A Phase I Study of Image Guided Dose Escalation With Intensity Modulated Radiation Therapy (IMRT) to Histologically Confirmed Regions of Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Phase I IMRT Prostate Ca
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Version Date: 03/31/2015
NCI Protocol #:05-C-0191H
A Phase I Study of Image Guided Dose Escalation with Intensity Modulated 
Radiation Therapy (IMRT)
to Histologically Confirmed Regions of Prostate Cancer 
Principal Investigator:
Aradhana Kaushal, M.D.1
Study Chairperson:
Peter Pinto, MD2
Associate Investigators:
Kevin Camphausen, M.D.1
Theresa Cooley- Zgela, RN4
Peter Choyke, M.D.3
Referral Contact:
Theresa Cooley- Zgela, RN4
1Radiation Oncology Branch, CCR, NCI
Bldg 10/ Rm B2/3500
10 Center Drive
Bethesda, MD 20892
Phone (301)496-5457
Fax: (301)480-5439
2Urologic Oncology Branch, CCR, NCI
3Molecular Imaging Program, NCI
4 Office of the Clinical Director, NCI

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PRECIS 
BACKGROUND
x
This study represents a progression from findings in four previous NCI 
ROB protocols (02-C-0167A, 02-C-0207E, 03-C-0190B, 04-C-0171). In 
these previous works we have begun to develop techniques to obtain MR 
biological images and co-register tissue in prostate cancer patients.  
OBJECTIVES
x
The scientific objective of this protocol is to determine the maximum 
tolerated dose (MTD) of external beam radiation to regions of interest 
within the prostate based acute toxicity.
x
Secondary objectives of this study are to relate patterns in gene and 
protein expression to response and toxicity and to evaluate the frequency 
of late term toxicity.
ELIGIBILITY
x
Patients with prostate cancer without evidence of metastasis will be 
eligible for this study. 
DESIGN
x
This phase I trial will use intensity modulated radiation therapy (IMRT) to 
deliver escalating doses of external beam radiation to regions of 
histologically confirmed prostate cancer. The study will be conducted 
using a standard 3-6 dose-escalation with an initial 3 patients in each dose 
cohort and the potential expansion of the cohort to 6 patients.
x
Anatomic MRI and MR biological images, such as MRS, will be obtained 
Tissue will be acquired from sites of interest, with biopsy locations 
precisely translated (co-registered) to an MR image of reference. Tissue 
samples will be processed for cDNA microarray testing and stored for 
future analysis in the Radiation Oncology Branch, NCI.   A gold seed will 
be left at the biopsy site as a fiducial marker to direct future radiation 
therapy. If necessary, additional fiducial markers will be placed for target 
localization during treatment.
x
Once MR guided biopsies are obtained and fiducial markers placed, the 
patient will undergo a standard CT simulation for radiation therapy 
treatment planning. The MR and CT images will be fused. Areas of 
pathologically confirmed malignancy will undergo dose escalation as 
described above. Areas of image abnormality that could not be biopsied or 
were without definite pathologic evidence of malignancy will be given 
intermediate doses. The remainder of the prostate gland will receive 
standard dose (7560 cGy.)[1, 2]
x
The trial will accrue 18 to 36 patients with an anticipated accrual period of 
2 years.

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SCHEMA
Pathologic Diagnosis of Prostate Cancer
REGISTER:
Those who require radiation therapy to the prostate gland alone.
Perform MRI guided biopsies of areas suspicious for cancer. Leave fiducial markers at these locations.
INELIGIBLE
Patients who require whole 
pelvis radiation therapy.
Treatment 
x
The MRI scan of the prostate will be registered to the treatment planning CT scan. 
x
The prostate and a 3 mm margin will be treated to 7560 cGy in 42 fractions (180 cGy daily).
o
Less than 25% of the rectal volume will receive 70 Gy.
o
We will endeavor to limit the maximum dose prostatic urethra, rectum, and bladder to 78 Gy.
x
The MRI defined volumes within the prostate will also be treated in 42 fractions. Dose escalation will be 
achieved by selectively increasing the daily dose to these volumes. 
x
The tissue containing fiducial markers placed in regions of pathologically confirmed cancer and areas of 
image abnormality will be boosted as described by dose level. 
x
The maximum dose 7 mm or more beyond the prostate will be no more than 100% of the prescription 
dose of 7560 cGy.
x
There will be daily localization of the prostate and fiducial markers using portal imaging.
Follow Up:
x
Toxicity
x
MRI to evaluate for changes in imaging.
x
Genomic and proteomic study of biopsied tissue

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Table of Contents
1. Introduction
1.1 Study Objectives…………………………………………………
5
1.2 Background and Rationale……………………………………...
5
2. Eligibility Assessment and Enrollment………………………………….
13
2.1 Eligibility Criteria…………………………………………………
13
2.2  Eligibility Evaluation……………………………………………
14
2.3  Patient Registration……………………………………………..
14
3. Study Implementation…………………………………………………….
14
3.1 Study design……………………………………………………...
14
3.2 Protocol Administration………………………………………….
16
3.2.1
MR imaging guidelines………………………………….
16
3.2.2  Tissue collection…………………………………………
17
3.2.3 Radiation Therapy………………………………………….
19
3.3 Treatment modifications…………………………………………
21
3.4 On-Study Evaluation…………………………………………….
21
3.5 Concurrent Therapies……………………………………………
22
3.6 Surgical guidelines ……………………………………………..
22
3.7 Radiation therapy guidelines ………………………………
22
3.8 Off study criteria…………………………………………………
22
3.9 Post-study evaluation…………………………………………...
22
4. Supportive Care…………………………………………………………..
23
5. Data Collection and Evaluation………………………………………….
23
6. Human Subjects Protection……………………………………………..
25
6.1 Rationale for subject selection…………………………………
25
6.2 Participation of children…………………………………………
26
6.3 Evaluation of Risks/Discomforts……………………………….
26
6.4 Risk/Benefit Analysis……………………………………………
26
6.5 Consent and assent processes and documents……………..
27
7. Data Reporting……………………………………………………………
27
7.1 Patient Registration ……………………………………………
27
7.2 Data Submission……………………………………………….
27
7.3 Definitions………………………………………
7.4 NCI-IRB Reporting…………………………………………….
31
8. Pharmaceutical Information…………………………………………….. 
31
9. References……………………………………………………………….. 
34
10. Appendices
I. Partin tables 
IIA RTOG Acute GI/ GU Toxicity
IIB RTOG Late GI/ GU Toxicity
IIC EPIC
III. MRI- Guided Biopsy Procedure Data Form
IV. AUA Symptom Score 
V. Sexual Health Inventory for Men (SHIM)

