A Phase I/II Study of Salvage High-dose-rate Brachytherapy, ExternAl Beam COmbined and Short-term Hormonal Therapy for the Treatment of Node-positive Locally Recurrent Prostate Cancer After Prior Definitive Radiotherapy
Phase: PHASE1
Conditions: Prostate Cancer - Recurrent
Sponsor: Loyola University

Official Title: A Phase I/II study of salvage high-dose-rate Brachytherapy, ExternAl beam 
COmbined and short-term hormonal therapy for the treatment of Node-positive locally recurrent 
prostate cancer after prior definitive radiotherapy. 
NCT Number: NCT03553602 
 

LU 210546 
Version 10/23/17 
 
BEACON – A phase I/II study of high-dose-rate Brachytherapy and External beam and short-
term Androgen deprivation COmbined for the treatment of Men with Fluciclovine PET Pelvic 
Nodal Uptake in locally recurrent prostate cancer after prior definitive radiotherapy 
 
 
Participating Institutions: Loyola University Medical Center 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
 
Principal Investigator:  
Abhishek Ashok Solanki, MD MS 
Assistant Professor 
Department of Radiation Oncology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maguire Bldg, Room 2944 
Maywood, IL 60153 
Phone: (708) 216-2556 
Fax: (708) 216-6076 
Email: abhishek.solanki@lumc.edu 
 
Co-Investigators: 
         Matthew Harkenrider, MD 
Assistant Professor 
Department of Radiation Oncology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maguire Bldg, Room 2944 
Maywood, IL 60153 
Phone: (708) 216-2575 
Fax: (708) 216-6076 
Email: mharkenrider@lumc.edu 
 
 
Bital Savir-Baruch, MD 
 
Assistant Professor 
 
Department of Nuclear Medicine 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
Email: Bital.Savir-Baruch@lumc.edu 
 
Chelsea Miller, MD 
Resident Physician 
Department of Radiation Oncology 

LU 210546 
Version 10/23/17 
 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maguire Bldg, Room 2944 
Maywood, IL 60153 
Phone: (708) 216-2575 
Fax: (708) 216-6076 
Email: Chelsea.Miller001@lumc.edu 
 
Sub-Investigators: 
Robert Flanigan, MD 
 
Professor and Chairman 
Department of Urology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
Email: mailto:rflanig@lumc.edu 
 
Ahmer Farooq, DO 
 
Assistant Professor 
Department of Urology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
Email: afarooq@lumc.edu 
 
Kristin Baldea, MD 
 
Assistant Professor 
Department of Urology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
Email: kbaldea@lumc.edu 
 
Elizabeth Henry, MD 
Assistant Professor 
Department of Medical Oncology 
Stritch School of Medicine, Loyola University Chicago 
2160 S. 1st Avenue 
Maywood, IL 60153 
Email: kbaldea@lumc.edu 
 
 
Research Coordinator:  
Beth Chiappetta, RN 
 
Research Nurse 

LU 210546 
Version 10/23/17 
 
 
Loyola University Medical Center 
 
Radiation Oncology Department 
 
Maguire Center 105-2944 
 
Phone: (708) 216-2568 
 
Email: mailto:bchiappetta@lumc.edu 
 
Biostatistician:  
William Adams, MA 
 
Biostatistician 
 
Division of Biostatistics 
 
Clinical Research Office, Loyola University Chicago 
 
2160 S 1st Ave 
 
Maywood, Il 60153 
 
Email: wadams@luc.edu 
 
Research Office: 
Clinical Research Office (CRO) 
 
Stritch School of Medicine, Loyola University Chicago 
 
2160 S 1st Ave 
Fahey Building 001 
Maywood, IL 60153 
Phone: (708) 216-7881 
Fax: (708) 216-4792 

LU 210546 
Version 10/23/17 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
PI Signature: ______________________________________________ 
 
 
Date: _____________________________________________________ 
 

LU 210546 
Version 10/23/17 
 
 
STUDY SUMMARY 
Title 
BEACON - A phase I/II study of high-dose-rate Brachytherapy and 
External beam and short-term Androgen deprivation COmbined for the 
treatment of Men with Fluciclovine PET Pelvic Nodal Uptake in locally 
recurrent prostate cancer after prior definitive radiotherapy 
Short Title 
Combined salvage high dose rate brachytherapy, external beam and short-
term hormonal therapy for local recurrent prostate cancer with fluciclovine 
PET uptake in pelvic nodes after radiotherapy 
Protocol Number 
*** 
Methodology 
Phase I/II Non-randomized trial 
Study Duration 
5 years 
Study Center(s) 
Loyola University medical Center, Stritch School of Medicine, Loyola 
University Chicago 
Objectives 
1. To determine the 3 month grade ≥3 radiation-related genitourinary 
and gastrointestinal toxicity of this treatment approach (primary 
endpoint) 
2. To describe the acute and late toxicity profile with this approach 
3. To evaluate disease control efficacy outcomes (biochemical 
progression-free survival, local control, regional recurrence, cause-
specific survival, overall survival, etc.) 
4. To evaluate patient reported health related quality of life following 
this treatment approach 
5. To describe the dosimetry in patients undergoing this approach 
Number of Subjects 
24 

LU 210546 
Version 10/23/17 
 
Diagnosis and Main 
Inclusion Criteria 
• 
Biopsy-proven local recurrence of prostate adenocarcinoma (biopsy 
within 182 days) 
• 
Pathologic Fluciclovine uptake in pelvic lymph nodes without 
distant metastases 
• 
Current AUA International Prostate Symptom Score (IPSS) score 
<20 
• 
Initial disease stage cT1-3a NX or N0  
• 
Treated with prior definitive radiation therapy using any 
radiotherapeutic modality (prior whole pelvis RT ineligible) 
Duration of 
Administration 
2 brachytherapy implants, ~5-8 weeks of daily radiation, 6 months 
hormonal therapy 
Statistical Methodology 
This study is designed as a two stage Phase I/II, non-randomized study.  In 
the first stage, 7 patients will be accrued.  If there are 2 or more toxic 
responses in these 7 patients, the study will be stopped for safety reasons.  
Otherwise, 17 additional patients will be accrued for a total of 24 patients.  
Assuming that the true toxicity rate in the population is 10% or less, the 
study is powered to reject the null hypothesis that the toxicity rate is 33% 
or higher. A toxicity event is defined as an acute grade >3 radiation-related 
toxicity as assessed by the Common Toxicity Criteria for Adverse Events 
version 4.  
Standard non-parametric or parametric methods will be used to describe 
these patients’ demographic and clinical information as well as their 
dosimetric information.  The primary aim of the study is to estimate the 
toxicity rate of HDR brachytherapy among patients with recurrent prostate 
cancer. A one-tailed test for a difference in proportions will be used to 
determine whether the observed toxicity rate is lower than the 
hypothesized toxicity rate. The null hypothesis that the toxicity rate is 33% 
or higher will be rejected if more than 19 (non-toxic) responses are 
observed in 24 patients.  When the true toxicity rate is 10.0%, this design 
yields a type I error rate of .046 and power of 81%. 
We also will describe the freedom from biochemical recurrence, relapse-
free survival, local control, elsewhere-prostate control, freedom-from local 
failure, freedom from distant metastasis, freedom from hormonal therapy, 
disease-free survival, cause-specific survival, and overall survival. 
 

LU 210546 
Version 10/23/17 
 
 
Study Schema 
 
 

LU 210546 
Version 10/23/17 
 
 
Table of Contents 
Title page.......................................................................................................................... i 
Signature page ............................................................................................................... iv 
Study Summary .......................................................................................................... v-vi 
Study Schema ............................................................................................................... vii  
List of Abbreviations ......................................................................................................x 
1.0 Background and Rationale ......................................................................................1 
1.1 Disease Background and Lessons from Other Malignancies .....................................1 
1.2 Evidence for Salvage Local Therapy to the Prostate ..................................................1 
1.3 Salvage Brachytherapy ...............................................................................................2 
1.4 Rationale for Salvage Regional Therapy to the Pelvic Lymph Nodes in Prostate Cancer
 .......................................................................................................................................3 
1.5 Rationale for current study ..........................................................................................4 
2.0 Study Objectives........................................................................................................5 
2.1 Primary Objective .......................................................................................................5 
2.2 Secondary Objectives..................................................................................................5 
2.3 Endpoints ....................................................................................................................5 
3.0 Patient Eligibility ......................................................................................................6 
3.1 Inclusion Criteria ........................................................................................................6 
3.2 Exclusion Criteria .......................................................................................................8 
4.0 Pretreatment Evaluations/Management .................................................................8 
4.1 Additional Mandatory Pretreatment Evaluations/Interventions .................................6 
5.0 Registration Procedures ...........................................................................................8 
5.1 Access to Registration.................................................................................................9 
5.2 Registering a Participant  ............................................................................................9 
5.3 Other Relevant Clinical Trials ....................................................................................9 
6.0 Radiation Therapy ....................................................................................................9 
6.1 Brachytherapy Implant Procedure ..............................................................................9 

