Hypofractionated Adaptive Image-Guided Radiation Therapy for Localized Adenocarcinoma of the Prostate
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Cover Page 
Clinical Protocol:  Hypofractionated Image-Guided Radiation Therapy 
for Localized Adenocarcinoma of the Prostate 
NCT Number: NCT00809991 
Date: 1/9/2024
RE: Protocol with included statistical plan 

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Clinical Protocol:  Hypofractionated Image-Guided Radiation Therapy for Localized 
Adenocarcinoma of the Prostate 
 
 
Phase: II 
 
 
Principal Investigator: 
Danny Y. Song, M.D.  
 
 
 
 
Department of Radiation Oncology 
and Molecular Radiation Sciences 
 
 
 
 
Johns Hopkins University School of Medicine 
 
 
 
 
401 N Broadway, Suite 1440 
 
 
 
 
Baltimore, MD  21231 
 
 
 
 
Phone: (410) 502-5875 
 
 
 
 
Fax: 
(410) 502-1419 
 
 
 
 
Email: dsong2@jhmi.edu 
 
 
 
Co-Investigators:                  Theodore L. DeWeese, M.D. 
Fariba Asrari, M.D. 
Stephen Greco, M.D.  
Curtiland Deville, M.D.  
 
 
 
Time required to complete the study: The study was resumed August 2011and is 
expected to be complete November 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
  
1.0 
         BACKGROUND AND RATIONALE…………………………….…………………3 
2.0 
         OBJECTIVES…………………………………………………………………………5 
3.0 
         PATIENT SELECTION……………………………………………………………...7 
4.0 
         PRETREATMENT EVALUATIONS……………………………………………….8 
5.0 
         RADIATION THERAPY AND RESEARCH INTERVENTIONS………………..9 
6.0 
         PATIENT ASSESSMENTS………………………………………………………....14 
7.0 
         DATA ANALYSIS AND STATISTICAL CONSIDERATIONS……………..…..15 
8.0 
         REPORTING OF SERIOUS OR UNEXPECTED ADVERSE EVENTS……..…17 
9.0 
         DISPOSITION OF DATA………………………………………………………..….19 
10.0 
         PROTOCOL MODIFICATIONS……………………………………………..…….19 
11.0 
         DEPARTURE FROM PROTOCOL…………………………………………..……19 
12.0 
         CRITERIA FOR WITHDRAWAL FROM STUDY………………………...……..19 
13.0 
         ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL………...……….19 
14.0 
         ETHICAL AND REGULATORY CONSIDERATIONS…………………..……...20 
15.0 
         DATA SAFETY AND MONITORING PLAN……………………………..………21 
16.0 
         LIST OF DATA COLLECTION SHEETS………………………………….……..21 
17.0 
         REFERENCES…………………………………………………………….…………22 

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1.0 
BACKGROUND AND RATIONALE 
 
Radiation therapy is an effective and frequently utilized modality for the 
treatment of clinically localized prostate cancer.  Traditionally, external beam radiation has 
been delivered in a fractionated manner using daily doses of 1.8-2.0 Gy.  This daily dose 
was derived from early animal experiments and clinical experience, supported by 
mathematical models of normal tissue and tumor response to fraction size.  The most 
widely used of these models is the linear-quadratic formula, which predicts responses to 
different fraction sizes based on the alpha/beta ratio of any given tissue.1   
 
One of the main motivations for delivering a treatment at low dose rate or with 
many fractions is that late-responding normal tissue are generally more sensitive than 
early-responding tissues (i.e. tumor) to increases in fraction size. So increasing the number 
of fractions generally spares late-responding tissues more than the tumor. This can be 
quantified in terms of the alpha/beta ratio: 
• Small alpha/beta ratio (2-4 Gy), typical of late sequelae, means high 
sensitivity to fractionation changes. 
• Large alpha/beta ratio (>8 Gy), typical of tumor control, means low 
sensitivity to fractionation changes. 
 
