Randomized Trial of Image -Guided Stereotactic Radiation Therapy (IG-SRT) in Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University

 
 
 
 
 
 
  
 
 
IRB protocol: 1604017139 
Version 1.0 – 08.24.2016 
NCT#: NCT02911922 
 
TITLE: Randomized trial of image -guided stereotactic radiation therapy (IG-SRT) in 
prostate cancer  
 
IRB Protocol #: 1604017139   
Version 1.0 – 08.24.2016 
 
Principal Investigator: 
 
Dr. Josephine Kang 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
   
     212-746-3601 
 
     jok9106@med.cornell.edu 
 
Co-Principal Investigator:   
Dr. Silvia Formenti 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
   
     212-746-3608 
 
 
formenti@med.cornell.edu 
 
 
 
 
Co- Investigators                :       Leonard Farber 
Lower Manhattan Cancer Center  
21 West Broadway 
New York, NY 10007 
 
     abf9018@med.cornell.edu 
 
 
 
 
 
Michael Smith 
Lower Manhattan Cancer Center  
21 West Broadway 
New York, NY 10007 
 
 
 
 
      mis9146@med.cornell.edu 
 
 
 
Encouse Golden 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
   
     212-746-3611 
 
 
eng2003@med.cornell.edu 
 
 

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Bao Li 
56-45 Main Street 
3S – Room 387 
Flushing, NY 11355 
 
 
bal9018@med.cornell.edu 
 
 
 
 
Jim Hu 
25 East 68th Street 
Starr Pavilion, 9th Floor, Room 900 
New York, NY 10065 
 
 
jch9011@med.cornell.edu 
 
Nurse Practitioner:  
 
Maria Fenton Kerimian 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
   
     212-746-6074 
 
    mak9186@med.cornell.edu 
 
 
Study Coordinator:                       Sharanya Chandrasekhar 
 
 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
 
     212-746-7277 
    shc2043@med.cornell.edu 
 
 
Data Coordinator:                         Christina Castro 
 
 
525 East 68th street 
Box 169, 
 
      New York, NY – 10065 
 
     212-746-2546 
    chc2071@med.cornell.edu 
 
 
 
 
 
 
 
 
 
 
 

Protocol # 1604017139 
Version Date 08.24.2016 
 
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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCMC. 
 
 

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List of Abbreviations 
 
All abbreviations used throughout the protocol must be defined.  
 
 
AE 
Adverse Event 
CBC 
CBCT 
CFR 
Complete Blood Count 
Cone Beam Computed Tomography 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
CTV 
DSMB 
Common Terminology Criteria for Adverse Events 
Clinical Target Volume 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
DVH 
EPIC 
ERB 
FDA 
Dose Volume Histogram 
Expanded Prostate Cancer Index Composite Instrument 
Endorectal Balloon 
Food and Drug Administration 
Fx 
GCP 
Fraction 
Good Clinical Practice 
GI 
GTV 
Gy 
GU 
HIPAA 
Gastrointestinal 
Gross Target Volume 
Gray 
Genitourinary 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HRQOL 
ICF 
IG 
IMRT 
IND 
Health-related Quality of Life 
Informed Consent Form 
Image Guided 
Intensity Modulated Radiation Therapy 
Investigational New Drug 
IRB 
NCCN 
PEG 
PHI 
Institutional Review Board 
National Comprehensive Cancer Network 
Polyethylene Glycol 
Protected Health Information 
PI 
PSA 
Principal Investigator 
Prostate Specific Antigen 

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PTV 
REDCap 
Planning Target Volume 
Research Electronic Data Capture 
RS 
RT 
SAE 
SBRT 
SUSAR 
TRUS 
UAP 
WCMC 
Rectal Spacer 
Radiation Treatment 
Serious Adverse Event 
Stereotactic Body Radiation Therapy 
Suspected Unexpected Serious Adverse Reaction  
Transrectal Ultrasound 
Unanticipated Problem 
Weill Cornell Medical College 
 
 
 
 

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Protocol Summary 
 
Randomized trial of image -guided stereotactic radiation therapy (IG-SRT) in prostate 
cancer 
IRB Protocol #:   
 
Short Title:  
 
 
Randomized trial of image-guided prostate SRT 
Principal Investigator:  
Dr. Josephine Kang 
Sample Size: 
 
N = 40 
Accrual Ceiling: 
 
This study plans to enroll a total of 40 patients  
Study Population: 
 
Patients with low-risk or favorable intermediate-risk prostate 
cancer as defined by 1.2016 NCCN criteria   
Accrual Period: 
 
4 years  
Study Design: 
 
Randomized, two-arm study. 
 
 
Patients will be randomized to either rectal spacer placement or 
endorectal balloon placement, daily prior to each radiation 
treatment.   
Study Duration: 
 
5 years   
Study Agent/  
Intervention Description: 
 
1. Endorectal balloon (ERB): Immobilization device manually placed into the rectum prior to 
radiation treatment planning CT and daily treatment delivery, to immobilize the prostate and 
reduce prostate motion. 
2. Rectal spacer (RS): Biodegradable gel that is transperineally injected between the rectum and 
prostate under transrectal ultrasound guidance, to increase physical distance and thereby reduce 
radiation dose to the anterior rectal wall. The spacer begins to biodegrade in 2-3 months, and is 
fully absorbed within 6 months. 
 
Primary Objective:  
  
1. To compare acute GI/GU toxicity (as defined by CTCAE v4.0) 
2. To compare rectal dose (V35, max rectal dose) 
 
 
Secondary objective:  
1.  To compare health-related quality of life (HRQOL) measured using the Expanded Prostate 
Cancer Index Composite (EPIC) instrument for bowel, urinary and sexual domains 
2. To compare biochemical recurrence-free survival at 1, 2 and 5 years 
3. To compare the dose distribution of the 2 techniques, specifically: 
a) coverage of the PTV  
b) DVH of  organs at risk  (OAR) 

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c) prostate motion and shifts required during treatment  
 
4.  To compare late GI/GU toxicity (as defined by CTCAE v4.0) 
 
Exploratory Objectives: 
 
1. To explore microbiome changes associated with normal tissue toxicities resulting from 
radiation 
2. To collect complete blood count (CBC) measurements at pre-treatment, 1, 3 , 6 and 12 months 
post-treatment to assess impact of SBRT, if any, on baseline values  
 
Endpoints: 
 
 
The primary endpoints of this study are  
a) Acute GI/GU toxicity 
b) Rectal dose (Dmax, V35) 
 
The secondary endpoints of this study are: 
 
a. EPIC bowel, urinary and sexual domain outcomes 
 
b. Biochemical recurrence-free survival 
 
c. Late GI/GU toxicity 
 
d. Dose distribution 
 
e. Microbiome alterations 
 
f. CBC measurements 

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SCHEMA 
  
 
 
 
 
 
 
 
 
 
 
 
Follow-up visits at 3-4, 12 and 24 weeks, then q6 months 
At each follow-up: CTCAE toxicity assessment, EPIC evaluation, PSA measurement 
Microbiome sample collection: during CT simulation, during first RT treatment and last RT 
treatment, and at first post-RT follow up. 
14 CBC collection: pre-RT, and at each post-RT follow-up for up to 1 
year. 
 
