Endoesophageal Brachytherapy for Patients With Esophageal Cancer: A Balloon Repositioning, Multichannel Radiation Applicator for Optimizing Treatment Delivery
Phase: NA
Conditions: Esophageal Cancer
Sponsor: Case Comprehensive Cancer Center

CASE 5217 
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Version Date: 22 NOVEMBER 2017 
STUDY NUMBER:  CASE 5217 
ClinicalTrials.gov NCT #: NCT03335813
Protocol Date:  22 November 2017 
STUDY TITLE: 
Endoesophageal Brachytherapy for Patients with Esophageal Cancer: 
A Balloon Repositioning, Multichannel Radiation Applicator for 
Optimizing Treatment Delivery (IRB# IP 30) 
PRINCIPAL INVESTIGATOR: John F. Greskovich Jr., MD 
Case Comprehensive Cancer Center 
Cleveland Clinic Florida  
Maroone Cancer Center 
2950 Cleveland Clinic Blvd. 
Weston, Florida 33331 
(954) 659-5840
greskoj1@ccf.org
SUB-INVESTIGATORS: 
Tolga Erim, D.O. 
Case Comprehensive Cancer Center 
Cleveland Clinic Florida  
Maroone Cancer Center 
2950 Cleveland Clinic Blvd 
Weston, Florida 33331 
(954) 659-5000
erimt@ccf.org
Shengqiang Gao, Ph.D. 
Case Comprehensive Cancer Center 
Cleveland Clinic  
9500 Euclid Avenue  
Cleveland, OH 44195 
(216) 445-6674
gaos@ccf.org

 
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STUDY COORDINATOR: 
Kim Thomas  
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic Florida 
Maroone Cancer Center 
2950 Cleveland Clinic Blvd.  
Weston, Florida 33331 
 
 
(954) 487-2254 
 
 
 
 
thomask11@ccf.org 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
Cleveland Clinic - Innovative Practice Group 
 
 
 
SUPPORT/FUNDING: 
 
Cleveland Clinic 
 
 
SUPPLIED AGENT(S):  
N/A 
 
 
IND #:  
 
 
 
N/A 
 
 
 
 
 
OTHER AGENT(S): 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SUMMARY OF CHANGES 
 
Please provide a list of changes from the previous approved version of the protocol starting at 
IRB approval. This table will remain blank until initial IRB approval. The list shall be a brief 
overview. When appropriate, a brief justification for the change should be included. This is a 
running list for the life of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
 
 
Protocol Number/Title 
 
 
CASE 5217 
 
Study Phase 
 
 
PILOT TRIAL 
 
Brief Background/Rationale
 
 
 
 
This innovative study will be an improvement over our 
previously designed 3-tube endoesophageal 
brachytherapy technique in patients who are candidates 
for esophageal brachytherapy. The brachytherapy 
planning process will utilize our multichannel balloon 
applicator as described within. 
 
 
Primary Objective  
 
Pilot study of multichannel endoesophageal brachytherapy 
applicator to determine dose distribution and conformality 
of a 6 channel balloon repositioning applicator. 
 
 
Secondary Objective(s) 
 
1. To compare conformality and normal tissue doses versus 
previous 3-tube design. 
2. To evaluate acute toxicity of multichannel 
endoesophageal brachytherapy applicator. 
 
 
Exploratory Objective(s) 
 
None 
 
 
Correlative Objective(s) 
 
None 
 
 
Sample Size 
 
Number expected to accrue:   5 
Age: ≥18 
Gender: Male and Female 
 
 
Disease sites/Conditions 
 
Esophagus / Esophageal Cancer 
 
 
Interventions 
 
Agent/Route: Endoesophageal Brachytherapy 
Cycle Length: Weekly 
Number of cycles: Between 3 and 6 cycles 
 

 
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ABBREVIATIONS  
 
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC Protocol Review and Monitoring Committee
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
IPC 
Innovative Practice Committee 
 
 

 
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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Esophageal Cancer  
1.2  
Preclinical Data 
1.3  
Clinical Data to date 
1.4 
Rationale 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study design, and cohorts 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Radiation Therapy  
 
6.1.1 General Guidelines and Timing 
 
6.1.2 Equipment and Techniques to be used 
 
6.1.3 Target Volumes 
6.7 
Criteria for Removal from Study 
6.8 
Duration of Follow-Up 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Radiation Therapy Adverse Events 
8.3 
Definitions 
8.4 
Serious Adverse Event Report Form 
8.5 
Reporting Procedures for Serious Adverse Event  
8.6 
Serious Adverse Events and OnCoreTM    
8.7 
Data Safety Toxicity Committee 
8.8 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
 