LU 210546 
Version 10/23/17 
 
6.2 Brachytherapy Treatment Planning ..........................................................................10 
6.3 Brachytherapy Volume Delineation .........................................................................10 
6.4 Brachytherapy Dose Specifications ..........................................................................10 
6.5 External Beam Radiotherapy Treatment Planning…………………………………11 
7.0 Hormone Therapy ...................................................................................................12 
7.1 Anti-Androgen Therapy……………………………………………………………13 
7.2 LHRH Agonist Therapy……………………………………………………………14 
8.0 Study Procedures ....................................................................................................15 
8.1 Screening/Baseline Procedures .................................................................................15 
8.2 Follow-up Procedures ...............................................................................................16 
8.3 Study Parameters ......................................................................................................16 
8.4 Removal of Subjects from Study ..............................................................................17 
9.0 Measurement of Effect ...........................................................................................17 
9.1 Antitumor Effect-Solid Tumors ................................................................................17 
10.0 Adverse Effects ......................................................................................................19 
10.1 Data Safety Monitoring Plan ..................................................................................19 
10.2 Adverse Event Monitoring ......................................................................................20 
10.3 Definitions...............................................................................................................20  
10.4 Steps to Determine if an Adverse Event Requires Expedited Reporting ................21 
10.5 Exceptions to AE & SAE Definitions .....................................................................22 
10.6 Reporting Requirements for Adverse Events .........................................................22 
10.7 Stopping Rules ........................................................................................................23 
11.0 Data Collection ......................................................................................................23 
11.1 Online Database ......................................................................................................23 
12.0 Statistical Considerations .....................................................................................23 
12.1 Study Design/Study Endpoints ...............................................................................23 
12.2 Sample Size and Accrual ........................................................................................24 
12.3 Data-Analyses Plan .................................................................................................24 

LU 210546 
Version 10/23/17 
 
13.0 Study Management ...............................................................................................25 
13.1 Conflict of Interest ..................................................................................................25 
13.2 Institutional Review Board (IRB) Approval and Consent ......................................25 
13.3 Informed Consent ....................................................................................................26 
13.4 Protected Health Information ..................................................................................26 
13.5 Data Management and Monitoring/Auditing ..........................................................26 
13.6 Data Submission Guidelines ...................................................................................27 
13.7 Adherence to the Protocol .......................................................................................27 
13.8 Amendments to the Protocol  ..................................................................................28 
13.9 Record Retention ....................................................................................................29 
13.10 Obligations of Investigators ..................................................................................29 
13.11 Study Recruitment ................................................................................................29 
References ......................................................................................................................30 
Appendices .....................................................................................................................32 
Appendix A: NCI CTCAE v4.03 ....................................................................................32 
Appendix B: IPSS Assessment .......................................................................................33 
Appendix C: Epic-26 Assessment ..................................................................................34 
Appendix D: ECOG Performance Scale .........................................................................36 

LU 210546 
Version 10/23/17 
 
 
Abbreviations 
ADT  
androgen deprivation therapy 
AE 
 
adverse event 
BR 
 
biochemical recurrence 
CRF 
 
Case Report Form 
CSS 
 
cause specific survival  
CTCAE v4.03 Common Toxicity Criteria for Adverse Events, version 4.03 
CTV  
clinical target volume 
DM 
 
distant metastasis 
DFS 
 
disease-free survival 
DRE  
digital rectal exam 
DSMP  
Data Safety Monitoring Plan 
EBRT   
external beam radiotherapy 
EPC 
 
elsewhere prostate control 
EPF 
 
elsewhere prostate failure 
FDA  
Food and Drug Administration 
FFBR  
freedom from biochemical recurrence 
FFDM  
freedom from distant metastasis 
FFEPF  
freedom from elsewhere prostate failure 
FFHT  
freedom from hormone therapy 
FFLF  
freedom from local failure 
FFRF  
freedom from regional failure 
GCP 
 
good clinical practice 
GI 
 
gastrointestinal 
GS 
 
Gleason score 
GTV  
gross tumor volume 
GU 
 
genitourinary 
HDR  
high-dose rate 
HiFU  
high intensity focused ultrasound 
I-125  
Iodine-125 
IPSS  
International Prostate Symptom Score 
Ir-192  
Iridium-192 
IRB 
 
Institutional Review Board 
LC 
 
local control 
LDR  
low-dose rate 
LF 
 
local failure 
LRPC  
locally recurrent prostate cancer 
MP-MRI 
multi-parametric MRI 
OS 
 
overall survival 
PCA 
 
patient controlled analgesia 
Pd-103  
Palladium-103 

LU 210546 
Version 10/23/17 
 
PSA 
 
prostate specific antigen 
PTV 
 
planning treatment volume 
RC 
 
regional control 
RF 
 
regional failure 
SAE 
 
serious adverse event 
UPR 
 
unanticipated problems 
 

1 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background and Lessons From Other Malignancies 
Prostate cancer is the most common cancer diagnosed in men and ranks second in 
cancer-related deaths among all men in the United States in 2012. In 2014, 
177,489 men were diagnosed with prostate cancer, with 27,244 annual deaths.1 
Radiotherapy is a curative treatment option for these patients, yet a significant 
proportion of patients, particularly those with more aggressive disease, will go on 
to develop biochemical recurrence after curative treatment, and thereafter 
typically develop nodal and/or distant metastases from their progressed 
malignancy. For the patients who specifically present with nodal recurrence after 
curative radiotherapy, palliative androgen deprivation therapy (ADT) has been the 
primary treatment. However, ADT is not curative, and patients typically progress 
to castrate resistant disease over time and ultimately develop clinical progression 
of disease. In patients with a long life expectancy, identifying a way to salvage the 
patients who have local and regional disease alone could result in more durable 
disease outcomes and potential prevent morbidity and mortality. 
In many disease sites, patients who had regional recurrence of disease are treated 
with aggressive salvage therapy in order to try for cure of the malignancy.  An 
example of this includes patients who have mediastinal recurrence after SBRT or 
lobectomy for lung cancer.  These patients are typically treated with definitive 
doses of concurrent chemoradiotherapy or sometimes with repeat SBRT in the 
setting of a local recurrence.2–4 In head and neck cancer, patients are typically 
treated with regional chemoradiotherapy if they have had treatment of the primary 
but develop recurrence in the cervical lymph nodes. Additionally, reirradiation is 
an established treatment approach for patients with recurrence of disease. 
Thus, an important question is whether the principles of all of these other 
malignancies can be applied to prostate cancer, as radiation has the potential to 
deliver curative treatment to regional disease in the definitive setting and 
brachytherapy can deliver curative treatment for local disease.5–7  
Evidence for Salvage Local Therapy to the Prostate in Prostate Cancer 
Even after initial treatment of prostate cancer with definitive radiation, biologic 
PSA failure can occur in up to 50% of patients.8,9 However, in the patients who 
develop biochemical progression, up to 55% of those patients will have local 
recurrence alone, with the majority of those recurrences at the site of the dominant 
primary tumor.10 For these men with local recurrence alone, treatment options 
include both palliative and definitive approaches. Often times, in this setting, men 
are treated with a palliative approach of continued PSA surveillance without 
intervention or androgen deprivation therapy (ADT). However, neither of these 
modalities is curative. Furthermore, the use of ADT is associated with side effects 

2 
 
of up to 80% of patients, including hot flashes, fatigue, gynecomastia and sexual 
dysfunction, leading to a 16.4% treatment cessation.11,12 
Standard curative treatment options in the salvage setting after radiotherapy 
include salvage prostatectomy, cryosurgery, or brachytherapy to the prostate 13  
The decision of which salvage treatment modality to utilize is difficult, as there 
are no randomized data supporting one modality over another. Parekh, et al 
reported a systemic review comparing the oncologic benefits and toxicity profiles 
of radical prostatectomy, brachytherapy, cryotherapy, and high-intensity 
frequency ultrasound (HiFU) in the salvage setting after definitive external 
radiation.  They found a similar rate of failure-free survival at 5 years across all 
salvage modalities, ranging from 52-56%. Salvage brachytherapy had a failure-
free survival of 55.6%.  Regarding toxicities, compared to the other modalities, 
brachytherapy had the lowest rate of incontinence (6.16%) and the second lowest 
rate of bladder neck stricture (7.48%). The rate of fistula formation was greatest 
in the HifU group, followed by brachytherapy, although this rate was still quite 
low at 3.09%.  Prostatectomy carried the highest rates of incontinence (49.7%) 
and stricture (26.09%).14   
1.2 
Salvage brachytherapy 
An additional treatment option in the setting of locally recurrent prostate cancer 
(LRPC) after definitive EBRT that has gained recent attention is the use of 
interstitial brachytherapy.13 Brachytherapy is beneficial in the salvage setting due 
to its inherent ability to deliver a higher dose to a smaller area, thus sparing the 
previously irradiated surrounding normal tissues, and decreasing toxicity. This 
includes both low-dose-rate (LDR) and high-dose-rate (HDR) brachytherapy 
techniques, which have been studied in a variety of phase I/II trials and 
retrospective series, with the majority of available data reporting on LDR 
brachytherapy technique. Overall, the limited data on salvage brachytherapy show 
promising results, with both the achievement of biochemical disease control and 
the with treatment related toxicities, which are either comparable to or better than 
alternative salvage options.  
There are limited retrospective data on the use of salvage LDR brachytherapy. 
Grado, et. al. describes a cohort of 46 men treated with LDR brachytherapy for 
LRPC after definitive EBRT, utilizing I-125 or Pd-103 radioactive seeds treating 
to 130-140Gy median matched peripheral dose. He reports a 5 year cause specific 
survival of 79%, a local control rate of 97% at latest follow-up with a low, 6% 
rate of severe urinary or rectal toxicities. 15 Another group, Beyer, et. al reported 
on a cohort of 17 men treated with LDR brachytherapy after definitive EBRT 
using I-125 or Pd-103, treated with a median peripheral dose of 97-100Gy. Their 
reported 5 year OS was 93% and freedom from biochemical relapse was 53%.16 
There is a current ongoing RTOG/NRG trial evaluating the use of salvage LDR 
brachytherapy in men treated with prior EBRT with initially diagnosed T1-T2c, 