 
Low, Intermediate-Risk 
And High-Risk Prostate Cancer  
 
(Excludes cT3a-T4) 
 
GROUP 1 (n=20) 
Endorectal Balloon (ERB) 
 
ERB placed before RT treatment planning 
CT, and is repositioned prior to each 
fraction 
 
GROUP 2 (n=20) 
Rectal Spacer (RS) 
 
Ultrasound-guided transperineal 
placement of a biodegradable spacer 
(RS) between the prostate and rectum 
before RT treatment planning CT, and 
prior to fraction 1 
RANDOMIZE 
 
 
Prostate IG-SRT (7.25Gy x 5 fractions) 
 

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Table of Contents 
PROTOCOL SUMMARY ............................................................................................................................................................. 6 
SCHEMA ......................................................................................................................................................................................... 8 
1.0 STUDY OBJECTIVES ..................................................................................................................................................... 11 
1.1. 
PRIMARY OBJECTIVES ................................................................................................................................................................. 11 
1.2 
SECONDARY OBJECTIVES ................................................................................................................................................................. 11 
1.3 
EXPLORATORY OBJECTIVES ............................................................................................................................................................. 11 
2 
BACKGROUND ............................................................................................................................................................... 11 
2.1 
PROSTATE CANCER RADIOTHERAPY ............................................................................................................................................... 11 
2.2 
INVESTIGATIONAL AGENT OR DEVICE ........................................................................................................................................... 12 
2.2.1 
Endorectal balloon ........................................................................................................................................................... 12 
2.2.2 
Rectal spacer....................................................................................................................................................................... 12 
2.3 
RATIONALE ........................................................................................................................................................................................ 13 
2.4 
RISK/BENEFIT ASSESSMENT .......................................................................................................................................................... 15 
2.4.1 
Endorectal Balloon: ......................................................................................................................................................... 15 
2.4.2  Rectal Spacer:........................................................................................................................................................................... 15 
2.5 
CORRELATIVE STUDIES BACKGROUND .......................................................................................................................................... 15 
2.5.1 
Microbiome sampling. ..................................................................................................................................................... 15 
2.5.2 
CBC assessment .................................................................................................................................................................. 16 
3. 
SUBJECT SELECTION ................................................................................................................................................... 16 
3.1 
STUDY POPULATION ......................................................................................................................................................................... 16 
3.2 
INCLUSION CRITERIA ........................................................................................................................................................................ 16 
3.3 
EXCLUSION CRITERIA ....................................................................................................................................................................... 16 
4 
REGISTRATION PROCEDURES ................................................................................................................................. 16 
4.1 
PATIENT REGISTRATION .................................................................................................................................................................. 16 
5.1 
PRE-STUDY VISIT .............................................................................................................................................................................. 18 
5.2 
PLANNING CT/MRI ......................................................................................................................................................................... 18 
5.3 
RADIATION TREATMENT PLANNING ............................................................................................................................................. 19 
5.3.1 
Total Prescribed Dose ..................................................................................................................................................... 19 
5.3.2 
Dose Coverage .................................................................................................................................................................... 19 
5.3.3 
Radiotherapy Delivery .................................................................................................................................................... 19 
5.3.4 
Image Guidance ................................................................................................................................................................. 19 
5.3.5 
Treatment planning parameters ................................................................................................................................ 19 
5.3.6 
Dosimetry ............................................................................................................................................................................. 19 
5.47 
RADIATION TREATMENT ........................................................................................................................................................... 20 
5.5 
SUPPORTIVE CARE GUIDELINES ..................................................................................................................................................... 20 
5.6 
DURATION OF THERAPY AND CRITERIA FOR REMOVAL FROM STUDY ..................................................................................... 20 
5.7 
DURATION OF FOLLOW UP .............................................................................................................................................................. 20 
6 
DOSE MODIFICATIONS ............................................................................................................................................... 20 
7. 
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................................ 21 
7.1 
ADVERSE EVENT DEFINITION ......................................................................................................................................................... 21 
7.2 
RECORDING OF ADVERSE EVENTS .................................................................................................................................................. 21 
7.2.1 
Reporting of AE to WCMC IRB ..................................................................................................................................... 21 
7.3 
DEFINITION OF SAE ......................................................................................................................................................................... 21 
7.3.1 
Reporting of SAE to IRB .................................................................................................................................................. 22 

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7.3.2 
Expedited Adverse Event Reporting .......................................................................................................................... 22 
7.3.3 
AE/SAE Follow Up ............................................................................................................................................................ 23 
8 
PHARMACEUTICAL INFORMATION ....................................................................................................................... 23 
9 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................................... 23 
9.1 
LABORATORY CORRELATIVE STUDIES ........................................................................................................................................... 23 
9.1.1 
Microbiome collection ..................................................................................................................................................... 23 
9.1.2 
Coding of Specimens ........................................................................................................................................................ 24 
10 
MEASUREMENT OF EFFECT ...................................................................................................................................... 24 
10.1 
BIOCHEMICAL RECURRENCE-FREE SURVIVAL ....................................................................................................................... 24 
11 
DATA REPORTING / REGULATORY CONSIDERATIONS .................................................................................. 24 
11.1 
DATA COLLECTION ...................................................................................................................................................................... 24 
11.1.1 
REDCap ........................................................................................................................................................................... 24 
11.1.2 
Regulatory Considerations ...................................................................................................................................... 24 
11.1.3 
Data Management ...................................................................................................................................................... 25 
12. STATISTICAL CONSIDERATIONS ............................................................................................................................ 25 
12.1 
STUDY DESIGN/ENDPOINTS ..................................................................................................................................................... 25 
12.2 
SAMPLE SIZE/ACCRUAL RATE .................................................................................................................................................. 26 
12.3 
STRATIFICATION FACTORS ........................................................................................................................................................ 26 
12.4 
ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS .......................................................................................................... 26 
12.5 
ANALYSIS OF CORRELATIVE ENDPOINTS ................................................................................................................................ 27 
12.5.1 
Sample size justification ........................................................................................................................................... 27 
12.5.2 
Statistical analysis of microbiome and metagenome composition ......................................................... 27 
12.6 
REPORTING AND EXCLUSIONS ................................................................................................................................................... 29 
13.0 
DATA AND SAFETY MONITORING PLAN (DSMP) ......................................................................................... 29 
13.1 
MONITORING PLAN ..................................................................................................................................................................... 29 
13.2 
STOPPING RULES ......................................................................................................................................................................... 29 
14 
REFERENCES .................................................................................................................................................................. 29 
 

 
 
