration 
(the local laboratory may be used) 
• obtaining surgical history (e.g., tubal ligation or hysterectomy) 
• obtaining medical history (post-menopausal with a minimum of 1 year without menses). 
See Appendix B. 
 
Safety Assessments Adverse Events  
We will record all untoward medical events in the Adverse Event section of the CRF. Only post-
dose untoward medical occurrences will be tabulated as adverse events.  
 
Imaging Procedures  
 
The unenhanced ultrasound and Definity®-enhanced images will be performed, in the same 
session, using commercially available (FDA-approved) ultrasound systems with appropriate 
contrast-specific capabilities. The ultrasound examination, both unenhanced and contrast-
enhanced should be performed by qualified personnel with at least 3 years of experience in liver 
ultrasound or Fellows with appointment in Stanford Radiology 
 
Definity® will be administered intravenously into a central line or port or an upper extremity vein 
(e.g., a vein in the cubital fossa or dorsal aspect of the wrist or hand) using a catheter while 
observing aseptic technique. Immediately following the Definity® injection, 5 mL to 10 mL of saline 
will be administered to flush the intravenous line of any remaining contrast agent. Subjects will be 
monitored for any untoward medical occurrences listed in a study case report form or note for 30-
60 min after Definity® injection is initiated.  
 
Imaging parameters: 
 
Contrast-specific imaging will be performed with an abdominal matrix-array transducer (PM 
mode, Philips iU22 with X6–1; Philips Ultrasound, Bothell Wash) which is a low-mechanical-index 
(MI) nonlinear imaging (MI, 0.06) that allows visualization of the micro-bubbles nondestructively 
Time-gain controls will be aligned to the center line. Receive gain, dynamic range, image depth, and 
transmit focus will be optimized for each patient at the baseline examination, and then identical 
settings will be used at follow-up. Disruption-replenishment data will be collected for 
approximately 30 seconds following 1-second, 8-frame flash at an MI of 1.3. 
 
Unenhanced Ultrasound  


  
 
 
 
 
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During the unenhanced ultrasound examination, the morphology and localization of the target FLL 
will be evaluated using gray scale ultrasound and color/power Doppler modes. The target lesion 
will be identified using gray scale ultrasound and its location will be identified using Coineaud’s 
system. Then, either color Doppler imaging or power Doppler imaging should be used to study the 
morphology/vascularity of the target lesion and surrounding parenchyma. Specific measurements 
with Spectral Doppler may be used depending on the presence and/or visualization of vessels.  
 
Contrast-Enhanced Ultrasound Examination  
The following protocol will be used, according to published literature (23): 
 
An infusion of 1.3 mL of Definity diluted in 50 mL of saline will be administered using an injection 
pump. Two minutes will be allowed for the infusion to reach a steady level before disruption-
replenishment. Measurements will be performed two times (to assess reproducibility of the 
replenishment curves analysis following microbubble destruction and replenishment of 
microbubbles into the US field-of-view). 
 
4.1 General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant Medications  
Given that concomitant meds are neither indicated nor no counter-indicated as per the 
Definity Prescription Information the Concomitant Medication section of the Case Report 
Form (CRF) will not be filled.  
 
4.2 Criteria for Removal from Study 
 
Subject will be discontinued from the study if the subject:  
• 
withdraws consent.  
• 
during the course of the study manifests condition matching exclusion criteria. 
• 
will not be able to adhere to protocol timeline due to scheduling or other conflict 
• 
has an adverse event that, in the opinion of the Investigator, requires the subject’s  
Discontinuation.  
 
5 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
 
5.1 Investigational Agent/Device/Procedure   
 
DEFINITY® Vial for (Perflutren Lipid Microsphere) Injectable Suspension is Lantheus 
Medical Imaging Inc.’s non-blood based ultrasound contrast agent approved by the United 
States Food and Drug Administration (FDA). DEFINITY® is the first approved ultrasound 
contrast agent in the U.S. that offers flexible dosing and administration through IV bolus 
injection or continuous IV infusion. (21) 
 
 The FDA has approved activated DEFINITY® for use in patients with suboptimal 
echocardiograms to opacify the left ventricular chamber and to improve the delineation of 
the left ventricular endocardial border.  


  
 
 
 
 
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DEFINITY® is comprised of lipid-coated microspheres filled with octafluoropropane gas. 
DEFNITY® does not contain any human or animal materials. The microspheres contained 
in DEFINITY® have a mean diameter of 1.1 to 3.3 microns (in vitro measurements). The 
microspheres are stable and small enough to pass through the pulmonary capillaries. 
(21,22, 23) 
The safety of DEFINITY® is well documented in multiple clinical trials involving over 1,700 
patients at more than 20 U.S. medical centers.  Age, gender, race and ethnicity did not affect 
the overall incidence of adverse events. 
The overall incidence of treatment-related adverse events was 8.4%. The most frequently 
reported treatment-related adverse experiences were in the Central and Peripheral 
nervous system (3.1%), Body as a Whole (2.4%) and Gastrointestinal system (1.8%). The 
most frequently reported treatment-related adverse experiences were: 
 
Headache 
 
  
2.3% 
Back/renal 
pain 
1.2% 
Flushing 
1.1% 
Nausea 
1.0% 
 
In clinical trials, serious cardiopulmonary events occurred in 19 (1.1%) patients. None of 
these events, which included 8 deaths and 11 other serious adverse events, was attributed 
to DEFINITY®, but to progression of underlying disease. 
 
CONTRAINDICATIONS 
DEFINITY® is not to be administered in patients with known or suspected right-to-left, bi-
directional or transient right-to-left cardiac shunts, by intra-arterial injection, or to patients 
with known hypersensitivity to perflutren. In post marketing use, rare but serious 
cardiopulmonary or anaphylactoid reactions have been reported during or shortly 
following perflutren-containing microsphere administration. The risk for these reactions 
may be increased among patients with unstable cardiopulmonary conditions. It is not 
always possible to reliably establish a causal relationship to drug exposure due to the 
presence of underlying cardiopulmonary disease. Thus all patients need to be assessed for 
the presence of any condition that precludes DEFINITY® administration and it is 
recommended that resuscitation equipment and trained personnel are readily available. 
 