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1.0   INTRODUCTION
1.1 STUDY OBJECTIVES
1.1.1Primary:
To determine the maximum tolerated dose (MTD) of external beam 
radiation to regions of interest within the prostate based on MRI. 
1.1.2 Secondary:
1.1.2.1 To correlate radiation response and/or toxicity with genomic 
and proteomic analyses.
1.1.2.2 To evaluate long-term effects and toxicity following selective 
intra-prostatic dose escalation. 
1.2 BACKGROUND AND RATIONALE
1.2.1 Intensity modulated radiation therapy (IMRT)
Several studies have established that escalating doses of external beam 
radiation therapy improves biochemical disease free survival in prostate 
cancer. These gains in biochemical disease free survival, however, come with 
the potential risks of long-term toxicity with dose escalation.
Intensity modulated radiation therapy (IMRT) is a newer form of radiation 
dose delivery that allows for delivery of high doses of radiation with rapid drop 
off of dose beyond the target. This combination of factors allows targeted 
dose escalation while decreasing or maintaining the amount of dose to a 
given volume of normal tissue. 
In IMRT the physician defines the target volume as well as the dose 
constraints on normal tissue. The treatment planning computer then does 
“inverse planning” to generate an acceptable plan that meets the target 
coverage and normal tissue dose constraints. If the physician remains 
unsatisfied with the plan, the priorities of tumor coverage and normal tissue 
limits can be adjusted and the plan re-generated.
Each IMRT system’s inverse planning algorithm is proprietary. In broad terms, 
however, the planning system simply attempts thousands of different plans 
until an acceptable one is found to present to the physician.
A consequence of this method is that IMRT systems produce plans with 
doses far in excess of the prescribed dose. These regions are known as “hot 
spots.” Randomly place hot spots of 20% within the target volume are 
common. Nevertheless, excellent clinical results have been obtained with this 
system.
Evolving research initiatives in the Radiation Oncology Branch (ROB) and the 
Radiation Oncology Sciences Program (ROSP), NCI, depend upon the 

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availability of tissue samples from patients receiving radiotherapy.  The tissue 
acquired in this preliminary effort is critical to the expansion of our knowledge 
of radiation induced gene and protein expression profiles, and will potentially 
generate novel hypotheses for molecular therapeutic strategies.  
1.2.2 Dose Escalation In Prostate Cancer
In a study of 301 patients, Pollack et al demonstrated that doses of 7800 
versus 7000 cGy produced significantly improved failure free survival in 
intermediate to high risk patients (70 versus 64%, p=0.03).[2]
Zeitman et al have recently reported on a trial comparing 7920 versus 7020 
cGy (actually cobalt Gray Equivalent dose) in patients with prostate cancer 
treated with a proton boost. The five-year biochemical failure rates were 
37.3% for the conventional dose group and 19.1% for the high dose group 
(p=0.00001).[3]
Increased toxicity accompanied dose escalation in Pollack’s experience. This 
toxicity was reduced if less than 25% of the rectal volume was irradiated to 
7000 cGy.[2]
Understanding the need to dose escalate while minimizing the amount of 
normal tissue irradiated, several investigators have explored dose escalation 
with IMRT.[4]
IMRT has been used by Zelefsky et al to dose escalate to doses of 86.4Gy to 
the entire prostate gland. In their experience with 772 patients and a median 
follow-up of 24 months, less than 5% developed acute Grade 2 rectal toxicity. 
Only one experienced urinary retention (Grade 3). Eleven patients (1.5%) 
developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced 
Grade 3 rectal toxicity requiring either one or more transfusions or a laser 
cauterization procedure. The 3-year actuarial PSA relapse-free survival rates 
for favorable, intermediate, and unfavorable risk group patients were 92%, 
86%, and 81%, respectively. IMRT has become the standard mode of 
conformal treatment delivery for localized prostate cancer at Memorial Sloan 
Kettering.[5]
1.2.3 Fraction Size and Dose-Volume Limits In Prostate Cancer
Based on laboratory research in classical radiation and the results of clinical 
trials, Fowler et al have proposed that using larger doses of radiation with 
each fraction may produce greater local control in prostate cancer. They 
actually suggest that this use of larger fraction size without dose reduction 
may be possible without increased late toxicity. [6, 7]
However, this theoretical work is belied by the results of RTOG study 9406. 
Results of this study demonstrate that doses of 7400 cGy in 200cGy daily 

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fractions produce less than 5% grade 3 acute toxicity and 2% late grade 3 
toxicity. Late toxicities were halved when 180 cGy daily fractions were 
used.[1]
In the current study, it may be possible to have the best of both worlds. IMRT 
treatment as proposed should allow the benefits of hypofractionation while 
maintaining the lower risk of late toxicities by ensuring that normal tissues 
continue to be treated at 180 cGy per day.
Patient-based self-assessment questionnaires provide valuable toxicity 
endpoints.  The Expanded Prostate Cancer Index Composite (EPIC) is a 
robust prostate cancer health related quality of life instrument that measures 
a broad spectrum of bowel symptoms, and has been validated inpatients 
receiving radiotherapy. 28. The American Urological Association (AUA) 
Symptom Score and The Sexual Health Inventory for Men (SHIM) 
questionnaires address the significant quality of life issues of urinary 
functioning and erectile dysfunction respectively.
On the present study, no volume 4 mm beyond PTV1 will be allowed to 
receive a dose beyond 100% of the prescription dose. This 100% at 4 mm 
dose constraint is derived from the RTOG 9406 experience. That study of 
three dimensional conformal therapy mandated 5 to 10 mm uniform margins 
on the prostate. Commonly, 7 mm margins were used. Consequently 
maintaining a dose of no more than 100% at a distance of 4 mm from PTV1 
(which is 3 mm from the prostate) should be very well tolerated.
PTV2 will be defined as regions of signal abnormality (plus a 2 mm margin) 
on MRI that do not have a pathologic confirmation of disease. Dose will be 
escalated by protocol (see section 3.1.2).
PTV3 will be defined as regions of signal abnormality (plus a 2 mm margin) 
on MRI that have pathologic confirmation of disease. Dose will be determined 
by protocol. If the patient previously had at least a sextant biopsy with 
documentation of the location of the positive cores, this information may be 
used to define a PTV3.The maximum protocol dose to PTV3 on this study is 
approximately 150 Gy. This is similar to the prescription dose of 145 Gy used 
with low dose rate (LDR) iodine 125 (I125) brachytherapy. LDR brachytherapy 
has been widely utilized to treat low risk prostate cancer with acute and late 
morbidity broadly comparable to external beam radiation therapy. 
While the prescription dose of 145 Gy covers the prostate in brachytherapy, 
doses near each I125 seed are necessarily far higher. Consequently, it 
appears that small volumes of prostate can tolerate doses far in excess of 
145 Gy without excessive toxicity. 

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Certainly, between brachytherapy and external beam irradiation there are 
major differences in dose deposited per unit time and total treatment time. 
These differences make direct dose comparisons difficult. Nonetheless, the 
experience with brachytherapy does provide a reasonable ceiling in the 
current dose escalation study. 
Furthermore, brachytherapy has demonstrated that urethral toxicity may 
occur with higher doses to the urethra.[8] For this reason, doses to the 
prostatic urethra, as defined by the attending physician, will be limited to 78 
Gy (approximately the maximum dose allowed in the Pollack and RTOG 9406 
experience).
As per the Pollack experience, less than 25% of the rectal volume will be 
irradiated to 7000 cGy.[2] Maximum dose to the bladder and rectum will be 
limited to 7800 cGy.
1.2.4 MRI and the Detection of Prostate Cancer
At present there are no imaging techniques that can accurately delineate 
tumors within the prostate gland.  Transrectal ultrasound, although in wide 
use for guiding biopsies, is not sensitive for the detection of prostate cancer 
despite the advent of color Doppler and ultrasound contrast agents.[9, 10]
Computed tomography is also insensitive for localized prostate cancer.[11]
PET scanning with Fluorodeoxyglucose (FDG) is limited by artifacts related to 
the urinary bladder and by relatively low avidity of FDG for prostate 
cancer.[12, 13]
While other PET agents are under investigation, none has 
yet emerged as clearly superior to any other.[14]
MRI offers a 3D dataset, multiple imaging planes, and unparalleled soft tissue 
resolution, making it the modality of choice for imaging the prostate gland.  
MRI has been shown to provide better visualization of the prostate and 
surrounding structures than either ultrasound or CT.[15] T2-weighted scans 
depict the normal peripheral zone as high in signal and tumors are depicted 
as relatively low in signal, a characteristic appearance that can detect 60 to 
80% of prostate cancers, but that is limited by non-specificity, with prostatitis 
and hyperplasia mimicking tumor. Evidence of extraprostatic spread of tumor 
includes hypointense stranding in the periprostatic fat, obliteration of the 
rectoprostatic angle, or clear-cut extracapsular extension. Staging accuracies 
of extracapsular extension for high field strength MR images are as high as 
82% to 88% in single institutional series.[16-18]
In patients with known prostate cancer, based on our experience with ongoing 
protocol NCI #02-C-0207E, we have been able to identify and biopsy regions 
of signal abnormality by MRI. In 50% of patients these biopsies have yielded 
specimens containing prostate cancer.