It is generally assumed that the mechanistic basis for the different fractionation 
response of tumors and late-responding normal tissues relates to the larger proportion of 
cycling cells in tumors. But prostate tumors contain unusually small fractions of cycling 
cells.2 Brenner and Hall as well as Duchesne and Peters have reasoned that prostate tumors 
might not respond to changes in fractionation in the same way as other cancers; both papers 
hypothesize that prostate tumors might respond to changes in fractionation or dose rate 
more like a late-responding normal tissue.3,4 In mathematical terms, the suggestion is that 
the alpha/beta ratio for prostate cancer might be low, comparable to that for late-responding 
tissues or even lower. Previous estimates of alpha/beta ratios of normal tissue and tumor 
tissue have generally been 3 and 10, respectively.  Recent evidence has estimated the 
alpha/beta ratio of prostate cancer to be as low as 1.5.  If these hypotheses are true, then 
the optimal therapeutic ratio for prostate cancer would be achieved using daily doses higher 
than 2 Gy.5   
 
 
Several preliminary clinical reports have found reasonable PSA control rates 
and no increase in late toxicity (90 days of greater following radiation, as defined by 
RTOG) using doses of 2.5 to 3 Gy.  Kupelian from the Mayo Clinic found PSA-free 
survival rates of 97%, 88%, and 70% in low-, intermediate-, and high-risk patients, 
respectively.  The dose regimen used was 70 Gy in 2.5 Gy daily fractions.  Both acute and 
late toxicity were not higher than seen with typical dose regimens.6  A group from Christie 
Hospital reported 82%, 56%, and 39% 5-year biochemical disease free survival rates (low, 
intermediate, and high risk, respectively) in patients treated with 50 Gy in 16 fractions 
(3.125 Gy per fraction), with acceptable bowel and bladder toxicity; however, they did find 
a trend toward general worsening of bowel function at 2 years.7  More recently, Lock et al. 
reported on a Phase II study evaluating 63.2 Gy in 20 fractions over 4 weeks.  At median 
follow-up of 36 months, late grade 2 and 3 GU toxicity was 14% and 5%, and late grade 2 
and 3 GI toxicity of 25% and 3%8.  Biochemical disease-free survival at 3 years was 98%.  
Martin et al. reported from the Princess Margaret Hospital Phase II study of 60 Gy in 20 
fractions, and found that only 1/92 patients experienced Grade 3 toxicity at a median 

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follow-up of 38 months.9  Rene et al. treated 129 patients with 66 Gy in 22 fractions, and 
at median follow-up of 51 months the 5-year biochemical control rate was 98%.  At last 
follow-up, there was 2% and 1.5% rates of persistent grade 2 or greater GU and GI toxicity, 
respectively.10 
 
For purposes of comparison to standard fractionation results, Zelefsky et al. 
reported 17% grade 2 or greater GI and 13% grade 2-3 GU toxicity in patients receiving 
75.6 Gy in standard fractionation; Storey et al. reported 21% 5-year grade 2 or greater GI 
and 9% grade 2 or greater GU toxicity using 78 Gy in 2 Gy fractions11,12.  Therefore, 
although our prior regimen of 67.2 Gy in 21 fractions was not well tolerated (see section 
2.0 below), many other published series suggest that a slightly lower dose or a slightly 
more protracted course appears to have similar toxicity and control rates to a traditional 8 
week regimen. 
 
These results, although promising, require further validation.  If the hypothesis 
that prostate cancer alpha/beta ratio is lower than normal tissue is correct, then the optimal 
fractional dose may be even higher than the doses tested thus far, but if incorrect, the result 
may be increased normal tissue toxicity.   
 
2.0 
OBJECTIVES 
 
This will be a Phase II study evaluating the effectiveness and toxicity of a 
regimen of 3.6 Gy daily fractions to a total dose of 57.6 Gy.  This choice of daily dose is 
based on the prior published experiences showing safety and efficacy of hypofractionated 
regimen of 2.5 Gy, 2.7 Gy, 3.0, and 3.63 Gy daily fractions.  The total dose is calculated 
to be iso-effective for late effects to a conventionally fractionated total dose of 79.2 Gy, 
which has been shown to be effective and safe in large prospective studies.13 ,14  If the 
alpha/beta ratio for prostate is between 1.5-3.0, then this regimen should be at least as 
effective for tumor control as 79.2 Gy given in conventional 1.8 Gy fractions, a dose within 
the range of evidence-based standard practice14,15.  This dose has been modified from a 
prior version of this protocol which treated patients to 67.2 Gy in 21 fractions.  In this 
experience, 16 patients were enrolled and treated; 4 patients have experienced Grade 3 
urinary symptoms, and 4 patients have experienced Grade 2 rectal bleeding.  Based on the 
urinary Grade 3 toxicity rate as well as the persistence of the urinary toxicity in the patients 
who developed Grade 3 symptoms, the  dose has been reduced to one that is has a biological 
equivalent dose for late effects (BED = 3) of 127 (compared to 139 for the prior regimen).  
Also, in contrast to our prior dose regimen which tested a dose regimen which was novel, 
this dose is within the range of doses used in a prior Phase II study which reported 
acceptable toxicity and early efficacy results16.  Other modifications which should 
ameliorate toxicity include the delivery of 4 fractions per week instead of 5 (based on 
reports from Stanford which found that increasing the overall time to complete treatment 
resulted in reduced toxicity, while other data suggest that modest prolongations of 
treatment course do not significantly impact control rates in prostate cancer)17,18, and the 
use of nominal doses prescribed to the mean, rather than minimal doses to a volume.  Also, 
a run-in safety phase has been added (section 2.1). 
 
