Phase II Study of Stereotactic Ablative Radiotherapy (SABR) for Low Risk Prostate Cancer With Injectable Rectal Spacer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Texas Southwestern Medical Center

Official Title: Phase II Study of Stereotactic Ablative Radiotherapy (SABR)
for Low/Intermediate Risk Prostate Cancer with Injectable Rectal Spacer
NCT Number: NCT02353832
Document Date: 05/09/2019
Version 9

STU092013-013, Folkert, STU092013-013.Folkert.Form.A, Mod_33, 08-19-19CONFIDENTIAL
This material is the property of the UTSW Simmons Cancer Center.
Do not disclose or use except as authorized in writing by the study sponsor.
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018
Phase II Study of Stereotactic Ablative Radiotherapy (SABR)
for Low/Intermediate Risk Prostate Cancer with Injectable Rectal Spacer
STU 092013-013
Principal Investigator:
Michael Folkert, M.D., Ph.D.
Department of Radiation Oncology
University of Texas Southwestern Medical Center (UTSW-MC)
Robert Timmerman, M.D.
Department of Radiation Oncology, UTSW-MC
Sub-Investigator(s):
Yair Lotan, M.D.
Department of Urology, UTSW-MC
Claus Roehrborn, M.D.
Department of Urology, UTSW-MC
Raquibul Hannan, M.D., Ph.D.
Department of Radiation Oncology, UTSW-MC
Neil Desai, M.D.
Department of Radiation Oncology, UTSW-MC
Brad Hornberger
Department of Urology, UTSW-MC
Michael Zelefsky, M.D.
Department of Radiation Oncology
Memorial Sloan Kettering Cancer Center (MSKCC)
Marisa Kollmeier, M.D.
Department of Radiation Oncology, MSKCC
Sean McBride, M.D..
Department of Radiation Oncology, MSKCC
Biostatistician:
Chul Ahn, Ph.D.
Biostatistics, UTSW-MC
Initial Version
05/19/2014
Version 2
03/09/2015
Version 3
06/12/2015
Version 4
07/31/2015
Version 5
12/08/2015
Version 6
02/17/2016
Version 7
04/19/2016
Version 8
09/28/2018

STU092013-013, Folkert, STU092013-013.Folkert.Form.A, Mod_33, 08-19-19CONFIDENTIAL
This material is the property of the UTSW Simmons Cancer Center.
Do not disclose or use except as authorized in writing by the study sponsor.
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018
Version 9
5/9/2019
UT Southwestern Medical Center (UTSW)
Harold C. Simmons Cancer Center
Attn: Clinical Research Office
5323 Harry Hines Blvd. MC 9179
Dallas, Texas 75390-9179

STU092013-013, Folkert, STU092013-013.Folkert.Form.A, Mod_33, 08-19-19CONFIDENTIAL
This material is the property of the UTSW Simmons Cancer Center.
Do not disclose or use except as authorized in writing by the study sponsor.
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018
Signature Page
The signature below constitutes the approval of this protocol and the attachments, and provides the
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including
all statements regarding confidentiality, and according to local legal and regulatory requirements and
applicable U.S. federal regulations and ICH guidelines.
Amendment/Version # 9
PROTOCOL NUMBER: STU 092013-013
PROTOCOL TITLE: Phase II Study of Stereotactic Ablative Radiotherapy (SABR) for Low/Intermediate
Risk Prostate Cancer with Injectable Rectal Spacer
Principal Investigator (PI) Name: Dr. Michael Folkert
PI Signature: _____________________________
Date:____________________

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TABLE OF CONTENTS
LIST OF ABBREVIATIONS.........................................................................................................4
STUDY SCHEMA........................................................................................................................5
STUDY SUMMARY.....................................................................................................................6
1.0
BACKGROUND AND RATIONALE...................................................................................7
1.1
Disease Background....................................................................................................7
1.2
Study Agent(s) Background and Associated Known Toxicities......................................8
1.3
Other Agents .............................................................................................................10
1.4
Rationale...................................................................................................................11
2.0
STUDY OBJECTIVES .....................................................................................................13
2.1
Primary Objectives.....................................................................................................13
2.2
Secondary Objectives................................................................................................13
2.3
Endpoints ..................................................................................................................13
3.0
SUBJECT ELIGIBILITY...................................................................................................14
3.1
Inclusion Criteria........................................................................................................14
3.2
Exclusion Criteria.......................................................................................................15
4.0
TREATMENT PLAN ........................................................................................................16
4.1
Treatment Dosage and Administration .......................................................................16
4.2
Toxicities and Dosing Delays/Dose Modifications.......................................................23
4.3
Concomitant Medications/Treatments ........................................................................23
4.4
Other Modalities or Procedures..................................................................................23
4.5
Duration of Therapy ...................................................................................................27
4.6
Duration of Follow Up ................................................................................................27
4.7
Removal of Patients from Protocol Therapy ...............................................................27
5.0
STUDY PROCEDURES...................................................................................................27

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5.1
Screening/Baseline Procedures .................................................................................27
5.2
Procedures During Treatment....................................................................................28
5.3
Follow-up Procedures ................................................................................................28
5.4
Summary of Data Submission....................................................................................29
5.5
Time and Events Table..............................................................................................30
5.6
Removal of Subjects from Study ................................................................................31
6.0
MEASUREMENT OF EFFECT.........................................................................................31
6.1
Antitumor Effect- Solid Tumors...................................................................................31
6.2
Safety/Tolerability ......................................................................................................34
7.0
ADVERSE EVENTS ........................................................................................................34
7.1
Experimental Therapy................................................................................................34
7.2
Adverse Event Monitoring..........................................................................................34
7.3
Steps to Determine If an Adverse Event Requires Expedited Reporting .....................37
7.4
Stopping Rules ..........................................................................................................38
8.0
DRUG INFORMATION ....................................................................................................38
9.0
CORRELATIVE/SPECIAL STUDIES ………………………………………………………….38
10.0
STATISTICAL CONSIDERATIONS...............................................................................38
10.1
Study Design/Study Endpoints...................................................................................38
10.2
Sample Size and Accrual...........................................................................................39
10.3
Data Analyses Plans..................................................................................................39
11.0
STUDY MANAGEMENT ................................................................................................40
11.1
Conflict of Interest......................................................................................................40
11.2
Institutional Review Board (IRB) Approval and Consent .............................................40
11.3
Required Documentation ...........................................................................................41
11.4
Registration Procedures.............................................................................................41
11.5
Data Management and Monitoring/Auditing................................................................41

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11.6
Adherence to the Protocol..........................................................................................41
11.7
Amendments to the Protocol......................................................................................42
11.8
Record Retention.......................................................................................................42
11.9
Obligations of Investigators........................................................................................43
12.0
REFERENCES ..............................................................................................................44
13.0
APPENDICES ...............................................................................................................46

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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
ASCO
Absolute Lymphocyte Count
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DOT
Disease Oriented Team
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
GCP
Good Clinical Practice
H&P
History & Physical Exam
HRPP
Human Research Protections Program
IHC
Immunohistochemistry
IND
Investigational New Drug
IV (or iv)
Intravenously
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
pCR
Pathologic Complete Response
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
p.o.
peros/by mouth/orally
PR
Partial Response
RCB
Residual Cancer Burden
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SCCC
Simmons Comprehensive Cancer Center
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells

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STUDY SCHEMA
Number of patients = 45 patients
PHASE II STUDY
Patients will be treated with 5 fractions of SABR/SBRT according to protocol
guidelines.  We have selected 9 Gy per fraction for 5 fractions (total dose = 45)
based on our phase I/II study experience without the rectal spacer.
No. Fractions
Dose per fraction (Gy)
Total Dose (Gy)
No. Patients
5
9
45
45
The phase II study will be completed when enrollment is completed and minimum
follow-up is reached, or if unexpected excess toxicity is noted.
Eligible
patient
SABR/SBRT
5 Fractions
Assess for Acute
Toxicity
Simulation under
SBRT/SABR
condition (MR for
radiation planning
and for spacer
evaluation)
Dosimetry
evaluation of rectal
dose
Determine
distance created
between prostate,
rectum and mid
prostate gland
Anoscopic
evaluation
1.5, 3, 6, 9
months
Follow for
toxicity and
PSA control
Rectal
Spacer
Insertion
CT scan
under
simulation
conditions
without
spacer to
assess rectal
dosimetry
without
spacer
MR fusion
allowed

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STUDY SUMMARY
Title
Phase II Study of Stereotactic Ablative Radiotherapy (SABR)
for Low/Intermediate Risk Prostate Cancer with Injectable Rectal Spacer
Short Title
SABR with Injectable Rectal Spacer for Low/Intermediate Risk Prostate
Cancer
Protocol Number
STU 092013-013
Phase
Phase 2
Methodology
Single arm, open label
Study Duration
Minimum 3 years; Voluntary 10 years at Investigator’s discretion
Study Center(s)
Multi-center
Objectives
To reduce rectal toxicity due to SABR
Number of Subjects
45
Diagnosis and Main
Inclusion Criteria
Low/Intermediate risk prostate cancer
Study Product(s), Dose,
Route, Regimen
Placement of rectal spacer followed by Stereotactic Ablative
Radiotherapy (SABR): 5 fractions (9 Gy per fraction) for a total of 45 Gy
Duration of Administration
2-3 weeks
Reference therapy
SABR

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1.0
BACKGROUND AND RATIONALE
1.1
Disease Background
Localized Prostate Cancer
There is estimated to be 238,590 new cases of prostate cancer diagnosed in the
United States in 2013 and 29,720 deaths [1] .  Among males, prostate carcinoma
was the 2nd leading cause of cancer mortality behind lung cancer. About 60% of
prostate cancer are diagnosed in men age 65 or older which impacts therapy
options as a result of competing co-morbidities. With introduction of PSA
screening, majority of prostate cancer is diagnosed in organ confined disease [2].
Radiotherapy options for organ confined prostate cancer have included
protracted radiation in the form of external beam delivered over 7-10 weeks of
daily therapy (including 2-D, 3-D conformal, and intensity modulated radiation
therapy or IMRT) [3-5] and also permanent brachytherapy seed implantation
using iodine or palladium [6-8].  Treatments have also been delivered using
shorter overall treatment times.  These include hypofractionated external beam
treatments and high dose rate (HDR) brachytherapy implants [9-12].  In addition,
studies using extreme hypofractionated approach including stereotactic body
radiation therapy (SBRT)/Stereotactic Ablative Radiotherapy (SABR) have
emerged, including the phase I/II study completed here at UT Southwestern [13,
14]. In addition to being more convenient for patients with fewer trips to the
treatment facilities, these treatment options completed over a shorter period have
unique long term effects in both tumor and normal tissues.  Depending on the
relative differences between tumor response and normal tissue injury, the timing
in which radiotherapy is delivered may have significant impact on the therapeutic
ratio (benefit/toxicity).  A commonly used mathematical model used to describe
these effects has been the “linear-quadratic” model proposed by Douglas and
Fowler[15].  In this model, the log survival vs. dose relationship is modeled by an
arithmetic power series truncated to the linear and quadratic terms.  The linear
coefficient in this progression is commonly called “alpha” while the quadratic
coefficient is called “beta.”  It has also been proposed that the linear term
described by alpha corresponds to the more infrequent effect of double strand
breaks within tissue DNA caused by radiation which disable the clonagenicity of
the cell with little chance of repair. In turn, the beta term reflects the
consequence of more than one single strand break in close enough proximity on
the DNA to disable the cell.  These single strand breaks occur much more
frequently than double strand breaks, but they may be more readily repaired
unless they happen so frequently that repair mechanisms become overwhelmed
such as might occur with large dose per fraction radiation.  Hence, at low dose
per fraction, alpha events dominate the cellular response while at large dose per
fraction, beta events become more important.  These events occur, at different
rates and proportions, in both tumor and normal tissues exposed to radiation.
It has been commonplace to describe tissue response properties of various
tissues toward radiation by their alpha to beta ratio.  The alpha and beta values
may be measured in vitro by exposing cell cultures to varying doses and
schedules of radiation.  Normal tissues, more capable of repairing radiation
injury, typically have a lower alpha/beta ratio in the order of 2-3.  Common
cancers of the lung, cervix and head and neck are quoted to have alpha/beta
ratios in the 10 range.  For such tumors, exploitation of the differences between
normal tissue and tumor response has led radiation oncologists to use more
protracted courses of radiation using small daily doses to high total cumulative
doses (so-called conventional fractionation, e.g., 2 Gy per fraction to a total dose
of 70-76 Gy).  Prostate cancer cell lines have been difficult to grow in tissue
culture and therefore there has been less direct evidence of the alpha/beta ratio.

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It was generally assumed to be similar to epithelial malignancies of the
gastrointestinal and bronchopulmonary tract leading to the conventional dose
fractionation schedules used in clinical practice or the low dose rate implants
used in permanent prostate seed brachytherapy.  More recent evidence,
however, has implied that the alpha/beta ratio for prostate cancer may be much
lower than expected.  In fact, using outcome data of patients treated with
different dose fractionation schemes (in vivo), it has been suggested that the
alpha/beta ratio for prostate cancer may be as low as 1.5-3 which is perhaps
even lower than the surrounding normal tissues.  If this were true, there would be
no advantage to protracted radiotherapy schedules.
The alpha beta notion described above has led to many hypofractionated studies
using modestly larger doses per fraction.  Randomized studies have been
published, including the Australian trial comparing 64 Gy in 32 fractions versus
55 Gy in 20 fractions in men with favorable risk prostate cancer[16]. Biochemical
outcomes were not different, and toxicity was similar, except for increased rectal
bleeding in the hypofractionated arm.  Another study compared 66 Gy in 33
fractions versus 52.5 Gy in 20 fractions[17].  While the outcome seem to favor
the longer fractionation, the study was not adequately designed to address this
question as the biologically effective dose of the hypofractionated arm was less
than the conventional fractionation arm.  In the US, Kupelian and colleagues
used 2.5 Gy per fraction and published mature results to 70 Gy total dose in 5.5
weeks[18].  Their patients had good PSA control rates and acceptable rates of
toxicity, especially if the volume rectum getting 70 Gy is limited to 10 cc.
Altogether, these trials show that the treatment can be delivered much more
quickly and conveniently using equivalent effective doses with hypofractionation
without compromising PSA control or significant toxicity so long as careful
technique and normal tissue dose tolerance is respected.  Furthermore,
investigation of hypofractionated strategies for the high risk patients is under
investigation. For example, a randomized phase III study using hypofractionated
strategy in high risk prostate cancer patients has been reported where 62 Gy/20
fractions was superior to standard 80 Gy/40 fractions[19].  Interestingly, 62 Gy in
20 fractions converts to roughly 48.1 Gy in 5 fractions[20].
1.2
Study Agent(s) Background and Associated Known Toxicities
1.2.1
Stereotactic Body Radiation Therapy (SBRT)/Stereotactic Ablative
Radiotherapy (SABR)
‘Stereotactic radiosurgery’ generally refers to a procedure design to treat deep-
seated brain tumors or abnormalities, and is commonly performed on a
specialized machine, such as the Gamma Knife.  This procedure involves
immobilizing the patient (cranial halo), affixing a stable 3-D coordinate system
(fiducial box and head frame), performing high resolution imaging (CT or MRI),
registering the images to the coordinate system using a computer, virtually
simulating delivery of very focal and conformal dose profiles of radiation with
steep dose gradients toward normal tissue, and finally carrying out the treatment
with sub-millimeter accuracy.  Typically very high doses of radiation (15-40 Gy)
are given in a single treatment with this technique.  Any adjacent normal tissues
that receive this dose may be significantly damaged, thus the requirement for
very conformal treatments with rapid dose fall-off.  An alternate strategy has
been to divide total radiation dose into two or three fractions, still with fairly large
dose per fraction (6-10 Gy), attempting to decrease adjacent normal tissue
toxicity.  These fractionated techniques are referred to as ‘stereotactic
radiotherapy,’ and are carried out with hope that surrounding normal tissue will
tolerate the treatment as a result of relatively more successful sublethal damage
repair as compared to tumor.
Translation of the stereotactic radiosurgery and radiotherapy concepts to
extracranial sites has not been straightforward [21-23].  With brain treatments,

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the skull serves as an excellent surface to rigidly couple the immobilization frame
using stainless steel pins under local anesthesia.  Once the skull is immobilized,
targets within the skull are likewise immobilized in that there is very little
movement of intracranial structures outside of fluid waves around the ventricles.
Such is not the case for extracranial sites.  Inherent motion, such as the heart
beating, lungs expanding and emptying, and bowels churning, results in
movement of potential targets.  In addition, the external surface anatomy does
not have structures amenable to rigid fixation to a frame.  In 1994, Lax, et al,
from the Karolinska Hospital in Sweden reported on the development and testing
of an extracranial frame that incorporated a fiducial stereotactic coordinate
system along its side panels [23].  The system used vacuum pillows to make
contact with three sides of the patient (maximizing surface area of contact) and
correlation of external anatomical reference points on the sternum and calf for
immobilization.  To decrease respiratory excursion, an abdominal press was
employed forcing the patient to perform relatively more chest wall rather than
diaphragmatic breathing.  A formal verification of reproducibility study was carried
out, and target motion was reduced to within 0.5 cm in the axial plane and 1.0 cm
in the caudal/cephalad plane.  With this degree of accuracy (compared to 0.05
cm target position accuracy for the Gamma Knife), stereotactic radiosurgery
could not be performed; however, they did set up a program treating patients with
extracranial stereotactic radiotherapy.
Stereotactic body radiation therapy (SBRT)/ Stereotactic ablative radiotherapy
(SABR) is a new therapeutic paradigm for treating localized tumors outside of the
central nervous system and involves delivering very high doses of focused
radiation using unique beam arrangements and special immobilization equipment
[24].  As already demonstrated in lung and liver cancers, these treatments offer
hope for improved local control of cancers that may translate into gains in
survival especially for smaller early stage lesions.  SABR employs daily treatment
doses dramatically higher than typical for conventionally fractionated radiation
therapy (CFRT).  In turn, it is incorrect to assume that SABR radiobiology is
similar to historical CFRT.  Indeed, a unique biology of radiation response for
very large dose per fraction treatments is being appreciated both in terms of
tumor control as well as normal tissue consequences translating into unique
clinical outcomes.  For example, local control with CFRT in early stage lung
cancer is consistently reported below 50% while several series using SABR show
local control around 90% [25, 26].
SABR has been defined by the American College of Radiology (ACR) and
American Society of Therapeutic Radiology and Oncology (ASTRO) to involve
the use of very large dose per fraction [27].  Indeed, dose per fraction of 8 Gy
minimum would obviously make SABR very different from even the more
abbreviated hypofractionation schemes described above.  Typically, only 1-5
fractions are used for SABR depending on the tolerance of adjacent or
intervening normal tissues.  Linear structures (like the spinal cord) and tubular
structures (like the bowels) are commonly called “serially functioning tissues”
akin to series electrical circuits because their function is disrupted if there is a
defect anywhere along their pathways [28, 29].  It has been shown that serial
functioning tissues are less tolerant to SABR than so-called “parallel functioning
tissues” like the peripheral lung and liver.  In response, typically more fractions
are employed (e.g., five fractions rather than one) when serially functioning tissue
cannot be avoided.  In the case of treating prostate cancer, the rectum is an
adjacent serially functioning tissue while the urethra is an intervening serially
functioning tissue traversing the very center of the prostate target.

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1.3
Other Agents
Rectal spacers
Our rectal toxicity data analysis suggests that rectal toxicity will likely be
circumvented if we are able to respect dose tolerances as defined in our
analysis.  This has also been the case in world of conventional fractionation
radiation therapy, where determination of rectal dose constraints (specifically,
limiting volume of rectum receiving 70 Gy in 2 Gy/daily fraction dose) by Pollack’s
group has provided a means of dose escalating radiation treatments without
increasing rectal toxicity[32].
When using such high dose per fraction, as is the case in SABR, three strategies
for improve rectal dose can be considered.  One strategy is to de-escalate the
total dose significantly (6-6.5 Gy/fraction).  While this lower dose may prove to be
effective for treatment of localized prostate cancer, and would certainly reduce
toxicity, as has been the case with other institution’s experience[14], the follow up
data from these institutions remain short, and if the alpha beta ratio hypothesis
proves to be inaccurate, then we may be subjecting patients to suboptimal
therapy.  Furthermore, such lower doses are likely to be less effective in patients
with more aggressive, high risk prostate cancer.  Dose escalation has proved to
be important in high risk prostate cancer even using conventional fractionation
strategies, and suggestion of importance of considering hypofractionation for
high risk prostate cancer was demonstrated in phase III randomized study from
Italy[19], suggesting that dose de-escalation strategies would limit our ability to
treat higher risk prostate cancer patients with SABR.
Second strategy is to continue to explore radioprotectors to try to reduce toxicity.
However, a suitable radioprotector drug, particularly when using SABR treatment
has not yet been discovered.  Third strategy is to consider methods to reduce
dose to the rectum via physical or dosimetric means.  In the case of
conventionally fractionated treatments, sophisticated treatment planning using
intensity modulated radiation therapy or 3D conformal therapy has allowed rectal
dose parameters to be respected to a point of acceptable rectal toxicity risks.
However, in the case of SABR, avoidance of such high doses with sophisticated
treatment planning using our parameters, though feasible in most cases, may
remain significantly challenging in patients with unfavorable anatomy.
Therefore, another potential strategy to improve dosimetry has been developed
recently.  This involves the use of an anatomic modulating strategy to distance
the anterior rectum from the prostate in order to reduce dose to the rectum.  This
approach is now being investigated both in conventional fractionated radiation
therapy and in SABR for prostate cancer patients, and involve the use of an
injectable rectal spacers [33-38].  These spacers would likely be particularly
effective at reducing the high dose associated with vascular/stromal injury and
will likely lead to significant reduction of high grade rectal toxicity events. It
should also improve acute lower grade events, as such events also will likely be
mitigated if we can limit the 24 Gy dose/5 fractions to treate < 50% of rectal
circumference. Multiinstitutional clinical trial of rectal spacers ability to improve
dosimetric parameters when using conventional intensity modulated radiation
therapy has been completed with positive outcome[39] further supporting use of
this strategy.  This same group has recently published safety profile of use of this
spacer for conventional IMRT based radiation therapy for prostate cancer[40].
Effectiveness in reducing acute toxicity using another rectal spacer for
brachytherapy/IMRT application has been reported in abstract form[41].  Its
safety/efficacy in SABR has not yet been established.

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1.4
Rationale
Stereotactic Body Radiation therapy (SBRT)/ Stereotactic ablative body radiation
therapy (SABR) in Localized Prostate Cancer.
Studies using SBRT/SABR approaches for extreme hypofractionation to reduce
further treatment time, convenience, and possibly treatment efficacy,  has been
performed at multiple institutions including ours [13, 14, 30, 31].  We were the
first institution to perform a multiinstitutional phase I dose escalation study which
was completed successfully.  This study included cohorts of 15 patients per dose
group with doses escalated from 45 Gy 47.5 Gy 50 Gy in 5 fractions. In the
phase I study at the 45 Gy dose (9Gy x 5 fractions) arm, first ten patients
underwent anoscopic evaluation by study P.I. (R.T.) at 6, 12, 24, and 36 weeks
post SABR.  10/10 (100%) patients were found to have development of a small
ulcer in the anterior rectum adjacent to the prostate, which was mostly
asymptomatic.  This mucosal lesion shrunk in size and disappeared in all 10
cases by 24-36 weeks post therapy ({Kim, 2014 #203} and personal
communication, R. Timmerman).
Using 90 day toxicity as the endpoint for dose escalation, acute toxicity at 50 Gy
was found to be tolerable[13], and we proceeded to treat additional patients in
phase II studying late toxicity using that dose.  An unacceptable 6.6 % (6/61) of
patients treated developed high grade rectal toxicity, 5 of whom required
colostomy {Kim, 2014 #203}.  The data from these patients were analyzed to
determine clinical and radiation dose parameters that may have been related to
such high grade toxic event. We found that  Grade 3+ delayed rectal toxicity felt
related to vascular/stromal damage was strongly correlated with volume of rectal
wall receiving 50 Gy (V50) > 3 cm3 (p=.002), and treatment of > 35%
circumference of rectal wall to 39 Gy (p=.03) related to stem cell eradication.
Grade 2+ acute rectal toxicity felt related to stem cell depletion was significantly
correlated with treatment of > 50% circumference of rectal wall to 24 Gy (p=.006)
{Kim, 2014 #203}.
1.4.1
Current Protocol
Prostate cancer has several good treatment options for organ confined disease
such as surgery and conventional radiation.  In addition, some men with indolent
disease are appropriately treated with watchful waiting.  However, all of the
established treatments continue to fail in a portion of patients via tumor
recurrence.  Furthermore, current treatments are often unpalatable for many
patients because they are either too invasive or too inconvenient.  It has also
been shown recently that higher risk prostate cancers may be better controlled
using large dose per fraction treatments such as might be delivered by
stereotactic body radiation therapy (SBRT/SABR)[19]. However, the results of
our phase I/II study clearly demonstrates that on long term follow up delayed
rectal toxicity events can occur, but this is likely preventable if we can respect
rectal tolerance by reducing the radiation dose to the rectal wall.  In addition to
having rectal tolerance parameters defined from our previous study, which we
will incorporate to this study, there are now rectal spacers made from
polyethyleneglycol hydrogel material available for use[33-38, 40, 41]. These
spacers are designed for stability for up to 1- 3 months, which will allow for
stability of anatomy during the SABR treatment phase.
We plan to perform a phase II study to assess safety and efficacy of the spacer
injection process, ability of the spacer to effectively provide the space necessary
to reduce acute events in the rectum, and also meet the SABR based rectal
constraints, and to monitor stability of this process during SABR.  Unlike IMRT,
which uses smaller dose/fraction, when using such high dose/fraction, even a
few mm of shift in spacer positioning may impact the dose that the rectum
receives, and therefore, a rigorous study of stability of material during the SABR

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treatments will need to be determined.  If there is some shift, by doing this study,
we may be able to determine the margin of error that will be necessary in
considering rectal organ dosimetry, based on the possible shift in positiong that
may occur with the spacer over time.
As the SABR therapy is strictly local, we will select for patients with prostate
cancer locally confined to the prostate gland.  As such, we will select eligibility
criteria of low and intermediate risk patients to minimize risk of extraprostatic
spread, seminal vesicle invasion, and nodal spread.  Hormonal therapy may also
be used to shrink prostates that are massively enlarged as this may also help
further reduce length of rectum that will be irradiated.  As the primary toxicity will
likely be mucosal damage, we will avoid enrolling patients with pre-existing
mucosal dysfunction (including those with previous radiation, TURP, very large
prostate glands, inflammatory bowel disease) and immunosuppressed individuals
based on our phase I experience[13].  In this way, patients will be uniformly
selected in a fashion that would identify patients likely to receive benefit from the
therapy.
Based on our phase I/II experience, we will select 9 Gy/fraction with a total of 5
fractions, as this dose was well tolerated, and appears thus far to have been
extremely effective at controlling the prostate cancer. With a median f/u of 25.5
months (range 1-68.4m), at last analysis, PSA control remains at 99%. Given
there will be only 5 treatments, daily enemas, rectal tubes, and even urethral
catheters for simulation are all feasible undertakings which were well tolerated,
and found to be helpful for optimizing setup and the therapy.
1.4.2
Who Would Benefit from this Treatment?
As noted above, there are several quite good but not perfect treatments for organ
confined prostate cancer that have significant follow-up and published
experience as well as an option for watchful waiting.  Still, there are populations
that might find the invasiveness of surgery and brachytherapy implants less ideal
and the inconvenience of IMRT and 3-D conformal therapy impractical.
Extended exposure to general anesthesia is inappropriate for some patients due
to significant co-morbid conditions.  We believe a very abbreviated, non-invasive,
outpatient treatment would be considered a favorable option in particular to the
underserved populations of men living in more remote areas including farmers,
ranchers, and those in rural communities.  Furthermore, if the concept of prostate
cancer having a very low alpha to beta ratio discussed previously is confirmed,
this treatment using SABR may in fact be a better option for some men with
prostate cancer. High risk patients benefit by the hypofractionated nature of the
treatment, and may also require doses higher than what can be delivered safely
with this approach (based on our phase I/II data, and other institutional
experiences as noted above).  These patients are in need of better therapy, and
higher dose SABR approach may prove to be an important therapeutic gain for
this group of patients.  Furthermore, findings of our study will have further clinical
ramifications beyond prostate cancer. It will be applicable to design of studies of
tumor sites in close proximity to bowel structures in general, where higher SABR
doses are being contemplated due to perceived clinical needs as such tumors
may not share the same alpha beta ratio as prostate cancer does.  Development
of an effective paradigm for spacer placement to displace critical structures
reliably away from the high dose region may lead to design of additional spacer
studies in other anatomical sites.

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2.0
STUDY OBJECTIVES
2.1
Primary Objectives
2.1.1
To reduce acute periprostatic rectal ulcer events from 90%+ to <70%
(particularly in the anterior rectum)
2.1.2
To establish rates of creation of >= 7.5 mm space (anticipated to be 95%
[39]).
This is to determine if use of rectal spacers are effective at improving protection
of rectum from high dose radiation, using rate of rectal ulceration as a surrogate
measure of acute effects. It is also to determine whether it provides sufficient
dosimetric benefits to warrant further clinical investigation in future SABR related
clinical studies.
2.2
Secondary Objectives
Secondary objective is to determine radiation related toxicity outcomes in the
acute and delayed setting, as well as to follow PSA control.  HRQOL will be
measured as part of current clinical practice, and not necessarily related to this
treatment protocol.
2.2.1
Assess for spacer related acute toxicity. Spacer related toxicity could be
related to the procedure itself (bleeding, infection, pain), or secondary
effects of spacer (erectile dysfunction, persistent pain and discomfort).
2.2.2
Determine spacer’s ability to decrease percent rectal circumference
(PRC) receiving 24 and 39 Gy by at least 50%.
2.2.3
Assess for acute (within 270 days of treatment) and chronic (>270 days
from treatment) SABR-related genitourinary (GU) and gastrointestinal
(GI) toxicities, as well as non-GU/GI toxicities during follow up.
2.2.4
Assess oncologic outcomes, including biochemical recurrence, overall
survival, disease-specific survival, rates of local/regional/distant relapse
2.2.5
Assess effect on quality of life (QOL)
2.3
Endpoints
2.3.1
Primary Endpoint
The primary endpoint of this study is to determine whether use of a rectal spacer
with SABR will decrease the rate of rectal toxicity when performing SABR
treatments for prostate cancer, and the effectiveness of space creation by the
spacer.  To this extent, our primary objectives are

to measure rectal mucosal ulceration rate, and

to determine ability of spacer to create >=7.5 mm space: rate of
space creation of >=7.5mm.
2.3.2
Secondary Endpoints

To assess spacer related acute toxicity, defined as toxicities
occurring in the two week period between spacer placement and
start of radiation treatment.

To determine spacer’s efficacy as measured by its ability to decrease
the PRC 24 Gy and 39 Gy parameters by at least 50%.  This will be
determined by using CT planning studies for dosimetric analysis
before and after spacer placement.

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
Acute GU and GI toxicity is defined as grade 1-5 toxicity occurring
prior to 270 days from the start of protocol treatment. It is graded
based on CTCAE v4.0.

Delayed GU and GI toxicity is defined as grade 1-5 toxicity occurring
after 270 days from the start of protocol treatment. It is graded based
on CTCAE v4.0.

Non GU and GI toxicity.

Biochemical failure RTOG-ASTRO definition (also known as Phoenix
definition) - Thus, when the PSA rises by more than 2 ng/ml above
the lowest level (nadir) achieved after treatment,, biochemical failure
has occurred and the date of the failure is recorded at the time the
nadir plus 2 ng/ml level is reached.

Overall survival

Disease-specific survival

Clinical progression including local/regional and distant relapse

HRQOL questionnaires
3.0
SUBJECT ELIGIBILITY
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion
criteria to be registered to the study. Study treatment may not begin until a subject is
registered.
3.1
Inclusion Criteria
3.1.1
All patients must be willing and capable to provide informed consent to
participate in the protocol.
3.1.2
Eligible patients must have appropriate staging studies identifying them
as AJCC stage T1 (a, b, or c) or T2 (a, b, or c) adenocarcinoma of the
prostate gland. The patient should not have direct evidence of regional or
distant metastases after appropriate staging studies.  Histologic
confirmation of cancer will be required by biopsy performed within 180
days of registration.
3.1.3
The patient’s Zubrod performance status must be 0-2.
3.1.4
The Gleason score should be less than or equal to 7.
3.1.5
The serum PSA should be less than or equal to 15 ng/ml
Study entry PSA must not be obtained during the following time frames:
(1) 10-day period following prostate biopsy; (2) following initiation of
ADT; (3) within 30 days after discontinuation of finasteride; or (4) within
90 days after discontinuation of dutasteride.
3.1.6
Age ≥ 18 years.
3.1.7
Patients may have used prior hormonal therapy, but it should be limited
to no more than 9 months of therapy prior to enrollment.
3.1.8
The ultrasound, MRI, or CT based volume estimation of the patient’s
prostate gland should be ≤80 grams.
3.1.8.1 For patients with prostate size > 60 grams cytoreduction
therapy with ADT is recommended

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3.2
Exclusion Criteria
3.2.1
Subjects who have had previous pelvic radiotherapy or have had
chemotherapy or surgery for prostate cancer.
3.2.2
Subjects who have plans to receive other concomitant or post treatment
adjuvant antineoplastic therapy while on this protocol including surgery,
cryotherapy, conventionally fractionated radiotherapy, hormonal therapy,
or chemotherapy given as part of the treatment of prostate cancer.
3.2.3
Subjects who have undergone previous transurethral resection of the
prostate (TURP) or cryotherapy to the prostate.
3.2.4
Subjects who have significant urinary obstructive symptoms; AUA score
must be ≤ 18 (alpha blockers allowed).
3.2.5
Subjects who have a history of significant psychiatric illness.
3.2.6
Men of reproductive potential who do not agree that they or their partner
will use an effective contraceptive method such as condom/diaphragm
and spermicidal foam, intrauterine device (IUD), or prescription birth
control pills.
3.2.7
Prior invasive malignancy (except non-melanomatous skin cancer)
unless disease free for a minimum of 3 years (e.g., carcinoma in situ of
the breast, oral cavity, or cervix are all permissible).
3.2.8
Severe, active co-morbidity, defined as follows:
3.2.8.1
Unstable angina and/or congestive heart failure requiring
hospitalization within the last 6 months.
3.2.8.2
Transmural myocardial infarction within the last 6 months.
3.2.8.3
Acute bacterial or fungal infection requiring intravenous
antibiotics at the time of registration.
3.2.8.4
Chronic Obstructive Pulmonary Disease exacerbation or other
respiratory illness requiring hospitalization or precluding study
therapy within 30 days before registration.
3.2.8.5
Hepatic insufficiency resulting in clinical jaundice and/or
coagulation defects; note, however, that laboratory tests for
liver function and coagulation parameters are not required for
entry into this protocol.
3.2.8.6
Acquired Immune Deficiency Syndrome (AIDS) based upon
current CDC definition; note, however, that HIV testing is not
required for entry into this protocol. The need to exclude
patients with AIDS from this protocol is necessary because the
treatments involved in this protocol may be significantly
immunosuppressive.  Protocol-specific requirements may also
exclude immuno-compromised patients.
3.2.8.7
Patients with history of inflammatory colitis (including
Crohn’s Disease and Ulcerative colitis) are not eligible.
3.2.9
Subjects with a known allergy to polyethylene glycol hydrogel (spacer
material) or contraindication to spacer products (Duraseal or
SpaceOAR).
3.2.10 Subjects with evidence of extraprostatic extension (T3a) or seminal
vesicle involvement (T3b) on clinical evaluation.
3.2.11 Subjects with uncontrolled bleeding disorder which cannot be controlled
with anticoagulants

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4.0
TREATMENT PLAN
4.1
Treatment Dosage and Administration
RADIATION THERAPY
4.1.1
Dose Specifications
4.1.1.1
Stereotactic Targeting and Treatment
The term “stereotactic” for the purposes of this protocol implies the targeting, planning, and
directing of therapy using beams of radiation along any trajectory in 3-D space guided by one
or several fiducials of known 3-D coordinates.  This differs from conventional radiation therapy
in which therapy is directed toward skin marks or bony landmarks and assumed to correlate to
the actual tumor target based on a historical simulation.  It should be understood that
Stereotactic Body Radiation Therapy (SBRT/SABR) has become a treatment that is well
beyond just stereotactic targeting.   Indeed SABR is mostly about ablative range dose per
fraction, accounting properly for errors including motion, careful construction of dosimetry that
compacts high dose into the tumor and not normal tissues, and extra careful treatment conduct.
This protocol will require treatments to be conducted with the use of a fixed 3-D coordinate
system defined by fiducials.  The coordinate system defined by the fiducials should be directly
related to the radiation producing device (e.g., couch and gantry) in a reproducible and secure
fashion.   Capability should exist to define the position of targets within the patient according to
this same 3-D coordinate system.  As such, the patient is set up for each treatment with the
intention of directing the radiation toward an isocenter or target according to the known 3-D
coordinates as determined in the process of treatment planning.  The nature of the fiducials
themselves may include radio-opaque markers or rods placed at known locations in a frame or
fixed structure adjacent to the patient as well as use of the tumor itself as a fiducial (e.g.
acquiring tomographic views of the tumor simultaneously with the treatment).  Metallic “seeds”
or markers placed within the tumor will be allowed so long as they are not prone to migration
movement.
4.1.1.2
Dose Fractionation
Patients will receive 5 fractions of radiation.  A minimum of 36 hours and a maximum of 8 days
should separate each treatment.  No more than 3 fractions will be delivered per week (7
consecutive days).  Total dose will be 45 Gy.
4.1.1.3
Premedications
Unless contraindicated, it is recommended that all patients receive corticosteroid premedication
(e.g. Decadron 4 mg p.o. in a single dose, or equivalent) 15-60 minutes prior to each of the five
treatments for the intended purpose of modulating immediate acute inflammatory effects. It is
strongly recommended that all patients be treated prophylactically with drugs intended to avoid
urinary retention associated with SABR.  This class of drugs include alpha blockers (e.g.,
tamsulosin aka Flomax, doxazosin aka Cardura, terazosin aka Hytrin, etc) and 5-alpha
reductase inhibitors (e.g., finasteride aka Proscar, dutasteride aka Avodart, etc), or drugs with
similar intended effect.  It is recommended to start the therapy at least one day prior o the first
SABR treatment and continue for 3 months post finishing all SABR therapy.  The drugs should
be taken at standard doses for obstructive indications, and contraindications to these drugs
should be respected.  Analgesic premedication, such as Tylenol 650 mg 30 minutes prior to
therapy and as needed every 6 hours, to avoid general discomfort during long treatment
durations also is recommended when appropriate.
4.1.1.4
Supportive medicines
Consider Tamsulosin (e.g., Flomax) during treatment period to reduce urinary symptoms.
Consider using 5-alpha reductase inhibitor like Finasteride (e.g. Proscar) to relieve potential
obstructive issues.  For both drugs, standard doses will be utilized as needed unless
contraindicated. Also consider 1 tablespoon of Milk of Magnesia, taken the night before
simulation/treatment (Note: Inform patient that this will cause diarrhea). Fleet’s enema should
be taken 2 hrs, before simulation/treatment. An antibiotic (Bactrim or similar) may be prescribed
to alleviate UTI if necessary.  This should be taken at standard doses as needed.

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4.1.2
Technical Factors
4.1.2.1
Physical Factors
Only photon (x-ray) beams produced by linear accelerators, betatrons, or microtron
accelerators with photon energies 6-21 MV will be allowed.  Cobalt-60 and charged particle
beams (including electrons, protons, and heavier ions) are not allowed.
4.1.2.2
Dose Verification/Rectal Dose Verification at Treatment
Personal dosimeter measurements (e.g. diode, TLD, etc.) may be obtained for surface dose
verification for accessible beams. This information is not required by the protocol.
4.1.3
Localization, Simulation, and Immobilization
4.1.3.1
Patient Positioning
Patients will be positioned supine in a stable position capable of allowing accurate
reproducibility of the target position from treatment to treatment.  Positions uncomfortable for
the patient should be avoided so as to prevent uncontrolled movement during treatments.  A
variety of immobilization systems may be utilized including stereotactic frames that surround
the patient on three sides and large rigid pillows (conforming to patients external contours) with
reference to the stereotactic coordinate system (see Section 6.1). Patient immobilization must
be reliable enough to insure that the Gross Tumor Volume (GTV) does not deviate beyond the
confines of the Planning Treatment Volume (PTV) as defined in Section 6.4 with any significant
probability (i.e., < 5%).
4.1.3.2
Inhibition of Effects of Internal Organ Motion
Special considerations must be made to account for the effect of internal organ motion (i.e.,
breathing, etc.) on target positioning and reproducibility.  In some cases, the intrafractional
tumor motion is small and no special maneuvers are required to achieve motion limits as
defined in section 6.4 (this may be true for many cases of prostate cancer).  Treating in the
prone position will accentuate internal organ motion problems related to breathing and should
be avoided unless special measures are taken to account for this motion.  When accounting for
intrafractional motion, acceptable maneuvers including reliable abdominal compression,
accelerator beam gating with the respiratory cycle, and active breath-holding techniques.
Internal organ inhibition maneuvers must be reliable enough to insure that the Gross Tumor
Volume (GTV) does not deviate beyond the confines of the Planning Treatment Volume (PTV)
as defined in Section 6.4 with any significant probability (i.e., < 5%).  Assessment of this motion
will be left to the institution and may include identifying the position of radio-opaque seeds
implanted into the prostate prior to each treatment. This type of interfractional motion analysis
with correction is only required by protocol just prior to each separate treatment.  Intrafraction
assessment during the course of each treatment (dynamic and adaptive maneuvers) is allowed
and encouraged especially if treatment times are long.  Based on our prior experience, we do
not anticipate significant issues with adequately controlling for inter and intrafractional motion
using our setup techniques, including pretreatment enema.
4.1.3.3
Localization and treatment maneuvers
A more direct method of localization of the prostate gland than conventional treatment (i.e., one
that uses skin and boney landmarks solely as a surrogate to the prostate position) must be
used in this protocol.  Acceptable methods would include daily ultrasound or placing a radio-
opaque seed or marker that can be visualized and triangulated using dual  imaging or markers
that emit a signal that can be used to detect position electronically, all placed prior to simulation
and planning.  Also, it would be acceptable to perform computed tomography such as axial,
spiral or conebeam CT prior to each treatment in the treatment position to identify the tumor
target directly.  Image quality should be good enough to identify the prostate borders.
In addition to the identification of the prostate in the preceding paragraph, the rectum should
also be identified.  We will perform daily enemas prior to each treatment. Prior to positioning at
least 30 minutes and no more than 2 hours before each treatment, patients should undergo an
effective bowel evacuation.  Typically, this will involve 1-2 Fleet’s enemas. This maneuver is to
clear the rectum of stool and significant gas accumulation.

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Isocenter port localization films (anterior/posterior and lateral) should be obtained at each
treatment on the treatment unit (or patients should undergo a tomographic imaging study
utilizing the linear accelerator couch, if available) immediately before treatment to ensure
proper alignment of the geometric center (i.e., isocenter) of the simulated fields.   Verification
CT scans and portal films may be taken at the discretion of the participating institution, but are
not required for protocol participation.
4.1.4
Treatment Planning/Target Volumes
4.1.4.1
Image Acquisition
Computed Tomography (CT) will be the primary image platform for targeting and treatment
planning.  The planning CT scans must allow simultaneous view of the patient anatomy and
fiducial system for stereotactic targeting.  Treatment planning images should be performed in
the treatment position using all aids/maneuvers described above including urethral tube,
bladder contrast, urethrogram, and rectal evacuation with enemas.  The treatment planning
scans may use a small caliber radio-opaque urethral catheter to allow visualization of the
prostatic urethra as it will be a high dose spillage avoidance structure for treatment planning as
indicated in section 6.4.2 below. Alternatively, MRI delineation or urethrogram may be used.
Axial acquisitions with gantry 0 degrees will be required with spacing ≤ 3.0 mm between scans.
Images will be transferred to the treatment planning computers via direct lines, disc, or tape.
CT simulation will be performed for this study.  The first simulation (scan #1) will involve all of
the above procedures, and will be performed prior to rectal spacer placement.  The patient will
then undergo rectal spacer placement, and return for repeat simulation (scan #2) under exact
same condition as above.
Image fusion with other imaging modalities such as MRI that might be useful in delineating the
target and normal tissues will be performed. T2 MRI sequence optimized for seed
localization will be allowed. This will only be performed for second simulation with rectal
spacer in place, which will be the study used for final treatment.
Planning will be performed twice for this study using same guidelines as below.  Once without
the rectal spacer, using CT simulation scan #1.  Then plan will be performed again with the
rectal spacer in place using CT simulation scan #2. We anticipate that the rectal dose
constraints will be far easier to meet with rectal spacer placed.  The dosimetrist and physicians
will be expected to create as conformal a plan as feasible to truly determine the extent of rectal
dose sparing that can be achieved without sacrificing PTV coverage, and other normal tissue
tolerance limits.
The entire prostate without the seminal vesicles will constitute the CTV target for this protocol.
It is not required to identify a GTV within the prostate, but if institutions have special techniques
to identify the gross tumor, such as MRI with high Tesla strength, it is encouraged to collect the
contours.  CTV target volume (entire prostate gland) will be outlined by an appropriately trained
physician.  The target will generally be drawn using CT soft tissue windows.  An additional 0.3-
0.5 cm in the axial plane and 0.3-1.0 cm in the longitudinal plane (cranio-caudal) will be added
to the CTV to constitute the planning treatment volume (PTV) depending on the institution’s
accuracy and treating physician’s preference. UT Southwestern has determined that uniform
expansion of 0.3 cm is sufficient margin for PTV.
4.1.4.2
Dosimetry
Three-dimensional coplanar or non-coplanar 3-D beam, arc rotation, or Intensity Modulated
Radiotherapy (IMRT) beam arrangements will be custom designed for each case to deliver
highly conformal prescription dose distributions.  Non-opposing, non-coplanar beams are
preferable.  Typically, 10-15 beams of radiation will be used with roughly equal weighting.
Generally, more beams are used for larger lesion sizes.  When static beams are used, a
minimum of 10 non-opposing beams should be used.  For arc rotation techniques, a minimum
of 300 degrees (cumulative for all beams) should be utilized.  For this protocol, the isocenter is
defined as the common point of gantry and couch rotation for the treatment unit. Field aperture

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size and shape should correspond nearly identically to the projection of the PTV along a
beam’s eye view (i.e. no additional “margin” for dose build up at the edges of the blocks or MLC
jaws beyond the PTV).  As such, prescription lines covering the PTV will typically be the 60-
90% line (rather than 95-100%); however, higher isodoses (hotspots) must be manipulated to
occur within the target and not in adjacent normal tissue.  The isocenter in stereotactic
coordinates will be determined from system fiducials (or directly from the tumor) and translated
to the treatment record.
The treatment dose plan will be made up of multiple static beams or arcs as described above.
The plan should be normalized to a defined point corresponding closely to the center of mass
of the PTV (COMPTV).  Typically, this point will be the isocenter of the beam rotation; however, it
is not a protocol requirement for this point to be the isocenter.  Regardless, the point identified
as COMPTV must have defined stereotactic coordinates and receive 100% of the normalized
dose.  Because the beam apertures coincide nearly directly with the edge of the PTV (little or
no added margin), the external border of the PTV will be covered by a lower isodose surface
than usually used in conventional radiotherapy planning, typically around 80% but ranging from
60-90%.  The prescription dose in five fractions will be delivered to the margin of the PTV and
fulfill the requirements below.  As such, a “hot spot” will exist within the PTV centrally at the
COMPTV with a magnitude of the prescription dose times the reciprocal of the chosen
prescription isodose line (i.e., 60-90%).
For purposes of dose planning and calculation of monitor units for actual treatment, all tissues
within the body should be modeled in the planning system as to their electron density. Proper
heterogeneity correction algorithms should be approved by the PI.
Successful treatment planning will require accomplishment of all of the following criteria:
1)
Normalization
The treatment plan should be normalized such that 100% corresponds to the center of
mass of the PTV (COMPTV).  This point will typically also correspond (but is not required
to correspond) to the isocenter of the treatment beams.
2)
Prescription Isodose Surface Coverage
The prescription isodose surface will be chosen such that 95% of the target volume
(PTV) is conformally covered by the prescription isodose surface and 99% of the target
volume (PTV) receives a minimum of 90% of the prescription dose.
3)
Target Dose Heterogeneity
The prescription isodose surface selected in number 2 (above) must be ≥ 60% of the
dose at the center of mass of the PTV (COMPTV) and ≤ 90% of the dose at the center of
mass of the PTV (COMPTV). The COMPTV corresponds to the normalization point (100%)
of the plan as noted in 1) above.
4)
High Dose Spillage
a) Location
Any dose greater than 105% of the prescription dose should occur primarily
within the PTV itself and not within the normal tissues outside of the PTV.
Therefore, the cumulative volume of all tissue outside of the PTV receiving a
dose greater than 105% of prescription dose should be no more than 15% of the
PTV volume. However, if possible, attempts should be made to avoid higher
than the prescription isodose to the prostatic urethra within the prostate. Ideally,
these hot spots will be manipulated to occur within the peripheral zones of the
prostate.  IMRT and other techniques will be encouraged to accomplish this goal.
b) Volume
Conformality of PTV coverage will be judged such that the ratio of the volume of
the prescription isodose meeting criteria 1) through 4) to the volume of the PTV is
ideally less than 1.3.
5)
Respect all critical organ dose-volume limits listed in Section 4.1.5 below.
6)
Urethral “hot spot” avoidance.  It is recommended that efforts be made by the use of
compensation or intensity modulation to avoid excessive dose to the urethra.  The
prostatic urethra should be identified as an avoidance structure such that dose beyond
the prescription dose ideally does not fall on this structure.  As an example, if the

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treatment dose covering the PTV corresponds to the 80% isodose line for a given patient,
hot spots of 20% higher dose will exist within the prostate.  The intensity modulation
techniques should be employed to distribute these hot spots away from the prostatic
urethra and more into the peripheral zones of the prostate.  Part of the rationale for daily
image guidance on this protocol is to carry out this intention of avoiding a “hot spot” to the
urethra in practice during treatment as depicted on the treatment plan.
4.1.5
Critical Structures
4.1.5.1
Critical Organ Dose-Volume Limits
The following table lists maximum dose limits to a point or volume within several critical organs.
These are limits, and treatment delivery that exceeds these limits will constitute a possible
protocol violation (See Section 4.1.7).  The dose is listed as total over 5 fractions and per
fraction.
These limits were formulated with the approval of the study committee using known tolerance
data, radiobiological conversion models, norms used in current practice at academic centers.
Participating centers are encouraged to observe prudent treatment planning principles in
avoiding unnecessary radiation exposure to critical normal structures irrespective of these
limits.
In order to verify each of these limits, the organs must be contoured such that appropriate dose
volume histograms can be generated.  Instruction for the contouring of these organs will follow
below.
Organ
Volume/Parameters
Dose (cGy)
Spinal Cord
Maximum point  dose
22 Gy (4.4 Gy per fraction)
Less than 8 cc
20 Gy (4 Gy per fraction)
Cauda Equina
Maximum point  dose
27.5 Gy (5.5 Gy per fraction)
Less than 10 cc
25 Gy (5 Gy per fraction)
Sacral Plexus
Maximum point  dose
30 Gy (6 Gy per fraction)
Less than 10 cc
27.5 Gy (5.5 Gy per fraction)
Rectal wall
Less than 3 cc
50 Gy
Percent Rectal Circumference*
< 33% of circumference
39 Gy
< 50% of circumference
24 Gy
Rectum superior to prostate
Maximum point dose
30 Gy (6 Gy per fraction)
Less than 10 cc
25 Gy (5 Gy per fraction)
Small intestine
Maximum point  dose
29 Gy (5.8 Gy per fraction)
Less than 10 cc
19.5 Gy (3.9 Gy per fraction)
Prostatic urethra
Maximum point  dose
No more than 105% of prescription dose
Bladder
Maximum point  dose
No more than 105% of prescription dose
Less than 18 cc
18.3 Gy (3.65 Gy per fraction)
Penile bulb
Maximum point  dose
No more than 100% of prescription dose
Less than 3 cc
30 Gy (6 Gy per fraction)
Femoral heads
Less than 10 cc cumulative 30 Gy (6  Gy per fraction)
Skin within fold (e.g., the gluteal fold)
Maximum point  dose
20 Gy (4 Gy per fraction)
Skin not within fold
Maximum point  dose
27.3 Gy (5.45 Gy per fraction)
Seminal Vesicles
No dose constraint
Collect dose statistics for documentation only
Neurovascular bundle (right and left)
Maximum point dose
No more than 105% of prescription dose
*Planning efforts should be made to keep the percent rectal circumference receiving 39 Gy < 20% and <
24 Gy under 25% in the post-spacer plan.

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4.1.5.2 Contouring of Normal Tissue Structures
4.1.5.2.1
Spinal Cord
The spinal cord will be contoured as one structure based on the bony limits of the spinal
canal.  The spinal cord should be contoured anywhere it is visualized in the treatment plan
(typically superior to L2). Contouring this structure is unnecessary if it is >3cm above the
superior extent of the PTV.
4.1.5.2.2
Cauda Equina
The cauda equina will be contoured as one structure based on the bony limits of the spinal
canal.  The cauda equina should be contoured starting superiorly at the bottom of the spinal
cord (typically around L2 and terminal at the inferior extent of the thecal sac (typically at S3).
4.1.5.2.3
Sacral Plexus
The left and right sacral plexus will be contoured collectively as one structure.  The location
of the sacral plexus will be approximated by contouring the space defined medially by the
sacral foramina from S1-S3 including contouring within the sacral foramina, posteriorly along
the limits of the true pelvis, laterally to 2-3 cm lateral to the sacral foramina, and anteriorly
about 3-5 mm from the posterior limits of the contour.
4.1.5.2.4
Peri-prostatic Rectal wall
The circumference of the rectum adjacent to the prostate will be contoured. Only the outer
rectal wall will be included in these contours.  Rubber catheter and MRI can be used to help
delineate rectal volume.
4.1.5.2.4.1
Peri-prostatic Rectum
Starting inferiorly just above the anal sphincter, the outer rectal wall should be contoured
up to 1 cm above the superior extent of the prostate.
4.1.5.2.4.5
Percent Rectal Circumference
L24 = axial length of rectal wall treated by 24 Gy
L39 = axial length of rectal wall treated by 39 Gy.
At the level of mid prostate gland, the L24 and L39 were estimated by measuring the
distance from the 24 Gy, and 39 Gy isodose lines at the right and left edge of the rectal
wall to the mid anterior rectal wall.
Percent Rectal Circumference (PRC): The circumference of the rectum at the same level
was estimated using formula π x diameter. The percent rectal circumference (PRC)
treated by 24 Gy, and 39 Gy at mid prostate gland level was estimated by formula L24or
39/(circumference).
4.1.5.2.5
Rectum Superior to Prostate
Starting inferiorly at the superior extent of the Peri-prostatic Rectuml described above, the
entire wall and lumen of the rectum should be contoured up to the level of the sacral
promontory.
4.1.5.2.6
Small Intestine
The small intestines should be contoured as a conglomerate of all bowel loops within each
CT cut starting at the first appearance of small intestine in the pelvis and extending
superiorly up to the level of the sacral promontory within each cut.
4.1.5.2.7
Prostatic Urethra
The prostatic urethra will be identified by the urethral catheter plus 1-2 mm of tissue radially
into the prostate, or on comparison with MRI.  The inferior aspect of the prostatic urethra
coincides with the apex of the prostate (urethrograms may be helpful in identifying the apex).
The superior aspect of the prostatic urethra coincides with the base of the prostate at the
bladder inlet.

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4.1.5.2.8
Bladder
The bladder should be contoured in its entirety absent its contents.  As such, only the wall of
the bladder is included in the dose volume analysis.  The bladder wall may be approximated
by contouring the outer outline of the entire bladder and subtracting this volume from the
same volume minus 0.5 cm in all directions (to define the inner surface of the bladder).
4.1.5.2.9
Penile Bulb
The penile bulb will be contoured starting superiorly at the inferior aspect of the pelvic
diaphragm (urethral sphincter) and extending inferiorly and anteriorly up to 3 cm.
4.1.5.2.10 Femoral heads
The femoral heads will be contoured bilaterally as one structure.
4.1.5.2.11 Skin
The skin will constitute the external contour minus 5 mm.  The skin within folds, especially in
the gluteal folds as the skin surfaces make contact, will be contoured as a separate
structure.
4.1.5.2.12 Seminal vesicles
The seminal vesicles should be contoured right and left as one structure.  There is no
protocol dose constraint for these structures, but they will be contoured to collect dose
deposition data.
4.1.5.2.13
Anus
Anus will be contoured as one structure starting just inferior to rectum.
4.1.5.2.14 Neurovascular Bundles
The neurovascular bundles will be contoured as separate structures within 1cm of the
prostate volume, as visualized on the planning MRI.
4.1.6
Documentation Requirements
In general, treatment interruptions should be avoided by preventative medical measures and
nutritional, psychological, and emotional counseling.  Treatment breaks, including
indications, must be clearly documented on the treatment record.
4.1.7
Compliance Criteria
4.1.7.1
Dosimetry Compliance
Section 4 describes appropriate conduct for treatment planning dosimetry. In addition to the
criteria in section 4.1.4.2, the table in Section 4.1.5 lists dose volume limits for specific
organs and structures.  Exceeding these limits by more than 2.5% constitutes a minor
protocol violation.  Exceeding these limits by more than 5% constitutes a major protocol
violation.
4.1.7.2
Treatment Delivery Compliance
Set-up films will be compared to digitally reconstructed radiographs from the same beam’s
eye view.  Deviations of less than 0.5 cm will be considered compliant.  Deviations from 0.5-
0.75 cm will be considered minor protocol deviations.  Deviations greater than those listed
as minor will be considered major protocol deviations.
4.1.8
R.T. Quality Assurance Reviews
Dr. Timmerman, along with a medical physicist, will perform an RT Quality Assurance Review
once 5 cases have been enrolled at the University of Texas Southwestern. They will perform the
next review after complete data for the next and subsequent 5-10 cases enrolled has been
received at the University of Texas Southwestern. The final cases will be reviewed within 3
months after this study has reached the target accrual or as soon as complete data for all cases
enrolled has been received, whichever occurs first.

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4.2
Toxicities and Dosing Delays/Dose Modifications
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient will
be assessed for the development of toxicity according to the Time and Events table (Section 5).
Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events
(CTCAE), version 4.0. Dose adjustments should be made according to the system showing the
greatest degree of toxicity.
4.2.1
Radiation Adverse Events
4.2.1.1
Gastro-intestinal
Monitored treatment related toxicity associated with gastrointestinal function will include
colitis, dehydration, diarrhea, enteritis, fistula, nausea, vomiting, obstruction, proctitis, fecal
incontinence, stricture/stenosis, hemorrhage, and ulcer.  The consequences of gastro-
intestinal toxicity should all be graded according to the Common Terminology Criteria For
Adverse Events (CTCAE).
4.2.1.2
Renal/Genitourinary/Sexual/Reproductive
Monitored treatment related toxicity associated with renal and genito-urinary function will
include cystitis, fistula, urinary incontinence, urinary obstruction, stricture/stenosis,
hemorrhage, and urinary retention.  Monitored treatment related toxicity associated with
sexual and reproductive function will include erectile dysfunction and ejaculatory
dysfunction.  The consequences of renal/genitourinary/sexual and reproductive toxicity
should all be graded according to the Common Terminology Criteria For Adverse Events
(CTCAE).  In addition, patients will fill out the AUA scoring sheets reflecting basic urinary
function at regular intervals according to the study calendar in Appendix VI.
4.2.1.3
Neurology
Monitored treatment related toxicity associated with neurology function will include myelitis,
motor and sensory neuropathy, plexopathy, and pain.  The consequences of neurology
toxicity should all be graded according to the Common Terminology Criteria For Adverse
Events (CTCAE).
4.2.1.4
Constitutional Symptoms
Monitored treatment related toxicity associated with constitutional function will include
fatigue, fever, and weight loss.  The consequences of constitutional toxicity should all be
graded according to the Common Terminology Criteria For Adverse Events (CTCAE).
4.2.1.5
Skin
Monitored treatment related toxicity associated with skin function will include fibrosis, rash
(desquamation), ulceration, and telangiectasia.  The consequences of skin toxicity should all
be graded according to the Common Terminology Criteria For Adverse Events (CTCAE).
4.2.1.6
Quality of Life and Other Toxicities
Other treatment related toxicity attributed to the therapy will be captured, recorded and the
consequences of should all be graded according to the Common Terminology Criteria For
Adverse Events (CTCAE).  Quality of life after prostate cancer treatment will be assess
using the Expanded Prostate Cancer Index Composite (EPIC) formalism [41].  Validation
and description of this scale can be found at the website:
http://roadrunner.cancer.med.umich.edu/epic/epicmain.html
4.3
Concomitant Medications/Treatments
Permitted Supportive Therapy
All supportive therapy for optimal medical care will be given during the study period at the
discretion of the attending physician(s) within the parameters of the protocol and documented on
each site’s source documents as concomitant medication.
Below is a non-comprehensive list of categories of medications permitted.
4.3.1
Obstructive flow medicines (alpha blockers) 5 alpha reductase inhibitors)
4.3.2
Antiemetics

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4.3.3
Anticoagulants
4.3.4
Antidiarrheals
4.3.5
Analgesics
4.3.6
Hematopoietic Growth Factors
4.3.7
Herbal products
4.3.8
Nutritional supplementation
4.3.9
Antibiotics for Rectal spacer procedure at Urologist discretion.
4.3.10 Rectal corticosteroid medications
4.4
Other Modalities or Procedures
4.4.1
RECTAL SPACER AND FIDUCIAL PLACEMENT
Fiducial placement for image guidance is a routine procedure being performed by
qualified/trained physicians at UTSW and Parkland Medical Center.  There will be
no significant changes in this routine procedure.  Fiducials will be placed by
qualified physicians no less than 10-14 days prior to SABR planning CT simulation.
In addition, rectal spacer placement will be performed by qualified trained
physicians, many of whom are members of the Urology department (Physicians
and P.A.s) or the Radiation Oncology departments of UTSW and MSKCC
(Physicians with significant brachytherapy and fiducial placement experience).
Technique for spacer insertion is outlined below, based on excellent methods
paper from [37]).
Rectal Spacer (SpaceOAR):
The rectal Spacer system consists of components for the preparation of the
absorbable hydrogel spacer with its delivery mechanism provided in a single-use
kit. The spacer hydrogel is formed by simultaneously injecting two solutions, the
precursor and the accelerator, into the perirectal space. The solutions mix during
injection, initiating a cross-linking reaction that result in the formation of a soft
PEG-based gel within 10 s, without a measurable temperature rise. The hydrogel
remains in the body for 12 weeks (SpaceOAR), after which hydrolysis causes the
implant to liquefy, resulting in complete absorption.
Hydrogel injection technique:
The hydrogel is injected transperineally using hydrodissection to facilitate
placement. The potential perirectal space for hydrogel placement is between
Denonvilliersfascia and the rectal wall (Fig. 1). Denonvilliers’ fascia consists of a
single fibromuscular structure covering the posterior aspect of the prostate. This
important anatomical boundary separates the prostate from the anterior rectal
wall. It is important that the hydrogel is injected on the posterior side of
Denonvilliers ’ fascia and anterior to the anterior rectal wall to minimize the risk of
pushing cancer cells away from the high dose radiation fi eld [42]. In addition,
care must be taken to avoid inadvertent injection into the rectal wall which can
potentially lead to ischaemia or increased rectal wall stresses. The spacing
hydrogel is injected using a transperineal approach under TRUS guidance. A
transrectal approach cannot be used because of potential bacterial
contamination. Hydrodissection is a technique used to separate tissue planes
through the use of fluid.  The insertion of the hydrogel spacer is facilitated with
the use of hydrodissection. Small volumes of fluid are carefully injected through
an 18-G needle between Denonvilliers’ fascia and the anterior rectal wall to open
the potential space before injecting the hydrogel. By this means, enough space
for the spacer hydrogel is created and steady dispersion of the spacing agent is
ensured.
Insertion Procedure: The insertion procedure itself is a short procedure that can
be performed under local, spinal or light general anaesthesia in an outpatient
setting. Prophylactic antibiotics will be given.  Transperineal fiducial placement
will be performed before the hydrogel injection.\ The patient will be placed in the

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lithotomy position. A TRUS probe, covered by a stand-off balloon will be used for
ultrasonography imaging and proper needle and anatomical visibility (Figure 2A).
The device is mounted to an adjustable stepper unit, freeing both the physician’s
hands. Under real-time TRUS guidance in the sagittal plane, the injection needle
(18G × 15 cm), with an attached syringe containing saline or lidocaine 0.5 – 1.0%
diluted in 15 mL saline, is inserted ∼1 cm above the TRUS probe through the
perineum and carefully advanced to the pelvic floor muscles at an angle parallel
to the TRUS probe. After penetration of the rectourethralis muscle, the tip is
positioned inferior to the prostatic apex, just between Denonvilliers’ fascia and
the anterior rectal wall. Hydrodissection is started using small volumes of fluid to
slowly open up the potential space between Denonvilliers’ fascia and the anterior
rectal wall. Once the correct space starts to open, the needle is advanced into
the space, and saline injection/needle advancement continued until the needle tip
reaches mid-gland. By this means, space for the spacer hydrogel is created ( Fig.
2b ). After confirming the correct position of the needle with both sagittal and
axial ultrasound views, and aspirating to ensure the needle tip was not in vessel,
the saline syringe is removed. The syringe assembly is then attached,
maintaining needle position, and 10 mL of hydrogel will be administered in one
continuous motion in 8 – 10 s without moving the needle during injection (figure
2c). In the case of insufficient hydrodissection or unintentional rectal wall
perforation, spacer hydrogel injection is aborted. The distance from the rectal
wall to the prostate/Denonvilliers’ fascia will be measured before and after the
injection procedure.  Adverse events, if any, during and after the spacer injection
procedure will be assessed and documented.
Figure 1. Anatomy of Rectum/Prostate Region (Sagittal View) taken from [37]

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Figure 2. Procedure for TRUS guided transperineal spaceOAR placement. Taken from [37]
4.4.2
Hydrogel Placement Procedure Related Adverse Events
Safety events that could be attributed to device and procedure will continuously be monitored:
4.4.2.1 Gastro-intestinal
Monitored treatment related toxicity associated with gastrointestinal function will include colitis,
dehydration, diarrhea, enteritis, fistula, nausea, vomiting, obstruction, proctitis, fecal incontinence,
stricture/stenosis, hemorrhage, and ulcer.  The consequences of gastro-intestinal toxicity should all be
graded according to the Common Terminology Criteria For Adverse Events (CTCAE). This will be
monitored periprocedural period, and for the duration of spacer presence in the body (3 months) post
procedure.
4.4.2.2 Renal/Genitourinary/Sexual/Reproductive
Monitored treatment related toxicity associated with renal and genito-urinary function will include cystitis,
fistula, urinary incontinence, urinary obstruction, stricture/stenosis, hemorrhage, and urinary retention.
Monitored treatment related toxicity associated with sexual and reproductive function will include erectile
dysfunction and ejaculatory dysfunction.  The consequences of renal/genitourinary/sexual and
reproductive toxicity should all be graded according to the Common Terminology Criteria For Adverse
Events (CTCAE). This will be monitored periprocedural period, and for the duration of spacer presence in
the body (3 months) post procedure.
4.4.2.3 Infection
Monitored procedure related toxicity including fever, urinary tract infection, bacteremia, sepsis. This will be
monitored in the periprocedural period and for the duration of spacer presence (3 months) post procedure.

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POST TREATMENT: GI, GU EVENTS, BASED ON CTCAE V4.0.
4.5
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may
continue until:

Disease progression

Inter-current illness that prevents further administration of treatment

Unacceptable adverse event(s)

Subject decides to withdraw from the study, OR

General or specific changes in the patient’s condition render the
subject unacceptable for further treatment in the judgment of the
investigator.
4.6
Duration of Follow Up
Initial follow-up visit at 6 weeks from the end of treatment.
4.6.1
After initial follow-up visit, follow-up will be done at 3, 6, 9, and 12 months post therapy.
4.6.2
Then every six months until five years post treatment.
4.6.3
Then annually for years 5-10; follow up after year 3 on protocol is performed on a
voluntary basis at the enrolling investigator’s discretion; all patients should be followed even off
protocol as per standard clinical practice.
4.7
Removal of Subjects from Protocol Therapy
Subjects will be removed from therapy when any of the criteria listed in Section
5.5 apply. Notify the Principal Investigator, and document the reason for study
removal and the date the subject was removed in the Case Report Form. The
subject should be followed-up per protocol.
5.0
STUDY PROCEDURES
5.1
Screening/Baseline Procedures
Assessments performed exclusively to determine eligibility for this study will be
done only after obtaining informed consent. Assessments performed for clinical
indications (not exclusively to determine study eligibility) may be used for
baseline values even if the studies were done before informed consent was
obtained.
All screening procedures must be performed prior to registration. The screening
procedures include:
5.1.1
Informed Consent
5.1.2
Medical history
Complete medical and surgical history, history of infections
5.1.3
Demographics
Age, gender, race, ethnicity
5.1.4
Review subject eligibility criteria
5.1.5
Review previous and concomitant medications
5.1.6
Physical exam including vital signs, height and weight
Vital signs (temperature, pulse, respirations, blood pressure), height,
weight

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5.1.7
Performance status
Performance status evaluated prior to study entry according to Appendix II.
5.1.8
Serum chemistries (within 90 days prior to registration)
PSA, BUN, creatinine, CBC w/ diff
5.1.9
Tumor assessment
5.1.10
CT or MRI prostate (within 90 days prior to registration)
Diagnostic MRI is preferred, at physician’s discretion; a pre-spacer
simulation CT scan may be used to satisfy this requirement
5.1.11
QOL questionnaires (AUA; EPIC – may be done after registration)
5.1.12
Prostate biopsy (within 180 days prior to registration)
Repeat prostate biopsy for patients with biopsy >180 days from study entry is not
required unless the PSA taken prior to study entry is greater than the PSA taken at the
time of biopsy by more than 5 ng/ml.
5.2
Procedures During Treatment
Study Parameters:.

For each patient, plan will be evaluated to assess:

Was >=7.5 mm space created between prostate and rectum by the
spacer?

(Yes/No, document space distance)

Was PRC 24 Gy and 39 Gy of treatment plan with spacer reduced by
at least 50% compared to prerectal spacer plan?

(Yes/No, and documentation of PRC 24 Gy and 39 Gy)

Document spacer related toxicity during and 3 months post procedure.
5.2.1
At Each Treatment Cycle

Physical exam, vital signs (once per course)

CT or MRI (cone beam CT acceptable) prior to each treatment
fraction

AE evaluation (once per course)
5.3
Follow-up Procedures
5.3.1
Initial follow-up visit at 6 weeks from the end of treatment.
For each patient, anoscopic evaluation of the periprostatic rectum will be
performed at 6, 12, 24, and 36 weeks by the treating physician, and
presence or absence of ulcer will be documented.
5.3.2
After initial follow-up visit, follow-up will be done at 3, 6, 9, and 12
months post therapy.
5.3.3
Then every six months until five years post treatment.
5.3.4
Then annually for years 5-10; follow up after year 3 on protocol is
performed on a voluntary basis at the enrolling investigator’s discretion; all
patients should be followed even off protocol as per standard clinical practice.
5.4
Summary of Data Submission

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Item
Due
Demographics
Within 2 weeks of study entry
Eligibility and Entry Characteristics
including baseline H&P and PSA
Within 2 weeks of study entry
Pathology Report
Within 2 weeks of study entry
AUA and EPIC baseline forms
Within 2 weeks of study entry
SABR dosimetry information
Within 1 week after completion of SABR
Follow-up H&P data including PSA,
anoscopic findings
After last SABR treatment, post SABR
follow-up at 1.5, 3, 6, 9, 12 months, then
every 6 months to 5 years; then annually
for years 5-10
AUA and EPIC post treatment forms
After last SABR treatment, post SABR
follow-up at 1.5, 3, 12, and 18 months
Adverse Event assessment
After each SABR treatment, then post
SABR follow-up at 1.5, 3, 6, 9, and 12
months, then every 6 months to 5 years;
then annually for years 5-10. Followup
after year 3 on protocol is performed on
a voluntary basis at the enrolling
investigator’s discretion; all patients
should be followed even off protocol as
per standard clinical practice.

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5.5
Time and Events Table
Pre-Treatment
During
Treat-
ment
Follow-Up (months after therapy)
Within
180
days
prior
to
study
entry
Within
90
days
prior
to
study
entry
Within
30
days
prior
to
study
entry
After
study
entry
With
each
treatmen
t
1.5
3
6
9
12
18
24
30
36
42
i
48 i
54
i
60
i
Every 12
months
for years
5-10 i
Prostate Biopsy
with Gleason
Score for
Diagnosis
Xe
PSA
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rectal Spacer
Measurements
Xaa
Rectal
Dosimetric
Parameters
Measurements
Xaa
History/
physical
X
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CT or MRI of
prostate
Xccc
Xbb
Xb
AUA Symptom
index
X
X
X
X
X
EPIC
Questionnaire
Xh
Xh
X
X
X
X
BUN, creatinine,
CBC, & platelets
Xc
Blood Draw for
Translational
Research
X f
Xg
X
Tumor response
evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event
evaluation
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
Anoscopic
Evaluation
X
X
X
X
X = required
aBaseline PSA should be recorded as pre-hormonal level if taking hormones even if >60 days prior to
entry.
aa When plan is available to review prior to treatment
bbCT simulation in Radiation Oncology Department with immobilization and set up as directed in section
6.3.1 for baseline study prior to rectal spacer placement. [The first CT simulation may be substituted for
diagnostic scan at physician’s discretion; in this case, the first (pre-spacer) CT simulation will be done
prior to study entry. A second CT simulation will be performed after rectal spacer placement. Limited
protocoled MRI for fusion/planning will be performed.]
ccc MRI is preferred; CT can be performed instead; pre-spacer CT performed within 30 days prior to study
entry may be substituted at physician’s discretion
bCT or MRI prior to each treatment fraction may include conebeam CT.
cFor reference but not eligibility
dAt time of PSA failure or suspected progression

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eRepeat prostate biopsy for patients with biopsy >180 days from study entry is not required unless the
PSA taken prior to study entry is greater than the PSA taken at the time of biopsy by more than 5 ng/ml.
f1 week prior to first treatment, if patient consents to tissue procurement study.
gImmediately after first treatment, immediately before second treatment, immediately after fifth treatment if
patient consents to tissue procurement study.
hEpic questionnaire can be completed either prior to or after study entry.
i Follow up after year 3 on protocol is performed on a voluntary basis at the enrolling investigator’s
discretion; all patients should be followed even off protocol as per standard clinical practice.
j Required once during treatment course
5.6
Removal of Subjects from Study
Subjects can be taken off the study treatment and/or study at any time at their own request, or
they may be withdrawn at the discretion of the investigator for safety, behavioral or administrative
reasons. The reason(s) for discontinuation will be documented and may include:
5.5.1
Subject voluntarily withdraws from treatment (follow-up permitted);
5.5.2
Subject withdraws consent (termination of treatment and follow-up);
5.5.3
Subject is unable to comply with protocol requirements;
5.5.4
Subject demonstrates disease progression (unless continued treatment with study drug is
deemed appropriate at the discretion of the investigator);
5.5.5
Subject experiences toxicity that makes continuation in the protocol unsafe;
5.5.6
Treating physician judges continuation on the study would not be in the subject’s best
interest;
5.5.7
Subject becomes pregnant (pregnancy to be reported along same timelines as a serious
adverse event);
5.5.8
Development of second malignancy (except for basal cell carcinoma or squamous cell
carcinoma of the skin) that requires treatment, which would interfere with this study;
5.5.9
Lost to follow-up. If a research subject cannot be located to document survival after a
period of 2 years, the subject may be considered “lost to follow-up.” All attempts to
contact the subject during the two years must be documented Measurement of Effect
5.6
Antitumor Effect- Solid Tumors
5.6.1
Disease Parameters
Measurable Disease: Tumor lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is to be recorded) with a
minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice
thickness recommended to be no greater than 5 mm). Lymph nodes merit special
mention since they are normal anatomical structures which may be visible by imaging
even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by
CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short
axis of the node is the diameter normally used by radiologists to judge if a node is
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in
which the image is obtained (for CT scan this is almost always the axial plane; for MRI
the plane of acquisition may be axial, sagittal or coronal). The smaller of these measures
is the short axis. For example, an abdominal node which is reported as being 20 mm x 30

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mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this
example, 20 mm should be recorded as the node measurement. All other pathological
nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
Note: Previously irradiated lesions are non-measurable except in cases of documented
progression of the lesion since the completion of radiation therapy.
Non-measurable disease.
All other lesions are considered non-measurable, including small lesions (longest
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well
as truly non-measurable lesions. Lesions considered truly non-measurable include:
leptomeningeal disease, ascites, pleural or pericardial effusion, and inflammatory breast
disease, lymphangitic involvement of skin or lung, abdominal masses /abdominal
organomegaly identified by physical exam that is not measurable by reproducible imaging
techniques.
Target lesions.
All measurable lesions up to a maximum of five lesions total (and a maximum of two
lesions per organ) representative of all involved organs should be identified as target
lesions
Non-target lesions. All other lesions (or sites of disease) including any measurable
lesions over and above the five target lesions should be identified as non-target lesions
and should also be recorded at baseline. Measurements of these lesions are not
required, but the presence or absence of each should be noted throughout follow-up.
6.1.2
Other Response Parameters
Disease-Free Interval: The disease-free interval will be measured from
the date of accession to the date of documentation of progression or until
the date of death (from other causes).
Time to Biochemical Failure: The RTOG-ASTRO definition (also known
as the Phoenix definition) of PSA failure will be used. Thus, when the
PSA rises by more than 2 ng/ml above the lowest level (nadir) achieved
after treatment, biochemical failure has occurred and the date of the
failure is recorded at the time the nadir plus 2 ng/ml level is reached.
Time to Local Progression: The time to progression will be measured
from the date of study entry to the date of documented local progression
as determined by clinical exam.
Time to Distant Failure: The time to distant failure will be measured from
the date of study entry to the date of documented regional nodal
recurrence or distant disease relapse. Patients with evidence of
biochemical failure, but a negative prostate biopsy, will be considered as
distant failure only.
Overall Survival: The survival time will be measured from the date of
accession to the date of death. All patients will be followed for survival.
Every effort should be made to document the cause of death.
Disease-Specific Survival Disease-specific survival will be measured
from the date of study entry to the date of death due to prostate cancer.
The following will be considered as failure events in assessing disease
specific survival:

Death certified as due to prostatic cancer.

Death from other causes with active malignancy (clinical or biochemical
progression).

Death due to complications of treatment, irrespective of the status of
malignancy.

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
Death from other causes with previously documented relapse (either
clinical or biochemical) but inactive at the time of death will not be
considered in disease-specific survival, but will be analyzed separately.
6.1.4
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or
calipers. All baseline evaluations should be performed as closely as possible to the
beginning of treatment and never more than 28 days before the beginning of the
treatment.
The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during follow-up.
Imaging-based evaluation is preferred to evaluation by clinical examination when both
methods have been used to assess the antitumor effect of a treatment.
5.6.5
Response Criteria
5.6.5.1 Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.
Disappearance of all target lesions. Any pathological lymph
nodes (whether target or non-target) must have reduction in
short axis to <10 mm (the sum may not be “0” if there are target
nodes). Determined by two separate observations conducted
not less than 4 weeks apart. There can be no appearance of new
lesions.
Partial Response (PR): At least a 30% decrease in the sum of
the longest diameter (LD) of target lesions, taking as reference
the baseline sum LD. There can be no appearance of new
lesions.
Progressive Disease (PD): > 20% increase in the SLD taking as
reference the smallest SLD recorded since the treatment started
(nadir) and minimum 5 mm increase over the nadir.
Stable Disease (SD): Neither sufficient shrinkage to qualify for
PR nor sufficient increase to qualify for PD, taking as reference
the smallest sum LD since the treatment started. There can be
no unequivocal new lesions.
5.6.5.2 Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target
lesions and normalization of tumor marker level. All lymph nodes
must be non-pathological in size (< 10 mm short axis).
Incomplete Response/Stable Disease (Non-CR/Non-PD):
Persistence of one or more non-target lesion(s) and/or
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new
lesions and/or unequivocal progression of existing non-target
lesions

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5.6.5.3 Evaluation of Best Overall Response
The best overall response is the best response recorded from
the start of the treatment until disease progression/recurrence
(taking as reference for progressive disease the smallest
measurements recorded since the treatment started). The
subject’s best response assignment will depend on the
achievement of both measurement and confirmation criteria.
Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, NE = not evaluable, PD = progressive disease, PR =
partial response, SD = stable disease.
Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, NE = not evaluable, PD = progressive disease
A ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is
increasingly used as endpoint for assessment of efficacy in some trials so to assign this
category when no lesions can be measured is not advised.
5.6.6
Duration of Response
Duration of overall response: The duration of overall response is
measured from the time measurement criteria are met for CR or PR
(whichever is first recorded) until the first date that recurrent or
progressive disease is objectively documented (taking as reference for
progressive disease the smallest measurements recorded since the
treatment started).
The duration of overall CR is measured from the time measurement
criteria are first met for CR until the first date that recurrent disease is
objectively documented.
Duration of stable disease: Stable disease is measured from the start of
the treatment until the criteria for progression are met, taking as

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reference the smallest measurements recorded since the treatment
started.
5.6.7
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from
start of treatment to time of progression.
5.7
Safety/tolerability
Analyses will be performed for all subjects having received at least one dose of
study drug. The study will use the CTCAE version 4.0 for reporting of non-
hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and
modified criteria for hematologic adverse events.
6.0
ADVERSE EVENTS
7.1
Experimental Therapy
For the most recent safety update, please refer to the current Investigator’s
Brochure or Study Agent Prescribing Information.
7.1.1 Risks Associated with Placement of Rectal Spacer
Gastrointestinal- colitis, dehydration, diarrhea, enteritis, fistula, nausea, vomiting,
obstruction, proctitis, fecal incontinence, stricture/stenosis, hemorrhage, and
ulcer
Renal/Genitourinary/Sexual/Reproductive - cystitis, fistula, urinary incontinence,
urinary obstruction, stricture/stenosis, hemorrhage, and urinary retention.
Infection – fever, urinary tract infection, bacteremia, sepsis
6.2
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every
clinical trial, are done to ensure the safety of subjects enrolled in the studies as
well as those who will enroll in future studies using similar agents. Adverse
events are reported in a routine manner at scheduled times during a trial.
Additionally, certain adverse events must be reported in an expedited manner to
allow for optimal monitoring of subject safety and care.
All subjects experiencing an adverse event, regardless of its relationship to study
drug, will be monitored until:

the adverse event resolves or the symptoms or signs that constitute the
adverse event return to baseline;

there is a satisfactory explanation other than the study drug for the
changes observed; or

death.
6.2.1
Definition
An adverse event is defined as any untoward or unfavorable medical occurrence
in a human research study participant, including any abnormal sign (for example,
abnormal physical exam, imaging finding or clinically significant laboratory
finding), symptom, clinical event, or disease, temporarily associated with the
subject’s participation in the research, whether or not it is considered related to
the subject’s participation in the research.
Adverse events encompass clinical, physical and psychological harms. Adverse
events occur most commonly in the context of biomedical research, although on

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occasion, they can occur in the context of social and behavioral research.
Adverse events may be expected or unexpected.
Acute Adverse Events
Adverse events occurring in the time period from the signing of the informed
consent, through 30 days post treatment will be considered acute adverse
events. All acute adverse events will be assessed and reported as per below.
Late Adverse Events (as applicable)
Adverse effects occurring in the time period from the end of acute monitoring, to
5 years post treatment, will be defined as late adverse events. These events will
include all adverse events reported directly to a member of the study team and
will be captured, assessed, graded and reported as appropriate.
In addition, the study team will only review encounters in records from Radiation
Oncology and Urology providers and limit reporting to events in the GI/GU
system.
Adverse events encompass clinical, physical and psychological harms. Adverse
events occur most commonly in the context of biomedical research, although on
occasion, they can occur in the context of social and behavioral research.
Adverse events may be expected or unexpected.
Severity
Adverse events will be graded by a numerical score according to the defined NCI
Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and
version number 4.0 specified in the protocol. Adverse events not specifically
defined in the NCI CTCAE V4.0 will be scored on the Adverse Event log
according to the general guidelines provided by the NCI CTCAE V4.0 and as
outlined below.

Grade 1: Mild

Grade 2: Moderate

Grade 3: Severe or medically significant but not immediately life
threatening

Grade 4: Life threatening consequences

Grade 5: Death related to the adverse event
Serious Adverse Events
ICH Guideline E2A and the UTSW IRB define serious adverse events as those
events, occurring at any dose, which meets any of the following criteria:

Results in death

Immediately life-threatening

Results in inpatient hospitalization1,2 or prolongation of existing
hospitalization

Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect

Based upon appropriate medical judgment, may jeopardize the subject’s
health and may require medical or surgical intervention to prevent one of
the other outcomes listed in this definition.
Note: A “Serious adverse event” is by definition an event that meets any of the
above criteria. Serious adverse events may or may not be related to the research

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project. A serious adverse event determination does not require the event to be
related to the research. That is, both events completely unrelated to the condition
under study and events that are expected in the context of the condition under
study may be serious adverse events, independent of relatedness to the study
itself. As examples, a car accident requiring >24 hour inpatient admission to the
hospital would be a serious adverse event for any research participant; likewise,
in a study investigating end-stage cancer care, any hospitalization or death which
occurs during the protocol-specified period of monitoring for adverse and serious
adverse events would be a serious adverse event, even if the event observed is
a primary clinical endpoint of the study.
1Pre-planned hospitalizations or elective surgeries are not considered SAEs.
Note: If events occur during a pre-planned hospitalization or surgery, that prolong
the existing hospitalization, those events should be evaluated and/or reported as
SAEs.
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient
hospital stay equal to or greater than 24 hours. Hospitalization is used as an
indicator of the seriousness of the adverse event and should only be used for
situations where the AE truly fits this definition and NOT for hospitalizations
associated with less serious events. For example: a hospital visit where a patient
is admitted for observation or minor treatment (e.g. hydration) and released in
less than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is
not an AE and therefore is not to be reported either as a routine AE or in an
expedited report.
6.2.2
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs):
The phrase “unanticipated problems involving risks to subjects or others” is
found, but not defined in the HHS regulations at 45 CFR 46, and the FDA
regulations at 21 CFR 56.108(b)(1) and 21 CFR 312.66. For device studies, part
812 uses the term unanticipated adverse device effect, which is defined in 21
CFR 812.3(s). Guidance from the regulatory agencies considers unanticipated
problems to include any incident, experience, or outcome that meets ALL three
(3) of the following criteria:
•
Unexpected in terms of nature, severity or frequency given (a) the research
procedures that are described in the protocol-related documents, such as the
IRB-approved research protocol and informed consent document; and (b) the
characteristics of the subject population being studied;
AND
•
Related or possibly related to participation in the research (possibly related
means there is a reasonable possibility that the incident, experience, or outcome
may have been caused by the procedures involved in the research);
AND
•
Suggests that the research places subjects or others at greater risk of harm
(including physical, psychological, economic, or social harm) than was previously
known or recognized. Note: According to OHRP, if the adverse event is serious,
it would always suggest a greater risk of harm.
Follow-up
All adverse events will be followed up according to good medical practices.

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6.2.3
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer
Center (SCCC) Data Safety Monitoring Committee (DSMC)
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for
which the SCCC is the DSMC of record require reporting to the DSMC
regardless of whether IRB reporting is required. All SAEs/UPIRSOs occurring
during the protocol-specified monitoring period should be submitted to the SCCC
DSMC within 5 business days of the PI or delegated study team members
awareness of the event(s). In addition, for participating centers other than UTSW,
local IRB guidance should be followed for local reporting of serious adverse
events.
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC
DSMC Coordinator.  Hardcopies or electronic versions of the eIRB Reportable
Event report; FDA Form #3500A forms, or other sponsor forms, if applicable;
and/or any other supporting documentation available should be submitted to the
DSMC Coordinator.  The DSMC Coordinator forwards the information onto the
DSMC Chairman who determines if immediate action is required.  Follow-up eIRB
reports, and all subsequent SAE/UPIRSO documentation that is available are also
submitted to the DSMC Chair who determines if further action is required. (See
Appendix III of the SCCC DSMC Plan for a template Serious Adverse Event Form
which may be utilized when a sponsor form is unavailable and SAE submission to
the eIRB is not required).
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW
Simmons Comprehensive Cancer Center, the DOT Manager or lead coordinator
ensures that all participating sites are notified of the event and resulting action,
according to FDA guidance for expedited reporting. DSMC Chairperson reviews
all SAEs/UPIRSOs upon receipt from the DSMC Coordinator.  The DSMC
Chairperson determines whether action is required and either takes action
immediately, convenes a special DSMC session (physical or electronic), or
defers the action until a regularly scheduled DSMC meeting.
Telephone reports to: Dr. Michael Folkert MD, PhD
Phone number: 214-645-8525
Written reports to:
Investigator: Michael Folkert, MD, PhD
Department of Radiation Oncology
Clinical Research Office
The University of Texas Southwestern Medical Center
Attention: Sarmistha Sen, Project Manager
2201 Inwood Road
Dallas, Texas  75390-9303
FAX #: 214-648-5923
UTSW SCC Data Safety Monitoring Committee Coordinator
Email: SCCDSMC@utsouthwestern.edu
Fax: 214-648-7018 or deliver to NB 2.418
UTSW Institutional Review Board (IRB)
Submit via eIRB with a copy of the final sponsor report as attached supporting
documentation

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Reporting Unanticipated Problems Involving Risks to Subjects or Others
(UPIRSOs) to the UTSW HRPP/IRB
UTSW reportable event guidance applies to all research conducted by or on
behalf of UT Southwestern, its affiliates, and investigators, sites, or institutions
relying on the UT Southwestern IRB. Additional reporting requirements apply for
research relying on a non-UT Southwestern IRB.
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences,
outcomes, etc. that meet ALL three (3) of the following criteria:
1.
Unexpected in nature, frequency, or severity (i.e., generally not expected in a
subject’s underlying condition or not expected as a risk of the study;
therefore, not included in the investigator’s brochure, protocol, or informed
consent document),AND
2.
Probably or definitely related to participation in the research, AND
3.
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. Note: According to OHRP, if the adverse
event is serious, it would always suggest a greater risk of harm.
For purposes of this policy, UPIRSOs include unanticipated adverse device
effects (UADEs) and death or serious injury related to a humanitarian use device
(HUD).
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of
PI awareness.
For research relying on a non-UT Southwestern IRB (external, central, or single
IRB):
Investigators relying on an external IRB who are conducting research on behalf
of UT Southwestern or its affiliates are responsible for submitting LOCAL
UPIRSOs to the UT Southwestern IRB within 5 working days of PI awareness.
Investigators must report to their relying IRB according to the relying IRB’s policy.
In addition, the external IRB’s responses or determinations on these local events
must be submitted to the UT Southwestern IRB within 10 working days of receipt.
Events NOT meeting UPIRSO criteria:
Events that do NOT meet UPIRSO criteria should be tracked, evaluated,
summarized, and submitted to the UTSW HRPP/IRB at continuing review.
For more information on UTSW HRPP/IRB reportable event policy, see
https://www.utsouthwestern.edu/research/research-
administration/irb/assets/policies-combined.pdf.
1.
SAEs
Local serious adverse events (SAEs) for studies where SCC DSMC is the DSMC
of record require reporting to the DSMC coordinator within 2 working days of PI
awareness, or as described in the protocol.
2.
Unanticipated Problems
Local unanticipated problems require reporting to the UTSW IRB within 2 working
days of PI awareness of the event.

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Unanticipated problems, including those that occur as non-local events, require
reporting to the UTSW IRB within 10 working days of PI awareness of the event.
For further guidance for Investigators regarding safety reporting requirements for
INDs and BA/BE studies, refer to FDA Draft Guidance document:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidances/UCM227351.pdf
6.3
Steps to Determine If a Serious Adverse Event Requires Expedited
Reporting to the SCCC DSMC and/or HRPP
Step 1: Identify the type of adverse event using the NCI Common Terminology
Criteria for Adverse Events (CTCAE v4).
Step 2: Grade the adverse event using the NCI CTCAE v4.
Step 3: Determine whether the adverse event is related to the protocol therapy
Attribution categories are as follows:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE may NOT be related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Note: This includes all events that occur within 30 days of the last dose of
protocol treatment. Any event that occurs more than 30 days after the last dose
of treatment and is attributed (possibly, probably, or definitely) to the agent(s)
must also be reported accordingly up to 5 years post-treatment.
Step 4: Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as resulting from
administration of the agent. An adverse event is considered unexpected, for
expedited reporting purposes only, when either the type of event or the severity
of the event is not listed in:

the current known adverse events listed in the Agent Information Section
of this protocol (if applicable);

the drug package insert (if applicable);

the current Investigator’s Brochure (if applicable)

the Study Agent(s)/Therapy(ies) Background and Associated Known
Toxicities section of this protocol
6.4
Stopping Rules
Early stopping of this study will be based on unacceptable toxicity, defined as
grade 3 - 5 toxicity related to the following organ systems: infectious disease,
gastrointestinal, renal, genitor-urinary, sexual, reproductive, neurological, blood,
bone marrow, or constitutional symptoms OR any other grade 4 or 5 toxicity
attributed to the therapy or rectal spacer injection procedure occurring in higher
than 30% of treated patients.  If a single patient has more than one unacceptable
toxicity, they will only be counted as one unacceptable toxicity for this analysis.
The following early stopping rules will be implemented:
2 or more cases of unacceptable toxicities out of the first 5 evaluable patients, or
4 or more cases of unacceptable toxicities out of the first 10 evaluable patients, or
6 or more cases of unacceptable toxicities out of the first 15 evaluable patients
7 or more cases of unacceptable toxicities out of the first 20 evaluable patients

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If the number of unacceptable toxicities observed demonstrate via the monitoring
rules above that the  treatment-related unacceptable toxicity rate is 30% or more,
consideration will be initiated for stopping the study.  In this case, the study chair,
study PIs, and statistician will review the toxicity data along with the Data Safety
Monitoring Committee and make appropriate recommendations about continuing
the study.   Additionally, the treatment-related unacceptable toxicity rate will
continued to be monitored during the five year follow-up period.  If the
unacceptable toxicity rate exceeds 30% at any time during the five year follow-up
period, the study chair, study PIs, and statistician will review the toxicity data
along with the Data Safety Monitoring Committee and make appropriate
recommendations about reporting the information.
7.0
DRUG INFORMATION
Not applicable to this study.
8.0
CORRELATIVES/SPECIAL STUDIES
There are no correlative studies associated with this protocol.
9.0
STATISTICAL CONSIDERATIONS
9.1
Study Design/Study Endpoints
Phase II Study Endpoints
10.1.1
Primary Endpoint
The primary endpoint of this study is to determine determine whether use of a
rectal spacer with SABR will decrease the rate of rectal toxicity when performing
SABR treatments for prostate cancer and the effectiveness of space creation by
the spacer.  To this extent, our primary objectives are

to measure mucosal ulceration rate, and

to determine ability of spacer to create >=7.5 mm space: rate of
space creation of >=7.5mm,
10.1.2
Secondary Endpoints

To assess spacer related acute toxicity, defined as toxicities
occurring in the two week period between spacer placement and
start of radiation treatment.

To determine spacer’s efficacy as measured by its ability to decrease
the PRC 24 Gy and 39 Gy parameters by at least 50%.  This will be
determined by using CT planning studies for dosimetric analysis
before and after spacer placement.

Acute GU and GI toxicity is defined as grade 1-5 toxicity occurring
prior to 270 days from the start of protocol treatment. It is graded
based on CTCAE v4.0.

Delayed GU and GI toxicity is defined as grade 1-5 toxicity occurring
after 270 days from the start of protocol treatment. It is graded based
on CTCAE v4.0.

Non GU and GI toxicity.

Biochemical failure RTOG-ASTRO definition (also known as Phoenix
definition) - Thus, when the PSA rises by more than 2 ng/ml above
the lowest level (nadir) achieved after treatment,, biochemical failure
has occurred and the date of the failure is recorded at the time the
nadir plus 2 ng/ml level is reached.

Overall survival

Disease-specific survival

Clinical progression including local/regional and distant relapse

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
HRQOL questionnaires
9.2
Sample Size and Accrual
We plan to enroll 45 patients for this study. This sample size is based on
considerations of two primary endpoints: mucosal ulceration rate and rate of
space creation of >=7.5mm. Forty-five patients will ensure less than 13.5%
margin of error (95% confidence) for estimated mucosal ulceration rate and 6.5%
margin of error (95% confidence) for estimated rate of space creation of
>=7.5mm. The calculations assume new mucosal ulceration rate of <70% and
95% rate of space creation of >=7.5mm. This sample size also has >90% power
in detecting significant reduction in mucosal ulceration rate from current observed
rate of 90% (alpha=0.05, two sided exact test).
10.2.1 Patient Accrual and Study Duration
It is expected that it will take approximately 1-2 years to complete the accrual for
the phase II study.  Primary endpoints can be determined for each patient within
24-36 weeks of treatment initial period based on our phase I study’s experience
of anoscopic evaluation.  The analysis for secondary endpoints such as late
toxicity will be carried out after each patient has had at least 270 days (i.e., 9
months) of follow-up from the end of the acute period, a total of 540 days (i.e., 18
months) of follow-up. For other secondary endpoint of biochemical failure, an
additional 18 months of follow-up are needed to estimate the 3-year failure rate.
Study-related data will be stored for 5 years after termination of the study when
accrual is no longer taking place and all patients have discontinued follow-up
procedures.
9.3
Data Analyses Plans
10.3.1. The Analysis of Rectal Spacer Efficacy
For primary endpoints, numbers and rates of spacer related mucosal ulceration
and success of spacer to create >=7.5 mm space will be summarized along with
their 95% confidence intervals. Rectal ulceration rate will be measured at
specified time points by physician by anoscopic evaluation of the periprostatic
rectum.  Photographs and/or video images will be taken, and size and location of
ulcers if present will be documented at each visit. Rate of mucosal ulceration for
patients with spacers will also be compared with currently observed rate using
exact test.  Analysis on other measures will be all descriptive. Success in
decreasing the PRC 24 Gy and 39 Gy parameters by at least 50%will be
tabulated for examination in determining future studies.
10.3.2 The Analysis of Late GU/GI Toxicity: This analysis will be carried out
when each patient has had at least 270 days (i.e., 9 months) of follow-up after
the end of the acute period, a total of 540 days (i.e., 18 months) of follow-up. The
time to the occurrence of severe late GU/GI toxicity is defined as the time interval
from start of protocol treatment to the date of onset of grade 3-5 GU/GI toxicity.
The time analysis for recording severe late GU/GI toxicity for this protocol will be
limited to 540 days from start of protocol therapy.  If no such toxicity is observed
before the time of the analysis, the patient will be censored at the time of the
analysis. Numbers and rates of toxicities will be tabulated for report. We will not
be performing inferential statistical analysis as this study is not powered for such
analysis.
10.3.3 Estimation of Secondary Endpoints Related to the Efficacy: We will
examine all the secondary endpoints in relation to efficacy.
10.0
STUDY MANAGEMENT

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10.1
Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership,
royalties, or financial gain greater than the minimum allowable by their institution,
etc.) must have the conflict reviewed by the UTSW COI Committee and IRB
according to UTSW Policy on Conflicts of Interest. All investigators will follow the
University conflict of interest policy.
11.2
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in
accordance with federally mandated regulations. The IRB must approve the
consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply
with the applicable regulatory requirement(s), and should adhere to Good Clinical
Practice (GCP) and to ethical principles that have their origin in the Declaration of
Helsinki.
Before recruitment and enrollment onto this study, the subject will be given a full
explanation of the study and will be given the opportunity to review the consent
form. Each consent form must include all the relevant elements currently required
by the FDA Regulations and local or state regulations. Once this essential
information has been provided to the subject and the investigator is assured that
the subject understands the implications of participating in the study, the subject
will be asked to give consent to participate in the study by signing an
IRB-approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form
should be signed and personally dated by the subject and by the person who
conducted the informed consent discussion.
10.3
Required Documentation (for multi-site studies)
Before the study can be initiated at any site, the following documentation must be
provided to the Research Office.

A copy of the official IRB approval letter for the protocol and informed
consent

IRB membership list or Federal wide Assurance letter

CVs and medical licensure for the principal investigator and any associate
investigators who will be involved in the study

Form FDA 1572 appropriately filled out and signed with appropriate
documentation (NOTE: this is required if {institution} holds the IND.
Otherwise, the affiliate Investigator’s signature on the protocol is sufficient to
ensure compliance)

A copy of the IRB-approved consent form

CAP and CLIA Laboratory certification numbers and institution lab normal
values

Executed clinical research contract
10.4
Registration Procedures
All subjects must be registered with the Clinical Research Office, Department of
Radiation Oncology, UTSW, before enrollment to study.
New subjects will receive a 3-digit number.  The first subject enrolled receives
the number 101, the second subject enrolled receives the number 102, etc.

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Each newly consented subject should be numbered using the schema provided
above. Upon registration, the registrar will assign the additional registration code
according to the numbering schema outlined above, which should then be
entered as the patient study id in Velos upon updating the status to enrolled.
10.5
Data Management and Monitoring/Auditing
REDCap is the UTSW SCCC institutional choice for the electronic data capture
of case report forms for SCCC Investigator Initiated Trials. REDCap will be used
for electronic case report forms in accordance with Simmons Comprehensive
Cancer Center requirements, as appropriate for the project. All subjects
consenting to participate in any aspect of the trial must be registered on REDCap
before initiating protocol activities. All research data will be recorded and entered
into Case Report Forms using REDCap. Toxicity will be reviewed on an ongoing
basis and will be reported per SCCC-DSMC guidelines.
In order to facilitate remote source to case report form verification, the Simmons
Comprehensive Cancer Center study team will require other institutions
participating in this trial as sub-sites to enter data into the selected EDC system
and upload selected de-identified source materials when instructed
Trial monitoring will be conducted no less than annually and refers to a regular
interval review of trial related activity and documentation performed by the DOT
and/or the CRO Multi-Center IIT Monitor. This review includes but is not limited to
accuracy of case report forms, protocol compliance, timeless and accuracy of
Velos entries and AE/SAE management and reporting. Documentation of trial
monitoring will be maintained along with other protocol related documents and
will be reviewed during internal audit.
For further information, refer to the UTSW SCCC IIT Management Manual.
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety
Monitoring Committee (DSMC) is responsible for monitoring data quality and
patient safety for all UTSW SCCC clinical trials.  As part of that responsibility, the
DSMC reviews all local serious adverse events and UPIRSOs in real time as
they are reported and reviews adverse events on a quarterly basis.  The quality
assurance activity for the Clinical Research Office provides for periodic auditing
of clinical research documents to ensure data integrity and regulatory
compliance. A copy of the DSMC plan is available upon request.
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews
of ongoing clinical trials, for which it serves as the DSMC of record. The QAC
works as part of the DSMC to conduct regular audits based on the level of risk.
Audit findings are reviewed at the next available DSMC meeting.  In this way,
frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is
determined by the DSMC Chairman and a number of factors such as the phase
of the study; the type of investigational agent, device or intervention being
studied; and monitoring required to ensure the safety of study subjects based on
the associated risks of the study. Protocol-specific DSMC plans must be
consistent with these principles.
Clinical trials are assessed for safety on a continual basis throughout the life of
the trial. All SAE’s and any AEs that are unexpected and possibly/likely related to
study participation are reported to UTSW IRB through an electronic research
system per UTSW IRB guidelines. SAEs are reported to the sponsor per specific
sponsor requirements. These SAEs are reported to the SCCC DSMC on a real
time basis. All local SAEs will be reported to the SCCC DSMC. SAE reports can
be either scanned/emailed to the coordinator of SCCC DSMC or sent through
interoffice mail.

