Prospective Evaluation of Multi-Parametric MRI Guided Stereotactic Body Radiotherapy (SBRT) for Localized Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Rush University Medical Center

Date: 07/25/2018 
Amendment 5 
 
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Rush University Medical Center 
A PROSPECTIVE EVALUATION OF MULTI-PARAMETRIC MAGNETIC 
RESONANCE IMAGING (mpMRI) GUIDED STEREOTACTIC BODY 
RADIATION TREATMENT FOR LOCALIZED PROSTATE CANCER 
 
 
Study Chairs 
 
Radiation Oncology 
Dian Wang, MD., Ph.D. (Principal investigator) 
Departments of Radiation Oncology and Urology 
Rush University Medical Center 
500 S. Paulina St 
Atrium Building, Ground Floor 
Chicago, IL 60612 
Tel: 312-942-5751 
Fax: 312-942-2894 
Dian_Wang@Rush.edu 
 
 
Medical Physics: 
Julius Turian, Ph.D. 
Department of Radiation Oncology 
Rush University Medical Center 
500 S. Paulina St 
Atrium Building, Ground Floor 
Chicago, IL 60612 
Tel: 312-942-5751 
Fax: 312-942-2894 
Julius_Turian@rush.edu 
 
 
Radiology 
Stephanie Shors, MD. 
Department of Radiology 
Rush University Medical Center 
Stephanie_Shors@rush.edu 
 
Ryan Braun, MD. 
Department of Radiology 
Rush University Medical Center 
Ryan_Braun@rush.edu 
 
Gregory M. White, MD 
Department of Radiology 
Rush University Medical Center 
Gregory_M_White@rush.edu 
 
Meri Chen, MD 
Department of Radiology 
Rush University Medical Center 
Meri_chen@rush.edu 
 
 
 
Medical Oncology 
Nicklas Pfanzelter, MD 

Date: 07/25/2018 
Amendment 5 
 
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Section of Medical Oncology 
Rush University Medical Center 
Nicklas_Pfanzelter@rush.edu 
 
Timothy Kuzel, MD 
Section of Medical Oncology 
Rush University Medical Center 
Timothy_Kuzel@rush.edu 
 
John L. Showel, MD 
Section of Medical Oncology 
Rush University Medical Center 
John_Showel@rush.edu 
 
 
Biostatistics 
Youping Deng, Ph. D. 
Director of Bioinformatics and Biostatistics  
Rush University Cancer Center 
Department of Internal Medicine and Biochemistry 
Rush University Medical Center 
Kidston House, 630 S. Hermitage Ave. 
Room 408, Chicago, IL 60612 
Tel:312.563.4440 
Fax:312.563.4484 
Dry lab: 312.942.5642 
Wet lab: 312.563.2532 
Youping_Deng@rush.edu 
 
 
 
 
 
 
This protocol was designed and developed at Rush University Medical Center 
(RUMC), Chicago, IL.  It is intended to be used only in conjunction with 
institution-specific IRB approval for study entry. No other use or reproduction is 
authorized by RUMC nor does RUMC assume any responsibility for unauthorized 
use of this protocol. 

Date: 07/25/2018 
Amendment 5 
 
3 
 
INDEX 
 
 
Schema 
 
Eligibility Checklist 
 
1.0 
Introduction 
 
2.0 
Objectives 
 
3.0 
Patient Selection 
 
4.0 
Pretreatment Evaluations/Management 
 
5.0 
Registration Procedures 
 
6.0 
Radiation Therapy 
 
7.0 
Drug Therapy 
 
8.0 
Other Therapy 
 
9.0 
Patient Assessments 
 
10.0 
Data Collection 
 
11.0  
Statistical Considerations 
References 
Appendix I 
- Study Parameters 
Appendix II 
- Performance Status Scoring 
Appendix III 
- Staging System 
Appendix IV 
- BED Dose Calculations 

Date: 07/25/2018 
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Rush University Medical Center 
RUMC XXXX 
A PROSPECTIVE EVALUATION OF MULTI-PARAMETRIC MAGNETIC 
RESONANCE IMAGING (mpMRI) GUIDED STEREOTACTIC BODY 
RADIATION TREATMENT FOR LOCALIZED PROSTATE CANCER 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
1. Previous hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide) or LHRH antagonists (e.g. 
degarelix), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration 
(orchiectomy) is allowed for both cohorts. 
2. According to American College of Radiology, Prostate Imaging and Reporting and Data System (PI-RADS) 
version 2, Accessed March 20, 2015, from http://www.acr.org/Quality-Safety/Resources/PIRADS/. 
(http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/PIRADS/PIRADS%20V2.pdf) 
will be used to define multi-parametric MRI, mpMRI, positive and negative lesions using DCE, DWI, and T2 
sequences.  Lesions will be scored on a scale of 3-15.  mpMRI negative will be defined as class I or II 
lesions (total score <= 6).  mpMRI positive will be defined as class III, IV, or V lesions (total score 7-15). 
3. Whole pelvic IMRT vs. prostate and seminal vesicle IMRT is allowed at the discretion of treating physician. 
   
Patient Population: (See Section 3.0 for Eligibility) 
Histologically confirmed diagnosis of adenocarcinoma of the prostate within 365 days (1 year) of registration; 
PSA should not be obtained within 10 days after prostate biopsy. 
 
Required Sample Size: 67 for each cohort 
Diagnosis of Prostate Cancer 
Registration 
(You will be in one Group or the other based on mpMRI) 
Negative mpMRI2 
Positive mpMRI2 
Cohort 1  
36.25 Gy in 5 fractions of 7.25 Gy 
over two and a half weeks 
                              Cohort 2 
45 Gy in 25 daily fractions of 1.8 Gy to whole 
pelvis or prostate and entire seminal vesicle 
over 5 weeks followed by SIB SBRT 
consisting of 18 Gy in 3 fractions of 6 Gy to 
prostate and  21 Gy in 3 fractions of 7 Gy to 
mpMRI positive lesion(s) over one and half 
weeks3 

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RUMCXXXX 
Case # 
ELIGIBILITY CHECKLIST 
 
(page 1 of 3) 
 
  
_(Y) 
1. Does the patient have a histologically confirmed diagnosis of adenocarcinoma of the 
prostate within 1 years of registration? 
 
  
_(Y) 
2. Is the history/physical examination with digital rectal examination of the prostate within 
90 days prior to registration? 
 
____ (Y) 
3. Was the mpMRI completed within 90 days of registration?  
 
        _(Y) 
4. Is there a histological evaluation of the prostate biopsy with assignment of a Gleason 
score to the biopsy material; Gleason scores 2-10 within 1 year of registration? 
 
  
_(Y) 
5. Is the clinical stage a T1-4 (AJCC 7th edition) within 90 days of registration?  
 
  
(Y) 
6.  Is  the  PSA  within  60  days  prior  to  registration?  PSA should not be obtained 
within 10 days after prostate biopsy. 
 
  
_(Y) 
7. Is the ECOG Performance Status 0-1 within 60 days prior to registration? 
 
  
(Y) 
8. Has the patient provided study-specific informed consent prior to study entry? 
 
  
(Y) 
9.  Has the patient completed the international prostate symptom score (IPSS) and the 
Sexual Health Inventory for men (SHIM) questionnaire? 
 
  
(N) 
10. Does the patient have a prior or concurrent invasive malignancy (except non- 
melanomatous skin cancer) or lymphomatous/hematogenous malignancy unless 
continually disease free for a minimum of 5 years?  All patients with in situ carcinoma are 
eligible for this study (for example, carcinoma in situ of the oral cavity is eligible) except 
patients with carcinoma of the bladder (including in situ bladder cancer or superficial 
bladder cancer) 
 
  
(N) 
11. Is there evidence of distant metastases? 
 
  
(N) 
12. Is there evidence of regional lymph node involvement? 
 
  
(N) 
13. Has the patient had previous radical surgery (prostatectomy), cryosurgery, or HIFU 
for prostate cancer? 
 
  
(N) 
14 Has the patient had previous pelvic irradiation, or prostate brachytherapy?   
 
 
 
  
(N/Y) 
15.Has the patient had previous hormonal therapy, such as LHRH agonists (e.g., 
goserelin, leuprolide) or LHRH antagonists (e.g. degarelix), anti-androgens (e.g., 
flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy)? 
 
  
  
(N) 
16. Does the patient have a history of previous or concurrent cytotoxic chemotherapy   for 
prostate cancer? 
 
  
(N) 
17. Does the patient have severe, active co-morbidity, defined as unstable angina   and/or 
congestive heart failure requiring hospitalization within the last 6 months? 

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RUMC XXXX 
Case # 
ELIGIBILITY CHECKLIST  
 
(page 2 of 3) 
 
  
(N) 
18.  Has the patient had transmural myocardial infarction within the last 6 months? 
 
  
(N) 
19.  Does the patient have acute bacterial or fungal infection requiring intravenous antibiotics 
at the time of registration? 
 
  
(N)   20. Does the patient have chronic obstructive pulmonary disease exacerbation or other 
respiratory illness requiring hospitalization or precluding study therapy at the time of 
registration? 
 
  
(N)  21.  Does the patient have hepatic insufficiency resulting in clinical jaundice and/or coagulation 
defects? (Note that laboratory tests for liver function and coagulation parameters are not 
required for entry into this protocol. Patients on Coumadin or other blood thinning agents 
are eligible for this study.) 
 
  
(N)    22.  Does the patient have Acquired Immune Deficiency Syndrome (AIDS) based upon current 
CDC definition? (Note that HIV testing is not required for entry into this protocol. The need to 
exclude patients with AIDS from this protocol is necessary because the treatments involved 
in this protocol may be significantly immunosuppressive. Protocol-specific requirements 
may also exclude immuno-compromised patients.) 

Date: 07/25/2018 
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RUMC XXXX 
Case # 
ELIGIBILITY CHECKLIST 
 
(page 3 of 3) 
 
The following questions will be asked at Study Registration: 
 
 
  
 
1. 
Institutional person registering case. 
  
(Y) 2. 
Has the Eligibility Checklist been completed? 
  
(Y) 3. 
In the opinion of the investigator, is the patient eligible? 
  
 
4. 
Date informed consent signed 
  
 
5. 
Patient’s Initials (First Middle Last) 
  
 
6. 
Verifying Physician 
  
 
7. 
Patient ID 
  
 
8. 
Date of Birth 
  
 
9. 
Race 
  
 
10. 
Ethnicity 
  
 
11. 
Gender 
  
 
12. 
Country of Residence 
  
 
13. 
Zip Code (U.S. Residents) 
  
 
14. 
Method of Payment 
 
 
15. 
Calendar Base Date 
  
 
16. 
Registration date 
 
 
 
 
 
 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to registration. The 
completed, signed, and dated checklist used at study entry must be retained in the 
patient’s study file and will be evaluated during the IRB audit. 
 