 
 
Devices: 
In addition, there will be an Optical and Electromagnetic tracking tools attached to the 
Ultrasound Transducer that will not be in contact with the patient. There is very little risk 
to the patient associated with optical tracking as there is no transfer of energy to the 
patient. With electromagnetic tracking there may be electromagnetic interference with 
implantable devices such as pacemakers, etc. Electromagnetic tracking will not be used 
(Optical tracking ony) if the patient has an implantable medical device to eliminate risk 
from electromagnetic interference.  
 


  
 
 
 
 
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5.2 Availability 
 
Definity is available from the Hospital Pharmacy. 
 
5.3 Agent Ordering 
 
Definity® is FDA approved and routinely used for patients with suboptimal echocardiograms to 
opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial 
border. It may be requested from the central hospital pharmacy with a signed physician order for the 
subject with the quantity to dispense. It may also be bought from the central hospital pharmacy for 
storage within the department of Radiation Oncology. 
 
5.4 Agent Accountability 
 
Central pharmacy will deliver Definity® to the Department of Radiation Oncology, where it will be 
stored in a temperature controlled refrigerator in the locked office of Protocol Director, Dr. Daniel 
Chang. The study coordinator (ACRC) will keep both a temperature log and dispensing log according 
to IDS standards next to the refrigerator. All subjects will be entered into OnCore.  
 
6 
DOSE MODIFICATIONS 
 
There are no dose modifications planned for this study. 
 
7 
ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1 Potential Adverse Events 
 
The safety of DEFINITY® is well documented in multiple clinical trials involving over 1,700 
patients at more than 20 U.S. medical centers.  Age, gender, race and ethnicity did not affect the 
overall incidence of adverse events. 
 
The overall incidence of treatment-related adverse events was 8.4%. The most frequently 
reported treatment-related adverse experiences were in the Central and Peripheral nervous 
system (3.1%), Body as a Whole (2.4%) and Gastrointestinal system (1.8%). The most 
frequently reported treatment-related adverse experiences were: 
 
 
 
In clinical trials, serious cardiopulmonary events occurred in 19 (1.1%) patients. None of these 
events, which included 8 deaths and 11 other serious adverse events, was attributed to 
DEFINITY®, but to progression of underlying cardiovascular disease. 
 
Headache 
 
  
 2.3% 
Back/renal pain 
 1.2% 
Flushing 
 1.1% 
Nausea 
 1.0% 


  
 
 
 
 
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7.2 Adverse Event Reporting 
 
7.2.1 Adverse Events  
 
Adverse events will be assessed for 30-60 minutes after each injection of Definity®. 
 
Adverse events will be graded according to CTCAE v4.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific 
Case Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse 
Event (AE) to determine whether it is unexpected according to the Informed Consent, 
Protocol Document, or Investigator’s Brochure, and related to the investigation. All Serious 
Adverse Events (SAEs) will be tracked until resolution.   SAEs must be reported while on 
study and up to 30 days after the last dose of the study treatment is given.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to 
the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the 
study specific CRF regardless of the event’s relatedness to the investigation. Following 
review by the DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be 
reported to the IRB using eProtocol within 10 working days of DSMC review, or within 5 
working days for deaths or life-threatening experiences. 
 
7.2.2 AE Definition  
 
An adverse event (AE) is any untoward medical occurrence in a subject or a clinical trial 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with the use of the product.  
 
Any untoward medical occurrence that occurs outside the period of subject follow-up 
defined in the protocol is not required to be collected in the AE section of the CRF.  
 
An existing condition, which is detected by the diagnostic procedure conducted to test the 
efficacy of an investigational contrast agent, is not considered an AE.  
 
Symptoms or medically significant laboratory or instrumental (e.g., electrocardiographic) 
abnormalities of a pre-existing condition, such as cancer or other disease, should not be 
considered an AE. However, occurrence of new symptoms, laboratory or instrumental 
abnormalities, as well as worsening of pre-existing ones, are considered AEs.  
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose:  
• 
results in death,  
• 
is life-threatening (i.e., the subject was at risk of death at the time of the 
event/reaction; it does not refer to an event/reaction which hypothetically might 
have caused death if it were more severe),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization,  


  
 
 
 
 
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• 
results in persistent or significant disability/incapacity (where disability is defined 
as a permanent or substantial disruption of ability to carry out normal life 
functions, either reported or defined as per clinical judgment),  
• 
is a congenital anomaly/birth defect,  
• 
is an important medical event that may not result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based upon 
appropriate medical judgment, it may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes listed in the 
definition above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, and blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.  
• 
Any suspected transmission via a medicinal product of an infectious agent is also 
considered a SAE.  
• 
A non-serious adverse event is any adverse event that does not meet the criteria 
listed above for a  SAE.  
 
7.2.3 Unanticipated Problem (UP) 
 
Per Stanford IRB, UPs are events involving risks to participants or others and must meet 
ALL 3 criteria below: 
 
1.  Unexpected: in terms of nature, severity, or frequency, given (a) the 
research procedures described in the protocol-related documents, and (b) 
the characteristics of the subject population being studies; AND 
 
2.  Related to participation in the research:  or there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research; or if a device is 
involved, probably caused by, or associated with the device; AND 
 
3.  Harmful:  suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.  
 
UPs generally will warrant consideration of substantive changes in the research protocol or 
informed consent process/document, or other corrective actions, in order to protect the 
safety, welfare, or rights of subjects or others.(27)  Due to this, UPs will be reported 
promptly to Stanford IRB following the below guidelines. 
 
A UP may also be an AE or SAE and can be noted as both on CRFs and in OnCore.  
 
Reporting UPs 
UPs should be entered into OnCore and reported within 24 hours of learning of the 
event.  
 