Given the change in dose, the patients enrolled on the prior dose regimen will 
be considered separately from those enrolled onto the new regimen; however, they will still 
be monitored in follow-up according to the current version of the protocol.  Sample 
size/accrual goals will pertain to the new dose regimen. 

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Comparison of Biologically Equivalent Doses for Different Regimens 
 
Fraction Size 
# 
Fractions 
Acute 
(10) 
Prostate (1.5) 
Prostate (3) 
Late (3) 
Total Dose 
 
 
 
 
 
 
 
 
Conventional 
Fraction 
1.8 
44 
93 
174 
127 
127 
79.2 
Cleveland Clinic 
2.5 
28 
88 
187 
128 
128 
70 
Fox Chase 
2.7 
26 
89 
197 
133 
133 
70.2 
Christie 
3 
20 
78 
180 
120 
120 
60 
Prior Dose this Study 
3.2 
21 
89 
211 
139 
139 
67.2 
Proposed Regimen 
3.6 
16 
78 
176 
127 
127 
57.6 
 
2.1 Run-In Safety Phase 
 
Although this regimen is based upon already published experience, given 
the unpredicted toxicity encountered on the previous dose regimen, a ‘run-in’ phase 
will be incorporated so that the accrual will be held if the rate of Grade 3+ toxicities 
at 6 month follow-up visits convincingly exceeds 5% in evaluable patients.  Given 
this stopping guideline, the study regimen will be assessed using a one-sided exact 
binomial 95% confidence bound. Accrual will be held after 10 patients are treated, 
until these patients all reach minimum follow-up of 6 months.  The protocol will 
either be modified or terminated if 3 out of first 10 evaluable patients experience 
G3+ toxicity at a minimum follow up of 6 months (corresponding to lower one-
sided 95% confidence bound of 8.7%).  
 
If the study is not stopped by the above rule in the first 10 patients, then 
protocol accrual will continue to study completion (108 subjects).  At the final 
analysis, a sample size of 108 patients will allow a Grade 3+ toxicity estimate of 
+/- 4.5% if observed toxicity is 5%, and +/- 6.2% if observed rate is 10%, 
respectively. 
2.2 Primary Objective 
 
Assess the incidence of grade 2 and 3+ GU and GI toxicity and self-reported 
quality of life data with image-guided radiation therapy in doses of 3.6 Gy per day 
to a total dose of 57.6 Gy (16 fractions).   
2.3 Secondary Objectives 
1) Assess biochemical, clinical, and pathologic control rates associated with the 
hypofractionated dose regimen. 
2) Collect dose/volume and imaging data to allow normal tissue complication 
probability modeling and targeting assessment for patients treated with 
hypofractionated radiation therapy. 
 
3.0 
PATIENT SELECTION   
 
The target population will be patients with a diagnosis of adenocarcinoma of the 
prostate who are seen in consultation in the Department of Radiation Oncology 
(approximately 360 patients per year). 
3.1 Inclusion Criteria 
• Histologically confirmed adenocarcinoma of the prostate 
• Clinical stages T1a-T2b 

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• PSA of less than 10 ng/ml 
• Gleason score of 3+4 or lower 
• The patient has decided to undergo external beam radiation as treatment choice 
for his prostate cancer. 
• Signed study-specific consent form prior to registration 
3.2 Exclusion Criteria  
• Clinical stages T3-4 disease. 
• Gleason (4+3) or higher score. 
• PSA > 10 ng/ml. 
• History and/or clinical evidence of lymph node involvement (N1). 
• History and/or clinical evidence of distant metastases (M1). 
• Radical surgery for carcinoma of the prostate. 
• Previous Chemotherapy or pelvic radiation therapy. 
• Previous or concurrent cancers other than basal or squamous cell skin cancers 
or superficial bladder cancer unless disease free for at least 5 years. 
• History of inflammatory bowel disease. 
• Major medical or psychiatric illness which, in the investigator’s opinion, would 
prevent completion of treatment and would interfere with follow up. 
• Androgen suppression therapy within past year. Defined as: LHRH agonist or 
antagonist, or androgen blocker, not 5-alpha reductase inhibitor. 
 