 
Completed by  
 
Date 
 
 
 
 
 
 
 

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PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
1. BACKGROUND AND RATIONALE 
 
Prostate cancer is the most common non-skin cancer diagnosed in American men with an estimated 
230,000 new cases in 2014, accounting for 27% of new cancer cases in 2014 (1).  Radiotherapy is one of 
the primary modalities for treating adenocarcinoma of the prostate.  Currently, the standard radiotherapy 
technique for treating prostate cancer is 3D conformal radiotherapy (3DCRT).  Recently, newer 
techniques, such as image-guided intensity-modulated radiotherapy (IG-IMRT), have been developed to 
accurately deliver even more conformal radiation dose distribution than 3DCRT (2, 3).   IG-IMRT utilizes 
pretreatment 3D volumetric images such as CT images for target localization prior to IMRT (4-6).  The IG-
IMRT may offer potential benefits in tumor coverage and decreases in normal tissue complications (7-9).    
 
Prostate cancer is a prime example of a situation where IMRT can provide additional benefit as compared 
to 3DCRT (2,3).  Dose escalation using 3DCRT for localized prostate cancer has shown superior 
outcomes for patients with intermediate-risk and high-risk factors (8-13).  Unfortunately, dose escalation 
also increases the risk of radiation damage to surrounding normal tissues such as the bladder and rectum 
(14, 15).  For this reason, late toxicity in these organs, especially the rectum, is considered to be a limiting 
factor for high-dose 3DCRT.   Additionally, prospective randomized data from the RTOG (16) and several 
retrospective reviews (17-20) have indicated that prostate cancer patients who are at risk of disease 
spread to pelvic lymph nodes benefit from radiation to the pelvis.  Pelvic radiation in addition to dose 
escalation of the prostate increases the risk for acute and late radiation induced complications.  This is a 
situation where IMRT’s superior dose conformality is desirable to minimize the risk of complications to 
normal tissue while also assuring coverage of microscopic disease.  In support of this idea Teh et al (21) 
and Zelefsky et al (22) have demonstrated not only that high-dose IMRT is feasible and safe for patients 
with localized prostate cancer, but also improves dose conformity relative to tumor coverage, reduces 
exposure to normal tissue, and decreases GI toxicity in comparison with 3DCRT.    
 
With greater tumor conformality available from IMRT, it is possible to deliver an increased radiation dose 
to the prostate and still spare surrounding tissues.  Prostate radiation currently utilizes conventional 
fractionation schemes of 1.8 to 2.0 Gy per fraction.  These doses are based on empiricism, years of 
clinical experience, and classic radiobiology principles. Recent studies have shown that prostate cancer 
cells, which are slowly dividing cells, actually have a very low / ratio, estimated at 1.5-3 (23-26) which is 
actually less than most late responding tissues (usually given a value of 3). This suggests that prostate 
cancer cells might be more effectively treated with higher doses per fraction.  The Biologically Equivalent 
Dose (BED) is a calculation using the / ratio that can determine equivalent doses for different 
fractionation schemes (see Appendix V for BED Dosing comparison).  For example, a “conventional” 
prostate treatment of 72 Gy (36 X 2 Gy per fraction) would be equivalent, in terms of BED, to 63.8 Gy (25 
x 2.55 Gy/fx) if / ratio of 3.0 is used, or to 62.4 Gy (25 x 2.50 Gy/fx) if / ratio of 1.5 is used.  The 
concept of delivering a higher dose of radiation per fraction, but with fewer fractions and to a lower total 
dose, is known as hypofractionation.  Hypofractionated EBRT has the potential to reduce acute toxicity, 
because of the lower total dose, while providing biologically equivalent doses and, therefore, potentially 
equal tumor control.  Prostate cancer might especially benefit from hypofractionation because of its low 
/ ratio.  In fact, multiple clinical studies support this hypothesis.  Collins et al (27, 28)   reported their 22-
year experience on 232 patients treated with 36 Gy (6 X 6 Gy per fraction) from 1962 to 1984.  They have 
shown that this 6 X 6 Gy per fraction regimen produced comparable local response and minimal late 
morbidity in comparison with local contemporary “conventional” fractionation regimen.  Livesy et al (29) 
reported their experience in over 700 pts treated to 50.08 Gy (16 x 3.13 Gy/fxn) and showed similar tumor 
control and normal-tissue toxicity compared to standard treatments.  Additionally, the Cleveland Clinic has 
published their prospective, non-randomized short-course IMRT (SCIMRT) experience of 70 Gy (2.5 Gy X 
28) and reported equivalent biochemical control, acute and late toxicities, and quality of life when 
compared to the historical 3DCRT experience of 78 Gy (2 Gy X 39) (30-32).  Their data show a trend 
toward less Grade 2 and 3 rectal toxicity (5% for SCIMRT and 12% for 3D CRT p=0.24), and improved 
sexual functioning (p=0.017) compared to conventional fractionation regimens. Recently the long-term 
results after the above SCIMRT were updated (33). With a median follow-up of 66 months, 5-year 
biochemical relapse-free survival rates using the ASTRO definition were 97%, 88% and 70%, for low, 
intermediate and high-risk disease, respectively. The acute rectal toxicity scores were 0/20, 1/61, and 2 in 
19 patients.  The acute urinary toxicity scores were 0 in 9, 1 in 76, and 2 in 15 patients. The late rectal 

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Amendment 5 
 
 
toxicity scores were 0 in 71, 1 in 19, 2 in 7, and 3 in 3 patients. The actuarial late grade 3 rectal toxicity 
rate at 5 years was 3%. At their last follow-up, the rate of combined grade 2 and 3 late rectal toxicity at 5 
years was only 5%.  
 
Recent progress of Hypofractionated EBRT:  
There are additional benefits to hypofractionation besides radiobiology.  Using hypofractionation in 
conjunction with IMRT could result in more cost effective and safer care.  Fewer treatments make the 
process more convenient for patients and more cost effective for the institution.  There would be 
decreased facility burden, less personnel requirements (from radiation therapist to nurse, dosimetrists, 
physicists, and physicians).  In recent years researchers have looked at even shorter radiotherapy 
schedules. 
 
M. A. Ritter (2009) (34) reported results of a phase I/II NIH-sponsored clinical trial carried out by 5 
institutions that explored the tolerance and efficacy of increasingly hypofractionated radiation therapy for 
localized prostate cancer. Three increasing dose-per-fraction schedules were evaluated. These regimens 
were designed to maintain equivalent predicted late toxicity. Predicted tumor EQD2 doses were in excess 
of 82 Gy if the tumor α/β of 1.5 Gy is assumed.  Fraction size escalations were contingent upon 
acceptable acute and late toxicity. The three hypofractionated levels, 1, 2, and 3 were: 64.7 Gy/22 fx of 
2.94 Gy, 58.08 Gy/16 fx of 3.63 Gy and 51.6 Gy/12 fx of 4.3 Gy. All patients were treated with 
tomotherapy or linac based IMRT with daily image guidance. 
 
A total of 307 patients were accrued. Clinical parameters for these favorable-to-intermediate risk patients 
were: clinical stage T1/T2: 75%/25%; Gleason <7/7: 58%/42%; PSA <10/≥10: 82%/18%; median PSA: 
6.2 ng/ml. Levels 1, 2, and 3 are 42, 19, and 16 months, respectively. Toxicities were acceptable: 
Depending on the hypofractionation level, 20-30% of patients had acute Grade 2 GU symptoms during or 
shortly after treatment, primarily related to alpha blocker initiation. Average international prostate 
symptom scores (IPSS) returned to baseline by 3 months post treatment. Four to nine percent of patients 
had Grade 2+ GI symptoms during treatment, declining to 2% by 2 years. Actuarial rectal bleeding at two 
years was 8 +/- 1.7%, with all cases resolving either spontaneously or after minor intervention and with 
similar rates among hypofractionation levels (p = 0.2). The 5-year, nadir+2 actuarial biochemical 
progression-free survival (bPFS) for Level 1 was 94.7 +/-2.7%, with no difference between HPFX level 1, 
and levels 2 and 3 at 3 years (p = 0.95). Initial PSA, Gleason score, and T stage did not correlate with 
outcome (p = 0.63, 0.71, 0.96, resp.). To date, 8 patients had failed biochemically, but 3 were within the 
first 4 months of follow-up. The authors conclude that toxicities were acceptable and similar across all 
hypofractionation levels, consistent with the α/β of 3 assumed for late effects. Furthermore, actuarial 
bPFS rates at 3-5 years were high, comparable to expectations with dose escalated standard 
fractionation.  
 
Meanwhile, Stanford University reported on 41 low risk patients treated with 36.25 Gy in 5 fractions using 
stereotactic body radiotherapy (35, 36). The first 21 patients were treated on consecutive days but, due to 
higher than expected rectal toxicity treatments were modified to be given every other day (three fractions 
a week). With these changes no patients experienced Grade 3 or higher toxicity. Median follow up was 33 
months in this study.   
 
Considering the above investigations, Radiation Therapeutic Oncology Group (RTOG) has initiated a 
phase II trial (RTOG 0938) to randomize low-risk prostate cancer patients to receive either 36.25 Gy in 5 
fractions of 7.25 Gy over two and a half weeks (in 15-17 days) vs. 51.6 Gy in 12 fractions of 4.3 Gy over 
two and a half weeks (in 16-18 days). Patient accruals were just completed.   
Meanwhile, in 2014, American Society of Therapeutic Radiation Oncology (ASTRO) has reviewed the 
data of short radiation regimens including stereotactic body radiation treatment (SBRT, 5 daily fractions 
over 2 and half weeks) and has concluded that SBRT can be considered a primary form of treatment for 
prostate cancer. The results of long-term clinical trials supporting the safety and efficacy of stereotactic 
body radiation in treating prostate cancer led ASTRO to announce the decision. The results of clinical 
studies show patient outcomes with SBRT are at least as good as other forms of radiotherapy treatments. 

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Amendment 5 
 
 
 
Multi-parametric magnetic resonance imaging (mpMRI) and mpMRI-CT fusion guided 
Radiotherapy: Recent work suggested that multi-parametric magnetic resonance imaging (mpMRI), 
which combines a number of different MR imaging sequences such as dynamic contrast enhancement 
(DCE), diffusion-weighted imaging (DWI) and so on beyond the standard T1- and T2-weighted images, 
show a promise in detecting aggressive, high-grade, bulking invasive prostate cancer (37,38),  according 
to American College of Radiology, Prostate Imaging and Reporting and Data System (PI-RADS) version 2, Accessed 
March 20, 2015, from http://www.acr.org/Quality-
Safety/Resources/PIRADS/(http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/PIRADS/PIR
ADS%20V2.pdf).   mpMRI allows for reliable detection of adverse pathological features such as extra 
capsular extension, high-grade tumor and seminal vesicle invasion (39). Moreover, it has been shown to 
lead to substantial tumor upstaging and can thus affect treatment decisions. All these unfavorable tumor 
features are associated with heavy tumor burden and high risks for extra capsular extension and/or pelvic 
nodal involvement that require protracted high-dose radiation treatment. Furthermore, the co-registration 
of the mpMRI and ultrasound has recently been reported to significantly enhance the detection of high-
grade invasive prostate cancer (40). At our institution, recently we have successfully piloted the co-
registration of the advanced mpMRI and planning CT images using fiducial markers, to enhance the 
tumor target delineation and to deliver high dose radiotherapy planning for a prostatic lesion(s) only.    
 