  
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1.0 STUDY OBJECTIVES 
 
HYPOTHESIS: A rectal spacer will reduce rectal radiation, compared to endorectal balloon, and 
reduce the incidence of acute and late toxicities of IG-SRT to the prostate, with comparable QOL 
and tumor control results 
 
1.1. 
Primary Objectives 
 
1. To compare acute GI/GU toxicity (as defined by CTCAE v4.0) 
2.  To compare rectal dose (V35, max rectal dose) 
 
1.2 Secondary Objectives 
 
 
1.  To compare health-related quality of life (HRQOL) measured using the Expanded Prostate 
Cancer Index Composite (EPIC) instrument for bowel, urinary and sexual domains 
2. To compare biochemical recurrence-free survival at 1, 2 and 5 years 
3. To compare the dose distribution of the 2 techniques, specifically: 
a) coverage of the PTV  
b) DVH of  organs at risk  (OAR) 
c) prostate motion and shifts required during treatment  
4.  To compare late GI/GU toxicity (as defined by CTCAE v4.0) 
 
   1.3 
Exploratory Objectives 
 
1. To explore microbiome changes associated with normal tissue toxicities resulting from 
radiation 
2. To collect complete blood count (CBC) measurements at pre-treatment, 1, 3 , 6 and 12 months 
post-treatment to assess impact of SBRT, if any, on baseline values  
 
 
 
 
2  
BACKGROUND 
 
2.1 Prostate cancer radiotherapy  
 
Other than skin cancer, prostate cancer is the most commonly diagnosed cancer in men, and 
second leading cause of cancer death. 1 It is estimated that one out of seven men will be 
diagnosed with prostate cancer during their lifetime. The average age at diagnosis is 66. Due to 
the availability of prostate specific antigen (PSA) testing, the majority of men are diagnosed with 
organ-confined prostate cancer, which is further stratified by NCCN into low-, intermediate- and 
high-risk disease based on T-stage, initial PSA, and Gleason score. Intermediate-risk prostate 
cancer is classified as favorable versus unfavorable, depending on the number of intermediate-
risk group features.2  
 
Patients with low- and favorable intermediate-risk prostate cancer have multiple treatment 
options available, including surgery (e.g., radical prostatectomy ± pelvic lymph node dissection), 
brachytherapy or external beam radiation (EBRT). EBRT is the least invasive of the 

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aforementioned options. Standard EBRT is delivered over a time course of 9-10 weeks, and 
entails daily treatment of up to 50 treatment fractions. Due to the protracted course of standard 
EBRT, hypofractionated approaches have been investigated, with promising results thus far. 
Hypofractionated EBRT delivers higher dose per each fraction, thereby allowing a decrease in 
the total number of fractions required. There is now data supporting use of extremely 
hypofractionated EBRT for high risk prostate cancer, showing comparable results to standard 
EBRT; 3-6  
 
Extremely hypofractionated regimens are delivered most commonly within 5 fractions, allowing 
completion of treatment within 1-2 weeks. Such treatments are delivered using stereotactic or 
image-guided IMRT approaches, and most commonly referred to as prostate SRT. Single 
institutional and pooled reports have demonstrated similar efficacy and toxicity to conventionally 
fractionated regimens. 3,6,7  The NCCN treatment paradigm  currently includes SRT as an 
alternative to conventionally fractionated regimens at clinics with appropriate technology, 
physics and clinical expertise.2 
 
2.2 Investigational Agent or Device 
 
2.2.1 
Endorectal balloon 
 
The RectalPro endorectal balloon (ERB) by QLRAD, Inc. will be used for patients on the ERB 
arm. This ERB which has been utilized successfully in numerous studies without adverse 
outcomes.8-10 The ERB is an inflatable device, typically filled with approximately 60 ml of air or 
sterile water and introduced into the rectum to a set depth (most common: 12 cm) with locking 
stopper to fix positioning. 11 Endorectal balloons have been utilized during prostate radiation to 
reduce intrafraction prostatic motion, and improve reproducibility. Multiple published studies 
have reported significant decrease in prostate motion with use of a rectal balloon during 3-D 
conformal radiation as well as intensity-modulated radiation therapy (IMRT). 8,12-14 Studies have 
shown that ERB can be successfully used during prostate SRT to both reduce prostatic motion 
and improve set up reproducibility.11,15  
The ERB will be placed into the rectum prior to the radiation treatment planning CT, and prior to 
each radiation treatment. The balloon is promptly removed immediately upon completion of each 
radiation treatment. No changes to the device will occur.  
 
2.2.2 
Rectal spacer 
The SpaceOAR gel system will be utilized for all patients on the rectal spacer arm. This is an 
FDA-approved, biocompatible, absorbable hydrogel that will be injected transperineally with 
transrectal ultrasound (TRUS) guidance and local anesthesia to create a distance of 1.0-1.5 cm 
between the rectum and prostate. According to a multicenter, randomized trial, use of the 
SpaceOAR rectal spacer increased the mean perirectal space to 12.6 + 3.9 mm, compared to 1.6 
+ 2.0 mm in the control arm.16  Numerous studies have shown this procedure to be safe and well-
tolerated, with minimal risk of side effects.17-20 Approximately 3 months after injection, the 
hydrogel begins to liquefy and is slowly absorbed into the system and cleared via renal filtration.  
  

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The majority of published studies have looked at use of rectal spacers prior to standard 
fractionation external beam radiation and brachytherapy. 17-20  A prospective randomized study 
of 222 patients has demonstrated significant reduction in late bowel toxicity with use of rectal 
spacers. In this study, patients were randomized to hydrogel rectal spacer versus no spacer prior 
to undergoing fiducial-guided IGRT to dose of 79.2 Gy  No device-related adverse events, 
infection or serious bleeding were reported.16 There was a significant decrease in late rectal 
toxicity (7% vs 2%), and decreased likelihood of experiencing a 10-point decline in bowel 
quality of life EPIC score (12% vs 21%). By using a spacer, the volume of rectum receiving 70 
Gy or higher decreased from 12% to 3%, allowing the rectal wall to be excluded from exposure 
to high radiation doses in majority of patients. A comparable endpoint for 5-fraction SBRT, is  
the volume of rectum  receiving >35 Gy , a parameter we selected as a primary study endpoint. 
 
2.3 Rationale 
 
Stereotactic radiation therapy (SRT) delivers high doses of radiation to the prostate, most 
commonly 36.25 Gy, in 5 fractions over 1-2 weeks. Single-institution studies and pooled 
analyses demonstrate excellent outcomes, comparable to standard EBRT which requires up to 10 
weeks of daily treatment.3,6 Late grade 3 genitourinary and gastrointestinal toxicity also appears 
to be comparable to standard EBRT, ranging from 0.6 – 3% 3,6 with longest median follow-up of 
7 years.  
 