10.0 
CORRELATIVE/EXPLORATORY   
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.2 
Calendar 
 

 
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12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
  
APPENDICES  
 
 
 
APPENDIX I 
 
ECOG / Karnofsky Performance Status Criteria  
 
 
APPENDIX II 
 
Data Collection Sheet 
 

 
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1.0 
INTRODUCTION 
Esophageal cancer is a global health problem with over 400,000 new cases and a similar 
number of deaths occurring each year.1 Although the highest incidence rates are observed 
in Southern and Eastern Africa and Eastern Asia, 16,980 cases are diagnosed each year in 
the United States and 15,590 deaths are attributed to this cancer annually.2 Depending on 
a combination of patient factors and disease characteristics, patients are often treated with 
definitive chemoradiation therapy or surgical resection, with or without pre-operative 
chemoradiation therapy. For patients treated with a non-operative approach, phase III 
trials using concurrent chemoradiation therapy have revealed high local failure rates 
(crude local failure 45-55%) in patients receiving moderate radiation therapy doses (50 
Gy).3, 4 Even in patients undergoing dose escalation (64 Gy) using external beam 
radiation therapy, the local failure rate continues to be problematic (crude: 50%, 2 year 
actuarial: 56%).4 Unfortunately, the nearby organs at risk (such as the lungs, heart, and 
spinal cord) limit the amount of radiation therapy that can be delivered via standard 
external beam radiation therapy techniques. 
 
1.1 
Background  
Brachytherapy is a radiation therapy treatment technique that allows for high doses of 
radiation to be delivered directly to the tumor volume while sparing the surrounding 
normal structures. Specifically, high-dose-rate (HDR) brachytherapy delivered using 
modern devices allows for high doses of radiation to be delivered directly to the tumor in 
a short period of time (minutes). In an effort to intensify therapy, multiple institutions 
investigated the role of esophageal brachytherapy in nonoperable patients. For example, 
Tamaki and colleagues demonstrated a local control rate of 79% at 5 years for 54 patients 
undergoing external beam radiation therapy followed by a 2-3 fraction brachytherapy 
boost.5 Although some investigators such as Tamaki reported encouraging results, the 
concern with this approach was the high incidence of treatment-related toxicity.  
 
A prospective Radiation Therapy Oncology Group (RTOG) trial was subsequently 
performed in patients undergoing definitive concurrent chemoradiation therapy for non-
metastatic esophageal cancer.6 Patients were treated to a dose of 50 Gy with concurrent 
chemotherapy, a two week break, and then three fractions of HDR brachytherapy at 
weekly intervals to a dose of 15 Gy (5 Gy per fraction per week). The brachytherapy 
applicator was prescribed to treat the tumor volume plus a one-centimeter margin 
proximally and distally. The dose was prescribed to a one cm depth from the source axis. 
Unfortunately, the high treatment-related toxicity (1-year actuarial fistula rate: 18%) 
observed with this approach limited its routine use and led to the development of strict 
selection criteria for patients to treated with brachytherapy by the American 
Brachytherapy Society (ABS).7 According to the consensus guidelines, good candidates 
for the procedure as a boost to definitive treatment include those with a unifocal thoracic 
esophageal cancer ≤ 10 cm in length with no extraesophageal extension of disease, and 
no nodal or metastatic disease. Strict contraindications for esophageal brachytherapy 
included patients with an esophageal fistula, cervical esophageal location, or a stenosis 
that could not be bypassed during endoscopy. 
 
In addition to nonoperable patients with esophageal cancer undergoing definitive therapy, 
patients with recurrent or metastatic disease may symptomatically benefit from HDR 
brachytherapy. In fact, a randomized controlled trial was recently performed in 209 

 
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patients with dysphagia from inoperable esophageal or gastroesophageal junction cancer 
treated with stent placement or a single dose (12 Gy) brachytherapy application. This trial 
showed a higher incidence of complications in patients undergoing stent placement (33% 
vs. 21%, p=0.02) with an improvement in quality-of-life and better long-term relief of 
dysphagia in patients undergoing brachytherapy.8 Therefore, patients with unresectable 
local disease progression, thoracic esophagus lesions with distant metastasis, or those 
who recurred after definitive external beam radiation therapy can also be considered 
candidates for the procedure per the ABS guidelines.7 In addition to these criteria, 
reported institutional series support the use of HDR brachytherapy in patients with 
symptomatic stenosis, dysphagia, or tumor hemorrhage as an alternative to endoscopy 
with coagulation or stent placement.9 
 
1.2 
Preclinical Data  
As previously mentioned, one of the limitations of esophageal brachytherapy is the lack 
of the treating physician's ability to modulate the dose when using a single tube device. 
The currently utilized and innovative approach used in our department is a 3-tube 
technique. Use of the 3-tube technique improves the dose homogeneity and reduces the 
doses to heart, lungs, bronchus, trachea, and vertebral bodies.  
 
