Integrated 3D X-ray and Ultrasound Guided Radiation Therapy of Soft Tissue Targets
Phase: NA
Conditions: Adult Liver Carcinoma, Malignant Pancreatic Neoplasm, Prostate Carcinoma
Sponsor: Case Comprehensive Cancer Center

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                                Amendment #4 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:  
 
CASE 6Y14 
 
STUDY TITLE: 
 
Integrated 3D x-ray and ultrasound Guided Radiation 
 
 
Therapy of Soft Tissue Targets 
  
 
PRINCIPAL INVESTIGATORS: 
Ping Xia, Ph.D. 
 
 
Department of Radiation Oncology 
 
Cleveland Clinic  
 
Taussig Cancer Center 
 
9500 Euclid Avenue 
 
Cleveland, OH   44195 
 
(216)-444-1938 
 
 
CO-INVESTIGATORS: 
 
Kevin Stephans, MD 
 
 
Omar Mian, M.D .Ph.D.  
 
 
Rahul Tendulkar, M.D.  
 
 
Bingqi Guo, Ph.D.  
 
 
Matt Kolar, M.S 
 
 
 
 
Department of Radiation Oncology  
 
CA-5 
 
Taussig Cancer Center 
 
Cleveland Clinic  
 
9500 Euclid Avenue 
 
Cleveland, OH   44195 
 
 
 
 
 
STATISTICIAN: 
 
N/A  
 
SPONSOR: 
 
NIH 
 
 
CLINICAL FACILITY: 
 
Cleveland Clinic  
 
 
STUDY COORDINATOR: 
 
Julie Benchea 
 
 
DD4-422-31 
 
 
Cleveland Clinic  
 
 
9500 Euclid Avenue 
 
 
Cleveland, OH 44195 
 
 
216-445-9925 

 
 
 
 
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TABLE OF CONTENTS 
 
CASE COMPREHENSIVE CANCER CENTER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. . 
1 
1.0      Background and Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
3 
2.0      Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
3 
3.0      Patient/Sample Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
.  
3 
           3.1    Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
4 
           3.2    Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
4 
4.0     Registration Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
4 
5.0     Research Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
4 
6.0     Study Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
6 
7.0     Statistical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
.  
10 
8.0     Regulatory Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
10 
          8.1     Data Storage  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
10 
          8.2     Adverse Events and Data Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
10 
          8.3     Written Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
10 
          8.4     Sources of Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
.  
11 
          8.5     Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
11 
          8.6     Protection Against Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
11 
          8.7     Potential Benefits of the Proposed Research to the Subjects and Others . . . . 
. .  
12 
          8.8     Importance of the Knowledge to be Gained . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
12 
          8.9     Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
. .  
12 
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  
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1.0  
Background and Rationale  
 
Hypofractionated radiotherapy, the delivery of higher dose per fraction with reduced number 
of treatment fractions, is a promising treatment option for many disease sites.  Hypofractionated 
radiotherapy inherently requires a smaller patient setup margin which in turn necessitates the use 
of image guidance to alleviate the increased risk of geometric misses and deleterious clinical 
outcomes.   
The main thrust of modern image guidance is to localize the soft tissue target and represents a 
major paradigm shift from the verification of bony landmarks. The predominant form of image 
guidance is on-board kilo-voltage cone beam CT (KV-CBCT). Although KV-CBCT is highly 
effective in improving accuracy of the patient setup prior to treatment, CBCT has two major 
deficiencies when applied to verify hypofractionated radiotherapy or radiosurgery.   
First, KV-CBCT only provides a “snapshot” of patient anatomy at the time of imaging, but not 
during actual radiation delivery. Secondly, flat panel based KV-CBCT employed in radiation 
therapy is less than effective in discriminating a soft tissue target in a low contrast environment.  
Localization of abdominal lesions for hypofractionated treatment is challenging with KV-CBCT. 
Alternative imaging methods are needed. Ultrasound imaging is one of the important technologies 
that are capable of soft tissue localization in the abdomen. We have a commercially available 
ultrasound system in our department. This system has been predominantly used for prostate 
patients, localizing the prostate prior to treatment. Ultrasound imaging alone, however, suffers 
insufficient of field of view to visualize a proper patient position for radiotherapy.   
 
2.0  
Objectives 
Purpose of this protocol is to investigate the feasibility of combining on-board CBCT with 
ultrasound imaging to overcome the shortcomings of CBCT or ultrasound imaging alone for 
imaging guided radiotherapy delivery. Specifically, we will investigate (a) whether the ultrasound 
imaging can enhance soft tissue tumor localization; (b) whether the presence of a passive arm is 
interfering radiation delivery during each treatment; (c) whether the presence of the ultrasound 
probe will affect the choice of radiation beams and degrade treatment plan quality.  
 