During radiation treatment planning, the prostate volume is expanded several millimeters to 
create the planning target volume (PTV). The prostate is situated immediately anterior to the 
rectum. As a result, the rectal wall is almost always included in the target volume, and becomes 
the major dose-limiting organ. Studies on conventionally fractionated radiation and 
brachytherapy have demonstrated that increased dose to the rectum is directly correlated with 
increased risk of rectal toxicity.21-23 It is equally important to avoid high dose to the urethra, 
which runs centrally through the prostate, and be cognizant of dose to the bladder neck, which 
overlies the superior/anterior aspect of the prostate. Meticulous treatment planning techniques 
are required to accurately identify the prostate, and avoid depositing high dose to normal 
structures, particularly during SRT since the dose per fraction is much higher than EBRT. 
 
SRT delivers high dose to the target with a rapid dose fall-off. Thus, it is important to limit 
prostate motion as much as possible during treatment delivery. A small shift in the prostate can 
result in decreased dose to the target. There are multiple techniques to account for prostate 
motion during delivery of SRT. Such techniques include tracking via implanted radiofrequency 
transponders (e.g., Calypso), on-board kV imaging of prostate fiducials at 30-60 second intervals 
(e.g., Cyberknife), and use of multiple cone-beam CTs during treatment. 
 
Physical devices such as the ERB have shown promise in reducing prostate motion during 
treatment.13,14 By placing the ERB directly into the rectum and securing it in place, the prostate is 
displaced anteriorly, limiting posterior shifts. Studies have demonstrated that ERB improves 
rectal dosimetry, by distancing the posterior and lateral rectal wall from the radiation target and 
thereby sparing these regions of the rectum from excessive exposure to radiation.12,13 However, 
at least one study examining use of ERB during SRT suggests the reduction in radiation dose to 

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the posterior and lateral rectal wall results in higher dose to the anterior rectal wall.11 Increase in 
rectal wall dose has also been demonstrated for EBRT.14 Whether increased anterior rectal wall 
dose translates to a clinically meaningful detriment to acute and late GI toxicity remains 
unknown at this point in time, and further studies are needed. 
 
Rectal spacers are being utilized with increasing frequency to reduce dose to the rectum, but 
studies examining use of rectal spacers in SRT are limited. By inserting a rectal spacer between 
the prostate and rectum, a physical distance is constructed between the posterior aspect of the 
prostate and anterior rectal wall. As a result, a high dose can be delivered safely with standard 
margins, while sparing normal tissue. According to one study, after rectal spacer placement, a 
safety margin of 4 mm from CTV to PTV appears to be sufficient to cover all prostate 
movements, even without any correction. This is in contrast to motion studies on patients 
undergoing radiation without spacer placement, who have demonstrated intrafraction motion of 
up to 9 mm over the course of 8-16 minutes.24  Thus, there is suggestion that a spacer may act as 
a stabilizer.25  As a result, it is possible that use of a rectal spacer can limit prostate motion, while 
protecting the rectum. By reducing rectal dose, use of a rectal spacer may result in decreased 
acute and late toxicity. 
 
Our study seeks to help address this hypothesis. Despite the variety of accepted techniques for 
prostate SRT delivery, to our knowledge there are no studies comparing dosimetric endpoints, 
toxicity  and HRQOL endpoints after randomization to two different methods. Additional studies 
are needed to determine whether rectal spacers are superior to endorectal balloons.  
 
During SRT planning, increased dose heterogeneity allows improved dose fall-off at target 
boundaries, whereas improved dose homogeneity results in a slower dose fall-off gradient. For 
situations where the target is in close proximity to a normal organ, greater dose heterogeneity can 
be accepted in order to protect the normal organ. For prostate SRT with ERB, maximizing dose 
fall-off at the prostate-rectal wall interface may result in regions of high-dose deposition within 
the target volume, and care must be taken to avoid high-dose to the urethra, which lies within the 
target. On the other hand, delivery of prostate SRT with a rectal spacer allows dose homogeneity 
to be prioritized, 26 since dose fall-off at the target boundary is less of a concern due to the 
distance between the prostate and rectal wall. As a result, we hypothesize that a more 
homogeneous dose distribution to the prostate, with improved target coverage, can be achieved 
by using a spacer versus rectal balloon, while at the same time reducing dose to the rectal wall 
and avoiding urethral hotspots. Our primary endpoint will be dose to the rectum, measured as 
rectal Dmax (maximum dose received to the rectum) and rectal V35 (volume of rectum receiving 
35 Gy or more), and associated acute GI/GU toxicity. As secondary endpoints, we will assess 
late toxicity, EPIC HRQOL,biochemical recurrence free survival and compare dose-volume 
histograms of organs at risk (rectum, bladder), intra-fraction prostate motion.  
 
 
 
 
 
 

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2.4 Risk/Benefit Assessment  
 
2.4.1 
Endorectal Balloon: 
 
There are no documented reports of any significant complications resulting from ERB 
placement. We anticipate that the ERB will be in place for approximately 30-45 minutes during 
treatment planning CT, and approximately 10-15 minutes during each of the 5 radiation 
treatments. It is expected that ERB placement in the rectum may result in a sensation of pressure 
or discomfort, but there should not be any pain during or after the procedure. Any 
discomfort/pressure from the rectal balloon should resolve once the balloon is removed. 
 
2.4.2  Rectal Spacer: 
There are numerous reports on use of hydrogel rectal spacers during prostate RT, with no 
documented reports of any significant toxicity or complications. Spacers are FDA-approved, 
biocompatible, non-toxic and non-allergenic, and insertion is well-tolerated in published 
reports.27 Prior to spacer placement, lidocaine is injected into the perineal area to provide local 
anesthesia. There may be slight discomfort associated with the local anesthesia, and sensation of 
pressure during the rectal spacer placement. At time of spacer injection, 4 gold fiducial markers 
are introduced into the prostate for localization, a standard procedure prior to image-guided RT 
for prostate cancer. The risks of spacer placement are minimal, and include possible 
bleeding/hematoma formation, infection, and skin irritation.  
 
A potential benefit of using a rectal spacer includes improved dosimetry and decreased radiation 
dose to surrounding rectum, bladder neck and urethra. This may potentially translate into late 
acute- and long-term toxicity. Also, if our hypothesis is correct, that use of a spacer allows 
homogeneous dose distribution with better PTV coverage, it is possible that biochemical 
recurrence-free survival also improves as a result. 
 
2.5 Correlative Studies Background 
 
2.5.1 
Microbiome sampling.  
 
During radiation treatment for prostate cancer, the anterior rectal wall will receive a high dose of 
radiation. As a result, the rectal mucosa will undergo signs of radiation injury, characterized by 
inflammation as well as loss of the epithelial barrier.28,29  Clinically, mucositis manifests as 
bloating, rectal discomfort and loose stools.30,31 Recent studies have demonstrated a role for 
commensal intestinal microbiota on development and severity of mucositis. It has been 
suggested that certain microbiota predispose for radiation-induced diarrhea, but there are very 
few studies on this.32 To our knowledge, there are no studies on microbiome changes after 
exposure to ablative doses of radiation, and the correlation with rectal mucosa toxicity.   
 
