MRI-guided Stereotactic Body Radiotherapy (SBRT) With Simultaneous Integrated Boost for Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University

Identifiers: NCT03664193    
Unique Protocol ID: 1802019010 
Brief Title: 
MRI-guided Stereotactic Body Radiotherapy 
(SBRT) With Simultaneous Integrated Boost for 
Prostate Cancer (SIBRT) 
 
Version 3.1  
 
Version date: 20FEB2019 
 
IRB approval: 29MAY2019 
 
Document History 
 
 
Version 
Version date 
Amendment 4 
3.1 
02.20.2019 
Amendment 3 (Protocol) 
3.0 
01.28.2019 
Amendment 2 (Protocol) 
2.1 
10.30.2018 
Amendment 1 Protocol 
2.0 
10.05.2018 
Initial Protocol 
1.0 
06.13.2018 
 

 
 
 
 
 
 
  
 
 
 
 
 
 
TITLE: MRI-guided Stereotactic Body Radiotherapy (SBRT) with Simultaneous   
Integrated Boost for Prostate Cancer 
 
 
IRB Protocol #:   1802019010 
Version 3.1 
Version Date : 02/20/2019 
 
Principal Investigator:  
 
Josephine Kang,M.D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Principal Investigator:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co- Investigators: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Nurse Practitioner:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator: 
 
Sharanya Chandrasekhar, M.S, CCRP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
shc2043@med.cornell.edu 
 
 

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Data Coordinator: 
 
Pragya Yadav, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pry2003@med.cornell.edu 
 
Statistician: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
AUA 
Adverse Event 
American Urologic Association 
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 
PHI 
Institutional Review Board 
National Comprehensive Cancer Network 
Protected Health Information 
PI 
Principal Investigator 

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PIRADS 
PSA 
PSMA 
PTV 
REDCap 
Prostate Imaging Reporting and Data System 
Prostate Specific Antigen 
Prostate Specific Membrane Antigen 
Planning Target Volume 
Research Electronic Data Capture 
RS 
RT 
SAE 
SBRT 
SHIM 
SUSAR 
TRUS 
UAP 
WCMC 
Rectal Spacer 
Radiation Treatment 
Serious Adverse Event 
Stereotactic Body Radiation Therapy 
Sexual Health Inventory Men 
Suspected Unexpected Serious Adverse Reaction  
Transrectal Ultrasound 
Unanticipated Problem 
Weill Cornell Medical College 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Document History 
 
 
Version 
Version date 
Amendment 4 
3.1 
02.20.2019 
Amendment 3 (Protocol) 
3.0 
01.28.2019 
Amendment 2 (Protocol) 
2.1 
10.30.2018 
Amendment 1 Protocol 
2.0 
10.05.2018 
Initial Protocol  
1.0 
06.13.2018 
 
 
 
Summary of changes : Protocol version 3.1 02/20/2019 
 
1. Adding Co-investigators Dr. Vishesh Agrawal and Dr. Reza Farjam.  
 
NO CHANGES TO THE INFORMED CONSENT. 
 
 
Summary of changes : Protocol version 3.0 01/28/2019  
 
1. Clarification made in the protocol to clarify how the radiation dose is being prescribed and 
delivered, as follows: 
Page 22, section 5.3.2; also page 10 schema: We have clarified that the dose of 35 Gy in 5 
fractions is the minimum mean dose to be achieved. The prescribed dose can be 7-7.25 Gy; this is 
reflected throughout the protocol. 
2. On page 19, we have removed the exclusion criteria which previously excluded any patients 
who had a prior TURP (transurethral resection of the prostate), based on recent data suggesting 
that patients with TURP are not at increased risk of significant toxicitiy after radiation 
3. We have removed the SHIM questionnaire as it is redundant with the EPIC 26 quality of life 
questionnaire 
4. We are adding Jonathan Chen and Daniel Vanderbilt as co-investigators 
 
informed consent changes:  
 
SHIM questionnaire has been removed from the consent.  
 
 
 
 
Summary of changes : Protocol version 2.1 10.30.2018 
 
1. Radiation treatment planning : Contour  section 5.3.1 and 5.3.2 respectively. 

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a. Select PIRADS 3-5 and/or PSMA avid (if PSMA PET/MR is available) and/or 
biopsy positive nodules (chosen based on physician's clinical judgment and 
correlation with biopsy findings) 
 
b. The CTV (prostate +/- SV) will be treated to dose of 35 Gy in 5 fractions. There 
will be a simultaneous integrated boost to PIRADS 3-5 or PSMA avid nodules, 
delivering at additional 0.5, 1.0, 1.5 or 2 Gy per fraction for total mean dose of 
37.5, 40, 42.5 or 45 Gy to the contoured nodule. 
 
 
2. Inclusion Criteria #4 :  
 
a. Patient must have prostate MRI with a PIRADS 3-5 lesion or PSMA PET with an 
avid intraprostatic lesion 
 
There is no changed to the informed consent.  
 
 
 
 
Summary of changes : Protocol version 2.0 10.05.2018 
 
1. Changing the follow up from 1 month to 3-6 months  
2. Radiation treatment planning – Contouring – Section 5.3.1  
 
a. Select PIRADS 4-5 and/or PSMA avid (if PSMA PET/MR is available) and/or 
biopsy positive nodules (chosen based on physician's clinical judgment and 
correlation with biopsy findings) will be contoured as gross tumor volume(s) 
(GTV). 
 
ICF update 10.05.2018 :  
 
ICF was also updated to revise the follow up information from one month post RT to 3-6 months.  
 