 
 
Figure 1. Bar graphs demonstrating the improved dose homogeneity with the 3-tube 
approach. V100, V150, V200, and V300 represent the volume receiving 100%, 150%, 
200%, and 300% of the prescribed dose, respectively.  
 
 
Figure 2. Bar graphs demonstrating the reduced maximum doses of radiation to the 
nearby critical structures when utilizing a 3-tube technique compared to a single tube 
technique. 
 
As can be seen in Figure 3, with dose delivery using a single lumen (left picture), there 
are increased doses delivered to the surrounding normal structures. With use of the three-
tube technique (right), the prescription doses can be shaped to match the tumor volume 
more accurately.  

 
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A
B 
C 
Figure 4. Axial (A), 
sagittal (B), and 
coronal (C) CT 
treatment planning 
images for a patient 
with a locally 
advanced esophageal 
cancer undergoing 
HDR brachytherapy. 
Two transesophageal 
tubes (each 1.0 meter 
length) were used to 
deliver a dose of 5 Gy 
Figure 3. Axial CT 
treatment planning 
images for two 
patients undergoing 
HDR brachytherapy. 
Image on the left 
demonstrates the 
isodose distribution 
in a patient treated 
with a single tube, 
patient on right was 
treated with 3-tube 
technique. Note that 
all of the circles 
(representing 
isodose lines) are 
smaller with the 3-
tube technique.

 
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1.3 
Clinical Data to Date 
In an effort to further improve on our treatment technique, we have made substantial 
improvements by creating a novel balloon repositioning, multichannel brachytherapy 
applicator itself (i.e., 6 channels instead of 3-tubes). The following figures illustrate the 
current prototype of the new device designed specifically for this procedure. This new 
device contains a therapeutic balloon with a maximum diameter of 20 mm when inflated 
and an anchor balloon with a maximum diameter of 24 mm when inflated. A semi-hard 
tip was added to the end of the applicator tapering from the 10 mm diameter of the tube 
to 4-5 mm in diameter at the distal end to allow for easier placement through a narrow, 
stenotic tumor or strictured area, along with a guidewire channel added to the semi-hard 
tip. Finally, the seed channels have been designed to extend along the applicator and 
terminate at the midpoint of the anchor balloon to allow the inflated anchor balloon to 
push the seed channels closer to the gastroesophageal junction wall (closer to the tumor 
to improve dose delivery).  
 
A previous prototype incorporating many of the above improvements was tested in a 
porcine model which showed ease of placement of the device and successful anchoring at 
the gastroesophageal junction.   
 
 
Figure 5. Overview of the catheter with inflated balloons. 
 
 
 
 
 
 

 
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Figure 6. View of seed delivery channels (A) and cross-view (B) 
 
 
 
 
 

 
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Figure 7.Partial views of the catheter 
 
 
 
 
 
 
 
 
 
 

 
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Figure 8.Deflated applicator (without outer sheath) 
 
 
 
1.4 
Rationale  
Although patient access to endoscopy centers has expanded and the incidence of 
esophageal cancer continues to increase, one of the key limiting factors in the more 
widespread use of esophageal brachytherapy is the limitations of the current single 
catheter approach. Therefore, in an effort to improve on this technique, patients in our 
department have been treated using a novel 3-tube technique. This 3-tube technique 
makes the dose more conformal and reduces the "hot spots" of radiation (doses above the 
prescription dose) in the esophageal wall. We evaluated the clinical outcomes of the 
initial thirteen patients treated for medically unresectable, stage 0-IVA, esophageal 
cancer with our 3-tube design: Five patients were treated with HDR brachytherapy alone 
and eight were treated with a combination of HDR brachytherapy and external beam 
radiation therapy. Across all patients, the 18-month local control, disease-free-survival, 
and overall survival rates were 81%, 74%, and 92%, respectively. Moreover, no patients 
have suffered a fistula as a result of treatment and only two patients have required 
dilation for esophageal strictures. A majority of the patients (11 of 13) continue to be free 
of dysphagia at a median of 17 months of follow-up. These promising initial results have 
fueled our interest in further innovation of our delivery technique in an effort to broaden 
the utility of esophageal brachytherapy as well as provide more effect cancer-directed 
therapy while maintaining a patient's quality of life. 
 