Patients undergoing radiation for prostate cancer require digital rectal examination as part of 
routine physical and follow up visits. During this process, it is simple to acquire a small fecal 
sample to process. We plan to obtain samples at the time of the radiation planning CT, after the 

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first and last radiation treatment, and at the first follow up visit. If the patient prefers, he will 
have the option of providing us with a stool sample. 
 
2.5.2 
CBC assessment 
 
Radiation beams pass through the pelvic bone marrow. The acute and long-term impact on the 
white blood cells has not been well-studied. Since patients undergoing prostate radiation undergo 
routine blood tests, including CBC, we plan to record this data up to 12 months post-RT for our 
analyses. We hypothesize that there will be minimal impact on blood counts after prostate SBRT.  
 
3. SUBJECT SELECTION 
 
3.1 Study Population 
Men with a histologically confirmed diagnosis of low-, intermediate- or high-risk prostate 
adenocarcinoma, meeting the inclusion and exclusion criteria below, and electing to undergo 
definitive radiation treatment, will be eligible for participation in this study. Use of androgen 
deprivation therapy (ADT) will be left to the discretion of the treating physician(s). 
 
3.2 Inclusion Criteria 
1. Biopsy-proven diagnosis of prostate adenocarcinoma, diagnosed within 1 year of 
randomization 
2. Either NCCN-defined low-risk disease (T1c-T2a, Gleason score 3+3=6, PSA <10), 
intermediate-risk disease (Gleason score 3+4=7, 4+3=7, T2b-c and/or PSA 10-20; ) or high-risk 
disease due to Gleason score 8-10 and/or PSA >20 ng/ml, but not due to T3-T4 disease on 
physical exam. 
3. Age ≥ 18 
 
3.3 Exclusion Criteria  
1. History of prior pelvic radiation (external beam or brachytherapy) 
2. Prior or concurrent lymphomatous/hematogenous malignancy, or history of prior/concurrent 
invasive malignancy during the past 5 years 
3.  Very high risk prostate cancer (T3b-T4 on clinical exam, Primary Gleason pattern 5, or >4 
cores with Gleason score 8-10) 
4. History of prior chemotherapy for prostate cancer 
5. History of irritable bowel disease 
6. Evidence of lymph node involvement 
7. AUA score >15 
8. Prostate size > 90 cc 
 
 
 
4 
REGISTRATION PROCEDURES 
 
 
4.1 
  Patient Registration 
 
 

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Before any protocol specific procedures can be carried out, investigators/staff will 
fully explain the details of the protocol, the study procedures and the aspects of patient 
privacy regarding research information. Patients will be provided a comprehensive 
explanation of the proposed treatment including the type of therapy, the rationale for 
treatment on the protocol, alternative treatments that are available, any known adverse 
events, the investigational nature of the study and the potential risks and benefits of the 
treatment. The informed consent document will meet all requirements of the Institutional 
Review Board (IRB). All subjects/patients are informed in the consent that participation or 
refusal to participate in the research study will not affect any of the clinical treatment or 
services to which they would otherwise be entitled. 
The physicians who may obtain informed consent are listed on the title page of 
this protocol. The informed consent form will be signed by the participant and the 
registering physician. Once signed, a copy will be given to the patient and one will be 
maintained with the patient’s medical record. Once eligibility is confirmed and informed 
consent is documented, the patient will be registered by the study coordinator/data 
manager. 
Patients will be centrally registered with the Office of Billing Compliance. To register a 
patient, submit the following documents via the JIRA Registration Process:  
 
• Legible copy of the HRBAF 
• Signed informed consent  
 
 Registration must be completed within 24 hours of the signing of informed consent.  
 
 
14 Study Procedures 
 
Schedule of Evaluations 
 
 
   
Pre-
Study 
Planning 
CT 
Fx 
1 
Fx
2 
Fx 
3 
Fx 
4 
Fx 
5 
Post-RT 
Wk 3-4 
3 mos 
6 mos 
12 mos 
18 mos – 60 
mos 
(assessment 
every 6 
mos) 
 
Rectal Spacer Placement 
 
X 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
Endorectal Balloon Placement 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CBC w/diff, plts 
X 
  
  
  
  
  
  
X 
X 
X 
X 
X 
 
PSA 
 
X 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
X 
 
X 
 
X 
 
Acute/Late 
Toxicity 
Assessment 
(CTCAE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EPIC Questionnaire 
 
X 
 
  
 
  
 
  
 
  
 
  
 
  
 
X 
 
X 
 
X 
 
X 
 
X 
 
Microbiome sample collection 
 
 
 
X 
 
 X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
5.1 Pre-Study Visit 
At the initial screening visit, patient will undergo: 
o Informed consent 
o Medical history  
o Medication History 
o Physical Exam 
o Baseline EPIC Questionnaire 
o Routine labs (CBC), if not done within the past 4 weeks 
Eligible subjects will be randomly assigned to endorectal balloon versus rectal spacer placement 
in a 1:1 ratio, using a computer-generated randomization scheme developed by the data manager. 
 
Patients randomized to the rectal spacer arm will be sent to a urologist for rectal spacer 
placement and also, optionally, placement of 3-4 gold fiducial markers into the prostate, which is 
a standard procedure for many patients prior to prostate RT. This must occur at least 5 days prior 
to the planning CT and pelvic MRI. 
 
Patients randomized to the ERB arm do can be scheduled for CT sim and MRI directly without 
any intervening procedures. 
 
5.2 
Planning CT/MRI Patients will be instructed to undergo a Fleet enema prior to planning 
CT. All patients will be sent for a pelvic MRI. The ideal MRI will be 3Tesla and in a position 
similar to treatment position, without use of an endorectal coil which can distort the prostate 
shape. 
Patients who are on the rectal spacer arm should wait at least 5 days prior to MRI to allow for 
edema to resolve.  
Treatment planning CT will be performed with vac loc immobilization. Patients will be advised 
to drink 1 cup of water 1 hour prior to the CT simulation to allow for a comfortably full bladder, 
if possible. A rectal catheter will be utilized to dispel any excess bowel gas. Patients randomized 
to the ERB arm will undergo CT sim with the ERB in place. Microbiome sample collection 
(stool from digital rectal exam will be collected) 
 
 

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5.3 
Radiation Treatment Planning 
 
5.3.1 
Total Prescribed Dose 
Patients on each arm will receive 5 fractions of radiation, 7.25Gy per fraction, delivered every 
day or every other day excluding weekends), to total dose of 36.25 Gy. . 
 
5.3.2 
Dose Coverage 
For both arms, V36.25 Gy (volume of the PTV receiving 36.25 Gy) must be ≥ 95%  
 
5.3.3 
Radiotherapy Delivery 
Radiation can be delivered using IMRT or VMAT technique. If using fixed gantry angle IMRT, 
at least 5 gantry positions must be used.  
 