3.0   
Patient/Sample Selection 
We will recruit a total of 30  patients, 30 with prostate cancer that will undergo external beam 
treatment at the Department of Radiation Oncology. 
 
All patients undergoing radiation treatment for prostate cancer, with EBRT or SBRT are eligible.  
A completed patient eligibility checklist is required following the approved standard operating 
procedure of the enrolling institution. 
 
 
 
3.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 

 
 
 
 
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_____ 3.1.1 The patient must have prostate cancer by biopsy, with the intent of undergoing 
definitive dose radiation therapy to targets within  the prostate. Patients with prostatectomy 
receiving post-operative radiotherapy are also eligible.  
 
_____ 3.1.2 Age > 18 years. 
 
_____ 3.1.3 Performance status - Karnofsky PS ≥ 70  
 
_____ 3.1.4 Subjects must have the ability to understand and the willingness to sign a written 
informational form. 
 
3.2 
Exclusion Criteria  
 
The presence of the following will exclude a patient from study enrollment.  
 
_____ 3.2.1 Patients with uncontrolled inter-current illness or psychiatric illness/social situations 
that would limit compliance with study requirements.  
 
 
4.0   
Registration Procedures  
 
All patients enrolled on study will be entered into the Oncore database  
 
5.0   
Research Plan  
 
5.1  
Investigate whether the ultrasound imaging can enhance soft tissue tumor 
localization. 
(a)  Following the standard clinical procedure, daily KV-CBCT image for each patient will be 
acquired and used to guide for patient setup prior to treatment delivery. Because of limited soft 
tissue contrast in KV-CBCT to observe the soft tissue organ, such as the prostate, the added 
ultrasound image may enhance soft tissue localization prior to treatment for these patients.  
The ultrasound device will be calibrated to the treatment iso-center via an external camera system 
and infrared markers on the ultrasound (US) probe. A commercially available passive arm will be 
acquired and attached to the ultrasound probe. Following our current clinical protocol, the patient 
treatment position will be determined solely based the daily KV-CBCT. After KV-CBCT 
guidance, a pre-treatment US image will be acquired for the study but not used for patient 
positioning.  The success of this specific aim is defined as that the tumors can be visualized in the 
ultrasound images in at least 80% of patients enrolled.  
(b) Investigate whether the presence of a passive arm will interfere with radiation delivery 
during each treatment.  

 
 
 
 
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In order to monitor tumor or organ motion during radiation, the US probe will be placed using a 
passive arm, as shown in the figure below. This passive arm will be attached to the treatment couch 
and also in contact with the patient during the radiation. Although the passive arm is commercially 
available, we plan to test whether the presence of the US probe will interfere radiation delivery 
during each treatment.  Specifically, we will test: (a) whether the passive arm reduces the clearance 
between the patient and the gantry of the linear accelerator; (b) whether the passive arm can hold 
a consistent contact pressure with the patient under normal breathing motion; (c) whether the 
passive arm can be automatically released if a patient makes a large movement. The success of 
this specific aim is defined as that at least 80% of patients are able have the ultrasound probe 
attached during the entire treatment course.  
 
Figure 1.  
(c) Investigate whether the presence of the ultrasound probe will interfere with the choice of 
radiation beams and degrade plan quality 
The presence of the US probe and the passive arm may block the access of some radiation beams. 
The specific aim of this study to investigate whether altering the radiation beam directions will 
affect the treatment plan quality.  Our preliminary planning data[1] showed that it is necessary to 
choose different radiation beam angles, but the impact on treatment plan quality is not clinically 
significant for most patients. Patients for whom treatment plan quality is in the opinion of the 
treating physician adversely impacted by alteration of beam angles required by presence of the US 
probe will be treated with the non-altered plan, and thus be included in step 5.1(a), but excluded 
from 5.1(b&c), as US probe will be removed prior to treatment in these cases to allow for treatment 
with the best possible plan.  We expect this to be rare.   The success of this specific aim is defined 
as that the quality of the plans for 80% of patients will not be affected in the presence of the 

 
 
 
 
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ultrasound probe, defined as no more than a 2% decrease in tumor coverage, and also no more than 
a 2% increase in the dose to the most critical normal tissue for that tumor location (Prostate: dose 
to hottest 10 cc of rectum.) 
 