2.0  
OBJECTIVES 
 
2.1  
Primary Objective  
Pilot study of multichannel endoesophageal brachytherapy applicator to determine dose 
distribution and conformality of a 6 channel balloon repositioning applicator. 
 
2.2 
Secondary Objective(s) 
 
a. To collect data in order to show how the 6-tube endoesophageal brachytherapy technique will 
be an improvement (more conformed dose distribution) over our previously designed 3-tube 
endoesophageal brachytherapy technique in patients who are candidates for esophageal 
brachytherapy 
b. To evaluate acute toxicity of novel endoesophageal brachytherapy applicator. 
 
 

 
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3.0 
STUDY DESIGN 
 
This innovative study will be an improvement over our previously designed 3-tube 
endoesophageal brachytherapy technique in patients who are candidates for esophageal 
brachytherapy. The brachytherapy planning process will utilize our multichannel balloon 
applicator as described above. 
 
Intraoperative procedure 
In the operating room, the patient's pulse, pulse oximetry, and blood pressure are obtained prior 
to the procedure and during the procedure. The patient is typically medicated with Demerol (100 
mg IV) and Versed (4 mg IV) throughout the procedure and Benzocaine topically prior to the 
procedure as per standard anesthesia practices for esophageal brachytherapy patients. The 
endoscope is passed through the mouth under direct visualization and advanced distally, 
typically to the stomach or 2nd portion of the duodenum. The scope is then gradually withdrawn 
and the mucosa is examined. Of note, if a significant area of stenosis is identified, this is dilated 
to allow for a sufficient diameter for insertion of the brachytherapy applicator. Once the 
cancerous mucosa is visualized, radio-opaque markers (endoclips or metallic seeds) are placed 
with ~2 cm margins on the proximal and distal ends of the tumor. A guidewire is then passed to 
the stomach and the endoscope is removed. Over the guidewire, the brachytherapy applicator 
device is then placed under fluoroscopic guidance ensuring that the distal end travels past the 
most distal radio-opaque endoclip and typically into the stomach. The brachytherapy applicator 
is then stabilized and secured by inflating the anchor balloon and/or fixing to the mouth guard 
after removal of the guidewire. 
 
After applicator placement, the patient is transported to the Department of Radiation Oncology 
for a CT simulation. Metal dummy seeds are placed into the channels. The treatment balloon is 
inflated to move the channels in close proximity to the esophageal tumor. The patient is placed in 
the supine position and undergoes a planning CT scan of the neck and thorax. The CT images are 
downloaded into the Oncentra treatment planning system and then tumor volume as well as 
normal critical structures are outlined by the treating radiation oncologist. During the treatment 
planning phase, the patient is transported to the nursing unit for observation. Following 
completion of treatment planning, the patient is transported to the HDR brachytherapy treatment 
room and maintained on the transport cart in the supine position. The exterior portions of the 
brachytherapy channels are connected to the remote afterloader HDR device.  AnIridium-192 
seed will enter the channels to deliver the planned course of brachytherapy. After treatment 
delivery, the brachytherapy channels are disconnected from the HDR afterloader device.  After 
deflation of the anchor and treatment balloons and disconnection from the mouthpiece the 
multichannel applicator is removed gently from the patient. No devices will remain in the 
patient. The patient is subsequently transported to the nursing unit for vital sign monitoring for 
approximately one-half hour prior to discharge to home.  
 
Radiation therapy treatment planning 
Patients will be planned using our standard 3D, CT-based, Oncentra treatment planning 
system. The target volume will be identified during endoscopy and an approximately 2 cm 
proximal and distal margin will be added to account for microscopic tumor extension 
(beyond the gross macroscopic disease) and to account for any spatial inaccuracy of the 
applicator device positioning. The dose will be prescribed to treat the target volume with 
modification if necessary to decrease doses to the normal surrounding tissues. 
 

 
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Patients will be treated using standard radiation therapy dosing guidelines, typically in 2-
6 sessions separated by weekly intervals. In addition to identifying the treatment volume 
(CTV, PTV), the organs at risk will be identified. Typical dosimetry constraints, such as 
the dose delivered to 90% of the tumor volume (D90) and the volume of the tumor 
receiving the prescription dose (V100) will be reviewed to ensure that an acceptable 
treatment plan is designed. The use of our new applicator will improve the dose 
homogeneity as well as lower the dose to the nearby normal organs.  
 
