A Phase II Trial of Stereotactic Ablative Body Radiation Therapy (SABR) for Patients With Primary Renal Cancer (RCC)
Phase: PHASE2
Conditions: Renal Cancers
Sponsor: University of Texas Southwestern Medical Center

 
STU122013-030 Hannan FormA3-ResearchProtocol Mod_45 08-26-20 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center. Do not disclose or use except as authorized in 
writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
PROTOCOL NUMBER: STU 122013-030 
A Phase II Trial of Stereotactic Ablative Radiation Therapy (SABR)  
for patients with primary Renal Cell Cancer (RCC) 
 
Principal Investigator:  
Raquibul Hannan, MD, PhD 
 
 
 
 
University of Texas Southwestern 
 
 
 
 
5801 Forest Park Road 
 
 
 
 
Phone: 214-645-8525  
 
 
 
 
Fax: 214-645-8526 
 
 
 
 
Raquibul.Hannan@utsouthwestern.edu 
 
Co-Investigator(s): 
 
Jeffrey Cadeddu, MD 
 
 
 
 
Department of Urology  
 
 
 
 
 
Vitaly Margulis, MD 
 
 
 
 
Department of Urology 
 
 
 
 
 
Arthur Sagalowsky, MD 
 
 
 
 
Department of Urology 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Yair Lotan, MD 
 
 
 
 
Department of Urology  
 
 
 
 
 
 
 
 
Jeffrey Gahan, MD 
 
 
 
 
Department of Urology 
 
 
 
 
 
Ivan Pedrosa, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
Lori Watumull, MD 
 
 
 
 
Department of Radiology 
 
 
 
 
 
 
 
 
 
Robert Timmerman MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
Hak Choy, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jing Wang, PhD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
Payal Kapur, MD 
 
 
 
 
Department of Pathology 
 
 
 
 
 
 
 
 
 
James Brugarolas, MD, PhD 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
Kevin Courtney, MD 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 

 
STU122013-030 Hannan FormA3-ResearchProtocol Mod_45 08-26-20 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center. Do not disclose or use except as authorized in 
writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
 
 
 
Department of Clinical Sciences 
5323 Harry Hines Blvd 
Dallas, TX 75390-9066 
  
 
 
 
(214) 648-9418 
Chul.ahn@utsouthwestern.edu 
 
Study Drug/Intervention: 
Stereotactic Ablative Body Radiation (SABR) 
 
Funding Source:  
Department of Radiation Oncology at UTSW 
 
Initial version: 
Version 1 – 12/31/2018 
Amended: 
 
 
Version 
Date 
Version 1 
12/31/2013 
Version 2 
07/24/2014 
Version 3 
10/02/2014 
Version 4 
12/12/2014 
Version 5 
03/23/2016 
Version 6 
12/01/2017 
Version 7 
12/04/2018 
Version 8 
12/17/2018 
Version 9 
05/19/2020 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 
 
 
 
 
 
 

 
STU122013-030 Hannan FormA3-ResearchProtocol Mod_45 08-26-20 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center. Do not disclose or use except as authorized in 
writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
Version #9 
 
PROTOCOL NUMBER: STU 122013-030 
 
PROTOCOL TITLE: A Phase II Trial of Stereotactic Ablative Radiation Therapy (SABR) for patients 
with primary Renal Cell Cancer (RCC) 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 

___________________________122013-030_______________________________________ 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS......................................................................................................... 1 
STUDY SCHEMA ........................................................................................................................ 3 
STUDY SUMMARY ..................................................................................................................... 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................. 5 
1.1 
Disease Background .................................................................................................... 5 
1.2 
Stereotactic Ablative Body Radiation (SABR) ............................................................... 5 
1.3 
Rationale ..................................................................................................................... 6 
1.4 
Correlative/Exploratory Studies .................................................................................... 8 
2.0 
STUDY OBJECTIVES ................................................................................................... 10 
2.1 
Primary Objective ...................................................................................................... 10 
2.2 
Secondary Objectives ................................................................................................ 10 
2.3 
Exploratory Objectives ............................................................................................... 11 
2.4 
Endpoints .................................................................................................................. 11 
3.0 
Subject ELIGIBILITY .................................................................................................... 12 
3.1 
Inclusion Criteria ........................................................................................................ 12 
3.2 
Exclusion Criteria .......................................................... Error! Bookmark not defined. 
4.0 
TREATMENT PLAN: Stereotactic Body Radiation Therapy ....................................... 13 
4.1 
Definitions.................................................................................................................. 13 
4.2 
SABR Dose Delivery .................................................................................................. 14 
4.3 
SABR Technical Factors ............................................................................................ 15 
4.4 
Localization, Simulation, and Immobilization .............................................................. 16 
4.5 
Treatment Planning/Target Volumes .......................................................................... 17 
4.6 
Planning Priorities ...................................................................................................... 21 
4.7 
Critical Structures ...................................................................................................... 22 

___________________________122013-030_______________________________________ 
ii 
4.8 
SABR Compliance ..................................................................................................... 26 
4.9 
Toxicities and Dosing Delays/Dose Modifications ....................................................... 26 
4.10 
Duration of Therapy ................................................................................................... 27 
4.11 
Duration of Follow Up ................................................................................................ 27 
4.12 
Removal of Subjects from Protocol Therapy ............................................................... 27 
4.13 
Subject  Replacement ................................................................................................ 27 
5.0 
STUDY PROCEDURES ................................................................................................. 27 
5.1 
Screening/Baseline Procedures ................................................................................. 27 
5.2 
Procedures during Treatment ..................................................................................... 28 
5.3 
Follow-up Procedures ................................................................................................ 29 
5.4 
Time and Events Table .............................................................................................. 29 
5.5 
Removal of Subjects from Study ................................................................................ 30 
6.0 
Measurement of Effect ................................................................................................. 30 
6.1 
Antitumor Effect- Solid Tumors................................................................................... 30 
6.2 
Safety/tolerability ....................................................................................................... 34 
7.0 
ADVERSE EVENTS ...................................................................................................... 34 
7.1 
SABR ........................................................................................................................ 34 
7.2 
Adverse Event Monitoring .......................................................................................... 34 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ..................... 37 
7.4 
Stopping Rules .......................................................................................................... 39 
8.0 
CORRELATIVES/SPECIAL STUDIES ........................................................................... 39 
8.1 
Sample Collection Guidelines .................................................................................... 40 
8.2 
Assay Methodology ................................................................................................... 41 
8.3 
BOLD/TOLD MRI ....................................................................................................... 43 
8.4 
Tumor respiratory motion modeling ............................................................................ 43 
8.5 
Specimen Banking ..................................................................................................... 44 