In summary, IG-IMRT can accurately deliver highly conformal dose to the target while minimize radiation 
dose to the adjacent normal structures such as rectum and bladder. Prostate hypofractionation such as 
SBRT may have many potential benefits: biological, logistical, and financial, in radiotherapy management 
of prostate cancer. Nonetheless, the current approach is to deliver high-dose radiotherapy to entire 
prostate gland and a portion of anterior wall of rectum and posterior wall of bladder are in the high-dose 
field, which leads to a risk for the late toxicity such as rectal bleeding.  Treatment-related toxicity 
reductions are critically important for this cohort of patients since a long life expectancy (>10 years) is 
expected after a curative treatment. Therefore, it is highly desirable to identify the intra-prostatic lesions 
that are detected by mpMRI, and could be targeted by high- dose radiotherapy. Using this approach 
adjacent normal tissue such as  rectum and bladder will be further spared from high dose, which 
theoretically translates to the reduction of late tissue toxicity.     
 
In this protocol, we will utilize a pretreatment mpMRI to select and stratify patients (integral biomarker) for 
two separate SBRT regimens depending on whether prostate lesions are present.  For all patients with a 
diagnosis of localized prostate cancer, we plan to obtain a prostatic mpMRI. For the patients without any 
positive mpMRI lesions, a SBRT monotherapy (36.25 Gy in 5 fractions) will be delivered to the prostate 
only as done in the previous RTOG 0938 study.  For the patients with a positive mpMRI lesion(s), the 
prostatic lesion(s) will be identified and contoured by one of the radiology co-chairs.  The mpMRI and 
planning CT images will then be co-registered by the medical physics team. IG-IMRT (45 Gy in 25 
fractions of 1.8 Gy) will be given to whole pelvis or prostate and entire seminal vesicles over 5 weeks. 
This is followed by simultaneously integrated boost, SIB, SBRT 18 Gy in 3 fractions to the entire prostate 
and 21 Gy in 3 fractions of 7 Gy to the prostatic lesion(s) only. Biologic equivalent doses of this protracted 
course are higher than standard fractionation regimen, but lower than the combination regimen (external 
beam radiation treatment and high-dose-rate brachytherapy) used in the RTOG 0815 and RTOG 0924 
(see the comparison table in the Appendix IV)     
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To estimate the rate of late grade 3-5 genitourinary and gastrointestinal toxicity following mpMRI-
guided radiation treatment.  Late toxicity will be defined as toxicity occurring more than nine months 
from the start of radiotherapy. It is graded based on CTCAE v4.0.  
 

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Amendment 5 
 
 
2.2 
Secondary Objectives 
2.2.1 
To estimate acute toxicity 
2.2.2 
To estimate PSA failure in each cohort at 1, 2, and 5 years 
2.2.3 
To estimate disease free survival (DFS) in each cohort at 1, 2, and 5 years 
2.2.4 
To estimate tumor response in diffusion weighted imaging MRI after 5-weeks of RT for 
Cohort 2 only. 
 
3.0 
PATIENT SELECTION 
3.1 
Conditions for Patient Eligibility  
3.1.1 
Histologically confirmed diagnosis of adenocarcinoma of the prostate within 365 days (1 
year) of randomization 
3.1.1.1 Patients previously diagnosed with prostate cancer within 365 days (1 year) of the 
biopsy procedure. 
3.1.2 
History/physical examination with digital rectal examination of the prostate within 90 
days prior to registration 
3.1.3 
Histological evaluation of prostate biopsy with assignment of a Gleason score to the 
biopsy material 
3.1.4 
Clinical T stage (AJCC 7th edition) within 90 days of registration 
3.1.5 
PSA should be obtained within 60 days prior to registration. PSA should not be 
obtained within 10 days after prostate biopsy. (Every effort should be made to obtain all 
serum PSA values obtained in the 1 year prior to treatment to allow for calculation of 
PSA kinetics.)  
3.1.6 
ECOG Performance Status 0-1 within 60 days prior to registration 
3.1.7 
Age ≥ 18 
3.1.8 
Patient must be able to provide study-specific informed consent prior to study entry. 
3.1.9 
Previous hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide) or 
LHRH antagonists (e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide), 
estrogens (e.g., DES), or surgical castration (orchiectomy) is allowed at the discretion of 
treating physician. 
 
 
3.2 
Conditions for Patient Ineligibility  
3.2.1 
Prior or concurrent invasive malignancy (except non-melanomatous skin cancer) or 
lymphomatous/hematogenous malignancy unless continually disease free for a 
minimum of 5 years. All patients with in situ carcinoma are eligible for this study (for 
example, carcinoma in situ of the oral cavity is eligible) except for patients with 
carcinoma of the bladder (including in situ bladder cancer or superficial bladder 
cancer). 
3.2.2 
Evidence of distant metastases 
3.2.3 
Regional lymph node involvement 
3.2.4 
Previous radical surgery (prostatectomy), cryosurgery, or HIFU for prostate cancer 
3.2.5 
Previous pelvic irradiation, or prostate brachytherapy 
3.2.6 
Use of finasteride within 30 days prior to registration. PSA should not be obtained 
prior to 30 days after stopping finasteride. 
3.2.7 
Use of dutasteride within 90 days prior to registration. PSA should not be obtained 
prior to 90 days after stopping dutasteride. 
3.2.8 
Previous or concurrent cytotoxic chemotherapy for prostate cancer 
3.2.9 
Severe, active co-morbidity, defined as follows: 
3.2.9.1 Unstable angina and/or congestive heart failure requiring hospitalization within 
the last 6 months 
3.2.9.2 Transmural myocardial infarction within the last 6 months 
3.2.9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
3.2.9.4 Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration 
3.2.9.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for liver function and coagulation parameters are not 
required for entry into this protocol. (Patients on Coumadin or other blood thinning 
agents are eligible for this study.) 
3.2.9.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; 
note, however, that HIV testing is not required for entry into this protocol. The need 

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PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
to exclude patients with AIDS from this protocol is necessary because the treatments 
involved in this protocol may be significantly immunosuppressive. Protocol-specific 
requirements may also exclude immuno-compromised patients. 
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
4.1 
Highly Recommended Evaluations/Management 
4.1.1 
Visualization of the urethra at the time of CT simulation or CT scan for treatment 
planning or through fusion of images (e.g., MRI) with CT simulation images at that time 
is recommended. For patients where the maximum dose to a point that has a volume of 
0.03 cc exceeds 38.78 Gy in cohort 1 (5 fraction) or exceeds 22.47 Gy in cohort 2 SBRT 
boost component (3 fractions), visualization of the urethra would be required. 
4.1.2 
Baseline testosterone (optional) 
 
5.0 REGISTRATION PROCEDURES 
Eligible patients must sign the informed consent prior to radiotherapy. Inclusion and exclusion criteria will  
be verified by the principal investigator by completing and signing  the eligibility checklist and the registration 
case report form will be completed. The subject is considered registered and on study on the date the 
principal investigator signs the eligibility checklist. 
 
 
6.0 RADIATION THERAPY  
Protocol treatment must begin within 6 weeks after registration. This protocol requires the use 
of IG-IMRT. 
 
6.1 
Dose Specifications 
6.1.1 
Total Prescribed Dose 
In Cohort 1 of the study patients will receive 5 fractions of radiation to prostate only; each 
fraction size will be 7.25 Gy. The total dose will be 36.25 Gy. The 5 treatments will be 
scheduled to be delivered twice a week over approximately 15-17 days. A minimum 
of 2 days and a maximum of 5 days should separate each treatment. No more 
than 2 fractions will be delivered per week. The total duration of treatment will be no 
shorter than 15 days and no longer than 20 days. 
 
PTV: 36.25 Gy in 5 fractions of 7.25 Gy 
In Cohort 2 of the study patients will receive IG-IMRT 45 Gy in 25 daily fractions 
(1.8 Gy per fraction, 5 days a week) to whole pelvis or prostate gland and seminal vesicle 
followed by SIB SBRT, 18 Gy in 3 fractions to the entire prostate and 21 Gy in 3 fractions 
of 7 Gy to the prostatic lesion(s) only The 3 treatments will be scheduled to be delivered 
twice a week over approximately 10-12 days. A minimum of 2 day s and a maximum 
of 5 days should separate each SBRT treatment. No more than 2 SBRT fractions will 
be delivered per week.  SBRT must be initiated within 2 weeks after the 
completion of IG-IMRT. 
PTV1: 45 Gy in 25 fractions to either whole pelvis vs. prostate gland and entire 
seminal vesicle (can be treated at Rush Oak Park Hospital). 
PTV2: 18 Gy in 3 fractions of 6 Gy  
PTV3: 21 Gy in 3 fractions of 7 Gy 
 
6.1.2 
Dose Coverage 
For both cohorts, the isodose line used for the prescription dose should cover a minimum 
of 95% of the PTV. 
6.1.3 
Minimum Dose 
The minimum dose within the PTV to a point that is 0.03 cc in size must be ≥95% 
of the prescribed dose. 
 
6.2 
Supportive Measures 
6.2.1 
Urinary 
Symptomatic urinary medicines, (e.g. tamsulosin) are allowed at the discretion of the 
treating radiation oncologist or urologist. 
6.2.2 
Bladder 
Patients will be asked to have a full urinary bladder both during simulation and treatment 
for all techniques. Consistent bladder filling procedure should be used for an individual 
patient for simulation and for each treatment. Bladder filling may be achieved by asking 
patients to drink 16-24 oz of water or other fluid 2-3 hours prior to treatment and to not 

13 
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Amendment 5 
 
 
urinate between this time and treatment as they are able.  
Bowel 
Patients will be advised to adhere to a low gas, low motility diet commencing one day 
prior to the treatment. As an optional additionally preparation step, one tablespoon of 
Milk of Magnesia can be taken the night before the simulation and the night before each 
treatment. One Fleet’s enema will be administered 2-3 hours before the simulation and 
each treatment. 
 
6.3 
Technical Factors 
6.3.1 Radiotherapy 
This protocol will require treatments to be performed with an image-guided technique with 
the use of a 3-D coordinate system defined by 3D volumetric data. 
6.3.2 Radiotherapy Delivery 
6.3.2.1 Photons 
This protocol requires the use of IMRT (VMAT, DMLC or SMLC). The 
recommended photon energies for this protocol are 6-10 MV. The use of beams 
with higher energy is discouraged. These energies will result in an increased 
neutron dose reaching the patient’s total body. However, it is recognized that 
increasing the energy has advantages in improving dose distributions for larger 
patients. For this reason, beams as high as 15 MV will be allowed only when 
clinically significant improvement of the dose distribution is evident to the 
treatment planner.  
 
