Clinical trial NCT02722616
Conditions: Pancreatic Cancer Liver Cancer
Keywords: Ultrasound
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2016-05-01; Completion date: 2022-10-28
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is being done to collect data and analyze the motion of soft tissue in the abdomen (liver, pancreas, stomach and intestines) of people who have pancreatic and liver cancer as well as healthy volunteers.

During the study researchers will look at the movement of organs in the abdomen that naturally occurs with breathing and with a bowel movement.

This study will examine the differences between abdominal soft tissue motion in healthy volunteers and in cancer patients with the goal of developing a better way to manage and minimize the abdominal soft tissue motion. Accurate location of the tumor is very important in treatment delivery and reduction of toxicity.

Detailed description:
Within the last decade, Linac based stereotactic body radiation therapy (SBRT) has been shown to be an effective treatment option for pancreas1, 2 and liver3, 4 tumors. SBRT delivers high doses of radiation therapy to the tumor over only 1-5 treatments. Because of the spatial precision of SBRT, it is feasible to administer a high radiation dose in only a few treatments. By minimizing the amount of radiation to surrounding healthy tissue, it is possible to decrease the rate of toxicity/complication and increase the radiation dose to cancerous tissue, thereby allowing better local control.

SBRT of the abdomen has been limited by the movement of intra-abdominal organs that naturally occurs with respiration and bowel movement. Organ motion occurs both intra- and inter-fractionally. While intra-fractional motion is a result of respiration, peristalsis and cardiac motion, the magnitude of inter-fractional target motion is dependent of daily variations in organ filling, weight change, tumor growth and radiation induced changes of tissue. Tumor movement may lead to tumor displacement and suboptimal dose delivery. Accurate localization of the target is very important to improve treatment delivery accuracy and reduce toxicity of the treatment. To evaluate tumor motion due to breathing motion, a four dimensional (4D) CT simulation scan is performed. If the tumor moves more than 3 mm during a breathing cycle, breathing motion management is employed using Active Breathing Control (ABC) technique. ABC requires the patient to hold his/her breath within the proper tidal volume while treatment is delivered, while free breathing may be resumed between periods of treatment. This technique limits the delivery of RT to specific phases of the respiratory cycle so as to minimize the influence of breathing on the delineated tumor.

Despite significant progress made in ABC technique, tumor and organ motion could only be minimized and not eliminated completely with this technique. Assessing patient specific tumor/organ motion (both intra- and interfractional) throughout the course of SBRT treatment offers the possibility of ensuring delivery of the prescribed target dose while simultaneously minimizing normal tissue damage. In order to monitor the abdominal soft tissue motion, the Department of Radiation Oncology has developed a 4D ultrasound technique based on an ultrasound probe holder and a continuous motion monitoring software. The 4D ultrasound image is acquired by using a motorized 3D ultrasound probe and image continuously. 4D ultrasound is a new non-ionizing and non-invasive imaging technique that continuously monitors the tumor motion during the radiation treatment in real time.

Arms: arm 1: A 4D ultrasound scan of the pancreas will be acquired at the time at simulation and used as a reference ultrasound image for localizing tracking target. The ultrasound probe will be placed at the abdominal area to monitor the pancreas motion. The probe will remain in place during the CT scan. Patient setup and the ultrasound probe location will be recorded so that the same setup can be reproduced during treatment delivery. The ultrasound probe in the CT image will be contoured and radiation beams that directly pass through the ultrasound probe will be avoided.

On each treatment day, 4D ultrasound images will be acquired continuously during beam on time to monitor pancreas motion. Intra-fraction CBCT images acquired during treatment will be registered with reference CT images. Organ motion registered by ultrasound will be compared to motion recorded by CBCT and the accuracy of the ultrasound system will be evaluated. arm 2: A 4D ultrasound scan of the liver will be acquired at the time at simulation and used as a reference ultrasound image for localizing tracking target. The ultrasound probe will be placed at the abdominal area to monitor the liver motion. The probe will remain in place during the CT scan. Patient setup and the ultrasound probe location will be recorded so that the same setup could be reproduced during treatment delivery.