  
 
 
 
 
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7.2.4  AE Relationship to the Investigational Product:  
Every effort will be made to determine the cause of each adverse event. The correlation 
between the investigational product and the adverse event will be classified as follows:  
1. Probable  
a) The event follows a reasonable temporal sequence from administration of the 
investigational product;  
 
b) The event follows a known response pattern to the investigational product; 
  
c) The event cannot be reasonably explained by any of the following features: 
  
• the known characteristics of the subject’s clinical state, or 
• other therapy administered 
• or the diagnostic/interventional procedure; 
 
d) There is evidence of partial or complete disappearance of the event after 
withdrawal of the product (positive challenge).  
 
e) The event follows a known response pattern to the investigational product but 
the event could have been produced by any of the following features:  
 
• the subject’s clinical state, or 
• other therapy administered, or 
• the diagnostic/interventional procedure.  
 
f) The event does not meet any of the above criteria because of: 
• conflicting data and/or  
• dubious or insufficient/poor evidence, or 
• the event is not judged as related or not related.  
 
g) The event is either a pre-dose event or is definitely due to causes separate from  
the administration of the investigational product, i.e.  
• 
documented pre-existing condition  
• 
technical and manual procedural problems  
• 
concomitant medication  
• 
the subject’s clinical state  
• 
the event is judged as not related and does not fall under any of the above 
points.  
 
2. Possible  
3. Not Related  
4. Unknown  
 
7.2.5 AE Action Taken:  
0.  None  


  
 
 
 
 
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Page 19 of 30
1. Change in the investigational product administration (including brief interruption of 
administration of total dose and early termination of administration, i.e., dose 
reduction)  
2. Drug treatment required (a medication was prescribed or changed; record in the 
Concomitant Medication section of the CRF)  
3. Non-drug treatment required (a non-drug treatment was prescribed or changed, 
record under “Comments” in the Adverse Event section of the CRF)  
4. Hospitalization or prolonged hospitalization  
5. Diagnostic or clinical test(s) conducted (attach a copy of the results to the CRF)  
6. Subject discontinued from the study  
 
7.2.6 AE Subject Outcome:  
1. Recovered without sequelae.  
2. Recovered with sequelae (describe the sequelae under “Comments” in the Adverse 
Event section of the CRF)  
3. Not Recovered, event on-going (follow the subject until a definite outcome can be 
determined. When follow-up data are collected, report follow-up information under 
“Comments” in the Adverse Event section of the CRF; if the event is serious, fill in a 
follow-up SAER)  
4. Died (list primary cause of death under “Event Description” in the Adverse Event 
section of the CRF)  
 
8 
CORRELATIVE/SPECIAL STUDIES  
 
8.1 Laboratory Correlative Studies 
There are no Laboratory Correlative Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
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9 
STUDY CALENDAR 
 
 
 
 
Enrollment 
Baseline 
0-7Days after 
the first 
fraction of 
radiotherapy 
treatment 
2-4 Months 
from starting 
SABR 
Informed 
consent 
Xa 
 
 
 
H&P 
Xa,f 
 
 
 
Eligibility  
Xa 
 
 
 
Documentation of 
Consent 
Xa 
 
 
 
ECOG PS 
Xa,e 
 
 
 
Study Registration 
Xa 
 
 
 
Simulation CT 
 
X 
 
 
AE Evaluation 
 
Xb,d 
Xb,d 
Xb,d 
Definity® 
/Ultrasound 
 
X 
X 
X 
B-HCG or urine 
pregnancy test 
Xa,c 
 
 
 
 
 
a.  Prior to study procedures.  
b.  Baseline assessment prior to Definity© injection . 
c.  Required for women who are not post-menopausal as defined in Appendix B and who are not excluded from 
possibility of pregnancy by a physician. 
d.  Documented 30-60 minutes after Definity © injection 
e.  ECOG specified in medical note prior to eligibility confirmation, defined in Appendix C.  
f.  H&P done within 4 weeks of enrollment. 


 
 
 
 
 
 
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10 MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
10.1 Primary and Secondary Outcome measures 
 
10.1.1 Relevant Subset 
 
 
 
 
All patients will be considered for the secondary outcome. 
 
10.1.2 Measurement Definition 
 
Primary Objective: 
 
The primary objectives of this pilot study is to (1) determine the feasibility and 
reproducibility of 3D contrast enhanced ultrasound imaging in liver patients 
undergoing Stereotactic Ablative Radiotherapy and (2) evaluate whether there 
are treatment induced early changes in imaging metrics derived from 3D contrast 
enhanced ultrasound. 
 
10.1.3 Measurement Methods 
 
Contrast Agent Administration 
The US contrast agent will be perflutren lipid microspheres (Definity; Lantheus 
Medical Imaging, North Billerica, Mass). Patients will receive an infusion of 1.3 mL 
of perflutren lipid microspheres diluted in 50 mL of saline delivered up to 10 
mL/min by using an injection pump (Medfusion 3500; Smiths Medical, Dublin 
Ohio). Two minutes will be allowed for the infusion to reach a steady level before 
disruption-replenishment measurements were performed. 
 
 
Imaging System Parameters 
Contrast-specific imaging will be performed with an abdominal matrix-array 
transducer (PMPI mode, Philips iU22 with X6–1; Philips Ultrasound, Bothell 
Wash). Low-mechanical-index (MI) nonlinear imaging (MI, 0.06) will allow 
visualization of the microbubbles nondestructively. Persistence and other post-
processing will be disabled to minimize temporal and spatial averaging. Time-
gain controls will be aligned to the center line. Receive gain, dynamic range, image 
depth, and transmit focus will be optimized for each patient at the baseline 
examination, and then identical settings will be used at follow-up. Disruption-
replenishment data will be collected for approximately 30 seconds following each 
1-second, 8-frame flash at an MI of 1.3. Frame rates ranged from 7 to 12 Hz. Data 
will be stored in a compressed “native” format to allow linearization. 
 
10.1.4 Measurement Time Points 
The probe will be held steady throughout each acquisition. During the infusion, 
continuous 3D data will be collected and two disruption-replenishment 
acquisitions will be performed.  


