Magnetic Resonance Guided Focal Stereotactic Body Radiation Therapy for Localized Prostate Cancer
Phase: NA
Conditions: Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer
Sponsor: Case Comprehensive Cancer Center

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Protocol:  8.4.2020 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
Study Number:  
CASE 11813  
 
Clinicaltrials.gov #:  NCT02163317 
 
Study Title:  
Magnetic Resonance Guided Focal Stereotactic Body Radiation Therapy for 
Localized Prostate Cancer 
 
Principal Investigator:  Elisha Fredman, MD 
University Hospitals Cleveland Medical Center 
Case Western Reserve University 
11100 Euclid Avenue 
Cleveland, OH  44106 
 
 
 
Statistician:   
  
 
 
 
 
 
 
 
 
 
Sponsor:  
 
Case Comprehensive Cancer Center 
 
Support:  
 
Elekta SBRT Research Grant Program, Stockholm, Sweden. 
Invivo, Gainsville, FL,  
Philips Medical Systems, Cleveland, OH 

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SUMMARY OF CHANGES 
 
Protocol 
Date 
Section Change 
05.23.2014 
 
Initial IRB approval 
09.26.2014 
Cover 
page 
Updates to co-investigators on cover page 
04.08.2015 
7.3 
“Concomitant medication assessment including hormone therapy” was 
added to all visits past 30 days 
App. 3 
Updated EPIC QOL to include all pages 
02.04.2016 
4.3.12 
7.1 
7.3 
Added Bone Scan  
3.30.2016 
4.0 
4.3.1 
4.3.5 
Removed “within 1 year of screening”  
4.3.6 
Removed hematologic and hepatic function. Updated creatinine  
7.0 
7.3 
Updated study procedures to better align with SOC  
10.25.2016 
Cover 
page 
Removed Case Medical Center references  
4.3 
Removed 12 month reference missed in 3.30.2016 amendment  
12.15.2016 
Cover 
page 
Changed PI to Bryan Traughber, removed list of co-investigators  
9.2 
Updates to RECIST tumor response section  
5.10.2017 
Cover 
page  
Change PI from Traughber to Bryan Traughber 
7.1 and 
7.3 
update bullet point for screening visit #1 in section 7 on Pelvic mpMRI 
with contrast and multiparametric sequences to clarify timeframe within 
90 days of screening, corresponding change to calendar 
1.31.2018 
Cover 
page 
Change PI from Kumar back to Traughber  

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Protocol:  8.4.2020 
Protocol 
Date 
Section Change 
1.16.2020 
6.1, 7.1 
and 
misc.  
Section 7.1:  bone scan only to be completed when "clinically 
indicated" 
Section 6.1.1:  option for hydrogel spacer placement added during 
fiducial placement 
Stereo Tactic Targeting and Treatment:  Biopsy clarification – only to 
be done if no biopsy exists 
As practice patterns have changed, many patients are now coming with 
"mapping" biopsies including in-gantry MRI and MR/US fusion.  This 
does not need to be repeated for protocol, making it an unnecessary 
risk/procedure for the patient.  
Section 7.1:  Pelvic mpMRI changed to within 180 days of screening 
visit (from 90 day)  
Misc. administrative updates 
Consent updated accordingly for spacer, MRI, bone scan and biopsy  
8.4.2020 
Cover 
Page 
Change PI from Traughber to Fredman 
 
TABLE OF CONTENTS 
Table of Contents 
 
1.0 
Introduction 
1.1 
Study Conduct 
1.2 
Background 
2.0 
Study Objectives 
3.0 
Study Design  
3.1 
General Design 
4.0 
Subject Selection and Withdrawal 
4.1 
General Characteristics of the Proposed Subject Population 
4.2 
Anticipated Number of Research Subjects 
4.3 
Inclusion Criteria 
4.4 
Exclusion Criteria 
4.5 
Subject Recruitment and Screening 
4.6 
Inclusion of Women and Minorities 
5.0 
Registration 
5.1 
Early Withdrawal of Subjects 
6.0 
Study Treatment or Diagnostic Product Procedures 
6.1 
Description of Radiation Therapy 
6.2 
Definition of Radiation Therapy Adverse Events  
7.0 
Study Procedures 
7.1 
Screening Visits 
7.2 
Study Visits 
7.3 
Study Calendar  
8.0 
Correlative/Special Studies – not applicable 
9.0 
Safety and Effectiveness Assessments 
9.1 
Safety and Efficacy endpoints 

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Protocol:  8.4.2020 
9.2 
Effectiveness Assessments 
10.0 
Statistical Plan 
10.1 
Data collection 
10.2 
Statistics  
11.0 
Cost and Compensation  
12.0 
Risk Analysis 
12.1 
Anticipated Risks 
12.2 
Benefits 
12.3 
Alternatives to participation 
13.0 
Data Reporting 
14.0 
Regulatory Considerations 
14.1 
Written informed consent 
15.0 
Study Closure 
16.0 
Auditing and Inspecting 
17.0 
Ethics 
18.0 
Study Finances 
18.1 
Funding Sources 
18.2 
Conflict of Interest 
19.0 
Publication Plan 
 
References 
 
APPENDICES  
 
 
 
APPENDIX 1 
 
AJCC Staging 
 
 
 
APPENDIX 2 
 
ECOG Performance Status Criteria  
 
 
APPENDIX 3  
 
Toxicity Assessment Instruments 
 
 
IPSS 
 
 
EPIC 
 
 
EPIC Supplement Sexual Medication/Device Screening 
 
 
EQ-5D 
 
 
SHIM 

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Protocol:  8.4.2020 
1.0  
Introduction 
1.1  
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board, and according to Good Clinical Practice standards. No deviation from the protocol will be 
implemented without the prior review and approval of the IRB except where it may be necessary to 
eliminate an immediate hazard to a research subject. In such case, the deviation will be reported to 
the IRB according to its policies and procedures.  
 
1.2  
Background  
Despite many advances in imaging and therapy, prostate cancer remains the second most common 
cause of cancer-related death of men in the United States.  The management approach to men 
diagnosed with low risk prostate cancer remains a socioeconomic dilemma with no clear consensus 
whether prostatectomy or whole-gland radiation therapy improves outcomes and these treatments are 
often associated with significant long-term morbidity negatively impacting quality of life parameters 
that require long-term management. Another approach has been ‘active surveillance’ but often these 
men are under staged at the time of diagnosis, and will clinically progress and ultimately receive 
definitive therapy to the whole gland, while more frequently many men opt for partial gland ablative 
therapy with surveillance.   
 
Previous research has demonstrated the value of radiation dose escalation in patients with prostate 
cancer (Bolzicco 2010, Friedland 2009). However, to date, most paradigms have focused on dose 
escalation applied to the whole gland. It is recognized that higher doses to the whole gland are 
associated with higher treatment related toxicities (impotence, incontinence, rectal fissures) 
(Zelefsky). Now, with advanced delivery techniques such as intensity modulated radiation therapy 
(IMRT), proton therapy, and stereotactic body radiation therapy (SBRT) dose escalation can be 
achieved targeting sub-volumes of the prostate. Preliminary evidence suggests that sub-volume dose 
escalation based upon molecular and anatomical imaging may improve outcomes (Eggner 2007, Ellis 
2010). This research will evaluate the safety and efficacy of SBRT for focal partial gland therapy in 
prostate cancer.  
 
There is growing concern over the risk of over treating patients who may not be at risk of dying from 
the disease. Prostate cancer remains the sole malignancy where treatment is always delivered to the 
whole organ in routine practice. Many low risk patients therefore opt for Active Surveillance rather 
than immediate whole gland treatment to limit treatment related decrease in quality of life associated 
with either surgery or whole gland radiation. A growing body of evidence also suggests that treatment 
of the dominant prostatic lesion/s may be sufficient to prevent systemic disease progression, and that 
small lesions less than 5 mm may be indolent, thus if left untreated initially may not be likely to 
progress in a clinically significant manor. Additionally once a dominate lesion is treated, the patient 
may return to a course of active surveillance using PSA, physical examinations, and repeat MRI or 
biopsy as clinically indicated (Scardino 2009, Cosset 2013).  
 
Despite early success using molecular and anatomical data to identify sub-volumes of disease for 
image-guided therapy, physicians remain reticent to escalate dose based upon imaging findings alone, 
which are inherently limited by sensitivity and specificity (Ellis 2010, Pinto 2011). Therefore, a 
treatment planning methodology that provided direct 3D spatial correlation of imaging sets with the 
gold standard of histopathology would be highly effective to exclude normal tissue (false positives 
by imaging) and simultaneously allow radiation dose escalation to clearly delineated “true positive” 
target volumes. 

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Protocol:  8.4.2020 
By using high resolution 3T MRI imaging with parametric sequencing to identify areas suspicions 
for harboring malignancy, we believe that focal therapy could be safely delivered to property selected 
patients.  Biopsy confirmation of the imaging findings for both suspicious and non-suspicious regions 
based on MRI imaging would be used to confirm that cancer is present at the suspected locations 
using a patented methodology to define the treatment target volumes. Rather than treating the whole 
gland, therapy could then be targeted to partial prostate volumes with the goal of reducing treatment 
related morbidity and long term cost for treatment. 
 
A recent systematic review of the focal therapy in localized prostate cancer evaluated 2350 cases 
reported in 30 studies through October 2012, mainly delivered in low and intermediate disease, and 
some high-risk patients where imaging suggested unilateral disease. Post therapy incontinence, and 
erectile function toxicities were limited, with promising short- to medium term disease free survival 
outcomes (Valerio 2013). In a separate critical appraisal of focal therapy for localized prostate cancer, 
Eggener et al. (representing an international multidisciplinary task force with expertise in prostate 
cancer) evaluated “the focal lesion paradigm” (Eggener 2007) and the role of focal ablative therapy. 
This review panel concluded with encouragement for prospective clinical research in emergent focal 
technologies for the treatment of unifocal and biologically unifocal prostate cancer – as needed 
options for men resistant to active surveillance and watchful waiting.  A number of other authors from 
major universities, have more recently reported good outcomes with whole-gland, unilateral and focal 
ablative cryotherapy applications. These authors list focal ablative options to include focused 
ultrasound, brachytherapy, thermotherapy, photodynamic therapy, and stereotactic radiosurgery 
(Polascik 2008, Hou 2009, Pisters 2010, Boomers 2013). Radiation therapy is uniquely qualified for 
use in focal therapies as it stands alone as a standard of care for prostate cancer treatment with long 
term outcomes showing safety and efficacy for whole gland disease control, and growing evidence 
with partial gland focal therapy (Ellis 2010, Katz 2010, Cossett 2013).  
 
Focal image-guided radiation therapy is a novel alternative that may provide a cost-effective and less 
morbid treatment option for men diagnosed with low-risk disease.  Conceptually, focal therapy targets 
only diseased prostatic tissue and spares adjacent non-cancerous prostate tissue which may be as 
efficacious as whole-gland therapy but with less side effects. Further, clinical evidence suggests that 
the α/β ratio of prostate cancer is quite low providing an opportunity for greater therapeutic gain with 
hypofractionated courses of radiotherapy compared to traditional fractionated treatment. The 
hypothesis of this proposal is multiparametric MR data including T2 weighted, contrast enhanced, 
and diffusion weighted imaging when correlated with marked histopathology biopsy sites confirming 
tumor foci, will allow appropriate patient selection for focal radiation therapy with a higher sensitivity 
than routine MR imaging alone. Further, that using advanced imaging to guide dose modulation in 
focal stereotactic body radiation therapy (SBRT), also named stereotactic ablative radiotherapy, may 
provide equivalent outcomes to whole-gland therapy with shortened treatment courses and decreased 
toxicity. This prospective investigational review board (IRB) approved, single institution pilot study 
will be used to demonstrate clinical feasibility and may potentially lead to future federally funded 
Phase I/II and consortium supported multi-center clinical research trials for focal SBRT in localized 
low-risk prostate cancer patients.  
 
Most recently, parametric sequencing MRI have been reported to identify prostatic regions that are 
highly suspicious for tumor foci (Valerio 2013). The current study will be used to help select for the 
proper group of patients for whom focal therapy may be appropriately offered. Men who have a 
diagnosis of localized prostate cancer with only moderately elevated PSA and Gleason score of 7 or 
lower without either a dominate pattern 4 or a tertiary pattern 5 seen on initial pathology may be 

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Protocol:  8.4.2020 
eligible for evaluation, as these patients meet the institutional clinically accepted determination 
making them eligible for Active Surveillance (AS). Many men meeting AS criteria, however, prefer 
treatment with curative potential, and opt for partial gland therapy aiming at limiting potential 
treatment related toxicities that may be associated with treatment to whole gland. A staging 3T MRI 
is our adopted standard of care evaluation for men presenting for radiation therapy planning with 
parametric sequences. In the current study we will use the staging and treatment planning images to 
evaluate regions highly suspicious for tumor foci as a screening tool for appropriateness of focal 
therapy and for eligible patients, for use in guided biopsy to confirm pathology on the imaging studies.   
Standard radiotherapy for the treatment of prostate cancer is delivered at 1.8 to 2 Gy per fraction in a 
protracted course over 8 to 9 weeks to total doses in the range of 78 to 81 Gy. Following the published 
work of Hall and Brenner suggesting that prostate cancer may have a lower alpha beta ration 
describing the cell line’s ability to repair damage caused by ionizing radiation; many centers have 
routinely adopted into clinical practice that prostate cancer may be treated using larger doses per 
fraction ranging in size from 3 to 19 Gy in as many as 20 or as few as a single fraction of therapy 
(Brenner 1999).  The assumption is that the alpha beta ration of most tumors is as high as 10, while 
the surrounding normal tissues at risk of late radiation reactions is around 3 to 5 (Yoshioka 2013). 
Positive histopathology findings on co-registered diagnostic MRI data sets (T2 and parametric 
functional imaging) will be used to segment a dominant biologic target volume and improve disease 
mapping across the gland. Subjects will then be treated in a series of three SBRT (typically every 
other day) treatments to deliver a total dose of 29.25 Gy in 9.75 Gy fractions, yielding a total biologic 
equivalent dose (BED) of 273.15 allowing dose to reach the desired minimal BED of 268 with an 
assumed alpha beta of 1.2 for prostate cancer as suggested by Martinez (2011). A similar dose 
regimen has been published by Barkate et.al. using HDR brachytherapy in a three fraction dose 
escalation trial to deliver minimal dose of 30 Gy in 3 fractions over two days to a maximal dose of 
34.5 Gy at 11.5 Gy per fraction. (Barkati 2012). While the published 3 fraction HDR regimen gave a 
minimal dose of 10 Gy, we feel that 9.75 Gy per fraction is effectively equivalent when taking into 
account the additional 12 cGy per fraction we will be giving to allow for tracking of intrafraction 
prostate motion with Image Guided Radiation Therapy using a series of 4 cone beam CT image 
sessions obtained before, during and after each fraction, thus accounting for a daily fractionated dose 
of 987 cGy, or 9.9 Gy. What is uniquely novel in this protocol is not the total dose of radiation 
delivered but rather that it is to be delivered in a non-invasive fashion using SBRT, and more 
importantly delivered to a novel partial prostate volume using a patented methodology to define the 
volume at risk to be treated using focal therapy for prostate cancer. This methodology may be adopted 
as a template for directing therapy to partial organ volumes using other treatment modalities based on 
the results of this trial if the use of tracked histopathology location is found to have significant 
influence on the selected treatment volumes in this study beyond what would be used based on 
functional and anatomic imaging studies alone. 
2.0 
Study Objectives 
Hypothesis:  Multiparametric MRI with histopathological correlation can be used to treat sub-
volumes of the prostate with focal SBRT in low- and intermediate-risk patients leading to equivalent 
outcomes as whole-gland therapy with reduced toxicity and improved quality of life. 
 