On each treatment day, 4D ultrasound images will be acquired continuously during beam on time to monitor liver motion. The system will record all relevant images, but will not be used in clinical decision making. Intra-fraction CBCT images acquired during treatment will be registered with reference CT images. Organ motion registered by ultrasound will be compared to motion recorded by CBCT and the accuracy of the ultrasound system will be evaluated. arm 3: A reference ultrasound scan will be conducted on each subject during breath-hold. Subjects will be required to lie in supine position and engaged with ABC; an ultrasound probe will be placed at the abdomen area with minimal pressure applied. Continuous motion monitoring is achieved by acquiring 4D ultrasound images using a motorized 3D ultrasound probe to image the pancreas, liver and other intra-abdominal organs continuously. Several 4D ultrasound scans will be collected during subsequent breath-holds that serve as secondary images. Additional registration of ultrasound images will be performed with Velocity software to evaluate accuracy of automated registration software in the ultrasound system.
Interventions: intervention 1: Ultrasound scan of the pancreas intervention 2: Ultrasound scan of the Liver intervention 3: Reference ultrasound
Intervention descriptions: intervention 1: A 4D ultrasound scan will be acquired at the time at simulation and used as a reference ultrasound image for localizing tracking target. The ultrasound probe will be placed at the abdominal area to monitor the pancreas motion. The probe will remain in place during the CT scan. Patient setup and the ultrasound probe location will be recorded so that the same setup can be reproduced during treatment delivery. intervention 2: A 4D ultrasound scan will be acquired at the time at simulation and used as a reference ultrasound image for localizing tracking target. The ultrasound probe will be placed at the abdominal area to monitor the liver motion. The probe will remain in place during the CT scan. Patient setup and the ultrasound probe location will be recorded so that the same setup could be reproduced during treatment delivery. The ultrasound probe in the CT image will be contoured and radiation beams that directly pass through the ultrasound probe will be avoided. intervention 3: A reference ultrasound scan will be conducted on each subject during breath-hold. Subjects will be required to lie in supine position and engaged with ABC; an ultrasound probe will be placed at the abdomen area with minimal pressure applied. Continuous motion monitoring is achieved by acquiring 4D ultrasound images using a motorized 3D ultrasound probe to image the pancreas, liver and other intra-abdominal organs continuously. Several 4D ultrasound scans will be collected during subsequent breath-holds that serve as secondary images.

Protocol documents:
Prot_SAP_000.pdf: 
Ultrasound Monitoring of Abdominal Soft Tissue
NCT02722616
July 18, 2016


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 1 of 6 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
*************************************************************************************************** 
 
TITLE: “Ultrasound system for non-invasive, real-time monitoring of abdominal soft tissue” 
 
VERSION: October 11, 2014 
 
 
STUDY TEAM: 
Primary Investigator:  
Amol Narang, MD 
Weinberg 1440-Oncology 
401 North Broadway 
Baltimore, MD 21231-2410 
Phone: 410-955-7390 
Email: anarang2@jhmi.edu 
 
 
Additional Study Investigators: 
Kai Ding, PhD 
Joseph Herman, MD, M.Sc. 
Sook Kien Ng, PhD 
Lin Su, PhD 
Yin Zhang, PhD 
Amanda Blackford Sc.M. 
Peter Kazanzides, PhD 
Iulian Iordachita, PhD 
H. Tutkun Sen, MS 
 
 
1. Abstract (Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research) 
 
Within the last decade, Linac based stereotactic body radiation therapy (SBRT) has been shown to 
be an effective treatment option for pancreas1, 2 and liver3, 4 tumors. SBRT delivers high doses of 
radiation therapy to the tumor over only 1-5 treatments. Because of the spatial precision of SBRT, it 
is feasible to administer a high radiation dose in only a few treatments. By minimizing the amount 
of radiation to surrounding healthy tissue, it is possible to decrease the rate of toxicity/complication 
and increase the radiation dose to cancerous tissue, thereby allowing better local control. 
 
SBRT of the abdomen has been limited by the movement of intra-abdominal organs that naturally 
occurs with respiration and bowel movement. Organ motion occurs both intra- and interfractionally. 