 
 
 
 
 
 
 
 
 

 
 
  
9 
 
Protocol Summary 
 
MRI-guided Stereotactic Body Radiotherapy (SBRT) with Simultaneous   
Integrated Boost for Prostate Cancer 
 
 
IRB Protocol #:  1802019010 
 
Short Title:  
 
 
MRI-guided prostate SBRT with Focal Boost 
Principal Investigator:  
Josephine Kang 
Sample Size: 
 
N = 30 
Accrual Ceiling: 
 
This study plans to enroll a total of 30 patients  
Study Population: 
 
Patients with prostate cancer with visible focal lesion on MRI   
Accrual Period: 
 
3 years  
Study Design: 
 
Single-arm study for feasibility 
 
Study Intervention Description: 
 
Prostate SBRT: Prostate SBRT is a standard of care treatment for prostate cancer that has not 
spread to distant metastatic sites. Radiation is delivered to the prostate and seminal vesicles in 5 
treatment sessions (fractions). Doses ranging from 35-45 Gy in 5 fractions have demonstrated 
good outcomes with acceptable toxicity. In this initial study, MRI guided treatment planning and 
delivery will be used to deliver 7-7.25 Gy to the entire prostate and seminal vesicles, with a 
selective boost of  additional 0.5, 1.0, 1.5 or 2 Gy per fraction for total dose of 37.5, 40, 42.5 or 
45 Gy to  biopsy proven lesions, defined using MRI.  
 
Hypothesis:  MRI-guided treatment planning and delivery can selectively target  high-risk 
prostate nodules and deliver a higher radiation dose, to achieve maximal  local control 
without increasing treatment toxicity  
 
Primary objective: To assess feasibility  and safety of  delivering MRI-guided prostate 
SBRT with a simultaneous integrated boost to MRI-visible lesions.  
 
Feasibility is defined as a plan meeting treatment planning objectives and normal tissue constraints. 
Specifically the dose distribution of the MRI-guided technique, will be assessed with regard to 
fulfilling protocol requirements of: a) coverage of the planning target volume (PTV) , b) constraints 
to  organs at risk (OAR) by dose volume histogram (DVH) analysis and whether this can be done 
through standard set-up techniques or non-invasively through MRI based planning, c) coverage of 
high-risk prostate nodules. The total dose (either 37.5, 40, 42.5 or 45 Gy) will be determined by 
selecting the plan that delivers the highest dose to contoured visible nodules while maintaining 
normal tissue constraints to the urethra and rectum. We will track the number of treatment plans for 
each dose level (37.5, 40, 42.5 or 45 Gy) that can be delivered while meeting radiation planning 
objectives. 

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Safety of this approach will be determined by assessing acute GI/GU toxicity (CTCAE 4.0 criteria). 
Treatment will be deemed safe of there is no acute >G3 GI/GU toxicity within the first 30 days of 
treatment (CTCAE 4.0 criteria).  Given that the treatment plans will meet rigorous normal tissue 
constraints used for standard prostate SBRT,  we do not anticipate any increased toxicity on this 
study compared to standard prostate SBRT.  
 
  
Secondary objectives:  
1. To obtain  health-related quality of life (HRQOL) measured using: 1) the Expanded 
Prostate Cancer Index Composite (EPIC) short form questionnaire, 2) AUA. Assessment 
will occur at  baseline, and at first follow up. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 SCHEMA 
 
  
 
 
 
 
 
 
 
 
Blood samples for immune monitoring studies and stool samples for microbiome studies will be 
collected at baseline, end of Radiation at 3-6 months post follow up visit.  
 
  
 
 
Localized Prostate Cancer with MRI (PIRADS 3-
5) or PSMA PET-visible lesions  
 
(Low, Intermediate and High Risk as per NCCN 
Criteria) 
 
 
Prostate SBRT (35-36.25 Gy in 5 fx) 
w/SIB of 0.5-2 Gy per fx for total dose 
37.5, 40, 42.5 or 45 Gy 
 
 
Patients will have option of rectal spacer 
or balloon prior to treatment 
 
 
 
Follow up visit at 1 month: 
Assess GI/GU toxicity, EPIC, AUA   
 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY ............................................................................................................................................................. 9 
SCHEMA ...................................................................................................................................................................................... 11 
1 
STUDY OBJECTIVES ..................................................................................................................................................... 14 
1.1 
PRIMARY OBJECTIVES ...................................................................................................................................................................... 14 
1.2 
SECONDARY OBJECTIVES ................................................................................................................................................................. 14 
2 
BACKGROUND ............................................................................................................................................................... 14 
2.1 
PROSTATE CANCER RADIOTHERAPY ............................................................................................................................................... 14 
2.2 
BIOLOGICAL RATIONALE FOR SBRT .............................................................................................................................................. 15 
2.3 
SBRT OUTCOMES ............................................................................................................................................................................. 16 
2.4 
RATIONALE FOR SIMULTANEOUS INTEGRATED BOOST .............................................................................................................. 17 
2.5 
NEED FOR IGRT IN PROSTATE RADIOTHERAPY ........................................................................................................................... 18 
2.6 
VIEWRAY: A UNIQUE RADIATION DELIVERY APPROACH ............................................................................................................. 18 
2.8 RATIONALE FOR CORRELATIVE STUDIES BACKGROUND: MICROBIOME AND BLOOD SAMPLE COLLECTION .......................... 19 
3 
SUBJECT SELECTION ................................................................................................................................................... 20 
3.1 
STUDY POPULATION ......................................................................................................................................................................... 20 
3.2 
INCLUSION CRITERIA ........................................................................................................................................................................ 20 
3.3 
EXCLUSION CRITERIA ....................................................................................................................................................................... 20 
4 
REGISTRATION PROCEDURES ................................................................................................................................. 20 
4.1 
PATIENT REGISTRATION .................................................................................................................................................................. 20 
5 
STUDY PROCEDURES .................................................................................................................................................. 22 
5.1 
PRE-STUDY VISIT .............................................................................................................................................................................. 22 
5.2 
IMAGING STUDIES ............................................................................................................................................................................. 22 
5.3 
RADIATION TREATMENT PLANNING ............................................................................................................................................. 23 
5.3.1 
Contours ............................................................................................................................................................................... 23 
5.3.2 
Dose/Treatment Planning Parameters .................................................................................................................... 23 
5.4 
SUPPORTIVE CARE GUIDELINES ..................................................................................................................................................... 24 
5.5 
DURATION OF THERAPY AND CRITERIA FOR REMOVAL FROM STUDY ..................................................................................... 24 
5.6 
DURATION OF FOLLOW UP .............................................................................................................................................................. 24 
6 
DOSE MODIFICATIONS ............................................................................................................................................... 25 
7 
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................................ 25 
7.1 
ADVERSE EVENT DEFINITION ......................................................................................................................................................... 25 
7.2 
RECORDING OF ADVERSE EVENTS .................................................................................................................................................. 25 
7.2.1 
Reporting of AE to WCMC IRB ..................................................................................................................................... 25 
7.3 
DEFINITION OF SAE ......................................................................................................................................................................... 26 
7.3.1 
Reporting of SAE to IRB .................................................................................................................................................. 26 
7.4 
EXPEDITED ADVERSE EVENT REPORTING .................................................................................................................................... 26 
7.4.1 
AE/SAE Follow Up ............................................................................................................................................................ 27 
8 
PHARMACEUTICAL INFORMATION ....................................................................................................................... 27 
9 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................................... 27 
10 
MEASUREMENT OF EFFECT ...................................................................................................................................... 28 