6.3.2.2 IGRT and Fiducial markers Used for Target Localization and Field Adjustment 
6.3.2.2.1 Allowed x-ray IGRT techniques with or without real-time tracking:  
The x-ray IGRT system that can be used for this study are: 
 
2D and 3D IGRT systems are allowed for this protocol 
o 
These systems can use either kV or MV x-rays 
o 
A computerized method for image registration is required  
for determination of the patient shift information 
o 
The image registration can be either manual (drag and  
drop images) or automatic 
 
The use of target tracking during treatment is encouraged when this technology is available 
and strongly encouraged when the treatment time from initial beam-on to the end of 
dose delivery is longer than 7 minutes. Repeat IGRT procedures can be used to detect 
and correct field positions when real-time tracking is not available. Treatments that take 
less than 5 minutes do not require an end-of-treatment IGRT procedure. An end-of- 
treatment IGRT procedure should be obtained when real-time tracking is not used, and 
the time period from the last IGRT procedure exceeds 5 minutes. 
 
Use of fiducial markers: Fiducial markers (polyMark 1 mm diameter, 3 mm long) must be 
placed within the prostate, by an experienced urologist before the mpMRI exam. It is 
recommended that at least three (3) markers be placed: one in the apex, one in the base 
and one in the lobe for which the biopsy results were negative. Proper placement will 
facilitate easy alignment of the prostate prior to RT.     
 
Fiducial marker placement may be accomplished using standard of care approaches of 
either transrectal or transperineal/percutaneous strategies.  Fiducial marker placement 
may be accomplished with either freehand transrectal ultrasound guidance or with the 
assistance of a robotic needle guidance platform.  As is the standard of care, this 
procedure may be performed under local anesthesia with or without the supplementation 
of sedation protocols with monitored anesthesia care. 
 
At the discretion of the PI, additional adjunct procedures may be performed in conjunction 
with the fiducial marker placement procedure.  An example of such a procedure would be 
the placement of a polyethylene glycol spacer between the rectum and prostate.  The 
purpose of these procedures is to minimize quality of life complications of subsequent 
radiotherapy.    
 
6.4 
Set-up, Localization and Tracking 

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Amendment 5 
 
 
6.4.1 Patient Set-up for SBRT delivery 
Patients will be positioned supine in a comfortable posture. The immobilization device 
consists of a SBRT body frame (CIVCO Medical) with knee cushion and lower leg 
immobilization. The knees will be held in place by the mini vaclok connected to a U frame. 
The head should rest on a comfortable pillow and the arms should be cross over the chest 
holding an “O” ring. Prone position is discouraged but allowed if tracking is used. The degree 
of bladder fullness should be made to duplicate what is anticipated for daily treatment, i.e., 
if the patient is instructed to maintain a full bladder for treatment, he should be simulated 
as such. Consistent bladder filling procedure should be used for an individual patient for 
simulation and for each treatment. The degree of bladder filling for each patient entered 
into this study will be documented for future analysis. The use of rectal balloons will be 
allowed but are not required in this protocol. The use of a rectal balloon will be documented 
for each patient for future analysis. In order to facilitate urethra visualization an 8Fr straight 
catheter will be inserted into the bladder using standard sterile procedures. 
 
6.4.2 Localization 
Daily IGRT is required to locate prostate using fiducial markers. 
 
6.5 
Treatment Planning 
6.5.1 Simulation 
6.5.1.1 Computed Tomography (CT) 
CT will be the primary image platform for treatment planning. The simulation should 
be performed in the supine treatment position, with the fiducial markers/rectal 
balloon in place (where utilized). Axial cuts of 3 mm or less will be acquired 
throughout the pelvis and prostate from the top of the iliac crests superiorly to the 
perineum inferiorly. Patients enrolled in Arm2 of the protocol will require two CT 
simulations, one for each phase. 
For patients having one metallic hip replacement the CT reconstruction must include 
the Orthopedic Metal Artifact Reduction, OMAR, sequence. Patients with bilateral 
hip replacements will be excluded from the protocol due to very pronounced artifacts 
on CT images as well as distortions in the MR images.  
6.5.1.2 Multi-parametric Magnetic Resonance Imaging (mpMRI) 
mpMRI images with 3-4 mm slice thickness are required for this study. The following 
sequences are recommended: T1 FS Post, T2, Vibe Dixon, DWI and DCE. The MRI 
study must be performed following the implantation of fiducial markers in order to 
facilitate the image co-registration of the planning CT with Vibe Dixon MR sequence 
6.5.1.3 Contrast 
Oral contrast for small bowels is required. Intra-venous,IV, urethral, and bladder 
contrast are allowed but not required. 
 
6.5.2 Treatment Planning/Target Volumes 
6.5.2.1 The definition of volumes will be in accordance with the ICRU Report #50 and  
 
ICRU Report #62: Prescribing, Recording, and Reporting Photon Beam Therapy.  
6.5.2.2 The Gross Tumor Volume (GTV) for the purpose of this protocol is defined by  
 
mpMRI. 
• 
For the cohort 1, no GTV is contoured since mpMRI is negative. 
• 
For the cohort 2, GTV is a lesion(s) defined by mpMRI and should be 
contoured with assistance from one of radiology co-chairs.  
6.5.2.3 The clinical target volume 1 (CTV1) will be prostate only for the cohort 1, and  
 
entire seminal vesicle and prostate or the whole pelvis (see next paragraph)  for  
 
the cohort 2 in non-contrast axial CT scan images. 
• 
For cohort 1, CTV is the prostate only. 
• 
For cohort 2, CTV1 is either whole pelvis or entire seminal vesicle and 
prostate at the discretion of treating physician; CTV 2 is prostate only 
for SBRT boost; CTV3 is GTV for the SBRT boost. 
 
Details for whole pelvis CTV1:   The CTV1 will include the prostate and entire seminal vesicles 
(SV), the obturator, external iliac, proximal internal iliac and common iliac nodes, using the 
vascular structures, up to a level corresponding to the top of L4-L5. The presacral nodes from 
L5-S1 to S3 may be included if desired depending on whether the dose constraints to the 
rectum are achievable.  The CTV1 will extend superiorly from L4-5 to 0.5 cm below the tip of 
the urethral contrast dye (if used) and no less than the entire prostate gland. Lateral borders 

15 
PI Dian Wang, RUMC 
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Amendment 5 
 
 
will be at least 1 cm from the pelvic brim. In the lateral fields, the external and internal iliac 
nodes below the SI joints, and the posterior extension of the seminal vesicles should be 
covered. The usual posterior border is approximately S2-3, but CT anatomy should take 
precedence.  The inferior extent of the external iliac lymph nodes is at the top of the femoral 
heads.  The inferior extent of the external iliac nodes is at the top of the symphysis pubis.  The 
CTV1 will include 7 mm margin in 3-dimensions to the contoured iliac vessels, but not extend 
outside of the true pelvis, into the pelvic musculature nor into adjacent identifiable organs, 
such as the bladder, rectum or other bowel.  Extension of the CTV into adjacent bone may be 
carved out.   
 
Details for prostate only CTV1: prostate and entire seminal vesicles are included.  
 
6.5.2.4 The planning target volume (PTV) will be defined as the CTV plus margins.  
• 
For the cohort 1, PTV is CTV plus a 3 mm margin posteriorly and 5 
mm in all other dimensions. To meet the dose constraints, if 
necessary, the anterior margin can be reduced to 3 mm. 
• 
For the cohort 2, PTV1 is CTV1 plus a 5 mm margin in all directions; 
PTV2 is CTV2 plus a 3 mm margin posteriorly and 5 mm in all other 
dimensions. To meet the dose constraints, if necessary, the anterior 
margin can be reduced to 3 mm.  PTV3 is CTV3 plus 1-2 mm margin.  
6.5.3 Dosimetry 
6.5.3.1 The use of coplanar or non-coplanar static beam IMRT is permitted. A minimum of  
5 gantry angles is required. The use of coplanar or non-coplanar VMAT is 
permitted. For planning purposes PTV3 will, always, overlap PTV2 and the dose 
volume constraints will reflect this reality  
6.5.3.2 For all cases, the prescription isodose line must encompass a minimum of 95% of  
 
the PTV. For cohort 1, the maximum dose within the PTV is 7% above the  
 
prescribed dose for a point that is 0.03 cc in size.   
  
For cohort 2, the maximum total dose with the PTV is 10%  
  
above the prescribed dose for a point that is 0.03 cc in size.   
6.5.3.3 The prescription doses must not occur outside of the PTV. Any hotspots should  
 
be manipulated to avoid the prostate-rectal and prostate-bladder interfaces as  
 
  
defined by the CTV. 
 
6.6 Critical Structures 
6.6.1 Critical Organ Dose-Volume Limits 
6.6.1.1 The normal tissue volume to be contoured will include bladder, rectum, bilateral  
femoral heads (to the level of ischial tuberosity), seminal vesicles, penile bulb, 
skin, small bowel and urethra. For patients where the maximum point dose to a 
point that is 0.03 cc exceeds 7% prescription dose in the SBRT component, 
visualization of the urethra is required. 
6.6.1.2 The normal tissues will be contoured and considered as solid organs rather than  
 
contouring the bladder and rectal walls. 
6.6.1.3 The bladder should be contoured from its base to the dome. 
6.6.1.4 The rectum should be contoured from the anus (at the level of the ischial  
tuberosities) for a length of 15 cm or to the rectosigmoid flexure. This generally 
is below the bottom of the sacroiliac joints. 
6.6.1.5 The tissue within the skin and outside all other critical normal structures and  
 
PTVs are designated as unspecified tissue. 
6.6.1.6 The following tables list maximum dose limits to a point or volume within  
several critical organs. These are absolute limits, and treatment delivery that does 
not abide by these limits will constitute either an acceptable deviation or an 
unacceptable protocol violation deviation. 