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 2 of 6 
 
While intrafractional motion is a result of respiration, peristalsis and cardiac motion, the magnitude 
of interfractional target motion is dependent of daily variations in organ filling, weight change, 
tumor growth and radiation induced changes of tissue. Tumor movement may lead to tumor 
displacement and suboptimal dose delivery. Accurate localization of the target is very important to 
improve treatment delivery accuracy and reduce toxicity of the treatment. To evaluate tumor motion 
due to breathing motion, a 4-D CT simulation scan is performed. If the tumor moves more than 3 
mm during a breathing cycle, breathing motion management is employed using Active Breathing 
Control (ABC) technique. ABC requires the patient to hold his/her breath within the proper tidal 
volume while treatment is delivered, while free breathing may be resumed between periods of 
treatment. This technique limits the delivery of RT to specific phases of the respiratory cycle so as 
to minimize the influence of breathing on the delineated tumor. 
 
Despite significant progress made in ABC technique, tumor and organ motion could only be 
minimized and not eliminated completely. Assessing patient specific tumor/organ motion (both 
intra- and interfractional) throughout the course of SBRT treatment offers the possibility of ensuring 
delivery of the prescribed target dose while simultaneously minimizing normal tissue damage. In 
order to monitor the abdominal soft tissue motion, the Department of Radiation Oncology has 
developed a 4D ultrasound technique based on an ultrasound probe holder and a continuous motion 
monitoring software.  
 
The 4D ultrasound image is acquired by using a motorized 3D ultrasound probe and image 
continuously. 4D ultrasound is a new non-ionizing and non-invasive imaging technique that allows 
continuous image acquisitions for real-time motion monitoring during the radiation treatment. 
Ultrasound is a proven modality for soft tissue localization (ref-prostate-breast). Several studies (5, 6, 
7) have shown that even with older version of ultrasound system, the ultrasound images correlates 
with CT images within a small absolute magnitude of difference (about 3 mm), therefore we expect 
to have good agreement between the reference CT simulation and reference 4D ultrasound. 
Ultrasound motion monitoring during treatment delivery is based on real-time automatic registration 
of ultrasound images acquired on treatment days to reference ultrasound images acquired at the 
beginning of treatment, thus removing any inter-modality tracking uncertainty and inter-user 
variability. The ultrasound probe in the CT image will be contoured and radiation beams that 
directly pass through the ultrasound probe will be avoided. An SBRT treatment plan usually consist 
of multiple (9 – 12 beams for IMRT technique) co-planar beams delivered around the isocenter 
placed inside the tumor. Omitting the small range of angle directly passing through the ultrasound 
probe will not compromise the treatment plan dosimetry quality. 
 
The first arm of this study is designed to validate the accuracy and stability of the ultrasound system 
and establish an efficient workflow to be applied for cancer patients. Healthy volunteers are able to 
perform more regular breathing patterns and longer breath-holds. Scanning healthy volunteers 
allows more predictable data acquisition time point and opportunity to develop a general workflow 
that can be continuously optimized for patient scanning. Anatomical abnormalities (surgical 
implant, fibrosis and metastases) in patients might produce artifacts in ultrasound images that can 
reduce motion tracking accuracy. Ultrasound of healthy volunteer with better anatomical landmark 
visualization helps us to evaluate the stability and accuracy of the ultrasound system and 
registration software. 
 
For patient study, organ motion registered by ultrasound will be compared to motion recorded by 
CBCT and the accuracy of the ultrasound system will be evaluated. In addition, imaging and setup 
efficiency, cost and volume acquisition rate will be compared between CBCT based and 4D 
ultrasound based intra-fraction motion monitoring. 