3 
 
GS 2-7, PSA<20ng/mL, utilizing I-125 radioactive seeds treating to 140Gy 
minimum target dose or Pd-102 treating to minimum target dose of 120Gy.17 
There is evidence supporting salvage HDR for patients with locally recurrent 
prostate cancer, primarily delivered to the whole prostate gland due to uncertainty 
about the geographic location of the local recurrence with older imaging 
techniques. Yamada, et al reported their results of a phase II study of 42 patients 
treating LRPC with salvage HDR brachytherapy after prior definitive external 
radiation. Their prescribed dose was 32Gy delivered in four fractions over 30 
hours using a single implant. At a median follow-up up 26 months, they reported 
an actuarial 5-year biochemical recurrence free survival of 68.9% and a distant 
metastasis free survival of 81.5%. Regarding toxicities, acute genitourinary (GU) 
grade 1 and 2 toxicities rates were 38% and 40%, respectively, and 38% and 48% 
had late grade 1 or 2 GU toxicities. Only 1 of 42 patients developed late grade 3 
toxicity of urinary incontinence, and 3 patients (7%) developed a late grade 3 
urinary stricture corrected with urethral dilatation. Late grade 1-2 gastrointestinal 
(GI) toxicities occurred in 43% and 14% of patients, but there were no late grade 
3+ GI toxicities.18 Chen, et al reported a retrospective study of 52 patients 
receiving 36 Gy in six fractions given in two separate implants, 1 week apart. 5-
year biochemical control was 51%, with a 2% incidence of grade 3 or higher late 
GU toxicity and no late grade 3+ GI toxicity.19 
1.4 
Rationale for Salvage Regional Therapy to the Pelvic Lymph Nodes in Prostate 
Cancer 
There are emerging data that some patients who have recurrent disease in the 
pelvis may benefit from aggressive regional cancer-directed treatment with 
surgery or radiotherapy. Prospective studies have examined post-prostatectomy 
patients presenting with biochemical recurrence who underwent salvage pelvic 
lymph node dissection (PLND) of their [11C] choline PET/CT positive nodal 
disease. In a study by Rigatti et al 83.3% of patients with positive nodal 
metastases on [11C] choline PET/CT, had pathologic positive prostate cancer.20 
Following salvage lymph node dissection, a total of 41 patients (56.9%) had a 
subsequent biochemical response (defined as PSA <0.2). Ultimately, they found a 
5-yr biochemical-free survival rate of 19% and concluded that salvage lymph 
node dissection in patients with nodal uptake on [11C] choline PET/CT can lead 
to a delay of clinical progression and a complete biochemical response can be 
achieved in a small proportion.  
Another study by Suardi et al looked at the 5-yr results of patients following 
salvage PLND. They found that in their cohort of patients with a mean number of 
29.5 nodes removed at the time of surgery, 47 patients (79.6%) had positive 
lymph nodes. Overall, 35 patients (59.3%) experienced biochemical response 
following surgery and this led to a 22.1% 8-yr biochemical-recurrence free 
survival. Therefore based on these results they concluded in patients with a small 

4 
 
volume of nodal recurrence a meaningful biochemical complete response after 
salvage LND can be achieved.21 
With increasing use of imaging such as (18) F-fluciclovine PET/CT we are better 
able to detect occult nodal disease, even in those with low PSA levels.22 Given 
that surgical series have shown improved biochemical response in patients with 
positive pelvic nodes detected on functional imaging, radiotherapy has a distinct 
advantage in that it can target gross disease as well as microscopic disease, and is 
non-invasive and an option for most patients.  
The primary limitation to adding on radiotherapy to the pelvic nodes is the risks 
of reirradiation in areas of overlap. However, using modern sophisticated 
treatment planning methods such as intensity-modulated radiotherapy (IMRT) and 
volumetric arc therapy (VMAT), areas of overlap in critical structures can be 
minimized while delivering curative doses to target lesions.  
1.5 
Rationale for current study 
Salvage regional and local radiation is frequently utilized across multiple disease 
sites in oncology for patients who have failed initial radiotherapy. However, in 
prostate cancer, due to the concern that nodal involvement is a manifestation of 
widespread distant disease, this type of approach has not typically been pursued.  
However, with newer imaging modalities such as fluciclovine PET, PSMA pet, 
and C11 PET, we are identifying nodal disease and excluding distant disease 
better than we ever have before. Thus, in this modern era regional control may 
translate to improved long-term biochemical control, and prevent the morbidity 
and mortality associated with clinical progression of biochemically recurrent 
prostate cancer 
Thus, in patients who recur both in the prostate and in the pelvic lymph nodes, 
treating both with radiation could result in meaningful clinical efficacy for 
patients—similar to other disease sites. However, there are limited data exploring 
the feasibility and safety of this combination. Therefore, we propose this trial, 
combining salvage HDR brachytherapy to locally recurrent prostate cancer in the 
prostate and EBRT to the pelvis, both in the setting of short-term hormonal 
therapy, in patients who have developed local recurrence with regional pelvic 
nodal PET uptake after definitive radiation. We hypothesize that this approach 
can safely be performed without excess toxicity. Ultimately, we hope to use data 
from this Phase I/II study to create a multi-institutional phase III study in which 
we could analyze whether this treatment approach can improve disease control 
and survival outcomes when compared to standard palliative hormonal therapy. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 

5 
 
2.1.1 To determine the incidence of acute grade ≥3 radiation-related 
genitourinary (GU) and gastrointestinal (GI) toxicity of this treatment 
approach  
2.2 
Secondary Objectives 
2.2.1 To describe the acute and late toxicity profile with this approach 
2.2.2 To evaluate disease control efficacy outcomes (biochemical progression-
free survival, local control, regional recurrence, cause-specific survival, 
overall survival, etc.) 
2.2.3 To evaluate patient reported health related quality of life following this 
treatment approach 
2.2.4 To describe the dosimetry in patients undergoing this approach 
2.3 
Endpoints 
2.3.1 Primary Endpoint:  
2.3.1.1 3-month radiation-related grade ≥3 GU and GI toxicity as defined 
by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Link available in Appendix A).  
2.3.2 Secondary Endpoints: 
2.3.2.1 All-grade acute and late toxicity as defined by CTCAE v4.03 
criteria (see Appendix A) 
2.3.2.2 Freedom from biochemical failure 
2.3.2.3 Freedom from local failure 
2.3.2.4 Freedom from elsewhere prostate failure 
2.3.2.5 Freedom from regional failure 
2.3.2.6 Freedom from distant metastasis 
2.3.2.7 Freedom from hormone therapy 
2.3.2.8 Disease-free survival. 
2.3.2.9 Disease-specific survival 
2.3.2.10 Overall Survival. 

6 
 
2.3.2.11 Patient reported Health-related quality of life as measured by the 
IPSS and EPIC-26 assessments (see Appendices B and C). 
2.3.3 NCI CTCAE v4.03 toxicity criteria will be used to assess acute and late 
adverse events/toxicity endpoints (Appendix A).  Disease specific 
endpoints will utilize a combination of laboratory values, multidisciplinary 
clinical decisions, radiographic imaging, functional imaging, and initiation 
of salvage therapy. 
3.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and 
exclusion criteria to be registered to the study. Study treatment may not begin until a 
subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 Biopsy proven locally recurrent adenocarcinoma of the prostate after the 
completion of definitive radiation therapy for initially diagnosed prostate 
cancer.  
3.1.1.1 Biopsy must be performed within 182 days of trial registration 
3.1.1.2 Biopsy should be at least a standard sextant TRUS-guided biopsy  
3.1.2 Initial cancer diagnosis that fits these specific criteria: 
3.1.2.1 Stages cT1-T3a 
3.1.2.2 Nx or N0 
3.1.2.3 Mx or M0 
3.1.3 Eligible initial definitive radiotherapy modalities include: 
3.1.3.1 External beam radiotherapy, with photon or proton beam therapy  
3.1.3.11 
Conventional 
or 
moderately 
hypofractionated 
radiotherapy 
3.1.3.12 
Extremely 
hypofractionated 
external 
beam 
radiotherapy (Stereotactic body radiation therapy) 
3.1.3.13 
Treatment of the pelvic nodes with prior course 
of radiotherapy is not allowed. 