4.0 
PRETREATMENT EVALUATIONS 
4.1 Subject Screening Procedures  
• History and physical (including digital rectal examination). 
• Histological diagnosis and Gleason score provided on the pathology report.  All 
patients, per institutional policy, will have pathology reviewed at Johns 
Hopkins. 
• Prostate specific antigen (PSA) within 6 months prior to registration.  
• Quality of life measures:  IPSS, and EPIC bowel and sexual questionnaires (See 
Appendix 1 for questionnaires). 
• Patients will not be required to have pelvic lymph node imaging (i.e. CT scan) 
or a bone scan if they have not previously had them performed, given the low 
incidence of positive findings in this population and the current standard of care 
for work-up. 
4.2 Registration Procedures 
4.2.1 Subject Identification 
 
 Patient confidentiality will be maintained in accordance with 
Health Information Portability and Accountability Act (HIPAA) guidelines.  
All participants must sign an informed consent that will describe the 
objectives of the study and potential risks.  All patient data reported on the 
case reports forms will be identified by the patient’s initials and study code 
number only.  Patients shall not be identified by name.  This should serve 
to protect the confidentiality of subjects enrolled on the trial.  Clinical data 
and records for all subjects studied including history and physical findings, 
laboratory data, and results of interventions are to be maintained by the 

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investigators in a secure, locked location.  Computerized data will require 
password authorization(s) for access.   
4.2.2 Description of the Recruitment Process 
 
Potential subjects will be identified at the time of consultation in the 
Department of Radiation Oncology by Dr. Song or Dr. DeWeese.  All 
patients meeting above stated eligibility criteria will be offered participation 
in the study by the consulting physician or by the protocol team study nurse. 
4.2.3 Description of the Informed Consent Process   
 
Only physicians who are also investigators or research nurses listed 
on the project will perform the informed consent interview.  The informed 
consent interview will take place prior to the day the patient is to be treated 
to ensure that the patient has adequate time to discuss the research project 
with family, friends, and/or other Health Care providers.  During the 
informed consent interview the interviewer (investigator physician or 
research nurse) will take as much time as needed to ensure that the potential 
subject understands the research project and also clearly understands that 
he does not have to participate in this project to receive his cancer treatment 
at Johns Hopkins.  If the patient decides to enroll into the research project 
he will sign three copies of the informed consent form.  One will be for his 
own records, one will be kept in the Clinical Research Office at Johns 
Hopkins, and the third one will be kept in his medical records.   
 
5.0 
RADIATION THERAPY AND RESEARCH INTERVENTIONS 
 
Rather than receiving ~ 42 fractions of radiation over 8 ½ weeks, patients enrolling 
on the study will receive radiation in 16 fractions over 4 weeks.  There will be no alteration 
in what patients experience in a treatment session other than a slightly longer (estimated at 
2-3 minutes) duration of beam-on time.   
5.1 Simulation procedure 
5.1.1 
 
Prior to simulation, patients may undergo transrectal or 
transperineal insertion of 2-3 Calypso™ transponder beacons, polyethylene 
glycol hydrogel injection into Denonvilliers’ fascia, or gold seeds to 
improve accuracy in daily prostate alignment and decrease residual 
positioning errors.19  Patients may be treated without implanted markers if 
daily on-board CT imaging is available, or in cases where hydrogel has been 
injected. In cases where Calypso beacons or hydrogel are not utilized, a 
rectal balloon will be inserted at simulation and during daily therapy to 
minimize variability in rectal contents/dosimetry.20 
5.1.2 
 
Patients will undergo CT simulation in the Department of Radiation 
Oncology.  CT slice thickness of 3mm will be used.  For accurate 
delineation of the prostate, MRI simulation images will be fused with the 
CT images.  MRI will be performed in the Department of Radiation 
Oncology, with acquisition of T1-weighted (3mm slices) and T2-weighted 
(1mm slice thickness) images.  Image fusion will be performed using the 
image fusion functionality in Pinnacle treatment planning system. 

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Simulation is to be performed in the supine position, with either an 
alpha cradle or adaptable leg bolster.  Patients will be instructed to empty 
their rectum prior to simulation, and to have a moderately full bladder (drink 
30 cc of water 30-60 minutes prior to simulation).  Oral contrast will be 
utilized at the discretion of the treating physician, but in general is 
discouraged given the confounding effect on dose calculation in the 
radiation planning algorithm due to heterogeneity correction.   
 
In order that extreme rectal filling not be present at the time of the 
planning CT scan as well as during treatment, patients will be advised to: 
a) Take 2 tablespoons of magnesium hydroxide (milk of magnesia) 
beginning 12 hours before the simulation.   
b) Avoid solid food starting at 5PM on the day prior to simulation; 
clear liquids may be ingested. 
c) Take one Fleet’s enema the morning of the simulation. 
 