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11 
DATA REPORTING / REGULATORY CONSIDERATIONS .................................................................................. 29 
11.1 
DATA COLLECTION ...................................................................................................................................................................... 29 
11.2 
REDCAP ....................................................................................................................................................................................... 29 
11.3 
REGULATORY CONSIDERATIONS ............................................................................................................................................... 29 
11.4 
DATA MANAGEMENT .................................................................................................................................................................. 29 
12 
STATISTICAL CONSIDERATIONS ............................................................................................................................ 30 
12.1 
STUDY DESIGN/ENDPOINTS ..................................................................................................................................................... 30 
12.1.1 
Primary Objectives ..................................................................................................................................................... 30 
12.1.2 
Secondary Objectives ................................................................................................................................................. 30 
12.1.3 
Correlative Study Objectives ................................................................................................................................... 31 
12.2 
SAMPLE SIZE/ACCRUAL RATE .................................................................................................................................................. 31 
12.3 
STRATIFICATION FACTORS ........................................................................................................................................................ 31 
12.4 
ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS .......................................................................................................... 31 
13 
DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................................................. 32 
13.1 
MONITORING PLAN ..................................................................................................................................................................... 32 
13.2 
STOPPING RULES ......................................................................................................................................................................... 32 
14 
REFERENCES .................................................................................................................................................................. 33 
 
 
 

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1 
STUDY OBJECTIVES 
 
HYPOTHESIS: MRI-guided treatment planning and delivery can selectively target  high-risk 
prostate nodules and deliver a higher radiation dose, to achieve maximal  local control 
without increasing treatment toxicity  
 
1.1 
Primary Objectives 
 
  
1.11 Determine the feasibility and safety  of delivering SBRT w/SIB without increased 
acute G3 GI/GU toxicity.  
 
Feasibility is defined as a plan meeting treatment planning objectives and normal tissue 
constraints. Specifically the dose distribution of the MRI-guided technique, will be assessed with 
regard to fulfilling protocol requirements of: a) coverage of the planning target volume (PTV) , b) 
constraints to  organs at risk (OAR) by dose volume histogram (DVH) analysis and whether this 
can be done through standard set-up techniques or non-invasively through MRI based planning, c) 
coverage of high-risk prostate nodules. The total dose delivered (either 37.5, 40, 42.5 or 45 Gy 
mean dose to the contoured nodule) will be determined by selecting the plan with the highest dose 
to visible nodules while maintaining normal tissue constraints to the urethra and rectum. We will 
track the number of treatment plans for each dose level (37.5, 40, 42.5 or 45 Gy) that can be 
delivered while planning objectives. 
 
Safety of this approach will be determined by assessing acute GI/GU toxicity (CTCAE 4.0 
criteria). Treatment will be deemed safe of there is no acute >G3 GI/GU toxicity within the first 
30 days of treatment (CTCAE 4.0 criteria).  Given that the treatment plans will meet standard 
normal tissue constraints used for prostate SBRT, we do not anticipate any increased toxicity on 
this study compared to standard prostate SBRT.  
 
 
1.2 
Secondary Objectives 
 
 
1.21 To obtain  health-related quality of life (HRQOL) measured using: 1)the Expanded Prostate 
Cancer Index Composite (EPIC) short form questionnaire, 2) AUA. Assessment will occur at  
baseline, and at first follow up which will occur 3-6 months after completion of radiation.  
 
 
 
 
2 
 
BACKGROUND 
 
2.1 
Prostate cancer radiotherapy  
 
Next to 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 

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prostate cancer during their lifetime. Due to the availability of prostate specific antigen (PSA) 
testing, the majority of men are diagnosed with non-metastatic prostate cancer, which is further 
stratified by NCCN into low-, intermediate- and high-risk disease based on T-stage, initial PSA, 
and Gleason score.2 Men with localized prostate cancer have multiple treatment options available. 
Options include active surveillance (if low risk), surgery (e.g., radical prostatectomy ± pelvic 
lymph node dissection), brachytherapy or external beam radiation (EBRT). Although there is no 
difference in cancer control outcomes between surgery and radiation, EBRT is less invasive, and 
results in less long-term urinary and sexual side effects.3  
 
Standard fractionation EBRT is delivered over 9-10 weeks, with 1.8 to 2.0 Gy administered daily, 
in up to 50 treatment sessions. The inconvenience associated with the protracted length of a 
standard course of prostate treatment has stimulated interest in delivering more radiation dose per 
session, to reduce the duration of treatment. Compared to conventional fractionation, 
hypofractionation (higher dose of radiation given in fewer sessions) allows for reduced number of 
treatment visits, increasing patient convenience while lowering health care costs. 
 