7 
 
3.1.3.14 
No prior radiotherapy to the intended target for 
this course of radiotherapy other than prostate 
radiotherapy  
3.1.3.2 Definitive Brachytherapy: 
3.1.3.21 
Low-dose rate 
3.1.3.22 
High-dose rate 
3.1.3.23 
Combined EBRT and brachytherapy 
3.1.3.24 
Treatment 
of 
the 
pelvic 
nodes 
with 
prior 
supplemental EBRT is not allowed. 
3.1.4 Fluciclovine-positive pelvic nodes (as determined by an interpreting 
radiologist or nuclear medicine physician) in the pelvic nodal region 
(defined as the pelvic nodal regions up to the common iliac nodal region) 
without any evidence of lymph node involvement outside of this area or 
distant metastases 
3.1.4.1 This will be based on the following imaging workup: 
3.1.4.11 
CT A/P or MRI Pelvis 
3.1.4.12 
Bone scan 
3.1.4.13 
Fluciclovine PET/CT 
3.1.5 Candidate for hormonal therapy. 
3.1.6 Current ECOG Performance status Scale 0-2 (Appendix D) 
3.1.7 Current International Prostate Symptom Score (IPSS) < 20 (Appendix B) 
3.1.8 Age >18 
3.1.9 The patient must be medically suitable to receive general or spinal 
anesthesia. 
3.1.10 AST, ALT, and alkaline phosphatase < 2 x upper institutional limit within 
3 months of registration. 
3.1.11 The patient must be able and willing to sign a study-specific written 
informed consent form before study entry. 
3.2 
Exclusion Criteria 

8 
 
3.2.1 Preregistration GI or GU toxicity (for any reason) grade ≥ 3 as defined in 
CTCAE version 4.03. That is, grade ≥ 3 GU or GI toxicity after first 
course of radiotherapy 
3.2.2 Treatment to a “whole pelvis” field with initial radiotherapy 
3.2.3 Prior radiotherapy to the region of the body that is intended to be the target 
with the current course of RT. 
3.2.4 Patients with distant metastases (such as to the bone, visceral organs, and 
lymph nodes other than the pelvic nodes including the common iliac 
nodes). 
3.2.5 Patients receiving any other investigational agents. 
3.2.6 Uncontrolled inter-current illness including, but not limited to, ongoing or 
active infection, severely symptomatic congestive heart failure, cardiac 
arrhythmia, recent myocardial infarction in last 6 months, or psychiatric 
illness/social situations that could limit compliance with study 
requirements. 
3.2.7 Patients who have received chemotherapy or immunotherapy within one 
month prior to study enrollment, other than ADT.  
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
4.1 
Additional Mandatory Pretreatment Evaluations/Interventions 
4.1.1 Documentation of pharmacologic agents used by patient to treat urinary, 
bowel or erectile dysfunction. 
4.1.2 Baseline Quality Of Life assessments, including IPSS, EPIC-26 
assessments (Appendices B and C)  
4.1.3 Eastern Cooperative Oncology Group (ECOG) performance assessment  
(Appendix D) 
4.1.4 Any preoperative assessments needed for the brachytherapy implant 
operative procedure 
4.1.5 AST, ALT, and alkaline phosphatase < 2 x upper institutional limit within 
3 months of registration. 
5.0 
REGISTRATION PROCEDURES 
Patients may not begin protocol treatment prior to registration. All patient registration 
will be centralized through the Department of Radiation Oncology Research Office. All 

9 
 
eligibility criteria must be met in order for a patient to be registered. To register a patient 
call (708) 216-2568, Monday-Friday 9:00am-5:00pm 
5.1 
Access to Registration 
The Department of Radiation Oncology Research Office Study Coordinator, Beth 
Chiappetta, will coordinate all patient registrations. For any questions regarding 
patient registration please call: (708) 216-2568. 
5.2 
Registering a Participant 
Obtain and file participant’s signed and witnessed informed consent document in 
the Radiation Oncology Research Office. 
5.3 
Other Relevant Clinical Trials 
At Loyola University Medical Center, there are no other clinical trials that will 
affect enrollment into this study, and this study will not affect enrollment into 
other clinical trials available at the institution.  
6.0 
RADIATION THERAPY 
RT will start ~2 months after the start of ADT when possible (with RT starting earlier or 
later based on physician discretion). Either Brachytherapy or EBRT can be delivered 
first, or brachytherapy can be intercalated with EBRT course based on treating physician 
discretion. 
6.1 
Brachytherapy Implant procedure:  
6.1.1 Patients will undergo 2 implants with 1 fraction of 12 Gy delivered with 
each implant, scheduled 1-2 weeks apart when possible, although longer 
or shorter intervals are acceptable with PI approval. 
6.1.2 The implant procedure will be done under general anesthesia. The patient 
should be placed in the lithotomy position, generally after appropriate 
anesthesia. Then the perineum will be prepped and draped. A Foley 
catheter should be inserted for better visualization of the urethra and the 
bladder for the duration of the implant. Then, a single fiducial marker 
should be placed in the area of the target lesion as close to the lesion 
center as possible. Then, the brachytherapy loading catheters should be 
placed with the aid of a Liberty Medical template to allow for at least 
adequate coverage of the target lesion. Once adequate placement is 
confirmed by transrectal ultrasound (TRUS), the template will be sutured 
to the perineum. The patient's legs should be returned to a neutral position. 
After the patient is awoken from anesthesia and has stabilized, he will then 
be transferred to the Radiation Oncology Department for CT simulation, 
treatment planning, and radiation delivery.  

10 
 
6.1.3 Patient controlled analgesia (PCA), IV, or PO pain medications may be 
used during the post-operative period for pain control and throughout the 
day of the procedure as needed. 
6.1.4 After completion of each of the brachytherapy treatments (upon 
completion of MRI and Treatment planning), all catheters should be 
removed. 
6.2 
Brachytherapy Treatment Planning  
6.2.1 CT Simulation: CT simulation will be performed per standard protocol for 
evaluation of catheter position and treatment planning.  
6.2.2 Diagnostic MRI: When possible, patient will undergo a diagnostic MRI 
after the implant with the catheters in position to aid in treatment planning. 
This will be registered to the CT image set. 
6.2.3 Volume delineation: Target volumes and organs at risk (OARs) will be 
contoured using brachytherapy planning software. The patient’s prior 
multi-parametric MRI and the fiducial placed during the procedure can be 
used to help define the target. 
6.2.4 Source Loading: The HDR treatment will be delivered on the day of the 
catheter placement, after visual inspection of the catheters prior to delivery 
of the treatment is performed, and any necessary catheter adjustments are 
made prior to the treatment.  If the catheters cannot be satisfactorily 
repositioned and cannot be corrected by a new plan with appropriate 
coverage of the target and sparing of the OARs, then we will consider 
postponing or aborting the treatment 
6.3 
Brachytherapy Volume Delineation: 
6.3.1 Target Volume: The target volume will consist of the prostate and 
proximal seminal vesicles encompassing the area of local recurrence. The 
Planning Target Volume (PTV) will be defined as the GTV, plus a 0-5 
mm margin, restricted to adjacent OARs applicable.  
6.3.2 Critical Structures: Critical structures to be contoured include the bladder, 
Foley bulb, rectum, and urethra. Critical structures must be contoured on 
every CT slice that contains a target volume and in at least 3 slices (9 mm) 
above and below the CTV 
6.4 
Brachytherapy Dose Specifications:  
6.4.1 For each brachytherapy procedure, the prescription dose to the PTV and 
GTV will be the highest deliverable dose up to 12 Gy in one fraction.  
Priority will be given to the normal tissue dose constraints over the 

11 
 
prescription dose. That is, the maximum dose will be that which is 
achievable without violating the normal tissue dose constraints. Priority 
will be given to GTV coverage first and then CTV coverage. If necessary, 
treatment to areas of the prostate/seminal vesicles judged to be at low risk 
of involvement can be omitted if it is felt that delivering full dose to these 
areas would result in unacceptable significant risk of toxicity. 
In general, the volume of the GTV getting 100% of the prescription dose 
should be ≥95% when possible (V100 ≥ 95%) and, again, when possible, 
prescription dose should be delivered to at least 90% of the GTV (D90 ≥ 
100%).The same coverage goals apply to the PTV, although this is less of 
a priority and can also be a lower dose than that prescribed to the GTV 
due to normal tissue constraints. 
The normal tissue dose constraints will be as follows: 
Bladder: 
D 0.1 cc ≤ 95% 
 
 
D 1 cc ≤ 75% 
 
 
V75% ≤ 1 cc 
Foley Bulb: 
D 0.1 cc ≤ 80% 
Rectum: 
D 1 cc ≤ 75% 
 
 
V75% ≤ 1 cc 
Urethra: 
Max point dose ≤ 120% 
 
 
D 1 cc ≤ 110% 
6.5 
External Beam Radiotherapy Treatment Planning 
6.5.1 Patients will undergo CT simulation prior to treatment planning. 
6.5.2 The GTV will be any nodes in the pelvis (up to the common iliac nodes) 
felt by the treating physician to be involved with the cancer based on 
radiographic, pathologic, or fluciclovine PET. The prostate and SV will 
not be treated with EBRT. 
6.5.3 The CTV_5040 will include the GTV with 5 mm margin as well as the 
pelvic lymph nodes as defined by RTOG guidelines. If patients have 
common iliac involvement or if the treating physician deems it necessary, 
the para-aortic nodes will be included in the CTV up to the level of the 
renal vessels. This CTV will be expanded by 0.6 cm to create PTV_5040. 
This will be treated to 5040 cGy in 28 fractions of 180 cGy. 