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This yield, while impressive for an experimental system in the early stages of 
clinical development, is suboptimal. During the course of this protocol, in 
addition to standard MR imaging sequences, we will continue to obtain and 
experiment with novel MR sequences to give better delineation of prostate 
cancer. Target volumes, however, will be defined by pathologic correlation 
with imaging as described above.
1.2.5 The ‘APT-MRI’ system
In collaboration with Department of Biomedical Engineering at Johns Hopkins 
we have developed a system that provides transrectal needle access to the 
prostate while a patient is imaged inside of a ‘closed’ scanner.  This system, 
called the APT-MRI system (Access to Prostate Tissue under MRI-guidance), 
will be utilized in this study to acquire needle biopsy tissue in accurate 
reference to DCE-MRI images.
The method is very similar to transrectal ultrasound guided biopsy of the 
prostate, except that it is applicable within a closed high-field MRI scanner.  In 
canine studies, accurate needle placement in a variety of clinical applications 
(e.g. biopsy, injections, and seed placement) were demonstrated.[19] This 
system was adapted to clinical use and investigated for feasibility, tolerability, 
and needle targeting accuracy under protocols 03-C-0190 and 02-C-0167.
Clinical results to date show that the APT-MRI system is safe, well tolerated, 
and can target prostatic sites with millimeter accuracy.[20] We used the ‘APT-
MRI’ system to place gold fiducial markers within the prostate gland in 
patients with localized prostate cancer in order to assess not only needle 
placement accuracy, but also the accuracy with which the tissue itself was 
targeted (i.e. leaving a permanent marker allows for measurement of the 
impact of tissue deformation, produced during needle insertion, on targeting 
accuracy).  Subsequently, the system was also used for four 1.5T MRI-guided 
prostate biopsy procedures in three patients.  
The mean MR procedure duration was 72 minutes and was well tolerated. 
Using axial MR images, needle and marker placement errors were assessed 
(see figures 1& 2). The mean needle placement accuracy was 1.9 mm for the 
fiducial marker placement studies and 1.8 mm for the biopsy procedures.  
The mean fiducial marker placement accuracy was 4.8 mm and the mean 
transverse fiducial marker placement accuracy was 2.6 mm. The gold fiducial 
markers were subsequently used to assess daily setup errors and off-line 
organ motion during a standard course of external beam radiation therapy for 
prostate cancer.

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Figure 1: Targeting, needle, and fiducial-marker visualization images.  Images 
from two patients (Rows A and B, respectively), show images acquired during 
the fiducial-marker placement procedure.  Column 1: Targets are selected on 
axial, T2-weighted fast spin-echo images.  The site pre-selected for targeting is 
represented by a white dot in all images. Column 2: The needle tip void is 
visualized in axial, T1-weighted fast spin-echo images.  Column 3: The marker 
void is visualized on axial, T2*-weighted gradient-echo images.  Note that there 
is minimal tissue motion throughout each procedure.
Target location
Needle inserted Marker deposited
A
B
Target
Target
Needle void
Needle void
Marker void
Marker void

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Figure 2: Needle and fiducial-marker placement accuracy.  Error histograms 
show needle tip location errors (Panel A), fiducial marker location errors (Panel 
B), and fiducial marker in-plane location errors (Panel C) for all 16 gold fiducial 
markers placed.  Mean placement errors for each are 1.9 mm, 4.8 mm, and 2.6 
mm, respectively.  Because tissue core biopsies are typically 1.5 cm long, the 
last measure, fiducial marker in-plane placement error, is the best predictor of 
tissue acquisition accuracy. 
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Fiducial marker location error / 
Count
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Marker in-plane location error / 
Count
A
B
C
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0
1
2
3
4
Needle location error / (mm)
Count

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Figure 3:  A case example whereby T2W FSE images (2C) shows a 
suspicious lesions in the peripheral zone which was targeted for biopsy 
(red dot).  Dynamic contrast MRI color-coded for contrast kinetics (2D) 
shows normal activity in the central gland and neurovascular bundles, and 
activity suspicious of malignancy in the peripheral zone (arrow) 
corresponding to the targeted site.  The biopsy needle can be visualized 
on axial images (2E - signal void) prior to tissue acquisition in close 
proximity to the intended target (red dot). 
1.2.6   Fiducial Markers
Using MRI for anatomic guidance and visualization, between 2 and 6 gold 
fiducial markers will be placed within the prostate of patients with cancer prior 
to external beam radiotherapy.  Our experience with ongoing protocol 03-C-
0190C has demonstrated that these fiducial markers can be accurately 
placed using MRI guidance (see figure 3).  
While placement of the gold markers has no direct therapeutic benefit for the 
patient per se, intraprostatic fiducial markers (placed under ultrasound) have 
shown value in assessing daily setup errors and off-line organ motion during 
external beam radiation therapy for prostate cancer.[21-23] These markers 
can also be utilized to aid in CT-MRI fusion[24] and result in better target 
delineation for treatment planning as well as daily localization.
IMRT with its very tight margins is at high risk of missing tumor beam as a 
result of organ motion and inaccurate patient positioning.  Current measures, 
such as patient immobilization devices and laser-tattoo alignments, do not 
address prostatic motion relative to bony landmarks.  Variations in bladder 
and rectal filling have been shown to affect prostate position within the pelvis, 
to an extent which may require field adjustments during the course of 
radiotherapy.[25] Since the rectum tends to become progressively less 
distended during a course of pelvic radiotherapy (mean decrease in diameter 
1.5cm), the predominant prostatic motion is in the posterior and inferior 
direction.  In one study 11% of patients showed an inferior shift of the prostate 
of more than 1cm and 30% showed a posterior shift of more than 1cm.[22]

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Portal x-ray imaging is a technique used to monitor the accuracy of beam 
isocenter positioning relative to bony landmarks during radiotherapy.  Since 
the prostate is not visible on portal imaging, radiopaque fiducial markers are 
surrogates for organ localization in portal images.[26] Studies show that the 
degree of possible migration of the fiducial markers is negligible and within 
the limits of accuracy of CT measurements (2mm).[27]
As prostate motion is the major source of error in radiation treatment 
delivery[21], some investigators have recommended that radio-opaque 
markers be placed in the prostate prior to the start of radiotherapy.
1.2.7 Genomic Analysis
Serum and tissue will be stored in the Radiation Oncology branch. Future 
genomic and proteomic analysis may be performed as in 3.2.3.
2.0  Eligibility Assessment and Enrollment
2.1  ELIGIBILITY CRITERIA
2.1.1 Inclusion Criteria
2.1.1.1
ECOG performance status of 0,1, or 2
2.1.1.2
Pathology report confirming adenocarcinoma of the prostate
2.1.1.3
Risk of lymph node metastasis less than 10% as defined by the 
Partin tables (see appendix I)
2.1.1.4
Tumor visible on MRI
2.1.1.5
No prior surgery, radiation, or chemotherapy for prostate 
cancer. 
2.1.1.6
Age greater than 18 y/o and less than 90 years old.
2.1.2  Exclusion Criteria
2.1.2.1 Cognitively impaired patients who cannot give informed consent. 
2.1.2.2 Patients with metastatic disease.
2.1.2.3 Contraindication to biopsy

Bleeding disorder

PT/PTT t 1.5 times the upper limit of normal

Platelets d 50K

Artificial heart valve
2.1.2.4 Contraindication to MRI
x
Patients weighing >136 kgs (weight limit for the scanner tables)
x
Allergy to MR contrast agent
x
Patients with pacemakers, cerebral aneurysm clips, shrapnel 
injury or implantable electronic devices.
2.1.2.5 Pre-existing and active prostatitis or proctitis.