 
 
 
 
 
 
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10.1.5 Image analysis and derived measures 
Volume of interest (VOIs) encompassing the lesions will be defined on the 3D 
DCE-US. After linearization of the 3D DCE-US signal (to make it proportional to 
contrast concentration), time intensity curves (TIC) will be generated for the 
mean contrast concentration within the VOI. After standard TIC fit curve 
parameters will be extracted to serve as measures that describe perfusion. These 
measures include: relative blood volume, mean flow velocity, and relative blood 
flow = relative blood volume x mean flow velocity.   
 
10.2 Secondary Outcome 
In this pilot study of 20 patients, we will focus on the primary objective: feasibility, 
reproducibility and assessment of changes in metrics (indices) derived from 3D contrast 
enhanced ultrasound. Our secondary objective is to evaluate the feasibility of contrast-enhanced 
ultrasound-to-CT fusion by assisting three-dimensional (3D) perfusion ultrasound (US) imaging 
with optical and electromagnetic tracking of the ultrasound probe on patients with liver cancer 
that will undergo CT for treatment planning and/or response evaluation. Thus the secondary 
outcome will be the relative number of ultrasound examinations in which fusion to CT was 
possible. 
 
11 REGULATORY CONSIDERATIONS 
11.1 Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. The DSMC will audit study-related activities to 
determine whether the study has been conducted in accordance with the protocol, 
local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP).  This may include review of the following types of documents participating in 
the study: regulatory binders, case report forms, eligibility checklists, and source 
documents.  In addition, the DSMC will regularly review serious adverse events and 
protocol deviations associated with the research to ensure the protection of human 
subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an 
expedited fashion, as needed. 
11.2 Data Management Plan 
Case Report Forms (CRFs) are printed or electronic documents designed to record all 
protocol-related information on each trial participant. CRFs should summarize the 
clinical findings and observations necessary to ensure safety of participants on the 
study, and to document the study outcomes.  CRFs are required by the SRC for all 
Interventional studies. Study-specific CRFs will document treatment outcomes for 
data analysis. CRFs will be developed manually and will be maintained by the study 
coordinator. 
 
 
12 STATISTICAL CONSIDERATIONS 
 
12.1 Statistical Design 
 
The primary objectives of this pilot study is to (1) determine the feasibility and 


 
 
 
 
 
 
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Page 23 of 30 
reproducibility of 3D contrast enhanced ultrasound imaging in liver patients undergoing 
Stereotactic Ablative Radiotherapy and (2) evaluate whether there are treatment induced 
early changes in imaging metrics derived from 3D contrast enhanced ultrasound. 
Specifically, we will perform exploratory analysis for testing the following hypotheses: 
 
12.2 Outcome Measurements: 
 
Primary endpoints: 
• To characterize the reproducibility of 3D DCE-US by estimating the concordance 
correlation coefficient (30,31) for repeated 3D DCE-US measures (see Section 
10.1.6, Image analysis and derived measures). 
• To determine the variance in the relative changes of repeated 3D DCE-US measures. 
• To provide summary statistics of the relative changes in 3D DCE-US measures 
before and after SABR. 
 
Secondary endpoint: 
• To provide relative number of 3D DCE-US examinations in which fusion to CT is 
possible with tracking of the ultrasound transducer.  
 
12.3 Analysis plan: 
 
This is an exploratory pilot study designed with a primary objective to evaluate (1) the 
feasibility and reproducibility of 3D DCE-US in cancer patients undergoing SABR for liver 
lesions and (2) the magnitude of the differences in perfusion measures before and after 
SABR. Future studies will seek to understand if 3D DCE-US perfusion baseline values or 
changes have predictive power for clinical endpoints in SABR treatments. The knowledge 
gained from this study will aid in calculating the appropriate sample size for such studies.  
The main focus here is on understanding the discrepancies in measures from repeated 
acquisitions and differences in measures before and after SABR.  Thus the data will be 
analyzed as follows:  
 
• Estimation the concordance correlation coefficient (30, 31) for repeated 3D DCE-US 
measures (see Section 10.1.6, Image analysis and derived measures) as a measure of 
reproducibility. Concordance correlation values between 0.9 and 0.95 will be 
interpreted as moderate reproducibility and values between 0.95 and 0.99 will be 
interpreted as substantial reproducibility based on the following scale for the 
concordance correlation coefficient:  Poor, < 0.9; moderate, 0.9 – 0.95; substantial 
0.95 – 0.99, nearly perfect >0.99. 
• Histogram analysis and summary statistics (mean, median, variance, and maximum) 
of the relative changes (difference/average) of repeated 3D DCE-US measures. (Small 
variance and zero mean of the relative changes will be indicative of highly 
reproducible 3D DCE-US measures). 
• Histogram analysis and summary statistics (mean, median, variance, and maximum) 
of the relative changes (difference/baseline) in 3D DCE-US measures before and after 
SABR. Large mean differences will be indicative of treatment (SABR) effect. 


 
 
 
 
 
 
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• Calculation of proportion of 3D DCE-US examinations in which fusion to CT is possible 
with tracking of the ultrasound transducer. Calculation of proportion of 3D DCE-US 
examination in which repeated scans is successful. These proportions are metrics of 
feasibility (target 80%-90%). Successful fusion to CT in particular is important metric 
is 3D DCE-US is to be explored as add-on imaging for treatment planning in further 
studies. 
 
12.4 Sample Size 
 
20 patients. 
 
12.5 Sample size justification 
This study is an exploratory study and there is currently not sufficient information to 
perform a sample size calculation. 
 
13 REFERENCES 
 
1.  
Therasse P , Arbuck SG , Eisenhauer EA , et al . New guidelines to evaluate the response to 
treatment in solid tumors: European Organizationfor Research and Treatment of Cancer, National 
Cancer Institute of the United States,National Cancer Institute of Canada . J Natl Cancer Inst 
2000;92 ( 3 ): 205 – 216 . 
 
2.       Choi H , Charnsangavej C , Faria SC , et al .Correlation of computed tomography and  
positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at 
a single   institution with imatinib mesylate: proposal of new computed tomography response 
criteria . J Clin Oncol 2007 ; 25 ( 13 ): 1753 – 1759 . 
 
3.  
Nathan PD , Vinayan A , Stott D , Juttla J ,Goh V . CT response assessment combining 
reduction in both size and arterial phase density correlates with time to progression 
in metastatic renal cancer patients treated with targeted therapies . Cancer Biol Ther 
2010 ; 9 ( 1 ): 15 – 19 . 
 