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Date: 07/25/2018 
Amendment 5 
 
 
Cohort 1 (5 Fraction SBRT) 
 
Dosimetry Parameters 
for 5 fraction arm 
Organ 
Volume 
Dose (Gy) 
Prostate (PTV) 
Maximum point dose 
(0.03cc) 
≤ 38.78 Gy 
107% of prescription 
dose * 
Minimum dose received by 
95% of PTV 
≥ 36.25 Gy 
100% of prescription 
dose 
Minimum dose received by 
PTV 
≥ 34.4 Gy 
95% of prescription dose 
Rectum 
Maximum point dose 
(0.03cc) 
≤ 38.06 Gy 
105% of the prescription 
dose 
Less than 3 cc 
≤34.4 Gy 
95% of prescription dose 
90% rectum 
≤ 32.625 Gy 
90% of prescription dose 
80% rectum 
≤29 Gy 
80% of prescription dose 
50% rectum 
≤18.125 Gy 
50% of prescription dose 
Bladder 
Maximum point dose 
(0.03cc) 
≤38.06 Gy 
105% of prescription 
dose 
90% Bladder 
≤ 32.625 Gy 
90% of prescription dose 
50% Bladder 
≤18.125 Gy 
50% of prescription dose 
Penile bulb 
(recommended) 
Maximum point dose 
No more than 100% of 
prescription dose 
Less than 3 cc 
≤20 Gy 
54% of prescription dose 
Femoral heads  
Less than 10 cc cumulative 
(both sides) 
20 Gy 
54% of prescription dose 
Skin 
(recommended) 
Maximum point dose 
30 Gy 
81% of prescription dose 
Urethra dose 
≤ 38.78Gy * 
107% of prescription 
dose 
Small bowel 
Maximum point dose 
≤ 15Gy  
41% of prescription dose 
 
*Visualization of the urethra would be required to confirm urethral dose is ≤38.78Gy – 107% of 
prescription dose where the max point dose (0.03cc) within the PTV exceeds 38.78Gy – 107% of 
prescription dose 

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Date: 07/25/2018 
Amendment 5 
 
 
Cohort 2 (IG-IMRT 45 Gy in 25 daily fractions to prostate and entire seminal vesicle 
followed by SBRT 21 Gy in 3 fractions to prostate tumor only) 
 
 
Initial IMRT phase PTV1 will receive treatment prescription 
 
Dosimetry Parameters for 45 Gy in 25 
treatment schedule cohort (Initial IMRT 
phase) 
Organ 
Volume 
Dose (Gy) 
PTV1 
Prescription dose to 98% of the PTV1 
≥ 45 Gy, 100% of prescription dose 
Minimum dose to 0.03 cc of the PTV1 
≥ 42.75 Gy,  95% of prescription dose 
Maximum dose to 0.03 cc of the PTV1 
(Per protocol) 
≤ 48.2 Gy 
Maximum dose to 0.03 cc of the PTV1  
(Variation acceptable)  
≤ 48.2 Gy -49.5 Gy 
Maximal dose to 0.03 cc of the PTV1 
(Deviation unacceptable) 
≤ 49.5 Gy 
Rectum 
Maximum point dose(0.03cc) 
≤ 49.5 Gy, 110% of the prescription dose 
 
90% rectum (Per protocol) 
≤ 40.5 Gy, 90% of prescription dose 
85% rectum (Variation acceptable) 
≤ 40.5 Gy, 90% of prescription dose 
50% rectum 
≤ 34 Gy;  75% of prescription dose  
Bladder 
Maximum point dose(0.03cc) 
≤ 49.5 110% of prescription dose 
80% Bladder 
≤ 40.5 Gy, 90% of prescription dose 
50% Bladder 
≤ 36 Gy, 75% of prescription dose 
Penile 
bulb*  
Mean dose 
≤ 30 Gy, 67% of prescription dose 
Femoral 
heads* 
Maximal point dose 
≤ 27 Gy, 60% of prescription dose 
 
Small 
bowel 
Maximal dose to 0.03 cc  
≤ 50 Gy 
90% Small bowel 
≤ 45 Gy 
*recommended only 
 
 

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Date: 07/25/2018 
Amendment 5 
 
 
 
 
Dosimetry Parameters for 3 treatment schedule 
cohort (SIB SBRT boost) *** 
Organ 
Volume 
Dose (Gy) 
PTV2 
Maximum point dose (0.03 cc) 
≤ 22.47 Gy,  107% of prescription dose * 
Minimum dose received by 95% 
of PTV 
≥ 18 Gy, 100% of prescription dose 
Minimum dose received by PTV 
≥ 17.1 Gy, 95% of prescription dose 
PTV3** 
Maximum point dose (0.03 cc) 
≤ 22.47 Gy,  107% of prescription dose* 
Minimum dose received by 95% 
of PTV 
≥ 21 Gy, 100% of prescription dose 
Minimum dose received by PTV 
≥ 19.95 Gy, 95% of prescription dose 
 
 
Rectum 
Maximum point dose(0.03cc) 
≤ 22.02 Gy, 105% of the prescription dose for PTV3 
Less than 2 cc 
≤ 19.5 Gy, 93% of prescription dose for PTV3 
90% rectum 
≤ 18.0Gy, 86% of prescription dose for PTV3 
80% rectum 
≤ 16.0 Gy, 76% of prescription dose for PTV3 
50% rectum 
≤ 13.6 Gy;  65% of prescription dose for PTV3 
Bladder 
Maximal point dose (0.03 cc)  
≤ 22.02 Gy, 105% of the prescription dose for PTV3  
80% Bladder 
≤ 17 Gy, 80% of prescription dose for PTV3 
50% bladder 
≤ 14.7 Gy, 70% of prescription dose for PTV3 
Penile 
bulb*  
Mean dose 
≤ 12.6 Gy, 60% of prescription dose for PTV3 
Femoral 
heads * 
Maximum point dose 
≤ 12.6 Gy, 60% of prescription dose for PTV3 
Small 
bowel 
Maximal point dose 
≤ 3 Gy 
Urethra 
Maximal point dose  
22.47 Gy – 107% of prescription dose (0.03 cc) 
*recommended only 
** PTV3 overlaps with PTV2 for SIB planning and delivery 
*** The OAR’s dose constraints for cohort 2 phase 1 and 2 were set based on cumulative EQD2 
calculations using α/β=3.   
 
 
6.6.1.7 
For future analysis, DVH will be generated for inner rectal wall and inner  
bladder wall. The inner rectal wall and the inner bladder wall for this DVH will be 
contoured for a distance of 18mm beyond the most inferior and superior contoured 
prostate slice. If a rectal balloon is used, the inner anterior rectal wall should be 
extracted from the rectum wall contour with a 3mm margin concentric ring inside 
the rectum contour. The inner rectal wall needs to be the same length as the rectum. 
 
6.7 
Image/Signal-Guidance for Target Localization 
6.7.1 After patient is set up on the treatment table, The Exactrac systems that locate the fiducial 
markers, placed inside the prostate, will be used to align the patient with the treatment machine 

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Amendment 5 
 
 
geometry based on the treatment plan. The alignment result will be evaluated by the attending 
physician and/or attending physicist and be approved for treatment by attending physician. The 
alignment data will be recorded. A rectal balloon may be used to immobilize the prostate. 
6.7.2 If a tracking system is available for prostate localization, it will be used during the treatment to 
track the target motion. A correction action will be performed if the target migrated more than 2 
mm for more than 20 seconds in any of three orthogonal coordinates. 
6.7.3 Cone-beam CT (CBCT) will be taken prior to radiation delivery but after image-guidance and also 
taken immediately after the SBRT. CBCT images will be used to assess the level of bladder and 
rectal filling and the presence of gas in the rectum. The rotation of the prostate will also be 
assessed prior to treatment. If significant deviations are found the patient will repeat the treatment 
preparation procedures. For some special cases, CBCT images may be taken more frequently 
during the treatment per physician’s clinical judgment. 
6.7.4 The initial localizations and alignment is based on the center of mass of the fiducial markers. 
Small rotations may be corrected at initial localization stage, and intra-fractional rotations will be 
ignored. Further adjustment during the treatment will be translational shift of the center of 
mass determined via IGRT technique, using remote couch motion. 
6.7.5 In view of intrafraction motion and to ensure the target coverage during treatment, periodic 
target localization will be employed during fix gantry angle IMRT, every 7 minutes from initial 
beam-on. The physicist will be on-site for image guidance and treatment. For Rapid Arc delivery 
the position of the target will be rechecked after every 180 degrees arc.  
6.7.6 For any image-guidance procedure, comparison with reference images or baseline data should 
be performed and reviewed and approved by both physician and physicist on site. 
6.7.6.1 
The comparison can be done both manually and automatically. For any  
image-guidance method, if any deviation is larger than 2 mm, correction should be 
performed. 
6.7.6.2 
All image/signal-guidance data should be recorded and saved for post treatment  
review and analysis. In some cases, re-planning (either offline or online) based 
on anatomy of the day may be performed. Such request will be made by the 
attending physician. 
 
6.8 
R.T. Quality Assurance Reviews 
All treatment prescription and verification images of each case will be reviewed by study chair/ 
physics co-chairs before treatment, and will also be archived for later review when a later toxicity 
occurs. 
 
6.9 
Radiation Therapy Adverse Events 
6.9.1 All patients will be seen weekly by their radiation oncologist during radiation therapy. Any 
observations regarding radiation reactions will be recorded and should include attention to the 
following potential side effects: 
6.9.1.1 
Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal  
   
urgency, proctitis, or hematochezia; 
6.9.1.2 
Bladder complications including urinary frequency/urgency, dysuria, hematuria, 
urinary tract infection, and incontinence; 
6.9.1.3 
Radiation dermatitis. 
6.9.2 Clinical discretion may be exercised to treat side effects from radiation therapy at the discretion 
of treating physician. Examples of typical medications used in the management of rectal side 
effects, such as diarrhea, include diphenoxylate or loperamide. Bladder or rectal spasms are 
usually treated with anticholinergic agents or tolterodine. Bladder irritation may be managed with 
phenazopyridine. Erectile dysfunction is often treated with medical management or mechanical 
devices. 
6.9.3 Adverse Events (AEs) and Serious Adverse Events (SAEs) and Unanticipated Problems 
(UP) Reporting Requirements 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4. The CTCAE version 4 is identified and located on the CTEP web site at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4. 
 
6.9.3.1 Definition of an AE: Any untoward or unfavorable medical occurrence in a human 
subject including any unintended abnormal sign, symptom, or disease whether or 
not it is considered related to the human subject’s participation in research.  
6.9.3.2 Definition of a Serious Adverse Event (SAE): Any adverse experience occurring 

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Amendment 5 
 
 
during any part of protocol treatment and 30 days after that results in any of the 
following outcomes: 
 Death; 
 A life-threatening adverse experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect; 
 Important medical events that do not result in death, are not life threatening, or do 
not require hospitalization may be considered an SAE, when, based upon medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
6.9.3.3 Definition of an Unanticipated Problems (UP): Includes any incident, experience, 
or outcome that meet all of the following criteria: 
 Unexpected 
 Related, probably related, or possibly related to participation in the research 
 Suggests that the research places participants or others at a greater risk of harm 
6.9.3.4 Reporting Requirements 
All SAEs must be submitted to the Rush University Medical Center IRB and the Rush 
Protocol Review and Monitoring Committee within 48 hours of  learning of the event. 
UPs must be submitted to the Rush University Medical Center IRB and Rush Protocol 
Review and Monitoring committee within 10 days of learning of the event. 
 
 
7.0 
DRUG THERAPY 
Hormone therapy is allowed for this study at the discretion of treating physician. The previous hormonal 
therapy, such as LHRH agonists (e.g., goserelin, leuprolide) or LHRH antagonists (e.g. degarelix), anti-
androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy) is 
acceptable for this study.  In principle, hormone therapy is not recommended to the patients with low-risk 
factors (PSA<10, GS 6 or less, and T1-T2a), a short-term hormone therapy (4 to 6 months) is acceptable 
to the patients with intermediate-risk factors (T2b-2c or PSA >10 or GS 7). A long-term hormone (28-32 
months) therapy is highly recommended to the patients with high-risk factors (GS 8 or more, PSA >20 or 
T3-4).   
 