___________________________122013-030_______________________________________ 
iii 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 44 
9.1 
Study Design/Study Endpoints ................................................................................... 44 
9.2 
Sample Size and Accrual ........................................................................................... 45 
9.3 
Data Analyses Plans .................................................................................................. 45 
10.0 
STUDY MANAGEMENT ............................................................................................ 45 
10.1 
Conflict of Interest ...................................................................................................... 45 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................. 46 
10.3 
Required Documentation (for multi-site studies) ......................................................... 46 
10.4 
Registration Procedures............................................................................................. 46 
10.5 
Data Management and Monitoring/Auditing ................................................................ 46 
10.6 
Adherence to the Protocol .......................................................................................... 48 
10.7 
Amendments to the Protocol ...................................................................................... 48 
10.8 
Record Retention ....................................................................................................... 49 
10.9 
Obligations of Investigators ........................................................................................ 49 
11.0 
REFERENCES........................................................................................................... 49 
12.0 
APPENDICES ............................................................................................................ 54 
12.1 
Appendix A: ECOG Performance Scale ..................................................................... 54 
12.2 
Appendix B: RTOG Acute Toxicity Scale: ................................................................... 55 
12.3 
Appendix C: RTOG/EORTC Late Radiation Morbidity Scoring Schema ...................... 59 

___________________________122013-030_______________________________________ 
Page 1 of 59 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AS 
Active Surveillance 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
NSS 
Nephron Sparing Surgery 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RCC 
Renal Cell Cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SABR 
Stereotactic Ablative Radiation Therapy 
SBRT 
Stereotactic Body Radiation Therapy 
SRM 
Small Renal Mass 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 

___________________________122013-030_______________________________________ 
Page 2 of 59 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
 

___________________________122013-030_______________________________________ 
Page 3 of 59 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SABR 
Eligibility:  
 Biopsy proven RCC 
 T1a, ≤5 cm lesion 
 Evidence of >2mm tumor growth in 
<1 year on MRI or CT with contrast 
 Primary Endpoint: Local Control at 1 
year, defined as 
o <4mm growth and  
o no pathologic evidence of viable tumor  
 Patients offered SOC at local failure 
 MRI (or CT w/ C) Q6 months 
 Serum and Urine studies 
evaluating renal function Q6 
months 
 Tumor biopsy at 1 year  
 Baseline serum and urine studies  
 Baseline renal scan 

___________________________122013-030_______________________________________ 
Page 4 of 59 
STUDY SUMMARY 
Title 
Stereotactic Ablative Radiation Therapy (SABR) for patients with primary 
Renal Cancer (RCC) 
Short Title 
SABR for primary RCC 
Protocol Number 
The standard protocol number used to identify this study 
Phase 
Phase II 
Methodology 
Single arm open label 
Study Duration 
5 years 
Study Center(s) 
Single-center  
Objectives 
To eliminate growth and viable tumor in biopsy proven small primary 
RCC by SABR 
Number of Subjects 
16 
Diagnosis and Main 
Inclusion Criteria 
biopsy proven and growing small primary RCC   
Study Product(s), Dose, 
Route, Regimen 
Stereotactic Ablative Radiation Therapy (SABR): 3 fractions of 12Gy, or 
4 fractions of 10Gy or 5 fractions of 8 Gy 
Duration of administration 
1-3 Weeks. 
Reference therapy 
Lesion growth is being compared to pre-treatment growth 
Statistical Methodology 
Exact binomial test 
 
 
 

___________________________122013-030_______________________________________ 
Page 5 of 59 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
The incidence of kidney cancers has been on the steady rise since 2004 with a rise of 4.1% 
per year [1].  In 2012 an estimated 64,770 cases diagnosed and 13,570 deaths occurred due 
to kidney cancers, the majority (92%) of which were renal cell cancers (RCC) [1].  This places 
kidney cancers within the ten highest cancers in terms of incidence as well as death.  More 
than half of these cases were diagnosed at the local stage.  The common use of ultrasound, 
computed tomography, and magnetic resonance imaging resulted in an increase in the 
incidental discovery of small renal tumors (<4 cm) [2, 3]. Surgery remains the mainstay of 
curative treatment for renal cell carcinomas. However, depending on patient health status 
and tumor size, observation and in situ tumor ablation are alternatives.  The objective of 
surgery is to excise all tumors with an adequate normal tissue margin [2]. As such, nephron-
sparing surgery (NSS), primarily in the form of partial nephrectomy, is commonly utilized as a 
treatment for small renal tumors.  Accepted indications for NSS include presence of a solitary 
kidney, reduced renal function, and medical conditions with future risk for reduced renal 
function [4-7]. In fact, multiple studies have shown that partial nephrectomy achieved similar 
results when compared to radical nephrectomy in properly selected patients [4-11].  In an 
effort to provide the advantages of NSS while reducing its morbidity, laparoscopic and robotic 
partial nephrectomy has been developed [12, 13].   
 
Ablative treatments for renal cell carcinoma, although not completely non-invasive, are 
currently being developed that further reduce the morbidity associated with NSS.  
Cryoablation and radiofrequency ablation (RFA) comprise the ablative modalities that are in 
clinical use [9, 14-20].   In all cases, kidney tumors are biopsied prior to or after ablation for 
histologic diagnosis.  Unfortunately, the long-term oncologic efficacy of the ablative 
technologies remains unknown and no published study has reported rates of cancer-specific 
death, metastatic progression, or local disease recurrence after presumed successful 
ablation.   
 
Conventional radiotherapy has not been used to treat primary renal tumors. Many technical 
challenges associated with treatment of kidney tumors including limited radiation tolerance of 
the normal kidneys and the surrounding tissues and difficulty of target localization have 
prevented routine use of radiotherapy for tumors of the kidney. However, the advent of image 
guided stereotactic radiosurgery system, which is completely non-invasive, has made 
feasible what was once technically prohibitive. Stereotactic radiosurgery has been used 
successfully to treat tumors of various anatomic sites including the brain, the liver, and the 
lung [21-23].  
 
1.2 
Stereotactic Ablative Body Radiation (SABR) 
Stereotactic ablative radiation therapy (SABR) also known as Stereotactic Body Radiation 
Therapy (SABR) is an emerging treatment paradigm defined in the American Society of 
Therapeutic Radiology and Oncology guidelines as a “treatment method to deliver a high 
dose of radiation to the target, utilizing either a single dose or a small number of fractions with 
a high degree of precision within the body” [24] . Potential indications for SABR include a 
broad spectrum of tumor types and locations. The safety and efficacy of SABR to multiple 
sites is excellent as documented in multiple studies [25-27].   
 
The concept of stereotactic radiosurgery involves tightly conforming dose of therapeutic 
radiation confined to a small region of the body. This results in eradication or ablation of the 
target tumor with sparing of surrounding normal tissues. The largest experience with 
stereotactic radiosurgery is for the treatment of intracranial tumors. This requires a rigid 
immobilization device, which often is directly attached to the bony skull. Until recently, 

___________________________122013-030_______________________________________ 
Page 6 of 59 
fractionated extracranial stereotactic radiosurgery has not been possible due to many 
technical challenges. The critical issues include accuracy of targeting the tumor, required 
rapid dose fall-off away from the tumor, and adjustment for target movement during the 
therapy. These factors could not be addressed simultaneously until the advent of stereotactic 
body radiotherapy. 
 