5.3.4 
Image Guidance 
a. Arm 1: Endorectal Balloon: Patients randomized to this arm will receive image guidance with 
cone beam CT (CBCT) prior to, and during, each radiation treatment. The CBCT image will be 
examined by the radiation oncologist to ensure that the prostate is in appropriate position, and 
necessary shifts, if required, will be made prior to and during treatment to account for both inter- 
and intrafraction motion. 
 
b. Arm 2: Rectal Spacer: Patients randomized to this arm can be tracked either using 3D systems 
(CBCT), or 2D systems (ExacTrac, on board imaging, electronic portal imaging device, etc). 
Prostate position will be verified using the fiducials with 2 mm allowance around fiducial 
location at planning CT to fiducial location at time of actual treatment. 
 
5.3.5 Treatment planning parameters 
a. The clinical target volume (CTV) will consist of the prostate +/- proximal 1-2 cm of the 
seminal vesicles. This will be defined on the axial CT scan, with correlation to the pelvic MRI 
(fused, when possible, using the gold fiducials for patients on the rectal spacer arm).  
b. The PTV will be defined as 5 mm isotropic margin with 3 mm posterior margin. If necessary 
to meet dose constraints, the superior and anterior margin can be reduced to 3 mm. 
c. Normal tissues to contour: bladder, rectum, bilateral femoral heads, penile bulb, small bowel 
that is close to target volume. Rectum should be contoured from anus to the rectosigmoid 
flexure. 
d. Patients on the rectal spacer arm will have the spacer delineated, based on MRI. 
 
5.3.6 Dosimetry 
a. Maximum dose allowed to PTV is 38.78 Gy (107% of prescription dose). At least 95% of the 
PTV must receive 36.25 Gy. No aspect of the PTV should fall below 34.4 Gy. 
b. Critical organ limits: 
 
1. Rectum: Maximum point dose 38.06 Gy (105% prescription dose), D1cc 38.5 Gy 
 
2. Bladder: Maximum point dose 38.06 Gy (105% prescription dose) 
 
3. Penile Bulb: No more than 100% of prescription dose; D3cc 20 Gy 
 
4. Femoral heads: Maximum point dose 30 Gy 
 
5. Small bowel: Maximum point dose 25 Gy 

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5.47 Radiation Treatment 
Radiation treatments will be delivered on an outpatient basis. Approximately 2-3 hours before 
each radiation treatment session, the patient will undergo a fleet enema. On each treatment day, 
he will drink 1 cup of water approximately 1 hour before treatment time to allow bladder to be 
comfortably full, if patient can tolerate this.  
 
a. ERB arm: Before treatment, the endorectal balloon (RectalPro by QLRAD, Inc) will be 
positioned and locked into place. CBCT will be done to verify position and 
reproducibility. A second CBCT will be performed in between the treatment to account 
for any intrafraction motion. 
 
b. RS arm: Before treatment, CBCT will be performed to ensure the bladder is full to 
similar extent as time of simulation (this can impact seminal vesicle position), and also to 
look for excess gas in the rectum. If the rectum has excess gas, patient will be given the 
opportunity to dispel the gas or a rectal catheter can be temporarily placed to release the 
gas, and the catheter will be removed prior to start of treatment. Appropriate image 
guidance techniques will be utilized (please see 5.3.4 Image guidance).  
 
5.5 
Supportive Care Guidelines 
a. Urinary: A proportion of patients undergoing prostate SRT can expect increase in urinary 
frequency or urgency. If this becomes bothersome to the patient, medication to alleviate 
symptoms can be prescribed at the discretion of the treating radiation oncologist and 
documented in patient chart. 
b. Bowel: Bowel symptoms during time of prostate SBRT are rare. If patients develop rectal 
urgency, tenesmus or diarrhea, medication to alleviate symptoms can be prescribed at the 
discretion of the treating radiation oncologist, and documented in patient chart. 
 
 
 
 
5.6 
Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), radiation treatment is anticipated to 
complete within 2 weeks time. Patients can be removed from the study at any point should they 
decide they no longer wish to participate. They will continue to receive routine medical care as 
necessary outside the confines of this study. 
 
5.7 
Duration of Follow Up 
 
Patients will be followed for after removal from study or until death, whichever occurs first.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
 
6 
DOSE MODIFICATIONS 
None. 
 

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7. ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by patients or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1 
Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose.  
 
 
Adverse Event Characteristics and Related Attributions 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
 
• Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
7.2 
Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be maintained 
by the research staff and kept in the patient’s research chart.    
 
 
7.2.1 
Reporting of AE to WCMC IRB 
 
All AEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed
iate_Reporting_Policy.pdf.  
 
7.3 
Definition of SAE 
 

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SAE’s include death, life threatening adverse experiences, hospitalization or prolongation 
of hospitalization, disability or incapacitation, overdose, congenital anomalies and any 
other serious events that may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
7.3.1 
Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy
.pdf.  
 
7.3.2 
Expedited Adverse Event Reporting 
 
 
The principal investigator is responsible for monitoring the safety of patients who enroll in the study.  
All AEs occurring after any administration of the study drug will be followed until resolution.  The 
descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be used for adverse 
event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html). 
A serious adverse event (SAE) is any adverse drug experience that occurs at any dose that results in 
any of the following outcomes: 
- 
Death. 
- 
Life-threatening adverse drug experience. 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
- 
For the purpose of this study, hospitalizations for protocol-scheduled procedures, blood 
product transfusions, or for social reasons (i.e., awaiting transport home) will not be 
considered SAEs. 
- 
Persistent or significant disability/incapacity. 
- 
A congenital anomaly/birth defect. 
• Important medical events: Defined as AEs that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed above, even though these events may not be immediately life-threatening or 
result in death or hospitalization. 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy.pdf.  
 

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7.3.3 
AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the patient 
discontinues participation from the study. 
 
 
8 
PHARMACEUTICAL INFORMATION 
 
There is no investigative agent used on this protocol. 
 
9 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 
Microbiome collection 
 
9.1.1.1 Collection of Specimen(s): Fecal samples will be obtained via digital rectal exam and placed into an 
eppendorf tube. Alternatively, patients will have the option of providing stool samples from home into 
a plastic container. 
 
9.1.1.2  Handling of Specimens(s):  Samples will be promptly frozen at 20 degrees C, and transferred within the 
next week to a -80 degree freezer or liquid nitrogen for long-term storage. DNA extractions and 
16sRNA analysis will be performed once all samples are collected.  
 
The microbial DNA will be isolated and used to provide DNA sequence information. We will 
perform taxonomic characterization of bacteria (using 16S rRNA) and fungi (using ITS 
sequences). Prokaryotic diversity will be screened using massively parallel DNA sequencing, 
exploiting a multiplexing technique to generate 16S rRNA sequence tags, followed by analyses 
(statistical, clustering, and phylogenetic) to estimate the distribution of phylotypes, differential 
abundance, and the relative contributions between phylotypes and community dissimilarities to 
the overall diversity in individuals.  
 