12 
 
6.5.4 A simultaneous integrated boost (SIB) to the involved nodes will be 
created. The GTV will receive up to 7000 cGy in 28 fraction of 250 cGy 
as part of this SIB.  
6.5.5 Of note, normal tissue tolerances will typically take priority over total 
dose to the GTV, and PTV_5040. It is encouraged that the target volumes 
be restricted in areas of overlap with prior the prior RT based on treating 
physician discretion while ensuring adequate coverage of gross disease. 
This PTV will be the PTV_high_risk. For example, if the lower obturator 
nodes received ≥50 Gy with the prior radiotherapy plan, then in areas of 
this nodal region that do not have gross disease treatment can be omitted 
to avoid overlap between the current field and prior field in the rectum and 
bladder and femoral heads. If the treating physician and PI feel it is 
necessary to violate the normal tissue constraints, this is acceptable. 
6.5.6 Normal Tissue Constraints: 
Minimize areas of overlap with prior radiotherapy, particularly areas of 
cumulative doses > 80 Gy in the rectum, bladder, and femoral heads. 
Bowel space: V55 < 1 cc, V60 < 0.1 cc.  
Rectum: V70 < 10%, Max dose < 7350 
Sigmoid: V70 < 10%, Max dose < 7350 
Bladder: V70 < 10%, Max dose < 7350 
Femoral Heads: V50 < 10% 
Guidelines for PTV and GTV coverage (can be violated based on normal 
tissue goals): V100 > 95%, V95 > 99% 
6.5.7 Daily CBCT will be performed setting up to the GTV lesions, with 
priority of coverage of these lesions. Second priority will be set up to the bony 
anatomy. 
 
7.0 
HORMONE THERAPY 
Other than androgen deprivation therapy, patients must not receive other cancer-directed 
therapy (including standard fractionated radiotherapy, chemotherapy, biological therapy, 
and surgery) while on-study except at disease progression.  
Standard institutional practices for neoadjuvant/concurrent and adjuvant short-
term (6 months) androgen deprivation hormonal therapy will be used with the salvage 

13 
 
radiotherapy regimen. When possible, radiotherapy will begin approximately 2 months 
after the start of hormonal therapy. Some patients may have received prior hormonal 
therapy, but still require 6 months with the trial. 
 
7.1  
Anti-Androgen Therapy: Casodex (Bicalutamide) 
For further information, consult the package insert.  
 
7.1.1  Timing: Oral anti-androgen therapy will begin approximately within 10 
days of the start of the LHRH agonist. It should continue until the 
completion of radiotherapy. 
 
7.1.2  Bicalutamide is a nonsteroidal antiandrogen, which has no androgenic or 
 
progestational properties. The chemical name is propanamide, N-[4-
cyano- 
3(trifluoromethyl)phenyl]- 3- [(4-fluorophenyl)sulphonyl]- 2- hydroxy- 2- 
methyl, (+,-). Bicalutamide is a racemic mixture with the antiandrogen 
activity residing exclusively in the (-) or R-enantiomer. Bicalutamide has a 
long half-life compatible with once-daily dosing.  
7.1.3  Supply: Commercially available. 
7.1.5  Administration: Bicalutamide is administered orally at a dose of one 50 
mg tablet per day. Bicalutamide will begin approximately within (before, 
same day as, or after) 10 days of the date of the first LHRH agonist 
administration, and continue until the end of the radiation therapy. 
Administration will be suspended only if there is an apparent or suspected 
reaction to the drug. During RT interruptions, bicalutamide will be 
continued.  
7.1.6  Toxicity: Consult the package insert for comprehensive toxicity 
information. In animal experiments, birth defects (abnormal genitalia, 
hypospadias) were found in male offspring from female animals dosed 
with bicalutamide during pregnancy. Although offspring from male 
animals dosed with bicalutamide did not show any birth defects, patients 
enrolled in this trial are advised not to cause pregnancy nor donate sperm 
while receiving protocol therapy or during the first 3 months after 
cessation of therapy. The use of barrier contraceptives is advised. The 
most frequent adverse events reported among subjects receiving 
bicalutamide therapy are breast tenderness, breast swelling, and hot 
flashes. When bicalutamide 50 mg was given in combination with an 
LHRH analog, the LHRH analog adverse event profile predominated with 
a high incidence of hot flashes (53%) and relatively low incidences of 
gynecomastia (4.7%) and breast pain (3.2%). Other side effects include 
impotence and loss of libido, fatigue, and rarely, photosensitivity and 
diarrhea.  
7.1.7  Dose Modifications: AST and ALT will be measured pretreatment and 
during the first week of EBRT. If the AST or ALT rises to ≥ 2x the 
institutional upper limit of normal, 
bicalutamide must be discontinued. 

14 
 
Elevated AST/ALT values to < 2x the institutional upper limit of normal 
are subject to dose modifications or discontinuation of anti-androgen at the 
discretion of the treating physician. 
 
7.2 
LHRH Agonist Therapy (leuprolide, goserelin) 
For additional information, consult the package inserts. 
 
7.3.1  Timing: The first LHRH administration will occur together with the start 
of anti-androgen treatment ~8 weeks prior to the start of RT. The total 
duration of LHRH therapy will be 6 months. The total administered 
duration as well as the specific agent used must be documented. 
7.3.2  Description: LHRH agonists are long-acting analogs of the native LHRH 
peptide and are effective at reducing serum testosterone. Analogs 
approved by the FDA (or by Health Canada for Canadian institutions) can 
be used in this study. 
7.3.3  Supply: Commercially available.  
7.3.4  Storage: LHRH analogs should be stored as directed by the commercial 
supplier. 
7.3.5  Administration: LHRH analogs are administered with a variety of 
techniques, including subcutaneous insertion of a solid plug in the 
abdominal wall (Zoladex), intramuscular injection (Lupron), subcutaneous 
injection (Eligard), or insertion of a long-acting cylinder that slowly 
releases the agent (Viadur). The manufacturer’s instructions should be 
followed. 
7.3.6  Toxicity: Consult the package insert for comprehensive toxicity 
information. Class-related toxicity is generally a manifestation of the 
mechanism of action and related to low testosterone levels. In the majority 
of patients testosterone levels increase above normal in the first week, 
declining thereafter to baseline levels or below by the end of the second 
week of treatment. The most common side effect of LHRH analogs is 
vasomotor hot flashes; edema, gynecomastia, bone pain, thrombosis, and 
gastrointestinal disturbances have occurred. Potential exacerbations of 
signs and symptoms during the first few weeks of treatment is a concern in 
patients with vertebral metastases and/or urinary obstruction or hematuria 
which, if aggravated, may lead to neurological problems such as 
temporary weakness and/or paresthesia of the lower limbs or worsening of 
urinary symptoms. Other side effects include impotence and loss of libido, 
weight gain, depression, dizziness, loss of bone density, anemia, increased 
thirst and urination, unusual taste in the mouth, skin redness or hives, pain 
at injection site, and muscle mass and strength loss, hair changes, penile 
length and testicular volume loss, increased cholesterol, hypertension, 
diabetes exacerbation, emotional lability, nausea, vomiting, and rarely, 
allergic generalized rash and difficulty breathing. 
 