To validate the above hypothesis in this prospective study, the specific aims include: 
 

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Protocol:  8.4.2020 
1) Evaluate the correlation of histopathology findings in comparison to regions of the prostate 
reported to be suspicious for harboring tumor burden on multiparametric MRI report/s; 
2)  Demonstration of the dosimetric and radiobiological advantages of focal SBRT versus 
whole-gland radiation therapy; 
3)  Evaluation of clinical outcomes in focal SBRT for localized prostate cancer. 
 
3.0 
Study Design  
3.1   
General Design 
This 2-year pilot study will include patients with positive diagnostic prostate biopsy, with or without 
positive digital rectal exam (clinical stage T2a or T1cN0M0), Gleason score ≤7(3+4), with a PSA 
≤10ng/mL and routine imaging that includes bone scan and MRI of the pelvis.  
 
Patients eligible for either whole-gland therapy or active surveillance will be evaluated by staging 
MRI and the scan used to screen for disease burden within the gland. Patients identified with a focal 
dominate lesion greater than 5 mm in size confirmed with imaging and biopsy will be eligible for this 
trial. Patients found to have no focal abnormalities will be offered other disease management options 
off study, such as active surveillance or whole gland therapy with traditional fractionated external 
beam radiation therapy (EBRT) and/or brachytherapy.  
 
Eligible patients (≤6 total per year) will sign consent to enroll and be treated with focal SBRT on 
study at a dose of 29.25 Gy in 3 fractions (9.75 Gy per fraction) to involved sub-volume of the prostate 
using volumetric modulated arc therapy (VMAT) with the Synergy BMX2 with Agility collimator 
(Elekta, Stockholm, Sweden and Atlanta, GA). 
 
4.0   
Subject Selection and Withdrawal 
4.1 General Characteristics of the Proposed Subject Population 
Histologically confirmed diagnosis of adenocarcinoma of the prostate. Gleason scores ≤7(3+4); 
Clinical stage T1-2a; PSA ≤10 ng/mL (PSA should not be obtained within 10 days after prostate 
biopsy). 
 
4.2   
Anticipated Number of Research Subjects 
24 screened and 12 enrolled over 2 years. 
 
4.3  
Inclusion Criteria 
Patients with positive diagnostic prostate biopsy with or without positive digital rectal exam (DRE) 
(clinical stage </=T1-T2a or T1cN0M0), Gleason score ≤7(3+4), with a PSA ≤10ng/mL and routine 
staging work-up consistent with a diagnosis of localized prostate cancer. Patients eligible for either 
whole-gland therapy or active surveillance will use the staging MRI to screen for intraprostatic 
disease burden. Patients having a single focal dominate lesions greater than 5 mm in size confirmed 
with imaging and biopsy will be eligible for this trial. Patients (≤6 total per year) will be treated with 
focal SBRT delivering on study to 29.25 Gy in 3 fractions (9.75 Gy per fraction) to involved sub-
volume. Eligible patients must be able to undergo an MRI with contrast. 

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Protocol:  8.4.2020 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date __________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature: ________________________________ Date __________ 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
_____4.3.1 
Patients must have a histologically confirmed diagnosis of adenocarcinoma of  
 
 
the prostate. 
 
 _____4.3.2  Patient must have a history/physical examination with digital rectal examination of the 
prostate within 90 days prior to screening 
 
 _____4.3.3   Age >18 years.  Because no dosing or adverse event data are currently available on 
the use of the study treatment in patients <18 years of age, children are excluded from 
this study. 
 
_____4.3.4      ECOG Performance status must be level 0 or 1 within 60 days prior to registration    
            [See Appendix A].   
 
 
 
 
ECOG PS = ______________ 
           
 
Date: ___________________ 
 
 
_____ 4.3.5   Patient must have a histological evaluation of the prostate biopsy with assignment of  
 
 
a Gleason score to the biopsy material; Gleason scores ≤7(3+4)   
 
_____ 4.3.6  Patients must have adequate renal function as defined below: 
 
 
 
   
Serum Creatinine < or = 1.5 times the ULN (Normal: ≤1.17 mL/min/1.73 m2) 
 
 
 
Serum Creatinine:  ____________ 
 
 
 
Date of Test:          ____________ 
 
 
_____ 4.3.7   Clinical stage a </=T1-T2a (AJCC 7th edition) 
 
_____ 4.3.8 
PSA ≤10 ng/mL within 90 days prior to registration. PSA should not be obtained 
within 10 days after prostate biopsy. 
 
_____ 4.3.9 
Subjects must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
_____ 4.3.10 Patient willing and able to complete the Expanded Prostate Cancer Index  

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Protocol:  8.4.2020 
Composite (EPIC) questionnaire (Baseline, 6, 12 and 24 months post end of radiation 
therapy) 
 
_____4.3.11 Patients must be able to undergo an MRI with contrast 
 
_____4.3.12 Bone scan, when clinically indicated, completed within 90 days 
 
 
4.4. 
Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment. 
 
_____4.4.1 
Evidence of distant metastases  
 
_____4.4.2 
Regional lymph node involvement 
 
_____4.4.3 
Previous radical surgery (prostatectomy), cryosurgery, or HIFU for prostate cancer 
 
_____4.4.4 
Previous pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy 
 
_____4.4.5 
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) 
 
_____4.4.6   Use of finasteride within 30 days prior to registration. PSA should not be obtained  
prior to 30 days after stopping finasteride. 
 
_____4.4.7  
 Use of dutasteride within 90 days prior to registration. PSA should not be obtained 
prior to 90 days after stopping dutasteride. 
 
_____4.4.8   Previous or concurrent cytotoxic chemotherapy for prostate cancer 
 
_____4.4.9   Severe, active co-morbidity, defined as follows: 
  
_____4.4.10   Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months 
 
_____4.4.11   Transmural myocardial infarction within the last 6 months 
 
 
_____4.4.12   Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
 
_____4.4.13  Chronic obstructive pulmonary disease exacerbation or other respiratory illness  
requiring hospitalization or precluding study therapy at the time of registration 
 
_____4.4.14   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). 

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Protocol:  8.4.2020 
 
_____4.4.15  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 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 
 
_____4.4.16 Patients unable to undergo an MRI with contrast. 
 
4.5  
Subject Recruitment and Screening 
Subjects will be recruited from patients presenting to Urology and/or Radiation Oncology for 
consultation with a diagnosis of localized prostate cancer. 
 
4.6  
Inclusion of Women and Minorities   
Men and members of all races and ethnic groups are eligible for this trial. Women will not be eligible 
for this trial. 
 
5.0  
Registration  
All subjects who have been consented are to be registered in the OnCore Database. For those subjects 
who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through a study coordinator and will be provided a study number by 
calling telephone number: 216-286-6641 
 
5.1 
Early Withdrawal of Subjects 
Criteria for Removal from Study 
Subjects may be removed from the study upon request or at the discretion of the Principal Investigator 
for safety reasons, failure of subject to adhere to protocol requirements, subject consent withdrawal, 
or disease progression. Withdrawn subjects may be replaced. 
 
Follow-up for Withdrawn Subjects 
Subjects may withdraw from the study at any point. If subjects withdraw prior to delivery of SBRT, 
they may be replaced with an additional subject(s). Follow up for withdrawn subjects will continue 
per standard of care for disease stage as reported through the staging biopsy, off study. All routine 
standard of care imaging and physical exams to monitor disease progression, may be conducted as 
similar to that care described on trial. Data collected following consent and registration through the 
screening biopsy will be reported for all subjects, including those withdrawn prior to SBRT.  
 
6.0 
Study Treatment or Procedures  
 Completion of the Staging MRI with contrast is mandatory for all patients. 
 Minimum and maximum (1-2) dominant intraprostatic tumor foci are suggested on MRI during 
screening 
 Visualization of the urethra on CT scan for treatment planning will be accomplished through 
fusion of pelvic MRI with CT simulation images.  
 Baseline testosterone 

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Protocol:  8.4.2020 
 In addition to standard of care IPSS and SHIM questionnaires, EPIC, EQ5D, and Utilization of 
Sexual Medications/Devices Supplement will be obtained at baseline, and 6, 12 and 24 months 
post end of radiation therapy.  
 
6.1.1 Description of Radiation Therapy 
Radiation treatment will be delivered using Elekta S Agility, LINAC-based technology (SBRT). Prior 
to SBRT 3-5 fiducial markers will be placed in the prostate for image guidance during radiation 
therapy. Fiducial marker placement will be conducted using standard of care FDA approved 
ultrasound guidance device and will incorporate findings from MRI image sets to guide the selection 
of biologic target volumes suggested on imaging to represent tumor burden within the prostate. If 
eligible, patient may also have a hydrogel spacer placed to maximally spare the rectum, as per 
standard of care.  At least 1 week will elapse between fiducial marker and hydrogel spacer placement 
and treatment planning simulation to allow for fiducial settling and any potential for migration. Using 
a LINAC-based SBRT system, the technique of motion control will be abdominal compression and 
/or rectal balloon, combined with 4D CT simulation. This information related to treatment and 
treatment planning will be recorded and processed in the UHCMC Seidman Cancer Center 
Department of Radiation Oncology password protected electronic medical record per institutional 
policy. 
 
Imaging the Prostate 
All patients will undergo a Serum Creatinine clearance study prior to MRI exams. Patients who are 
unable to undergo a staging MRI scan with contrast during screening will not be eligible for the study. 
Prior to radiation therapy, all patients will have a staging 3T MRI (utilizing a body coil) of the pelvis 
to include standard (T2 weighted) and multiparametric MRI sequences (to include Dynamic Contrast 
Enhanced and Diffusion Weighted scans or mpMRI) with gadolinium contrast. Axial, sagittal and 
coronal MRI scans are required for all MRI scans.  
 
CT and MRI Treatment Planning Simulation 
Each patient will have a treatment planning simulation prior to delivery of SBRT at least 1 week 
following the insertion of radio-opaque fiducial markers implanted in the prostate for target 
localization and daily set up during fractionated dose delivery. A custom made immobilization device 
consisting of a whole body vac bag and vacuum wrapping (Medical Intelligence BodyFix) will be 
made for every patient. A CT scan with and without contrast of the pelvis will be performed with the 
immobilization device in place. If the patient is not a candidate for CT contrast, non-contrast CT will 
be performed. Treatment planning CT scans must take into account the respiratory motion. A 4DCT 
or combination of end-inspiration and end-expiration CT scans will be taken.  A treatment planning 
MRI (with contrast is preferred and using standard MRI and mpMRI sequences as described above 
for the staging MRI) will be acquired following placement of fiducial markers and prior to delivery 
of SBRT. A rectal balloon may be used during simulation and treatment, as tolerated by each subject. 
 
Dose Specifications 
Radiation will be delivered in to 29.25 Gy in 3 fractions (9.75 Gy per fraction) to involved sub-
volume/s of the prostate using VMAT by the Synergy S with Agility collimator (Elekta, Stockholm, 
Sweden and Atlanta, GA) as focal therapy. Dose escalation to organs-at risk surrounding the prostate 
target volume is not allowed. Dose constraints of normal tissues surrounding the target will be set to 
limit toxicity. Although this three fraction SBRT regimen is novel, the tolerance levels selected for the 
normal organs are consistent with Radiation Therapy Oncology Group (RTOG) protocol RTOG 0938  

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Protocol:  8.4.2020 
“A randomized phase II trial of hypofractionated radiotherapy for favorable risk prostate cancer” 
(Hhttp://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0938 H 
accessed 
12/09/2013) and selected to provide the minimal Biological Equivalent Dose (BED) or Equivalent 
Dose in 2 Gy fractions (EQD2) felt to be required at a high dose per fraction to provide a high 
likelihood for tumor control as noted above in the concluding paragraph of the introduction (page 9).   
 
This protocol requires the use of SBRT that uses inverse treatment planning (dose specifications are 
provided below in further detail). It is thought that SBRT treatment plans and delivery for this pilot 
series may be achievable without increase in normal tissue toxicity compared to whole organ 
treatment using either SBRT or HDR brachytherapy as defined above.  If a patient is determined to 
have failed therapy using acceptable clinical standards, such as the Phoenix definition (a rise in PSA 
following nadir of 2 ng/mL) or biopsy proven locally recurrent or persistent disease, the patient may 
be offered other curative therapy or therapies off study, depending on the patient’s clinical status and 
intent to treat.  
 