8.0 
OTHER THERAPY 
8.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication. 
 
8.1.1  Diarrhea/rectal frequency/urgency may be managed with diphenoxylate or loperamide.Bladder  
irritation may be mitigated with phenazopyridine. Urinary frequency/urgency can be managed 
with anticholinergic agents or alpha-blockers such as tamsulosin. Erectile dysfunction can be 
managed with phosphodiesterase (PDE) inhibitors such as sildenafil. 
 
9.0 
PATIENT ASSESSMENTS  
9.1  Study Parameters 
  See Appendix I for a summary of study assessments and time frames.  
 
9.2 Pre-Treatment Evaluation 
9.2.1   PSA should not be obtained for at least 10 days after prostate biopsy. 
9.2.2   Patients must have the following evaluations prior to starting study treatment: 
 
History/Physical exam including a digital rectal exam 
 
Performance status 
 
Prostate biopsy with Gleason Score 
 
PSA 
 
Adverse Event Evaluation 
 
mpMRI 
 
Bone Scan and CT or MRI of Pelvis 
o 
Required for Cohort 2, but optional for Cohort 1. If the mpMRI includes 
the pelvis, an additional CT or MRI is not needed.  
9.2.3   Recommended pre-treatment evaluation (not required) 

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Amendment 5 
 
 
 
Imaging of urethra (see section 4.1) 
 
Testosterone 
 
9.3 Evaluation During Treatment 
9.3.1   Required evaluations during study treatment (to be completed weekly while on treatment): 
 
Physical exam 
 
Performance status 
 
Adverse event evaluation 
 
9.3.2  Optional Evaluation for Cohort 2 Only 
 
Non-contrast MRI of pelvis/prostate after first 5 weeks of radiation treatment 
 
9.3.3   Delay in treatment is discouraged unless the patient’s medical condition or side-effects of  
treatment merit a delay. Delay of treatment will be at the discretion of the treating radiation  
oncologist. 
 
9.4 Evaluation Following Treatment 
9.4.1  Required Evaluations Following Study Treatment (every 6 months until month 24): 
 
Physical exam including a digital rectal exam 
 
Performance status 
 
PSA 
 
Adverse event evaluation 
9.4.2  After the second year (24 months) following radiation, follow-up will continue every 6 months for  
  years 3, 4, and 5; then annually thereafter. 
9.4.3  A needle biopsy is encouraged: from the site of original tumor within the prostate and/or other   
  site of original tumor identified by the transrectal ultrasound, as indicated for rising PSA or  
  clinical failure. 
9.4.4  A bone scan will be performed as clinically indicated, e.g., if the patient develops a PSA   
  recurrence with a rapid doubling time (< 6 months) or if the patient develops symptoms    
  suggesting the presence of metastatic disease. 
9.4.5  When documentation of disease progression is noted within 5 years, follow up will be as per  
  protocol. When the disease progression occurs after 5 years, follow up will be at the discretion   
  of the treating physician. 
 
9.5 Criteria for Biochemical Recurrence 
9.5.1 Biochemical (PSA) recurrence is defined according to the proposed new Radiation Therapy  
     Oncology Group/American Society for Therapeutic Radiology and Oncology (RTOG-ASTRO)  
      criteria also known as the RTOG Phoenix definition: an increase of the PSA level at least  
    2 ng/mL greater than the minimum level reached after therapy (lowest PSA+ 2 criterion)  
   (H. Sandler, personal communication, December 2005). All PSA levels done during a  
    follow-up interval will be recorded on the data forms. 
 
9.6  Criteria for Local Recurrence 
        9.6.1  
 Clinical criteria for local recurrence are progression (increase in palpable abnormality) at  
any time, failure of regression of the palpable tumor by 2 years, and redevelopment of a 
palpable abnormality after complete disappearance of previous abnormalities. Needle biopsy 
is recommended. The presence of palpable disease must be recorded on the data 
collection forms for initial and follow-up evaluations of the patient. 
9.6.2    Histologic criteria for local recurrence are presence of prostatic carcinoma upon 
biopsy and positive biopsy of the palpably normal prostate more than 2 years after 
the start of treatment. 
9.7  Criteria for Nonlocal Recurrence 
9.7.1   
Distant metastasis will be documented if clinical or bone scan evidence is demonstrated.  
     
Ultrasound evaluation of the prostate with needle biopsy as indicated by the findings is       
     
recommended at the time distant metastasis is reported. 
 
Regional metastasis will be documented if there is radiographic evidence (CT or MRI) of 
lymphadenopathy and histologic confirmation. 
 
9.8  Other Response Parameters 
9.8.1 
Disease-Free Survival 

22 
PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
Disease-free survival will be measured from the date of registration to the date of 
documentation of recurrence or until the date of death. This endpoint includes all measures 
of disease including physical exam, PSA, bone scans, CT/MRI, and biopsies. 
9.8.2 
Time to Local Progression 
The time to progression will be measured from the date of registration to the date of 
documented local progression. Patients who have a normal exam and no evidence of having 
a PSA recurrence will be considered controlled locally. Patients with a residual abnormality 
or a PSA failure shall undergo biopsy to distinguish between local and distant failures. If 
their exam is normal or if they are post orchiectomy, they will be censored at the last 
point in time they were considered locally controlled and considered "not evaluable" for 
further assessment of local control. 
9.8.3 
Time to Distant and/or Regional Failure 
The time to distant or regional failure will be measured from the date of registration to the 
date of documented regional nodal recurrence or distant disease relapse. Patients with 
evidence of biochemical failure, but a negative prostate biopsy, will be considered as distant 
or regional failure only. 
9.8.4 
Disease-Specific Survival 
Disease-specific survival duration will be measured from the date of registration to the date 
of death due to prostate cancer. Causes of death may require review by the study chair or 
their designee. Death due to prostate cancer will be defined as: 
9.8.4.1 Primary cause of death certified as due to prostate cancer 
9.8.4.2 Death in association with any of the following conditions: 
9.8.4.2.1 
Further clinical tumor progression occurring after initiation of  
 
 
"salvage" anti-tumor (e.g., (androgen suppression) therapy 
9.8.4.2.2 
A rise (that exceeds 1.0 ng/mL) in the serum PSA level on at  
 
 
least two consecutive occasions that occurs during or after  
 
 
"salvage" androgen suppression therapy 
9.8.4.2.3 
Disease progression in the absence of any anti-tumor therapy 
9.8.4.2.4 
Death from a complication of therapy, irrespective of disease  
 
 
status. 
 
9.8.5 
Freedom from Biochemical (PSA) Recurrence (FFBR) 
The time to PSA failure will be measured from the date of registration to the date of a rise by 
2 ng/mL or more above the nadir PSA. Nadir PSA is defined as the lowest PSA value 
after randomization and before the call date PSA. That is, the time of failure will be the 
date of the first PSA that is 2 ng/mL or more above the lowest prior post-randomization PSA 
value. 
 
9.8.6 
Overall Survival 
Survival duration will be measured from the date of registration to the date of death from any 
cause. A post-mortem examination will be performed whenever possible. 
 
9.8.7 
Primary Outcome Measure 
Acute and late toxicity (primary endpoint) will be measured according to the NCI Common 
Toxicity Criteria (CTCAE v4.0) at designated follow-up visits.   
 
9.9 Criteria for Discontinuation of Protocol Treatment 
9.9.7 
Patients who are experiencing excessive adverse events as deemed by their treating 
physician may be discontinued from the initiated protocol treatment. All attempts should 
be made to manage adverse events adequately so as to avoid this circumstance. 
 
9.9.8 
Study analyses will be based on “intent to treat”. If protocol treatment is discontinued, follow 
up and data collection will continue as specified in the protocol. 
 
10.0 
DATA COLLECTION 
Data will be collected on study specific case report forms. The timing of the form collection is detailed 
in the table below. Toxicities, PSA, biochemical and local recurrence, distant progression, second 
primary malignancy, and death will be documented on the case report forms and stored at Rush 
University Medical Center.  
 
FORM 
DUE 

23 
PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
Registration 
Prior to beginning protocol therapy 
Baseline 
After registration 
Prior to beginning protocol therapy 
On Treatment 
Weekly while receiving protocol therapy 
Follow-Up 
Every 6 months post RT for 24 months 
Every 6 months after 24 months for years 3, 4 
and 5, and then annually 
 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 Primary Endpoint 
18-month late GU/GI toxicity   
 
11.2 Secondary Endpoints 
11.2.1 Acute GU toxicity 
11.2.1.1 PSA failure 
11.2.1.2 Disease free survival 
 
 
Patient Groups 
There are two separate and independent patient cohorts as defined by the 
Hypofractionation schedule: Cohort 1 patients treated with 36.25 Gy (5 fractions of 7.25 Gy 
over two weeks), and Cohort 2 patients treated with IG-IMRT 45 Gy in 25 daily fractions 
(over 5 weeks) to entire seminal vesicle followed by a SBRT of 21 Gy in 3 fractions to the 
prostatic tumor only (over one and a half weeks). 
 
11.3 Sample Size Derivation and Accrual 
11.3.1 Sample Size 
Overview: The primary goal of this phase II study is to estimate the rate of late grade 3-5 
genitourinary and gastrointestinal toxicity following treatment with either SBRT alone vs. 
IMRT followed by SBRT as a boost.  Late toxicity will be defined as toxicity occurring more 
than nine months from the start of radiotherapy. It is graded based on CTCAE v4.0 
 
Sample size derivation: The study is designed to test whether the 18-month late GU/GI 
toxicity following the protocol treatment is above 10%. The sample size is determined so that 
the probability of rejecting the treatment because of excessive late toxicity is 90% if the true 
late toxicity rate is 20%. Using confidence level of 95% and statistical power of 80%, we 
require a sample size of 61 patients to have a statistical power of 80% with one-tailed z-test 
of proportions. Considering 10% ineligible cases due to loss of follow-up or death, the total 
sample size of the study is 67 patients for each cohort. 
 
References for the above statistical considerations: 
Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel 
Dekker. New York. 
Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. Third 
Edition. John Wiley & Sons. New York. 
Lachin, John M. 2000. Biostatistical Methods. John Wiley & Sons. New York. 
Machin, D., Campbell, M., Fayers, P., and Pinol, A. 1997. Sample Size Tables for Clinical 
Studies, 2nd Edition. Blackwell Science. Malden, Mass. 
Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood 
Cliffs, New Jersey. 
11.3.2 Accrual and Duration 
It is expected that it will take approximately 5 years to complete accrual. The analysis for late 
toxicity will be carried out after each patient has had at least 18 months of follow-up. For 
another secondary endpoint of biochemical failure, an additional two years of follow-up are 
needed to estimate the 3-year failure rate. 
 