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2.1.2.6 Other medical conditions deemed by the PI or associates to make 
the patient ineligible for protocol investigations, procedures, and high-dose 
external beam radiotherapy.
2.2  PRE-TREATMENT RESEARCH ELIGIBILITY EVALUATION
2.2.1 Clinical Evaluation 

History and Physical Examination.

Pathology report confirming adenocarcinoma of the prostate 
(outside report acceptable for study entry; pathology review by 
NIH to be done prior to treatment initiation).
2.2.2 Laboratory Evaluation
x
PSA
x
PT/PTT
x
CBC
2.3   PATIENT REGISTRATION
Authorized staff must register with the Central Registrar’s Office an eligible 
candidate within 24 hours of signing the consent. A registration checklist from the 
Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and 
faxed to the Central Registrar’s Office at 301-480-0757. Verification of 
Registration will be forwarded electronically via e-mail to the research team. A 
recorder is available during non-working hours. 
3.0  STUDY IMPLEMENTATION
3.1   STUDY DESIGN
3.1.1 Overall Trial Design
Patients with prostate cancer who have no evidence of metastasis will be 
eligible for this study. This phase I trial will use intensity modulated radiation 
therapy (IMRT) to deliver escalating doses of external beam radiation therapy 
to regions of histologically confirmed prostate cancer while regions of signal 
abnormality on MR imaging without pathologic confirmation will receive 
intermediate doses.
Anatomic MRI and MR biological images will be obtained Tissue will be 
acquired from sites of interest, with biopsy locations precisely translated (co-
registered) to an MR image of reference.  A fiducial marker (gold seed) will be 
left at the biopsy site as a fiducial marker to direct future radiation therapy. 
The patient will undergo a standard CT simulation for radiation therapy 
treatment planning. The MR and CT images will be fused. Areas of 
pathologically confirmed malignancy will undergo dose escalation as 

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described below. Areas of image abnormality that could not be biopsied or 
were without definite pathologic evidence of malignancy will be given 
intermediate doses. The remainder of the prostate gland will receive standard 
dose (as per the Radiation Therapy Oncology Group (RTOG) 9406 study) 
7560 cGy in 180 cGy daily fractions.[1] Treatments will occur at the NCI, 
Department of Radiation Oncology on weekdays. There will be no treatments 
on weekends or holidays. 
3.1.2 Dose Escalation
The primary objective of this study to determine the MTD of radiation to 
regions of interest (as determined by MRI and pathology) within the prostate 
gland. 
As random “hot spots” of radiation are not uncommon with IMRT (see 1.2.1), 
we will begin at a very conservative dose of 125% and escalate as follows in 
cohorts of 3 patients each.
*The reference dose for calculation of these percents is 7560 cGy
3.1.3 Criteria for Dose Escalation
Each dose cohort will accrue 3 patients.  If there are no DLT in 3 patients then 
patients will be accrued to the next dose level. If two or more patients experience 
a DLT then the MTD will be exceeded and the prior lower dose cohort will be 
considered the MTD.  If a DLT occurs in one of three patients then an additional 
3 patients will be accrued to that dose level. If fewer than 2 of 6 patients 
experience an acute DLT in the expanded cohort then patients will be accrued to 
the next dose cohort. If 2 or more of 6 patients experience a DLT then the MTD 
will be exceeded and the prior, lower dose cohort will be considered the MTD. 
For the purposes of dose escalation, DLT will be evaluated at 12 weeks after 
completion of radiation therapy.  The course of radiation therapy lasts 7 to 8 
weeks or 42 fractions 5 days per week. For patients in the next (higher) dose 
cohort, escalation of the total dose will not occur until after fraction 34 of the 
Cohort
Prescription 
Dose to Areas of 
Path Confirmed 
Tumor*
Prescription 
Dose to Areas of
Image 
Abnormality 
Only*
Max Dose 
Allowed Beyond 
PTV1 + 4mm*
I
125%
115%
100% 
II
138%
125%
100%
III
150%
138%
100%
IV
165%
150%
100%
V
180%
165%
100%
VI
200%
180%
100%

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radiation. Therefore, we will allow the accrual of up to 3 patients in the next dose 
cohort into the study before currently enrolled patients have reached the 12 week 
endpoint.  This will be allowed as long patients at the current dose cohort have 
been followed for a minimum of 7 weeks. 
3.1.4 Definition of Dose Limiting Toxicity (DLT)
An acute   DLT will be defined as RTOG grade 3 or greater, acute GI or GU 
toxicity (see appendix IIA) within 3 months after the completion of radiation. 
Thus, accrual to an escalated dose cohort may need to be delayed so that all 3 
patients in the current cohort are followed for 2 months. Given that the volume of 
normal tissue irradiated to standard dose or higher will be substantially limited, 
late toxicity is less of a concern than acute toxicity. 
3.1.5 Definition of Maximum Tolerated Dose (MTD)
The primary objective is to estimate the MTD of external beam radiation that 
results in limiting acute toxicity. The MTD is defined as the dose level 
immediately below the dose level at which 2 or more in a cohort of either 3 or 6 
patients experienced a DLT attributed to radiation therapy. If DLT does not occur 
at the highest dose level the protocol will be amended to escalate by 10% in 
cohorts of 3 patients each with the standard 3-6 dose escalation procedure.
3.2  PROTOCOL ADMINISTRATION
3.2.1   MR Imaging Guidelines 
In all patients, conventional anatomic imaging (Fast spin echo T2 weighted 
scans) in the axial and coronal oblique planes will be obtained for research 
purposes to define the extent of the tumor.  An endorectal coil may be 
indicated for prostate exams.  
Following conventional anatomic imaging, one or more of the following 
research biological imaging tests will be performed.  Examples include but are 
not exclusive to:
a) MR Spectroscopic Imaging (MRSI)
Using standard FDA approved spectroscopy software (General Electric 
Medical Systems, Milwaukee, WI), this will be performed using multiple 
voxels at multiple slices (“multivoxel-multislice MR spectroscopy”) 
which will generate a spectroscopic map of the area of interest 
reflecting the relative concentrations of various metabolites in the 
hydrogen resonance spectrum including citrate, choline, creatine, 
choline and lipids. This procedure may require approximately 30-45 
minutes of scanning. 
b) Dynamic Contrast Enhanced MRI