4.  
Hahn OM , Yang C , Medved M , et al . Dynamic contrast-enhanced magnetic resonance   
  imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma . 
 J Clin Oncol 2008 ; 26 ( 28 ): 4572 – 4578 . 
 
5.  
Smith AD , Lieber ML , Shah SN . Assessing tumor response and detecting recurrence in 
metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation 
on contrast-enhanced CT . AJR Am J Roentgenol 2010 ; 194 ( 1 ): 157 – 165 . 
 
6.  
Lamuraglia M , Escudier B , Chami L , et al . To predict progression-free survival and overall  
survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-
enhanced Doppler ultrasound . EurJ Cancer 2006 ; 42 ( 15 ): 2472 – 2479 . 
 
7.  
Albiges L , et al .Metastatic renal cell carcinoma treated with sunitinib: early evaluation of 
treatment response using dynamic contrast-enhanced ultrasonography. Clin Cancer Res 2010 ; 16 
( 4 ):1216 – 1225 . 
 
8.  
Guibal A , Taillade L , Mulé S , et al . Noninvasive contrast-enhanced US quantitative assessment 
of tumor microcirculation in a murine model: effect of discontinuing anti-VEGF 


 
 
 
 
 
 
IRB-30071 / Protocol Version 29Aug2019  
 
 
 
Page 25 of 30 
therapy . Radiology 2010 ; 254 ( 2 ): 420 – 429 . 
 
9.  
Pollard RE , Broumas AR , Wisner ER , Vekich SV , Ferrara KW . Quantitative contrast 
enhanced ultrasound and CT assessment of tumor response to antiangiogenic therapy 
in rats . Ultrasound Med Biol 2007 ; 33 ( 2 ): 235 – 245 . 
 
10 .  
Niermann KJ , Fleischer AC , Huamani J , et al. Measuring tumor perfusion in control 
and treated murine tumors: correlation of microbubble contrast-enhanced sonography 
to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron 
emission tomography . J Ultrasound Med 2007 ; 26 ( 6 ): 749 – 756 . 
 
11.  
Quantitative Mapping of Tumor Vascularity Using Volumetric Contrast-Enhanced Ultrasound 
Hoyt, Kenneth; Sorace, Anna; Saini, Reshu Investigative Radiology. 47(3):167-174, March 2012. 
 
12.  
Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at 
dynamic contrast-enhanced US with quantification--preliminary results. Lassau N, Koscielny S, 
Chami L, Chebil M, Benatsou B, Roche A, Ducreux M, Malka D, Boige V. Radiology. 2011 
Jan;6 8(1):291-300. Epub 2010 Oct 27. 
 
13.  
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to 
treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. 
 
14.  
Lassau N, Chami L, Benatsou B, Peronneau P, Roche A. Dynamic contrast-enhanced 
ultrasonography (DCE-US) with quantification of tumor perfusion: a new diagnostic tool to 
evaluate the early effects of antiangiogenic treatment. Eur Radiol 2007;17 Suppl 6:F89–98. 
 
15.  
Cosgrove D. Angiogenesis imaging-ultrasound. Br J Radiol 2003;76: Spec No 1:S43–9. 
 
16.  
Lassau N, Koscielny S, Opolon P, et al. Evaluation of contrast enhanced color Doppler ultrasound 
for the quantification of angiogenesis in vivo. Invest Radiol 2001;36:50–5. 
 
17.  
Lamuraglia M, Escudier B, Chami L, et al. To predict progression-free survival and overall 
survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-
enhanced Doppler ultrasound. Eur J Cancer 2006;42:2472–9. 
 
18.  
Escudier B, Lassau N, Angevin E, et al. Phase I trial of sorafenib in combination with IFN-α-2a 
in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin 
Cancer  Res 2007;13:1801–9. 
 
19.  
Lassau N, Lamuraglia M, Chami L, et al. Gastrointestinal stromal tumours treated with imatinib: 
monitoring response with contrastenhanced sonography. AJR Am J Roentgenol 2006;187:1267–
3. 
 
20. 
Ross Williams , BASc John M. Hudson , MSc , PhD, Peter N. Burns , PhD. Dynamic 
Microbubble Contrast enhanced US to Measure Tumor Response to Targeted Therapy: A 
Proposed Clinical Protocol with Results from Renal Cell Carcinoma Patients Receiving 
Antiangiogenic Therapy. Radiology: Volume 260: Number 2—August 2011;page: 581-591. 
 
21. 
DEFINITY® Prescribing Information: http://www.definityimaging.com 
 
22. 
 McCulloch M et al Ultrasound contrast physics: A series on contrast echocardiography. article  


 
 
 
 
 
 
IRB-30071 / Protocol Version 29Aug2019  
 
 
 
Page 26 of 30 
J Am Soc Echocardiogr 2000: 13: 959-67. 
 
23. 
 Lindner JR et al. Microvascular rheology of Definity microbubbles after intra-arterial and 
intravenous administration J Am Soc Echocardiogr 2002; 15(5): 396-403. 
 
24. 
 Pysz MA, Foygel K, Panje CM, Needles A, Tian L, Willmann JK. Assessment and monitoring 
tumor vascularity with contrast-enhanced ultrasound maximum intensity persistence imaging. 
Investigative Radiology. 2011 Mar.;46(3):187–95. 
 
25.  
 Lefort T, Pilleul F, Mulé S, Bridal SL, Frouin F, Lombard-Bohas C, et al. Correlation and 
Agreement Between Contrast-Enhanced Ultrasonography and Perfusion Computed Tomography 
for Assessment of Liver Metastases from Endocrine Tumors: Normalization Enhances 
Correlation. Ultrasound Med Biol. 2012 Jun.;38(6):953–61. 
 
26. 
Meijerink MR, van Waesberghe JHTM, van Schaik C, Boven E, van der Veldt AAM, van den 
Tol P, et al. Perfusion CT and US of colorectal cancer liver metastases: a correlative study of two 
dynamic imaging modalities. Ultrasound Med Biol. 2010 Oct.;36(10):1626–36. 
 