Data Collection: 
The focus of the data collection includes but is not exclusive (or limited) to:  
 
A. Date of the procedure 
 
B. Radiation therapy dosimetry and treatment planning parameters 
 
C. Patient tumor characteristics 
 
D. Video of the endoscopy procedure 
 
E. All CT imaging datasets acquired for patient treatment 
 
F. Screen shots from the treatment plan 
 
G. Comments and feedback from members of the treatment team 
 
H. Acute toxicity 
Data Collection (cont’d) 
I. Tumor Response: CR, PR, SD, PD 
J. Esophageal Ulceration (Yes / No) 
K. Esophageal Fistula (Yes / No) 
L. Esophageal Stricture (Yes / No) 
M. Need for Dilation (Yes / No)      
 
 
Figure 9. Diagram 
demonstrating the 
treatment volume for a 4 
cm esophageal tumor 
treated with a HDR 
brachytherapy 
applicator. A 2 cm 
margin is added on 
either end to account for 
microscopic tumor 
extension and to account 
for any spatial 
inaccuracy of the 
applicator device 
positioning.9  

 
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Data Analysis: 
As this application is specifically for a new device to deliver the same doses of radiation 
therapy previous administered using single or multi-tube approaches, we will analyze 
data on patient outcome and dosimetry data in comparison with our historical controls. 
Specifically, we will use endoscopic follow-up images and correlate the visual changes 
with the radiation therapy doses delivered to the tumor, esophageal wall, and nearby 
organs at risk.  
 
3.1  
Study design / cohorts  
 
There is only one cohort for this trial. Subjects will be eligible based on meeting the 
inclusion/exclusion criteria. 
 
3.2 
Number of Subjects 
 
Approximately 5 subjects will be enrolled in this trial.  
 
 
3.3 
Replacement of Subjects  
 
If subject does not receive the esophageal brachytherapy treatment, they will be excluded from 
the trial and another subject will be selected.   
 
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
The initial treatment session will occur after the patient has been found to be eligible, the consent 
form has been completed, and the treatment plan has been created. The patient will undergo 
subsequent weekly treatments for 3 to 6 weeks after the initial treatment. 
 
The subject will be expected to participate in the trial throughout its entirety. The participation 
period is 6 months of which the patient will be evaluated and seen at months 3 and 6. 
 
4.0 
SUBJECT SELECTION 
 
Each of the criteria in the sections that follow must be met in order for a subject to be considered 
eligible for this study. Use the eligibility criteria to confirm a subject’s eligibility.  
 
4.1 
Inclusion Criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment: 
 
1. Biopsy-proved esophageal adenocarcinoma or squamous cell carcinoma 
 
2. Disease that can be encompassed in the radiotherapy treatment field 
 
3. Age ≥ 18 years: Because no dosing or adverse event data are currently available on the  
use of esophageal brachytherapy in subjects ≤18 years of age, children are excluded from 
this study.” 

 
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4. Women of childbearing potential must practice adequate contraception 
 
5. Subjects must have the ability to understand and the willingness to sign a written  
 
informed consent document. 
 
 
4.2 
Exclusion Criteria  
The presence of any of the following will exclude a subject from study enrollment. 
 
1. Concurrent chemotherapy at the time of brachytherapy treatments 
 
2. Tracheal or bronchial involvement 
 
3. Cervical esophagus location 
 
4. Stenosis that cannot be bypassed or dilated to allow for applicator placement 
 
5. Not willing or unable to provide informed consent 
 
6. History of esophageal fistula 
 
 
4.3 
Inclusion of Women and Minorities  
Men and women at or over the age of 18, and members of all races and ethnic groups are eligible 
for this trial. 
 
 
5.0 
REGISTRATION 
All subjects who have been consented are to be registered in the OnCore™ Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Cleveland Clinic Florida’s Maroone Cancer Center and 
will be provided a study number by contacting Kim Thomas at (954) 487-2254 or 
thomask11@ccf.org.   
 
Eligible subjects will be enrolled into the trial and treated as per standard of care. 
 

 
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6.0 
TREATMENT PLAN 
 
6.1 
 Radiation Therapy 
 
6.1.1  General Guidelines and Timing 
Radiation therapy treatment planning 
Patients will be planned using our standard 3D, CT-based, Oncentra treatment planning 
system. The target volume will be identified during endoscopy and an approximately 2 cm 
proximal and distal margin will be added to account for microscopic tumor extension 
(beyond the gross macroscopic disease) and to account for any spatial inaccuracy of the 
applicator device positioning. The dose will be prescribed to treat the target volume with 
modification if necessary to decrease doses to the normal surrounding tissues. 
 