Data Safety Monitoring (DMC) Plan-As part of the data safety monitoring plan, all patients will 
be seen at least once a week by a physician while the patient is under treatment and an 

24 
PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
assessment of symptoms made.  If a SAE is noted a report will be generated immediately and 
the IRB notified.  In addition, all the patient data and toxicity information will be reviewed once 
at least once a month by the PI. The DMC meeting will be held every January and July, to 
review and report safety issues. The DMC meeting results will be included in the interim 
reports, submitted to the Rush IRB every January and July. 
 
11.3.3 Analysis of the Acute GI and GU adverse events (Secondary Endpoint)  
Adverse acute events are evaluated by the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). The treatment-related attribution includes 
definitely, probably or possibly related to treatment. An acute adverse event is defined as 
the first occurrence of worst severity of the adverse event ≤30 days after the completion 
of RT. For each cohort, we will evaluate the acute radiation therapy-related adverse events. 
Specifically, we are interested in the percentage of acute GI and GU Grade 3+ adverse 
events that occur in each arm, which is considered to be similar to the high RT dose arm of 
RTOG 0126 in terms of RT dose. For this arm, a reported 1% of patients experienced 
Grade 3+ GI/GU acute toxicity, with no patient experiencing Grade 4 or 5 toxicities. If 
either hypofractionated arm has an acceptable percentage, then that arm will be deemed 
to have an acceptable adverse event profile. We will report the percentage for each arm 
as well as the one-sided 97.5% confidence interval. Note that the number of patients in the 
high dose arm of RTOG 0126 (a Phase III) trial is much greater than each arm of this 
Phase II study. For each arm, if the lower limit of the interval is >1% then that arm will 
be further investigated for acceptability in terms of CTC toxicity 
 
11.3.4 PSA Failure 
Failure occurs when the PSA is first noted to be 2 ng/mL or more than the current nadir 
value (PSA > current nadir + 2) post RT completion. PSA failure at 1, 2, and 5 years will be 
estimated for each cohort by the cumulative incidence method (41). Also, confidence 
intervals will be reported. 
 
11.3.5 Disease-Free Survival (DFS) 
The disease-free survival duration will be measured from the date of registration to the date 
of documentation of disease progression or until the date of death from any cause. DFS at 
1, 2, and 5 years will be estimated for each c o h o r t  by the Kaplan-Meier method 
(42). Also, 95% confidence intervals will be reported. 
 
11.4 Interim Reports to Monitor Study Progress 
The study chairs will meet every 6 months to monitor the trial for safety. Interim reports with 
descriptive statistics will be prepared twice a year until the initial paper reporting the treatment 
results has been accepted for publication. In general, the interim reports will contain information 
about the patient accrual rate with a projected completion date for the accrual phase; data quality; 
compliance rate of treatment delivery with the distributions of important prognostic baseline 
variables; and the frequencies and severity of adverse events. The interim reports will not contain 
results from the treatment comparisons with respect to the primary or secondary endpoints. 
 
11.5 Gender and Minorities 
In conformance with the National Institute of Health Revitalization Act of 1993 with regard to 
inclusion of women and minority in clinical research, we will make every effort to accrue minority 
patients.  However, there is no specific projection for this institutional trial, mainly due to limitation 
of patient source. 
 

25 
PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
REFERENCES 
 
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer JClin 2014;64:9-29.  
2. S.A. Mangar. R.A. Huddart. C.C. Parker, et al., Technological advances in radiotherapy for the treatment of 
localised prostate cancer. European Journal of Cancer. 41 (2005)  908-21. 
3. C.R. King, T.A. DiPetrillo and D.E. Wazer, Optimal radiotherapy for prostate cancer: Predictions for 
conventional external beam, IMRT, and brachytherapy from radiobiologic models. Int. J. Radiat. Oncol. Biol. 
Phys. 46 (2000), pp. 165–17 
4. T. Kron, G. Grigorov, E. Yu, et al., Planning evaluation of radiotherapy for complex lung cancer cases using 
helical tomotherapy.  Physics in Medicine & Biology. 49 (2004) 3675-3690 
5. J.S. Welsh. R.R. Patel, M.A. Ritter, et al., Helical tomotherapy: an innovative technology and approach to 
radiation therapy Technology in Cancer Research & Treatment. 1 (2002) 311-316. 
6. Maggio A, Fiorino C, Mangili P, et al.  Feasibility of safe ultra-high (EQD (2)>100 Gy) dose escalation on 
dominant intra-prostate lesions (DILs) by helical tomotherapy. Acta Oncol 2011:50:25-34. 
7. S.A. Mangar,. R.A. Huddart. C.C. Parker, et al.,  Technological advances in radiotherapy for the treatment of 
localised prostate cancer. European Journal of Cancer. 41 (2005) 908-921 
8. A. Pollack, G.K. Zagars , G.  Starkschall , et al. Prostate cancer radiation dose response: results of the M.D. 
Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys. 53  (2002) 1097-1105.  
9. Zelefsky, MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional 
conformal radiotherapy and intestity-modulated radiotherapy for flocalized prostate cancer. Int J Radiat 
Oncol Biol Phys 2008;70:1124-1129 
10. A.L Zietman, M.L. DeSilvo, J.D. Slater, et al  Comparison of Conventional-Dose vs High-Dose Conformal 
Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate A Randomized Controlled Trial  
JAMA 294 (2005) 1233-39   
11. G.E. Hanks, A.L. Hanlon and B. Epstein et al., Dose response in prostate cancer with 8–12 years’ follow-up, 
Int J Radiat Oncol Biol Phys 54 (2002), pp. 427–435 
12. M.J. Zelefsky, Z. Fuks, M. Hunt et al., High dose radiation delivered by intensity modulated conformal 
radiotherapy improves the outcome of localized prostate cancer. J Urol 166 (2001), pp. 876–881  
13. Kuban DA, Tucker SL, Dong L, et al. Long term results of the M.D. Anderson randomized dose escalation 
trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70(1):67-74. 
14. L.J. Boersma, M. van den Brink, A.M. Bruce, et al., Estimation of the incidence of late bladder and rectum 
complications after high-dose (70-78 Gy) conformal radiotherapy for prostate cancer using dose-volume 
histograms, Int J Radiat Oncol Biol Phys 41  (1998).  83-92.   
15.  Jackson, M.W. Skwarchuk and M.J. Zelefsky et al., Late rectal bleeding after conformal radiotherapy of 
prostate cancer. II. Volume effects and dose-volume histograms, Int J Radiat Oncol Biol Phys 49 (2001), pp. 
685–698. 
16. M. Roach, III, M. DeSilvio, C. Lawton, et al., Phase III Trial Comparing Whole-Pelvic Versus Prostate-Only 
Radiotherapy and Neoadjuvant Versus Adjuvant Combined Androgen Suppression: Radiation Therapy 
Oncology Group 9413  J Clin Oncol  21 (2003) 1904–1911 
17. G.K. Zagars, A. Pollack and A.C. von Eschenbach, Addition of radiation therapy to androgen ablation 
improves outcome for subclinically node-positive prostate cancer. Urology 58 (2001), pp. 233–239   
18. C.A. Lawton, K. Winter, D. Grignon, et al., Androgen suppression plus radiation versus radiation alone for 
patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on 
national prospective randomized trial Radiation Therapy Oncology Group 85-31. J Clin Oncol. 23 (2005) 
800-807    
19. R. Whittington, S.B. Malkowicz, M. Machtay et al., The use of combined radiation therapy and hormonal 
therapy in the management of lymph node-positive prostate cancer. Int J Radiat Oncol Biol Phys 39 (1997), 
pp. 673–680  
20. E.M. Messing, J. Manola, M. Sarosdy, et al., Immediate Hormonal Therapy Compared with Observation 
after Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer N 
Engl J Med 341  (1999) 1781-1788   
21. B.S. Teh, W.Y. Mai and B.M. Uhl et al., Intensity-modulated radiation therapy (IMRT) for prostate cancer 
with the use of a rectal balloon for prostate immobilization Acute toxicity and dose–volume analysis, Int J 
Radiat Oncol Biol Phys 49 (2001), pp. 705–712.  
22. M.J. Zelefsky, Z. Fuks, L. Happersett, L., et al.  Clinical experience with intensity modulated radiation 
therapy (IMRT) in prostate cancer. Radiotherapy and Oncology  55  (2000) 241-249. 
23. G.M. Duchesne, L.J. Peters,  What is the / ratio for prostate cancer? Rational for hypofractionated high-
dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 44  (1999)  747-748-993. 
24. D.J. Brenner and E.J. Hall, Fractionation and protraction for radiotherapy of prostate carcinoma, Int J Radiat 
Oncol Biol Phys 43 (1999), pp. 1095–1101 

26 
PI Dian Wang, RUMC 
Date: 07/25/2018 
Amendment 5 
 
 
25. J. Fowler, R. Chappell and M. Ritter, Is alpha/beta for prostate tumors really low?, Int J Radiat Oncol Biol 
Phys 50 (2001), pp. 1021–1031. 
26. J.Z. Wang, X.A. Li and C.X. Yu et al., The low alpha/beta ratio for prostate cancer What does the clinical 
outcome of HDR brachytherapy tell us?, Int J Radiat Oncol Biol Phys 57 (2003), pp. 1101–1108 
27. C.D. Collins, Radical external beam radiotherapy for localized carcinoma of the prostate using a 
hypofractionation technique, Clin Oncol (R Coll Radiol) 3 (1991), p. 358. 
28. R.W. Lloyd-Davies, C.D. Collins and A.V. Swan, Carcinoma of prostate treated by radical external beam 
radiotherapy using hypofractionation Twenty-two years’ experience (1962–1984), Urology 36 (1990), pp. 
107–111. 
29. E. Livsey, R.A. Cowan and J.P. Wylie et al., Hypofractionated conformal radiotherapy in carcinoma of the 
prostate Five-year outcomes analysis, Int J Radiat Oncol Biol Phys 57 (2003), pp. 1254–1259. 
30. D.S. Mohan, P.A. Kupelian and T.R. Willoughby, Short-course intensity-modulated radiotherapy for localized 
prostate cancer with daily transabdominal ultrasound localization of the prostate gland, Int J Radiat Oncol 
Biol Phys 46 (2000), pp. 575–580.  
31. P.A. Kupelian, C.A. Reddy and E.A. Klein et al., Short-course intensity-modulated radiotherapy (70 GY at 
2.5 GY per fraction) for localized prostate cancer Preliminary results on late toxicity and quality of life, Int J 
Radiat Oncol Biol Phys 51 (2001), pp. 988–993. 
32. P.A. Kupelian, C.A. Reddy and T.P. Carlson et al., Preliminary observations on biochemical relapse-free 
survival rates after short-course intensity-modulated radiotherapy (70 Gy at 2.5 Gy/fraction) for localized 
prostate cancer, Int J Radiat Oncol Biol Phys 53 (2002), pp. 904–912 
33. P.A. Kupelian, V.V. Thakkar and D. Khuntia, C.A. Reddy, E.A. Klein, and A. Mahadevan. Hypofractionated 
intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: long-term 
outcomes. Int J Radiat Oncol Biol Phys 63 (2005), pp. 1463–1468 
34. Ritter MA, Forman, JD, Kupelian, PA, et al. A phase I/II trial of increasingly hypofractionated radiation 
therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:Suppl: S80-81. 
35. King CR, Brooks JD, Gill H, et al. Stereotactic Body Radiotherapy for Localized Prostate Cancer: Interim 
Results of a Prospective Phase II Clinical Trial. Int J Radiat Oncol Biol Phys 2008. 
36. King CR, Lehmann J, Adler JR, et al. CyberKnife radiotherapy for localized prostate cancer: rationale and 
technical feasibility. Technol Cancer Res Treat. 2: 25-30, 2003. 
37. Barentsz JO, Richenberg J Clements R, et al.  ESUR prostate MR guidelines 2012. Eur Radiol. 2012; 22: 
746-757.  Current clinical guidelines for multiparametric prostate MRI. 
38. Hoeks CM, Schouten MG, Bomers JG, et al. Three-Tesla magnetic resonance-guided prostate biopsy in 
men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal 
ultrasound biopsies: detection of clinically significant prostate cancers.   Eur Urol. 2012 Nov;62(5):902-9. 
doi: 10.1016/j.eururo.2012.01.047. Epub 2012 Feb 1. 
39. Panje C, Panje T, Putora PM, et al.  Guidance of treatment decisions in risk-adappted primary radiotherapy 
for prostate cancer using multiparametric magnetic resonance imaging: a single center experience.  Radiat 
Oncol. 10(1):47, 2015.  
40. Marks L, Young S, Natarajan S.  MRI–ultrasound fusion for guidance of targeted prostate biopsy. Curr Opin 
Urol. Author manuscript; available in PMC 2013 February 26. 
41. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 16: 
141- 1154, 1988. 
42. Kaplan EL, Meier P. Non-parameteric estimation from incomplete observations. Journal American Statistical 
Association. 53: 457-481, 1958. 
 