27. 
 Rognin N , Frinking P , Costa M , Arditi M .In-vivo perfusion quantifi cation by 
contrastultrasound: validation of the use of linearized video data vs. raw RF data. In: Proceedings 
of the IEEE Ultrasonics Symposium. Piscataway, NJ: Institute of Electrical and Electronics 
Engineers, 2008 ;1690–1693. 
 
28.  
. Bogaard JM , Smith SJ , Versprille A , Wise ME , Hagemeijer F . Physiological interpretation of 
the skewness of indicator-dilution curves: theoretical considerations and a practical application . 
Basic Res Cardiol 1984 ; 79 ( 4 ): 479 – 493. 
 
29. 
 Mischi M , den Boer JA , Korsten HH . On the physical and stochastic representation of an 
indicator dilution curve as a gamma variate .PhysiolMeas2008;29(3):281–294 . 
 
30.  
Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989 
Mar;45(1):255-68. PubMed PMID: 2720055. 
 
31. 
Carol A. E. Nickerson. A Note On "A Concordance Correlation Coefficient to Evaluate 
Reproducibility". Biometrics, Vol. 53, No. 4 (Dec., 1997), pp. 1503-1507 
 
 
 
 
 
 
 
 
 
 
14 APPENDICES 
14.1 APPENDIX A: Participant Eligibility Checklist  
 


 
 
 
 
 
 
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Page 27 of 30 
I. Protocol Information 
Protocol Title: 
Feasibility of 3D perfusion ultrasound of liver cancer 
SABR planning and response evaluation  
Protocol Number: 
IRB-30071 / HEP0048 
Principal Investigator: 
Dr. Daniel Chang 
 
II. Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
III. Inclusion/Exclusion Criteria 
Inclusion Criteria 
Yes 
No 
15 Supporting 
Documentation* 
1. Ability to understand and 
willingness to sign the written 
informed consent document. 
 
 
      
2. Patient with primary liver tumor 
or metastasis scheduled for 
Stereotactic Ablative 
Radiotherapy (SABR) 
 
 
      
3. Patient is at least 18 years of age. 
No gender/race-ethnic 
restrictions. 
 
 
      
4. Performance status (ECOG) 
between 0-3 
 
 
      
5. History and Physical done within  
4 weeks of enrollment. 
 
 
      
Exclusion Criteria 
 
1. Patient has previously been 
enrolled in and completed this 
study. 
 
 
      
2. Known right to left cardiac shunt, 
bidirectional or transient. 
 
 
      
3.  Patient has any medical condition 
or other circumstances which 
would significantly decrease the 
chances of obtaining reliable data, 
achieving study objectives, or 
completing the study and/or post-
dose follow-up examinations. 
 
 
      


 
 
 
 
 
 
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4. History of hypersensitivity 
perflutren 
 
 
      
5. History of pulmonary 
hypertension 
 
 
      
6. Patients who are pregnant or are 
trying to become pregnant 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-
report, and medical record review.   
 
IV. Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [
eligible / 
ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements 
as required by Stanford School of Medicine’s Research Management Group. 
 
Signature: 
Date: 
Treating Physician Printed Name: 
 
Signature: 
Date: 
Study Coordinator Printed Name: 
 
Signature: 
Date: 
Secondary Reviewer Printed Name: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.2 Appendix B 
 
Definition of Menopausal Status: 


 
 
 
 
 
 
IRB-30071 / Protocol Version 29Aug2019  
 
 
 
Page 29 of 30 
 
 
Menopausal will be defined according to the following criteria: 
 
Post-menopausal: 
 
•  Woman 60 years of age or older 
•  Woman aged 45-59 years with spontaneous cessation of menses for at least 12 
months prior to registration 
•  Woman aged 45-59 years with cessation of menses for less than 12 months prior 
to registration AND an FSH level in the postmenopausal range (or >34.4 IU/L if 
institutional range is not available) 
•  Woman aged 45-59 years on hormone replacement therapy who have 
discontinued hormone replacement therapy at diagnosis of breast carcinoma and 
have an FSH level in the postmenopausal range according to 
institutional/laboratory standards (or 34.4 IU/L if the institutional range is not 
available) 
•  Prior bilateral oophorectomy 
•  Woman younger than 60 years of age who have had a prior hysterectomy (without 
bilateral oophorectomy) AND who have an FSH level in the postmenopausal 
range (or >34.4 IU/L if institutional range is not available) 
Pre- or peri-menopausal:  Not meeting definition for postmenopausal outlined above 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.3 Appendix C 
 
 


 
 
 
 
 
 
IRB-30071 / Protocol Version 29Aug2019  
 
 
 
Page 30 of 30 
 
ECOG Performance Status* 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
 

ICF_000.pdf: 
Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 1 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
CONSENT FORM 
 
Are you participating in any other research studies? ____ Yes _____ No 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of liver perfusion (how blood flows to 
the liver over time). We hope to learn whether perfusion characteristics of liver 
metastases may be predictive of response to treatment and whether liver perfusion 
characteristics can be used to follow response to treatment. You were selected as a 
possible participant in this study because you are identified as having liver metastases.  
 
If you decide to terminate your participation in this study, you should notify Daniel 
Chang, M.D. at 650-724-3547. 
 
This research study is looking for 20 people with a primary or metastatic liver tumor, 
which can be imaged with Contrast 3D Ultrasound.  Stanford University expects to 
enroll 20 research study participants.  
 
DURATION OF STUDY INVOLVEMENT  
 
This study will take approximately sixty minutes of your time for each Ultrasound scan.  
There will be 3 ultrasound scans, one prior to your scheduled Stereotactic Ablative 
Radiotherapy (SABR) treatment, one 0-7 days after your first fraction of radiotherapy 
treatment, and one 2-4 months from the start of your treatment.  
 