Extremely hypofractionated regimens are delivered most commonly within 5 fractions, allowing 
completion of treatment generally within 1-2 weeks. Such treatments are delivered using 
stereotactic or image-guided IMRT approaches, most commonly referred to as prostate stereotactic 
body radiation therapy (SBRT). Single institutional and pooled reports have demonstrated similar 
efficacy and toxicity to conventionally fractionated regimens. 4-6  The NCCN treatment paradigm  
currently includes SBRT as an alternative to conventionally fractionated regimens at clinics with 
appropriate technology, physics and clinical expertise.2 SBRT enables patients to undergo a non-
invasive treatment and be done in five treatments, achieving outcomes equivalent to long-course 
EBRT or surgery, without a surgical procedure, general anesthesia and the risk of associated 
complications. 
 
 
 
2.2 
Biological rationale for SBRT 
 
Proponents of prostate cancer hypofractionation argue that the rectum and bladder are less 
sensitive to increases in dose per fraction than prostate cancer and that therefore hypofractionation 
should yield negligible increases in late toxicity while providing improved cancer control. The / 
is a theoretical measure of a tissue’s predicted response to a dose of radiation, relative to the size 
of the dose delivered per fraction. Conventional daily doses of radiation are based on the presumed 
high / ratios of most malignant tumors. Higher / ratios mean that tumor response is less 
dependent on the amount of radiation administered with each fraction when compared to adjacent 
normal tissue, and therefore that a lower radiation dose per treatment can typically be used. Lower 
tumor / ratios mean that a larger dose of radiation per treatment can provide improved efficacy 
in terms of therapeutic ratio, tumor control versus risk of complications. A large body of work 
theorizes that the / for prostate cancer is low (~1.5), implying that a hypofractionated schedule 
could improve prostate cancer control, while maintaining a low risk of severe normal tissue  

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complications (see Table 1). 7 The radiobiological linear-quadratic cell survival model was used 
to calculate the biologically equivalent doses for tumor control and complications to normal 
organs, using standard 2 Gy fractions delivered five times a week.8-10   
 
 
Table 1. Equivalent total doses in 2 Gy per fraction (EQD2) based on / Biologically 
Effective Doses (BED) 
 
 
 
 
2.3 
SBRT Outcomes  
 
To date, results from prospective and retrospective studies demonstrate good biochemical control 
and low toxicity for SBRT, with commonly used doses ranging from 35-45 Gy in 5 fractions (see 
Table 2). SBRT compares favorably to outcomes for standard fractionation EBRT to 81 Gy, which 
has 10-year biochemical RFS of 91%, 78% and 62%, respectively, for low-, intermediate- and 
high-risk prostate cancer, and late Grade 3 gastrointestinal (GI) and genitourinary toxicity of 1% 
and 5%, respectively.11 There is a lack of consensus regarding the appropriate dose to use for 
prostate SBRT. Extrapolating from dose escalation studies in conventionally fractionated 
EBRT,12,13 a higher dose in SBRT is hypothesized to result in improved local control. However, 
delivery of higher dose results in small but significant increase in GU toxicity. Katz and Kang 
showed significantly higher late grade 2-3 GU toxicity with 36.25 Gy compared to 35 Gy (13.2 vs 
8.8%, P<0.05). With  35 Gy in five fractions, the majority of toxicity was grade 2, and overall 
toxicity was low without impacting GU quality of life. As shown in Table 2, late grade 3 GU/GI 
toxicity after SBRT appears to be comparable to that of conventionally fractionated EBRT, ranging 
from 0.6 – 3% 4,6 with longest median follow-up of 7 years.  
 
 
Table 2. Biochechemical control after prostate SBRT. *prospective 
Study 
SBRT Dose 
(5 fx) 
FU  
# Pts Risk Categories 
bPFS 
Toxicity ≥3 
Bolzicco
14* 
35 Gy 
36m  
71 
Low (41%), Int 
(42%), High (17%) 
3y 94.4% 
GI 0%, GU 
1% 
King15* 
35-36.25 Gy 
5y  
41 
Low, Favorable Int 
Risk 
5y 92.7% 
GI 0%, GU 
3.5% 
 /  (Gy)
EQD2 
Standard (1.8 
Gy x 45 fx)
EQD2 SBRT 
(7 Gy x 5 fx)
EQD2 SBRT 
(7.5 Gy x 5 fx)
EQD2 SBRT 
(8 Gy x 5 fx)
EQD2 SBRT 
(8.5 Gy x 5 fx)
EQD2 SBRT 
(9 Gy x 5 fx)
Total Dose (Gy)
81
35
37.5
40
42.5
45
Tumor
1.5
76.37 Gy
85 Gy
97.65 Gy
110 Gy
123.07 Gy
135 Gy
Fibrosis/stricture
2
76.95 Gy
78.75 Gy
89.06 Gy
100 Gy
111.56 Gy
123.7 Gy
Telangiectasia
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy
Rectum 
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy
Bladder
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy

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McBride
16* 
36.25-37.5 
Gy 
44.5
m  
45 
Low 
3y 97.7% 
GI 4.4%, GU 
2.2% 
Madsen1
7* 
33.5 Gy 
41m  
40 
Low 
4y 90% 
GI 0%, GU 
0% 
Fuller18
* 
38 Gy/ 4 fx 
60m  
259 
Low (43%), Int  
(57%) 
5y Low 
100%, 
 Int 88.5% 
GI 0%, GU 
3.1% 
Kim19 
45-50 Gy 
42m  
47 
Low (38%), Int (62%) 
4y 98% 
GI 0%, GU 
0% 
Loblaw2
0* 
35 Gy 
55m  
84 
Low 
5y 98% 
GI 1%, GU 
1% 
Mantz21
* 
40 Gy 
60m 
102 
Low, Fav Int 
5y 100% 
GI 0%, GU 
0% 
Chen22 
35-36.5 Gy 
2.3y 
100 
Low (37%), Int 
(55%), High (8%) 
2y 99% 
GI 0%, GU 
1% 
Katz 
and 
Kang5 
35-36.25 Gy 
72m  
477 
Low (68%), Int (32%) 
7y Low 
95.6%, 
Fav Int 
93.5%,  
Unfav Int 
79.3% 
GI 0%, GU 
2% 
Katz 
and 
Kang23 
35-36.25 Gy 
84m  
515 
Low (63%), Int 
(30%), High (7%) 
8y Low 
93.6%,  
Int 84.3%,  
High 65.0% 
GI 0%, GU 
2% 
Katz24 
35-36.25 Gy 
108m  230 
Low 
10y 93% 
GI 0%, GU 
2% 
Abbreviations: FU, follow up; Gy, Gray; Fx, fractions; m, months; y, years; IQR, interquartile 
range 
*SBRT monotherapy patients 
** Heterogeneous SBRT planning such that at least 1% of PTV receives ≥ 150% of prescription 
dose. 
 
2.4 
 Rationale for Simultaneous Integrated Boost 
 
Both EBRT and SBRT target the entire prostate gland with radiation. Studies on patterns of failure 
following conventional EBRT demonstrate that 85-100% of local failures occur in the region of 
macroscopic tumor.25,26 Modern treatment planning systems have the ability to selectively target 
visible lesions within the prostate to a higher dose, resulting in heterogeneous dose distributions 
that target high-risk nodules to increased dose and surrounding prostate to a lower dose. By 
selectively targeting high-risk nodules to a higher dose, local control could be maximized 
without increasing treatment toxicity. Recently, results of a phase 3 multicenter randomized 

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controlled trial (Focal lesion ablative microboost in prostate cancer, “FLAME” NCT01168479) 
were reported, with patients randomized between standard treatment (conventionally fractionated 
EBRT to dose of 77 Gy in 35 fractions) versus dose-escalated treatment arm (77 Gy in 35 fractions 
to the entire prostate, with an integrated boost up to 95 Gy based on multi-parametric MRI-defined 
tumor within the prostate).27 All patients had target volumes delineated on a multi-parametric MRI 
(T2-weighted, diffusion-weighted and dynamic contrast-enhanced MRI) with margin of 5-8mm 
around the prostate, and no margin around the dose escalation target volume. There was no 
difference in late (2-year) GI and GU toxicity between the two groups, suggesting feasibility of a 
focal dose escalation approach. A phase II trial is currently ongoing in the Netherlands 
(Hypofractionated focal lesion ablative microboost in prostate cancer, “hypo-FLAME” 
NCT02853110), to look at feasibility of a focal ablative boost with SBRT, using dose of 35 Gy in 
5 fractions with a boost to visible nodules up to 50 Gy. 
Similar to FLAME, hypo-FLAME uses a pre-treatment multi-parametric MRI to delineate target 
volumes. While MRI imaging informed the definition of the boosted target in these trials, the 
delivery was not MRI guided, and as a result larger treatment margins were required. MRI 
guided radiation, a property unique to ViewRay, will  be exploited in the current trial to 
deliver precise treatment with resultant lower dose to surrounding normal structures. 
 
2.5 
Need for IGRT in prostate radiotherapy  
 
SBRT delivers high dose to the target with a rapid dose fall-off. Thus, it is important to account 
for prostate motion as much as possible during treatment delivery (intrafraction motion), and 
between each treatment fraction (interfraction motion). A small shift in the prostate, if unaccounted 
for, can result in significantly decreased dose to the target. Position changes are inevitable due to 
bowel gas/stool fluctuation, bladder filling and/or prostate edema from radiation.28 There are 
multiple techniques to account for prostate motion during delivery of SBRT. 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. Traditional image-guided radiation is unable to provide real-time feedback 
of target position. Treating multiple radiation targets (prostate, seminal vesicles, high-risk nodules) 
with steep dose gradients becomes particularly challenging with standard image guidance systems, 
because adjustments are made offline or at prolonged select intervals during treatment delivery.  
 
 
2.6 
ViewRay: a unique radiation delivery approach 
 
The ViewRay MRIdian Linac system is a radiation delivery machine that integrates a linear 
accelerator with real-time MRI imaging. The ViewRay machine allows fusion of MR imaging with 
treatment planning. The uniqueness of this approach is the image guided delivery component,  
based on precise MRI-based detection of target and normal tissue during treatment in real-time. 
The ViewRay will provide real-time MRI imaging to ensure that the high-dose region is precisely 
targeted. MRI guided radiation has the benefit of not requiring fiducial implantation or excess 
radiation exposure from multiple cone beam CT. Furthermore, motion monitoring can be 

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performed with images acquired up to 4 frames a second, allowing live feedback of treatment 
position. 
 
ViewRay offers  the ideal system for delivery of prostate SBRT, due to its ability to provide image 
guidance “live”, during treatment. Real-time MRI imaging allows superior soft-tissue 
differentiation with excellent visualization of the prostate. This ViewRay platform offers the ideal 
setting for this study, that aims at precisely delivering prostate SBRT with a simultaneous 
integrated boost to visible nodules.  
 
The goal of this study is to assess feasibility and safety of using the ViewRay to deliver prostate 
SBRT with SIB. Feasibility is defined as the ability to deliver treatment as planned (within the 
constraints defined in Section 5.3 Radiation Planning) and safety is defined  as lack of acute G3 
GI or GU toxicity within 30 days. The proposed SBRT dose (35-36.25 Gy in 5 fractions to the 
whole prostate) has been reported in the literature to be safe and well tolerated (Table 2), with no 
acute G3 toxicity. The proposed boost dose of an additional 0.5, 1.0, 1.5 or 2 Gy per fraction (total 
dose 37.5-45 Gy, depending on normal tissue constraints) is within the range of current standard 
of care SBRT doses, and is expected to be well-tolerated if normal tissue constraints are met. By 
applying rigorous normal tissue constraints and capitalizing on the imaging capability of the 
ViewRay we plan to deliver a treatment that is non-invasive and exceptionally precise. 
 