There are several options for delivery of stereotactic radiotherapy dose to the target volume 
including TrueBeam, Cyberknife and Vero. The treatment machines have several factors in 
common. They are able to deliver the intended dose utilizing high energy (>4 MV) X-ray 
photons with accurate and reproducible treatment set up. The modern linear accelerator has 
been successfully used to deliver stereotactic radiotherapy. A landmark study by 
Timmerman, et al., reported a complete response rate of 27% for patients with in-operable 
non-small cell lung cancer after stereotactic radiotherapy with modern linear accelerator [28]. 
The stereotactic body radiotherapy is not limited to any particular machine. What is critical is 
the ability to deliver high dose accurately and safely. 
 
The immobilization of the patient to minimize the movement of the target organ is also an 
important requirement during the stereotactic radiotherapy treatment.  Stereotactic 
radiotherapy allows rapid reduction in the delivered dose away from the target bed. This is 
accomplished by utilizing multiple beams to converge on the target from various coordinates. 
In addition, the system must allow monitoring of the target via the direct imaging of the target 
itself with cone-beam CT (CBCT). The combination of tightly conforming dose to the intended 
target as well as verification of the target position during the treatment spares significant 
portion of the normal tissue from high dose radiotherapy. The real time tracking of the target 
position and stereotactic delivery of high dose to the target have not been possible until the 
advent of the stereotactic treatment system.   
 
1.3 
Rationale 
 
SABR has been implemented successfully in the definitive management of many cancers 
including in the definitive setting of primary lung and prostate cancers [28-31] and currently 
under investigation in many other sites including breast, pancreas and liver [32-36].  In the 
metastatic setting, SABR has been successfully applied to the local control of metastatic 
lesions in multiple organ sites including CNS, lung, liver, pancreas, prostate and bone [32, 
37-39]. In renal cancers, SABR has shown efficacy ranges of 90-100% and 82-95% for CNS 
and extra-CNS metastasis respectively [40-44].  
 
Despite the extensive and growing experience with SABR in multiple cancer sites, its 
application to primary renal cancers has been limited to few retrospective reviews and two 
phase I studies [45, 46].   The first retrospective study by Dr. Beitler’s group reported treating 
9 patients treated to primary tumors in the kidney ranged from 1.5cm-10cm with a median 
follow up of 27 months[45]. He reported 4/9 patients to be alive with all survivers having 
tumor sizes <3.4 cm. Their dose was 40Gy in five fractions. Only two patients experienced 
nausea/vomiting and no other toxicity was reported.  A second retrospective study reported in 
ASTRO 2004 from Cabrini medical center reported treatment of 33 primary renal lesions with 
a local control of 94% at median follow up of 17 months (Gilson et. al. 2004). In the 
Karolinska Institute experience, 8 patients received SABR to primary RCC with 8Gy x5 or 
10Gy x3 [46]. At 4 year follow up five patients were alive with no recurrence and one patient 
had a local failure at 15 months with. Median survival was 58 months. They reported no 
changes in creatinine levels after SABR and no toxicity.  Karolinska institute followed this 
report with the publication of a prospective phase II study of RCC patients that treated 10 
patients with primary RCC with an overall survival (OS) of 32 months and 96% grade I and 
grade II toxicity [47].  Lastly, a phase I dose escalation study that enrolled 15 patients at 
Boston has been presented in the 2013 ASTRO meeting (Kaplan et. al. 2013) that examined 
dose levels of 7 Gy x 3, 9 Gy x 3, 11 Gy x 3, 13 Gy x3, and 16 Gy x 3. They reported two 

___________________________122013-030_______________________________________ 
Page 7 of 59 
failures in the lower 7 and 9 Gy dose levels only. The toxicities were two patients having 
acute grade 1 nausea, five experiencing acute grade 1 fatigue and one patient having late 
grade 3 renal dysfunction.  
 
Radiation induced renal complications can be slow and non-inflammatory. The extent of 
radiation induced kidney damage is related to the volume of renal parenchyma receiving 
radiotherapy, total dose given to the kidney, dose per treatment, and other underlying 
medical conditions such as diabetes and hypertension.  Acute radiation nephritis can be seen 
months after exposure to radiotherapy [48]. The clinical symptoms related to acute radiation 
nephritis include hypertension, edema, proteinuria, anemia, and uremia. In standard 
fractionated treatment to both kidneys about 50% of the patients will develop the clinical 
manifestation described above a dose of 23 Gy [49]. Among the clinical symptoms, the 
development of hypertension is the most important prognostic sign correlated with severe 
morbidity and death. However, when 50% or less of a single kidney is irradiated to a high 
dose (>26 Gy), clinical radiation induced nephropathy is rare [49].  
 
In this phase II trial, the volume of high dose radiotherapy (>10 Gy) will be restricted to <50% 
of the entire kidney.  The current study will also implement fractionated stereotactic 
radiosurgery to treat a unilateral kidney tumor. Fractionated radiotherapy is advocated to 
further reduce the potential toxicity arising from a large single fraction regimen. In fact, 
fractionated radiotherapy has been the standard treatment for many tumors in variety of 
locations to reduce the toxicity associated with radiotherapy. A fractionated stereotactic 
regimen has the potential to reduce the normal tissue toxicity that often accompanies 
radiotherapy.   
 
Successful implementation of stereotactic radiosurgery of renal tumors may become an 
effective and the least invasive treatment modality. This study will refine the current 
understanding of the image guided conformal therapy to the kidney using stereotactic body 
radiotherapy. 
 
Based on the published retrospective and the two prospective phase I trials, the dose 
fractionations evaluated in this trial is 8Gy x5, 10Gy x 4 and 12 Gy x 3.  In a retrospective 
study published paper by Wersäll, et al, from the Karolinska Hospital, 50 patients with kidney 
cancer, both primary and metastatic, were retrospectively analyzed [50].  High rates of local 
control were achieved with doses ranging from 25 Gy to 45 Gy.  The most common doses 
used were 40 Gy in 5 fractions and 45 Gy in 3 fractions.  Another retrospective study used 
the dose of 40Gy in 5 fractions and both studies reported excellent control rate [45]. 
Therefore 8Gy x 5 is evaluated in this study. The 4 and 3 fraction equivalent doses to this 
dose levels are 10Gy and 12 Gy respectively, which are the two other dose levels included in 
this trial. Justification of the three fraction dose equivalent of 12Gy x 3 comes from the phase 
I study that did not see any failures at this level.  
 
The study population for this trial is patients with biopsy proven primary RCC that are 
candidates for active surveillance (AS). Keeping patient safety in perspective, it is reasonable 
to offer an experimental treatment such as this to a patient population that would have 
otherwise been put in AS. At any sign of progression, the patients that have undergone 
SABR in this trial will be offered the standard of care (SOC) of radical nephrectomy, partial 
nephrectomy or ablation as deemed appropriate by the treating urologist—which is same as 
what would have been offered to them had they been in AS. The AUA defines AS patients to 
be those with small renal mass (SRM) with <3cm tumors. The NCCN recommends AS for 
patients with T1a tumors or tumors <4 cm. A number of retrospective and one prospective 
study reported on the natural history of SRMs [51-55]. A meta-analysis reviewed multiple 
retrospective studies and reported an average growth rate of 0.28 cm/year for these tumors 
[51]. They further reported a growth of 0.4 cm/year in the subset of patients that had biopsy 
confirmed RCC. Keeping clinical application in perspective, it is logical to use SABR only to 
tumors that are growing, since one third of the SRMs do not grow. Therefore, patients 

___________________________122013-030_______________________________________ 
Page 8 of 59 
showing growth >2mm in two scans will be enrolled and treated with SABR in this trial. The 
primary endpoint in this trial is local control and the hypothesis tested is that SABR to the 
SRMs will lead to an elimination of tumor growth. The local control will be defined using MRI 
or contrast CT and <4mm increase in single scan or <2.0mm increase in two different scans 
in the setting of an absence of radiographic  indication of tumor viability will constitute local 
control [56]. Kidney function will be monitored closely to evaluate radiation induced kidney 
toxicity.  
 
1.4 
Correlative/Exploratory Studies 
1.4.1 
SABR induced immune response 
Previous studies have demonstrated multiple immunogenic properties of radiation 
therapy (RT), especially when given at high doses such as with SABR [57, 58].  Since SABR is a 
highly focused therapy, it does not inherently immunocompromise the host. In addition, as 
opposed to conventional radiation fields, SABR is a highly focused therapy that spares the 
surrounding lymph nodes which are vital for an effective immune response. By not surgically 
removing the tumor, the body retains the antigen depot (dying tumor cells) within the host. 
Furthermore, since SABR causes local inflammation, dendritic cells (DCs) are attracted into the 
tumor. The antigen-presenting properties and the induction of immunogenic cell death by SABR 
are well documented [59].  SABR-induced tumor cell death is primarily via mitotic catastrophy or 
necrosis, both of which are known to be immunogenic cell deaths as opposed to apoptosis, which 
is immunologically tolarogenic [60].  In vivo studies have shown that radiation induces release of 
damage (or danger)-associated molecular patterns (DAMPs) such as HMGB1, HSP and 
calreticulin into the extracellular matrix and thereby promotes the recruitment and activation of 
antigen-presenting cells (APCs) such as DCs for antigen presentation [61-63]. Subsequently, the 
APCs migrate to the draining lymph nodes for the presentation of the antigens and efficiently 
present tumor antigens in the cell surface MHC molecules to T cells [64]. The T cells initiate an 
adaptive immune response resulting in antibody production and the expansion of cytotoxic T 
cells. These are delivered to both the primary and metastatic tumor sites. Increased trafficking of 
CD8+ T cells to both irradiated tumor and their draining lymph node has been demonstrated [64, 
65]. Furthermore, RT causes a dose-dependent increase in MHC I tumor neo-antigen 
presentation by the tumor cells [66]. This, in conjunction with a demonstrated increase in FAS 
death receptors on the tumor cell surface in response to radiation, renders tumor cells particularly 
susceptible to CD8+ T cell-mediated cytotoxic attack [67, 68].  
 
The correlative studies will explore the mechanisms of possible immune enhancement by SABR. 
Activation of each arm of the immune response will be evaluated separately utilizing different 
assays. The humoral response will be evaluated using ELISA to measure the titer of tumor-
specific antibodies generated by SABR against tumor tissue collected from the respective 
patients and established human renal cancer cell line Caki-2 (clear cell) and ACHIN 
(adenocarcinoma).  An overall increase in tumor antigen-specific antibody will be measured using 
immunoblotting with patient sera as a source of primary antibody.  
 
Enhancements of increased cytotoxicity to renal cancer cells can be measured by cytotoxicity 
assays.  Antibody-dependent cell-mediated cytotoxicity (ADCC) measures the cell-killing ability of 
certain lymphocytes that require the target cell to be marked by an antibody and thus measures 
the humeral response [69]. On the other hand, lymphocyte-mediated cytotoxicity assay will 
measure the formation of tumor-specific CTLs among the lymphocytes collected from patients 
with the controls being lymphocytes collected from the same patients before SABR. Since it is not 
practical or feasible to obtain sufficient quantities of tumor cells from each patients to assess a 
quantitative cytotoxicity by these assays, established allogenic human renal cancer cell line Caki-
2 and ACHIN will be used for this purpose. It is a generally accepted principle of tumor 
immunology that there will be many common tumor antigens between different patient tumors of 
same site origin, and therefore tumor cell lines as well [69]. In fact, the tumor antigens (PSA, 
CEA, CA 19-9 etc.) that are in clinical practice are reported to be present in a significant portions 

___________________________122013-030_______________________________________ 
Page 9 of 59 
of patients of the respective tumor site.  This concept of commonality of tumor antigens between 
allogenic tumor cell lines and patients is put into clinical practice by the GVAX anti-tumor vaccine 
which is currently in early phase clinical trials for pancreatic, melanoma and renal cancer [70, 71]. 
GVAX consists of multiple human tumor cell lines of the respective site, that is modified to 
express GM-CSF, and killed with radiation prior to injection in patients. The presence of common 
tumor antigens in the cell lines and patient’s tumors, leads to induction of an immune response. 
The LNCaP and PC-3 cell lines has been shown to express many of the common renal cancer 
antigens, and therefore, is an appropriate surrogate to be used instead of patient’s own cells and 
has been used in similar in vitro cytotoxicity assays [72-76].   
 
Cytokines are hormonal messengers responsible for most of the effects in the immune system 
such as activation of innate versus adaptive immune response, cellular versus humeral immune 
response [77, 78]. For example, an increased level of IL-2 and IFN-γ suggests activation of Th1 
cells leading to activation of macrophages and suggests a cell-mediated adaptive immune 
response whereas IL-4 and IL-5 may indicate Th2 activation and induction of humoral immunity 
[69, 78].  An increase in IL-17 may suggest activation of autoimmune responses [79]. Therefore, 
measurements of serum cytokine levels have generally been used previously in clinical trials as 
surrogates to assess specific activation of immune pathways [80, 81].  Serum cytokines from this 
clinical trial before and after SABR will be measured using an extensive array of cytokines to 
explore the specific immune pathways that are initiated by SABR. The planned array of cytokines 
will measure levels of the following cytokines before and after treatment for each patients: 
Th1/Th2/Th17 cytokines: IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; 
pro-inflammatory cytokines: GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α; 
Chemokines: Eotaxin, MIP-1β, TARC, IP-10, IL-8, MCP-1, MCP-4, KC, and others including IL-6, 
IL-12, TGF-β and HMGB1.   
 
Many surrogate markers for activated and proliferating lymphocytes have been described. Some 
of these markers include CD25, CD71, CD45RO, CD107a, CD54, CD69, Ki67 and ICOS/CD278 
[82-85]. These markers are easily measured with antibodies specific for the markers that are 
tagged with a fluorophore utilizing FACS analysis. Also using FACS, activation markers on other 
immune cells such as CD80 and CD 86 on DCs, and inhibitory markers on monocytes such as 
PD-1 can be measured as surrogates of immune activation or inhibition.  These measurements 
from PBMCs collected from patients before and after treatment will give us further information 
regarding the intensity of the immune response.  Additionally, PD-L1, the ligand of PD-1, often 
expressed in tumor cells, can be quantified from patient pre-treatment tumor biopsy.  
 
The relative levels of different monocyte subpopulations in the tumor biopsy sample after 
treatment as well as in the peripheral circulation often dictate the overall outcome of an immune 
response, and has been reported in previous immunotherapy trials [86]. Exploration of possible 
mechanisms of treatment failure can be explored from this analysis as well. Therefore, different 
subpopulation of monocytes and lymphocytes will be quantified in patient PBMCs (and in tumor 
biopsy samples where applicable) collected before and after treatment utilizing markers specific 
for those cells. 
 
Many studies have suggested that imaging characteristics of tumor may be used to predict 
treatment outcome of radiation therapy for various tumors, such as lung [87], prostate[88], 
cervical[89]. By analyzing CT and MRI images on patient enrolled in this trial, we plan to explore 
whether image characteristics of CT and MRI acquired prior to the SBAR treatment, such as 
intensity features, texture features and geometry features, are correlated with the treatment 
outcome of SABR for RCC. Through analysis of the change of these image characteristics in the 
follow-up scans, we will also explore whether the change of these features can be used for early 
prediction of SABR treatment response.        
 
Multiple clinical and pre-clinical studies have demonstrated the dependence of tumor radiation 
resistance with tumor hypoxia, including those performed in our institution [90-94]. Using a 
combination of blood oxygen level dependent (BOLD) and tissue Oxygen Level Dependent 

___________________________122013-030_______________________________________ 
Page 10 of 59 
(TOLD) MRI, accurate insight regarding tumor oxygenation can be obtained. In RCC, tumor 
hypoxia and its dependence on treatment outcome, specifically with SABR, has not been 
explored before.  Therefore, BOLD and TOLD MRI sequences will be incorporated in the baseline 
and six month post-treatment scans for patients enrolled in this trial. 
1.4.2 
Tumor respiratory motion modeling 
Respiratory motion causes significant geometric and dosimetric errors in the administration of 
stereotactic radiotherapy (SBRT) for renal cell cancer (RCC). The purpose of this study is to create 
and validate patient-specific motion models of the abdominal anatomy with high spatial and 
temporal resolution. These models will be used to develop novel four-dimensional (4D=3D+time) 
techniques for radiotherapy treatment planning and real-time motion-adaptive dose delivery.  
 
 
This study will involve the acquisition of real-time optical surface monitoring data from human 
patients with primary lesions, following their 4D computed tomography scan (4DCT - standard-of-
care at our clinic). These data will be to build a 4D motion model that describes the spatial location 
of each voxel in the CT volume as a function of time. In the treatment room, before dose delivery, 
the model will be updated and validated using three 15s long kV fluoroscopic sequences, each 
acquired from a different angle, and time-correlated with optical surface monitoring. The data and 
the findings of this study will be used solely for research and will not affect a patient's clinical 
treatment plan or dose delivery.  The data acquired in this study will vastly improve our knowledge 
of how respiratory motion affects tumors and organs at risk within the abdominal anatomy and 
enable the development of better motion-managed radiation therapy paradigms that may help other 
patients with thoracic and abdominal cancers. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 
2.1.1 
To evaluate if SABR to SRMs is able to eliminate its growth and viable tumor.  
2.2 
Secondary Objectives 
 
2.2.1 
To describe the adverse events associated with the administration of SABR to 
SRMs 
 
2.2.2 
To measure the growth rate of SRMs after SABR treatment. 
 
2.2.3 
To measure the changes in kidney function, creatinine levels, renal perfusion and 
GFR after SABR treatment. 
 
 
2.2.4 
To measure tumor viability pathologically one year after SABR treatment with a 
biopsy. 
 
2.2.5 
To assess radiographic changes of the SRM after SABR treatment, including 
tumor viability, %enhancement, necrosis, T2 signal, tumor cellularity with 
diffusion-weighted imaging 
 
2.2.6 
To assess local, regional and systemic progression of disease after SABR to 
SRM  
 
2.2.7 
To assess time to progression (TTP) of disease from the first SABR treatment. 
 

___________________________122013-030_______________________________________ 
Page 11 of 59 
2.2.8 
To assess progression free survival (PFS). PFS is defined as the length of time 
from start of treatment to the time of loco-regional disease progression (as 
defined in Section 2.4) or death from any cause. 
 
2.2.9 
To assess overall survival (OS). OS is defined as the duration of time from start 
of treatment to the time of death from any cause. 
 
2.2.10 To assess tumor growth, local failure and indeterminate disease response (IDR) 
as defined in section 6.1.4 
 
2.3 
Exploratory Objectives 
2.3.1 
To evaluate the cytokine changes brought on by SABR to SRM and to evaluate 
generation of any immune response specific to tumor cells.  
2.3.2 
To evaluate whether radiographic spatial-temporal tumor features extracted from 
CT and MRI can be used to predict treatment response of tumor to SABR.  
2.3.3 
To evaluate if tumor oxygenation as measured by BOLD/TOLD MRI sequences 
is able to predict tumor response to SABR. 
2.3.4 
To model kidney and tumor motion with respect to respiration 
 
2.4 
Endpoints 
2.4.1 
Primary Endpoint:  
Local control of the SRMs will be defined as <4mm increase in the longest tumor 
diameter compared to pre-treatment scan on an MRI or contrast-enhanced CT scan in 
the setting of no radiographic or pathologic evidence of viable tumor.  
2.4.2 
Secondary Endpoints:  
2.4.2.1 Adverse Events: Acute and late adverse events will be assessed using NCI’s 
CTCAE v4.0 toxicity criteria and RTOG/EORTC criteria (Appendix A and B).  
 
2.4.2.2 Growth Rate: Growth of the longest diameter of the SRMs after SABR treatment 
will be compared to baseline and expressed as growth rate of cm/year.  
 
2.4.2.3 Loco-regional and systemic progression: Loco-regional and systemic 
progressive disease will be defined based on local, regional and systemic 
progression as defined by AJCC (7th edition) kidney cancer staging and any 
stage >T1a (>4cm) constitutes a progression.   
 
 
2.4.2.4 Kidney function: To assess kidney function creatinine levels and renal perfusion 
scan will be performed at baseline and periodically after SABR (See section 5).  
 
2.4.2.5 Radiographic changes: Radiographic changes of the SRM after SABR treatment 
will be assessed using MRI interpretation by a radiologist. 
 
2.4.2.6 Tumor Growth, Local failure and Indeterminate Disease Response as defined in 
section 6.1.4 
2.4.3 
Exploratory Endpoint: 
2.4.3.1 Immune Response:  Immune response will be measured using ELISpot assay, 
T-cell proliferation assay, Immunoblot and ELISA. 
 

___________________________122013-030_______________________________________ 
Page 12 of 59 
2.4.3.2 Spatial-temporal radiographic tumor features predictive value: Predictive value 
of each feature for SABR treatment response will be assessed using the area 
under the receiver operating characteristic curve.  
 
2.4.3.3  To develop a 4D model of patient-specific tumor motion 
 
3.0 
SUBJECT ELIGIBILITY 
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 
Age ≥ 18 years. 
 
3.1.2 
Renal mass ≤ 5cm 
 
3.1.2.1 The treating renal mass must be ≤ 5cm. Other renal masses (cysts etc.) 
of any size will not make the subject ineligible.   
 
3.1.3 
Biopsy proven Renal neoplasm  
3.1.3.1 All histology of renal cancers are included, including oncocytoma 
 
3.1.4 
Growth of renal mass >2mm in radiographic scans must be demonstrated within 
a one year period.  
 
3.1.5 
Ability to understand and the willingness to sign a written informed consent. 
 
3.1.6 
Subject is able to undergo either an MRI or administration of contrast agent for 
CT. 
 
3.1.7 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) for the 
duration of the study. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.6.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
3.2 
Exclusion Criteria 
 
3.2.1 
Subject has received any treatment for the treating renal mass; such as RFA or 
cyroablation. 
3.2.1.1 If other renal masses received RFA or cryoablation or surgery, then these 
patients are eligible.  
 
3.2.2 
Subjects received previous abdominal radiation 
 

___________________________122013-030_______________________________________ 
Page 13 of 59 
3.2.3 
Evidence of Metastatic Disease, unless disease-free for ≥ 3 years prior to 
registration, (non-melanomatous skin cancer and in-situ cancers are okay). 
 
3.2.4 
Female subjects who are pregnant or planning to become pregnant during the 
course of SABR. 
 
4.0 
TREATMENT PLAN: Stereotactic Body Radiation Therapy 
4.1 
Definitions 
Stereotactic body radiation therapy (SABR), also known as stereotactic ablative 
radiotherapy (SABR), is a treatment conduct used to deliver highly focused and accurate 
radiation dose to demarcated targets outside of the brain where the entire course of therapy for 
an individual target is delivered in few fractions (≤5, oligofractionation).  SABR has been defined 
and its appropriate conduct extensively reviewed by several professional radiotherapy societies.  
For this protocol, we will maintain definitions of SABR from the ACR/ASTRO consensus and 
conduct from the same along with requirements laid out by the AAPM.  When and if there is a 
discrepancy between these professional society guidelines and this protocol, the protocol should 
be followed. 
4.1.1 
Elements and Technologies of SABR  
4.1.1.1 
Secure Immobilization 
 
With more dose per fraction being delivered and more emphasis on quality assurance of 
set-up and delivery, typical SABR treatment sessions are longer than with conventional 
radiotherapy.  Accuracy of set-up must be assured throughout the duration of treatment.  
Controlling variables such as patient discomfort and unintended movements improves accuracy 
and allows for small uncertainty margins that would generally lead to more favorable dose 
distributions.  Immobilization should focus on patient comfort as pain confounds accurate set-up.  
While historically immobilization with stereotactic radiotherapy involved rigid, fixed immobilization 
(typically to bone), modern extracranial stereotactic radiotherapy delivery involves employing 
large surface area of contact with molded cushions, body frames, etc., to distribute body weight 
more evenly.  Laying patients on flat couches and relying solely on image-guidance for 
reproducible set-up is strongly discouraged. 
4.1.1.2 
Effective Delineation of Targets 
The edge of the intended target should be distinct from uninvolved normal tissue such 
that there is little need for expansions for subclinical extension or uncertainty.  A variety of 
appropriate imaging can be used to define targets clearly so long as these imaging platforms can 
be accurately and reliably “fused” with the planning data set and brought into the context of 
stereotactic targeting conveyed in the next paragraph. Patient’s baseline MRI will be fused to the 
planning CT (preferably with IV contrast if patient is able to tolerate) for this purpose whenever 
applicable. 
4.1.1.3 
Stereotactic Targeting 
The term ‘stereotactic’ for the purposes of this protocol implies the targeting, planning, 
and directing of therapy using beams of radiation along any trajectory in 3-D space toward a 
target of known 3-D coordinates.  The coordinate system is defined by reliable ‘fiducials’.  A 
fiducial may be external or internal to the patient’s body.  External fiducials may relate to a frame 
or treatment device.  Internal fiducials may be implanted markers OR reliably identified anatomy 
including the tumor itself (e.g., acquiring tomographic views of the tumor simultaneously with the 
treatment).  In all cases, the relationship between the fiducial and the actual tumor position in real 
time should be reliably understood for both planning and treatment.  The coordinate system 
defined by the fiducials should be directly related to the radiation-producing device (e.g., couch 
and gantry) in a reproducible and secure fashion.  Capability should exist to define the position of 

___________________________122013-030_______________________________________ 
Page 14 of 59 
targets within the patient according to this same 3-D coordinate system.  As such, the patient is 
set up for each treatment with the intention of directing the radiation toward an isocenter or target 
according to the known 3-D coordinates as determined in the process of treatment planning.   
4.1.1.4 
Motion Assessment and Management 
Motion assessment involves a query to appreciate the nature of both tumor target and 
normal tissue displacement that may occur during a typical SABR treatment session.  Dynamic 
imaging is typically required for such an assessment such as fluoroscopy, ultrasound, 4-D CT, 
etc.  It is not enough to understand how surrogates for targets move (e.g., the diaphragm for a 
lung tumor).  Instead, the actual motion of the target must be reasonably understood.  In turn, this 
assessment may either allow appropriate expansions of targets to encompass this movement (if 
the expansion would only be minimal) OR to trigger the use of motion control.  Motion 
management is a logical reaction to excessive motion appreciated from the motion assessment 
where either the natural physiological motion is modified (e.g., dampened) or countered with an 
active process (e.g., gating or tracking). 
4.1.1.5 
Compact Dosimetry 
There is no intention to perform adjuvant therapy for microscopic infiltration or 
involvement with SABR.  It follows that while the target should be hit hard with radiation to disable 
cancer proliferation, uninvolved normal tissues should be likewise spared as much as possible.  
In striking contrast to radiotherapy given historically and conventionally where areas ‘at risk’ were 
bathed in small daily dose fractions, similar approach with SABR would be prohibited by late 
toxicity.  Instead, dose outside the target should fall off rapidly in all directions to avoid such 
toxicity.  Gradients may appropriately be even steeper next to critical serially functioning normal 
structures (ie, tubes and wires of the body). 
4.1.1.6 
Image Guidance 
With such compact dosimetry delivering potent tumorical dose surrounding small to 
medium sized targets perhaps in association with critical normal structures, geometric errors in 
beam positioning could be catastrophic both in regard to tumor control and toxicity.  Image 
guidance increases the confidence that beams are in alignment during dose delivery allowing 
reduction of margins that might otherwise be added for uncertainty. 
4.2 
SABR Dose Delivery 
4.2.1 
Treatment Sites 
 
Treatment of primary tumors of the kidney will be allowed on this protocol.  
4.2.2 
Target Prescription Dose 
 
SABR prescription dose will be delivered to the periphery of the planning target volume 
for each lesion treated.  Investigators will have discretion in choosing from allowable dose levels 
from the table below.  Treating physicians should choose their dose based on established 
planning guidelines at their center including their ability to respect normal tissue tolerance listed in 
the protocol.  It is not required that all targets be treated with the same dose fractionation. 
 
Allowed prescription dose:  
 Number of 
Fractions 
Total Cumulative Dose 
Encompassing 95% of Planning 
Target Volume  
3 
36 Gy 
4 
40 Gy 

___________________________122013-030_______________________________________ 
Page 15 of 59 
5 
40 Gy 
4.2.3 
Treatment Timing and Duration 
For a given lesion (target), a minimum of 40 hours and a maximum of 8 days should 
separate consecutive treatments.   All treatment must be completed within 21 days. 
4.2.4 
Daily Treatment 
Ample time should be scheduled for each treatment to insure careful execution of the 
SABR for the lesion.  Avoid long treatment sessions as the resulting discomfort for the patient 
from prolonged immobilization may confound accuracy. 
4.2.4.1 
Daily Image Guidance 
Appropriate SABR includes more sophisticated image guidance to reduce uncertainties 
and allow smaller treatment margins.  Confidently identifying the stereotactic fiducials (e.g., 
implanted markers, close body tissue surrogates, or even the tumor itself) before and during 
treatment mostly eliminates interfraction error and reduces intrafraction error allowing the smaller 
margins critical to the overall SABR approach. 
 
4.3 
SABR Technical Factors 
4.3.1 
Physical Factors and Treatment Platforms 
Only photon (x-ray) beams produced by linear accelerators with photon energies of 4-10 
MV will be allowed. Cobalt-60 and charged particle beams (including electrons, protons, and 
heavier ions) are not allowed.  Photon beam energies > 10 MV but < 18 MV will be allowed only 
for a limited number (≤50% of all beams or all beam angles) beams that must travel more than a 
cumulative distance of 10 cm through soft tissue (not lung) to reach the isocenter OR a shorter 
distance if the tumor abuts the chest or abdominal wall (i.e., to spare skin dose).  
Most commercially available photon producing treatment units are allowed except the 
exclusions noted above. As such, conventional linear accelerators, specialized linear accelerators 
with image guidance (e.g., Novalis, True Beam, Agility, Artiste, etc.) are allowed. These units can 
be used with conformal dose delivery or IMRT.  Specialized dose painting accelerators (e.g., 
Cyberknife, or Tomotherapy) are allowed provided they meet the technical specifications of the 
protocol. 
4.3.2 
Minimum Field Aperture (Field Size) Dimension 
Because of uncertainties in beam commissioning resulting from electronic disequilibrium 
within small beam apertures, an equivalent square field dimension of 3.0 cm is required for any 
field used for treatment delivery for sites using standard 3-D conformal techniques where nearly 
all of the PTV is encompassed for each beam. It is understood that this may exceed the technical 
requirements for small lesions [< 2.0 cm axial gross tumor volume (GTV) dimension or < 1.0 cm 
craniocaudal GTV dimension]. In such cases, the prescription dose is still prescribed to the edge 
of the defined planning treatment volume (PTV). For sites using dose painting including IMRT 
techniques (e.g., Cyberknife, Tomotherapy, etc.) where by design the entire PTV is not 
encompassed for each beam, smaller beam apertures are allowed.  In addition, if the site has 
specifically commissioned the beams employed in credentialing and treatment to be applicable to 
smaller field sizes, they may reduce the minimum field aperture requirement to the size 
commissioned provided they provide documentation of such commissioning and get pre-approval 
by the physics co-PI for the study. 
4.3.3 
The Use of Intensity Modulated Radiation Therapy (IMRT)  
The protocol allows for IMRT provided the site is credentialed for IMRT and SABR. 
However, SABR is, in general, a 3-D conformal treatment. Indeed, IMRT can result in dosimetric 

___________________________122013-030_______________________________________ 
Page 16 of 59 
inaccuracies especially in circumstances where tumor motion is either unknown or not properly 
accounted. Some platforms inherently use IMRT and must pass credentialing where motion is 
incorporated correctly (e.g., Tomotherapy). When using other platforms, IMRT is generally 
discouraged. When required for successful compliance, IMRT should only be utilized if tumor 
motion is less than 5 mm (e.g., confirmed inherently with free breathing or with abdominal 
compression), OR if motion control effectively diminishes motion effects (e.g., gating, breath hold, 
or tracking) below 5mm. 
 
4.4 
Localization, Simulation, and Immobilization 
4.4.1 
Patient Positioning 
Patients will be positioned in a stable position capable of allowing accurate reproducibility 
of the target positions from treatment to treatment. Positions uncomfortable for the patient should 
be avoided so as to prevent uncontrolled movement during treatments. A variety of immobilization 
systems may be used, including stereotactic frames that surround the patient on three sides and 
large rigid pillows (conforming to patients’ external contours) with reference to the stereotactic 
coordinate system. Patient immobilization must be reliable enough to insure that the gross tumor 
volume (GTV) does not deviate beyond the confines of the planning treatment volume (PTV) with 
any significant probability (i.e., < 5%) during the treatment. 
4.4.2 
Assessment of the Magnitude of Internal Organ Motion 
 
Special considerations must be made to account for the effect of internal organ motion 
(e.g., primarily breathing associated motion but also bowel peristalsis motion) on target 
positioning and reproducibility. As a first step, it is required that each site quantify the specific 
motion of a target so as to determine if management strategies listed in the next section are 
required to meet protocol guidelines. The GTV to PTV expansion limits, as defined below, are no 
greater than 0.5 cm in the axial plane and 1.0 cm in the craniocaudal plane.  If tumor motion 
combined with set-up error causes any PTV to be greater than the GTV beyond these limits, then 
a motion management strategy (or plan to reduce setup error) must be employed with validation 
of success. Patient should be instructed to be in normal free breathing at time of initial tumor 
motion assessment. Deep inspiration or expiration breath hold is not allowed for initial tumor 
motion assessment as such assessment generally overestimates free breathing tumor motion. 
Options for motion assessment included real time fluoroscopy, 4-D CT scanning, or other 
methods approved by the study team. 
4.4.3 
Management of the Effects of Internal Organ Motion 
 