PROCEDURES 
 
If you choose to participate, Daniel Chang and his research study staff will ask you to 
participate in this study by undergoing an Ultrasound scan prior to your first 
Stereotactic Ablative Radiotherapy (SABR) treatment, one 0-7 days after your first 
fraction of radiotherapy treatment, and once in 2-4 months from the start of your 
treatment. These Ultrasound scans will be compared to the CT or MRI scans that will 
be done at approximately 2-4 months after the start of the SABR as part of routine 
care. They will be done in addition to and not instead of these routine scans. Each scan 
will be performed with an electromagnetic or optical tracking device attached to the 
Ultrasound probe. 
 
Definity will be administered through an IV (intravenously) into a central line or port or an upper 
extremity vein (wrist, hand, arm) using an IV catheter. 1.3mL of Definity will then be injected for 
6-8 minutes. The contrast-enhanced ultrasound will be performed within these 8 minutes. 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 2 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
All participants will be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants will 
sign an IRB approved informed consent prior to participation in any study specific procedure. 
The participant will receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document will be retained in the medical record or research file.  
 
If the subject is female and of child-bearing potential, pregnancy will be tested by: 
• 
Serum βHCG or urine pregnancy test within 24 hours prior to the start of Definity® 
administration (the local laboratory may be used) 
• 
Surgical history (e.g., tubal ligation or hysterectomy) 
• 
Medical history (post-menopausal with a minimum of 1 year without menses). 
 
If you are a woman who is able to become pregnant, it is expected that you will use an 
effective method of birth control to prevent exposing a fetus to a potentially dangerous 
agent with unknown risk. If you are pregnant or currently breast-feeding, you may not 
participate in this study. You understand that if you are pregnant, if you become 
pregnant, or if you are breast feeding during this study, you or your child may be 
exposed to extra radiation.      
 
If you have had a previous reaction to contrast agents or a history of severe allergies, 
please notify the operator/investigator.  If you have kidney problems, please tell the 
operator. 
 
To confirm to the extent medically possible that you are not pregnant, you agree to 
have a pregnancy test done before beginning this research study. You must agree to 
avoid sexual intercourse or use a birth control method judged to be effective by the 
investigator and which will not interfere with the proposed investigation. You must 
accept the risk that pregnancy could still result despite the responsible use of a reliable 
method of birth control. You agree to notify the investigator as soon as possible of any 
failure of proper use of your birth control method, or if you become pregnant, either of 
which may result in your being withdrawn from the study. 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study staff. 
• Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Protocol Director or research study staff to reschedule as soon as 
you know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, doctor 
visits, or hospitalizations that you may have. 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 3 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
• Tell the Protocol Director or research staff if you believe you might be pregnant 
or gotten your partner pregnant. 
• Tell the Protocol Director or research staff if wear any implantable medical 
devices such as pacemakers, etc.  
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about staying 
in the study. 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  
 
Your decision will not affect your ability to receive medical care for your disease and 
you will not lose any benefits to which you would otherwise be entitled.  
 
If you decide to withdraw your consent, to participate in this study, you should notify 
Daniel Chang, M.D. at 650-724-3547. 
 
The Protocol Director may also withdraw you from the study without your consent for 
one or more of the following reasons: 
 
• Failure to follow the instructions of the Protocol Director and study staff 
• Pregnancy 
• The study is cancelled 
• Other administrative reasons 
• Unanticipated circumstances 
 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study. 
These deserve careful thought. You should talk with the Protocol Director if you have 
any questions.  
 
You will undergo 3 additional Ultrasound scans which will take up to 1 hour of your time 
in total each session. Unlike CT scans, the Ultrasound Imaging does not require 
radiation.  The contrast should not be administered to patients with blood flow shunting 
from one to the other heart chamber; also, in patients with known allergies to perflutren 
(Definity), the agent should not be administered.  


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 4 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
DEFINITY®  
The safety of DEFINITY® is well documented in multiple clinical trials involving 
over 1,700 patients at more than 20 U.S. medical centers.  Age, gender, race and 
ethnicity did not affect the overall incidence of adverse events. 
The overall incidence of treatment-related adverse events was 8.4%. The most 
frequently reported treatment-related adverse experiences were in the Central 
and Peripheral nervous system (3.1%), Body as a Whole (2.4%) and 
Gastrointestinal system (1.8%). The most frequently reported treatment-related 
adverse experiences were: 
Headache 2.3% 
Back/renal pain 1.2% 
Flushing 1.1% 
Nausea 1.0% 
Follow Definity administration, there have been reported adverse reactions 
involving the heart and the lungs. Most serious reactions occur within 30 
minutes of administration; however, you will be in the care of the physician 
performing the scan and the hospital staff for greater than 30 minutes post 
Definity injection. 
You should not participate in this study if you have a history of hypersensitivity to 
Definity, have a history of pulmonary hypertension (increased pressure in the 
pulmonary arteries), if you are pregnant or trying to become pregnant, or if you have 
other any other medical conditions which would prevent you from participating in this 
study. 
The risks of taking blood include pain, a bruise at the point where the blood is taken, 
redness and swelling of the vein and infection, and a rare risk of fainting. 
       There will be an Optical and/or Electromagnetic tracking tools attached to the Ultrasound 
Transducer that will not be in contact with the patient. There is very little risk to the patient 
associated with optical tracking as there is no transfer of energy to the patient. With 
electromagnetic tracking there may be electromagnetic interference with implantable 
devices such as pacemakers, etc. Electromagnetic tracking will not be used (powered off) if 
you have told the Program Director that you are wearing any implantable medical device to 
eliminate risk from electromagnetic interference.  
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 5 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
POTENTIAL BENEFITS                              
 
Although there will be no direct benefit at the time of the study, the knowledge we gain 
may provide future benefit to subjects who are diagnosed primary liver metastases and 
need to be monitored for treatment response. 
 
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
   
ALTERNATIVES 
 
The alternative is not to participate. Your treatment and care will not be affected by 
your decision to participate or not participate.  Participation/non-participation will not 
affect the routine radiologic evaluation of studies and clinical care of the patients. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate. Your questions should be 
answered clearly and to your satisfaction.  
 
If you decide not to participate, tell the Protocol Director. You will still receive care for 
your disease and will not lose any benefits to which you would otherwise be entitled.  
 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your condition or your willingness to continue 
participation in this study.  
 