If a patient is determined to have a distended rectum (greater than 3 
cm in diameter on any axial CT slice posterior to the prostate or proximal 
seminal vesicles) at the time of initial scanning, patient will be given 
opportunity to evacuate and a repeat CT scan performed until treating 
physician determines it is satisfactory.  Otherwise if unsuccessful, the 
patient will be rescheduled for simulation on another day, with repeated 
instructions on bowel preparation as noted. 
5.2 Target and Normal Tissue Volumes 
 
The target volume definitions are, for the most part, based upon the ICRU 
Report 58, Dose and Volume Specification for Reporting Interstitial Therapy. 
a) Gross Target Volume (GTV): The GTV is the entire prostate as defined 
on T2-weighted MRI sequences.   
b) Clinical Target Volume (CTV): In the case of intermediate risk disease, 
the CTV will include the prostate and will also encompass the proximal 
1-2 cm of seminal vesicle (overlap of seminal vesicle with 1-2cm 
expansion on prostate; in Pinnacle this can be accomplished by 
contouring entire seminal vesicle, then using auto-expand ROI function 
with prostate as ‘source’ and seminal vesicle turned on as ‘avoid 
exterior’).  For low risk patients the CTV is equal to the prostate GTV. 
c) Planning Target Volume (PTV): The PTV is the CTV plus 7mm margin 
expansion in all directions except posteriorly, for which a 5mm 
expansion will be utilized.  
d) Rectum will be contoured from approximately the level of the bottom 
of the ischial tuberosities (where the rectum joins the anal canal) 
superiorly to the rectosigmoid junction (generally below the sacroiliac 
joints, or until the rectum no longer is adjacent to the sacrum). 
e) Penile bulb (contoured on the proximal/superior 3 slices or 1cm on CT) 
f) Bladder (entire bladder) 
g) Bowel (contoured up to the level of the top of the sacroiliac joints) 
h) Femoral heads 
 
 

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5.3 Treatment Planning 
 
Intensity-modulated radiation will be utilized to achieve a plan meeting the 
criteria for dose coverage of the PTV and minimizing dose to critical structures.  
Dose-volume histograms (DVHs) must be generated for all critical normal 
sructures.   
 
5.3.1 Dose 
 
Prescription dose will be 3.6 Gy per fraction x 16 fractions.  The 
nominal dose will be the median dose received by the prostate (or CTV for 
intermediate risk patients), +/- 0.1 Gy. Minor variation (marginal coverage): 
Minor variation will be deemed if any portion of PTV receives < 93% of 
the prescription dose (minimum PTV dose less than 53.6 Gy), or any portion 
of CTV receives <95% of prescription dose (minimum CTV or prostate 
dose < 54.7 Gy). 
a) Major variation:  Major variation will be deemed if any portion of PTV 
receives <90% of prescription dose (minimum PTV dose less than 51.8 
Gy), or any portion of CTV receives <93% of prescription dose (53.6 
Gy). 
5.3.2 Dose Constraints 
 
Based on an alpha/beta ratio of 3 for rectum and 3 for bladder late 
toxicity, as well as dose constraints for rectal and bladder toxicity as 
determined from prior studies with conventional fractionation, dose 
constraints will be: 
a) no more than 20% of rectum receives greater than 51 Gy 
b) no more than 40% of rectum receives greater than 43 Gy 
c) no more than 30% of bladder receives greater than 47 Gy  
d) no more than 10% of femoral heads receive greater than 36 Gy 
e) no more than 5% of bowel receives greater than 39 Gy 
21,22,23,24 
5.3.3 Dose Heterogeneity 
 
Maximum dose to the PTV volume should not exceed prescription 
dose by more than 5% (i.e. maximum PTV dose of 60.48 Gy).  Maximum 
point dose to any tissues or other structures outside the PTV including 
unspecified tissue should not exceed prescription dose by more than 7% (i.e. 
maximum dose of 61.63 Gy).  Entire PTV volume should receive at least 
93% of prescription dose (i.e. 53.6 Gy), and entire CTV volume should 
receive at least 95% of prescription dose (i.e. 54.7 Gy).   
5.4 Image-Guided and Adaptive Therapy 
5.4.1 
 
If Calypso beacons are utilized, temporary intrafraction motion is 
expected to occur and will be monitored.  Thresholds of prostate/beacon 
motion of 5mm (3mm in posterior direction) for interrupting therapy will 
be utilized.  If the prostate does not move back to within these thresholds 
within five minutes (as tolerated by the patient lying on the table) then 
therapist will perform re-alignment to new position based on transponder 

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beacon system.  If daily on-board CT is utilized, a pre-treatment image will 
be obtained and necessary positioning adjustments made prior to beam-on. 
5.4.2 
 
If gold markers are utilized, a daily pre-treatment lateral and 
anterior-posterior kV image will be obtained to assess for necessary 
adjustments in patient positioning.  Weekly verification CT simulation may 
also be performed according to physician discretion. 
 