Intraoperative procedure 
In the operating room, the patient's pulse, pulse oximetry, and blood pressure are obtained 
prior to the procedure and during the procedure. The patient is typically medicated with 
Demerol (100 mg IV) and Versed (4 mg IV) throughout the procedure and Benzocaine 
topically prior to the procedure as per standard anesthesia practices for esophageal 
brachytherapy patients. The endoscope is passed through the mouth under direct visualization 
and advanced distally, typically to the stomach or 2nd portion of the duodenum. The scope is 
then gradually withdrawn and the mucosa is examined. Of note, if a significant area of 
stenosis is identified, this is dilated to allow for a sufficient diameter for insertion of the 
brachytherapy applicator. Once the cancerous mucosa is visualized, radio-opaque markers 
(endoclips or metallic seeds) are placed with ~2 cm margins on the proximal and distal ends 
of the tumor. A guidewire is then passed to the stomach and the endoscope is removed. Over 
the guidewire, the brachytherapy applicator device is then placed under fluoroscopic 
guidance ensuring that the distal end travels past the most distal radio-opaque endoclip and 
typically into the stomach. The brachytherapy applicator is then stabilized and secured by 
inflating the anchor balloon and/or fixing to the mouth guard after removal of the guidewire. 
 
6.1.2 Equipment and Techniques to be used 
After applicator placement, the patient is transported to the Department of Radiation Oncology 
for a CT simulation. Metal dummy seeds are placed into the channels. The treatment balloon is 
inflated to move the channels in close proximity to the esophageal tumor. The patient is placed in 
the supine position and undergoes a planning CT scan of the neck and thorax. The CT images are 
downloaded into the Oncentra treatment planning system and then tumor volume as well as 
normal critical structures are outlined by the treating radiation oncologist. During the treatment 
planning phase, the patient is transported to the nursing unit for observation. Following 
completion of treatment planning, the patient is transported to the HDR brachytherapy treatment 
room and maintained on the transport cart in the supine position. The exterior portions of the 
brachytherapy channels are connected to the remote afterloader HDR device.  AnIridium-192 
seed will enter the channels to deliver the planned course of brachytherapy. After treatment 
delivery, the brachytherapy channels are disconnected from the HDR afterloader device.  After 
deflation of the anchor and treatment balloons and disconnection from the mouthpiece the 
multichannel applicator is removed gently from the patient. No devices will remain in the 
patient. The patient is subsequently transported to the nursing unit for vital sign monitoring for 
approximately one-half hour prior to discharge to home. 
 
 

 
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6.1.3 Target Volumes 
Patients will be treated using standard radiation therapy dosing guidelines, typically in 2-6 
sessions separated by weekly intervals. In addition to identifying the treatment volume (CTV, 
PTV), the organs at risk will be identified. 
  
6.1.4 Dose to Target and Organs at Risk Constraints 
Typical dosimetry constraints, such as the dose delivered to 90% of the tumor volume (D90) 
and the volume of the tumor receiving the prescription dose (V100) will be reviewed to 
ensure that an acceptable treatment plan is designed. The use of our new applicator will 
improve the dose homogeneity as well as lower the dose to the nearby normal organs.  
 
 
6.7 
Criteria for Removal from Study 
In the absence of treatment delays due to adverse events, treatment may continue for up to 6 
cycles or until one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 
• General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator,  
 
• Subject decision to withdraw from treatment (partial consent) or from the study (full consent), 
 
• Pregnancy during the course of the study for a child-bearing participant 
 
• Death 
 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
The date and reason for discontinuation must be documented. Every effort should be made to 
complete the appropriate assessments.  
 
 
6.8 
Duration of Follow Up 
Subjects will be followed for 6 months after the initial procedure or until death, whichever 
occurs first.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
 

 
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8.0 
ADVERSE EVENTS AND POTENTIAL RISKS  
 
8.1 
Radiation Therapy  
All patients will be seen weekly by their treating radiation oncologist while undergoing EBRT. 
Any observations with respect to the following symptoms/side effects will be recorded: 
 
• Bowel/rectal irritation manifesting as cramping, diarrhea, urgency, proctitis, or 
hematochezia 
• Urinary frequency, urgency, dysuria, hematuria, urinary tract infection, or incontinence 
• Radiation dermatitis 
 
Clinical discretion may be used in managing radiotherapy-related side effects. Diarrhea/rectal 
frequency/urgency may be managed with diphenoxylate or loperamide. Bladder irritation may 
be mitigated with phenazopyridine. Urinary frequency/urgency can be managed with 
anticholinergic agents or alpha-blockers such as tamsulosin. Erectile dysfunction can be 
managed with phosphodiesterase (PDE) inhibitors such as sildenafil. 
 