8.0 
STUDY PROCEDURES 

15 
 
8.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the studies were done before informed consent was 
obtained. 
All screening procedures must be performed within 3 months prior to registration 
unless otherwise stated. The screening procedures include: 
8.1.1 Informed Consent 
8.1.2 Medical History 
Complete medical, surgical, and oncologic history including previous 
radiotherapy history. 
8.1.3 Demographics 
Age, gender, race, ethnicity. 
8.1.4 Review subject eligibility criteria 
8.1.5 Review previous and concomitant medications 
8.1.6 Physical exam 
8.1.7 Performance status 
ECOG performance status evaluated prior to study entry according to 
Appendix D. 
8.1.8 Adverse event assessment 
Baseline adverse events from prior radiotherapy regimen will be assessed. 
See section 10.0 for adverse event monitoring and reporting. 
8.1.9 Tumor assessment 
To be performed with at least a PSA, DRE, multi-parametric MRI of the 
prostate, bone scan and functional imaging (Fluciclovine PET is 
encouraged). 
8.1.10 Baseline quality of life assessment 

16 
 
Documentation of patient’s AUA IPSS score, and completion of EPIC-26 
instrument; documentation of medication used to treat urinary, bowel, or 
erectile dysfunction 
8.1.11 Labs 
AST, ALT, Alkaline Phosphatase, and any labs required for the 
brachytherapy procedure as part of usual care. 
8.2 
Follow-up Procedures 
Patients will be followed as described in Section 8.3. 
8.3 
Study Parameters 
 
Pre-
study 
Start of 
EBRT 
Week 4 
post-
treatmen
t 
Month  
3 & 6 
Month 
12 
Follow-
up Q 6 
months* 
Time of 
Biochemic
al 
Recurrence 
Informed 
Consent 
X 
 
 
 
 
 
 
History and PE, 
including DRE 
X 
 
X 
X 
X 
X 
 
Medication 
Assessment 
X 
 
X 
X 
X 
X 
 
Performance 
Status 
X 
 
X 
X 
X 
X 
 
Toxicity 
Assessment 
 
 
X 
X 
X 
X 
 
PSA 
X 
 
 
X 
X 
X 
 
Bone scan  
X 
 
 
 
 
 
X 
MP-MRI 
X 
 
 
 
 
X¥ 
PET/CT 
X 
 
 
 
 
 
IPSS score 
X 
 
X 
X 
X 
X 
 
EPIC-26 
X 
 
X 
X 
X 
X 
 
AST/ALT/ALK 
PHOS 
X 
X 
 
 
 
 
 
 
* Until disease progression, death, or follow up period is complete 

17 
 
 
¥If MP-MRI reveals any suspicious lesions, then biopsy is encouraged. 
 
DRE – Digital Rectal Exam 
 
PE – Physical Exam 
 
MP – Multi-parametric 
 
EBRT – External Beam Radiotherapy 
 
8.4 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral, or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
8.4.1 Patient voluntarily withdraws prior to treatment; 
8.4.2 Patient withdraws consent (termination of treatment and follow-up); 
8.4.3 Patient is unable to comply with protocol requirements; 
8.4.4 Patient develops interval co-morbidity that makes continuation in the 
protocol unsafe; 
8.4.5 Treating physician(s) judge(s) the study would not be in the patient’s best 
interest; 
8.4.6 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
8.4.7 If a research subject cannot be located to document survival after a period 
of 2 years; the subject may be considered “lost to follow-up”. All attempts 
to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
9.0 
MEASUREMENT OF EFFECT 
9.1 
Antitumor Effect- Solid Tumors 
9.1.1 Definitions: 
Evaluable for toxicity: All patients will be evaluable for toxicity 
immediately following brachytherapy. 
Evaluable for disease control assessment: All patients with at least 2 
follow-up PSAs will be evaluable for disease control. After brachytherapy, 
these patients will have their disease status classified according to the 
definitions stated below. 

18 
 
Biochemical (PSA) recurrence (BR): Based on RTOG Phoenix definition: 
an increase of the PSA level at least 2 ng/ml greater than the minimum 
level after therapy (REF: phoenix paper) 
All patients with BR should undergo at least MP-MRI of the 
prostate and bone scan. Biopsy of any suspicious lesions within the 
prostate gland on MP-MRI is encouraged. 
Freedom from Biochemical (PSA) Recurrence (FFBR):  
The time to PSA failure will be measured from the date of treatment to the 
date of a rise by 2 ng/mL or more above the nadir PSA. The time of failure 
will be the date of the first PSA that is 2 ng/mL or more above the lowest 
prior post-treatment PSA value. If the rise in PSA to > nadir + 2 occurs 
during the first 36 months followed by a subsequent non-hormonal 
induced PSA decrease, patients will not be considered PSA failures. 
 
As a benign “spike” or “bounce” in the PSA value has been 
described in as many as 35% of patients 12-36 months following 
brachytherapy, intervention for a PSA failure should be based on a 
positive prostate biopsy at least 24 months post-treatment and/or 
clinical evidence of 
distant relapse (i.e., bone scan, CT scan, etc). 
 
Local Failure (LF): This rating will be assigned when there is biopsy-
proven disease progression or recurrence at the lesion within the prostate 
treated with protocol therapy. Histologic criterion for local failure is the 
presence of prostatic carcinoma upon biopsy more than 2 years after the 
start of treatment. Residual carcinoma on biopsy should show minimal 
radiation effect and should be in clinical scenario of increasing PSA. 
 
Local Control (LC): Absence of local failure. This will be assumed in 
patients with a controlled PSA and for those with PSA failure but no 
radiographic, clinical, or biopsy-proven disease at the lesion treated with 
protocol therapy. 
 
Freedom from Local Failure (FFLF): The time to local progression will 
be measured from the date of treatment to the date of local failure. 
 
Elsewhere Prostate Failure (EPF): This rating will be assigned when 
there is biopsy-proven disease progression/recurrence at outside the lesion 
treated with protocol therapy but within the prostate or seminal vesicles. 
Elsewhere Prostate Control (EPC): Absence of EPF. Will be assumed in 
patients with a controlled PSA and in patients with PSA failure but no 
radiographic, clinical, or biopsy-proven disease at the site treated with 
protocol therapy. 

19 
 
Freedom from Elsewhere Prostate Failure (FFEPF): The time to 
elsewhere prostate failure will be measured from the date of treatment to 
the date of EPF. 
 
Regional Failure (RF): Visible disease on imaging that occurs in lymph 
nodes within the usual regional spread pattern of prostate cancer 
Regional Control (RC): Absence of regional/nodal recurrence. 
Freedom from Regional Failure (FFRF): The time to regional failure will 
be measured from the date of treatment to the date of RF. 
Distant Metastasis (DM): Visible disease on imaging that occurs 
elsewhere in the body including non-regional lymph nodes. 
Freedom from Distant Metastasis (FFDM): The time to distant metastasis 
will be measured as the date of treatment to the date of DM. 
Freedom from hormone therapy (FFHT): The time from the date of 
treatment to first administration of androgen deprivation therapy 
 
Disease-free Survival (DFS): Defined as the duration of time from the date 
of completion of treatment to either BR, LF, EPF, RF, DM, or death. 
 
Cause-specific Survival (CSS): Defined as the duration of time from the 
date of completion of treatment to death from prostate cancer.  
Overall Survival (OS): Defined as the duration of time from the date of 
completion of treatment until death from any cause. 
10.0 
ADVERSE EFFECTS 
10.1 
Data Safety Monitoring Plan 
This trial will be conducted in accordance with the Data Safety Monitoring Plan 
(DSMP) of the Cardinal Bernardin Cancer Center of Loyola University Medical 
Center.  
10.2 
Adverse Event Monitoring 
All patients experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until: 
• The adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline; 
• Any abnormal laboratory or imaging results have returned to baseline; 

20 
 
• There is a satisfactory explanation other than the study treatment for the 
changes observed; or 
• Death. 
10.3 
Definitions 
10.3.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment, which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. 
 
An adverse event will be determined to be radiation-related or non-
radiation-related based on review by the treating physician and principle 
investigator. 
10.3.2 Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI 
CTCAE version 4.03. The link to CTCAE version 4.03 is available in 
Appendix A. 
If no CTCAE grading is available, the severity of an AE is graded as 
follows: 
Mild (grade 1): The event causes discomfort without disruption of normal 
daily activities 
 
Moderate (grade 2): The event causes discomfort that affects normal daily 
activities or requires pharmacologic intervention to treat. 
 
Severe (grade 3): The event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status or requires an 
operative procedure to treat. 
 
Life-threatening (grade 4): The patient was at risk of death at the time of 
the event. 
 