5.5 Patient Management During Treatment 
 
All patients will be seen weekly by the radiation oncologist or nurse (weekly 
on-treatment visit) during treatment, as well as upon completion of radiation.  
Radiation reactions to be captured: 
a) Rectal or small bowel symptomatology (cramping, diarrhea, rectal urgency, 
hematochezia) 
b) Bladder symptomatology (frequency, urgency, nocturia, dysuria) 
c) Radiation dermatitis 
d) Side effects will be treated based on the discretion of the radiation 
oncologist, and documentation kept in the medical record. Rectal side 
effects such as diarrhea may be treated with diphenoxylate or loperamide. 
Bladder or rectal spasms can be treated with anticholinergic agents or 
tolterodine. Irritative or obstructive voiding symptoms can be managed with 
alpha-blockers or phenazopyridine.  
 
6.0   
Patient Assessments 
 
6.1 Study Calendar 
Parameter 
Pre-
Study 
Entry 
Weekly 
during 
RT 
Within 1 
week 
prior to 
or after 
finish of 
RT 
Semiannually 
post-RT  
(until year 5) 
H&P 
x 
  
  
  
PSA 
x 
  
x 
x 
Quality of life assessment [a] 
x 
  
  
x[b] 
Toxicity assessment using NCI CTC v 4 
  
x 
  
x[b] 
a. IPSS, EPIC sexual, EPIC bowel  
b. Until 3 years then annually until year 5 
 
6.2 Follow-Up Schedule 
6.2.1 
 
Patients will be assessed for Quality of life and Toxicity every 6 
months (+/- 30 days) until 3 years following completion of radiotherapy, 
then annually (+/- 30 days) until year 5.  PSA measurements will be 
obtained every 6 months until year 5.  The patient will be off study after 5 
years.  
6.2.2 

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Patients who develop a rise in PSA compared to the prior PSA will 
have PSA drawn every 3 months until PSA either declines, or rises to a 
value 2 ng/ml or more above the nadir.  The nadir PSA is defined as the 
lowest PSA value after initiation of treatment.  Time of failure will be the 
date of the first PSA that is 2 ng/ml or more above the nadir.   
6.2.3 
 
At 2 years post-radiation, patients will be encouraged but not 
required to undergo biopsy for histopathologic assessment of disease 
response. 
 
7.0 
Data Analysis and Statistical Considerations  
7.1 Primary Objective 
7.1.1  
 
Assess the incidence of grade 2 and 3 or greater late GU and GI 
toxicity and self-reported quality of life data with hypofractionated image-
guided radiation.  Assessment will be performed at median 4 years and 
again once all patients reach 5 years of follow-up (except for run-in safety 
phase). 
7.2 Secondary Objectives 
7.2.1 
 
Assess biochemical and clinical control rates associated with the 
hypofractionated dose.  Assessment will be performed at median 4 years 
and again once all patients reach 5 years of follow-up. 
7.1.1.1 
 
Freedom from Biochemical (PSA) Failure: Measured from 
the date of enrollment to the date of a rise by 2 ng/ml or more above 
the nadir PSA.   
7.1.1.2 
 
Clinical Disease-Free Survival, measured from the date of 
enrollment to the date of documented radiographic, clinical evident 
progression or date of death. Progression may be documented by 
imaging studies such as CT or bone scan, or biopsies.   Patients with 
new palpable abnormality on digital rectal examination will also be 
offered biopsy to confirm local failure.   
7.2.2 
 
Collect dose/volume and imaging data to allow normal tissue 
complication probability modeling and targeting assessment for patients 
treated with hypofractionated radiation therapy. 
 
7.3 Sample Size 
7.3.1 Primary Endpoints 
 
The primary goal of the study is to estimate the risk of late grade 2 
and 3 or greater GU or GI toxicity.  The expected rate of grade 3 or greater 
toxicity is 5% for GI + GU. A sample size of 108 patients will allow a Grade 
3+ toxicity estimate of +/- 4.5% if observed toxicity is 5%, and +/- 6.2% if 
observed rate is 10%, respectively. 
 