 
 
2.8 Rationale for Correlative Studies Background: Microbiome and blood sample collection 
Patients accrued to the study will have the option to donate a stool specimen and a blood sample 
both before and after radiation, to study their changes in the microbiome and circulating immune 
correlates during and after radiotherapy. 
  
The host microbiome is an emerging topic of investigation, with growing evidence that commensal 
microbiota impacts anti-tumor immune response, and sensitivity to systemic therapies and 
immunotherapy.  Commensal bacteria outnumber human cells by at least 10-fold, colonizing host 
mucosal surfaces and playing critical roles in metabolism, defense against pathogens, and crosstalk 
between the environment and immune system. Preclinical studies suggest that microbiota impact 
the immune system through a number of mechanisms, including possible modulation of myeloid-
derived cells; stimulation of T helper cells, and enhancement of memory T-cell response. 
Dysbiosis, or shifts in microbial composition, may modulate response to cancer therapy. We 
hypothesize that the underlying microbial community composition may have an impact on the 
ability of radiation to generate an effective immune response, or be impacted by radiation.  
 
It is unknown how radiation impacts the complex interplay between the microbiome, immune 
system and tumor response. Through serial collection of gut microbiome samples, peripheral 
immune correlates and subsequent analyses, we hope to generate  preliminary data on how the 
microbiome  exposed to radiation is modulated  during radiotherapy and explore associations of  
individual changes  with immune correlates. 

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3 
SUBJECT SELECTION 
 
3.1 
Study Population 
 
Men with a histologically confirmed diagnosis of non-metastatic prostate adenocarcinoma, 
meeting the inclusion and exclusion criteria below, and electing to undergo definitive radiation 
treatment with SBRT, will be eligible for participation in this study. 
 
3.2 
Inclusion Criteria 
 
1. Biopsy-proven diagnosis of prostate adenocarcinoma 
2. NCCN defined low-, intermediate- and high-risk prostate cancer 
3. Age ≥ 18 
4. Patient must have prostate MRI with a PIRADS 3-5 lesion or PSMA PET with an avid 
intraprostatic lesion 
 
3.3 
Exclusion Criteria  
 
1. History of prior pelvic radiation (external beam or brachytherapy) 
2. Inability to undergo MRI 
3. Patients with metastatic disease (other than pelvic lymph nodes) are ineligible for this study 
4. AUA score >17 
 
 
 
 
4 
REGISTRATION PROCEDURES 
 
 
4.1 
  Patient Registration 
 
 
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. 

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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.  
 
 
 

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5 
STUDY PROCEDURES 
 
              
Pre-Study Fx 1 Fx2 Fx 
3 
Fx 
4 
Fx 
5* 
Post-RT Visit (3-6  
month s/p RT) 
Informed consent 
X  
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA 
 
X 
 
  
 
  
 
  
 
  
 
  
 
 X 
 
Acute/Late 
Toxicity 
Assessment (CTCAE) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
EPIC-26, AUA 
 
X 
 
  
 
  
 
  
 
  
 
  
 
X 
Imaging: 
Planning 
CT/MR;  
 
       X 
 
 
 
 
 
 
Optional: blood draw 
and 
microbiome 
sample 
      X 
 
 
 
 
 X 
X 
*at physician’s discretion, lymph nodes may be targeted in the radiation field, either in 5    
fractions or over 5-6 weeks using standard fractionation 
 
 
 
 
 
5.1 
Pre-Study Visit 
 
At the initial screening visit, patient will undergo: 
o Informed consent 
o Medical history  
o Baseline EPIC-26 Questionnaire, AUA   
 
5.2 
Imaging Studies 
 
Patients enrolling on the protocol will be treated as follows. Placement of a rectal spacer is 
optional; patients who refuse or decline a rectal spacer will have the option to be treated with an 
endorectal balloon (ERB). Patients will be instructed to undergo a Fleet enema prior to planning 
CT and prior to each SBRT treatment. 
 
All patients will be sent for a pelvic MRI for treatment planning purposes, or have an MR on the 
Viewray machine. This should ideally be done within 1-2 weeks of the treatment planning CT. 
The ideal MRI, if not done on the Viewray, will be 3Tesla and in a position similar to treatment 
position, without use of an endorectal coil which can distort the prostate shape. If rectal spacer is 

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placed, the treatment planning MRI should be performed after the spacer placement.  
  
Treatment planning CT will be performed with vac loc immobilization. Patients will be advised to 
drink 1-2 cups of water 1 hour prior to the CT simulation to allow for a comfortably full bladder, 
if tolerated. A rectal catheter will be utilized to dispel any excess bowel gas, if necessary.  A 
urethral catheter to delineate the urethra at time of simulation can be considered if it is difficult to 
visualize the urethra on initial MRI. Oral contrast may be administered as per standard protocol if 
lymph nodes are being targeted.  
 
 
5.3 
Radiation Treatment Planning 
 
5.3.1 
Contours 
 
The treatment planning CT will be fused to the T2 sequence of the planning MRI. The prostate +/- 
seminal vesicles (SV) +/- pelvic lymph nodes will be contoured as the clinical target volume (CTV) 
as per usual practice. Select PIRADS 3-5 and/or PSMA avid (if PSMA PET/MR is available) and/or 
biopsy positive nodules (chosen based on physician's clinical judgment and correlation with 
biopsy findings) will be contoured as gross tumor volume(s) (GTV). There will be no planning 
target volume (PTV) expansion for the GTV. The PTV expansion for the CTV will be 0-5 mm on 
the prostat, depending on physician discretion as per standard care. 
 