8.3 
Definitions  
 
8.3.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject.  
 
8.3.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in 
any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time of 
the event.  It does not refer to an adverse event which hypothetically might have caused 
death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 

 
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o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may fulfill 
the criteria of “medically important” and as such may be reportable as a serious adverse 
event dependant on clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
• Results in persistent or significant disability/incapacity.  The definition of disability is 
a substantial disruption of a person’s ability to conduct normal life’s functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result death, be 
life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood disease or 
disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
For the purpose of this study the following events would not be considered adverse events and 
would not be recorded in the database: 
• Abnormal laboratory findings considered associated to the original disease 
 
8.3.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events (both serious and 
non-serious) observed by the clinical team or reported by the subject which occur after the 
subject has signed the informed consent are fully recorded in the subject’s medical records. 
Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, result 
in a delay or dose modification of study treatment, or judged relevant by the investigator), should 
be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational therapy/agent- (this must be 
assigned by an investigator, sub-investigator, or treating physician) 
• Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no 
action, received conmed or other intervention, etc. 
• Outcome of event 

 
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Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for agent AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.4  
SAE Report Form 
 
SAE’s related to radiation therapy only will be recorded into OnCore and reported to IRB 
according to local IRB policies and procedures.  
 
SAEs related to agent therapy will be recorded on the FDA Form 3500A (MedWatch) but should 
only be reported as instructed below. The electronic FDA SAE reporting forms should not be 
used.   
 
8.5  
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur [Please insert 
appropriate time frame, e.g. on or following first day of RT, on day of registration, etc.] through 
30 days after the final dose of study radiation therapy/drug. Adverse events, both serious and 
non-serious, and deaths that occur during this period will be recorded in the source documents. 
All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
subject’s stable or chronic condition or intercurrent illness(es). Related AEs will be followed 
until resolution to baseline or grade 1 or stabilization.  
 
8.5.1 SAE Reporting Requirements 
• Participating investigators (all sites) must report all serious adverse events to the Lead 
Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of discovery or 
notification of the event. The participating investigator must also provide follow-up 
information on the SAE until final resolution.  
o John F. Greskovich Jr., M.D.: (954) 659-5840 / Fax: (954) 487-2816 
o Study Coordinator: Kim Thomas (954) 487-2254 / thomask11@ccf.org.  

 
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• The Lead Site Principal Investigator will review the SAE and report the event to the 
FDA, external collaborator(s), and IRB as applicable. 
• It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
Institutional Review Board Reporting Requirements: 
• Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events.  
 
8.6 
SAEs and OnCore 
• All SAEs will be entered into OnCore.   
• A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 
 
8.7  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or 
external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to the sponsor and/or other 
regulatory bodies  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
  
8.8 
Data and Safety Monitoring Plan 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section #8. 
  
 
 
10.0 
CORRELATIVE STUDIES  
 
N/A 
 
 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
 
11.2 
Calendar  
Patients will be treated weekly for 3 to 6 weeks. 
Follow up visits will take place at 3 and 6 month intervals. 
A visit window of +/- 1 day is allowed for treatment/procedure visit 
A visit window of +/- 7 days is allowed for the 3 and 6 month follow-up visits. 
 
 

 
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12.0  MEASUREMENT OF EFFECT  
     -Tumor Response: CR, PR, SD, PD 
     -Esophageal Ulceration 
     -Esophageal Fistula 
     -Esophageal Stricture 
     -Need for Dilation      
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer Center, 
to provide data collection for both accrual entry and trial data management. OnCore™ is a 
Clinical Trials Management System housed on secure servers maintained at Case Western 
Reserve University. OnCore™. Access to data through OnCore™ is restricted by user accounts 
and assigned roles. Once logged into the OnCore™ system with a user ID and password, 
OnCore™ defines roles for each user which limits access to appropriate data. User information 
and password can be obtained by contacting the OnCore™ Administrator at OnCore-
registration@case.edu. 
 
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case Report 
Form completion in the OnCore™ database. A calendar of events and required forms are 
available in OnCore™. 
 