7.3.2 Secondary Endpoints 

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We seek to estimate the risk of biochemical (PSA) control at 5 years 
with a confidence interval of +/- 10%.  For conventionally fractionated 
high-dose regimens, the expected rate of control is 93% and 85% for low 
and intermediate risk groups, respectively.25  In order to test the null 
hypothesis that the proportion of patients in our cohort who maintain 
biochemical control at 5 years is less than or equal to 75%, a sample size of 
108 patients will be required.  This sample size was determined using the 
Type I error rate of 0.05 and Type II error rate of 0.2. 
The time of failure for the PSA control endpoints will be measured from the 
date of completion of radiation to the date of documentation of the event of 
interest.   In the presence of multiple endpoints of failure, the time to the 
first failure of any type would be the most clinically relevant endpoint to 
the treatment outcome and the first failure will affect subsequent endpoints. 
Therefore, if a patient experiences a competing event prior to the event of 
interest, the patient will be censored at the date of first occurrence of the 
competing event. The survival function of these endpoints will be estimated 
using the Kaplan-Meier method.  
 
 
7.3.3 Accrual and Study Duration 
 
Of approximately 66 patients per month seen in consultation for 
prostate cancer in the department of radiation oncology, we anticipate 
approximately 25% of patients to be eligible.  All eligible patients will be 
offered enrollment on the study, and we estimate a 35% accrual rate with 
5% dropout rate, resulting in an average of 5 patients enrolled per month. If 
these projections are correct, it should take 20 months for full patient accrual 
of 108.  The study resumption date was August 2011, with a projected 
closure date of November 2015. (adjusted October 2013) 
7.3.4 Incidence of Adverse Events 
 
Time to adverse events will be measured from the time that protocol 
treatment started (i.e., the start of RT) to the time of the worst severity of 
the adverse event. Adverse events are scored according to the NCI CTCAE 
v4.0 criteria.26 
7.3.5 Safety Run-In 
 
See section 2.1 
8.0 
REPORTING OF SERIOUS OR UNEXPECTED ADVERSE EVENTS
 
8.1 The following guidelines will be followed for reporting serious or unexpected 
 
adverse events. 
8.1.1 
All  fatal events, both anticipated and unanticipated, must be reported to 
the JHM IRB within a time period as specified by current institutional 
guidelines after the PI learns of the event, whether or not the PI believes the 
event to be related to the study.  All other events, which are both serious 
and unanticipated, must be reported to the JHMI IRB within a time period 
as specified by current institutional guidelines after the PI learns of the 
event.  Events which are serious but anticipated, should be reported as part 
of the continuing review application.  If any of these Serious Adverse 

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Events requires a change to the protocol or consent form, the PI must make 
those changes promptly and submit the revised documents to the JHM IRB.  
8.1.2 
Important Adverse Events that are unanticipated must be reported to the 
JHM IRB within a time period as specified by current institutional 
guidelines.  If the Important Adverse Event requires changes to the protocol 
or consent form, the PI must make those changes promptly and submit the 
revised documents to the JHM IRB. 
8.1.3 
All other unanticipated Adverse Events or changes to the protocol and 
consent form must be reported to the JHM IRB, within a time period as 
specified by current institutional guidelines. 
 
8.2 Definitions 
Serious Adverse Event: an event that is  
• 
Fatal  
• 
Life-threatening   
• 
Persistent or significantly disabling or incapacitating  
• 
Inpatient hospitalization or prolongation of hospitalization  
• 
Congenital anomaly or defect and/or  
• 
A significant medical incident (considered to be a serious study related 
event because, based upon appropriate medical judgment, it may jeopardize 
the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.) 
Important Adverse Event: means an event, although not a Serious Adverse Event, 
which still presents an undesirable occurrence that interferes with the subject’s 
usual activities and may be persistent or require treatment.  (For example, serious 
rash, cough, or fever.) 
Unanticipated Adverse Event: means an event that results from a study intervention 
and was not expected or anticipated from prior experience.  This includes expected 
events that occur with greater frequency or severity than predicted from prior 
experience. 
 
8.3 Following a Study Related Adverse Event 
 
If a patient experiences an adverse event while on study, the following steps 
will be taken: 
1) Establish the cause and severity of the adverse event and determine if said 
event is related to study participation.  
2) Principal Investigator will decide what treatment(s), if any, is/are required. 
3) Depending on the type and severity of adverse event, an appropriate follow-
up schedule will be constructed which will allow for determination of event 
outcome. 
4) Patient will be followed by principal investigator until the adverse event has 
resolved.   
 