Dose Coverage 
The isodose line used for the prescription dose should cover a minimum of 95% of the PTV. This will 
be recorded in the Department electronic medical record for each patient. 
 
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. This will be recorded in the electronic medical record for each patient. 
 
Critical Structures 
Critical Organ Dose-Volume Limits 
The normal tissue volume to be contoured will include bladder, rectum, bilateral femora (to the level 
of ischial tuberosity), seminal vesicles, penile bulb, neurovascular bundles, skin, and urethra. The 
normal tissues will be contoured and considered as solid organs rather than contouring the bladder 
and rectal walls. The bladder should be contoured from its base to the dome. 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. The tissue within the 
skin and outside all other critical normal structures and PTVs are designated as unspecified tissue. 
These data will be recorded in the electronic medical record for each patient. 
 
Supportive Measures 
Urinary 
Symptomatic urinary medicines, (e.g. tamsulosin) are allowed at the discretion of the treating 
radiation oncologist or urologist. 
 
Bladder 
Patients will be asked to have a full urinary bladder both during simulation and treatment. 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 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. One tablespoon of Milk of Magnesia will be taken the night before the simulation and the 

CASE 11813   
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Protocol:  8.4.2020 
night before each treatment. One Fleet’s enema will be administered 2-3 hours before the simulation 
and each treatment. Rectal balloons may be used when patients tolerate, both for simulation and 
during treatments at the discretion of the Radiation Oncologist.  
 
Supportive measures will be recorded in the usual fashion in the electronic medical record. 
 
SBRT Dose Constraints 
Dosimetry Parameters  
Organ 
Volume 
Dose (Gy) 
Prostate (PTV) 
Maximum point dose (0.03cc) 
≤ 31.298 Gy 
107% of prescription 
dose * 
Minimum dose received by 
95% of PTV 
≥ 29.25 Gy 
100% of prescription dose 
Minimum dose received by PTV 
≥ 27.79 Gy 
95% of prescription dose 
Rectum 
Maximum point dose 
(0.03cc) 
≤ 30.71 Gy 
105% of the prescription dose 
Less than 3 cc 
< 27.79 Gy 
95% of prescription dose 
90% rectum 
≤ 26.325 Gy 
90% of prescription dose 
80% rectum 
≤23.40 Gy 
80% of prescription dose 
50% rectum 
≤14.625Gy 
50% of prescription dose 
Bladder 
Maximum point dose 
(0.03cc) 
≤30.71 Gy 
105% of prescription dose 
90% Bladder 
≤ 26.325 Gy 
90% of prescription dose 
50% Bladder 
≤16.5 Gy 
50% of prescription dose 
Penile bulb 
(recommended) 
Maximum point dose 
No more than 100% of prescription dose 
Less than 3 cc 
15.795 Gy 
54% of prescription dose 
Femoral 
heads Skin 
(recommended) 
Less than 10 cc cumulative 
(both sides) 
15.795 Gy 
54% of prescription dose 
Maximum point dose 
23.69 Gy 
81% of prescription dose 
Urethra dose 
≤ 31.298Gy * 
107% of prescription dose 
 
*Visualization of the urethra would be required to confirm urethral dose is ≤31.298 Gy – 107% of 
prescription dose where the max point dose (0.03cc) within the PTV exceeds 31.298 Gy – 107% of 
prescription dose.  Prescription and treatment notes will be recorded in the electronic medical record. 
 
 
 

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Protocol:  8.4.2020 
Technical Factors 
Stereotactic Targeting and Treatment 
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 sub-volume/s of the prostate using VMAT by the Synergy S 
Agility collimator (Elekta, Stockholm, Sweden and Atlanta, GA). A computerized method for image 
registration is required for determination of the patient shift information. Serial MRI images with 
parametric sequencing will be used both to evaluate intra fraction response and post therapy response. 
The intrafraction image (between the second and third fraction) will be evaluated for yield in intra-
therapy response, that may be useful future in clinical applications such as in MRI-Linac based 
adaptive radiotherapy planning. Post therapy serial MRI will also be used to evaluate radiographic 
determined response to therapy, versus pre and mid treatment scans and as compared to clinical 
features such as PSA follow-up.  
 
All available image sets will be co-registered using clinical software such as MIM Maestro (MIM 
software, Cleveland, OH) and PercuNav (Invivo, Gainsville, FL) and/or evaluated using our available 
in-house developed software for image registration verification, as is customary for clinical cases. 
Imaging data will thus be transferred to our Linac based treatment planning system Pinnacle, Philips 
Medical Systems (Cleveland, OH) for SBRT delivery. We will also use 3D cone-beam kV CT for 
alignment of in-vivo fiducials to track and adjust for internal target motion detection. 
 
As previously described (6.1 Description of Radiation Therapy) a minimum of three and maximum 
of five radio-opaque fiducial markers will be inserted in to the prostate for use in fractionated dose 
target positioning during SBRT (delivered in three fractionated doses on 3 different days, typically 
every other day). At least one fiducial marker for treatment planning will be guided to a prostatic 
region reported on mpMRI to be highly suspicious for tumor burden.  
 
For patients who have not previously received a targeted biopsy (in-gantry MRI or US-MRI fusion), 
during this fiducial marker placement procedure, and just prior to needle insertion to place the fiducial 
marker, a guided biopsy will be targeted to the location of disease suggested by mpMRI using FDA 
approved devices for image guided biopsy procedures. An FDA approved sterile surgical needle will 
be introduced either transrectally or transperineally through which the biopsy needle will pass. 
Following extraction of tissue sample, a fiducial marker will be placed in each of 3-5 biopsy cavities 
and recorded for spatial in-vivo orientation with to the anatomic and functional image sets (US, CT, 
MRI and mpMRI).  
 
If additional mapping biopsies are necessary, other sextant regions of the prostate reported as normal 
by screening MRI will be biopsied as is typical for a mapping biopsy procedure to improve disease 
staging and localization of true positive disease during the screening procedure. Thus, a total of 12 to 
15 biopsies will be obtained from each patient for screening eligibility to aid in a determination of 
likelihood that disease is not multifocal and to enable delivery of focal partial organ therapy. Each 
biopsy site will be tracked using a combination of permanent and virtual fiducial markers. Virtual 
markers will be electronically tracked in the regions suggested to be negative for the presence of 
disease on imaging at the sites of all other sextant biopsy locations using the biopsy needle tip as a 
temporary fiducial imaged by ultrasound at the time of biopsy and fused back to the mpMRI and 
planning CT scan if the patient goes on to be treated on protocol.  
 
It should be noted that the permanent fiducial markers placed for screening would not preclude 
prostatectomy, or could be used for directing radiotherapy if the patient is found to be ineligible for 

CASE 11813   
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Protocol:  8.4.2020 
partial prostate treatment based on more extensive pathology being found on the screening biopsy. 
Conversely, should the patient elect to remain in active surveillance despite qualifying for the 
protocol, the fiducials would serve to help direct subsequent biopsies required for active surveillance. 
Inserted permanent fiducial markers will satisfy the following requirements for prostate cancer: (1) 
good radiographic visibility on kV imaging/diagnostic Xrays, (2) minimal distortion of delivered 
dose, (3) minimal artifacts on MRI and CT images used for treatment planning, and (4) minimal 
migration during treatment. Temporary markers (biopsy needle tip tracking) will be used to track 
mapping biopsy locations (≤12 additional sites) and all biopsy locations will be recorded and tracked 
for in-situ position and for subsequent correlation to pathology findings and sequential MRI scans. 
Individual biopsy tissue samples will be labeled and processed by the institution’s clinical pathology 
laboratory for prostate biopsy reporting. 
 
Three D (3D) mapping will be used with SBRT using cone beam CT (CBCT). Doses reported for kV 
cone beam CT on the Elekta Synergy machine are in the range of <3 cGy per image Alaei (2010).  
The doses for 3D imaging systems are anticipated in this study to be around 12 cGy per fraction 
assuming 4 CBCT’s daily during treatment cGy. Thus one may assume that the total dose delivered 
daily may actually be at least 9.87 cGy when taking into account the prescribed dose of 9.75 Gy and 
the 12 cGy daily IGRT. This would yield a total BED of 273.15 for an alpha beta of 1.2 allowing us 
to reach the desired minimal BED of 268 suggested by Martinez (2011).  
 
Localization 
We will use a set-up CBCT, as well as repeat CBCT after every 3.25 Gy and following completion 
of therapy daily to assess intrafraction prostate organ motion. One goal of the project will be to use 
these data to assess the need for continuous IGRT such as that achievable with MRI Linac based 
SBRT applications. The Hexapod couch will be used to correct for rotation using the fiducial markers 
for each IGRT image set during treatment. A minimum of 4 IGRT CBCT’s will be acquired daily as 
initial setup and after every 3.25 Gy has been delivered to assess intrafraction prostate motion. At the 
discretion of the radiation oncologist/physicist, monitoring of intrafraction motion may be required 
more frequently. 
 
Imaging studies for staging, treatment planning and response to therapy monitoring 
 
Multiparametric and Magnetic Resonance Imaging (mpMRI) 
Prior to radiation therapy, all patients will have standard of care staging and treatment planning MRI’s 
of the pelvis, with contrast unless clinically contraindicated, using standard morphologic imaging 
sequences, per institutional standard of care imaging protocols for anatomic detail and localization. 
Additional functional mpMRI sequences will also be acquired and evaluated to enable morphologic 
and/or quantification of various tissue parameters as are routinely ordered prior to radiation therapy.  
The duration of the entire mpMR imaging procedure (patient on the scanner table) will be no longer 
than at total of 90 minutes, which is within the range for a standard single diagnostic MRI scan. 
Quantitative MRI data may include analysis of some or all of the following parameters:  
  
Diffusion weighted imaging (DWI):  
 Measurement of b-value assesses different levels of diffusivity within tumor tissue and normal 
tissue.  
 Apparent diffusion coefficient (ADC) will be calculated as a quantitative measure from 
multiple b-values by measurement of ROI in the target lesion.   

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Protocol:  8.4.2020 
 Dynamic contrast enhanced MRI (DCE-MRI): 
 Typical quantitative parameters will be obtained describing tissue enhancement pattern and 
perfusion, contrast agent exchange rates of tissues and distribution of contrast between the 
various tissue spaces using standard evaluation models.  
 Quantitative assessment will be performed with post processing techniques as commercially 
available as well as post processing software under investigation or development to 
demonstrate feasibility with currently available and future techniques.  
  
These sequences will be recorded for virtual comparison to the standard MRI sequences to determine 
if the investigational functional data correlates with histopathology data, and to determine if these 
data would have changed the radiation therapy contouring and dose delivery. Any change in treatment 
planning due to functional MRI versus standard sequences alone will be recorded, and evaluated for 
utility in the determination of tumor response to therapy. 
 
Target Delineation 
All clinically relevant radiologic images will be transferred to the Radiation Oncology Pinnacle 
(Philips, Cleveland, OH) treatment-planning system. Using the various MRI sequences and the CT 
image data sets, a composite gross tumor volume (GTV) will be generated. The focal GTV will be 
contoured and approved by the attending radiation oncologist and urologist. The 4D CT will be fused 
with the treatment planning CT and an internal target volume (ITV) will be generated. The location 
of tumor foci from each positive biopsy core will also be segmented and expanded by 5mm to add to 
the PTV along with imaging data sets. An additional 0.3-0.5 cm margin will be placed around the 
image data set ITV to generate a final PTV to account for set-up variation. The use of abdominal 
compression may be used to decrease the volume of ITV since there is no real-time target tracking. 
Surrounding normal structures, including the rectum, small bowel, bladder, femora, seminal vesicles, 
penile bulb, and skin will be contoured. Skin is defined as a 0.5 cm concentric ring beneath the skin.   
 
Mid Treatment and Post SBRT (MRI) with multiparametric sequences (mpMRI) 
Each subject will be offered up to 4 additional MRI scans: 1 during therapy (between the 2nd and 3rd 
fractionated treatments), at 6 months following the end of radiation therapy, and again at 12 and 24 
months. All mpMRI will be requisitioned in the same manner as described above (Staging MRI) as 
described above at page 16 (6.1 Imaging the Prostate), with the exception that contrast with 
gadolinium is preferred. If patients are unwilling or clinically unable to undergo contrast or have all 
follow-up MRI scans, the patient will remain on study and followed for PSA response and toxicity 
outcomes.   
 
Computed Tomography (CT) 
CT will be fused with MRI scans and used as a primary image platform for treatment planning. It is 
preferred that CT with contrast be acquired, unless clinically contraindicated. The simulation should 
be performed in the supine treatment position, in the custom made immobilization device, with the 
fiducial markers and rectal balloon in place (where utilized). Axial cuts of 2.0 mm or less will be 
acquired throughout the pelvis and prostate from the top of the iliac crests superiorly to the perineum 
inferiorly. 
 
Contrast 

CASE 11813   
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Protocol:  8.4.2020 
CT scans with and without IV contrast are required, unless contraindicated. Dose calculations will be 
based on the non-contrast study, and the contrast study if obtained will be used to delineate prostate 
and surrounding organs at risk including bladder. 
 
6.2 
 
Radiation Therapy Adverse Events 
All patients will be seen in the radiation oncology department during radiation therapy. Any 
observations regarding radiation reactions will be recorded and should include attention to the 
following potential side effects: 
 Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, 
proctitis, or hematochezia 
 Bladder complications including urinary frequency/urgency, dysuria, hematuria, urinary tract 
infection, and incontinence 
 Radiation dermatitis 
 
Clinical discretion may be exercised to treat side effects from radiation therapy. Examples of typical 
medications used in the management of 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. A record of the incidence and management of side 
effects will be recorded in the electronic medical record as a usual course of care and the data will be 
reported in a Case Report Form.  
 
Definition of an Adverse Event (AE): Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical treatment 
or procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). [CTEP, NCI Guidelines Adverse 
Event Reporting Requirements. January 2005; http://ctep.cancer.gov/reporting/adeers.html] 
  
Definition of an SAE: Any adverse experience occurring 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.  
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4 for reporting of adverse events (AEs). 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. 
 
 
 

CASE 11813   
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Protocol:  8.4.2020 
The SAEs will be reported per Case Comprehensive Cancer Center policy. 
 