In parallel studies, potential relationships with the fungal community will be characterized. An 
important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, 
strain, gene) at which to examine a scientific question 33-36. We will therefore also examine 
whether there are metagenome sequence content differences in patients displaying acute/late 
rectal mucosal toxicity versus those who remain unaffected. High-throughput sequencing will be 
performed for transcriptome analysis. 
 
We will examine whether there are metagenome sequence content changes during radiation 
treatment, and study whether differences in gene content indicate differences in functional 
pathways between the normal and irradiated microbiome using pathway analysis.   
 

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Samples will be collected by the research team and the samples will be stored in -80C freezer in 
Dr. Silvia Formenti’s lab until we establish a lab for sample analysis.  
 
9.1.2 
Coding of Specimens 
 
All patients enrolled will be given a unique identifier (study ID number). Only the data 
manager will know the code linking patient and study ID number. Patients will be assigned a 
unique code number. All specimens collected will be de-identified and assigned the same 
unique study number of the corresponding patient and will also be marked with the collection 
time point. Clinical information regarding toxicities and response will likewise be stored in a 
de-identified database using only the unique identifier (study ID number). 
 
 
10 
MEASUREMENT OF EFFECT 
 
10.1 Biochemical Recurrence-Free Survival  
 
Biochemical recurrence-free survival will be measured using the Phoenix criterion of PSA 
nadir + 2 ng/mL as evidence of biochemical failure. 
 
 
11 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients.  
 
11.1.1 
REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool 
for the creation of customized, secure data management systems that include Web-
based data-entry forms, reporting tools, and a full array of security features including 
user and group based privileges, authentication using institution LDAP system, with a 
full audit trail of data manipulation and export procedures.  REDCap is maintained on 
CTSC-owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through 
a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
 
11.1.2 
Regulatory Considerations 
 

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All protocol amendments and consent form modifications will be made by the 
Principal Investigator.   
 
11.1.3 
Data Management 
 
All patient data will be entered and maintained in REDCap.  These data include clinical data 
and all patient safety data. The REDCap provides audit trails that track creation and 
modification of records that include user id and timestamp. Once entered, the data is 
subjected to validation procedures that are executed either immediately or upon saving the 
eCRF page or during the batch validation process. Validation failures that are identified 
before the page is saved can be corrected immediately. Validation failures during saving of 
the eCRF page and during batch validation processes will generate a discrepancy. Depending 
on the database account privileges, the data managers may be able to correct a discrepancy or 
if not, route it to the project data manager at WCMC who can take appropriate action to 
correct the problem. Data clarification forms can also be printed out when necessary to be 
sent to the project data manager at JCTO. Once the discrepancy is closed, by marking 
“resolved” or “irresolvable”, the data is marked clean and an audit trail is generated by the 
system. 
All key end points will be source verified by a second person at each site and errors will be 
corrected. Once the data is verified and all discrepancies are closed, the data can be 
locked/frozen. Locking and freezing can be done at different granular levels and will follow 
institutional SOPs and any specific requirements for the project. 
Security measures that will be taken in order to protect patient data will include firewall 
technology and database level security which will be achieved by assigning roles and 
privileges to different levels of users and by requiring that the users authenticate themselves 
using user id and password. Additional security for data transfer between remote clients and 
servers will be achieved by using digital certificates/SSL. All data will be backed-up to tape 
periodically according to the Institutional SOPs. All data will be stored for at least 5 years 
following the termination of this study. 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1  Study Design/Endpoints 
 
The primary endpoints of this study are  
a) Acute GI/GU toxicity 
b) Rectal dose (Dmax, V35) 
 
The secondary endpoints of this study are: 
 
a. EPIC bowel, urinary and sexual domain outcomes 

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b. Biochemical recurrence-free survival 
 
c. Late GI/GU toxicity 
 
d. Dose distribution 
 
e. Microbiome alterations 
 
f. CBC measurements 
12.2 Sample Size/Accrual Rate 
The primary aim of this study is to compare the acute GI/GU toxicity proportion between 
patients receiving the endorectal balloon (Group 1) and patients receiving the rectal spacer 
(Group 2). With 20 patients in Group 1 and 20 patients in Group 2, a two group chi-square test 
with a 0.05 two-sided significance level will have 80% power to detect the difference between a 
endorectal balloon (Group1) acute grade I/II GU toxicity proportion of 72% and a rectal spacer 
(Group 2) acute grade I/II GU toxicity proportion of 29% (i.e., 60% reduction). Assuming acute 
grade I/II GU toxicity proportions of 72% and 29% in Groups 1 and 2, respectively, a 95% 
confidence interval for the difference in the toxicity proportion (43%) can be constructed to be 
within ± 27.9% of the observed difference in the toxicity proportion between Groups 1 and 2. 
This same calculation would also apply to acute grade I/II GI toxicity, which is hypothesized to 
be 77% in Group 1 and 31% in Group 2 (i.e., 20 patients per group would provide 86% power 
for this GI toxicity comparison with a two-sided alpha level of 5%).  
Randomization: 
A series of randomized blocks of 4 will be generated with a 1:1 allocation ratio. This will 
provide assurance that after four patients are enrolled in the study, there will be two patients 
assigned to Group 1 and two patients assigned to Group 2. This procedure will allow for a 
similar number of endorectal balloon patients (Group 1) and rectal spacer patients (Group 2), in 
the event that the planned sample size of 20 patients per group is not achieved. 
 
12.3 Stratification Factors 
 
Patients will not be risk-stratified. 
 
12.4 Analysis of Primary and Secondary Endpoints 
 
Primary Endpoint: 
The primary endpoint of the acute grade I/II GU/GI toxicity proportions will be calculated in 
both groups and 95% confidence intervals will be estimated via binomial proportions. The chi-
square test or Fisher’s exact test will be used, as appropriate, to compare the toxicity proportions 
between the two arms. Ninety-five percent confidence intervals for the difference in the toxicity 
proportions between the two groups will be estimated via binomial proportions. The co-primary 
endpoint of rectal dose (Dmax, V35) will be compared between the two groups using the two-
sample t-test/Wilcoxon rank-sum test or chi-square test/Fisher’s exact test, as appropriate, for 
continuous and categorical formulations of rectal dose, respectively. 