Fatal (grade 5): The event caused death. 
10.3.3 Serious Adverse Events (SAE) 

21 
 
A serious adverse event is defined in regulatory terminology as any 
untoward medical occurrence that: 
10.3.3.1 Results in death. 
If death results from (progression of) the disease, the disease 
should be reported as the event itself. 
10.3.3.2 Is life-threatening. 
If the patient is at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death 
if it were more severe. 
10.3.3.3 Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥24 hours. 
10.3.3.4 Results in persistent or significant disability or incapacity. 
10.3.3.5 Is an important medical event. 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event”. 
10.4 
Steps to Determine if an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of AE using the NCI CTCAE v4.03. 
Step 2: Grade the AE using CTCAE v4.03. 
Step 3: Determine whether the AE is related to radiation therapy. 
Attribution categories are as follows: 
• Definite: The AE is clearly related to the radiation treatment. 
• Probable: The AE is likely related to the radiation treatment. 
• Possible: The AE may be related to the radiation treatment. 
• Unrelated: The AE is clearly NOT related to the radiation treatment. 
Step 4: Determine the prior experience of the AE. 
Expected events are those that have been previously identified as resulting 
from administration of a similar radiotherapy treatment delivery. An AE is 

22 
 
considered unexpected, for expedited reporting purposes only, when either the 
type of event or the severity of the event is not listed in: 
• The current known AE’s listed in this protocol. 
• The consent form. 
• The current Investigator’s Brochure 
10.5 
Exceptions to AE and SAE Definitions 
For the purposes of this study, neither the condition, prolonged hospitalization, 
nor surgery are reported as AEs or SAEs under the following circumstances: 
• 
Hospitalization or prolonged hospitalization is for a diagnostic or elective 
surgical procedure for a preexisting condition. Surgery should not be 
reported as an outcome of an AE if the purpose of surgery is elective or 
diagnostic and the outcome is uneventful. 
• 
Hospitalization or prolonged hospitalization is due to social reasons (e.g. 
awaiting transport home) 
10.6 
Reporting Requirements for Adverse Events 
10.6.1 Expedited Reporting 
• The Principal Investigator must be notified within 24 hours of learning of 
any serious adverse events, regardless of attribution, occurring during the 
study or within 30 days of the administration of radiation therapy. 
• The institutional officials must be notified within 10 business days of “any 
unanticipated 
problems 
involving 
risk 
to 
subjects 
or 
others” 
(UPR/UPIRSO). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the Institutional 
Review Board (IRB) approved protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report 
updated sponsor safety report), interim result or other finding that 

23 
 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others 
6. Any complaint of a subject that indicates an unanticipated risk that 
cannot be resolved by the Principal Investigator. 
10.6.2 Routine Reporting 
All other adverse events such as those that are expected, or are unlikely or 
definitely not related to the study participation are to be reported annually 
as part of routine data submission. 
10.7 
Stopping Rules 
Grade 3 or 4 toxicities will be evaluated by the primary investigator, and if 
radiation therapy is thought to contribute to the toxicity, the institutional officials 
will review it in detail.  The nature of the toxicity will undergo a thorough review 
and determine if the study should be stopped for fear of excessive risk to future 
patients. Grade 5 toxicities (death) will be evaluated by the primary investigator 
and the institutional officials for review.  If radiotherapy is felt to directly 
contribute to death then the institutional officials will determine if the study 
should be stopped. 
11.0 
DATA COLLECTION 
11.1 
Online Database 
Data collection will utilize the REDCap database. REDCap is a secure web-based 
application designed for building and collecting data sets. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design/Study Endpoints 
The primary outcome will be any radiotherapy-related acute or chronic grade 3-5 
toxicity as defined previously in the document.   The study is designed as a two 
stage Phase II study as described below. 
12.2 
Sample Size and Accrual 
Primary Aim 
In this single-arm oncology trial evaluating the safety and efficacy of HDR 
brachytherapy for recurrent prostate cancer, one goal is to determine the toxicity 

24 
 
of single fraction focal treatment.  Simon’s two-stage 23 design is used to power 
this aim.  The primary hypothesis is that the acceptable toxic response rate is less 
than or equal to 10.0% (p1).  The unacceptable toxic rate is set at 33% (po). 
More concisely: 
Ho: po > .33 
HA: p1 < .10 
The null hypothesis is that the unacceptable toxic response rate is at least 33%.  
This will be tested against a one-sided alternative that the toxicity rate is 10% or 
less.   
In the first stage, 7 patients will be accrued.  If there are 2 or more toxic responses 
(radiation-related acute grade >=3 GU or GI toxicity) in these 7 patients, the study 
will be stopped for safety reasons.  Otherwise, 17 additional patients will be 
accrued for a total of 24 patients.  Note that, under these conditions, the 
probability of stopping early is 73% if the toxic response rate is truly higher than 
10.0%. 
At the end of the second stage, the null hypothesis that the toxicity rate is 33% or 
higher will be rejected if more than 19 (non-toxic) responses are observed in 24 
patients.  When the true toxicity rate is 10.0%, this design yields a type I error rate 
of .046 and power of 81%. 
Secondary Aim 
We also will describe the freedom from biochemical recurrence,  relapse-free 
survival, local control, elsewhere-prostate control,  freedom-from local failure, 
freedom from distant metastasis, freedom from hormonal therapy, disease-free 
survival, cause-specific survival, and overall survival. 
12.3 
Data Analyses Plans 
For this single group trial, summary frequencies and statistics will be provided for 
all relevant patient characteristics and clinical measures, including demographics 
(e.g., age, cancer stage, educational attainment, etc) as well as clinical outcomes 
(e.g., laboratory monitoring, adverse event monitoring, etc.).  These include valid 
counts with percentages for categorical and ordinal variables as well as median 
with interquartile range or mean with standard deviation or standard error for 
continuous variables.  
For the primary aim, a one-tailed one-sample test for proportions will be used to 
test whether the observed toxicity rate is lower than the hypothesized toxicity rate.  
For relapse-free survival, death will not be considered a competing event.  

25 
 
Instead, a two-sided one-sample log-rank test will be used to estimate the 
probability of being relapse free 24 months following treatment. 
The instantaneous risk of relapse or death may be estimated as a function of age, 
cancer stage, and other covariates using semi-nonparametric Cox proportional 
hazards models.  For these models, the number of covariates used for the 
adjustment will be determined by the number of events.  Approximately one 
predictor for every 10 relapse or mortality events may be used to determine 
adjusted survival probabilities as described by Peduzzi et al. 24  For all Cox 
proportional hazards models, the proportional hazards assumption will be 
evaluated using Martingale residuals as described by Lin, Wei, and Ying.25  If the 
proportional hazards assumption is violated, parametric accelerated failure time 
models may be used assuming the true underlying hazard distribution is 
identified.     
13.0 
STUDY MANAGEMENT 
13.1 
Conflict of Interest 
13.1.1 Any investigator who has a conflict of interest (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their 
institution, etc.) must properly disclose this conflict of interest per the 
University conflict of interest policy. All investigators will follow the 
institutional conflict of interest policy. 
13.2 
IRB Approval and Consent 
13.2.1 It is expected that the IRB will have the proper representation and function 
in accordance with federally mandated regulations. The IRB should 
approve the consent form and protocol. 
13.2.2 In obtaining and documenting informed consent, the investigator should 
comply with the applicable regulatory requirements, and should adhere to 
Good Clinical Practice (GCP) guidelines and to ethical principles that are 
outlined in the Declaration of Helsinki. 
13.2.3 Prior to recruitment and enrollment onto this study, the patient will be 
provided with a full explanation of the study and will be given the 
opportunity to review the consent form. Each consent form must include 
all the relevant elements currently required by the Food and Drug 
Administration (FDA) regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participation in 
the study, the patient will be asked to give consent to participate in the 
study by signing an IRB-approved consent form. 

26 
 
13.2.4 Prior to a patient’s participation in the study, the written informed consent 
form should be signed and personally dated by the patient and by the 
individual who conducted the informed consent discussion. 
13.3 
Informed Consent  
The investigator is responsible for ensuring that no patient participates in any 
study-related examination or activity before that patient has given informed 
consent.  The informed consent will be provided both through the written 
informed consent document and through verbal review of all information 
contained therein.  Information provided in this way is to include potential 
benefits, aims of the study, potential harms or side effects and methods of the 
study.  The patient will be given opportunity to ask questions about any aspect of 
the information and will be given time to review the information on their own.  
The patient may, after having been provided with this detailed written and verbal 
information, provide written consent.  The patient will then be provided a copy of 
the executed informed consent for their reference.  The patient is free to withdraw 
consent at any time and for any reason.  The only consequence of consent 
withdrawal is that the patient is no longer able to participate in the study.   
13.4 
Protected Health Information 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), patients who have provided written informed consent must also sign a 
subject authorization to release medical information to the study sponsor and 
allow a regulatory authority, or the IRB access to the subject’s medical 
information relevant to the study. This authorization may be combined with the 
informed consent form in accordance with the institutional practice. 
13.5 
Data Management and Monitoring/Auditing 
Study-specific instructions regarding the entry and submission of data using CRFs 
is available through the Radiation Oncology Research Office. The Internal and 
Affiliate Data Compliance Policies of the Cardinal Bernardin Cancer Center’s 
DMC will be strictly enforced.     
13.5.1 Study Chart 
In addition to the regular hospital chart, a separate patient folder will be 
kept which will include the patient’s signed and dated informed consent 
document. 
13.5.2 Patient Registration (please refer to Sections 3.0 & 5.0) 
Please refer to Sections 3.0 & 5.0 for more extensive instructions. Before a 
patient can be treated on study, please complete and submit the following 

27 
 
items to confirm patient eligibility and receive a subject registration 
number: 
1. Eligibility CRF. 
2. Signed and dated informed consent document. 
3. Clinical, laboratory and imaging workup, as well as baseline 
quality of life assessment 
 
13.6 
Data Submission Guidelines 
Once a subject is confirmed and enrolled to the study, the following CRFs should 
be submitted to the Radiation Oncology Research Office. Specific timeframes 
will be defined according to the study parameters table (Section 8.3), but in 
general, on-study data should be submitted no later than 5 business days after the 
date of subject registration. Accrual on a trial may be suspended if data is not 
submitted within 90 days after the data’s due date (as it is defined by the protocol) 
13.6.1 All patient data will be entered into our brachytherapy REDCap database, 
including baseline information, all follow-up information, including but 
not limited to disease control parameters as detailed in section 9.0, and 
patient reported and physician graded toxicity. Additionally, adverse 
events and survival status will be reported in the database as well.  
13.7 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol. 
13.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior IRB 
approval.  
For any such emergency modification implemented, an IRB modification 
form must be completed within five (5) business days of making the 
change. 
13.7.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval 
by the Principal Investigator and the IRB. According to the IRB, a 
protocol deviation is any unplanned variance from an IRB approved 
protocol that: 
 
• Is generally noted or recognized after it occurs 

28 
 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected 
• Did not result from willful or knowing misconduct on the part of 
the investigator(s). 
An unplanned protocol variance is considered a violation if the variance: 
 
• Has harmed or increased the risk of harm to one or more research 
participants 
• Has damaged the scientific integrity of the data collected for the 
study 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, state laws, or university policies 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
Protocol Deviations: Personnel will report to any sponsor or data and 
safety monitoring committee in accordance with their policies. Deviations 
should be summarized and reported to the IRB at the time of continuing 
review. 
Protocol Violations: Study personnel should report violations within one 
(1) week of the Primary Investigator becoming aware of the event. 
13.8 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator. It should also be noted 
that when an amendment to the protocol substantially alters the study design or 
the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent 
to the IRB for approval prior to implementation. 
13.9 
Record Retention 
Study documentation includes all data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 

29 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator 
must retain all study documentation pertaining to the conduct of a clinical trial.  
Study documents should be kept on file until three (3) years after the completion 
and final study report of this investigational study. 
13.10 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at this 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion.  
The Principal Investigator will be responsible for assuring all the required data 
will be collected and entered into the REDCap database. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the 
completion of the study, all data entry will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the 
data. 
13.11 Study recruitment 
Electronic letters describing the trial design and eligibility criteria will be sent to 
regional physicians treating prostate cancer in order to notify them and their 
patients of potential of this trial. An initial consultation with the treating Loyola 
radiation oncologist will be required.  

30 
 
References: 
1.  
Prostate Cancer Statistics. 2016. 
2.  
Hearn JWD, Videtic GMM, Djemil T, Stephans KL. Salvage Stereotactic Body Radiation 
Therapy ( SBRT ) for Local Failure After Primary Lung SBRT. Radiat Oncol Biol. 
2014;90(2):402-406. doi:10.1016/j.ijrobp.2014.05.048. 
3.  
Parks J, Kloecker G, Woo S, Dunlap NE. Stereotactic Body Radiation Therapy as Salvage 
for 
Intrathoracic 
Recurrence 
in 
Patients 
With. 
2014;0(0):1-7. 
doi:10.1097/COC.0000000000000039. 
4.  
Meng M, Wang H, Zaorsky NG, et al. Clinical evaluation of stereotactic radiation therapy 
for recurrent or second primary mediastinal lymph node metastases originating from non-
small cell lung cancer. 2013;6(17). 
5.  
Tward JD, Kokeny KE, Shrieve DC. Radiation therapy for clinically node-positive 
prostate adenocarcinoma is correlated with improved overall and prostate cancer-specific 
survival. Pract Radiat Oncol. 2013;3(3):234-240. doi:10.1016/j.prro.2012.11.011. 
6.  
Henríquez I, Sancho G, Hervás A, et al. Salvage brachytherapy in prostate local 
recurrence after radiation therapy: predicting factors for control and toxicity. Radiat 
Oncol. 2014;9:102. doi:10.1186/1748-717X-9-102. 
7.  
Demanes DJ, Martinez A a., Ghilezan M, et al. High-dose-rate monotherapy: Safe and 
effective brachytherapy for patients with localized prostate cancer. Int J Radiat Oncol Biol 
Phys. 2011;81(5):1286-1292. doi:10.1016/j.ijrobp.2010.10.015. 
8.  
Shipley WU, Thames HD, Sandler HM, et al. Radiation Therapy for Clinically Localized 
Prostate Cancer. JAMA. 1999;281(17). 
9.  
Zelefsky MJ, Kuban D a., Levy LB, et al. Multi-institutional analysis of long-term 
outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J 
Radiat Oncol Biol Phys. 2007;67(2):327-333. doi:10.1016/j.ijrobp.2006.08.056. 
10.  
Zumsteg ZS, Spratt DE, Romesser PB, et al. Anatomical patterns of recurrence following 
biochemical relapse in the dose escalation era of external beam radiotherapy for prostate 
cancer. J Urol. 2015;194(6):1624-1630. doi:10.1016/j.juro.2015.06.100. 
11.  
Ahmadi H, Daneshmand S. Androgen deprivation therapy for prostate cancer: long-term 
safety 
and 
patient 
outcomes. 
Patient 
Relat 
Outcome 
Meas. 
2014;5:63-70. 
doi:10.2147/PROM.S52788. 
12.  
Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the Treatment of Prostate 
Cancer. Eur Urol. 2007;51(2):306-314. doi:10.1016/j.eururo.2006.08.043. 
13.  
Michalski JM, Pisansky TM, Lawton CAF, Potters L. Prostate Cancer. Clin Radiat Oncol. 

31 
 
2016:1038-1095.e18. doi:10.1016/B978-0-323-24098-7.00053-8. 
14.  
Parekh A, Graham PL, Nguyen PL. Cancer control and complications of salvage local 
therapy after failure of radiotherapy for prostate cancer: A systematic review. Semin 
Radiat Oncol. 2013;23(3):222-234. doi:10.1016/j.semradonc.2013.01.006. 
15.  
Grado GL, Collins JM, Kriegshauser JS, et al. Salvage brachytherapy for localized 
prostate cancer after radiotherapy failure. Urology. 1999;53(1):2-10. doi:10.1016/S0090-
4295(98)00492-0. 
16.  
Beyer DC. Permanent brachytherapy as salvage treatment for recurrent prostate cancer. 
Urology. 1999;54(5):880-883. doi:10.1016/S0090-4295(99)00241-1. 
17.  
Crook J, Pisansky TM, Clinic M, et al. Nrg Oncology Rtog 0526.; 1818. 
18.  
Yamada Y, Kollmeier M a., Pei X, et al. A Phase II study of salvage high-dose-rate 
brachytherapy for the treatment of locally recurrent prostate cancer after definitive 
external 
beam 
radiotherapy. 
Brachytherapy. 
2014;13(2):111-116. 
doi:10.1016/j.brachy.2013.11.005. 
19.  
Chen CP, Weinberg V, Shinohara K, et al. Salvage HDR Brachytherapy for Recurrent 
Prostate Cancer After Previous Definitive Radiation Therapy: 5-Year Outcomes. Int J 
Radiat Oncol. 2013;86(2):324-329. doi:http://dx.doi.org/10.1016/j.ijrobp.2013.01.027. 
20.  
Rigatti P, Suardi N, Briganti A, et al. Pelvic/Retroperitoneal Salvage Lymph Node 
Dissection for Patients Treated With Radical Prostatectomy With Biochemical Recurrence 
and 
Nodal 
Recurrence 
Detected 
by 
[11C]Choline 
Positron 
Emission 
Tomography/Computed 
Tomography. 
Eur 
Urol. 
2011;60(5):935-943. 
doi:http://dx.doi.org/10.1016/j.eururo.2011.07.060. 
21.  
Suardi N, Gandaglia G, Gallina A, et al. Long-term Outcomes of Salvage Lymph Node 
Dissection for Clinically Recurrent Prostate Cancer: Results of a Single-institution Series 
with 
a 
Minimum 
Follow-up 
of 
5 
Years. 
Eur 
Urol. 
2015;67(2):299-309. 
doi:http://dx.doi.org/10.1016/j.eururo.2014.02.011. 
22.  
Savir-Baruch B, Zanoni L, Schuster DM. Imaging of Prostate Cancer Using Fluciclovine. 
PET Clin. 2017;12(2):145-157. doi:http://dx.doi.org/10.1016/j.cpet.2016.11.005. 
23.  
Simon R. Optimal two-state designs for Phase II clinical trials. Control Clin Trials. 
1989;10:1-10. 
24.  
Peduzzi P, Concato J, Kemper E, Holford T, Feinstein A. A simulation study of hte 
number of events per variable in logistic regression analysis. J Clin Epidemiol. 
1996;49(12):1373-1379. 
25.  
Lin D, Wei L, Ying Z. Checking the Cox Model with Cumulative Sums of Martingale-
Based Residuals. Biometrika. 1993;80:557-572. 

32 
 
 
Appendix A: 
NCI-CTCAE version 4.03 available at 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_5x7.pdf) 
 
 
 

33 
 
Appendix B:  
 

34 
 
Appendix C: 
 

35 
 
 
 
 

36 
 
Appendix  D: 
ECOG Performance Scale 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry 
out any work activities. Up and about more than 
50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally 
confined to bed or chair 
5 
Dead 
 
* As published in Am. J. Clin. Oncol.: 
 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982.