Significance of Adverse 
Event 
Study Related 
(Possible/Probable/Definite) 
Not Study Related 
(Unrelated/Unlikely) 
Attribution of Adverse Event Expected 
Unexpected 
Expected 
Unexpected 
Fatal Events (Grade 5) 
5 working days 
5 working 
days* 
Summarize in 
Continuing 
Review 
10 working 
days 
Life-Threatening or 
disabling (Grade 4) 
Summarize in 
Continuing 
Review 
10 working 
days 
Summarize in 
Continuing 
Review 
Summarize in 
continuing 
review report 
Severe and undesirable  
(Grade 3) 
Summarize in 
Continuing 
Review 
10 working 
days 
Not reportable 
to IRB 
Summarize in 
continuing 
review report 
Moderate and Mild 
Grades 1 & 2 
Not reportable to IRB 
Unanticipated Problem that is 
a reportable Event 
5 working days and reportable to HHS agency head and OHRP 
*All study related, unexpected deaths should be carefully assessed against the definition of 
unanticipated problem. 
 
The SAE is to be entered into Oncore and the regulatory coordinator and DSTC coordinators will 
then work with the PI to submit it to the IRB and DSTC. The SAE is to be placed into Oncore within 
2 working days of notification to the study coordinator. 
 
7.0  
Study Procedures  
Screening procedures will be performed up to 28 days before registration unless otherwise stated. 
Study visits will have a 2-3 study window unless otherwise stated.  
 
 7.1 
Screening Visits 
Screening Visit – visit #1 
 
Informed Consent (for patients who meet screening criteria) 
 
Demographics 
 
Medical  History 
 
Height 
 
Weight 
 
Vitals including blood pressure, pulse, respiratory rate, temperature 
 
Physical examination 
 
Concomitant medication assessment  
 
ECOG performance status  
 
Assessment of baseline symptoms 
 
Quality of Life scores (standard of care) IPSS and SHIM  
 
Research Quality of Life scores (EPIC, EPIC Supplement Sexual Medicines/Devices, EQ-
5D) 
 
Laboratory Studies: 
o Complete Blood Count (CBC) with differential, platelets  

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              Page 20 of 57 
Protocol:  8.4.2020 
o Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
o Calculated creatinine clearance will be done if creatinine and/or BUN are abnormal 
o Testosterone     
 
Pelvic mpMRI with contrast and multiparametric sequences (SOC for staging) (must be 
within 180 days of screening visit) 
 
Bone Scan when clinically indicated per standard-of-care (must be within 90 days of 
screening visit) 
 
PSA (must be within 90 days of screening visit) 
 
DRE (must be within 90 days of screening visit) 
 
7.2  
Study Visits 
Biopsy and Fiducial Placement – visit #2 
 
Weight 
 
Vitals including blood pressure, pulse, respiratory rate, temperature 
 
Physical examination 
 
Guided biopsy 
 
Fiducial placement 
 
MRI and CT scans for RT SIM – visit #3 
 
RT CT (with contrast unless contraindicated) for simulation 
 
Pelvic MRI with Contrast  
 
Pelvic CT for SIM 
 
SBRT #1  – visit #4 
 
 RT treatment  
  
SBRT #2  – visit #5 
 
RT treatment   
 
MRI  – visit #6  
 
Pelvic mpMRI with Contrast  
 
SBRT #3  – visit #7 
 
Adverse events assessment (may be completed by telephone call within 7 days post visit 7) 
 
RT treatment 
 
Follow up, every 3 months for up to 24 months – visits #8 - #16  
 
Weight 
 
Vitals including blood pressure, pulse, respiratory rate, temperature 
 
Physical examination 
 
ECOG performance status 
 
Quality of life Score standard of care IPSS and SHIM Scores 
 
Adverse events assessment 
 
Post SBRT Follow up Measurements  
 
PSA to be completed at ALL follow up visits 

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              Page 21 of 57 
Protocol:  8.4.2020 
 
DRE to be completed at ALL follow up visits 
 
Serum Creatinine and BUN Blood Draw at 6, 12, and 24 months follow up prior to MRI 
 
Pelvic MRI to be completed at 6, 12, and 24 month follow up visits with contrast  
 EPIC EQ D5, Sexual Medication/Device screening to be completed at 6, 12 and 24 
months 
 
Any positive results for staging Post RT (positive digital rectal exam or evidence of biochemical 
failure using the clinical nadir +2 definition (serum PSA rise above 2ng/mL from the post therapy 
nadir (Phoenix, Abramowitz 2007) may trigger clinical indication for SOC staging MRI to rule out 
disease progression. If acquired, this data will be collected for comparison to other serial MRI data. 
Should a patient be deemed to have failed therapy using the Phoenix criteria (nadir +2ng/mL PSA) 
the subject/s will be referred for consultation for review of options for salvage therapy, and if the 
patient elects a second treatment the subject will be taken off study.  

CASE 11813   
              Page 22 of 57 
Protocol:  8.4.2020 
 7.3 
Study Calendar  
 
Study Days 
Screen 
Visit 1 
 
Biopsy and 
Fiducial  
Placement 
Visit 2 
MRI* & CT 
Scans for RT 
SIM Visit 3 
SBRT  
#1 
 
Visit 4 
SBRT 
 #2 
 
Visit 5 
MRI 
 
Visit 6 
SBRT 
 #3  
 
Visit 7 
30 days  
post RT 
Visit 8 
3 mo   
post RT  
Visit 9 
6 mo 
post RT 
Visit 10 
9 mo 
post RT 
Visit 11 
12 mo 
post RT 
Visit 12 
15, 18  & 21 
months 
post RT 
Visits 13-15 
24 mo 
Post RT 
Visit 16 
REQUIRED 
ASSESSMENTS 
 
 
2-3 wks  
Post Fiducials 
2-3 wks  
Post SIM 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vitals (BP 
Respiration Pulse 
Temp) 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
assessment 
including hormone 
therapy 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Baseline Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPSS/SHIM 
 QoL Scores 
X 
 
 
 
 
 
 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Adverse Event 
Assessment 
 
 
 
 
 
 
X2 
X 
X 
X 
X 
X 
X 
X 
CBC w diff 
/platelets 
/testosterone  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guided biopsy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fiducial placement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RT simulation  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 RT TREATMENT 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 

CASE 11813   
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Protocol:  8.4.2020 
Study Days 
Screen 
Visit 1 
 
Biopsy and 
Fiducial  
Placement 
Visit 2 
MRI* & CT 
Scans for RT 
SIM Visit 3 
SBRT 
 #1 
 
Visit 4 
SBRT 
 #2 
 
Visit 5 
MRI 
 
Visit 6 
SBRT 
 #3  
 
Visit 7 
30 days  
post RT 
Visit 8 
3 mo   
post 
RT  
Visit 9 
6 mo post 
RT 
Visit 10 
9 mo 
post RT 
Visit 11 
12 mo 
post RT 
Visit 12 
15, 18  & 21 
months 
post RT 
Visits 
13-15 
24 mo 
Post RT 
Visit 16 
 DISEASE 
ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pelvic MRI * 
X3,4 
 
X* 
 
 
X* 
 
 
 
X* 
 
X* 
 
X* 
Pelvic CT for SIM 
 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA 
X4 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
DRE 
X4 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
EPIC EQ D5, Sexual 
Medication,   Device 
Screening 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
1: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium.  Calculated creatinine clearance will be done if creatinine and/or BUN are abnormal 
2: Post treatment A/E assessment may be a telephone call within 7 days post end of therapy.  
3: SOC Staging MRI 
4: Must have been completed within 90 days of screening visit 
  
a: Physician or Nurse Practitioner consult at post RT visits 
*  Serum Creatinine And BUN  Blood Draw performed prior to pelvic MRI with contrast (mandatory for eligibility)per institutional guidelines.  
      

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Protocol:  8.4.2020 
8.0  
Correlative / Special Studies  
not applicable 
 
9.0  
Safety and Effectiveness Assessments 
The primary goal of this pilot study is to determine if MRI with multiparametric sequences mpMRI 
can be used as a mapping tool for correlation with histopathology results, providing a more informed 
method for the delivery of focal hypofractionation treatments. Hypofractionated radiation using 
SBRT is a promising tool for delivery with intent to cure. The use of focal partial prostate SBRT 
should show lower toxicity, and will be evaluated for equivalent efficacy. A co-primary end point of 
the pilot study will be to show that patients maintain acceptable HRQOL status as compared to 
baseline. There will be two co- primary endpoints based on summary scores from the bowel and 
urinary domains of the EPIC questionnaire. Although HRQOL is collected at multiple time points, it 
has been decided that EPIC, EQ D5 and Sexual Medication/Device Screening data collected at 6, 12 
and 24 months post therapy will be compared to baseline to test the primary hypothesis. The 
percentage of patients with change in EPIC bowel domain score (baseline to 1-year) that was worse 
than 5 points and a change in EPIC urinary domain score that was worse than 2 points are felt to be 
clinically meaningful endpoints to assess for tolerability and safety. A rate for the worse-than-5 point 
change in bowel score of up to 35% of patients will be considered acceptable, with a rate ≥55% 
specified as unacceptable. Similarly, a rate for the worse-than-2 point change in urinary score of up 
to 40% will be considered acceptable, with a rate ≥60% unacceptable. The PSA results along with 
serial MRI assessments will be used to test the hypothesis of equivalent disease control compared to 
historical data for whole gland therapy using SBRT. Standard of care quality of life assessments 
International Prostate Symptom Score (IPSS) and sexual health inventory for men (SHIM) scores will 
be acquired as part of the standard care prior to and following SBRT. When collected, this data will 
be collected and reported. 
Analysis of the Primary Endpoints 
Treatment efficacy will be analyzed through PSA response, clinical exam, with the addition of serial 
MRI evaluations. Confirmation of multiparametric MR targets for focal SBRT with image guided 
biopsy, histopathology and fiducial marker position tracking will be evaluated for reporting accuracy 
of multiparametric and standard MRI sequences to detect disease. Prostate MRI including T2-
weighted, contrast-enhanced, and diffusion weighted imaging along with computer aided detection 
(CAD) may be used to identify suspicious lesions for targeted biopsy and fiducial placement.  Chi-
square and cluster analysis will be used to correlate degree of suspicion on MR pulse sequences with 
incidence of cancer detected on biopsy and subsequently targeted for focal therapy.  Post therapy 
MRI will be used to report response to therapy as either complete, partial, stable or progressive by 
RECIST criteria.  
9.1  
Safety and Efficacy Endpoints 
Assessment of early clinical outcomes in focal SBRT for low risk prostate cancer patients.  Twenty-
four hormone naïve low to intermediate risk prostate cancer patients will be screened for PSA level, 
acute toxicities and quality of life (QOL) measures at baseline and twelve will be followed at 
longitudinal follow-up appointments. 
 

CASE 11813   
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Protocol:  8.4.2020 
Acute and Late GI and GU Adverse Events (AEs) 
Adverse events are evaluated by the CTEP Active Version of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE). We will record in Oncore the highest grade reported during a reporting 
period. 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. 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 
may occur, which is considered to be similar to the high RT dose arm of RTOG 0126 in terms of RT 
dose. If our partial prostate hypofractionated regimen has an acceptable percentage, then it will be 
deemed to have an acceptable adverse event profile. We will report the percentage for the regimen as 
well as the one-sided 97.5% confidence interval. For example, the number of patients in the high dose 
arm of RTOG 0126 Phase II reported that 1% of patients experienced Grade 3+ GI/GU acute toxicity, 
with no patient experiencing Grade 4 or 5 toxicities (citation) should be greater than this pilot study. 
A late adverse event is defined as the first occurrence of worst severity of adverse event >180 days 
after RT completion. Late Grade 3+ GU/GI toxicity information will be collected and reported also.  
 
PSA Failure 
Failure occurs when the PSA is first noted to be 2 ng/mL or more than the patient’s nadir value post 
RT completion (Phoenix, Abramowitz 2009). PSA failure at 6, 12 and 24 months following RT will 
be estimated for the series by the cumulative incidence method (Gray 1988). Also, confidence 
intervals will be reported. 
 
Disease-Free Survival (DFS) 
The disease-free survival duration will be measured from the date of treatment to the date of 
documentation of disease progression or until the date of death from any cause. DFS at 6, 12 and 24 
months for each patient and the series by the Kaplan-Meier method (Kaplan 1958). Also, 95% 
confidence intervals will be reported. 
 
Analysis for Endpoints Related to HRQOL 
We will use three instruments to measure HRQOL: the Expanded Prostate Cancer Index Composite 
(EPIC), the Utilization of Sexual Medications/Devices, and EQ-5D. Protocol eligible patients will be 
included in the HRQOL analysis only if they have provided baseline and at least one subsequent 
measurement.  All HRQOL instruments (EPIC, the Utilization of Sexual Medications/Devices and 
EQ-5D) will be collected on all cases participating in the trial. The standard departments QOL 
instruments may also be used to report outcomes with both the International Prostate Symptom Score 
(IPSS) and Sexual Health Information Measurement (SHIM) obtained from chart review. 
The EPIC Supplement Utilization of Sexual Medications/Devices, and EQ-5D will be collected at 
pretreatment (baseline) and at 6, 12 and 24 months after radiation therapy ends. Patient self-
assessment of symptoms will be performed using four primary EPIC scales: urinary, bowel, hormonal 
and sexual symptoms. The Utilization of Sexual Medications/Devices and EQ-5D Questionnaires are 
found in Appendix 3.  
For all primary HRQOL analyses we will estimate the degree of change from baseline to 6, 12 and 
24 months as continuous variables. For this endpoint, in each domain, the actual change score will be 
used as the statistic and a t-test will be used to evaluate if the change is different from 0. Confidence 
intervals also will be computed  

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Protocol:  8.4.2020 
The primary objective in HRQOL analysis is to estimate the change from baseline to 24 months.  The 
response will be the change of measurement from baseline to 24 months (or the last available HRQOL 
data point where data are missing). The one-sample t- test will be used to test the null hypothesis that 
response change is 0. For the regimen to maintain the overall significance level for testing three 
HRQOL instruments. In addition, we will describe the distributions of HRQOL data collection 
patterns over all collection points in each treatment arm.   
Demonstrate dosimetric and biological advantage of focal SBRT versus whole-gland therapy 
Treatment plans from focal versus simulated whole-gland SBRT for each patient will be compared 
for target volume size, dose distribution, and dose reduction to organs at risk (OAR). Additional 
assessments for planning volumes based solely on imaging versus with correlated histopathology to 
define PTVs will be collected, evaluated and reported. Biological modeling will be used to evaluate 
tumor control probability and normal tissue complication probability (NTCP) between the two 
treatment paradigms (focal versus virtual simulation of whole gland treatment using conventional 
treatment per institutional standards). Standard independent methods of dosimetry calculations will 
be evaluated by Medical Physics staff and reported by Medical Physics co-investigators, utilizing 
such programs as Pinnacle and MUcheck, and Monte Carlo simulations. Subject data sets 
appropriately de-identified by a study co-author may be additionally evaluated utilizing advanced 
software MRI analysis for predictive modeling and comparison to tumor volume selection as 
identified with histopathology validation.  
We estimate that 12 patients will be treated on study, and that 24 patients may be screened. MRI 
and histopathology data will be collected for all patients consented to the study and screened. 
Interim Reports to Monitor Study Progress  
Patients will have imaging sessions (MRI and CT Simulation) for treatment planning and delivery of 
radiation therapy. Interim imaging reports will be provided to the funding partners following the first 
3-6 subjects screened, along with case study descriptions, and limited de-identified treatment plan 
screen shots along with composite image sets. Other interim reports will evaluate workflow and 
carepath processes. 
 