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Secondary Endpoints: 
Secondary endpoints will be compared between the two groups using the chi-square test or 
Fisher’s exact test, as appropriate, for 1) EPIC bowel, urinary, and sexual domain outcomes, and 
2) late GI/GU toxicity. Secondary endpoints will be compared between the two groups using the 
two-sample t-test or Wilcoxon rank-sum test, as appropriate, for 1) dose distribution and 2) CBC 
measurements.  
The secondary endpoint of biochemical recurrence-free survival (BRFS) will be estimated using 
the Kaplan-Meier method, and 95% confidence intervals for the BRFS estimates will be 
calculated using Greenwood’s formula. Median BRFS will also be estimated along with a 95% 
confidence interval. These calculations will be stratified by Group 1 vs. Group 2 and the log-rank 
test will be used to compare Kaplan-Meier BRFS between the two arms (for exploratory 
purposes only). 
The frequency of subjects experiencing specific toxicities will be tabulated for each arm. 
Toxicities will be assessed and graded according to CTCAE v. 4.0 terminology. Exact 95% 
confidence intervals around the toxicity proportions will be calculated to assess the precision of 
the obtained estimates. 
All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha level. 
Ninety-five percent confidence intervals for all parameters will be calculated to assess the 
precision of the obtained estimates. All analyses will be performed in SAS Version 9.4 (SAS 
Institute, Inc., Cary, NC) and Stata Version 14.0 (StataCorp, College Station, TX). 
 
12.5 Analysis of Correlative Endpoints 
 
Microbiome 
 
12.5.1 
Sample size justification 
A minimum of 25 patients will be required for this analysis. We calculated the minimum 
detectable difference based on single feature comparison between the subjects who will exhibit 
signs of mucosal injury (GI toxicity) versus those who will not. The feature could be the single 
taxon relative abundance or diversity index in describing microbiome distribution. If data are not 
normally distributed, we will normalize the data by either arcsine (i.e. for the relative abundance 
of each taxon or cluster) or log-normal. Based on the two-sided one sample paired t-test, to 
compare the microbiome change between before treatment and after treatment or the microbiome 
difference between affected versus non-affected patients (assuming rate of acute GI toxicity to be 
70% grade 1, 5% grade 2)37, the minimal detectable differences in term of σ at null with 
power=80% and α =0.05 is 0.58 σ.   
 
12.5.2 
Statistical analysis of microbiome and metagenome composition  
Statistical analysis of microbiome and metagenome composition will be performed in the R 
statistical programming environment 38 using package phyloseq 39, which incorporates and builds 
upon community ecology packages such as ade4 and vegan and employs the flexible graphic 

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system ggplot2, to easily visualize complex data relationships. For 16S data, we will evaluate the 
adequacy of sequencing efforts using rarefaction plots. Alpha diversity index for each will be 
characterized through dominance, equitability, richness, evenness. The diversity metrics will be 
calculated at OTU and higher taxonomical levels to best characterize the community structure. 
We will test for associations of each of these alpha diversity metrics with the time relative to 
radiation exposure, using one-way ANOVA after even-sampling the observations to a depth cut-
off maximizing the number of samples and depth. In addition, rank-abundance plots will be used 
to visualize differences in abundance of dominant taxa in the clinical and phenotypic groups. We 
will utilize skyline plots to visualize the patterns of community structure in terms of relative 
abundances in the collected samples between before and after the radiation treatment or between 
case and control samples. Similarly, for metagenomic data, skyline plots will be used to reveal 
functional compositions of the samples. Heat-maps will be plotted to visualize clustering patterns 
in the data. 
 
   Univariate analyses. To circumvent instabilities associated with rare species, which are 
difficult to detect uniformly in all samples, we will focus our primary univariate analyses only on 
highly abundant taxa, i.e. those present at 1% or more relative abundance across all specimens. 
This approach will also help to reduce multiple comparison-related Type I-error inflation, which 
will be formally controlled by false discovery rate (FDR) 40. The differences in presence or 
absence of specific taxa and functional categories will be assessed by χ2-test at all taxonomical 
levels. Paired-Sample Wilcoxon Signed Rank Test will be used to establish the differences in 
relative abundance of taxa between before and after the radiation treatment or between paired 
breastl samples. Depending on the dynamics observed, subsequent analyses may focus on less 
abundant taxa, and at higher depth, as indicated above. 
 
   Multivariate analyses. Multivariate association of the entire microbiome/metagenome with 
clinical and phenotypic factors will be examined with Principal Coordinate Analysis (PCoA) on 
Jensen-Shannon, weighted and unweighted Unifrac, and χ2 (correspondence analysis) distances. 
Likewise, these distances will be used to build non-parametric multivariate ANOVA models 
(ADONIS) 41 to allow for simultaneous measurement of univariate and interaction effects of the 
clinico-phenotypic variables on the microbiome. Starting with the microbiota and metagenomic 
features significantly different in univariate analyses, we will use the dimension-reduction 
method, canonical correlation analysis (CCA) to identify the bacteria taxa which are related 
radiation treatment, according to benchmarked methodologies of our prior studies 42,43. We will 
utilize a phylogenetic structure-constrained penalty function to impose phylogenetic 
relationships among bacteria on the model selection 44.  
 
Longitudinal analysis: We will study the evolution of microbiome over time and how that 
evolution associated with the radiation treatment.  The relative abundances at each taxonomical 
level will be first normalized by log-ratio transformation 45. Then the transformed relative 
abundance of each individual taxa at multiple time points will be fitted by the linear mixed 
model along with the time effect and all subject-specific characteristics as the independent 
covariates. For the nonlinear trend, we will combine the nature splines with linear mixed model 
in the data analysis.  The same model will be applied on the indices calculated in the ecology 
microbial analysis.   For the joint analysis of more than one taxon. we will use MCMCglmm R 

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package to implement the multivariate generalized linear mixed model. This package gives a 
large flexibility in analyzing correlated multiple longitudinal response by allowing different 
types of covariance structure 46.  
 
 
12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their 
first radiation treatment.  
 
12.6.2 Evaluation of response.  Disease control is monitored via PSA blood test for most 
routine cases. 
 
13.0 Data and Safety Monitoring Plan (DSMP) 
 
The WCMC Data and Safety Monitoring Committee (DSMC) is the central monitoring board 
for this study. 
 
13.1 
Monitoring plan 
 
This study will be conducted in accordance with the guidelines in the 2001 NCI approved 
data Safety and Monitoring plan for the WCMC Cancer Institute Monitoring will occur on a 
yearly basis from the date the first patient is enrolled. Reports to the Data Safety and 
Monitoring Committee will include the following information: accruals, targets, responses, 
adverse events and evidence of reporting to appropriate review committees. The WCMC 
Data and Safety Monitoring Board (DSMB) will review the IRB approved protocol, the data 
and safety monitoring plan and any stopping guidelines during protocol initiation. During the 
course of the study, the DSMB will review cumulative study data twice a year to evaluate 
safety, efficacy, study conduct, and scientific validity and integrity of the trial. The WCMC 
DSMB may also convene as needed if stopping criteria are met or other safety issues arise 
that the Principal Investigator and/or IRB would like the WCMC DSMB to address. 
 
 
13.2 Stopping rules  
 
There are no stopping rules for this study.  
 
 
 
 
14.0 
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