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This imaging study uses 1mmol/kg of an FDA approved Gadolinium 
chelate administered slowly by intravenous injection. Serial 3D 
dynamic enhanced MRI may be performed through the area of interest 
over a period of approximately 10 minutes.  These data will be sent 
electronically to an independent workstation where a pixel by pixel 
time-signal intensity curve will be generated.  This data will be 
automatically fit to a two compartment pharmacokinetic model using a 
custom designed image processing algorithm which will be used to 
generate semiquantitative parameters reflecting flow (“A”) and vessel 
permeability (kep). These parameters will be used to create color 
encoded maps which reflect the vascular flow and permeability of 
various regions.  
c) BOLD
To accomplish this, the patient will first breathe room air via a 
regulated and non-magnetic tank set at 10L/min for 5 minutes via a 
specially designed breathing apparatus designed by Hugh Preas, M.D. 
of the Anesthesia Department.  This breathing apparatus consists of a 
mouth piece and a clamp is place on the nose.  It is non-invasive, and 
the patient can let go of the mouth piece if they find it uncomfortable. 
Following this baseline study, the inhaled gas will be switched to 
regulated medical grade carbogen (5% carbon dioxide and 95% 
oxygen) in non-magnetic tanks administered at 10-15L/min for 7 
minutes.  This will improve the oxygenation of tissue by a combination 
of hyperoxia due to the high oxygen content and vasodilation due to 
carbon dioxide.  Following carbogen inhalation the patient will be 
switched back to the room air at prior rates for 5 minutes.  Images will 
be analyzed by measuring the difference in signal between the room 
air and carbogen scans and color maps reflecting per cent change in 
signal intensity will be generated for comparison.
d) OTHER Sequences
Other MRI sequences may be obtained. However, these other 
sequences will involve novel pulse sequences or post-processing of 
image data that will be transparent to the patient and will not require 
any additional procedures to be performed.
Of note, given the time required to perform and analyze these 
sequences as well as the length of the biopsy procedure, patients may 
have the target imaging with various high resolution sequences done 
at a separate time from the biopsy itself.
3.2.2  Tissue Collection
3.2.2.1    General co-registration guidelines

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Co-registration of the biopsy site to an MRI image will be accomplished by 
one of the following options: 1) real-time MR guidance of the biopsy 
procedure, 2) placing fiducial markers visible on MRI to identify sites 
selected for future biopsy, 3) fusing images from CT or Ultrasound-guided 
biopsy procedures to MR images, 4) repeat MRI immediately after a 
biopsy procedure to identify needle tracts.  
Tissue will be collected with standard biopsy procedures (outlined below).  
NSAIDS should be discontinued one week prior to a biopsy procedure 
unless it is deemed unsafe or violates with the treatment protocol.  Note 
that a separate consent specific to each biopsy procedure will be 
obtained.  
3.2.2.2
Prostate biopsy
Needle biopsies will be performed in collaboration with surgeons from the 
Urologic Oncology Branch-NCI, and Radiologists from the Clinical Center-
NIH.  During each procedure, 2-10 samples will be obtained using 14-18
gauge tru-cut needles.  
Biopsies will be performed according to standard techniques as follows.  
Patients undergo antibiotic prophylaxis with a quinolone antibiotic for one 
or two days before biopsy and the morning of biopsy. If the patient is 
known to be allergic to this antibiotic or if they experience an allergic 
reaction to it, a different one, such as Bactrim, will be prescribed. A
rectal enema is self-administered.  Patients void and then are placed in 
the prone position or in the left- or right-lateral decubitus position.  A 
transrectal ultrasound or MRI probe (custom designed coil, approved by 
NMR Center Research Safety Subcommittee) is inserted and imaging 
measurements of the prostate obtained. After initial imaging is obtained, 
transperineal (or transrectal) introduction of 10-20 cc 1% lidocaine or 
10cc of 0.25% bupivacaine is administered along the paraprostatic 
neurovascular bundle and the tip of the seminal vesicle.  After 3 minutes 
of dwell time, transperineal (or transrectal), targeted prostate biopsy is 
performed as directed by imaging and 3-D spatialization (i.e. in the x,y,z 
coordinates).    The patient recovers in the supine position and is 
allowed to ambulate shortly thereafter with a normal mean blood 
pressure.  The patient is required to void without difficulty prior to 
discharge.  Prostate biopsy is extremely well tolerated with complications 
occurring in 1% due mostly to infection, which can be treated in most 
cases with parenteral or enteral antibiotics as adjudged by the clinician.
3.2.2.3
Tissue Handling
Dr. Kaushal should be notified prior to specimen collection.  Unless 
otherwise directed by Dr. Kaushal, samples will be delivered to Building 
10, RmB3/43, phone 496-5457. 

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Samples will be divided at the time of the procedure.  Half will be 
immediately fixed in formalin and submitted to the Laboratory of 
Pathology, NCI, for histopathological analysis.  The remaining tissue will 
be placed in freezer vials and immediately frozen in liquid nitrogen. 
3.2.2.4 Tissue Analysis
A diagnostic pathological evaluation will be performed on the specimens in 
collaboration with the laboratory of pathology – NCI.  Supplementary tests, 
including but not exclusive to immunohistochemistry and counts of 
microvessel density, may be performed in a pilot exploratory fashion at the 
discretion of the principal investigator.
Tissue samples may then be processed for microarray testing.  RNA will 
be isolated and pooled from the cell population of interest.  Depending on 
the number of cells captured, amplification strategies may be explored.  
Using the total RNA, probes will be prepared and hybridized to a human 
microarray chip. Microarray analysis will then proceed with the mAdb 
analysis tools available to NIH investigators (nciarray.nci.nih.gov). Other 
software will be used as needed.
Tissue specimens collected in the course of this research project may be 
banked and used in the future to investigate new scientific questions 
related to this study.  However, this research may only be done if the risks 
of the new questions were covered in the consent document. 
No germline mutation testing will be performed on any of the samples 
collected unless the patient gives separate informed consent.  Tests will 
be pilot studies related to the Branch’s work on such topics as molecular 
imaging, molecular profiling, and novel molecular therapeutics.  If any 
research tests are considered to be themselves of more than minimal risk 
to the patients, separate permission will be requested from the IRB to 
perform that test, and a new consent will be obtained.
At the completion of the protocol, the investigator will dispose of all 
specimens in accordance with the environmental protection laws, 
regulations and guidelines of the Federal Government and the State of 
Maryland.
Any loss or unintentional destruction of the remaining samples will be 
reported to the IRB.
3.2.3 Radiation Therapy 
3.2.3.1 Treatment planning

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PTV1 will be defined as the prostate with a 3 mm uniform margin. The 
prescription dose to PTV1 will be 7560 cGy in 180 cGy daily fractions.  
Consistent with the RTOG 9406 data, no volume 4 mm beyond PTV1 will 
be allowed to receive a dose beyond 100% of the prescription dose. This 
will be the highest priority constraint for treatment planning. Lesser doses 
to PTV2 and PTV3 will be accepted in order to maintain this constraint. 
PTV2 will be defined as regions of signal abnormality (plus a 2 mm 
margin) on MRI that do not have a pathologic confirmation of disease. 
Dose will be escalated by protocol (see section 3.1.2).
PTV3 will be defined as regions of signal abnormality (plus a 2 mm 
margin) on MRI that do have pathologic confirmation of disease. Dose will 
be determined by protocol. If the patient previously had at least a sextant 
biopsy with documentation of the location of the positive cores, this 
information may be used to define a PTV3. In this case, the physician will 
determine the volume.
If indicated, the seminal vesicles may also be contoured and treated. 
When indicated, the seminal vesicles may be treated to 5400 cGy in 180 
cGy.
3.2.3.2 Summary Of Dose Constraints:
Highest Priority:
x
PTV1 will be defined as the prostate with a 3 mm uniform 
margin. The prescription dose to PTV1 will be 7560 cGy in 
180 cGy daily fractions.  No volume 4 mm beyond PTV1 will 
be allowed to receive a dose beyond 100% of the 
prescription dose.
x
The prostatic urethra, as defined by the attending physician, 
will attempt to be limited to 7800 cGy.
x
Maximum dose to the rectum and bladder will also attempt to 
be limited to 7800 cGy.
x
Less than 25% of the rectal volume will be irradiated to 7000 
cGy.
Secondary Priority:
x
PTV2 and PTV3 will be taken to full dose as per protocol.
x
No more than 40% of the bladder will receive more than 
6500 cGy.
3.2.3.2 Radiation Treatment
Patients should begin their radiation treatment once pathology is available. 
In general patients will receive external beam radiation n the NCI 
Radiation Oncology Clinic daily, Monday – Friday except holidays.