9.2 
Effectiveness Assessments 
Clinical information from subjects will be recorded onto Case Report Forms and subsequently 
transferred into OnCore.  Patients who additionally consent to a separate Urology Registry will have 
their data added to the Urologic Oncology & Minimally Invasive Therapies Database for UHHS 
Faculty. 
 
Should any unanticipated adverse events occur during the course of the study, the clinical research 
coordinator will ensure that they are documented by the investigator and reported to the appropriate 
Institutional Review Board per its then-current guidelines.  If the determination is made that an 
unanticipated adverse event presents an unreasonable risk to subjects, the clinical evaluation will be 
paused, or if deemed appropriate (to enable further investigation), the subject will be withdrawn as 
soon as safely possible.   
 
Adverse events, grade 3 and above, will be captured in OnCore and will be reported in accordance 
with the Data and Safety Monitoring Plan (DSMP) that is approved by the Cancer Center Protocol 
Review and Monitoring Committee (and aligned with the NCI-approved plan).   

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Protocol:  8.4.2020 
Antitumor Effect – Solid Tumors 
For the purposes of this study, subject PSA, DRE and PSA data will be recorded in Oncore as 
evaluations for response to radiation therapy, per standard of care procedure during post radiation 
therapy follow-up visits. In addition to PSA and DRE evaluations, RECIST (v.1.1) measurements 
will be acquired using mpMRI surveillance. Response and progression will be evaluated in this study 
using the new international criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. We will also analyze volumetric response to 
therapy based on serial MRI data that will be evaluated using radiation oncology treatment planning 
computers.  
 
Definitions 
Evaluable for toxicity All patients will be evaluable for acute toxicity within 90 days from the time 
of the end of the course of radiation therapy. 
 
Evaluable for objective response  
 
Evaluable Non-Target Disease Response Patients who have lesions present at baseline that are 
evaluable, but do not meet the definitions of measurable disease, have completed a course of SBRT, 
and have had their disease re-evaluated by imaging will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
 
 
Disease Parameters  
Radiologic Surveillance 
Standard of care follow-up post RT will include contrast enhanced MRI and parametric imaging 
unless clinically contraindicated should include contrast.   
 
Measurement of Response 
Measurement of Response Prior to Study Entry 
The revised RECIST guideline, v. 1.1. [European J of Cancer. 45: 228-247, 2009] will be used as 
applicable to the protocol. See 
Hhttp://ctep.info.nih.gov/protocolDevelopment/docs/recist_guideline.pdfH for further details. 
Additional definitions beyond the RECIST guidelines specific to this protocol are incorporated to 
define local control as described below (Eisenhauer 2009). We will evaluate and report RECIST 
measures minimally at 12 and 24 months post radiation therapy.  
 
Response Criteria: Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target  
 
 
 
 
lesions taking as reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of 
 
 
 
 
target lesions, taking as reference the smallest sum on  
 
 
 
 
 
study (includes the baseline sum if that is the smallest 
 
 
on study). The sum must also demonstrate an absolute increase of at 
least 5 mm. The appearance of new lesion(s). 
 

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Protocol:  8.4.2020 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient  
  
 
 
increase to qualify for PD, taking the smallest sum diameters as 
  
 
 
reference while on study. 
 
3D Lesion Volumes 
In addition to RECIST criteria evaluation on follow-up scans, we will report 3 D volumetric data of 
individual lesions based on pre and post treatment images over time, for comparison to 2 D RECIST 
measurements (Guiou 2012 and Eisenhauer 2009).  
 
Measurable Disease Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be 
recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm with calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease All other lesions (or sites of disease), including small lesions (< 5 mm 
longest diameter) will be considered non-measurable disease. The presence of lymph nodes 
suspicious for metastatic disease during screening will be defined as an ineligibility criterion.   
 
Target lesions  Only a single target lesion which is biopsy positive will be selected for focal therapy 
and identified as the dominant target lesion and recorded and measured at baseline.  Target lesion 
should be selected on the basis of size (lesions with the longest diameter). We will use T2 weighted 
MRI image sets with contrast for the baseline measurement. 
 
Non-target lesions  All other suspicious lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment. The 
same method of assessment and technique should be used to characterize the dominant lesion at 
baseline and during follow-up. Use of 3T MRI T2 scans with contrast is required for the baseline 
measurement and is the preferred method and technique for all imaging-based evaluations. The 
mpMRI image data will additionally be recorded, evaluated and reported separately.  
 
Response Criteria 
Evaluation of Target lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 

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Protocol:  8.4.2020 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.   
Note: the appearance of one or more new lesions is also 
considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
Evaluation of Non-Target lesions less than 5mm and /or detected on screening biopsy to involve less 
than 5% of the submitted tissue for carcinoma. 
 
Response 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 
10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, 
they must normalize for a patient to be considered in complete 
clinical response.  
 
 Non-CR/ Non-PD 
[Incomplete 
response/ 
Stable 
Disease (SD)] 
 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status. It must 
be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of ‘non-target’ lesions only is 
exceptional, the opinion of the treating physician should prevail in 
such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator).  
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
> 4 wks. Confirmation ** 
 
CR 
 
Non-CR/Non-PD 
 
No 
 
 
PR 
 
 
> 4 wks. Confirmation ** 

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Protocol:  8.4.2020 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
 > 4 wks from baseline ** 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
 
Any 
PD *** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*         See RECIST manuscript for further details on what is evidence of a new lesion. 
**       Only for non-randomized trials with response as primary endpoint. 
***     In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesion 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD * 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any  
Yes 
PD 
*        ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised. 
 
RECIST (Eisenhauer 2009) Tumor Response 
Tumor measurements will be defined by the PI or treating physician, and confirmed by an objective 
radiation oncologist or radiologist not associated with this study.   
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for stable disease (SD), partial response (PR) or complete response (CR) 
- whichever is first recorded, until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started) 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented. CR will be reported as unconfirmed 
CR until a repeat image shows duration of response. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 

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Protocol:  8.4.2020 
Biochemical Disease-Free Survival: The absence of PSA Clinical Nadir plus 2 ng/mL (Phoenix, 
Abramowitz (2007). 
 
10.0 
Statistical Plan 
10.1 
Data Collection     
All study-related data will be entered into OnCore.  Access will be limited via a password known 
only to the investigator and designated research personnel (study nurse(s), data manager(s)). 
 
10.2   Statistics  
Statistical Considerations  
Chi-square and cluster re-sampling analyses will be used to correlate suspicion on multiparametric 
magnetic resonance imaging and the incidence of cancer detected on biopsy.   
 
The primary goal of this study is to evaluate acute and late toxicities. In addition clinical data will be 
collected to monitor for tumor control. Digital rectal examination (DRE) and serum prostate antigen 
(PSA) will be evaluated every 3 months for two years. Toxicity will be evaluated EPIC  EQ D5, 
Sexual Medication, Device Screening Questionnaires completed by the patients or in conversation 
with the patient by the clinical staff, at baseline, 6, 12 and 24 months following the end of radiation 
therapy (+/- 14 days). Rates of acute and late side effects and adverse events will be summarized as 
proportions, with 95% confidence intervals.  
 
Biochemical failure will be based on PSA values using the Phoenix definition (clinical nadir 
+2ng/mL). Data from all patients will be pooled.  Survival rates estimated from the Kaplan-Meier 
curves will be estimated with 95% confidence intervals.  We will also track virtual treatment plans 
based on standard models for treatment to the whole gland versus partial gland MRI-TPUS validated 
planning to report change in dosimetric parameters of the focal SBRT versus traditional whole-gland 
treatment plans for statistical comparison.  
 
Either a positive DRE or rising PSA may be used as clinical indication for additional MRI 
surveillance. When additional MRI are available, tumor volume will be summarized by mean ±STD 
and the difference between two time points (pre and post treatment) will be examined using paired T-
test. Radiographic efficacy will be summarized by calculating Kaplan-Meier curves for the 
following:  disease-free survival, time to local progression, time to distant failure. Descriptive reports 
of RECIST (1.1) and volumetric findings will be provided. 
 
Acute/Late Toxicity and Quality of Life Measurements 
Using multivariate analysis, we will report acute and late (>180 days post SBRT) rates of GI toxicity 
with dose-volume histogram. We will also report time to event analyses collected for all available 
HRQOL data collected.  
 
Temporal pattern of quality of life scores will be summarized graphically; and repeated measures 
analysis of variance (ANOVA) will be conducted to test for changes in scores over time. The 
predictive value of demographic, pathological and clinical factors on the scores will be examined by 
mixed models assuming missing values are missing at random.   
 
Sample Size 
Twelve patients will be evaluated in this pilot study. As a proof-of-principle study, it’s not design to 
have the appropriate power (80%) for detecting significant difference in clinic outcomes (i.e. 

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Protocol:  8.4.2020 
toxicities, survival or QOL), but to provide some preliminary data for future studies. A sample of 12 
patients, however, achieves 78% power to detect 8% difference of urinary toxicity against historical 
controls under whole gland therapy using a two-sided binomial test with the target significance level 
of 0.2. We anticipate that a minimum of twenty four patients will be screened leading to twelve 
patients who will be treated and evaluated on-study in this pilot study. 
 
11.0 
COSTS AND COMPENSATION 
The costs of procedures, tests, visits and hospitalizations in connection with the radiation therapy are 
standard of care and will be billed to the subject’s insurer and/or to the subject.  This includes costs 
for pre-treatment diagnostic scans, fiducial markers and fiducial marker placement, treatment 
planning, radiation therapy treatments, and post-operative follow-up for radiation therapy, are 
standard of care and will be charged accordingly. Therefore, subjects and their insurers will be fully 
responsible for the costs related to this research evaluating and comparing standard of care 
procedures.   
 
Subjects will not be paid for their participation in this study.  
 
 
12.0 
Risks   
12.1   Anticipated Risks 
Risks include those that result from the special nature of radiosurgery standard of care, including 
errors in giving the radiation.  This may include giving radiation to normal tissue around the tumor 
and not to the cancer, or giving the wrong dose of radiation, either too much or too little.  Any of 
these problems could potentially be severe, possibly even fatal.  
 
Subjects may have a number of CT scans, nuclear scans and MRI scans that are part of the regular 
care for this condition, whether or not they participate in this research. These studies will not add to 
the risk of the research. However, subjects with concerns about the overall radiation exposure or MRI 
safety issues should be discussed with a study physician. 
 
The risks associated with the MRI scans are the same risks as those posed by clinically indicated tests 
(non-research). A known risk related to MRI examinations is that the MRI magnet could attract 
certain kinds of metal that may cause injury to the patient. In order to avoid that, patients will be 
screened for any hazardous metal object that they may have or is implanted inside their body which 
includes pacemakers, intracranial aneurysm clips, heart valve prostheses and other implanted devices 
that are not compatible with MRI. Although there is no risk from ionizing radiation with MRI, 
subjects will be exposed to strong magnetic fields and radio waves, neither of which are associated 
with any known detrimental health effects. 
 
We will use an MRI contrast agent that is approved by the FDA and commercially available. There 
is a risk of an allergic or fibrotic reaction, which occurs more often with iodine based contrast (for 
CT) than with MRI contrast agents. Every effort will be made to minimize the risk of such reactions 
in this study by excluding subjects who have a history of kidney disease, which is the cohort who 
most frequently exhibits an allergic reaction. Generally, an injection of 10-20 ml IV contrast agent 
will be used, provided that the subject has no known reaction to contrast agents used in previous MRI 
scans. As with all such injections, bleeding, bruising, dizziness, fainting or infection may occur. Also, 

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Protocol:  8.4.2020 
the injection may be painful but the discomfort should be brief and efforts will be made to minimize 
the pain.  
 
All data will be entered and managed in computer systems having limited access and password 
protected. There is some risk that subjects’ personal protected health information could be breached 
and health information made available to unauthorized individuals. 
 
Adverse events are not anticipated as related to the delivery of focal therapy, beyond the normal risks 
of radiation therapy with curative intent for localized prostate cancer.  
 
Intravenous MRI contrast agents will be applied to stage each patient’s stage of disease, looking for 
local disease extension. Subjects who have a history of adverse reactions to contrast media will be 
excluded from that portion of the study as will subjects with a history of kidney disease or unacceptable 
values of creatinine and/or Glomerular Filtration Rate [GFR] (see exclusion criteria). Subjects who 
have a history of adverse reactions to contrast media will be excluded from the study as will subjects 
with a history of kidney disease or unacceptable values of creatinine and/or Glomerular Filtration Rate 
[GFR] (see exclusion criteria). 
 