13.2 
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. 
13.2.1 Written Informed consent 
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. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 

 
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information that includes all hospital records relevant to the study, including subjects’ medical 
history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and international 
regulations. No records will be destroyed until the Principal Investigator confirms destruction is 
permitted.  
 
13.2.4  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 site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  
For multi-center studies, participating sites must inform the sponsor-investigator of pending 
audits.  
 
14.0 
STATISTICAL CONSIDERATIONS 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, changes made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  
 
A variety of statistical methods will be employed to analyze the trials’s data. Data will be 
periodically analyzed using descriptive statistics and correlative measures for significance 
when comparing demographic and dosimetric data. Typical dosimetry constraints, such as 
the dose delivered to 90% of the tumor volume (D90) and the volume of the tumor receiving 
the prescription dose (V100) will be reviewed to ensure that an acceptable treatment plan is 
designed. The use of our new applicator will improve the dose homogeneity as well as lower 
the dose to the nearby normal organs.  
 
As this application is specifically for a new device to deliver the same doses of radiation 
therapy previous administered using single or multi-tube approaches, we will analyze data on 
patient outcome and dosimetry data in comparison with our historical controls. Specifically, 
we will use endoscopic follow-up images and correlate the visual changes with the radiation 
therapy doses delivered to the tumor, esophageal wall, and nearby organs at risk.  One of the 
limitations of esophageal brachytherapy is the lack of the treating physician's ability to 
modulate the dose when using a single tube device.  
 
The currently utilized and innovative approach used in our department is a 3-tube technique. 
Use of the 3-tube technique improves the dose homogeneity and reduces the doses to heart, 
lungs, bronchus, trachea, and vertebral bodies. In addition to nonoperable patients with 
esophageal cancer undergoing definitive therapy, patients with recurrent or metastatic disease 
may symptomatically benefit from HDR brachytherapy. In fact, a randomized controlled trial 

 
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was recently performed in 209 patients with dysphagia from inoperable esophageal or 
gastroesophageal junction cancer treated with stent placement or a single dose (12 Gy) 
brachytherapy application. This trial showed a higher incidence of complications in patients 
undergoing stent placement (33% vs. 21%, p=0.02) with an improvement in quality-of-life 
and better long-term relief of dysphagia in patients undergoing brachytherapy.8 Therefore, 
patients with unresectable local disease progression, thoracic esophagus lesions with distant 
metastasis, or those who recurred after definitive external beam radiation therapy can also be 
considered candidates for the procedure per the ABS guidelines.7 

 
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REFERENCES 
References 
 
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 
CA Cancer J Clin. 2011;61: 69-90. 
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65: 5-
29. 
3. al-Sarraf M, Martz K, Herskovic A, et al. Progress report of combined 
chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an 
intergroup study. J Clin Oncol. 1997;15: 277-284. 
4. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology 
Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-
dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20: 1167-1174. 
5. Tamaki T, Ishikawa H, Takahashi T, et al. Comparison of efficacy and safety of low-
dose-rate vs. high-dose-rate intraluminal brachytherapy boost in patients with superficial 
esophageal cancer. Brachytherapy. 2012;11: 130-136. 
6. Gaspar LE, Winter K, Kocha WI, Coia LR, Herskovic A, Graham M. A phase I/II 
study of external beam radiation, brachytherapy, and concurrent chemotherapy for 
patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group 
Study 9207): final report. Cancer. 2000;88: 988-995. 
7. Gaspar LE, Nag S, Herskovic A, Mantravadi R, Speiser B. American Brachytherapy 
Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Clinical 
Research Committee, American Brachytherapy Society, Philadelphia, PA. Int J Radiat 
Oncol Biol Phys. 1997;38: 127-132. 
8. Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus 
metal stent placement for the palliation of dysphagia from oesophageal cancer: 
multicentre randomised trial. Lancet. 2004;364: 1497-1504. 
9. Lettmaier S, Strnad V. Intraluminal brachytherapy in oesophageal cancer: defining its 
role and introducing the technique. J Contemp Brachytherapy. 2014;6: 236-241. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to 
carry on all pre-disease performance 
without restriction.  
 
100 
 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., 
light housework, office work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work.  
 
2 
In bed < 50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any work 
activities. Up and about more than 
50% if waking hours. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
3 
In bed > 50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
 
40 
 
Disabled, requires special care 
and assistance. 
 
30 
 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care. Totally confined to bed or chair. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent.  
 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX II 
 
DATA COLLECTION SHEET