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3.3 TREATMENT MODIFICATIONS
Modifications to the radiation treatment will be discussed with the Principal 
Investigator or Study Chairperson. Isocenter adjustments will be performed for 
prostate motion greater than 5 mm. In each dose cohort, the attending physician 
may accept a final plan that delivers 107 to 93% of the prescription dose to PTV 
1-3. Larger deviations will require prior approval of the PI.
3.4 ON-STUDY EVALUATION
3.4.1  Pre-Procedure (baseline)
x
Informed consent obtained
x
Clinical evaluation
x
History and physical exam
x
Vital signs
x
Pathology report confirming adenocarcinoma of the 
prostate
x
Laboratory evaluation
x
PSA
x
PT/PTT
x
CBC
x
EPIC (Appendix IIIC)
x
AUA Symptom Score (Appendix IV)
x
Sexual Heath Inventory for Men (SHIM) (Appendix V)
3.4.2 Biopsy & Fiducial Marker Placement 
x
See Appendix III for MRI- Guided biopsy and FM data form
x
Post fiducial marker placement MRI’s may be performed to 
evaluate for marker migration
3.4.3 Radiation Treatment Phase
x
Weekly AP (or PA) and lateral port films
x
The following acute rectal toxicity endpoints will be measured.
x
RTOG acute toxicity grading- GI & GU (Appendix IIA) 
weekly and at completion of therapy
3.4.4 Post Active Treatment Evaluation (follow- up)
x
Upon completion therapy, patients will be evaluated at 2, 4, 8, 
and 12 weeks for acute effects of radiation therapy. Patients will 
be evaluated at 6, 9, 12, 18 and every 6 months afterward for 
late effects until 36 months. 
x
Follow-up visits will include:
x
A directed history and physical examination, 
x
PSA evaluation 
x
Rectal toxicity assessment including:

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x
RTOG acute toxicity grading- GI & 
GU(Appendix IIA)
x
RTOG Late toxicity grading- GI & GU 
(Appendix IIB)
x
EPIC (Appendix IIIC)
x
AUA Symptom Score (Appendix IV)
x
Sexual Health Inventory for Men (SHIM) ( 
Appendix V)
x
Follow-up MRI may be obtained after completion of therapy to 
better delineate the time of course of signal change after 
radiation therapy.
x
Patients may volunteer for additional imaging and tissue 
acquisition procedures if deemed desirable by the PI or study 
chairperson.
3.5  CONCURRENT THERAPIES
This study allows imaging and tissue procurement in localized prostate cancer patients 
without metastasis. Usually, such patients do not receive hormonal or chemotherapy. Some 
patients do receive hormone therapy prior to being seen by a radiation oncologist. Such 
patients will remain eligible for this study. However, it is preferred that they discontinue 
hormone therapy while receiving radiation.
3.6 SURGICAL GUIDELINES
None other than those required for standard biopsy procedures.  Where clinically 
indicated, biopsies will be performed under appropriate analgesia, local/systemic 
anesthesia and/or conscious sedation with patient monitoring in compliance with 
hospital standards, no general anesthesia will be administered for research 
purposes only. Only biopsies that are “minimal risk” and do not require general 
anesthesia will be performed for research purposes only.  Please refer to 
section3.2.2. for details on the biopsy procedures.
3.7 RADIATION THERAPY GUIDELINES 
Radiation Therapy is part of the primary protocol treatment and is therefore 
included in section 3.2.3
3.8  OFF STUDY CRITERIA
3.8.1 Patients may be taken off study for the following non-medical or 
administrative reasons:
x
Patient refuses the procedure or further treatment
x
It is deemed in the patient’s best interest as determined by the PI.
x
Serious protocol violation as determined by the PI.

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3.8.2     Development of a concurrent serious medical condition that 
precludes the completion of fiducial marker placement, radiation therapy or 
follow- up.
3.8.3     Tumor progression (if occurs during treatment, at the end of 
radiation therapy unless the completion of local therapy is not indicated)
3.8.4     Initiation of cytotoxic chemotherapy (if occurs during treatment, at 
the end of radiation therapy unless the completion of local therapy is not 
indicated)
3.8.5    Development of a concurrent serious medical condition during active 
treatment and not attributable to therapy that precludes the completion of 
active treatment.
3.8.6 The completion of 36 months (3 years) follow-up. 
3.9 POST-STUDY EVALUATION

At the time a patient comes off study the reason for withdrawal should be 
documented.
x
The patient should be registered off- protocol by completing the Off Study/ 
Death Notification Form available from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) and faxing it to 
the Central Registrar’s Office at 301-450-0757.
4.0  SUPPORTIVE CARE
These procedures may require supportive care including nursing care, local 
anesthetic, analgesics, anti-emetics, and antibiotic prophylaxis.  Please refer to 
section 3.2.2.2 – 3.2.2.3 for details.  In the event that a patient has a reaction 
(allergic) to the contrast agent or medications, all appropriate medical measures 
will be taken.
The most common acute side effects of radiation therapy for prostate cancer, 
urethritis, cystitis and proctitis, may be treated with medications consistent with 
the standard of practice in the radiation oncology community.  It is anticipated
that a minority of patients may require short-term in-patient care for problems 
related to this protocol, namely an inability to void immediately post-op. In such 
circumstances, patients will be admitted to the Clinical Center under the care of 
the Urologic Oncologist.  Medications should be listed in the patient’s records.
5.0  DATA COLLECTION AND EVALUATION
5.1 Data Collection

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x
Clinical data and acquired samples/images will be recorded in a NCI CCR 
database.
x
Clinical data collection will include: demographic information, pathologic 
diagnosis, clinical stage, PSA values, history including concurrent 
therapies, time of biopsy, locations of biopsies, pathology repots of 
biopsies, dose of radiation delivered, and toxicity assessment.
x
Tissue experiments to be performed are pilot and preliminary in nature.  
Data from assays run at the NIH will be collected in laboratory notebooks, 
and the NCI online microarray database.
x
MRSI and dynamic MRI measurement along with corresponding sites of 
tissue acquisition will be digitally archived and processed using computer 
software in the Radiology department of the Clinical Center, NIH, and the 
Radiation Oncology Branch, NCI.
5.2  Response Criteria
Response of tumor will be determined by tracking serum PSA levels. 
Three consecutive rises of the PSA post-treatment will define disease 
recurrence. The time of disease recurrence will be back-dated to the first 
rise in PSA. This methodology is as prescribed by the American Society of 
Therapeutic Radiation Oncology (ASTRO.) 
5.3  Toxicity Criteria
x
Acute toxicities will be evaluated by the CTC, Version 3.0. 
(http://ctep.info.nih.gov). 
x
We will also utilize the RTOG acute and Late toxicity GI/ GU scales as 
in appendices II A & B
5.4  Statistical Section
This is a phase I study to determine the maximum tolerated dose (MTD) with 
MRI-guided radiation dose escalation to regions of interest within the prostate 
gland.  The dose cohorts and MTD are defined in Section 3.1.1. With this design, 
the probabilities of dose escalation are 0.91, 0.49, 0.17, and 0.03 if the 
probability of a DLT is 0.1, 0.3, 0.5, and 0.7, respectively. 
Secondary analyses include (i) evaluating the frequency of late term toxicities, 
and (iii) correlating radiation response and /or toxicity with genomic and 
proteomic analyses.  We will tabulate the frequency of late term toxicities.  We 
will analyze differences in gene expression between responders and non-
responders as well as between patients with toxicity and without toxicity by 
conducting, on a gene by gene basis, two-sample t-tests at the 0.001 level.  We 
will also conduct permutation tests to test for overall differences in gene 
expression between these patient groupings. All secondary analyses will be 
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The total number of patients accrued to this trial will be 18 to 36 patients. We 
anticipate accruing these patients within 2 years.
5.5  Data Safety and Monitoring Plan
5.5.1 Plan for monitoring the progress of the trial and the safety of 
participants