6.0  
Study Parameters 
The study parameters collected are the US images acquired prior to each treatment and during 
radiation delivery.  Pre-treatment KV-CBCT images will also be collected for dosimetric analysis. 
Specifically, the tumor location detected from combined US/KV-CBCT images will be compared 
with using KV-CBCT alone. Using the KV-CBCT the gold standard,  3D radiation dose 
distributions will be re-calculated according to the tumor localizations using KV-CBCT alone and 
using combined US/KV-CBCT.  For SBRT prostate cancer, we will compare the following 
dosimetric endpoints, extracted from dose volume histograms.  
 Organ Name 
Endpoint 1 
Constraints 
PTV_HD* 
V5000 cGy 
> 50% 
PTV_LD* 
V3625 cGy 
> 95% 
PROSTATE 
V3625 cGy 
> 95% 
BLADDER 
D0.03 cc 
< 5250 cGy  
RECTUM_ANT 
D0.03 cc 
<5000 cGy 
RECTUM_LAT 
D3cc 
< 4000 cGy 
RECTUM_POST 
V0.03 cc 
< 2250 cGy 
URETHRA 
V0.03cc 
< 5000 cGy 
URETHRA 
D1cc 
< 4500 cGy 
 
PTV_HD = planning target volume in high dose prescription dose of 5000  cGy 
PTV_LD = planning target volume in low prescription dose of 3625 c Gy. 
 
For patients treated with conventional multiple fractionation, we will compared the following 
dosimetric endpoints, extracted from dose volume histograms. 
 

 
 
 
 
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Organ Name 
Endpoint 1 
Constraints 
Planned  
comments 
CTV_7800 
V7800 cGy 
> 99% 
 
 
PTV_7800 
V7800 cGy 
> 95% 
 
 
BLADDER 
V7000 cGy 
< 10% 
 
 
BLADDER 
V6000 cGy 
< 20% 
 
 
RECTUM 
V7000 cGy 
< 10% 
 
 
RECTUM 
D10cc  
< 7000 cGy 
 
 
RECTUM 
V5000 cGy 
< 30% 
 
Without pelvic  
nodes 
RECTUM 
V5000 cGy 
< 50% 
 
With pelvic nodes 
FEMORAL HEAD_L 
V5000 cGy 
< 5% 
 
 
FEMORAL HEAD_R 
V5000 cGy 
< 5% 
 
 
PENILE BULB 
Dmean 
< 5250 cGy 
 
 
 
 
For patients with prostatectomy receiving post-operative radiotherapy with conventional multiple 
fractionation, we will compared the following dosimetric endpoints, extracted from dose volume 
histograms. 
 
Organ Name 
Endpoint 1 
Constraints 
Planned  
comments 
CTV_7000 
V7000 cGy 
> 99% 
 
 
PTV_7000 
V7000 cGy 
> 95% 
 
 
BLADDER 
V6500 cGy 
< 40% 
 
 
BLADDER 
V4000 cGy 
< 60% 
 
 
RECTUM 
V6300 cGy 
< 10 % 
 
 
RECTUM 
D10 cc 
<6300 cGy 
 
 

 
 
 
 
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RECTUM 
V4500 cGy 
< 30 % 
 
Without Pelvic 
nodes 
RECTUM 
V4500 cGy 
< 50% 
 
With pelvic nodes 
FEMORAL HEAD_L 
V5000 cGy 
< 5% 
 
 
FEMORAL HEAD_R 
V5000 cGy 
< 5% 
 
 
PENILE BULB 
Dmean cGy 
< 5250 cGy 
 
 
 
7.0  
Statistical Considerations 
Because of limited funding from NIH, the number of patients that are planned to be enrolled into 
this protocol will be small and potentially lacking of the statistical power. The primary purpose of 
this study is a feasibility study to test whether a combined CBCT and ultrasound image guidance 
is clinically feasible. Our analysis is primarily descriptive  and does not require any advanced 
statistics to analyze the endpoints.   As a measure of protocol success we expect that: 
 
1) Over 80% of patients have ultrasound images which are clinically adequate for treatment 
set-up in the judgment of the treating physician.   
2) Over 80% of patients are able to undergo ultrasound based tumor tracking during 
treatment. 
3) The quality of treatment plans for more than 80% of patients will not be affected.  
4) No adverse events related to the ultrasound probe are noted during treatment.  
   
8.0 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
8.1  
Data Storage 
Data will be stored electronically on a secure server in a password protected file. Access to data 
will be restricted with only principal and co-investigators as well as study coordinators and 
appointed regulatory reviewers having access to the file’s contents. 
 