The rectum will be drawn from the bottom of the ischial tuberosities to the sigmoid flexure. The 
urethra will be delineated on MRI from the prostatic apex, to entry of urethra into the penile bulb, 
using a 5 mm brush. The physician will have the option of placing a urethral catheter at time of 
sim as per standard care. 
 
The bladder, femoral heads, penile bulb will also be contoured as normal structures. 
 
5.3.2 
Dose/Treatment Planning Parameters 
 
The CTV (prostate +/- SV) will be treated to minimum mean dose of 35 Gy in 5 fractions. The 
prescribed dose to the CTV will be 7-7.25 Gy per fraction. There will be a simultaneous integrated 
boost to PIRADS 3-5 or PSMA avid nodules, delivering at additional 0.5, 1.0, 1.5 or 2 Gy per 
fraction for total mean dose of 37.5, 40, 42.5 or 45 Gy to the contoured nodule. The highest mean 
radiation dose possible (37.5, 40, 42.5 or 45 Gy) that can be delivered while respecting normal 
tissue constraints to rectum and urethra will be selected.  
 
Volume of the PTV receiving prescribed SBRT dose should be ≥ 95%; acceptable deviation is 
dose >90% 
 
Critical organ limits (SBRT monotherapy): 

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1. Rectum: Maximum dose to 1 cc 38.5 Gy, Max dose to 3 cc 34.4 Gy,, Max point dose 40 
Gy. Acceptable deviation is maximum dose to 1 cc 39 Gy, max dose to 3 cc 36 Gy and max 
point dose of 42 Gy. 
 
2. Bladder: Maximum dose to 1 cc 38.5 Gy, Max point dose 40 Gy. Acceptable deviation is 
max point dose of 42 Gy. 
3. Penile Bulb: No more than 105% of prescription dose; D3cc 25 Gy. This is a soft 
constraint. 
 
4. Femoral heads: Maximum point dose 30 Gy 
 
5. Small bowel: Maximum point dose 25 Gy   
      6. Urethra: Max dose 40 Gy. Will allow up to 42 Gy. 
 
 
 
5.4 
Supportive Care Guidelines 
 
a. Urinary: A proportion of patients undergoing prostate SBRT 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 can occur. 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. 
 
 
 
 
5.5 
Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays, the SBRT is anticipated to complete within 2-3 weeks time. 
Patients will undergo radiation 2-3 times a week, but treatment can be slowed down to once a week 
at the physician’s discretion; these differing fractionation patterns fall within standard of care for 
SBRT. 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. 
 
Patients will be placed in a prospective database patients undergoing prostate SBRT in our 
department. As per our usual care, they will fill out AUA and EPIC-26 quality of life forms at each 
follow up visit. 
 
5.6 
Duration of Follow Up 
 
Patients will be followed as per standard care. For purposes of this study, patients will be followed 
with CTCAE toxicity evaluation, EPIC-26 quality of life questionnaire, AUA scores up to first 
follow up visit at approximately  3-6 months after completion of radiation; afterwards they will be 
prospectively followed as per usual care in our department with quality of life questionnaires and 
toxicity evaluation, AUA scores. 

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6 
DOSE MODIFICATIONS 
 
None. 
 
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 treatment, and does not imply any judgment about causality.   
 
 
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 grade 3 or higher 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:  

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http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed
iate_Reporting_Policy.pdf.  
 
7.3 
Definition of SAE 
 
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.  
 
7.4 
Expedited Adverse Event Reporting 
 
 
The principal investigator is responsible for monitoring the safety of patients who enroll in the 
study.  All AEs occurring after treatment 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 experience that results in any of the following 
outcomes: 
- 
Death. 
- 
Life-threatening adverse experience. 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
- 
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. 

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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_Po
licy.pdf.  
 
7.4.1 
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 Correlative Study: Blood draws for immune correlates and microbiome collection 
Patients will have the option of having a blood draw prior to, at the completion of radiation and at 
3-6 months post treatment  follow up. They will also have the option of providing a stool sample 
for microbiome analysis at baseline, end of completion and 3-6 month follow up. This is an 
exploratory study where specimens will be stored for future analyses. 
 
Blood Sample Collection and Procedure 
Blood samples (40-ml) will be collected in heparinized “Green Top” tubes (for PBMC and 
plasma isolation) and processed within 4 h of sample receipt. The PBMC will be isolated 
using a 1.077 g/ml Ficoll layer to enrich the leukocytes and remove the dead cells and any 
red cells, and cryopreserved in 10% DMSO, 90% human AB serum at 10 x 106 cells/vial 
and stored in liquid nitrogen for batch analysis. Plasma will also be aliquoted and stored at 
-800C for batch analysis. We anticipate analyses of T cell subsets and neutrophil/lymphocyte 
ratios, as well as cytokine measurement and proliferation analyses (all markers of peripheral 
immune correlates to assess status over time) once funding is secured. 
  
 
Microbiome collection 

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Collection of Specimen(s): Patients will be provided with a stool collection container and be 
instructed on providing a specimen appropriately, which can be done from home or in the clinic. 
 
Handling of Specimens(s):  Samples received 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). 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.  
  
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.   
 
Samples will be collected by the research team and the samples will be stored in -80C freezer in 
Dr. Silvia Formenti’s lab until sample analysis.  
 
 
10 MEASUREMENT OF EFFECT 
 
This is a feasibility study. Feasibility will be achieved if a treatment plan can be achieved with 
the parameters described below: 
 
Specifically the treatment must fulfill all three aspects of  a) coverage of the prostate PTV as defined 
in 5.3 to dose of 35 Gy in 5 fractions, b) no more than acceptable radiation dosage to organs at risk 
(OAR) by DVH analysis (refer to section 5.3), and c) full coverage of high-risk prostate nodules, 
as defined by mean dose to contoured nodules. The total mean dose to be delivered (either 37.5, 40, 
42.5 or 45 Gy) will be determined by selecting the plan with the highest dose to visible nodules 
while maintaining normal tissue constraints. The first primary endpoint will be degree of  
feasibility, as measured by the percentage of treatments that are delivered according to plan.  
 