 
 
Authorization to Use Your Health Information  
for Research Purposes  
 
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form 
and as required or allowed by law.  Please read it carefully before signing 
it.   


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 6 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this study is to test the feasibility of contrast enhanced 3D 
Ultrasound of the liver to evaluate whether perfusion characteristics 
(measurement of blood flow) of primary or metastatic liver tumors can 
predict tumor response to treatment. You were selected as a possible 
participant in this study because you are identified as having primary liver 
tumor metastases and you are scheduled to be treated with Stereotactic 
Ablative Radiotherapy (SABR) for the first time.  Your liver perfusion data 
will be deidentified and then analyzed. Images without any identification 
may be used in clinical presentations or publications. 
 
Do I have to sign this authorization form? 
Signing this form is not a condition for receiving any medical care outside 
of this study. You do not have to sign this authorization form.  But if you do 
not, you will not be able to participate in this research study.  
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 
the study, except to the extent that the law allows us to continue using 
your information (e.g., necessary to maintain integrity of research).  If you 
wish to revoke your authorization for the research use or disclosure of your 
health information in this study, you must write to:  
 
Dr. Daniel Chang   
Associate Professor  
Department of Radiation Oncology  
Stanford University Medical Center  
875 Blake Wilbur Drive CC-G231 
Stanford, California 94305-5105 
 
What Personal Information Will Be Used or Disclosed? 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 7 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
Your health information related to this study may be used or disclosed in 
connection with this research study which may include MRN, age at onset 
of disease, extent of disease, current age, weight, height, therapies to 
date (e.g. medications, interventions), imaging information and any other 
information related to primary liver tumor metastases.  
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
• The Protocol Director (Dr. Daniel Chang) 
• The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
• Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
• The Office for Human Research Protections in the U.S. Department 
of Health and Human Services  
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on January 1, 2059, or when the research project ends, whichever 
is earlier.  
 
 
 
  
_____________________________________                 
____________ 
Signature of Adult Participant 
 
 
 
Date 
 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 8 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
 
 
_____________________________________          
Print Name of Adult Participant 
 
 
 
 
FINANCIAL CONSIDERATIONS 
 
Payment: You will not be paid to participate in this research study. 
 
Costs: If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with the study that are not a part of your routine 
medical care.  However, there may be additional costs to you.  These include basic 
expenses like transportation and the personal time it will take to come to the study 
visits.  You and/or your health insurance must pay for services, supplies, procedures, 
and care that are required during this study for routine medical care.  You will also be 
responsible for any co-payments and/or deductibles as required by your insurance.  
Participation in this study is not a substitute for health insurance. 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information 
will not be disclosed except as authorized by you or as required by law.  However, 
there is always some risk that even de-identified information might be re-identified. 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals. However, your identity will not be disclosed. Patient 
information may be provided to Federal and other regulatory agencies as required. The 
Food and Drug Administration (FDA), for example, may inspect research records and 
learn your identity if this study falls within its jurisdiction. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol 
Director and the research study staff will assist you in obtaining appropriate medical 
treatment.  In the event that you have an injury or illness that is directly caused by your 
participation in this study, reimbursement for all related costs of care first will be sought 
from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by your 
insurance.  If costs of care related to such an injury are not covered by your insurer, 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 9 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
managed care plan or other benefits program, you may be responsible for these costs.  
If you are unable to pay for such costs, the Protocol Director will assist you in applying 
for supplemental benefits and explain how to apply for patient financial assistance from 
the hospital. You do not waive any liability rights for personal injury by signing this form. 
 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
CONTACT INFORMATION  
 
If you have any questions, concerns or complaints about this research study, its 
procedures, risks and benefits, or alternative courses of treatment, you should ask 
Daniel Chang, M.D. at 650-724-3547.  You should also contact him at any time if you 
feel you have been hurt by being a part of this study.  
 
Independent Contact: If you are not satisfied with how this study is being conducted, or if you 
have any concerns, complaints, or general questions about the research or your rights as a 
participant, please contact the Stanford Institutional Review Board (IRB) to speak to someone 
independent of the research team at (650)-723-5244 or toll free at 1-866-680-2906.   
You can also write to the Stanford IRB, Stanford University, 1705 El Camino Real, Palo Alto, CA 
94306. 
 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that 
might be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 10 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion or undue influence on the subject's decision. 
 
May we contact you about future studies that may be of interest to you?   Yes    No 
 
Signing your name means you agree to be in this study and that you were given a 
copy of this consent form. 
 
 
_____________________________________                 
____________ 
Signature of Adult Participant 
 
 
 
   
Date 
 
 
_____________________________________ 
Print Name of Adult Participant 
 
 
____________________________________              
___________ 
Signature of Person Obtaining Consent  
 
   
Date 
 
 
____________________________________ 
Print Name of Person Obtaining Consent 
 
The following witness line is to be signed only if the consent is provided as a summary form and accompanied by a 
short form foreign language consent.  
 
 
_____________________________________          
 
 ____________ 
Signature of Witness                                            
 
 
Date 
(e.g., staff, translator/interpreter, family member) 
 
_____________________________________ 
Print Name of Witness 
 
• Translated short form must be signed and dated by both the participant (or their LAR) AND the witness. 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Daniel Chang, MD   
 
Protocol Title:    Feasibility study of contrast-enhanced 3D perfusion ultrasound for liver cancer 
SABR planning and response evaluation 
 
          
 
Page 11 of 11 
 
NCT:  NCT02424955                                                                                                          
 
IRB USE ONLY 
Approval Date:    August 11, 2021 
Expiration Date:  August 11, 2022 
• The English consent form (referred to as the "Summary Form" in the regulations): 
− Must be signed by the witness AND the Person Obtaining Consent (POC). 
− The non-English speaking participant/LAR does not sign the English consent. 
− The non-English speaking participant/LAR should not sign the HIPAA participant line 
− If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must ensure that 
1) the LAR's Description of Authority is completed and 2) that any questions or options presented by the 
consent form are documented and initialed by the POC on the Summary Form, per the participant's wishes, 
as they are understood during the consent process.