8.2  
Adverse Events and Data Monitoring 
This protocol is a feasibility study.  No clinical adverse events are expected.  We will record 
number of patients who have the ultrasound probe attached during treatment and number of 
patients who have the ultrasound probe removed. When the treatment completed, no study related 
follow up is required.  
 
 
 
8.3  
Written Informed Consent 

 
 
 
 
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Provision of written informed consent must be obtained prior to any study-related procedures. The 
Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and be 
allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. Additionally, documentation of the 
consenting process should be located in the research chart. 
 
8.4  
Sources of Materials  
The research project will involve acquiring ultrasound images in addition to the standard x-ray 
images acquired for the treatment procedures.  All other medical records and data will also be 
collected per standard practice to manage the treatment of the patient.  
 
The medical records and data collected during the studies will consist of identifiable information 
that can be linked back to the patient (e.g. patient names, treatment dates, history numbers, dates 
of progression and/or response). We will obtain privacy authorizations from patients before we 
collect and store data and medical information. Only the research team listed in this proposal will 
have access to the subjects’ identities and any data or records disclosed to a third party will be de-
identified. 
 
8.5   
Potential Risks 
Other than the potential of mild discomfort from the placement of the ultrasound probe, there is 
no risk associated with the additional on-board ultrasound imaging.  During treatment planning, 
we will make sure that the US probe and the passive arm are not blocking the radiation beams, and 
conduct a run dry run (before radiation treatment) to make sure adequate clearance between the 
passive arm and the gantry of the linear accelerator.  
 
All other potential risks are associated with the standard clinical practice of radiation treatment.  
These will be managed with established procedures in place.  
 
8.6  
Protection Against Risk 
No adverse effects are expected from the additional ultrasound imaging in the research.  
 
Protections against Breach of Confidentiality: 
All research personnel involved in this study will comply with HIPAA regulations. The following 
measures will be taken to minimize the risk of breaching patient confidentiality: 
• 
Patients’ clinical data (hard and soft copies) will be stored in electronic format and stored 
in a password protected server located in a locked sever room at main Campus of Cleveland 
Clinic.  

 
 
 
 
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• 
Only research staff and authorized regulatory agencies will have access to the data. The 
secured data includes: case report forms, source documentation, signed consent forms, and 
any material containing patient identifying information. 
• 
This data will be securely stored in electronic format in Cleveland Clinic and data pertinent 
to this protocol will be stored in a password protected server that is located in a locked 
server room. 
• 
No information by which patients can be identified will be published. 
 
8.7   
Potential benefits of the proposed research to the subjects and others 
There is no additional benefit to the study participants.  However, participants could potentially 
receive an indirect benefit of a feeling of altruism knowing their participation will pave the way 
for future patients whose treatment may be guided by the integrated 3D x-ray/ultrasound imaging 
system. 
 
8.8   
Importance of the knowledge to be gained 
The research aims to develop a novel non-invasive approach of image guidance of 
hypofractionated SBRT of patients with abdominal and pelvic tumors with the capability of 
continuous monitoring during radiation delivery.  Successful monitoring of target position during 
treatment is expected to reduce margins required during radiation treatment, and thereby reduce 
dose to surrounding normal tissue.  This has been demonstrated clinically using real-time tracking 
technology using implanted markers in prostate cancer, but in this study would be able to be done 
non-invasively using ultrasound.   
 
The analysis of the recalculated dosimetry will show the uncertainty of dose delivery using current 
CBCT and ultrasound image guidance methods and shed light on the degree of improvement that 
can be achieved when they are combined. The data from the feasibility studies will be immensely 
useful for designing a treatment protocol with adequate statistical power to prove the improvement 
in treatment accuracy and efficacy.  In turn, a cost-benefit analysis can then be made in terms of 
resource allocation, treatment efficiency and margin reduction.  The information will be most 
significant as a baseline for assessing the cost-effectiveness of the next generation of advanced 
IGRT machines such as those employing on-board MRI.   
 
8.9   
Retention of records  
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, and all correspondence for as long as needed to comply with 
national and international regulations. No records will be destroyed until the Principal Investigator 
confirms destruction is permitted.  
 
 
 
8.10  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification. The purpose of an audit or inspection is to 

 
 
 
 
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systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol, Good Clinical Practice (GCP), guidelines of the International 
Conference on Harmonization (ICH), and any applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 References: 
 
1. 
Zhong, Y., et al., Assessing feasibility of real-time ultrasound monitoring in stereotactic 
body radiotherapy of liver tumors. Technol Cancer Res Treat, 2013. 12(3): p. 243-50.