In addition, we will use the MRI images obtained for staging to also map locations of intraprostatic 
tumor foci, to map the location/s of disease. Just prior to fiducial marker placement, patients will be 
consented for a biopsy procedure during fiducial marker placement for radiation therapy set up, for 
the purpose of establishing a map of known disease within the gland. Biopsy cavities will be marked 
with in-vivo fiducials and/or using temporary in-situ marker tracking, such as the use of the echogenic 
needle tip coordinates on ultrasound. Such recorded TRUS ultrasound coordinates will be tracked and 
evaluated  for subsequent correlation of histopathology data and the mpMRI images – using all 
available image data (for example the treatment simulation MRI and CT) to inform our treatment 
planning to improve se localization of known true positive tumor foci.  
 
Additional biopsy samples will be acquired just prior to fiducial marking (permanent or temporary as 
defined above) in a sextant fashion to map disease across the prostate gland for use in treatment 
planning and staging. The risks associated with prostate biopsy sampling are similar in nature to those 
associated with the patient’s diagnostic biopsy that confirmed the presence of adenocarcinoma. These 
risks include the risk associated with bleeding, and the possibility of infection that could be serious. 
There is additional discomfort that may be associated with the insertion of use of a rectal ultrasound 
probe that may be managed by light sedation. The fiducial marker placement procedure will be 
lengthened by several minutes during which time biopsy mapping will occur. This procedure will 
include the use of general sedation, which is customary with transperineal fiducial marker placement 
and or biopsy procedures. However, additional risk may be associated with the use of such sedation 
measures over an increased timeframe during the additional biopsy sampling procedure. 
 

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Protocol:  8.4.2020 
12.2   Benefits 
There are potential benefits for individuals who may elect to participate in this particular study. The 
staging biopsy and image guided fiducial marker placement with correlation to serial MRI scans 
may allow improved staging information for these screened patients. Our efforts to apply advanced 
imaging with histopathology correlation may allow us to refine treatment planning contours, aimed 
a reduction in toxicity while completing therapy with curative intent. It is, however, unknown if this 
treatment schema will be proven safe and effective. The diagnosis and treatment decisions will be 
based on the standard of care imaging. There may be a benefit for future patient populations using 
MRI with multiparametric sequences and histopathology correlation for the management of prostate 
cancer using focal SBRT.   
 
12.3 
Alternatives to participation 
This study does not involve a change to the clinical care of the participant. There will be no 
consequences to individuals who withdraw or step down from the study. The subject will not undergo 
the additional MRI scans, nor focal SBRT if a patient refuses to take part in the study. Only the 
clinically indicated diagnostic standard of care imaging will be performed. If a subject withdraws 
during the procedure of the study, the investigators will use the data as acquired up to the point of 
withdrawal. 
 
13.0 Data Reporting  
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer Center, to 
provide data collection for both accrual entry and trial data management. OnCore is a Clinical Trials 
Management System housed on secure servers maintained at Case Western Reserve University. 
OnCore properly used is compliant with Title 21 CFR Part 11. Access to data through OnCore is 
restricted by user accounts and assigned roles. Once logged into the OnCore system with a user ID 
and password, OnCore defines roles for each user which limits access to appropriate data. User 
information and password can be obtained by contacting the OnCore Administrator at oncore-
registration@case.edu. This study will utilize electronic Case Report Form completion in the OnCore 
database. A calendar of events and required forms are available in OnCore. 
 
14.0  Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
3B14.1 
Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the subject’s 
financial responsibility. Subjects must also be notified that they are free to discontinue from the study 
at any time. The subject should be given the opportunity to ask questions and allowed time to consider 
the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Shadow Chart 
in conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
 

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Protocol:  8.4.2020 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject 
must sign an authorization to release medical information to the sponsor and/or allow the sponsor, a 
regulatory authority, or Institutional Review Board access to subject’s medical information that 
includes all hospital records relevant to the study, including subjects’ medical history. 
 
Accessing Electronic Medical Records for University Hospitals Health System  
This study will access electronic medical records systems to obtain medical information for the 
subjects enrolled to this study.  
 
In order to insure patient safety, investigators and study personnel must have up-to-the-minute health 
information for subjects enrolled to this study. Therefore, electronic medical records must be utilized 
to obtain medical information in a timely manner.  
 
Institutional electronic systems will be used to manage subject data, such as the Mosaiq radiation 
oncology EMR; Athena; UH Physician Portal to access lab results and physician notes; PCOSS LITE 
as necessary to locate archived medical records; COPATH to locate archived pathology records; 
PACS to access radiological imaging results; MySecureCare (Sunrise Clinical Manager) to access 
some or all of the above information when this application is fully functional; OnCore clinical trials 
management system.  
 
Access to these systems is required for the life of this research study, per institutional policy.   
 
Information obtained from electronic systems will be copied into the Seidman Cancer Center Clinical 
Trials Unit research chart and/or printed (lab results, physician notes, etc.) and stored in the research 
chart. Research charts are kept secure and destroyed according to UH policy.  
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or data manager for 
this study via password-protected login. All study personnel involved in this research will adhere to 
the UH policies regarding confidentiality and Protected Health Information.  
 
15.0  Study Closure 
The PI will notify the IRB in writing when the study closes. 
 
16.0  Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Research Quality 
Assurance Office, IRB, the sponsor, and government regulatory bodies, of all study related documents 
(e.g. source documents, regulatory documents, data collection instruments, study data etc.). The 
investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
diagnostic laboratory, etc.). 
 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics Committee 
(IEC) or an Institutional Review Board (IRB) may visit the center to perform audits or inspections, 
including source data verification. The purpose of an audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to the 

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Protocol:  8.4.2020 
protocol, Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization 
(ICH), and any applicable regulatory requirements. 
 
17.0   Ethics 
Incorporate the following, as written 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board, the relevant federal regulations, and IRB policies and procedures and according to Good 
Clinical Practice standards. No deviation from the protocol will be implemented without the prior 
review and approval of the IRB except where it may be necessary to eliminate an immediate hazard 
to a research subject. In such case, the deviation will be reported to the IRB according to its policies 
and procedures. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this study. 
This consent form will be submitted with the protocol for review and approval by the IRB for the 
study. The formal consent of all subjects will be sought using the IRB-approved consent form. Before 
a subject undergoes any study procedure, an informed consent discussion will be conducted and 
written informed consent obtained with a consent form signed by the subject or legally acceptable 
surrogate if applicable. An investigator-designated research professional will obtain written informed 
consent from subjects. 
 
18.0  Study Finances 
18.1 Funding Sources 
Funding for this study will be provided through the Elekta SBRT Research Grant Program, 
Stockholm, Sweden. In addition, support will be provided by Invivo, a wholly owned subsidiary of 
Philips Medical Systems (PMS), Cleveland, Ohio. PMS will provide an FDA approved UroNav 
(Invivo) a Percunav system (a software system that supports ultrasound and mpMRI fusion and 
guided prostate interventions) for use in this research to guide biopsy and fiducial tracking as part of 
this research.  
 
18.2  Conflict of Interest 
Any investigator who has a conflict of interest with this study as defined by the Case Comprehensive 
Cancer Center policies. All investigators will follow the conflict of interest policy. 
 
Subject Stipends or Travel Reimbursements 
There will be no subject stipend or travel reimbursements.  
 
19.0  Publication Plan 
Any investigator involved with this study will be obligated to provide the sponsor and funding partner 
with complete test results and all data derived from the study. The PI has the responsibility to report 
the study findings.  
 
 Abstracts and manuscripts in peer-reviewed conferences and journals 
 Correlation of multiparametic MRI with histopathology for focal therapy 
 Dosimetric and radiobiological models of focal SBRT vs. whole-gland therapy 
 Clinical feasibility of focal SBRT on Agility MLC on Synergy S Platform 
 Acute toxicity associated with focal SBRT 

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Protocol:  8.4.2020 
 Late toxicity and early response to therapy 
 Development of clinical workflow and quality check lists for prostate SBRT programs 
 De-identified data sets (MRI, CT, dosimetric plans) for advanced concept development for 
prostate SBRT on Agility Synergy S Platform and the UroNav System 
 

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Protocol:  8.4.2020 
References 
Alaei P, Ding G, and Guan H. Inclusion of the dose from kilovoltage cone beam CT in the radiation 
therapy treatment plans. Medical Physics 2010; 37(1): 244-8. 
 
American 
Cancer 
Society: 
Cancer 
facts 
and 
figures 
2013. 
http://www.cancer.org/Research/CancerFacts Figures/CancerFactsFigures/cancer-facts-figures-2013 
 
Abramowitz MC, Li T, Buyyounouski MK, et al. The Phoenix definition of biochemical failure 
predicts for overall survival in patients with prostate cancer. American Cancer Society J Cancer 2007; 
112 (1): 55–60.  
 
Barkati M, Williams SG, Foroudi F et al. High-dose-rate brachytherapy as a monotherapy for 
favorable-risk prostate cancer: a Phase II trial. Int J Radiat Oncol Biol Phys 2012;82:1889–96.  
 
Bolzicco G, Favretto MS, Scremin E, et al. Image-guided stereotactic body radiation therapy for 
clinically localized prostate cancer: preliminary clinical results. Technology in Cancer Research & 
Treatment 2010; 9(5):473-7. 
 
Bomers JG, et al. MR imaging-guided focal cryoablation in patients with recurrent prostate cancer. 
Radiology 2013 Mar 22 [Epub ahead of print]. 
 
Brenner DJ, Hall EJ. Fractionation and protaraction for radiotherapy of prostate carcinoma. Int J 
Radiat Oncol Biol Phys 1999;43:1095-101. 
 
Chen LN, Suy S, Uhm S, et al. Stereotactic body radiation therapy (SBRT) for clinically localized 
prostate cancer: the Georgetown University experience. Radiation Oncology 2013; 8(58): 1-10.  
 
Cosset JM, Cathelineau X, Wakil G, et al. Focal brachytherapy for selected low-risk prostate cancers: 
A pilot study. Brachytherapy 2013;12:331-337. 
 
Egevad L, et al. Implications of the International Society of Urological Pathology Modified Gleason 
 
Eggener SE, Scardino PT, Carroll PR, Zelefsky MJ et al. for the International Task Force on Prostate 
Cancer and the Focal Lesion Paradigm. Focal therapy for localized prostate cancer: a critical appraisal 
of rationale and modalities. J Urol 2007;178(6):2260-7. 
 
Eisenhauer EA, Pherasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1) European J Cancer 2009;45:228-247. 
 
Ellis RJ, Kaminsky DA, Zhou EH, Fu P, Chen WD, Brelin A, Faulhaber PF, Bodner D. 10-year 
outcomes: the clinical utility of SPECT/CT Capromab Pendetide (PROSTASCINT) in a cohort 
diagnosed with localized prostate cancer. Int J Radiat Oncol Biol Phys 2010; 81(1):29-34. 
 
Ellis RJ and Kaminsky DA, Method of defining a biological target for treatment. United States Patent 
Office No. US 7,831,293 B2 Nov. 9, 2010.  
  

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Fang, LC, Merrick GS, Butler WM, Galbreath RW, et al. High-risk prostate cancer with Gleason 
Score 8–10 and PSA level ≤15ng/mL treated with permanent interstitial brachytherapy. Intl J Radiat 
Oncol Biol Phys 2011; 81(4): 992–996. 
 
Focal cryotherapy: an update from the COLD registry (November 18, 2011). 
http://prostatecancerinfolink.net/2011/11/18/focal-cryotherapy-and-update-from-the-cold-registry/   
(accessed 5/31/13) 
 
Friedland JL, Freeman DE, Masterson-McGary ME, Spellberg DM. Stereotactic body radiotherapy: 
an emerging treatment approach for localized prostate cancer. Technology in Cancer Research & 
Treatment.2009; 8(5):387-92. 
 
Grading System. Arch Pathol Lab Med 2012; 136:426-34. 
Gulati R, et al. What if I don’t treat my PSA-detected prostate cancer? Answers from three natural 
history modes. Cancer Epidemiol Biomarkrs Pref; 20(5) May 2011. 
 
Hodges JC. Lotan Y. Boike TP. Benton R. Barrier A. Timmerman RD.  
Cost-effectiveness analysis of SBRT versus IMRT: an emerging initial radiation treatment option for 
organ-confined prostate cancer. American Journal of Managed Care 2012;18(5):e186-93.  
 
Hou AH, Sullivan KF, Crawford ED. Targeted focal therapy for prostate cancer: a review. Curr Opin 
Urol 2009; 19(3):289-9. 
 
Jabbari S. Weinberg VK. Kaprealian T. Hsu IC. Ma L. Chuang C. Descovich M. Shiao S. Shinohara 
K. Roach M 3rd. Gottschalk AR.  Stereotactic body radiotherapy as monotherapy or post-external 
beam radiotherapy boost for prostate cancer: technique, early toxicity, and PSA response. 
International Journal of Radiation Oncology, Biology, Physics 2012; 82(1):228-34.  
 
Kaplan EL and Meier P.  Nonparametric Estimation from Incomplete Observations. J American 
Statistical Assoc 1958; 53(282): 457-481. 
 
Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. Stereotactic Body Radiotherapy as Boost for 
Organ-confined Prostate Cancer. 2010;9(6):575-582. 
 
Kelloff GJ, Choyke P, Coffey DS. Prostate Cancer Imaging Working Group. Challenges in clinical 
prostate cancer: role of imaging. AJR Am J Roentgenol. 2009 Jun;192(6):1455-70.  
 
Low RN. Fuller DB. Muradyan N. Dynamic gadolinium-enhanced perfusion MRI of prostate cancer: 
assessment of response to hypofractionated robotic stereotactic body radiation therapy.  
AJR. American Journal of Roentgenology. 197(4):907-15, 2011 Oct. 
 
Martino P, Scattoni V, Galosi AB, et al. Role of imaging and biopsy to assess local recurrence after 
definitive treatment for prostate carcinoma (surgery, radiotherapy, cryotherapy, HIFU). World 
Journal of Urology 2011; 29(5):595-605.  
 