PI will assume primary responsibility for monitoring the progress 
of the trial and the safety of participants.

As part of the NCI CCR, this trial may be selected at random to 
be monitored by the staff of Harris Technical, Inc.
x
Data will also be submitted to the NCI IRB annually for 
continuing review and at the completion of the study. 

In addition, at monthly research/ protocol meetings, senior staff 
of the NCI ROB will review protocol progress and provide 
feedback to the PI.
5.5.2 Plan for assuring the compliance with the requirements for 
reporting adverse events
x
Adverse events will be reported as in section 5.3 and 7.3
5.5.3 Plan for assuring that any action resulting in suspension of the 
trial is reported to the IRB
This is an intramural NCI CCR protocol without external sponsors. If the NCI IRB 
issued the suspension, it would necessarily be aware. If another group issued a 
suspension of the trial, the PI would assume responsibility for notifying the NCI 
IRB. 
5.5.4 Plan for assuring data accuracy and protocol compliance
x
Data will be collected as in section 5.1
x
Clinical data will be recorded in either the 4th Dimension 
Database or in the NCI CCR database or both.
x
Data integrity and protocol adherence are assured by regular 
data verification and protocol compliance checks performed by 
the research team (PI, research nurse, data manager and clinic 
nurse).
6.0 HUMAN SUBJECTS PROTECTIONS
6.1 RATIONALE FOR SUBJECT SELECTION
This is a study for patients with prostate cancer.  The patient population in 
whom this disease occurs is older adult males.  This disease does not 
occur in children; therefore, children will not be part of this study.  All 
ethnic groups/ race categories would be represented as they are 
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will not be included in this study, if they are unable to sign informed 
consent.  Physically impaired persons who otherwise satisfy eligibility 
criteria will be included in this study.  
6.2 PARTICIPATION OF CHILDREN
Adenocarcinoma of the prostate is not a disease of children, therefore, 
children will not be considered as research subjects for this study.
6.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The medical risks associated with this study are those normally expected 
risks associated with external beam radiotherapy for prostate cancer.  
Common acute and temporary side effects include fatigue, urethritis, 
cystitis and proctitis.  Uncommon long-term side effects may include 
urinary frequency, urgency, incontinence, rectal bleeding, perineal pain, 
tenesmus, erectile dysfunction, and infertility. Very rare long-term 
complications may include lymphedema, pathologic femoral neck 
fractures, and a second primary malignancy.
Patients on this study will be receiving treatment for their prostate cancer.  
Other potential benefits of participation may include fewer side effects of 
radiation treatment due to a better visualization of the anatomy and 
sparing of normal structures.   The information learned from this study 
may also benefit other patients with prostate cancer in the future.
6.4 CONSENT AND ASSENT PROCESSES AND DOCUMENTS
The Principal Investigator and associates will recruit patients.  The 
investigational nature and objectives of this study, the procedures involved 
and their attendant risks and discomforts, will be carefully explained to the 
patient, and a signed informed consent document will be obtained.  It is 
our goal to be as explicit as possible in verbal and written consent 
procedures to insure that all participants are joining the study without 
coercion.  
Patients who meet study eligibility criteria, and who are willing to 
participate in the study, will be consented by the PI or associate 
investigators. The consent form will be discussed with the patient in 
person.  Informed consent will involve careful explanation of all items 
outlined in the consent form.  This discussion includes the investigational 
nature of this study, and the possibility of lack of direct benefit to the 
research subject.  All information will be reported in summary fashion only. 
A separate anesthetic/operative consent will be obtained at the time of the 
procedure
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The patient’s rights representative is available to patients on this protocol at (301) 
496-2626 in Building 10, Room 1C132, NIH.  Patients may ask any questions 
about the study and may withdraw their consent at any time without 
compromising their medical care.  
7.0  DATA REPORTING
7.1 PATIENT REGISTRATION FORM
Demographic information and results of pretreatment studies should be entered 
and reported to Harris Technical, Inc., at the time of patient entry onto the trial 
(see section 2.3).
7.2  DATA SUBMISSION
x
Summary information will be submitted to the IRB annually for continuing 
review and at the completion of the study. 
x
Data may be reported in laboratory publications as derived from pilot 
studies.  Patients will not be indicated by name. 
x
The number of MR-identified abnormalities in the initial evaluation that are 
biopsied and whether or not they are confirmed pathologically as cancer 
will be reported in the annual continuing review application to NCI IRB.
7.3 Definitions
7.3.1 Adverse Events
An adverse event is defined as any reaction, side effect, or untoward 
event that occurs during the course of the clinical trial associated with the 
use of a drug in humans, whether or not the event is considered related to 
the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal 
findings on physical examination or laboratory evaluation. A new illness, 
symptom, sign or clinically significant laboratory abnormality or worsening 
of a pre-existing condition or abnormality is considered an AE.  All AEs 
must be recorded on the AE case report form unless otherwise noted 
above in Section 5.1.
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory 
resolution. AEs should be reported up to 30 days following the last dose of 
study drug.  
An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 

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x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, 
including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, 
the investigator will provide details about the action taken with 
respect to the test drug and about the patient’s outcome.
7.3.2 Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the 
purposes of IND safety reporting, ‘reasonable possibility’ means there is 
evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse 
event caused by a drug.
7.3.3.Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in 
the current application. "Unexpected” also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.
7.3.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the 
definition of a Serious Adverse Event or if it compromises the safety, 
welfare or rights of subjects or others.
7.3.5 Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in 
the view of the investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions

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x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
7.3.6 Disability
A substantial disruption of a person’s ability to conduct normal life 
functions.
7.3.7 Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient 
or subject, in the view of the investigator or sponsor, at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction 
that had it occurred in a more severe form, might have caused death.
7.3.8 Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research 
protocol.  
7.3.9 Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections 
Program (HRPP) policies, IRB requirements, or regulatory requirements 
for the protection of human research subjects.
7.3.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation 
to 
(a) the research risks that are described in the IRB-approved 
research protocol and informed consent document; Investigator’s 
Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social 
harm) than was previously known or recognized.