Safety of this approach will be determined by assessing acute GI/GU toxicity (CTCAE 4.0 criteria). 
Treatment will be deemed safe of there are no acute greater than  grade 3 GI/GU adverse events 
within the first 30 days of treatment (CTCAE 4.0 criteria).  The second primary endpoint will be 
safety, as measured by the percentage of treatments that are delivered without GI/GU toxicity within 
the first 30 days from start of treatment. Given that the treatment plans will meet standard normal 

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tissue constraints used for SBRT, and rigorous safety metrics need to be met before radiation is 
delivered, we do not anticipate any increased toxicity on this study compared to standard SBRT.  
 
 
 
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.  
 
11.2 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. 
 
 
11.3 Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.   
 
11.4 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. 

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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 
 
12.1.1 
Primary Objectives   
 
1. Determine the feasibility and safety of delivering SBRT w/SIB without increased acute 
G3 GI/GU toxicity.  
 
Feasibility is defined as a plan fulfilling the treatment plan defined before the start of treatment.  
Specifically the treatment must fulfill all three aspects of  a) coverage of the prostate PTV as defined 
in 5.3 to dose of 35 Gy in 5 fractions, b) no more than acceptable radiation dosage to organs at risk 
(OAR) by DVH analysis (refer to section 5.3), and c) full coverage of high-risk prostate nodules, 
as defined by mean dose to contoured nodules. The total mean dose to be delivered (either 37.5, 40, 
42.5 or 45 Gy) will be determined by selecting the plan with the highest dose to visible nodules 
while maintaining normal tissue constraints. The first primary endpoint will be feasibility, as 
measured by the percentage of treatments that are delivered according to plan.  
 
Safety of this approach will be determined by assessing acute GI/GU toxicity (CTCAE 4).  The 
second primary endpoint will be safety, as measured by the percentage of treatments that are 
delivered without greater than grade 3 GI/GU toxicity within the first 30 days from start of 
treatment. 
 
 
12.1.2 
Secondary Objectives 
 
 

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Secondary objectives include health-related quality of life (HRQOL) measures including: 1) the 
Expanded Prostate Cancer Index Composite (EPIC) short form questionnaire, 2) AUA symptom 
survey. These will be assessed at baseline and first follow-up (approximately 1 month, or 30 days, 
status post end of treatment). Follow-up measures as well as changes from baseline to follow-up 
will be studied.  
 
12.1.3 
Correlative Study Objectives 
 
 
Microbiome and labs will be collected for exploratory analyses to see how radiation impacts the 
host microbiome and peripheral immune correlates found in blood. This is an exploratory analysis. 
 
 
12.2 Sample Size/Accrual Rate 
 
We plan to accrue 30 patients over 3 years, or about 5 patients every 6 months. Using an exact 
Clopper-Pearson binomial two-sided interval, we will  be able to estimate the proportion of 
treatments that are feasible (comply with treatment plan) to within +/- 16%. This estimation 
conservatively assumes a 50% feasibility rate, leading to a 95% confidence interval from 31.3% 
to 68.7%.  
 
12.3 Stratification Factors 
 
Patients will not be risk-stratified. 
 
12.4 Analysis of Primary and Secondary Endpoints 
 
Primary Endpoint: 
The first primary endpoint of feasibility will be measured by the percentage of treatments that are 
delivered according to plan.The count and percent will be tabulated, and a 95% confidence interval 
estimated using an exact Clopper-Pearson binomial two-sided interval.  
 
The second primary endpoint of safety will be measured by the percentage of treatments that do not 
lead to a GI/GU adverse event (defined as >Grade 3) within 30 days of treatment.The count and 
percent will be similarly tabulated, and a 95% confidence interval estimated using an exact Clopper-
Pearson binomial two-sided interval.  
 

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Finally, the proportion of patients for whom the treatment was feasible and safe will be tabulated, 
and a 95% confidence interval estimated using an exact Clopper-Pearson binomial two-sided 
interval. 
 
Planned sub-group analyses include feasibility, safety, and combination of both within each of the 
four potential target dose levels (37.5, 40, 42.5 or 45 Gy). 
  
Secondary Endpoints: 
HRQOL measures at baseline and at follow up (3-6 months post treatment start) will be 
summarized numerically and graphically using mean (sd), median (interquartile range), or count 
(percent) as appropriate, and 95% confidence intervals estimated where possible. Changes in 
scoring from pre- to post-treatment will also be similarly studied. EPIC overall scores as well as 
domain summary scores (urinary incontinence, urinary irritative/obstructive, bowel, sexual, 
hormonal) and individual item responses will be studied. Similarly, overall score as well as 
individual item responses will be studied for the AUA symptom survey.  
  
13  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  
 

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If patients experience more than one grade 4 or higher toxicity within one month of RT, the 
study will not proceed further. 
 
 
14 REFERENCES 
 
 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. Jan-Feb 
2016;66(1):7-30. 
2. 
Network NCC. Prostate Cancer. 2016(01.2016). 
3. 
Lane A, Metcalfe C, Young GJ, et al. Patient-reported outcomes in the ProtecT 
randomized trial of clinically localized prostate cancer treatments: study design, and 
baseline urinary, bowel and sexual function and quality of life. BJU international. Dec 
2016;118(6):869-879. 
4. 
Katz A, Kang J. Stereotactic body radiotherapy with or without external beam radiation 
as treatment for organ confined high-risk prostate carcinoma: a six year study. Radiat 
Oncol. 2014;9:1. 
5. 
Katz AJ, Kang J. Stereotactic body radiotherapy as treatment for organ confined low- and 
intermediate-risk prostate carcinoma, a 7-year study. Frontiers in oncology. 2014;4:240. 
6. 
King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized 
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