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 3 of 6 
 
 
 
 
 
2. Objectives (include all primary and secondary objectives) 
Primary objectives:  
a. Establish effective workflow for real time monitoring of abdominal soft-tissue motion due to 
respiration using 4D ultrasound system  
b. Evaluate feasibility of real time motion monitoring of tumor and surrounding organ/tissue 
during pancreas and liver SBRT treatments using 4D ultrasound system 
c. Evaluate accuracy of the 4D ultrasound motion monitoring system compare to CBCT based 
intra-fraction motion monitoring during pancreas and liver SBRT treatments 
Secondary objective:  
a.  Evaluation of dosimetry differences due to target/organ motion observed  
 
 
3. Background 
SBRT of the abdomen has been limited by the movement of intra-abdominal organs that 
naturally occurs with respiration and bowel movement. Currently at Johns Hopkins Hospital, 
breathing motion management is employed using ABC technique for patient treated with 
pancreas and liver SBRT if the tumor and/or abdominal organs move more than 3 mm during a 
breathing cycle. While ABC device has been reported to reduce respiratory motion to below 2 
mm, small variation of breath-holds may lead to tumor displacement and suboptimal dose 
delivery. Assessing patient specific tumor/organ motion (both intra- and interfractional) 
throughout the course of SBRT treatment offers the possibility of ensuring accurate delivery of 
the prescribed target dose while simultaneously minimizing normal tissue damage. This can be 
achieved by using Clarity 3D ultrasound system together with ABC device for real-time 
tracking of the pancreas and liver during SBRT treatment. 
 
4. Study Procedures 
a. Arm 1: Validate the ultrasound tracking and establish  reference range of motion for abdominal 
soft tissue motion from healthy individuals. 
Fifteen healthy volunteers will be enrolled and informed consent obtained per study guidelines 
as described. A reference ultrasound scan will be conducted on each subject during breath-hold. 
Subjects will be required to lie in supine position and engaged with ABC; an ultrasound probe 
will be placed at the abdomen area with minimal pressure applied. Continuous motion 
monitoring is achieved by acquiring 4D ultrasound images using a motorized 3D ultrasound 
probe to image the pancreas, liver and other intra-abdominal organs continuously. Several 4D 
ultrasound scans will be collected during subsequent breath-holds that serve as secondary 
images. Registration of the reference and secondary ultrasound scans will be performed with 
automated registration algorithm built-in with the ultrasound system to evaluate abdominal soft-
tissues and organs motion. Additional registration of ultrasound images will be performed with 
Velocity software to evaluate accuracy of automated registration software in the ultrasound 
system.  
 
b. Arm 2: Monitor the abdominal soft tissue motion of pancreas patients treated with SBRT 
during the whole course of treatment. 
Thirty pancreatic cancer patients receiving SBRT treatment with ABC will be enrolled and 
informed consent obtained per study guidelines as described. A 4D ultrasound scan will be 
acquired at the time at simulation and used as a reference ultrasound image for localizing 


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 4 of 6 
 
tracking target. The ultrasound probe will be placed at the abdominal area to monitor the 
pancreas motion. The probe will remain in place during the CT scan. Patient setup and the 
ultrasound probe location will be recorded so that the same setup can be reproduced during 
treatment delivery. The ultrasound probe in the CT image will be contoured and radiation beams 
that directly pass through the ultrasound probe will be avoided.  
On each treatment day, 4D ultrasound images will be acquired continuously during beam on 
time to monitor pancreas motion. The system will record all relevant images, but will not be 
used in clinical decision making. These data will be used to evaluate the magnitude of target 
motion and dosimetry deviation due to the motion. Intra-fraction CBCT images acquired during 
treatment will be registered with reference CT images. Organ motion registered by ultrasound 
will be compared to motion recorded by CBCT and the accuracy of the ultrasound system will 
be evaluated. 
 
c. Arm 3: Monitor the abdominal soft tissue motion of liver patients receiving SBRT treatment 
with ABC during the whole course of treatment. 
Twenty hepatic cancer patients being treated with SBRT treatment will be enrolled and 
informed consent obtained per study guidelines as described. A 4D ultrasound scan will be 
acquired at the time at simulation and used as a reference ultrasound image for localizing 
tracking target. The ultrasound probe will be placed at the abdominal area to monitor the liver 
motion. The probe will remain in place during the CT scan. Patient setup and the ultrasound 
probe location will be recorded so that the same setup could be reproduced during treatment 
delivery. The ultrasound probe in the CT image will be contoured and radiation beams that 
directly pass through the ultrasound probe will be avoided. 
On each treatment day, 4D ultrasound images will be acquired continuously during beam on 
time to monitor liver motion. The system will record all relevant images, but will not be used in 
clinical decision making. These data will be used to evaluate the magnitude of target motion and 
dosimetry deviation due to the motion. Intra-fraction CBCT images acquired during treatment 
will be registered with reference CT images. Organ motion registered by ultrasound will be 
compared to motion recorded by CBCT and the accuracy of the ultrasound system will be 
evaluated. 
 