Martinez AA, Gonzalez J, Ye H, et al. Dose escalation improves cancer-related events at 10 years for 
intermediate- and high-risk prostate cancer patients treated with hypofractionated high-dose-rate 
boost and external beam radiotherapy. Int. J. Radiation Oncology Biol. Phys. 2011; 79(2): 363–370. 

CASE 11813   
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Michalski JM, Yan Y, Watkins-Bruner D, et al. Preliminary toxicity analysis of 3-dimensional 
conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the 
radiation therapy oncology group 0126 prostate cancer trial. Intl J Radiat Oncol Biol Phys. 
2013;87(5):932-8.  
 
Pinto AP, Chung PH, Rastinehad AR, et al. Magnetic resonance imaging/ultrasound fusion guided 
prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with 
multiiparametric magnetic resonance imaging. J Urol 2011;186(4):1281-1285. 
 
Pisters LL. Cryotherapy for prostate cancer: ready for prime time? Curr Opin Urol 2010; 20(3):218-
22. 
Polascik TJ, Mouraviev V. Focal therapy for prostate cancer. Curr Opin Urol 2008; 18(3):269-74. 
 
Rapiti E, et al. Importance and determinants of Gleason score undergrading on biopsy sample of 
prostate cancer in a population-based study. BMC Urol 2013; 13(19): 1-6. 
 
Scardio PT. Focal therapy for prostate cancer. Nat Rev Urol 2009;6:175.  
 
Valerio M, Ahmed HU, Emberton M, et al. The Role of Focal Therapy in the Management of 
Localised Prostate Cancer: A Systematic Review. European Urology 2013; E-pub ahead of print. Doi: 
10.1016/j.eururo.2013.05.048 
 
Ward JF, Jones JS. Focal cryotherapy for localized prostate cancer: a report from the national Cryo 
On-Line Database (COLD) Registry. BJU Int. 2012;109(11):1648-54.  
 
Wright JL, et al. Differences in prostate cancer outcomes between cases with Gleason 4+3 and 
Gleason 3+4 tumors in a population-based cohort. J Urol 2009; 182(6):2702-7. 
 
Yoshioka Y, Yoshida K, Yamazaki H, et al. The emerging role of high-dose-rate (HDR) 
brachytherapy as monotherapy for prostate cancer. Journal or Radiation Research, 2013, 54,781-788). 
 
Zhou EH, Ellis RJ, et al. Radiotherapy and survival in prostate cancer patients: a population-based 
study. Int. J. Radiation Oncology Biol. Phys 2009; 73(1):15–23. 
6B 

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APPENDIX 1 
AJCC STAGING SYSTEM 
PROSTATE, 7
th 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 unapparent 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). 

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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  
pN0 
No positive regional nodes 
pN1 
Metastases in regional node(s) 
 
Distant Metastasis (M)* 
M0 
No distant metastasis  
M1 
Distant metastasis 
   M1a 
Nonregional 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 
 
 

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APPENDIX 2 ECOG PERFORMANCE SCALE 
 
 
ECOG Performance Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light howework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours.. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
 

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APPENDIX 3 TOXICITY ASSESSMENT INSTRUMENTS 
International Prostate Symptom Score (I-PSS) 
 
Patient Name:________________________  Date of birth:_______  Date completed _________
 
 
Score: 
1-7: Mild 
8-19: Moderate 
20-35: Severe 
 
 
 
In the past month: 
Not at 
all 
Less than 
1 in 5 
Times 
Less than 
Half the 
Time 
About 
Half 
the 
Time 
More 
than Half 
the Time 
Almost 
Always 
Your 
score 
1. Incomplete Emptying How 
often have you had the sensation 
of not emptying your bladder? 
0 
1 
2 
3 
4 
5 
2. Frequency 
How often have you had to urinate 
less than every two hours? 
0 
1 
2 
3 
4 
5 
3. Intermittency 
How often have you found you 
stopped and started again several 
times when you urinated? 
0 
1 
2 
3 
4 
5 
4. Urgency 
How often have you found it 
difficult to postpone urination? 
0 
1 
2 
3 
4 
5 
5. Weak Stream 
How often have you had a weak 
urinary stream? 
0 
1 
2 
3 
4 
5 
6. Straining 
How often have you had to strain 
to start urination? 
0 
1 
2 
3 
4 
5 
None 
1 Time 
2 Times 
3 Times 
4 Times 
5 Times 
7. Nocturia 
How many times did you typically 
get up at night to urinate? 
0 
1 
2 
3 
4 
5 
Total I-PSS Score 
Quality of Life Due to Urinary 
Symptoms 
Delighted 
Pleased Mostly 
Satisfied 
Mixed 
Mostly 
Dissatisfied 
Unhappy Terrible 
If you were to spend the rest of 
your life with your urinary 
condition just the way it is now, 
how would you feel about that? 
0 
1 
2 
3 
4 
5 
6 

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About the I-PSS 
The International Prostate Symptom Score (I-PSS) is based on the answers to seven questions concerning 
urinary symptoms and one question concerning quality of life.  Each question concerning urinary symptoms 
allows the patient to choose one out of six answers indicating increasing severity of the particular symptom.  
The answers are assigned points from 0 to 5.  The total score can therefore range from 0 to 35 (asymptomatic 
to very symptomatic). 
 
The questions refer to the following urinary symptoms: 
Question  
Symptom 
1 
 
Incomplete emptying 
2 
 
Frequency 
3 
 
Intermittency 
4 
 
Urgency 
5 
 
Weak Stream 
6 
 
Straining 
7 
 
Nocturia 
 
Question eight refers to the patient’s perceived quality of life. 
 
The first seven questions of the I-PSS are identical to the questions appearing on the American Urological 
Association (AUA) Symptom Index which currently categorizes symptoms as follows: 
 
Mild (symptom score less than of equal to 7) 
Moderate (symptom score range 8-19) Severe 
(symptom score range 20-35) 
 
The International Scientific Committee (SCI), under the patronage of the World Health Organization (WHO) 
and the International Union Against Cancer (UICC), recommends the use of only a single question to assess 
the quality of life.  The answers to this question range from “delighted” to “terrible” or 0 to 6.  Although this 
single question may or may not capture the global impact of benign prostatic hyperplasia (BPH) Symptoms 
or quality of life, it may serve as a valuable starting point for a doctor-patient conversation. 
 
The SCI has agreed to use the symptom index for BPH, which has been developed by the AUA Measurement 
Committee, as the official worldwide symptoms assessment tool for patients suffering from prostatitis. 
 
The SCI recommends that physicians consider the following components for a basic diagnostic workup: 
history; physical exam; appropriate labs, such as U/A, creatinine, etc.; and DRE or other evaluation to rule 
out prostate cancer. 
 

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Expanded Prostate Index Composite (EPIC) 
Prostate cancer-specific HRQOL as measured by the Expanded Prostate Index Composite (EPIC) Instrument 
development was based on advice from an expert panel and prostate cancer patients, which led to expanding 
the 20-item University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) to the 50-item EPIC. 
Summary and subscale scores were derived by content and factor analyses. Test-retest reliability and 
internal consistency were high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each 
r ≥0.80 and Cronbach's alpha≥0.82) and for most domain-specific subscales. Correlations between function 
and bother subscales within domains were high (r >0.60). Correlations between different primary domains 
were consistently lower, indicating that these domains assess distinct HRQOL components. EPIC domains 
had weak to modest correlations with the Medical Outcomes Study 12-item Short-Form Health Survey (SF-
12). Moderate agreement was observed between EPIC domains relevant to the Functional Assessment of 
Cancer Therapy Prostate module (FACT-P) and the American Urological Association Symptom Index 
(AUA-SI), providing criterion validity without excessive overlap (Wei 2000). EPIC is a robust prostate 
cancer HRQOL instrument that measures a broad spectrum of symptoms; however, to decrease patient 
burden we will only use the domains most pertinent to this study: urinary, bowel, sexual, and hormonal. 
The domains were validated separately, and since each domain will be used intact, there is no threat to 
validity. This reduces patient burden 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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EPIC               Favorable Risk  Prostate  Cancer 
 
 
Utilization  of  Sexual  Medications/Devices 
Patient Initials 
Patient ID 
AMENDED DATA 
YES INSTRUCTIONS: This page must be completed by the medical staff (nurse, data manager, 
physician, etc.) Questionnaires for all time points are required even if submission time points 
deviate from the specified intervals. Only patient death or documented patient refusal will be an 
acceptable reason for omission of the QOL questionnaires. However, this page must be 
completed and submitted for every time point on the calendar regardless of whether the 
QOL questionnaire was completed. Every effort possible should be made to collect the 
data on time. 
1 
  
  TIME POINT(1) 
1 
Pretreatment 
2 
One year follow-up 
3 
Two year follow-up 
4 
Five year follow-up 
2 
  
  WAS PATIENT QUESTIONNAIRE COMPLETED?(2) 
1 
No (Skip to question 3) 
2 
Yes 
2A 
DATE PATIENT QUESTIONNAIRE COMPLETED 
_____-_____-_____(3) 
3 
 
REASON PATIENT QUESTIONNAIRE WAS NOT 
COMPLETED(4) 
0 
Not applicable, questionnaire was completed 
1 
Patient refused due to illness 
2 
Patient refused for other reason, 
specify___________________________(5) 
3 
Unable to contact patient 
4 
Institutional error 
5 
Tool not available in patient’s language 
6 
Other reason, 
specify  ___________________________(6) 
9 
Unknown 
4 
 
SPECIFY METHOD OF COMPLETION(7) 
1 
At appointment 
2 
By mail 
3 
By telephone 
9 
Unknown 
5 
 
DID THE PATIENT REQUIRE ANY ASSISTANCE IN 
COMPLETING THE QUESTIONNAIRE?(8) 
1 
No 
2 
Yes 
9 
Unknown if assistance was given 
6 
 
SPECIFY THE PERSON WHO ASSISTED THE 
PATIENT(9) 
1 
Staff member 
2 
Family 
3 
Other,  specify 
(10) 
9 
Unknown 
7 
 
EXTENT OF THE ASSISTANCE(11) 
1 
Read items to patient 
2 
Interpreted items for patient 
3 
Marked items per patient’s response 
4 
Combination of above, 
specify  __________________________(12) 
5 
Other,  specify 
(13) 
9 
Unknown 
  
- 
-  
 
Signature of person completing this form(14) 
Date form completed(15) 
 

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The Expanded Prostate Cancer Index Composite (EPIC) 
 
This questionnaire is designed to measure Quality of Life issues in patients with Prostate Cancer. To help 
us get the most accurate measurement, it is important that you answer all questions honestly and 
completely. 
 
Remember, as with all medical records, information contained within this survey will remain strictly 
confidential. 
 
Today’s Date: _____/_____/_____ 
 
Name: (Last, First, M.I.)__________________________________________________________ 
 
Date of Birth: _____/_____/_____ 
 
 
URINARY FUNCTION 
This section is about your urinary habits. Please consider ONLY THE LAST 4 WEEKS. 
 
1. Over the past 4 weeks, how often have you leaked urine? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
2. Over the past 4 weeks, how often have you urinated blood? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
3. Over the past 4 weeks, how often have you had pain or burning with urination? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
4. Which of the following best describes your urinary control during the last 4 weeks? 
No urinary control whatsoever..........................................................1 
Frequent dribbling.............................................................................2  
(Circle one number) 
Occasional dribbling .........................................................................3 
Total control ......................................................................................4 
 
 
5. How many pads or adult diapers per day did you usually use to control leakage during the last 4 
weeks? 
None.................................................................................................0 
1 pad per day....................................................................................1 
2 pads per day ..................................................................................2 
 (Circle one number) 
3 or more pads per day.....................................................................3 

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6. How big a problem, if any, has each of the following been for you during the last 4 weeks? 
 
 
7. Overall, how big a problem has your urinary function been for you during the last 4 weeks? 
No problem .......................................................................................1 
Very small problem ...........................................................................2 
Small problem...................................................................................3  
(Circle one number) 
Moderate problem.............................................................................4 
Big problem.......................................................................................5 
 
 
 
BOWEL HABITS 
The next section is about your bowel habits and abdominal pain. 
Please consider ONLY THE LAST 4 WEEKS. 
 
8. How often have you had rectal urgency (felt like I had to pass stool, but did not) during the last 4 
weeks? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3 
 (Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
9. How often have you had uncontrolled leakage of stool or feces? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
10. How often have you had stools (bowel movements) that were loose or liquid (no form, watery, mushy) 
during the last 4 weeks? 
Never................................................................................................1 
Rarely................................................................................................2 
About half the time............................................................................3 
 (Circle one number) 
Usually..............................................................................................4 
Always...............................................................................................5 
 
 
 
 
(Circle one number on each line) 
No 
problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Dripping or leaking urine 
0 
1 
2 
3 
4 
b. Pain or burning on urination 
0 
1 
2 
3 
4 
c. Bleeding with urination 
0 
1 
2 
3 
4 
d. Weak urine stream or incomplete emptying 
0 
1 
2 
3 
4 
e. Waking up to urinate 
0 
1 
2 
3 
4 
f. 
Need to urinate frequently during the day 
0 
1 
2 
3 
4 

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Protocol:  8.4.2020 
11. How often have you had bloody stools during the last 4 weeks? 
Never................................................................................................1 
Rarely................................................................................................2 
About half the time............................................................................3 
 (Circle one number) 
Usually..............................................................................................4 
Always...............................................................................................5 
 
 
12. How often have your bowel movements been painful during the last 4 weeks? 
Never................................................................................................1 
Rarely................................................................................................2 
About half the time............................................................................3  
(Circle one number) 
Usually..............................................................................................4 
Always...............................................................................................5 
 
 
13. How many bowel movements have you had on a typical day during the last 4 weeks? 
Two or less .......................................................................................1 
Three to four .....................................................................................2  
(Circle one number) 
Five or more......................................................................................3 
 
 
14. How often have you had crampy pain in your abdomen, pelvis or rectum during the last 4 weeks? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3 
 (Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
15. How big a problem, if any, has each of the following been for you? 
 