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7.4 NCI-IRB REPORTING
7.4.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths
The NCI-IRB requires that the following language be used for reporting 
events to the NCI-IRB:
The Protocol PI will report to the NCI-IRB:
x All deaths, except deaths due to progressive disease 
x All Protocol Deviations
x All Unanticipated Problems
x All serious non-compliance
Reports must be received by the NCI-IRB within 7 working days of PI 
awareness via iRIS.
7.4.2 NCI-IRB Requirements for PI Reporting at Continuing Review
For reporting of adverse events at time of continuing review, the NCI-IRB 
requires a summary report of adverse events that have occurred on the 
protocol since the previous continuing review and in aggregate. The 
method of presentation should provide the NCI-IRB with the information 
necessary to clearly identify risks to participants and to make a risk: 
benefit determination. Please sort the events by the system organ class 
and by grade. The summary report is based on the following guidance: 
any unexpected severity and/or unexpected frequency of expected events 
needs to be reported and interpreted in relation to the risk: benefit of study 
participants in the narrative.
Please use following table for reporting adverse events at time of CR:
System 
Organ 
Class
CTCAE 
Term
Grade
# of 
Events 
since 
last CR
Total # 
of 
Events
Attribution 
to Research
Serious?
Unexpected?
The protocol PI will report to the NCI-IRB: 
1.
A summary of all protocol deviations in a tabular format to include 
the date the deviation occurred, a brief description of the deviation and 
any corrective action.
2.
A summary of any instances of non-compliance
3.
A tabular summary of the following adverse events:

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x
All Grade 2 unexpected events that are possibly, probably or 
definitely related to the research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely 
related to the research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
8.0  PHARMACEUTICAL INFORMATION
8.1.  Levofloxacin:
Manufacturer: Ortho-McNeil
Commercial Name: Levaquin®
Description:  Levofloxacin is a synthetic broad spectrum antibacterial 
agent in the family of fluoroquinolones for oral administration.
Form:  Levofloxacin is available as (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-
10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyridol[1,2,3-del]-1,4-benzoxazine-
6-carboxylic acid hemihydrate.    It is available in 250, 500 and 750 mg 
film-coated tablets.  The inactive ingredients are starch, microcrystalline 
cellulose, crospovidone, magnesium stearate, hydroxypropyl 
methylcellulose, titanium dioxide, polyethylene glycol, polysorbate 80 and 
synthetic red and yellow iron oxides.
Supply:  Levofloxacin is commercially available and will be supplied by the 
Clinical Center pharmacy. 
Toxicities:  Nausea, diarrhea, vomiting, and abdominal pain are the most 
frequent side effects of levofloxacin. Bad taste in the mouth, restlessness, 
rash, sensitivity to sunlight and seizures are other possible side effects. 
Levaquin may cause dizziness or lightheadedness.\
Levofloxacin should be administered at least 2 hours before or 6 hours 
after magnesium/aluminum antacids, or sucralfate, Videx® (didanosine) 
chewable/buffered tablets or pediatric powder for oral solution, or other 
products containing calcium, iron or zinc.
8.2  Bupivacaine:
Manufacturer: Abbott Pharmaceutical
Commercial Name: Marcaine®

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Description:  Bupivacaine is a long-acting local anesthetic administered by 
parenteral injection. It is a homologue of
mepivacaine and is chemically related to lidocaine in the class of 
depolarizing local anesthetics.
Form:  Bupivacaine is available as 2-piperidinecarboxamide,1-butyl-N-
(2,6-dimethylphenyl)-, monohydrochloride, monohydrate.    It is available 
as a sterile injectable liquid in 0.25, 0.5, and 0.75% concentrations 
packaged in single use ampules ranging from 10 to 50 ml.  The inactive 
ingredients are sodium chloride and hydrochloric acid.
Supply:  Bupivacaine is commercially available and will be supplied by the 
Clinical Center pharmacy. 
Toxicities:  Adverse reactions and systemic toxicities are predominantly 
related to the dosage and of route injection. Maximal dosage is 150 mg in 
adult patients. A 10 ml dose of 0.25% contains 25 mg of bupivacaine.
Central nervous system toxicities include restlessness, anxiety, dizziness, 
tinnitus, blurred vision and tremors. Convulsions and seizures can result 
from excessive plasma levels. Cardiovascular toxicities from high doses or 
unintentional intravascular injection may lead to high plasma levels and 
related depression of the myocardium, decreased cardiac output, heart 
block, hypotension, bradycardia, ventricular arrhythmias, including 
ventricular tachycardia and ventricular fibrillation, and cardiac arrest. The 
use of low dosages of bupivacaine for regional blockade in peripheral sites 
not including the head and neck or obstetrical applications has a less than 
0.01% chance of adverse reaction. Severe cardiac or neurologic toxicity 
with its use in prostate biopsy has not been reported.
8.3 MRI CONTRAST AGENT – Gadopentate dimeglumine 
Manufacturer: Berlex Laboratories, Wayne NJ
Commercial name: Magnevist
Description: This is an FDA approved contrast agent in widespread use.  
Gadolinium produces MR contrast by altering the relaxivity of neighboring 
water protons.  Experience at NIH has been obtained with over 30,000 
intravenous injections.  
Form: Gadopentate dimeglumine is available as Gd-DTPA.    It is available 
as a sterile injectable liquid in single use ampules of 20 ml.  The inactive 
ingredients are meglumine and diethylenetriamine pentaacetic acid.
Supply:  Magnevist is commercially available and will be supplied by the 
Clinical Center Department of Radiology

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Toxicities:  The serious reaction rate (asthma, hives, seizures, 
hypotension) is less than 0.5%.  The dose is 0.1 mmol/kg BW 
administered IV bolus via mechanical injector.  There are no 
contraindications for its use.  Gd-DTPA can be used in patients with 
elevated Cr. Levels and does not have known nephrotoxicity.  Possible 
complications relate to extravasation of contrast in which localized 
swelling and pain may develop but because of the small volume (20cc) 
this does not lead to skin necrosis.  There may be headache, nausea, 
vomiting, and transient sensations of heat or cold or taste disturbances 
following injection of gadopentetate.
8.4Fleet Phospho-soda® enema
Manufacturer: C.B. Fleet Co. Inc., Lynchburg, VA
Description: A sodium phosphate solution for cleansing of the rectal 
mucosa prior to invasive procedures.
Form:  Each 118 ml delivered dose includes 19g of monobasic sodium 
phosphate and 7 g of dibasic sodium phosphate. Latex-free application 
bottles contain 133 ml of solution.
Supply:  Fleet® enema is commercially available and will be supplied by 
the Clinical Center pharmacy.
Toxicities:  Fleet® enema cannot be used in patients with congenital 
megacolon, bowel obstruction, imperforate anus, or congestive heart 
failure.  It must be used with caution in patient with impaired renal 
function, pre-existing electrolyte disturbances or a colostomy, or in 
patients on diuretics or other medications that may affect electrolyte 
levels.  Hypocalcemia, hyperphosphatemia, hypernatremia, or acidosis 
may occur.
9. 0 REFERENCES
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Zeitmna A, et al. A Randomized Trial Comparing Conventional Dose (70.2GyE) 
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Ragde, H., et al., Transrectal ultrasound microbubble contrast angiography of the 
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deoxyglucose: utility in localized and advanced prostate cancer. BJU Int, 1999. 84(9): p. 
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Tempany, C.M., et al., Staging of prostate cancer: results of Radiology 
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Coakley, F.V. and H. Hricak, Radiologic anatomy of the prostate gland: a 
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Hricak, H., et al., Carcinoma of the prostate gland: MR imaging with pelvic 
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Susil, R.C., Krieger, A., Derbyshire, J.A., Tanacs, A., Whitcomb, L.L., 
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Appendix IV

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Physician Signature ___________________________ Date _____________________
Appendix V

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Physician Signature _______________________ Date _____________________

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