 

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27 
 
APPENDIX I  
 
STUDY PARAMETER TABLE 
*See Sections 3.0 and 4.0 (pre-study entry) and 11.2 through 11.4 (during treatment/follow 
up) for details and/or exceptions. 
 
 
Pre-study Entry 
(may be required for eligibility) 
During Treatmentg 
Follow-up (months), 
Every 6 months for years 3, 4 and 5, then annually e 
 
≤60 days 
≤90 
day
≤180 
days 
≤365 
days 
Weekly during RT 
6 
12 
18 
24b 
History/physical 
exam including a 
digital rectal 
exam f 
X 
Physical exam  
X 
X 
X 
X 
Xb 
Performance 
status 
X 
X 
X 
X 
X 
Xb 
Prostate biopsy 
w/ Gleason score 
X 
 
PSA 
Xa 
X 
X 
X 
Xb 
Testosterone 
Xc 
mpMRI 
  
X 
 
Xc after 5-Week RT 
for Cohort  2 only 
(non-contrast) 
Imaging of 
urethra 
See Sect. 
4. 1c 
Bone Scan 
Xd  
 
T Stage 
Evaluation 
 
X 
 
 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
Xb 
a PSA should not be obtained for at least 10 days after prostate biopsy 
b After the second year (24 months) following radiation, follow-up will continue every 6 months for years 3, 4, and 5;    
   then annually thereafter. 
c Optional (Recommended) 
d Required for all of Cohort 2. Required for Cohort 1 when both PSA > 10 ng/mL and Gleason Score > 6.  
e + 30 days 
f Digital rectal exam to be performed within 90 days of registration 
g For patients in cohort 1 only, patients need to be seen only once during their 5 treatments 
 
 

Date: 07/25/2018 
Amendment 5 
 
28 
 
APPENDIX II 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
1 
 Death 

Date: 07/25/2018 
Amendment 5 
 
29 
 
APPENDIX III 
 
AJCC STAGING SYSTEM 
PROSTATE, 7th Edition 
DEFINITIONS OF TNM 
Source: Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
Primary Tumor, Clinical (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Clinically inapparent tumor neither palpable nor visible by imaging 
T1a 
Tumor incidental histologic finding in 5% or less of tissue resected 
T1b 
Tumor incidental histologic finding in more than 5% of tissue resected 
T1c 
Tumor identified by needle biopsy (e.g., because of elevated PSA) 
 
T2 
Tumor confined with prostate* 
T2a 
Tumor involves one-half of one lobe or less 
T2b 
Tumor involves more than one-half of one lobe but not both lobes 
T2c 
Tumor involves both lobes 
 
T3 
Tumor extends through the prostate capsule** 
T3a 
Extracapsular extension (unilateral or bilateral) 
T3b 
Tumor involves the seminal vesicle(s) 
 
T4 
Tumor is fixed or invades adjacent structures other than seminal vesicles such as external 
sphincter, rectum, bladder, levator muscles and/or pelvic wall 
 
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is 
classified as T1c 
 
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but 
as T2. 
 
 
Primary Tumor, Pathologic (pT) * 
pT2 
Organ confined 
pT2a 
Unilateral, one-half of one side or less 
pT2b 
Unilateral, involving more than one-half of side but not both sides 
pT2c 
Bilateral disease 
 
pT3 
Extraprostatic extension 
pT3a 
Extraprostatic extension or microscopic invasion of bladder neck** 
pT3b 
Seminal vesicle invasion 
 
pT4 
Invasion of rectum, levator muscles, and/or pelvic wall 
 
*Note: There is no pathologic T1 classification 
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). 
 
Regional Lymph Nodes (N) 
Clinical 
NX 
Regional lymph nodes were not assessed  
N0 
No regional lymph node metastasis 
N1 
Metastasis in regional lymph node(s) 
 
Pathologic 
pNX 
Regional nodes not sampled  

Date: 07/25/2018 
Amendment 5 
 
30 
 
pN0 
No positive regional nodes  
pN1 
Metastases in regional node(s) 
 
 
Distant Metastasis (M)* 
M0 
No distant Metastasis  
M1 
Distant metastasis 
M1a 
Non-regional lymph node(s)  
M1b 
Bone(s) 
M1c 
Other site(s) with or without bone disease 
 
*Note: When more than one site of metastasis is present, the most advanced category is used; 
pM1c is most advanced. 
 
 
Histologic Grade (G) 
Gleason X 
Gleason score cannot be processed  
Gleason ≤6 
Well-differentiated (slight anaplasia]) 
Gleason 7 
Moderately differentiated (moderate anaplasia) 
Gleason 8-10 
Poorly differentiated/undifferentiated (marked anaplasia) 
 
 
Anatomic Stage/Prognostic Groups* 
Stage I 
T1a-c 
T2a 
T1-2a 
N0 
N0 
N0 
M0 
M0 
M0 
PSA <10 
PSA <10 
PSA X 
Gleason ≤6 
Gleason ≤6 
Gleason X 
Stage IIA 
T1a-c 
T1a-c 
T2a 
T2b 
T2b 
N0 
N0 
N0 
N0 
N0 
M0 
M0 
M0 
M0 
M0 
PSA <20 
PSA ≥10<20 
PSA <20 
PSA <20 
PSA X 
Gleason 7 
Gleason ≤6 
Gleason ≤7 
Gleason ≤7 
Gleason X 
Stage IIB 
T2c 
T1-2 
T1-2 
N0 
N0 
N0 
M0 
M0 
M0 
Any PSA 
PSA ≥20 
Any PSA 
Any Gleason 
Any Gleason 
Gleason ≥8 
Stage III 
T3a-b N0 
M0 
Any PSA 
Any Gleason 
Stage IV 
T4 
Any T 
Any T 
N0 
N1 
Any N 
M0 
M0 
M1 
Any PSA 
Any PSA 
Any PSA 
Any Gleason 
Any Gleason 
Any Gleason 
 
*Note: When either PSA or Gleason is not available, grouping should be determined by T stage and/or either PSA 
or Gleason as available. 

Date: 07/25/2018 
Amendment 5 
 
31 
 
APPENDIX IV 
 
BED Dose Calculation 
Comparison 
 
Studies 
Treatment schema 
HDR or SBRT 
DOSE 
EQD2* PTV 
α/β=3 
EQD2  PTV 
α/β=1.5 
Cohort 11 
SBRT monotherapy 
(previously used in RTOG 
0938) 
SBRT 7.25 Gy x 
5 fractions 
74.3 Gy 
90.6 Gy 
 
 
Cohort 22 
 
 
IMRT 45 Gy followed by 
SBRT boost 
SBRT 6 Gy X 3 
to entire prostate 
 
SBRT 7 Gy x 3 
to mpMRI+ 
lesion 
75.6 Gy 
 
 
85.2 Gy 
81.0 Gy 
 
 
93.4 Gy 
RTOG 0321 
Phase II3 
EBRT 45 Gy followed by 
HDR boost 
HDR 9.5 Gy X 
2 fractions 
90.7 Gy 
102.1Gy 
RTOG 0815 
Phase III3 
IMRT 45 Gy followed by 
HDR boost 
HDR 10.5 Gy x 
2 fractions 
99.9 Gy 
114.4 Gy 
RTOG 0924 
Phase III3 
IMRT 45 Gy followed by 
HDR boost 
HDR 15 Gy  x 
1 fraction 
97.2 Gy 
113.1 Gy 
Standard  
Fractionation4 
IMRT 79.20 Gy in 44 
fractions (1.8 Gy/fraction) 
N/A 
76.0 Gy 
74.7 Gy 
1. Prescribed to 98% PTV, PTV=prostate plus 3-5 mm; In this protocol, all patients will have 3 fiducial markers 
placed into the prostate prior to radiation simulation and daily CBCT is used to localize fiducial markers prior to 
each radiation treatment and motion of fiducial markers will be tracked during course of SBRT.   
2. Simultaneously integrated boost (SIB) of 18 Gy in 3 fractions to 95% PTV including entire prostate plus 3-5 mm, 
and 21 Gy in 3 fractions to 95% of PTV including intra-prostatic lesion (GTV) by mpMRI, plus 2-3 mm.  In this 
protocol, all patients will have 3 fiducial markers placed into the prostate prior to radiation simulation and daily 
CBCT is used to localize fiducial markers prior to each radiation treatment and motion of fiducial markers will be 
tracked during course of SBRT.   
3. For EBRT, prescribed to 95-98% PTV including prostate pelvis plus/minus pelvic nodes plus 5-10 mm margin.  
For HDR brachytherapy boost, Prescribed to >90% PTV, PTV=prostate only, the prescription to >80% PTV is 
considered acceptable (minor variation).    
4. For IMRT, prescribed to 98% PTV, PTV = prostate plus 5 mm margin for prostate-RT only.  This is a commonly 
used regimen in RTOG 0126, RTOG 0815 and RTOG 0924.    
* EQD2 = Equivalent 2Gy dose = n * d * (d + α/β) / (2 + α/β)