 
 
16.   Overall, how big a problem have your bowel habits been for you during the last 4 weeks? 
No problem .......................................................................................1 
Very small problem ...........................................................................2 
Small problem...................................................................................3 
 (Circle one number) 
Moderate problem.............................................................................4 
Big problem.......................................................................................5 
 
 
 
(Circle one number on each line) 
No 
problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Urgency to have a bowel movement 
0 
1 
2 
3 
4 
b. Increased frequency of bowel movements 
0 
1 
2 
3 
4 
c. Watery bowel movements 
0 
1 
2 
3 
4 
d. Losing control of your stools 
0 
1 
2 
3 
4 
e. Bloody stools 
0 
1 
2 
3 
4 
f. 
Abdominal/Pelvic/Rectal pain 
0 
1 
2 
3 
4 

CASE 11813   
              Page 51 of 57 
Protocol:  8.4.2020 
SEXUAL FUNCTION 
The next section is about your current sexual function and sexual satisfaction. Many of the questions are 
very personal, but they will help us understand the important issues that you face every day. Remember, 
THIS SURVEY INFORMATION IS COMPLETELY CONFIDENTIAL. Please answer honestly about THE 
LAST 4 WEEKS ONLY. 
 
17. How would you rate each of the following during the last 4 weeks? 
 
 
18. How would you describe the usual QUALITY of your erections during the last 4 weeks? 
None at all.........................................................................................1 
Not firm enough for any sexual activity.............................................2 
Firm enough for masturbation and foreplay only..............................3 
 (Circle one number) 
Firm enough for intercourse .............................................................4 
 
 
19. How would you describe the FREQUENCY of your erections during the last 4 weeks? 
I NEVER had an erection when I wanted one ..................................1 
I had an erection LESS THAN HALF the time I wanted one............2 
I had an erection ABOUT HALF the time I wanted one....................3  
(Circle one number) 
I had an erection MORE THAN HALF the time I wanted one ..........4 
I had an erection WHENEVER I wanted one ...................................5 
 
 
20. How often have you awakened in the morning or night with an erection during the last 4 weeks? 
Never................................................................................................1 
Less than once a week.....................................................................2 
About once a week ...........................................................................3  
(Circle one number) 
Several times a week........................................................................4 
Daily..................................................................................................5 
 
 
21. During the last 4 weeks, how often did you have any sexual activity? 
Not at all............................................................................................1 
Less than once a week.....................................................................2 
About once a week ...........................................................................3 
(Circle one number) 
Several times a week........................................................................4 
Daily..................................................................................................5 
 
 
22. During the last 4 weeks, how often did you have sexual intercourse? 
Not at all............................................................................................1 
Less than once a week.....................................................................2 
About once a week ...........................................................................3  
(Circle one number) 
Several times a week........................................................................4 
Daily..................................................................................................5 
 
 
(Circle one number on each line) 
Very Poor 
to None 
Poor 
Fair 
Good 
Very 
Good 
a. Your level of sexual desire? 
0 
1 
2 
3 
4 
b. Your level of sexual desire? 
0 
1 
2 
3 
4 
c. Your ability to have an erection?  
0 
1 
2 
3 
4 
d. Your ability to reach orgasm (climax) 
0 
1 
2 
3 
4 

CASE 11813   
              Page 52 of 57 
Protocol:  8.4.2020 
23. Overall, how would you rate your ability to function sexually during the last 4 weeks? 
Very poor ..........................................................................................1 
Poor..................................................................................................2 
Fair....................................................................................................3  
(Circle one number) 
Good.................................................................................................4 
Very good .........................................................................................5 
 
 
24. How big a problem during the last 4 weeks, if any, has each of the following been for you? 
 
 
25. Overall, how big a problem has your sexual function or lack of sexual function been for you during 
the last 4 weeks? 
No problem .......................................................................................1 
Very small problem ...........................................................................2 
Small problem...................................................................................3 
 (Circle one number) 
Moderate problem.............................................................................4 
Big problem.......................................................................................5 
 
 
 
HORMONAL FUNCTION 
The next section is about your hormonal function. Please consider ONLY THE LAST 4 WEEKS. 
 
26. Over the last 4 weeks, how often have you experienced hot flashes? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
27. How often have you had breast tenderness during the last 4 weeks? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3  
(Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
28. During the last 4 weeks, how often have you felt depressed? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3 
 (Circle one number) 
About once a week ...........................................................................4 
Rarely or never .................................................................................5 
 
 
 
(Circle one number on each line) 
No 
problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Your level of sexual desire 
0 
1 
2 
3 
4 
b. Your ability to have an erection 
0 
1 
2 
3 
4 
c. Your ability to reach an orgasm 
0 
1 
2 
3 
4 

CASE 11813   
              Page 53 of 57 
Protocol:  8.4.2020 
29. During the last 4 weeks, how often have you felt a lack of energy? 
More than once a day.......................................................................1 
About once a day..............................................................................2 
More than once a week ....................................................................3 
 (Circle one number) 
About once a week ...........................................................................4 
 
Rarely or never .................................................................................5 
 
 
30. How much change in your weight have you experienced during the last 4 weeks, if any? 
Gained 10 pounds or more...............................................................1 
Gained less than 10 pounds.............................................................2 
No change in weight .........................................................................3  
(Circle one number) 
Lost less than 10 pounds..................................................................4 
Lost 10 pounds or more....................................................................5 
 
 
31. How big a problem during the last 4 weeks, if any, has each of the following been for you? 
 
 
 
 
 
OVERALL SATISFACTION 
 
 
32. Overall, how satisfied are you with the treatment you received for your prostate cancer? 
Extremely dissatisfied .......................................................................1 
Dissatisfied .......................................................................................2 
Uncertain ..........................................................................................3  
(Circle one number) 
Satisfied ............................................................................................4 
Extremely satisfied............................................................................5 
 
 
THANK YOU VERY MUCH! 
 
 
 
 
(Circle one number on each line) 
No 
problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Hot flashes 
0 
1 
2 
3 
4 
b. Breast tenderness/enlargement 
0 
1 
2 
3 
4 
c. Loss of Body Hair 
0 
1 
2 
3 
4 
d. Feeling depressed 
0 
1 
2 
3 
4 
e. Lack of energy 
0 
1 
2 
3 
4 
f. 
Change in body weight 
0 
1 
2 
3 
4 

CASE 11813   
              Page 54 of 57 
Protocol:  8.4.2020 
 
EQ-5D 
 
Patient Initials 
Patient ID 
AMENDED DATA 
YES INSTRUCTIONS: This page must be completed by the medical staff (nurse, data manager, 
physician, etc.) Questionnaires for all time points are required even if submission time points 
deviate from the specified intervals. Only patient death or documented patient refusal will be an 
acceptable reason for omission of the QOL questionnaires. However, this page must be 
completed and submitted for every time point on the calendar regardless of whether the 
QOL questionnaire was completed. Every effort possible should be made to collect the 
data on time. 
 
1 
  
  TIME POINT(1) 
• 
Pretreatment 
• 
One year follow-up 
• 
Two year follow-up 
• 
Five year follow-up 
 
2 
  
  WAS PATIENT QUESTIONNAIRE COMPLETED?(2) 
1 
No (Skip to question 3) 
2 
Yes 
 
2A 
DATE PATIENT QUESTIONNAIRE COMPLETED 
 
_____-_____-_____(3) 
 
 
 
3 
 
REASON PATIENT QUESTIONNAIRE WAS NOT 
COMPLETED(4) 
 
0 
Not applicable, questionnaire was completed 
1 
Patient refused due to illness 
2 
Patient 
refused 
for 
other 
reason, 
specify___________________________(5) 
3 
Unable to contact patient 
4 
Institutional error 
5 
Tool not available in patient’s language 
6 
Other reason, 
specify  ___________________________(6) 
9 
Unknown 
4 
 
SPECIFY METHOD OF COMPLETION(7) 
1 
At appointment 
2 
By mail 
3 
By telephone 
9 
Unknown 
5 
 
DID THE PATIENT REQUIRE ANY ASSISTANCE IN 
COMPLETING THE QUESTIONNAIRE?(8) 
1 
No 
2 
Yes 
9 
Unknown if assistance was given 
6 
 
SPECIFY THE PERSON WHO ASSISTED THE 
PATIENT(9) 
1 
Staff member 
2 
Family 
3 
Other,  specify 
(10) 
9 
Unknown 
7 
 
EXTENT OF THE ASSISTANCE(11) 
1 
Read items to patient 
2 
Interpreted items for patient 
3 
Marked items per patient’s response 
4 
Combination of above, 
specify  __________________________(12) 
5 
Other,  specify 
(13) 
9 
Unknown 
8 
PATIENT'S HEALTH SCORE(14) 
(completed  by  investigator  or  staff  based  on  patient’s 
answer  to  the  “Best  Imaginable  Health  Scale”  on 
page  3) 
_____________________________________________                                                                  ______________________ 
Signature of person completing this form(15) 
                                                                       Date form completed(16) 

CASE 11813   
              Page 55 of 57 
Protocol:  8.4.2020 
 
 
Date form completed 
- 
-  
 
Patient Instructions: Please answer one statement in each group below. 
 
Mobility 
 
Please circle one statement in each group below which best describes your health today. 
1 
I have no problems in walking about 
2 
I have some problems in walking about 
3 
I am confined to bed 
 
Self-Care 
 
Please circle one statement in each group below which best describes your health today. 
1 
I have no problems with self-care 
2 
I have some problems washing or dressing myself 
3 
I am unable to wash or dress myself 
 
Usual Activities 
 
Please circle one statement in each group below which best describes your health today. 
1 
I have no problems with performing my usual activities 
2 
I have some problems with performing my usual activities 
3 
I am unable to perform my usual activities 
 
Pain/Discomfort 
 
Please circle one statement in each group below which best describes your health today. 
1 
I have no pain or discomfort 
2 
I have moderate pain or discomfort 
3 
I have extreme pain or discomfort 
 
Anxiety/Depression 
 
Please circle one statement in each group below which best describes your health today. 
1 
I am not anxious or depressed 
2 
I am moderately anxious or depressed 
3 
I am extremely anxious or depressed 
 
The EQ5D Group. EQ5D- a new facility for the measurement of health-related quality of life. Health Policy 1990;(16)3:199-208 
 
 

CASE 11813   
              Page 56 of 57 
Protocol:  8.4.2020 
 
QF 
 
 
 
 
 
 
 
To help people say how good or bad 
a health state is, we have drawn a 
scale (rather like a thermometer) 
on which the best state you can 
imagine is marked by 100 and the 
worst state you can imagine is 
marked by 0. 
 
We would like you to indicate in this 
scale how good or bad is your own 
health today, in your opinion. Please 
do this by drawing a line from the 
box below to whichever point on the 
scale indicates how good or bad 
your current health is. 
 
 
 
Your own 
health 
state today 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient's signature 
 
 
 
Date 
 
Patient Initials 
 
 
Best Imaginable Health Scale 
100 
 
 
 
 
 
9 
0 
 
 
 
 
 
8 
0 
 
 
 
 
 
7 
0 
 
 
 
 
 
6 
0 
 
 
 
 
 
5 
0 
 
 
 
 
 
4 
0 
 
 
 
 
 
3 
0 
 
 
 
 
 
2 
0 
 
 
 
 
 
1 
0 
 
 
 
 
 
0 
Worst Imaginable Health Scale 
 
 

CASE 11813   
              Page 57 of 57 
Protocol:  8.4.2020 
SEXUAL HEALTH INVENTORY FOR MEN (SHIM) 
 
PATIENT NAME:                                       TODAY’S DATE: 
 
PATIENT INSTRUCTIONS 
 
Sexual health is an important part of an individual's overall physical and emotional well-being. Erectile 
dysfunction, also known as impotence, is one type of very common medical condition affecting sexual health. 
Fortunately, there are many different treatment options for erectile dysfunction. This questionnaire is designed 
to help you and your doctor identify if you may be experiencing erectile dysfunction. If you are, you may 
choose to discuss treatment options with your doctor. 
 
Each question has several possible responses. Circle the number of the response that best describes your own 
situation. Please be sure that you select one and only one response for each question. 
 
 
OVER THE PAST 6 MONTHS: 
Add the numbers corresponding to questions 1-5. TOTAL: 
The Sexual Health Inventory for Men further classifies ED severity with the following Breakpoints: 
 
1-7 Severe ED      8-11 Moderate ED      12-16 Mild to Moderate ED……17-21 Mild ED 
1. How do you rate your 
confidence that you 
could get and keep an 
erection? 
 
 
VERY LOW 
 
LOW 
 
MODERATE 
 
HIGH 
 
VERY HIGH 
 
1 
2 
3 
4 
5 
2. When you had 
erections with sexual 
stimulation, how often 
were your erections hard 
enough for penetration 
(entering your partner)? 
NO SEXUAL 
ACTIVITY 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(Much less than 
half the time)  
SOMETIMES 
(About half the 
time) 
MOST TIMES 
(Much more than 
half the time)  
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5 
3. During sexual 
intercourse, how often 
were you able to 
maintain your erection 
after you had penetrated 
(entered) your partner? 
DID NOT 
ATTEMPT 
INTERCOURSE 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(Much less than 
half the time)  
SOMETIMES 
(About half the 
time) 
MOST TIMES 
(Much more than 
half the time)  
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5 
4. During sexual 
intercourse, how difficult 
was it to maintain your 
erection to completion of 
intercourse? 
DID NOT 
ATTEMPT 
INTERCOURSE 
EXTREMELY 
DIFFICULT 
VERY 
DIFFICULT 
 
DIFFICULT 
SLIGHTLY 
DIFFICULT 
NOT 
DIFFICULT 
0 
1 
2 
3 
4 
5 
 
5. When you attempted 
sexual intercourse, how 
often was it satisfactory 
for you? 
DID NOT 
ATTEMPT 
INTERCOURSE 
ALMOST 
NEVER OR 
NEVER 
A FEW TIMES 
(Much less than 
half the time)  
SOMETIMES 
(About half the 
time) 
MOST TIMES 
(Much more than 
half the time)  
ALMOST 
ALWAYS OR 
ALWAYS 
0 
1 
2 
3 
4 
5