9.0 
DISPOSITION OF DATA 
 
Clinical records for all subjects studied including history and physical findings, 
laboratory and clinical data, and operative and dosimetric records are to be maintained by 

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the investigators in a secure location at Johns Hopkins Cancer Center.  Any records that 
are stored electronically will be password protected and only those who are involved in the 
research will have a password.  These records are to be stored for a minimum of 8 years 
after last clinical visit. 
 
10.0 
PROTOCOL MODIFICATIONS 
 
All revisions or amendments (that are not required for immediate patient safety) to 
the protocol must be approved by the Johns Hopkins Institutional Review Board prior to 
implementation.  
 
11.0 
DEPARTURES FROM PROTOCOL 
 
If there is a departure from the Clinical Protocol, the Principal Investigator will 
notify in writing both the local IRB at Johns Hopkins and the HSRRB at the time of annual 
review (continuing review).  The research coordinator will keep a log of all 
deviations/departures that occur on this project and this log will be reviewed by the 
research team on a monthly basis.  During the review the research team will discuss 
corrective action plans to minimize future deviations/departures.  If there are departures to 
the protocol that effects patient safety the principal investigator will notify in writing the 
IRB within 24 hours of discovering the departure/deviation.       
 
12.0  CRITERIA FOR WITHDRAWAL FROM STUDY 
 
Patients may be withdrawn from the study for the following reasons: 
a) Consent for participation is withdrawn 
b) Noncompliance to study procedures 
 
13.0  ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL 
 
Principal Investigator: 
 
Oversees all aspects of the trial.  Recruits and consents patients and administrates 
protocol specific procedures. Provides medical care to research subjects during the conduct 
of the study.   Follows and advises regarding the treatment of adverse events.  Reports 
SAE's to the IRB within the required time frame.  Amends the trial as necessary to reflect 
unforeseen adverse events, new scientific data and for the general intergrity of the study. 
Monitors the trial.  Is ultimately responsible for the conduct of protocol. 
 
Co-Investigators: 
 
If a physician: can recruit and consent patients and can administrate protocol 
specific procedures.  Can provide medical care to research subjects during the conduct of 
the study.  Has input on the course of action for adverse events.   
If not a physician: Collaborates with the Principal Investigator according to area of 
expertise.  
 
Research Nurses: 
 
Executes protocol specific procedures requiring nursing qualifications.  Provide 
nursing care to research subjects during the conduct of the study.  May consent patients for 
study enrollment. 
 
Data Manager/Study Coordinator: 
 
Collects data from subject's medical records and codes it onto the study's case report 
forms. Notifies principal investigator of any deviations that he/she finds while managing 

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the data.  Prepares annual IRB renewals and termination report upon study completion, 
assists with management of regulatory issues governing the trial.  Monitors the trial. 
 
14.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 
 
 
 
IRB: Prior to initiating the study, the Principal Investigator must obtain 
written approval to conduct the study from the appropriate IRB.  Should changes 
to the study protocol become necessary, protocol amendment will be submitted in 
writing to the IRB by the Principal Investigator for IRB approval prior to 
implementation. 
14.2 
         Informed Consent: All potential candidates for the study will be given a copy 
to read of the Informed Consent for the study.  The investigator will explain all 
aspects of the study in lay language and answer all the candidate’s questions 
regarding the study.  If the candidate desires to participate in the study, he/she will 
be asked to sign the Informed Consent.  No study procedures will be performed on 
a patient until after they have signed the informed consent document.  Subjects who 
refuse to participate or who withdraw from the study will be treated without 
prejudice. 
14.3 
         The principal investigator will ensure that the study is conducted in 
compliance with the protocol and according ICH Guidelines for Good Clinical 
Practices, the Declaration of Helsinki, and all regulatory and institutional 
requirements, including those for patient privacy, informed consent, Institutional 
Review Board approval and record retention. 
 
15.0 
DATA SAFETY AND MONITORING PLAN 
 
Following completion of the run-in phase of the trial (total 15 patients), the 
independent medical monitor (Dr. Richard Zellars) and study coordinator will review the 
data on a quarterly basis. The purpose will be to review the level of adverse events, given 
that the adverse events may occur on a delayed basis after treatment completion.  The 
independent medical monitor may elect at his/her discretion to notify IRB and CRC and/or 
halt protocol accrual if in his/her estimation there is appears to be an unacceptably high 
rate of toxicity in the study subjects. In addition, this trial will be audited annually by the 
central clinical research office at Johns Hopkins as well as the IRB. 
 
16.0 
LIST OF DATA COLLECTION SHEETS 
IPSS 
Sexual Health Inventory for Men 
EPIC Bowel 
 
 
 

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17
17.0 
REFERENCES 
 
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26 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf