A Phase I Trial of Highly Conformal, Hypofractionated, Focally Dose Escalated Post-Prostatectomy Radiotherapy
Phase: PHASE1
Conditions: Cancer Of Prostate, Prostate Neoplasms, Prostate Cancer, Neoplasms of Prostate, Prostatic Cancer
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Image guided radiation
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Abbreviated Title: Image guided radiation
NIH Protocol #: 18-C-0028 
Version Date: 06/03/2024
NCT Number: NCT03388619
Title: A Phase I Trial of Highly Conformal, Hypofractionated, Focally Dose Escalated Post-
Prostatectomy Radiotherapy
NCI Principal Investigator:
Deborah Citrin, MD 
Radiation Oncology Branch (ROB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
10 CRC, Rm B2-3500
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-760-6206
E-mail: citrind@mail.nih.gov
Commercial Devices: 
Radiation

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PRÉCIS
Background:
Prostate cancer that recurs after prostatectomy (rising PSA) with no evidence of metastatic 
disease is often treated with radiation to the entire prostate bed to a dose of 66-72 Gy over 6-7 
weeks. This treatment can provide PSA control in approximately 75% of patients, but may have 
associated genitourinary and gastrointestinal toxicity due to irradiation of the rectum, small 
bowel, and bladder. Imaging of prostate cancer has improved to the extent that recurrent disease 
is often identified in the prostate bed or in other pelvic sites. The current standard is to irradiate 
the entire prostate bed to the total dose. This trial will test the tolerability of accelerated 
treatment designed to yield a similar rate of late toxicity. In addition, in patients with visible 
tumor, it will test the feasibility of delivering a lower dose to the prostate bed and an integrated 
boost (simultaneous) to the visible tumor to allow a higher dose to visible tumor than can be 
delivered with standard approaches.
Objective:

Define the maximum tolerated dose (MTD) hypofractionation of image guided, focally 
dose escalated post-prostatectomy radiation.
Eligibility:

PSA recurrence after prostatectomy or indications for adjuvant radiation after 
prostatectomy. 

No evidence of distant metastases of prostate cancer (pelvic lymph nodes are allowed).

Age >18 years old 

ECOG performance status <1
Design:
This is a Phase I trial of hypofractionated, focal dose escalation with reduced dose prostate bed 
irradiation using image and pathologic guidance. The prostate bed will be treated with 
hypofractionated radiation and areas in the prostate bed or pelvis shown to have tumor on biopsy 
or with advanced imaging studies will be treated with an integrated boost to visible tumor. The 
treatment duration will be decreased sequentially in three Dose Level groups. Quality of life and 
functional outcomes such as urine, bowel, and erectile function will be assessed with 
questionnaires. A maximum of 48 patients will be enrolled.

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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................8
1.1
Study Objectives ...............................................................................................................8
1.1.1
Primary Objective......................................................................................................8
1.1.2
Secondary Objectives ................................................................................................8
1.1.3
Exploratory Objectives ..............................................................................................8
1.2
Background and Rationale................................................................................................8
1.2.1
Post prostatectomy radiation......................................................................................8
1.2.2
Hypofractionation in prostate cancer.......................................................................10
1.2.3
Quality of life after salvage radiation ......................................................................12
1.2.4
Biological versus standard optimization algorithms................................................13
1.2.5
Summary..................................................................................................................14
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................14
2.1
Eligibility Criteria ...........................................................................................................14
2.1.1
Inclusion Criteria .....................................................................................................14
2.1.2
Exclusion Criteria ....................................................................................................15
2.1.3
Recruitment Strategies.............................................................................................15
2.2
Screening Evaluation ......................................................................................................15
2.3
Participant Registration and Status Update Procedures..................................................16
2.4
Treatment Assignment Procedures .................................................................................16
2.5
Baseline Evaluation.........................................................................................................17
3
STUDY IMPLEMENTATION .............................................................................................17
3.1
Study Design...................................................................................................................17
3.1.1
Dose Limiting Toxicity............................................................................................18
3.1.2
Dose Escalation (Hypofractionation) ......................................................................19
3.2
Questionnaires (For English Speaking Patients Only)....................................................20
3.3
Study Calendar................................................................................................................21
3.4
Radiation Therapy Guidelines ........................................................................................22
3.4.1
Treatment Planning..................................................................................................22

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3.4.2
Dose constraints.......................................................................................................23
3.5
Follow Up .......................................................................................................................25
3.6
Cost and Compensation ..................................................................................................25
3.6.1
Costs ........................................................................................................................25
3.6.2
Compensation ..........................................................................................................25
3.6.3
Reimbursement........................................................................................................25
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................25
3.7.1
Criteria for removal from protocol therapy .............................................................25
3.7.2
Off-Study Criteria....................................................................................................25
3.7.3
Lost to Follow-up ....................................................................................................25
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................26
4.1
ADT ................................................................................................................................26
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................27
5.1
Biospecimen Collection ..................................................................................................27
5.1.1
Circulating immune cells during radiotherapy ........................................................28
5.1.2
Protein and RNA Analysis.......................................................................................29
5.1.3
Samples....................................................................................................................29
5.1.4
MRI of erectile tissue...............................................................................................30
5.2
Sample Storage, Tracking and Disposition.....................................................................30
5.3
Samples For Genetic/Genomic Analysis ........................................................................31
5.3.1
Description of the scope of genetic/genomic analysis.............................................31
5.3.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized................................................................................................32
5.3.3
Management of Results ...........................................................................................32
5.3.4
Genetic counseling...................................................................................................32
6
DATA COLLECTION AND EVALUATION .....................................................................32
6.1
Data Collection ...............................................................................................................32
6.1.1
Data Elements/Information......................................................................................33
6.2
Data Sharing Plans..........................................................................................................34
6.2.1
Human Data Sharing Plan .......................................................................................34
6.2.2
Genomic Data Sharing Plan.....................................................................................34
6.3
Response Criteria ............................................................................................................34
6.3.1
Response Criteria.....................................................................................................34

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6.3.2
Biochemical Progression-Free Survival ..................................................................35
6.4
Toxicity Criteria..............................................................................................................35
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....35
7.1
Definitions.......................................................................................................................35
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................35
7.2.1
Expedited Reporting ................................................................................................35
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................35
7.3
NCI Clinical Director Reporting.....................................................................................35
7.4
NIH Required NIH Required Data and Safety Monitoring Plan ....................................36
7.4.1
Principal Investigator/Research Team.....................................................................36
8
STATISTICAL CONSIDERATIONS ..................................................................................36
8.1
Statistical Hypothesis......................................................................................................36
8.1.1
Primary Objective....................................................................................................36
8.1.2
Secondary Objectives ..............................................................................................36
8.2
Sample Size Determination.............................................................................................36
8.3
Populations for Analyses ................................................................................................37
8.3.1
Definitions ...............................................................................................................37
8.4
Statistical Analyses .........................................................................................................37
8.4.1
General Approach....................................................................................................37
8.4.2
Analysis of the Primary Endpoints..........................................................................37
8.4.3
Analysis of the Secondary Endpoint(s) ...................................................................37
8.4.4
Safety Analyses .......................................................................................................38
8.4.5
Exploratory Analyses...............................................................................................38
9
HUMAN SUBJECTS PROTECTIONS................................................................................39
9.1
Rationale For Subject Selection......................................................................................39
9.2
Inclusion of women and minors......................................................................................39
9.3
Evaluation of Benefits and Risks/Discomforts ...............................................................39
9.3.1
Benefits....................................................................................................................39
9.3.2
Risks ........................................................................................................................39
9.4
Consent Process and Documentation..............................................................................40
10
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................41
10.1
Study Discontinuation and Closure.............................................................................41
10.2
Quality Assurance and Quality Control ......................................................................42

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10.3
Conflict of Interest Policy ...........................................................................................42
10.4
Confidentiality and Privacy.........................................................................................42
11
COMMERCIAL DEVICE INFORMATION.....................................................................43
11.1
Source..........................................................................................................................43
11.2
Toxicity .......................................................................................................................43
11.3
Administration procedures ..........................................................................................43
12
REFERENCES ...................................................................................................................44
13
APPENDICES ....................................................................................................................50
13.1
Appendix A: Performance Status Criteria...................................................................50
13.2
Appendix B: Qol Questionnaires ................................................................................51

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants 
who 
provided 
consent, 
using 
a 
previously 
approved 
consent 
form.

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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

Define the maximum tolerated dose (MTD) hypofractionated of image guided, focally 
dose escalated post-prostatectomy radiation.
1.1.2
Secondary Objectives

To evaluate the safety and tolerability of the image guided, hypofractionated, focally dose 
escalated post-prostatectomy radiation.

Estimate the rate of PSA control (biochemical progression free survival (bPFS) at 1 and 2 
years after treatment with image guided, hypofractionated, focally dose escalated post-
prostatectomy radiation).

Describe the effects of image-guided, focally dose escalated prostate bed radiation on 
patient reported outcomes (SHIM, AUA Symptom Index, EPIC-26).
1.1.3
Exploratory Objectives

Evaluate decision regret at the time of enrollment and at the end of follow up relating to 
the primary treatment for prostate cancer to determine if successful salvage mitigates 
decision regret.

Explore candidate biomarkers of radiation toxicity in blood and urine of patients 
receiving image-guided, hypofractionated, focally dose escalated post-prostatectomy 
radiation.

Explore MRI imaging parameters of erectile tissues in regard to testosterone and erectile 
dysfunction

To compare dosimetry of standard compared to biological optimization algorithms for 
treatment planning of post-prostatectomy radiation.

Explore changes in circulating T-cell subsets, circulating T-cell polarization, and 
circulating myeloid lineages during and after treatment with radiation.

Evaluate the feasibility of a patient specific circulating DNA copy number analysis for 
predicting biochemical recurrence

Explore changes in circulating exosome cargo before, during, and after a course of 
radiotherapy.
1.2
BACKGROUND AND RATIONALE
1.2.1
Post prostatectomy radiation
Prostate cancer is one of the most common malignancies in men in the United States, with an 
estimated 161,360 new cases and 26,730 deaths in 2017 [1]. Localized prostate cancer is often 
treated with radiotherapy or prostatectomy. Both treatments can be exceptionally effective for 
patients with low grade cancers or low pre-treatment PSA values. In patients with intermediate 
or high grade tumors (Gleason 7-10), histologic variants, locally advanced disease (disease that 
has spread beyond the prostate capsule or into the seminal vesicles), or a high pretreatment PSA, 
the rate of recurrence after potentially curative treatment, such as radiation or surgery, can be 

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much higher. Long term follow up of patients treated with prostatectomy have yielded 10 year 
recurrence free rates of 68% [2]. Subsets of patients at highest risk of failure can benefit from 
post-operative radiation to the prostate bed, even in the absence of a detectable PSA. When given 
in the absence of a PSA recurrence, the treatment is termed “adjuvant radiation.” Adjuvant 
radiation, given for high risk features such as seminal vesicle invasion, extra prostatic spread, or 
positive margin, has been shown to improve progression free survival and improve the overall 
survival of prostate cancer patients when compared to observation [3-6].
One concern with the use of adjuvant radiation is that some patients with high risk features will 
never develop PSA recurrence. Therefore, the benefit of post-prostatectomy radiation may be 
limited to those destined for eventual PSA recurrence, while many other patients receiving the 
treatment would never benefit. Thus, many patients with indications for adjuvant radiation after 
prostatectomy are instead monitored carefully after surgery for evidence of PSA recurrence. If 
the PSA rises after a prostatectomy and there is no evidence of extra-pelvic metastatic disease, 
patients are treated with radiotherapy to the prostate bed with curative intent, also known as 
“salvage” radiotherapy. Treatment with post-operative radiotherapy in the setting of PSA 
recurrence after radiation yields a 5 year progression free survival of 62-80%[7]. Comparisons of 
adjuvant and salvage radiation are currently ongoing [8], however both are considered 
reasonable options as per the current standard of care.
The volumes targeted by irradiation in the post-prostatectomy setting (adjuvant or salvage) are 
relatively standard and have been arrived at by consensus [9]. In general, the remaining seminal 
vesicles, if any, and the bed of the prostate are included. In some cases, a portion of the pelvic 
lymph nodes are included. Most commonly, this region receives a total dose of 66 to 72 Gy in 
1.8- 2 Gy fractions, given daily Monday through Friday, over 6-7 weeks. Although these 
treatments are delivered on an outpatient basis, they are a substantial investment of time and may 
require time away from work and incur transportation costs. 
In general, the use of adjuvant and salvage radiation is well tolerated, however a subset of 
patients will develop acute (during or within 90 days of radiation) or late (more than 90 days 
after completion of radiation) toxicity. Two recently published randomized trials provide 
estimates of toxicity with contemporary irradiation techniques [7, 10]. Grade 2 or higher acute 
genitourinary toxicity occurs in approximately 14% of patients, whereas Grade 2 or higher acute 
gastrointestinal toxicity occurs in 21% of patients (acute Grade 3 or higher GU and GI, 2% and 
0.5% respectively). Grade 2 or higher late genitourinary toxicity occurs in approximately 25% of 
patients, whereas Grade 2 or higher late gastrointestinal toxicity occurs in 18% of patients (late 
Grade 3 or higher GU and GI, 7% and 2% respectively). 
Radiation is often combined with androgen deprivation therapy (ADT) in patients with prostate 
cancer treated with salvage radiation after prostatectomy (detectable PSA). Two recently 
reported randomized trials of salvage radiation after prostatectomy delivered with or without 
ADT have shown a benefit in progression free survival or overall survival [7, 10]. These trials 
demonstrated no increase in bowel or bladder toxicity with the addition of ADT to radiation 
compared to radiation alone. Based on these results, the use of ADT with radiation is considered 
appropriate in some, but not all, patients receiving salvage radiation. The use of ADT is 
dependent of specific tumor and patient characteristics, including age, comorbidity, PSA at the 
time of radiation, Gleason score, margin status, presence of extra prostatic extension, and patient 
willingness. We will allow patients to receive ADT on this trial if deemed clinically appropriate, 

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as the bulk of data suggests that it has no impact on the toxicities we have defined as DLTs in 
this trial.
1.2.2
Hypofractionation in prostate cancer
Hypofractionation in radiotherapy is the use of fractional doses larger than the “standard” 1.8 Gy 
– 2 Gy fractions size, with the total dose delivered in a more rapid time frame. Hypofractionated 
approaches have long been used in the palliative setting to rapidly complete treatment in patients 
with limited life expectancies. The capacity to utilize modern advanced radiation techniques, 
such as intensity modulated radiation therapy and stereotactic body radiation therapy, to 
maximally treat tumor while minimizing the exposure of normal tissues to high doses has led to 
increased interest in hypofractionated approaches.
For certain cancers, the growth kinetics and radiation response further support the use of 
hypofractionated approaches over “standard” 2Gy per day fractionation approaches. A 
substantial body of evidence suggests that the α/β ratio for prostate cancer is lower than for many 
cancers, and even for many late responding normal tissues. The α/β ratio is a descriptive value 
based on the curvature of a cell survival curve [11]. The alpha beta ratio is the dose at which 
radiation cell killing from linear and quadratic components are equal. In general, early 
responding tissues, such as mucosa, bone marrow, and skin, have high α/β ratios (on the order of 
10) [11]. Late responding tissues, such as brain, spinal cord, muscle, and dermis have very low 
α/β ratios (on the order of 3) [11]. Tumors can have a range of alpha beta ratios, however certain 
histologies, such as prostate cancer, melanoma, and sarcoma, have been described to have very 
low α/β ratios. The clinical implication of this information is that tumors with low α/β ratios, 
such as prostate cancer, should respond favorably to large dose per fraction (hypofractionated) 
approaches.
Although much of this work in defining alpha beta ratios was initiated in vitro, studies of patients 
treated with radiotherapy have been used to confirm that the α/β ratio of prostate cancer is indeed 
low [12]. These findings have been used as the rationale for developing hypofractionated 
regimens for the treatment of patients with previously untreated prostate cancer [13]. Several 
randomized trials of hypofractionated radiotherapy compared to standard fractionation in patients 
with intact prostates have suggested that this approach is effective and well tolerated [14-16].
Mathematical calculations can be used to determine isoeffect levels (biologically equivalent 
dose) using the formula BEDx=TD(1+x/[α/β]), where x is the fraction size, TD is the total dose 
delivered, and α/β is the ratio of the tissue of interest. Few, if any, normal tissues have an α/β 
ratio less than 3. Thus, by using the α/β ratio of 3 to drive choice of an appropriate 
hypofractionated regimen, tissues with higher α/β ratios may actually benefit from 
hypofractionation as the BED of these fractionation regimens may be biologically “less dose” 
when considering a α/β higher than 3. For example, delivering 68.4 Gy in 2 Gy fractions is 
equivalent to delivering 56.4 Gy in 2.82 Gy fractions if using an α/β of 3(prostate cancer, late 
responding normal tissues). The similar regimen delivers a dose biologically equivalent to 60.25 
Gy in 2 Gy fractions (α/β ratio of 10, early responding tissues). Thus, the more sensitive normal 
tissues receive a reduced dose biologically while the tumor receives a biologically equivalent 
dose.
There is substantial interest in the use of hypofractionated radiotherapy for prostate cancer, 
largely because of the prevailing thought that prostate cancer exhibits a low α/β ratio. In addition, 
hypofractionated therapies are of increasing interest given enhanced conformality of radiation 

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treatments and enhanced convenience for patients. The vast majority of data evaluating outcomes 
of hypofractionated radiotherapy in the treatment of prostate cancer has been developed in the 
setting of an intact prostate (no prior surgery). The doses used in the setting of radiotherapy are 
substantially higher than those used in the post-prostatectomy setting (79-82 Gy compared to 66-
72 Gy). Additionally, the volumes treated in the intact prostate setting are generally smaller than 
those treated in the post-prostatectomy setting. Regardless, these studies do provide information 
on the efficacy and tolerability of hypofractionated radiotherapy in a similar region of the body. 
In many cases, these regimens, although hypofractionated compared to the current standard, 
were substantially less hypofractionated than the regimen proposed herein.
A recent multi-center randomized trial (PROFIT) evaluated the efficacy of hypofractionated 
radiation in patients with intermediate risk localized prostate cancer in which 1,206 patients were 
randomized to conventional dosing (78 Gy in 2 Gy fractions) versus hypofractionated radiation 
(60 Gy in 3 Gy fractions) [17]. At a median follow-up of 6 years, the biochemical disease free 
survival was 85% in both arms (the study endpoint was non-inferiority), with no significant 
differences in late > Grade 3 genitourinary or gastrointestinal toxicity. Similarly, RTOG 0415 
enrolled 1,115 men with low to intermediate risk prostate cancer to 73.8 Gy in conventional 
fractionation or 70 Gy in 2.5 Gy fractions. At a median follow-up of 5.8 years, there were more 
grade 2 toxicities in the hypofractionation arm, but grade 3 toxicities were similar. In this trial, 
the moderate hypofractionation regimen was also found to be non-inferior [18]. In the CHHiP 
trial, 3,216 men with intermediate risk prostate cancer were randomized to 74 Gy in conventional 
fractionation compared to 57-60Gy in 3 Gy fractions [14]. At 62 months of follow up, the 
hypofractionated regimen was not inferior. In this trial, there were more acute toxicities in the 
hypofractionated group and more late toxicity in the conventionally fractionated group. The 
HYPRO trial assessed 64.6 Gy in 3.4 Gy fractions (3 times per week) compared to 78 Gy 
standard fractionation. Other trials assessing superiority of hypofractionated radiotherapy versus 
conventionally fractionated radiotherapy in the setting of intact prostate have not found evidence 
of superiority [19-21]. As these dosing regimens are calculated for estimated equivalence of 
tumor control, these are findings are not particularly surprising.
In the post-prostatectomy setting, NRG Oncology has recently activated a trial of 
hypofractionated radiotherapy post-prostatectomy (NRG GU003). In this trial, 282 patients will 
be randomized to hypofractionated radiotherapy or conventionally fractionated radiotherapy 
(66.6 Gy in 1.8 Gy fractions versus 62.5 Gy in 2.5 Gy fractions). In the RTOG trial, the 
hypofractionated arm also includes a dose escalation component (the entire prostate bed receives 
the hypofractionated dose which is biologically equivalent to an escalated dose). Supporting 
studies for this trial included a series from the University of Wisconsin, which evaluated 65 Gy 
in 2.5 Gy fractions to the prostate bed with a resulting 4 year progression free survival of 67% at 
a median follow up of 34 months [22]. In this trial, late toxicity was highly favorable compared 
to historical series.
This trial is substantially different from published series in that it is not “moderate” 
hypofractionation. This approach is substantially more hypofractionated compared to regimens 
previously investigated in this context and much more in line with modern hypofractionated 
SBRT approaches that have been used for radiation of the intact prostate. Second, this trial 
includes an escalation component in which the imaged tumor is escalated while dose to the 
remaining prostate bed is reduced to a dose that is biologically equivalent to a “microscopic” 

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radiotherapy dose. Finally, the trial attempts to integrate novel quality of life, biomarker, and 
correlative endpoints to further explore the effects of this rapid treatment.
1.2.3
Quality of life after salvage radiation
Altering the dose per fraction given during radiation treatments not only impacts malignant cells, 
but also surrounding normal tissues. As the dose per fraction received by these tissues changes, 
so also may the rate of acute and late toxicity. Therefore, assessment of acute and late toxicity 
and resultant quality of life effects is an important component of outcomes assessment in altered 
fractionation radiation regimes. Validated measures such as the EPIC-26, AUA, and SHIM are 
key in assessing both objective and subjective patient reported outcomes post-treatment. They 
focus on bowel and urinary toxicity, as well as sexual and erectile function, which can all be 
negatively affected by treatments for prostate cancer, in both the upfront and salvage settings 
[23, 24]. 
While altered fractionation may have a potential benefit in tumor cell kill, novel fractionation 
modalities must also address patient quality of life particularly with adjuvant and salvage 
radiation therapy post-prostatectomy [25, 26]. Decision regret after prostate cancer is a 
recognized phenomenon occurring in 10-20% of patients after upfront treatment [27-30]. 
Decision regret has been associated with time since treatment, toxicities, and patient 
demographics [29-31]. Increased levels of regret have been associated with bowel or bladder 
toxicity from, but independent of, treatment modality [24, 27, 28], and may be more common in 
men who experience PSA recurrence or metastatic disease [31]. Despite these efforts, a 
comprehensive schema of factors involved in decision regret has not yet been established. It is 
important to explore factors such as mood and patients’ views on their disease in order to better 
understand the components of decision regret, and how they can best be mitigated. Uniquely in 
this research, we will address patients who have options for curative intent salvage treatments, 
rates of decision regret post-prostatectomy, and if subsequent regret can be mitigated by effective 
salvage therapies.
The questionnaires used in this trial are:

The Expanded Prostate Cancer Index Composite (EPIC-26) is a prostate cancer health-
related quality of life (HRQOL) patient self-administered instrument that measures 
urinary, bowel, sexual, and hormonal symptoms related to radiotherapy and hormonal 
therapy. The EPIC-26 was developed from the 50-item EPIC questionnaire and was 
validated using question responses from 252 subjects who had undergone brachytherapy, 
external beam radiotherapy, or prostatectomy for prostate cancer. A high correlation was 
observed between the EPIC-50 and EPIC-26 versions for the urinary incontinence, 
urinary irritation/obstruction, bowel, sexual, and vitality/hormonal domain scores (all r 
>/=0.96). The correlations between the different domains were low, confirming that 
EPIC-26 retained the ability to discern the distinct HRQOL domains. The internal 
consistency and test-retest reliability for EPIC-26 (Cronbach's alpha >/=0.70 and r 
>/=0.69, respectively for all HRQOL domains) supported its validity. EPIC-26 has been 
used in multiple RTOG protocols and phase II publications for hypofractionated 
radiotherapy to the prostate. 

Sexual Health Inventory for Men (SHIM) is a prostate specific questionnaire for 
assessment of erectile dysfunction. Initially derived from the IIEF, a shortened version to 
six questions the IIEF-6 or SHIM was created for increased usability in the clinic. 

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
American Urologic Association Symptom Index Score (AUA-SI) has been established as 
a measure of radiation morbidity in patients treated for prostate cancer with respect to 
urinary function and is used routinely as the basis for treatment decisions. Moderate 
agreement was observed between EPIC domains and the American Urological 
Association Symptom Index (AUA-SI), providing criterion validity without excessive 
overlap. 

PROMIS – Depression SF4a: The PROMIS Depression item bank assesses self-reported 
negative mood (sadness, guilt), views of self (self-criticism, worthlessness), and social 
cognition (loneliness, interpersonal alienation), as well as decreased positive affect and 
engagement (loss of interest, meaning, and purpose). The depression short forms are 
universal rather than disease-specific. All assess depression over the past seven days. 
PROMIS instruments are scored using item-level calibrations.

PROMIS – Anxiety SF4a: The PROMIS Anxiety item banks assess self-reported fear 
(fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, 
restlessness), and somatic symptoms related to arousal (racing heart, dizziness). Anxiety 
is best differentiated by symptoms that reflect autonomic arousal and experience of 
threat. Only one behavioral avoidance item is included in the adult item bank; therefore, 
behavioral fear avoidance is not fully evaluated. The anxiety measures are universal 
rather than disease-specific. All assess anxiety over the past seven days.

PROMIS – Psychosocial Impact Positive SF 4a assess positive psychosocial (emotional 
and social) outcomes of illness, previously conceptualized in various ways including 
post-traumatic growth, benefit-finding, and meaning making. Positive Illness Impact 
refers to positive psychosocial outcomes of illness that can occur as a result of 
confrontation with one’s mortality, such as greater life appreciation, interpersonal 
relationships and personal resources.

Decision Regret Scale (DRS) is a 5-item scale measuring distress or remorse after a 
health case decision. It has been psychometrically validated in the prostate cancer 
population. The score correlated with satisfaction with the decision (r=-0.40 to -0.60), 
decisional conflict (r=0.31 to 0.52), and overall rated quality of life (r=-0.25 to -0.27).
1.2.4
Biological versus standard optimization algorithms
Radiation treatment planning for intensity modulated radiation therapy typically uses inverse 
planning algorithms, whereby the physician defines dose limits to organs at risk of injury and 
defines the dose goals to the target. The computer then iteratively optimizes the radiation 
delivery such that it attempts to reach the dose goal to the target while respecting the organ at 
risk (normal tissue) dose constraints. A number of dose limits have been published for normal 
tissues and, in general, these are often adapted from those included on randomized trials or from 
the QUANTEC project [32]. Biological optimization uses biological modeling to incorporate 
local tumor control probability data (TCP) and normal tissue complication probability data 
(NTCP) into the planning process. This approach requires integration of TCP and NTCP data 
into the treatment planning process. Although patients will be treated using standard planning 
techniques, we will explore the capacity of this process to alter radiation treatment planning 
retrospectively from the imaging datasets obtained on this trial. 

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1.2.5
Summary
The goal of this study is to evaluate a new regimen that would reduce the duration of treatment 
compared to the current standard. For patients with no evidence of tumor on clinical evaluation 
(imaging or biopsy as clinically indicated) this would be accomplished by increasing the fraction 
size to the prostate bed to allow for more rapid treatment. Because the dose is delivered more 
rapidly, the total dose would be adjusted for biological equivalence to tumor when compared to 
standard fractionation. Thus, an equivalent biological dose would be delivered to the tumor bed 
more rapidly than the current standard. We anticipate that this approach will be tolerable as 
newer technologies have provided the capacity to enhance the conformality of dose around the 
target. In addition, daily imaging guidance allows increased confidence that normal tissue is 
maximally spared and tumor tissue is included. This approach has begun to be explored with 
conservative increases in fraction size (2.2 - 2.5 Gy) and appears safe [33-38]. In patients with no 
visible tumor, our study aims to accelerate using the most modern techniques, with daily image 
guidance, and with consideration of not only toxicity, but Quality of Life (QoL).
In patients with tumor identified on imaging studies or on clinical biopsy, we aim to reduce the 
dose delivered to the prostate bed to a level considered adequate of sterilizing microscopic 
disease and escalate dose to the areas of known recurrence. In general, the site of local 
recurrence after prostatectomy has historically not been known after prostatectomy based on 
limitations with imaging in the post-prostatectomy setting. Occasionally, an area would be 
palpated in the bed on digital rectal examination, but often not until the PSA was higher than 
what is traditionally used as a cut off for delivering radiation treatments. Historically, MRI was 
not performed and CT imaging gave poor soft tissue contrast in this anatomic location. More 
recently, it has become clear that recurrences can often be identified with high quality MR 
imaging using an endorectal coil or advanced imaging techniques, and in many cases these areas 
are biopsied for confirmation [39, 40]. Because the site of recurrence is known, this provides the 
opportunity in this patient subset to escalate dose to the recurrent disease while reducing the dose 
to the prostate bed.
Collectively, these approaches are evaluating the tolerability of more rapidly delivering radiation 
and reducing normal tissue exposure through the use of highly conformal radiation treatments. 
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1 Patients must have histologically or cytologically confirmed adenocarcinoma of the 
prostate.
2.1.1.2 Indications for post-prostatectomy radiation exist:
Disease progression (detectable PSA on two measurements obtained at least one month 
apart) or
indications for adjuvant radiation exist (if undetectable PSA): pathologic T3, T4, N+ 
disease or positive margins (within 1 year of prostatectomy).
2.1.1.3 Age >18 years. 

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2.1.1.4 ECOG performance status <1 (Karnofsky >60%, see Appendix A)
2.1.1.5 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.6 Radiation is teratogenic; thus, men must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation and up to 120 days after the last radiation. Should a woman become 
pregnant or suspect she is pregnant while her partner is participating in this study, she 
should inform her treating physician immediately.
2.1.1.7 HIV positive patients are included if CD4+ T-cell count > 200 cells/uL; on stable 
antiretroviral therapy for > 1 year with HIV viral load <200 copies/mL, and no history 
of opportunistic infections in > 1 year.
2.1.2
Exclusion Criteria
2.1.2.1 Patients who are receiving any other investigational agents concurrently.
2.1.2.2 Documented metastases of prostate cancer outside of the pelvis (pelvic lymph nodes are 
allowed only if within the prostate bed region). 
2.1.2.3 History of radiation that would overlap with the intended treatment to the prostate bed.
2.1.2.4 Known contraindications to radiation such as inflammatory bowel disease, active 
systemic lupus or scleroderma, or radiation hypersensitivity syndrome (Ataxia 
Telangiectasia or Fanconi’s Anemia)
2.1.2.5 Subjects with any coexisting medical or psychiatric condition which, in the opinion of 
the Investigator likely to interfere with study procedures and/or results.
2.1.2.6 Medically indicated use of known radiosensitizing drugs (such as protease inhibitors)
2.1.3
Recruitment Strategies
Participants will be identified from Dr. Citrin’s referral base, largely via referrals from the 
Urologic Oncology Branch, via the multi-disciplinary clinic, and via direct outside referrals to 
Dr. Citrin’s clinic. Dr. Citrin has developed an excellent professional relationship with numerous 
referring physicians in the surrounding area who refer patients. 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. 
2.2
SCREENING EVALUATION
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols). Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent.
Within 4 weeks prior to enrollment unless otherwise noted below:

Physical Evaluation: Complete medical history and physical examination, including vital 
signs and ECOG performance status.

Laboratory Evaluations 

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HIV Viral serology and HIV viral load
CD4+ T-cell count for HIV positive patients
PSA 

Radiographic Evaluations (within 4 months prior to enrollment): 
multiparametric MRI (mpMRI) of the prostate bed
CT of the abdomen and pelvis (with oral and IV contrast) may also be obtained for 
evaluation of eligibility, particularly if MRI is not felt to adequately have staged the 
pelvic and abdominal lymph nodes 
whole body bone scan or 18F NaF PET if felt to be required by the clinician; this 
imaging is not required if MRI and/or CT scans adequately staged the pelvic and 
abdominal lymph nodes, or if other standard scans were performed (e.g., 18F-
DCFPyL) that confirm the disease status

Histological or cytological pathology documentation, confirming adenocarcinoma of the 
prostate and for determination of whether indication for adjuvant radiation exists.

Collection of medical records pertaining to medical history as well as testing and 
procedures for the diagnosis under study (e.g., imaging results including 18F-DCFPyL 
PET/CT)
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.4
TREATMENT ASSIGNMENT PROCEDURES
Cohorts
Number
Name
Description
1
Recurrent tumor visible
Recurrent tumor visible
2
Recurrent tumor NOT visible
Recurrent tumor NOT visible
Arms
Number
Name
Description
Arm 1
Prostate bed with 
integrated boost
Radiation will be delivered to an escalated dose to areas 
of recurrent prostate cancer identified on imaging and a 
reduced dose will be delivered to the entire prostate bed.
Arm 2
Prostate bed 
irradiation only
Radiation will be delivered to the prostate bed only

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Arm Assignment
Patients in Cohort 1 will be directly assigned to Arm 1. Patients in Cohort 2 will be directly 
assigned to Arm 2. 
2.5
BASELINE EVALUATION
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of treatment:
Within 2 weeks prior to treatment initiation:

Clinical assessment with attention to any new medications or interventions since 
screening history and physical examination including vital signs and ECOG 
performance status. 

Hematological profile: CBC with differential and platelet count, 

Lymphocyte phenotype TBNK

Biochemical profile: electrolytes, creatinine, BUN, alkaline phosphatase, ALT, 
AST, total and direct bilirubin,

PSA, testosterone, 

Questionnaires: Expanded Prostate Cancer Index Composite (EPIC-26), SHIM, 
AUA-SI, PROMIS Depression SF4a, PROMIS Anxiety SF4a, PROMIS 
Psychological Impact Positive SF 4a, Decision Regret Scale. For English speaking 
patients only. 

Collection of blood and urine for correlative assays (see section 5.1 for further 
details).

If available, tissue blocks or sections from prostatectomy or biopsies will be requested
Within 4 months prior to treatment:

Radiographic evaluation: Multiparametric MRI of the prostate bed.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
There will be two Arms in this trial. Arm 1 includes patients with rising PSA after prostatectomy 
for whom recurrent tumor has been visualized in the pelvis, providing a target for dose 
escalation. Arm 2 includes patients with rising PSA with no visualized tumor on imaging or 
patients with indications for adjuvant radiation after prostatectomy. Patients in whom MRI is 
contraindicated may enroll on Arm 2 if no evidence of disease is noted on other imaging 
modalities.
In Arm 1 radiation will be delivered to an escalated dose to areas of recurrent prostate cancer 
identified on imaging and a reduced dose will be delivered to the entire prostate bed. 
In Arm 2 radiation will be delivered to the prostate bed only in patients for whom no recurrent 
tumor is visualized on imaging or if MRI imaging was contraindicated. 
On Dose Level 1 treatments will be delivered in 20 fractions (approximately 4 weeks), on Dose 
Level 2 - in 15 fractions (approximately 3 weeks), on Dose Level 3 - in 10 fractions 
(approximately 2 weeks).

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Treatment will be administered in daily fractions Monday through Friday except in the case of 
machine malfunction or federal holiday. 
Daily image guidance with cone beam CT will be preferred. kV/kV imaging is allowed if the 
Cone beam CT imager is unavailable. An additional post-treatment cone beam CT after each 
fraction may be obtained to assess intrafraction motion.
Table 1 Fraction Dose Escalation Schedule
Cohort 1, Arm1: Recurrent tumor 
visible, prostate bed with integrated 
boost
Cohort 2, Arm 2: Recurrent 
tumor NOT visible, prostate bed 
irradiation only
Dose level
Dose to prostate 
bed
Dose to tumor 
Dose to prostate 
bed
Dose to 
tumor
Level 1: 
20 fractions
45.8 Gy in
2.29 Gy fractions
60.4 Gy in
3.02 Gy fractions
56.4 Gy in
2.82 Gy fractions
-
Level 2: 
15 fractions
41.85 Gy in
2.79 Gy fractions
54.6 Gy in
3.64 Gy fractions
51.2 Gy in
3.41 Gy fractions
-
Level 3: 
10 fractions
36.4 Gy in
3.64 Gy fractions
47.1 Gy in
4.71 Gy fractions
44.2 Gy in
4.42 Gy fractions
-
Serial PSA and serial correlative studies will be collected for two years post-treatment.
3.1.1
Dose Limiting Toxicity
The DLT period includes treatment period (4, 3 or 2 weeks depending on Dose Level) and the 3 
following weeks. DLT is defined as any of the following:

Grade 3 rectal, small bowel, or urinary toxicity that does not resolve to Grade 2 or less 
within 4 days with appropriate medical management.

Other grade 3 in-field toxicities attributable to RT that do not resolve to Grade 2 or less 
within 4 days with medical management.

Delays of more than one week in completing radiation treatment due to toxicity 
(cumulative duration of delay over the course of the entire treatment).
Additionally, toxicities that occur more than 3 weeks after completion of treatment and during 
the 24 month follow up period will be followed and scored but will not be used for escalation 
with the following exception. If Grade >4 late bowel or bladder injury is observed in 2 patients at 
any Dose level, dose escalation will be terminated and the dose below that dose level in which 
the toxicity was observed will be considered the MTD. Early and late toxicities used for 
assessment of DLTs should be attributable (possible, probable or definite) to radiation. Changes 
in sexual and erectile function will not be considered a DLT. MTD will be determined for each 
Arm separately.

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3.1.2
Dose Escalation (Hypofractionation)
Dose hypofractionation escalation will follow the classical ‘3+3’ trial design. If none of the first 
three patients in a Dose level experiences a dose-limiting toxicity during the DLT period, another 
three patients will be treated at the next higher Dose level. However, if one of the first three 
patients experiences a dose-limiting toxicity during the DLT period, three more patients will be 
treated at the same Dose level. Dose escalation continues until the final Dose level meets safety 
criteria or at least two patients among a Dose level group of three to six patients experience dose-
limiting toxicities (i.e., ≥33% of patients with a dose-limiting toxicity at that Dose level).
Dose escalation (Table 1) will proceed in parallel in Arm 1 and Arm 2 in Dose level groups of 
3–6 patients. The MTD is the dose level at which no more than 1 of up to 6 patients experience 
DLT during the DLT period, and the dose below that at which at least 2 (of ≤6) patients have 
DLT as a result of treatment. 
Dose escalation will follow the rules outlined in the Table below for each Arm (1 or 2) 
independently as MTD and toxicities are expected to be different as a result of prior treatment.
Number of Patients with 
DLT
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 patients at the next dose level
> 2
Dose escalation will be stopped. This dose level will 
be declared the maximally administered dose 
(highest dose administered). Up to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously 
at that dose.
1 out of 3
Enter up to 3 more patients at this dose level.

If 0 of these 3 patients experience DLT, proceed 
to the next dose level.

If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose. UP to three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the MTD and is generally the recommended 
phase 2 dose. 6 additional patients may be entered at 
the recommended phase 2 dose.
There will be no radiation dose modifications except planned Dose levels. 

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If a patient did not experience DLT and did not finish treatment, he will not be evaluable for 
toxicity and will be replaced in the dose level.
If patients develop side effects considered DLT, they will be taken off protocol treatment and 
may receive additional radiation as needed in standard fractionation to complete the treatment. 
3.2
QUESTIONNAIRES (FOR ENGLISH SPEAKING PATIENTS ONLY)
(For English speaking patients only because questionnaires are not validated in other languages.)
Questionnaires will be collected on this trial, typically prior to visiting with the physician at each 
visit or within 1 week prior at the appropriate time points (Appendix B). Questionnaires may be 
completed in paper or electronically, but every effort will be made to have each patient complete 
questionnaires in the same format.
The timing of collection is noted on the study calendar in section 3.3. 
The total time anticipated to complete all questionnaires below is 20 minutes. 
Once data are abstracted, questionnaires will be maintained in the research chart (print or 
electronic). If stored, electronically, these files will have restricted access and be accessible only 
to members of the study team. In the event that questionnaires are stored electronically, paper 
copies will be shredded.

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3.3
STUDY CALENDAR
Follow Up,
Months7
Procedure
Screening
Baseline1
Active RT 
treatment
(2-4 weeks)
1
3
6, 9, 12, 15, 
18, 21, 24
RT treatment
X
Medical History/Records
X
Confirmation of Pathology
X
Physical exam, vital signs, 
ECOG
X
X
X
CBC with differential and 
platelet count 
X
Biochemical profile 2
X
PSA
X
X
X
X5
Testosterone
X
X
X5
HIV
X
CD4+ T-cell count for HIV 
positive patients
X
Lymphocyte phenotype 
TBNK
X
X
X
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
mpMRI
X
X8
Whole body bone scan or 
18F-NaF PET/CT imaging 9
X
CT of the abdomen and 
pelvis (if clinically indicated)
X
Blood for correlative studies
X
X3
X
X
X5
Urine for correlative studies
X
X3
X
X
X5
Questionnaires 6
X
X4
Archival tissue (if available, 
blocks or sections from 
prostatectomy or biopsies 
will be requested)
X
Contact by phone call, e-mail 
or other NIH approved 
remote communication 
platform every 3 months 
once off treatment and unable 
to return for visits
X
X
X

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1. Tests done at screening do not need to be repeated on baseline if performed in designated 
time frame prior to start of treatment
2. Biochemical profile: electrolytes, creatinine, BUN, alkaline phosphatase, ALT, AST, total 
and direct bilirubin
3. Sampling within 24 hours after the last dose of irradiation.
4. Every 6 months after treatment for 24 months
5. Every 3 months after radiation treatment for 24 months
6. Questionnaires: Expanded Prostate Cancer Index Composite (EPIC-26), SHIM, AUA-SI, 
PROMIS Depression SF4a, PROMIS Anxiety SF4a, PROMIS Psychological Impact 
Positive SF 4a, Decision Regret Scale. If the patient receives ADT, before initiation of 
ADT and within one week before starting radiation if ADT initiated more than one month 
prior to radiation. For English speaking patients only.
7. +/- 1 week for 1 month visit, +/- 2 weeks for 3 and 6 month visits. +/- 4 weeks for next 
visits. If subjects are not able or willing to come to NIH to FU visits, they will be followed 
every three months remotely (by phone call, e-mail for adverse events or other NIH 
approved remote communication platform), further tumor therapy and lab results. Lab 
results from outside laboratories are accepted. A clinical evaluation may be completed 
remotely with a member of the study team to determine if the physical exam, vital signs 
and ECOG may be omitted. A subject may be referred to a local providers for further 
assessment at the discretion of the investigator after a remote assessment (e.g., finding that 
requires clinical assessment/follow up). Subjects may also be referred to their local 
provider for labs. If biochemical failure per 6.3.1 is identified, the second measurement 
will be obtained for confirmation, ideally at the NIH Clinical Center. Imaging may be 
delayed, but will be completed as soon as feasible. Collection of research blood or urine 
will be omitted or collected in a delayed fashion.
8. Only at the 6 month follow up time point. 
9. Scans may be omitted if eligibility can be determined from MRI or other imaging results 
including 18F-DCFPyL.
3.4
RADIATION THERAPY GUIDELINES
3.4.1
Treatment Planning
A CT simulation will be performed in the radiation oncology branch. The bladder should be 
comfortably full. Contrast is optional, but discouraged as it may distort anatomy and complicate 
heterogeneity corrections. If possible, additional imaging will be fused to the planning CT scan 
(i.e., MRI or other imaging on which tumor was identified).
Treatment planning definitions
GTV: gross tumor volume
CTV: clinical target volume
PTV: planning target volume
Arm 1: prostate bed and tumor boost treatment

GTV lesion(s): image defined tumor

PTV lesion(s): GTV lesion + 3 mm posterior and superior margin and 3-5 mm margin in 
all other dimensions (inferior, lateral, anterior) on the GTV lesion(s). An expansion of the 

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PTV to a maximum of 7mm in any direction due to imaging or treatment set up 
uncertainty may be used at the discretion of the treating radiation oncologist. 

CTV prostate bed: The CTV of the prostate bed will use consensus definitions [9, 41]. 

Superiorly: The CTV should extend superiorly from the level of the caudal vas deferens 
remnant. In some cases, the vas deferens remnant may be difficult to visualize. In the 
absence of gross disease or seminal vesicle remnants, the superior limit of the CTV 
should extend at least 2 cm and need not extend more than 3-4 cm above the level of the 
pubic symphysis. The consensus definition calls for “inclusion of the seminal vesicle 
remnants, if present, in the CTV if there is pathologic evidence of their involvement. 
However, inclusion of any seminal vesicle remnants seen is recommended. 

Inferiorly: The CTV should extend inferiorly to > 8-12 mm inferior to vesicourethral 
anastomosis. With axial CT imaging, the anastomosis can often be seen in the retropubic 
region as one slice below the most inferior urine-containing image (the bladder must be 
modestly full). Inferiorly, the border of the CTV should be at least 8-12 mm below the 
VUA. If visualization of the VUA is problematic due to image quality or surgical clip 
artifacts, the inferior limit of the CTV can extend to a level just above the penile bulb. 

Anteriorly: Below the superior border of the pubic symphysis, the anterior border is at the 
posterior aspect of the pubis. The CTV extends posteriorly to the rectum where it may be 
concave at the level of the VUA. At this level the lateral border extends to the levator ani. 
Above the pubic symphysis the anterior border should encompass the posterior 1-2 cm of 
the bladder wall at the minimum and posteriorly it is bounded by the mesorectal fascia. 
At this level the lateral border is the sacrorectogenitopubic fascia or the obturator internus 
muscle. 

Posteriorly: The CTV extends posteriorly to the anterior rectal wall, but may be 
somewhat concave around the anterior-lateral aspect of the rectum to adequately 
encompass the prostate bed. 

PTV prostate bed: 7 mm margin on the prostate bed CTV. A 5-6 mm margin posteriorly 
may be used if necessary to meet dose constraints.
Arm 2. Prostate bed

CTV prostate bed: As above

PTV prostate bed: As above

Dose to the PTV will be escalated as defined in Section 3.1.2.
3.4.2
Dose constraints
Dose will be prescribed to 100%.
Max dose in PTV (highest dose PTV per plan): goal 107%, tolerated 115%
Min dose in PTV goal 95%
Contoured organs at risk: Bladder, bladder minus CTV, rectum, small bowel, femoral heads, 
penile bulb 

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DOSE LEVEL 1: 20 fractions
Normal organ limit
Dose level 1:
20 fractions
No more than 50% 
volume receives dose 
that exceeds
No more than 70% 
volume receives dose 
that exceeds
Bladder minus CTV
52.6 Gy
33.8 Gy
Normal organ 
limit
Dose level 1: 
20 fractions
No more than 
15% volume 
receives dose that 
exceeds
No more than 
25% volume 
receives dose that 
exceeds
No more than 
35% volume 
receives dose that 
exceeds
No more than 
50% volume 
receives dose 
that exceeds
Rectum 
60.0 Gy
56.2 Gy
52.6 Gy
48.2 Gy
Small bowel: V38 ˂ 195cc (peritoneal cavity)
Femoral heads: No more than 10% to 45 Gy
DOSE LEVEL 2: 15 fractions
Normal organ limit
Dose level 2:
15 fractions
No more than 50% 
volume receives dose 
that exceeds
No more than 70% 
volume receives dose 
that exceeds
Bladder minus CTV
47.8 Gy
31.1 Gy
Normal organ 
limit
Dose level 2: 
15 fractions
No more than 
15% volume 
receives dose that 
exceeds
No more than 
25% volume 
receives dose that 
exceeds
No more than 
35% volume 
receives dose that 
exceeds
No more than 
50% volume 
receives dose 
that exceeds
Rectum
54.4 Gy
51.1 Gy
47.8 Gy
44.5 Gy
Small bowel: V35 ˂ 195cc (peritoneal cavity)
Femoral heads: No more than 10% to 42 Gy
DOSE LEVEL 3: 10 fractions
Normal organ limit
Dose level 3:
10 fractions
No more than 50% 
volume receives dose 
that exceeds
No more than 70% 
volume receives dose 
that exceeds
Bladder minus CTV
41.4 Gy
27.5 Gy
Normal organ 
limit
Dose level 3: 
10 fractions
No more than 
15% volume 
receives dose that 
exceeds
No more than 
25% volume 
receives dose that 
exceeds
No more than 
35% volume 
receives dose that 
exceeds
No more than 
50% volume 
receives dose 
that exceeds
Rectum
46.8 Gy
44.1 Gy
41.4 Gy
38.7 Gy
Small bowel: V30 ˂ 195cc (peritoneal cavity)
Femoral heads: No more than 10% to 36 Gy. 

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3.5
FOLLOW UP
After treatment completion, patients will be invited to Clinical center or referred to their local 
provider for follow up visit 1 month and 3 month post treatment, and subsequently every 3 
months for 2 years. For evaluations during these visits, please, see Study Calendar 3.3.
3.6
COST AND COMPENSATION 
3.6.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by an insurance company. Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center. 
3.6.2
Compensation
Participants will not be compensated on this study.
3.6.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.7.1
Criteria for removal from protocol therapy

Completion of protocol therapy

Participant requests to be withdrawn from active therapy

Unacceptable Toxicity as defined in section 3.1.1

PI discretion
3.7.2
Off-Study Criteria

Completed study follow-up period

Participant requests to be withdrawn from study

Death

Recurrence of prostate cancer 

PI discretion

Non-compliance with follow-up visits or protocol mandated procedures

PI decision to close the study

Lost to follow up
3.7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 

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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Supportive care with blood components, antibiotics, analgesics, and general medical therapy will 
be provided if the need relates to the performance of protocol assessments (imaging procedures) 
or to treat side effects of therapy. Every effort will be made to refer the patient to their 
collaborating physician in the community for care unrelated to the protocol therapy or 
procedures. There are no limitations on the type of non-investigational concurrent medications 
allowed, as in general, these patients do not receive additional therapy for prostate cancer after 
radiotherapy, with the exception of hormonal therapy, which may be delivered as per the current 
standard of care.
Radiation related side effects will be managed as per the current standard of care without 
restrictions in medications or procedures that may be performed for management.
4.1
ADT
We will allow patients to receive ADT on this trial after enrollment if deemed clinically 
appropriate, as the bulk of data suggests that it has no impact on the toxicities we have defined as 
DLTs in this trial.
ADT will be delivered on this protocol as per the current standard of care with the duration of 
therapy to be determined by the treating physician if indicated. This may include an anti-
androgen, gonadotropin releasing hormone agonist, or the combination of both. As an 
alternative, patients may also receive ADT through their local care provider (medical oncologist, 
primary care physician, urologist) in collaboration with the research team.

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5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
Test/assay
Volume blood 
(approx)
Type of 
tube a
Collection point 
Location of 
specimen analysis
ELISA/Bioplex 
analysis of 
predictive 
biomarkers 
Plasma 8 mL
EDTA 
(lavender 
top)
See Study 
Calendar 3.3
Dr. Citrin’s Lab
Circulating DNA 
by whole genome 
sequencing with 
copy number 
analysis
5-10 mL
STREK
See Study 
Calendar 3.3
Dr. Sowalsky’s Lab
Exosome analysis 
(Surface receptor 
analysis by Nano 
FACS, RNA 
analysis)
Plasma 8 mL
EDTA 
(lavender 
top)
Study Calendar 
3.3
Dr. Jones Lab
Immune cell 
subsets and 
circulating 
endothelial cells by 
FACS
Whole blood 16 
mL
CPT 
citrate
Study Calendar 
3.3
DTB Clinical 
Translational Unit
ELISA analysis of 
predictive 
biomarkers
Urine 15 mL
Sterile 
cup
Study Calendar 
3.3
Dr. Citrin’s Lab
Whole genome 
sequencing
If available, 
tissue blocks or 
sections from 
prostatectomy or 
biopsies
Baseline
Dr. Sowalsky’s Lab
a.
Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
A number of exploratory correlative studies will be performed. These studies focus on two main 
areas: assessment of tumor radiation response (disease control) and prediction of normal tissue 
toxicity. Plasma and urine will be analyzed for the presence of markers of prostate cancer that 

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were initially described from proteomic analysis of prostate cancer patient’s blister samples from 
protocol 09-C-0120. A number of candidate markers were identified during the discovery 
proteomic analysis, and the plasma samples from this trial will be used to test these markers 
without the complication of residual normal prostate tissue which may impact their suitability as 
a biomarker of cancer post-radiation. The post-prostatectomy setting provides an excellent 
minimal disease state to test candidate biomarkers. 
5.1.1
Circulating immune cells during radiotherapy
During a course of radiotherapy, the target tissue is irradiated, including local immune cells. It is 
well known that radiation can cause changes in the local immune landscape, an effect that has 
been considered a major contributor to radiation injury [42-44]. Importantly, radiation can be 
considered immunosuppressive or immune activating depending on the field size, portion of the 
body targeted, and fractionation employed [45-48]. Recently, there has been tremendous interest 
in leveraging local and systemic immune changes caused by radiotherapy to enhance 
immunotherapy for cancer [49-54]. 
One previously observed change in immune cell subsets after irradiation is a change in the 
number and proportion of lymphocyte subsets, particularly CD4+ T cells and CD8+ T cells. 
Treatment induced lymphopenia can be quite striking in patients treated with combined radiation 
and chemotherapy [55, 56]. In elderly patients with high grade glioma, severe treatment related 
lymphopenia has been shown to correlate to inferior survival [57]. Treatment related 
lymphopenia has been observed in patients treated with post-prostatectomy radiotherapy with 
conventionally fractionated or moderately hypofractionated (2.35 Gy per fraction) approaches 
[58]. Although this report did not further classify lymphocyte subsets, we have accumulated data 
in anal cancer patients (Figure 1) and prostate cancer patients treated with radiotherapy on ROB 
protocols that suggests that CD4+ cells are disproportionally affected by radiotherapy +/- 
chemotherapy compared to other lymphocyte subsets. In our experience, the suppression of 
circulating lymphocyte subsets in prostate cancer patients is evident, but more variable in 
intensity and duration than what is seen when chemotherapy is delivered.
Figure 1. Treatment related lymphopenia. Immune cell subsets in HIV negative patients that receive 
Mitomycin-C, 5-fluorouracil, and radiation for anal cancer (protocol 11-C-0129). Radiation treatment was 
completed by 42 days. Total WBC (A), lymphocyte count (B), CD4+ T cells (C), and CD8+ T cells (D) were 

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assessed at multiple time points. Lines represent the trajectory for each patient. Toxicity grade (CTC AE) for 
each measure is noted. 
Based on these findings, we are interested in more comprehensively evaluating lymphocyte 
subsets in this patient cohort. This trial will also allow us to begin to ask, in an exploratory 
fashion, if more aggressive hypofractionation and the volume irradiated alters the degree of 
lymphopenia. These are areas of substantial interest to the radiation oncology and 
immunotherapy community.
Macrophages also are known to play a critical role in radiation injury and the immune 
environment after irradiation [42-44, 59]. Radiation is known to deplete tissue resident 
macrophages, resulting in recruitment of bone marrow derived monocytes to repopulate [60]. 
Further, the polarization of monocytes/macrophages and lymphocytes is known to impact 
radiation toxicity [42, 61]. This trial will assess immune the subsets and polarization over time, 
in an exploratory fashion. We envision that these findings may spur additional clinical and 
laboratory research studies. Similarly, circulating endothelial cells will be analyzed before, at the 
end of, and one month after radiation in a purely exploratory fashion.
Immune cell subsets and polarization will be analyzed at several timepoints throughout the 
protocol in an exploratory fashion. Peripheral blood mononuclear cells (PBMC) will be assessed 
using multiparameter flow cytometry for conventional CD4+ T-cells, CD8+ T-cells, Tregs, 
monocyte subsets and MDSC populations. Assessment may include functional markers, i.e. PD-
1, TIM-3, CTLA-4, CD40. PBMC will be analyzed for forward and side scatter, and a dump 
channel will be created to exclude cells expressing hematopoietic markers, such as CD45. 
Endothelial cells will be identified using co-expression of markers, such as CD31 and CD146 for 
mature endothelial cells and CD31 and CD133 for circulating endothelial progenitor cells (CEP). 
The cell populations will also be analyzed for viability using scatter profiles and a vital stain 
(e.g., Hoechst 33258). Percentages of stained cells will be determined and compared with 
appropriate negative controls.
5.1.2
Protein and RNA Analysis
In addition, protein analysis of plasma and urine will be conducted to explore if markers of 
senescence can predict for the risk of normal tissue injury after radiation. Dr. Citrin’s laboratory 
has extensively studied normal tissue injury as a consequence of stem cell senescence or as a 
consequence of elaboration of molecules associated with senescence [42, 43, 62-66]. A number 
of these molecules known to be secreted after senescence, known as the senescence associated 
secretory phenotype (SASP)[67], will be evaluated with multiplex ELISA or similar quantitative 
protein assays in plasma and urine. Finally, plasma samples may be used to purify exosomes for 
further analysis via flow cytometry, protein assays, or RNA based approaches. These studies are 
all exploratory.
5.1.3
Samples
5.1.3.1 Plasma
Plasma will be sampled at baseline (within 2 weeks prior to radiation), at the end of radiation, 1 
month after radiation, and every three months after radiation until 24 months.
Two 8 mL aliquots of blood will be obtained in EDTA containing tubes (Citrin/Jones) and one 
aliquot of whole blood in a STREK tube. CEC/CEP analysis will only occur at selected time 
points. For CEC/CEP and immune subset analysis, whole blood will be collected in two 8 mL 

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BD Vacutainer Cell Preparation Tubes (CPT/citrate) aliquots will be collected in citrate CPT 
tubes. CEC/CEP collections will occur prior to treatment (baseline, the last day of treatment, one 
month after treatment, and at one optional blood draw at a later follow up appointment. 
Following collection, EDTA tubes will be immediately placed on ice and transferred to the 
laboratory of Dr. Citrin for processing and storage, Building 10, B3-B100, Tel. 301-496-5457. 
Samples for DTB Clinical Translational Unit (CPT tubes): Please notify the lab by email (Min-
Jung Lee - leemin@mail.nih.gov; Akira Yuno – akira.yuno@nih.gov and Sunmin Lee – 
leesun@mail.nih.gov) that the blood draw has been scheduled. When the blood is being drawn, 
please call the Lab at 240-760-6330 to arrange for immediate pick- up. 
Plasma will be stored and batched for analysis.
Plasma assays in Dr. Citrin’s laboratory will include ELISA/Bioplex analysis of predictive 
biomarkers recently identified by the Citrin laboratory that correlate with tumor resistance to 
radiotherapy (70 analytes) or toxicity. Studies in Dr. Jones’ laboratory will include surface 
receptor analysis by nanoFACS and RNAseq, for exosome and extracellular RNA analysis.
5.1.3.2 Urine
Urine will be sampled at baseline and every three months after SBRT.
At least 15 mL of urine will be obtained in a sterile collection cup. Following collection, urine 
will be transferred to the laboratory of Dr. Citrin for processing, measurement of creatinine 
concentration, and storage.
Urine will be stored and batched for analysis.
Urine assays will include ELISA analysis of predictive biomarkers recently identified by the 
Citrin laboratory that correlate with tumor resistance to radiotherapy (70 analytes identified in 
tissue, screening for detection will occur in urine and plasma).
5.1.4
MRI of erectile tissue
The erectile tissue lies just beneath the prostate. After prostatectomy, the penile bulb (base of the 
corpus cavernosa and spongiosa) is used as a landmark for the inferior portion of the radiation 
target volume. Patients treated with radiation to the prostate on 13-C-0119 have undergone pre-
treatment and post-treatment MRI for evaluation of treatment response. On interesting 
component of this analysis has been the finding that erectile tissue shrinks substantially in 
patients treated with radiation and ADT. Because a treatment planning MRI is often obtained (as 
per standard) we have noted a major change in the erectile tissue from baseline until the time of 
radiation, corresponding to two months of treatment with ADT. Less change is found after the 
addition of radiation. Thus, much of the change observed in the erectile tissue may be due to 
ADT. We hope to expand these observations in an exploratory fashion to the post-prostatectomy 
setting. In this case, we plan to evaluate the width and imaging characteristics of erectile tissue at 
baseline and 6 months after treatment. The percent reduction in width of the erectile tissue and 
the volume of the penile bulb will be evaluated at 6 months after treatment. Changes in the 
imaging characteristics of erectile tissue in patients treated with ADT and without ADT will be 
evaluated separately.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management 

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system. Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed. Samples will not be sent outside NIH without appropriate approvals and/or 
agreements, if required. 
All samples collected on this protocol and stored in Dr Citrin or Dr. Sowalsky’s laboratories 
will be labelled and catalogued with LabMatrix. Labmatrix access within the laboratories is 
restricted to laboratory members processing and storing specimens.
Samples to be analysed in Dr. Citrin’s and Dr. Jones’ laboratory will be immediately 
processed and stored at -80º C until use in the ROB clinical specimen freezers.
Samples to be analysed by Dr. Sowalsky are processed appropriately and stored in secure 
freezers at -80° C until use. 
Samples stored in the DTB Clinical Translational Unit laboratory will be immediately 
processed. Specimens are stored in secure freezers at optimal temperatures for the sample 
type, i.e. -80° for plasma and liquid nitrogen for viably frozen cells. All freezers are 
continually monitored. Samples are 2D barcoded without identifying information. Access to 
the patient database and code key is limited to defined laboratory personnel, and access is only 
possible on limited computers with a password-restricted login. 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described 
above. The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
record any loss or unanticipated destruction of samples as a deviation. Reporting will be per 
the requirements of section 7.2.
Blood and urine samples may be subjected to protein or RNA analysis in the future to describe 
novel prognostic or predictive biomarkers.
If the patient withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not 
be able to be retrieved.
5.3
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.3.1
Description of the scope of genetic/genomic analysis
5.3.1.1 Tumor whole genome sequencing
If available, tissue blocks or sections from prostatectomy or biopsies will be requested to 
perform whole genome sequencing or RNA analyses. This data will be used for comparison to 
circulating DNA analyses as outlined below or as a compliment to exosome studies. These will 
be exploratory analyse to compare the circulating DNA copy number results or exosome 
analyses to previously resected tumour tissue. These analyses may only be carried out if 
circulating DNA analyses or exosome analyses are promising as defined below.
5.3.1.2 Circulating DNA
The anticipated analysis on circulating DNA will include whole genome sequencing with copy 
number analysis, performed by Dr. Sowalsky’s laboratory. 

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We will use the approach of whole genome sequencing with copy number analysis of circulating 
cell free DNA. Copy numbers that vary from expected at baseline will be used as a tumor marker 
in longitudinal sample assessment (copy number abnormality at baseline will be compared to a 
reference region at follow up time points). This is purely an exploratory analysis to determine 
feasibility of the approach.
5.3.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized

Samples will be bar coded for storage and personal identifiers will be removed. Names 
and demographic data will be linked to bar codes in the password protected LabMatrix 
database. This data will be accessible only by the PI and the research nurses within the 
ROB.

Samples provided to CCR collaborators will be barcoded. No personally identifiable 
information will be released to Dr. Sowalsky. 

Data from genomic and genetic data will be deposited in dbGAP and released in 
accordance with NIH guidelines.

As part of study efforts to provide confidentiality of subject information, this study will 
obtain a Certificate of Confidentiality. Please refer to Section 10.4.
5.3.3
Management of Results
We plan to contact participants if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
secondary findings that is current at the time of primary analysis. (A list of current guidelines is
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Unless 
requested otherwise, participants will be contacted at this time with a request to provide a sample 
to be sent to a CLIA certified laboratory. 
5.3.4
Genetic counseling
If the research findings are verified in the CLIA certified lab, the participant will be offered the 
opportunity to schedule a visit, in person (at our expense) or via telemedicine on an NIH 
approved platform to have genetic education and counseling with the NCI Genetics Branch to 
explain this result. If the subject does not want to come to NIH, a referral to a local genetic 
healthcare provider will be provided (at participant’s expense).
This is the only time during the course of the study that secondary findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
Participants will be requested to maintain up to date contact information to enable future contact.
6
 DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 

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data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention through at least 30 days after the last study 
treatment administration. Beyond 30 days after the last study treatment administration, only 
adverse events which are serious and related to the study intervention need to be recorded.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study (except for a rising serum PSA)

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.1
Data Elements/Information
The presence of any pre-administration event (baseline signs and symptoms present just before 
radiation) will be recorded in the clinical research database: 

The date and time of evaluation

The onset time

The resolution time or duration

Action taken

Status of symptom

Intensity

Date of birth

Demographic data

Prior and concurrent medications

Medical history and concurrent diseases

Results of baseline tests: physical examination; vital signs; lab tests

Questionnaire scores.
Personal data (including contact information) will be collected with the subject’s permission and 
only to the extent that is necessary for the purposes of the study. 

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Exceptions to data collection:

As androgen deprivation therapy (ADT) is given as part of standard of care, adverse 
events/toxicities that occur related to ADT will not be collected or reported.
The following data will be collected and evaluated according to the Study Calendar (Section 
3.3):

Physical examination

Concomitant medications

AEs

Use of ADT 

Presence or absence of biochemical relapse 

Questionnaire scores
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded and linked data in an NIH-funded or approved public repository.

Coded and linked data in BTRIS (automatic for activities in the Clinical Center)
How and where will the data be shared? 

An NIH-funded or approved public repository: clinicaltrials.gov, dbGAP

BTRIS (automatic for activities in the Clinical Center).

Publication and/or public presentations.
When will the data be shared?

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 3 months after 
treatment with a serum PSA measurement as per the study calendar. Response will be assessed 
based on PSA.
6.3.1
Response Criteria
Biochemical control: Biochemical control will be defined as a post-radiation PSA that does not 
rise beyond 0.1 ng/dL. 
Biochemical progression/biochemical failure: Serum PSA more than 0.1 ng/dL. At least 2 PSA 
measurements separated by 1 month are needed to confirm biochemical failure. If a PSA pre-

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treatment was >0.1 ng/dL, a post-treatment value >0.1 ng/dL will not be considered biochemical 
progression if subsequent values continue to trend downwards after completion of radiation.
6.3.2
Biochemical Progression-Free Survival
Biochemical progression free survival (bPFS) will be evaluated on this trial as a secondary 
endpoint. bPFS is defined as the duration of time from start of treatment to time of PSA 
progression or death, whichever occurs first. PSA progression (also known as biochemical 
failure) is defined based on elevation of PSA beyond 0.1 ng/dL. A total of 2 rising PSA values 
separated by at least 1 month are required to document biochemical recurrence. If the PSA 
remains elevated, the date of failure will be backdated to the first PSA measurement that 
exceeded 0.1 ng/dL. Only PSA values collected at the NIH Clinical Center will be used to 
evaluate disease status given the variability in ranges obtained in different laboratories. 
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 

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To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis, at a minimum bi-weekly, when patients 
are being actively treated on the trial to discuss each patient. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data from prior 
patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
STATISTICAL CONSIDERATIONS 
8.1
STATISTICAL HYPOTHESIS
8.1.1
Primary Objective

Define the maximum tolerated dose (MTD) of image guided, hypofractionated, focally 
dose escalated post-prostatectomy radiation. Assessment of toxicities for dose escalation 
will occur through 3 weeks after radiation.
8.1.2
Secondary Objectives

Define the toxicity profile of image guided, hypofractionated, focally dose escalated post-
prostatectomy radiation. Assessment of acute toxicities for dose escalation will occur 
through 3 weeks after radiation.

Describe the rate of PSA control (biochemical progression free survival, bPFS) at 1 and 2 
years after treatment with image guided, hypofractionated, focally dose escalated post-
prostatectomy radiation. We hypothesize that the rate of PSA control (bPFS) will 
compare favorably to the rate obtained with salvage radiation previously published series.

Describe the effects of image-guided, focally dose escalated prostate bed radiation on 
patient reported outcomes (SHIM, AUA Symptom Index, EPIC-26). We hypothesize a 
reduction in quality of life (urinary and gastrointestinal) after radiation that persists for 
several months but returns to baseline in most patients by 2 years after treatment. We 
hypothesize that erectile dysfunction will progress without improvement over time.
8.2
SAMPLE SIZE DETERMINATION
The planned sample size is a minimum of 4 patients (2 per arm) and a maximum of 48 (24 
patient’s maximum per arm) based on the 3+3 design detailed in 3.1.2. An expansion of six 
additional patients can occur at the MTD in each arm as noted in 3.1.2. Estimates for sample size 

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are based on the assumption that all dose levels will accrue a maximum of patients, thus sample 
size is likely over-estimated. We anticipate accrual will require 30 months.
8.3
POPULATIONS FOR ANALYSES
All enrolled patients that initiate treatment with radiation will be considered evaluable for 
toxicity, unless they are removed from protocol treatment for a reason other than a DLT (such as 
illness unrelated to radiation). Patients that complete at least one post-treatment PSA will be 
considered evaluable for biochemical control and biochemical relapse free survival. Patients that 
complete QoL measures at 3 months will be considered evaluable for these measures. 
8.3.1
Definitions
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with radiation, unless they are removed from protocol treatment before the end of the 
assessment period for a reason other than a DLT (such as illness unrelated to radiation).
Evaluable for response: Only those patients who complete radiation and have PSA measured 
after radiation will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated earlier. 
8.4
STATISTICAL ANALYSES
8.4.1
General Approach
This is a phase I study. There are two arms to this study for 1) patients with prior prostatectomy, 
rising PSA, and visible tumor on imaging, and 2) patients with prior prostatectomy with no 
visible tumor on imaging (rising PSA or indications for adjuvant treatment). Arms are enrolled 
and escalated separately. Dose level groups of 3-6 patients are evaluated at each dose level. The 
dose level on which 2 patients experience unacceptable toxicity is considered to have exceeded 
the MTD. The next lower dose level on which no more than 1/6 patients experience unacceptable 
toxicity is considered the MTD for each arm of the study.
8.4.2
Analysis of the Primary Endpoints
The primary endpoints will be to define the MTD of this approach. 
8.4.3
Analysis of the Secondary Endpoint(s)

Define the toxicity profile of image-guided, focally dose escalated prostate bed radiation 
in patients with a local or regional recurrence of prostate cancer after prostatectomy. All 
AEs except grade 1 with attribution to protocol treatment will be collected in tabulated 
way and analyzed.

 The rate of PSA control (biochemical progression free survival, bPFS) will be estimated 
by the Kaplan-Meier survival analysis and effects of clinical variables on bPFS will be 
assessed by the Cox proportional hazards model.

The quality of life scores will be summarized at baseline and for each visit. Linear mixed 
effects model will be used to model quality of life scores at baseline and during and after 
treatment in which random intercept and random slope are used to account for patient-
specific trajectory of quality of life scores. Changes of quality of life scores during and 
after treatment will be calculated from the estimated linear mixed effect model. The 

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similar analytical approach will be performed for depression scores and correlated with 
quality of life scores.
8.4.4
Safety Analyses
Adverse events will be coded as per the CTCAE v4.0. Each AE will be coded once for each 
patient based on the maximum severity during the assessment period. The relationship of AEs to 
study intervention will be recorded in addition to the onset date, end date, severity, expectedness, 
and outcome. 
Dose-limiting toxicities are defined as follows (during treatment and within the first three weeks 
after treatment): 

Grade 3 rectal, small bowel, or urinary toxicity that does not resolve to Grade 2 or less 
within 4 days with medical management

Other grade 3 in-field toxicities attributable to radiation that do not resolve to Grade 2 or 
less within 4 days with medical management

Delays of more than one week in completing radiation treatment due to toxicity 
(cumulative duration of delay over the course of the entire treatment).
Additionally, toxicities attributable to radiation after the DLT assessment period (3 weeks after 
radiation is completed) will be followed and scored but will not be used for escalation with the 
following exception. If Grade >4 late bowel or bladder injury (late toxicity is defined as 
occurring >90 days after completion of radiotherapy) is observed in 2 patients in any Dose level 
group, dose escalation will be terminated and the dose below that dose level in which the toxicity 
was observed will be considered the MTD. Early and late toxicities used for assessment of DLTs 
should be attributable (possible, probable or definite) to radiation. Sexual and erectile 
dysfunction as a result of radiation will not be considered a DLT. Note that MTD will be 
determined for each Group separately. 
Dose-limiting toxicities are defined as per section 3.1.1.
8.4.5
Exploratory Analyses

Evaluate decision regret at the time of enrollment and at the end of follow up relating to 
the primary treatment for prostate cancer to determine if successful salvage mitigates 
decision regret. The percentage of patients scored as having decision regret will be 
compared to the percentage of patients not exhibiting decision regret (regarding the 
initial surgery). It is hypothesized the effective salvage therapy will mitigate decision 
regret expressed at the time of enrollment.

Explore candidate biomarkers of radiation toxicity in blood and urine of patients 
receiving image-guided, hypofractionated, focally dose escalated post-prostatectomy 
radiation. Protein and metabolic biomarkers will be assessed in collected specimens.

Explore MRI imaging parameters of erectile tissues in regards to testosterone and erectile 
dysfunction. MRI imaging of erectile tissue will be compared to evaluate for changes in 
volume and tissue characteristics after radiotherapy.

To compare dosimetry of standard compared to biological optimization algorithms for 
treatment planning of post-prostatectomy radiation. Treatment planning will be optimized 

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with both approaches to allow comparison of normal tissue complication probability 
curves. Results will be reported in a descriptive fashion.
9
HUMAN SUBJECTS PROTECTIONS 
9.1
RATIONALE FOR SUBJECT SELECTION
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria. To date, there is no information that suggests that differences in disease response would 
be expected in one group compared with another. Efforts will be made to extend accrual to a 
representative population. If differences in outcome that correlate with ethnic identity are noted, 
accrual may be expanded or a follow-up study may be written to investigate those differences 
more fully.
9.2
INCLUSION OF WOMEN AND MINORS
Women are excluded from this trial as prostate cancer does not occur in females. Boys younger 
than 18 are excluded because they do not develop prostate cancer with the exception of rare 
histologies, such as rhabdomyosarcoma, for which radiation alone and the radiation doses chosen 
here are not an appropriate treatment. 
9.3
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
9.3.1
Benefits
The potential benefits of trial participation relate to potential curative treatment of recurrent 
prostate cancer. As information is gathered from this trial, clinical results will be shared with 
patients as they become available. Laboratory and clinical data will be frequently gathered and 
any new significant finding(s) found during the course of the research, which may affect a 
patient’s willingness to participate further, will be explained.
Confidentiality of information concerning participants will be maintained, including in all 
publications and presentations resulting from this study. Names of participants and/or material 
identifying participants will not be released without permission, except as such release is 
required by law. Records at the National Cancer Institute are maintained according to current 
legal requirements, and are made available for review, as required by the Food and Drug 
Administration or other authorized users, only under the guidelines established by the Federal 
Privacy Act.
9.3.2
Risks
9.3.2.1 Radiation Therapy
The risks of participation are primarily those of toxicity from irradiation. Subjects in cohort 1 
will be exposed to up to 60.4 Gy of radiation in 20 treatment sessions, or up to 54.6 Gy in 15 
sessions or up to 47.1 Gy in 10 sessions. Subjects in cohort 2 will be exposed to up to 56.4 Gy in 
20 treatment sessions, or 51.2 Gy in 15 sessions, or 44.2 Gy in 10 sessions. 
The available studies support that hypofractionated radiation can be safe and effective in this 
setting. Based on the experience of standard post-prostatectomy radiation, there is a moderate 
risk of low grade, chronic bowel or bladder toxicity and a decline in erectile function. There is a 
small risk of more severe injury to the bowel or bladder that could require a procedure 
(cystoscopy, endoscopy) for evaluation or treatment. Although extremely rare, patients receiving 

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post-prostatectomy radiation may have severe toxicity that could cause urinary obstruction, 
worsen post-surgical urinary incontinence, or require surgical correction. It is anticipated that the 
risks of this schedule of irradiation will be similar although they may be more or less in 
frequency or intensity. In addition, there smaller risks from blood draw, such as the risk of pain, 
infection or bleeding.
9.3.2.2 Research Blood Collection Risks
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. Up to 62 mL of blood may be collected at baseline and up to 52 
mL during each follow up visits. 
9.3.2.3 MRI risks
The risks associated with MRI are discomfort and claustrophobia.
9.3.2.4 Gadolinium Risks
The most common side effects include injection site pain, nausea, itching, rash, headaches and 
dizziness. Serious but rare side effects such as gadolinium toxicity and nephrogenic systemic 
fibrosis, or NSF, are most often seen in patients with severe kidney problems.
9.3.2.5 Other Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
9.3.2.6 Non-Physical Risks of Genetic Research
Risk of receiving unwanted information.
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
Risk related to possibility that information may be released.
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement 
agencies. Although there are no plans to release results to the patients, family members or health 
care providers, this risk will be included in the informed consent document. 
9.4
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant as applicable for review prior to consenting. A designated study investigator will 
carefully explain the procedures and tests involved in this study, and the associated risks, 
discomforts and benefits. In order to minimize potential coercion, as much time as is needed to 
review the document will be given, including an opportunity to discuss it with friends, family 
members and/or other advisors, and to ask questions of any designated study investigator. A 
signed informed consent document will be obtained prior to entry onto the study.

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The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant. Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (e.g., clinic consult room). When consent is conducted remotely, the participant will 
be informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or, 

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required. 
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, and regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review 
Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility

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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
10.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
10.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the National Cancer Institute has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
10.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 

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secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site(s) and by NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
11 COMMERCIAL DEVICE INFORMATION 
There will be no IDE obtained for the use of any of the commercial agents used in this study. 
This study meets the criteria under category #1 for exemption for an IDE as this investigation 
involves the use of an already cleared medical device in which the device is used or investigated 
in accordance with the indications in the cleared labeling.
11.1 SOURCE 
The radiation device is a commercial device that will be located in the NIH Clinical Center. 
11.2 TOXICITY 
Refer to section 9.3.2.1. 
11.3 ADMINISTRATION PROCEDURES
Refer to section 3.1.

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13 APPENDICES
13.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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13.2 APPENDIX B: QOL QUESTIONNAIRES 
QoL questionnaires will be maintained in a separate document/manual.