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10.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety,
and well-being of the study subject requires alternative treatment, the study shall
be conducted exactly as described in the approved protocol.
10.6.1
Exceptions (also called single-subject exceptions or single-subject
waivers): include any departure from IRB-approved research that is not
due to an emergency and is:

intentional on part of the investigator; or

in the investigator’s control; or

not intended as a systemic change (e.g., single-subject exceptions to
eligibility [inclusion/exclusion] criteria)
Reporting requirement: Exceptions are non-emergency deviations that require
prospective IRB approval before being implemented. Call the IRB if
your request is urgent. If IRB approval is not obtained beforehand,
this constitutes a major deviation.
10.6.2
Emergency Deviations: include any departure from IRB-approved
research that is necessary to:

avoid immediate apparent harm, or

protect the life or physical well-being of subjects or others
Reporting requirement: Emergency deviations must be promptly reported to the IRB
within 5 working days of occurrence.
10.6.3
Major Deviations (also called violations): include any departure from
IRB-approved research that:

Harmed or placed subject(s) or others at risk of harm (i.e., did or has
the potential to negatively affect the safety, rights, or welfare of
subjects or others), or

Affect data quality (e.g., the completeness, accuracy, reliability, or
validity of the data) or the science of the research (e.g., the primary
outcome/endpoint of the study)
Reporting requirement: Major deviations must be promptly reported to the IRB within 5
working days of PI awareness.
10.6.4
Minor Deviations: include any departure from IRB-approved research
that:

Did not harm or place subject(s) or others at risk of harm (i.e., did not
or did not have the potential to negatively affect the safety, rights, or
welfare of subjects or others), or

Did not affect data quality (e.g., the completeness, accuracy,
reliability, or validity of the data) or the science of the research (e.g.,
the primary outcome/endpoint of the study)
Reporting requirement: Minor deviations should be tracked and summarized in the
progress report at the next IRB continuing review.
10.7
Amendments to the Protocol
Should amendments to the protocol be required, the amendments will be
originated and documented by the Principal Investigator. A summary of changes
document outlining proposed changes as well as rationale for changes, when

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appropriate, is highly recommended. When an amendment to the protocol
substantially alters the study design or the potential risk to the patient, a revised
consent form might be required.
The written amendment, and if required the amended consent form, must be sent
to the IRB for approval prior to implementation.
10.8
Record Retention
Study documentation includes all Case Report Forms, data correction forms or
queries, source documents, Sponsor-Investigator correspondence, monitoring
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB
correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical
activities and all reports and records necessary for the evaluation and
reconstruction of the clinical research study.
Government agency regulations and directives require that the study investigator
retain all study documentation pertaining to the conduct of a clinical trial. In the
case of a study with a drug seeking regulatory approval and marketing, these
documents shall be retained for at least two years after the last approval of
marketing application in an International Conference on Harmonization (ICH)
region. In all other cases, study documents should be kept on file until three
years after the completion and final study report of this investigational study.
10.9
Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the
site in accordance with Title 21 of the Code of Federal Regulations and/or the
Declaration of Helsinki. The Principal Investigator is responsible for personally
overseeing the treatment of all study patients. The Principal Investigator must
assure that all study site personnel, including sub-investigators and other study
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations
and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for
assuring that all the required data will be collected and entered onto the Case
Report Forms. Periodically, monitoring visits may be conducted and the Principal
Investigator will provide access to his/her original records to permit verification of
proper entry of data. At the completion of the study, all case report forms will be
reviewed by the Principal Investigator and will require his/her final signature to
verify the accuracy of the data.

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11.0
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12.0
APPENDICES
All Patients (n = 91)
45 Gy (n = 15)
47.5 Gy (n = 15)
50 Gy (n = 61)
Grade
Acute
No. (%)
Late
No. (%)
Acute
No. (%)
Late
No. (%)
Acute
No.
(%)
Late
No. (%)
Acute
No. (%)
Late
No. (%)
0
39 (42.9)
38 (41.8)
9 (60.0)
10 (66.7)
7
(46.7)
8 (53.3)
23
(37.7)
20 (32.8)
1
33 (36.3)
27 (29.7)
6 (40.0)
4 (26.7)
4
(26.7)
2 (13.3)
23
(37.7)
21 (34.4)
2
17 (18.7)
21 (23.1)
0 (0.0)
1 (6.7)
4
(26.7)
5 (33.3)
13
(21.3)
15 (24.6)
3
1* (1.1)
3 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1* (1.6)
3 (4.9)
4
1 (1.1)
2 (2.2)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (1.6)
2 (3.3)
*For this patient, toxicity occurred on day 225 (acute period), but persisted to day 470, well into the
delayed toxicity time period.  Therefore, this patient was reported as having high grade acute and
delayed toxicity.  While 7 total toxicities are reported, this occurred in a total of 6 patients
APPENDIX I
Toxicity from Phase I/II study

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APPENDIX II
ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all predisease activities without
restriction (Karnofsky 90-100).
1
Restricted in physically strenuous activity but ambulatory and able to
carry work of a light or sedentary nature.  For example, light
housework, office work (Karnofsky 70-80).
2
Ambulatory and capable of all self-care but unable to carry out any
work activities.  Up and about more than 50% of waking hours
(Karnofsky 50-60).
3
Capable of only limited self-care, confined to bed or chair 50% or
more of waking hours (Karnofsky 30-40).
4
Completely disabled. Cannot carry on self-care. Totally confined to
bed or (Karnofsky 10-20).
5
Death (Karnofsky 0).
KARNOFSKY PERFORMANCE SCALE
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal
needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not
imminent
20
Very sick; hospitalization necessary; active support treatment is
necessary
10
Moribund; fatal processes progressing rapidly
0
Dead

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APPENDIX III
AJCC STAGING SYSTEM
PROSTATE, 7th Edition
DEFINITION OF TNM
Primary Tumor, Clinical (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Clinically inapparent tumor neither palpable or visible by imaging
T1a
Tumor incidental histologic finding in 5% or less of tissue resected
T1b
Tumor incidental histologic finding in more than 5% of tissue resected
T1c
Tumor identified by needle biopsy (e.g., because of elevated PSA)\
T2
Tumor confined with prostate*
T2a
Tumor involves one-half of one lobe or less
T2b
Tumor involves more than one-half of one lobe but not both lobes
T2c
Tumor involves both lobes
T3
Tumor extends through prostate capsule**
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumor involves the seminal vesicle(s)
T4
Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck,
external sphincter, rectum, levator muscles and/or pelvic wall.
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is
classified as T1c
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3, but
as T2.
Regional Lymph Nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node(s)
Primary Tumor, Pathologic (pT)
pT2*
Organ confined
pT2a
Unilateral, involving one-half of one lobe or less
pT2b
Unilateral, involving more than one-half of one lobe but not both lobes
pT2c
Bilateral disease
pT3
Extraprostatic extension
pT3a
Extraprostatic extension**
pT3b
Seminal vesicle invasion
pT4
Invasion of bladder, rectum
*Note: There is no pathologic T1 classification
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).

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APPENDIX III (continued)
AJCC STAGING SYSTEM
PROSTATE, 7th Edition
Distant Metastasis (M)*
MX
Presence of distant metastasis cannot be assessed (not evaluated by any
modality)
M0
No distant metastasis
M1
Distant metastasis
M1a
Nonregional lymph node(s)
M1b
Bone(s)
M1c
Other site(s) with or without bone disease
*Note:
When more than one site of metastasis is present, the most advanced category is used;
pM1c is most advanced.
Stage Grouping
Stage I
T1a, T1b, or T1c
N0
M0
PSA<10
Gleason≤6
T2a
N0
M0
PSA<10
Gleason≤6
T1-2a
N0
M0
PSA X
Gleason X
Stage IIA
T1a, T1b, or T1c
N0
M0
PSA <20
Gleason 7
T1a, T1b, or T1c
N0
M0
PSA≥10<20
Gleason≤6
T2a
N0
M0
PSA≥10<20
Gleason≤6
T2a
N0
M0
PSA<20
Gleason 7
T2b
N0
M0
PSA<20
Gleason≤7
T2b
N0
M0
PSA X
Gleason X
Stage IIB
T2c
N0
M0
Any PSA
Any Gleason
T1-2
N0
M0
PSA ≥20
Any Gleason
T1-2
N0
M0
Any PSA
Gleason ≥8
Stage III
T3a-b
N0
M0
Any PSA
Any Gleason
Stage IV
T4
N0
M0
Any PSA
Any Gleason
Any T
N1
M0
Any PSA
Any Gleason
Any T
Any N
M1
Any PSA
Any Gleason

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APPENDIX IV
GLEASON CLASSIFICATION
Histologic patterns of adenocarcinoma of the prostate
Pattern
Margins
Tumor Areas
Gland
Pattern
Gland
Size
Gland
Distribution
Stromal
Invasion
1
Well defined
Single, separate,
round
Medium
Closely
packed
Minimal,
expansile
2
Less definite
Single, separate rounded
but
more variable
Medium
Spaced up to
one gland
diameter,
average
Mild, in larger
stromal planes
3
Poorly defined
Single, separate
more irregular
Small,
medium,
or large
Spaced more
than one
gland
diameter,
rarely packed
Moderate, in
larger or
smaller
stromal
planes
or
3
Poorly defined
Rounded masses of
cribriform or papillary
epithelium
Medium
or large
Rounded
masses with
smooth sharp
edges
Expansile
masses
4
Ragged,
infiltrating
Fused glandular
masses or "hypernephroid"
Small
Fused in
ragged
masses
Marked,
through
smaller planes
5
Ragged,
infiltrating
Almost absent, few tiny
glands or signet ring
Small
Ragged
anaplastic
masses of
epithelium
Severe
between
stromal fibers
or destructive
or
5
Poorly defined
Few small lumina in
rounded
masses of solid epithelium
central necrosis
Small
Rounded
masses and
cords with
smooth sharp
edges
Expansile
masses
The Gleason Classification is a system of histologic grading based on over-all pattern of tumor growth at
relatively low-magnification (40 to 100x). Five patterns of growth are recognized and numbered in order of
increasing malignancy. Because of histologic variation in the tumor, two patterns are recorded for each
case, a primary or predominate pattern and a secondary or lesser pattern.
The Gleason Score is the sum of the primary and secondary pattern, If only one pattern is present, the
primary
and secondary pattern receive the same designation.
(Primary = 2, Secondary = 1, Gleason = 3)
(Primary = 2. Secondary = 2, Gleason = 4)
1. Gleason, D.F. et al: Prediction of prognosis for prostatic carcinoma by combined histologic grading and
clinical staging. J Urol 111:58, 1974.

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APPENDIX V
ON-STUDY AUA SYMPTOM SCORE (PQ)
PATIENT NAME _____________________________CASE # ________________
INSTITUTION NAME __________________________
TOTAL SCORE __________
PLEASE FILL OUT THIS SHORT QUESTIONNAIRE TO HELP US FIND OUT MORE ABOUT ANY URINARY
PROBLEMS YOU MIGHT HAVE. CIRCLE A NUMBER IN EACH COLUMN THAT BEST DESCRIBES YOUR
SITUATION. YOU MUST ANSWER ALL QUESTIONS.
Not at all
Less
than one
time in
five
Less than
half the
time
About
half
the time
More
than
Half the
time
Almost
always
1. Over the past month or so,
how often have you had a
sensation of not emptying your
bladder completely after you
finished urinating?
0
1
2
3
4
5
2. Over the past month or so,
how often have you had to
urinate again, less than two
hours after you finished
urinating?
0
1
2
3
4
5
3. Over the past month or so,
how often have you found you
stopped and started again
several times when you
urinated?
0
1
2
3
4
5
4. How often do you find it
difficult to postpone urination?
0
1
2
3
4
5
5. Over the past month or so,
how often have you had a
weak urinary stream?
0
1
2
3
4
5
6. Over the past month or so,
how often have you had to
push or strain to begin
urination?
0
1
2
3
4
5
Not at all
Once
every 8
hours
Once
every 4
hours
Once
every 3
hours
Once
every
2 hours
At least
once
every
hour
7. Over the past month or so,
how often did you most
typically get up at night to
urinate?
0
1
2
3
4
5
Total per column
________       ________     ________    ________    ________

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_________________________________________
_______________________________
Patient Signature
Date This Form was Completed
APPENDIX VI
EXPANDED PROSTATE CANCER INDEX COMPOSITE (EPIC)
Quality of life after prostate cancer treatment will be assessed using the Expanded
Prostate Cancer Index Composite (EPIC) formalism [41].  Validation and description of
this scale can be found at the website:
http://roadrunner.cancer.med.umich.edu/epic/epicmain.html
The actual forms used for this assessment can also be downloaded on a PDF file from
this website.  We will use the standard form for this protocol.

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APPENDIX VII
Risks to Subjects
Procedure
Risks
Measures to Minimize Risks
History and physical exam
(H&P), digital rectal exam
(DRE), PSA test at study entry
and 1, 3, 6, 9,  and 12 months
post-treatment, then every 6
months for 5 years; annually for
years 5-10)
Discovery of previously unknown
condition/progression of prostate
cancer
Will be performed by MD and/or
nurse practitioner with oncology
experience.
Anoscopic Evaluations at 6, 12,
24, 36 weeks
Discomfort, bleeding, bruising,
dizziness, fainting, infection
An experienced professional will
perform this procedure
Blood draws (at all study
timepoints)
Discomfort, bleeding, bruising,
dizziness, fainting, infection
Blood will be drawn by an
experienced phlebotomist.
Zubrod Performance status
evaluation; AUA Questionnaire
– to measure urinary symptoms;
EPIC Questionnaire – to assess
quality of life after prostate
cancer treatment
Discomfort, psychological stress
of answering personal questions
Subjects informed that they may
refuse to answer, take a break,
or discontinue participation at
any time
Metallic marker implantation into
prostate (once prior to
treatment)
Discomfort, bleeding, bruising,
dizziness, fainting, infection
An experienced professional will
perform this procedure.
Self-administered Fleet’s enema
(1 or 2 prior to screening visit
and each treatment)
Discomfort
Detailed instructions will be
provided.
Insertion of urethral catheter (at
treatment planning)
Very likely:  Pain or discomfort
during insertion; Less likely, but
serious: Bleeding from the
urethra or bladder, urethral
irritation with urge to urinate
frequently, urinary tract infection
Every effort will be made to
minimize discomfort. Antibiotics
will be prescribed as necessary.
The urethra may be numbed
with local anesthesia, and the
thinnest catheter possible will be
used.

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Stereotactic body radiation
therapy (5 treatments)
Dermatologic:
Very likely:  Skin redness or
tanning, rash, itching, peeling,
temporary hair loss in treatment
area
Referral to a dermatologist if
necessary.
Gastrointestinal.
Very likely: Nausea, diarrhea,
abdominal cramps, rectal
irritation with frequent urge to
have a bowel movement, bowel
movements with mucus;
Less likely:  Incontinence;
Less likely but serious:  Injury to
bowel, rectal bleeding, intestinal
obstruction
Premedication with
corticosteroid suggested.
Genitourinary.
Very likely:  Bladder irritation
with frequent urge to urinate,
burning on urination, injury to
urethra slowly causing a
narrowing (may need surgical
correction);
Less likely:  Incontinence;
Less likely but serious:
Injury to bladder, urethra or
other tissues in pelvis or
abdomen; urinary obstruction
Recommended premedication
with corticosteroid, alpha
blocker, 5 alpha reductase
inhibitor; imaging guidance prior
to each treatment suggested;
care taken to minimize dose to
bulbous urethra and bladder;
wedges or other modulation
methods to steer higher dose
away from prostatic urethra.
Sexual/Reproductive.
Very likely:  Impotence (may be
irreversible);
Less likely: Ejaculatory
dysfunction (may be
irreversible), sterility
Restriction of dose on penile
bulb.
Teratogenic:  possible harm to
an unborn child
Use of contraception required
for participation; need for
immediate reporting of causing
a pregnancy stressed
Constitutional:
Very likely:  fatigue
Participants will be educated
and asked to inform study
personnel if encounter
symptoms.
General discomfort from lengthy
(60 – 90 minutes) procedure
Premedication with analgesic
recommended.

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FAX transmittal of case report
forms (CRFs) to primary site
Loss of privacy
Sensitive patient information will
be blacked-out.  CRFs will only
be identified by subject initials
and unique, study identification
number before fax transmittal.
Unforeseen risks
E.g., unpredictable interaction
between SABR and concomitant
medications
Strong encouragement to report
any difficulties and keep
researchers aware of any
change in medications

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APPENDIX VIII
SpaceOAR Package Insert

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APPENDIX VIII (cont.)
SpaceOAR Package Insert