 
5. Inclusion/Exclusion Criteria 
a. Inclusion Criteria: 
I.  Arm 1: Healthy adult (age >18 years) 
II.  Arm 2: Pancreatic cancer patients (age >18 years) currently receive SBRT treatment at JHU 
III.  Arm 3: Hepatic cancer patients (age >18 years) currently receive SBRT treatment at JHU 
      
b. Exclusion criteria: Children (age < 18 years) are excluded. 
 
 
6. Drugs/ Substances/ Devices 
Probe holder  (passive): FISSO surgical arm (FDA approved) 
Probe holder (active): active arm with robotic control (developed by JHU robotic lab) 
 
 
7. Study Statistics 
a. Analytic plan for primary objectives: 
An effective workflow for real time monitoring of abdominal soft-tissue due to respiration 
using a 4D ultrasound system will be developed through the use of healthy controls.  As 


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 5 of 6 
 
described earlier, these controls will provide data for estimating the background reference 
for abdominal soft tissue.  Data collected on controls will be summarized with descriptive 
statistics.  Quantitative analysis of target/organ motion and displacement recorded in 4D 
real-time ultrasound scan will be carried out to assess both intra- and interfractional 
variation as described above in the study. This study will help us to ensure delivery of the 
prescribed target dose while simultaneously minimizing normal tissue damage.  We will 
consider the approach feasible if we are able to successfully complete the procedure and 
output the associated data for 50% of the study participants.  The software will output a 
motion curve over time.  We will calculate the difference between values on the curve and 
the values from CBCT at the specific time points that CBCT is performed, and summarize 
the differences using descriptive statistics.  A 95% confidence interval for the difference 
will be reported.  These data will be used to evaluate the accuracy of the 4D ultrasound 
system. 
b. Analytical plan for secondary objectives:  
Quantitative analysis dosimetry deviation due to patient specific tumor/organ motion (both 
intra- and interfractional) throughout the course of SBRT treatment will be carried out. The 
actual dose received will be compared to the intended dose, and their difference will be 
summarized with descriptive statistics. 
c. Sample size justification:  
The goals of this study are to test the feasibility of the approach and subsequently generate data for 
describing the accuracy of the 4D ultrasound motion monitoring system during pancreas and liver SBRT 
treatments.  The variability of the data obtained is currently unknown, so it is difficult to give preliminary 
estimates of the precision that specific sample sizes will yield.  We plan to enroll 15 healthy controls, 30 
pancreatic cancer patients, and 20 hepatic cancer patients for generating the pilot data. 
 
8. Risks 
a. 
Medical risks: None; data will be acquired but there will be no change in the radiation therapy 
intervention. 
b. 
Legal risks such as the risks that would be associated with breach of confidentiality: While data 
will be stored data in secure locked files (computer files will be password protected and any 
paper records will be stored in the research office at Johns Hopkins under lock and key) in 
which only the research team has access, there is always the risk that confidentiality will be lost 
c. 
Financial risks to the participants: None 
 
 
9. Benefits 
There is no benefit to the patient from participation in the study.  Potential benefits to society 
include those to future patients undergoing Linac based SBRT treatments, who may receive 
improved treatment as a direct result of the research performed in this study. 
 
 
10. Payment and Remuneration 
N/A 
 
11. Costs 
There will be no additional cost to the patient as a result of participation in this study. 
 
 
 
 


Date: July 18, 2016 
Principal Investigator: Amol Narang, MD 
Application Number: IRB00053267 
 
 
Page 6 of 6 
 
 
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