In some tumor locations, assessed tumor motion measurement indicates that tumor 
motion would exceed the required small tumor expansions per this protocol (resulting in marginal 
miss or excessive volume of irradiation) unless a motion management strategy is employed. 
Acceptable maneuvers for motion management include reliable abdominal compression, 
accelerator beam gating with the respiratory cycle, tumor tracking, and active breath-holding 
techniques or other methods approved by the study committee. Internal organ management 
maneuvers must be reliable enough to insure that the GTV does not deviate beyond the confines 
of the PTV with any significant probability (i.e., < 5%). 
4.4.4 
Localization 
 
Isocenter or reference point port localization imaging (anterior/posterior and lateral) for 
each separate lesion should be obtained at each treatment on the treatment unit (or patients 
should undergo a tomographic imaging study using the linear accelerator couch, if available) 
immediately before treatment to ensure proper alignment of the geometric center (i.e., isocenter) 
of the simulated fields for each lesion. All IGRT systems must be checked daily to guarantee 
coincidence between the imaging coordinate system and the treatment coordinate system. This 
test is required by the AAPM Task Group 142 report and is described in detail in both the 
ASTRO/ACR practice guideline on SABR available at:  

___________________________122013-030_______________________________________ 
Page 17 of 59 
 
http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/ro/stereo_body_radi
ation 
 
and the ACR Technical Standard on IGRT available at:  
 
http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/med_phys/monitor_I
GRT.  
 
This test is particularly important when the treatment equipment is not equipped with any device 
that allows direct visualization of anatomical structures using the treatment beam. For example, 
this test must be performed routinely for the CyberKnife, Tomotherapy units as well as any 
BrainLab equipment that does not include an electronic portal imaging device (EPID) that 
intercepts the treatment beam. 
4.4.5 
Isocenter and Lesion 
 
Isocentric beam delivery platforms are commonly used in radiotherapy (e.g., the common 
gantry-mounted linear accelerator).  For a given lesion where the isocenter is purposely placed at 
the geometric center of the target, isocentric setup allows accurate delivery, particularly with 
image-guidance, even in the presence of whole body rotational setup errors.  However, for these 
same platforms when treating to an isocenter apart from the target, considerable targeting error is 
introduced due to rotations.  As such, it is generally required that the lesion has an isocenter 
located in the center of the lesion for such platforms. In addition, some platforms, including the 
Cyberknife and Tomotherapy, are inherently non-isocentric.  These platforms take special 
account in the setup and treatment process to rigorously detect and account for rotations to avoid 
errors. 
 
4.5 
Treatment Planning/Target Volumes 
4.5.1 
Image Acquisition 
 
Computed tomography will be the primary image platform for targeting and treatment 
planning. The planning CT scans must allow simultaneous view of the patient anatomy and 
fiducial system for stereotactic targeting and should ideally be done with IV contrast unless the 
patient has allergic problems with contrast or has renal insufficiency. Contrast will allow better 
distinction between tumor or other normal anatomy. Axial acquisitions with gantry 0 degrees will 
be required with spacing ≤ 3.0 mm between scans. Images will be transferred to the treatment 
planning computers via direct lines, disc, or tape.  
4.5.2 
Targets 
The targeted lesion will be outlined and/or approved by an appropriately trained radiation 
oncology physician and designated the gross tumor volume (GTV).  Kidney lesion will be drawn 
with appropriate CT windowing, contrast, and with the information from fusion of MRI in 
delineating tumor from normal tissue.  GTV targets will not be enlarged whatsoever for 
prophylactic treatment (including no “margin” for presumed microscopic extension); 
rather, include only abnormal imaging signal consistent with gross tumor (i.e., the GTV 
and the clinical target volume [CTV] are identical). An additional 0.5 cm in the axial plane and 
1.0 cm in the longitudinal plane (craniocaudal) will be added to the GTV to constitute the PTV.  
As an alternative, sites equipped with 4-D CT scanning equipment may generate an 
Internal Target Volume (ITV) using the inspiration and expiration images or maximum/minimum 
intensity projections (MIP/MinIP) as appropriate. Sites should be aware that the MIP 
reconstruction for lung or MinIP reconstructions for liver may erroneously define an ITV in cases 
of significant irregular breathing or when tumors abut soft tissue structures (e.g., the diaphragm 
for MIP) or fat (for the MinIP). The 4-D scan acquired for planning, however, should be obtained 
after initial assessment of tumor motion confirming that the tumor motion will be no greater than 

___________________________122013-030_______________________________________ 
Page 18 of 59 
0.5 cm in the axial plane and 1.0 cm in the craniocaudal plane. An ITV should NOT be defined by 
the merger of a deep inspiration CT scan and a deep expiration CT scan as such would typically 
overestimate tumor motion. The ITV, then, is generated using a CT dataset where motion 
control/management maneuvers are already successfully employed. This ITV can be expanded 
by the institution’s geometric set-up uncertainty (e.g., 4-5 mm) to generate the PTV.  
As an example of this process, an experienced RTOG institution employs the following 
steps to assess motion, manage motion, acquire image datasets, and generated targets for lung 
targets. First a motion study is done (using fluoroscopy) to determine if the GTV is moving more 
than 1.0 cm. If it is, abdominal compression is applied with coaching (e.g., urging the patient not 
to “push back” against the abdominal plate) until the GTV moves less than 1.0 cm (verified again 
on fluoroscopy). Then, with compression/coaching applied when necessary, a 4-D CT is done. 
The 4-D CT  at 2 mm slice spacing allows the site to generate an ITV using either by a 
reconstructed MIP or with the expiratory/inspiratory phase scans, but this is a motion managed 
ITV (not necessarily free breathing). The site confirms that this motion managed ITV generated 
by the 4DCT (as opposed to the fluoroscopy assessment) has limited GTV motion per protocol 
requirements. As the site treats in a stereotactic body frame, the validated institutional setup error 
is small. The site compares the mid amplitude GTV expanded by 0.5-1.0 cm PTV as required by 
protocol requirements to the ITV plus setup error to insure they are consistent. The resulting PTV 
is small yet contains tumor motion and all setup errors. 
4.5.3 
Dosimetry 
 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom 
designed for each lesion to deliver highly conformal prescription dose distributions. Non-
opposing, non-coplanar beams are preferable. Typically, ≥ 10 static beams of radiation will be 
used with roughly equal weighting. Generally, more beams are used for larger lesion sizes. When 
static beams are used, a minimum of seven non-opposing beams should be used. For arc 
rotation techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized. For 
this protocol, when using a gantry mounted linear accelerator, the isocenter is defined as the 
common point of gantry and couch rotation for the treatment unit. For other types of treatment 
units (e.g., Tomotherapy or CyberKnife), a reference point in space that is typically positioned at 
the center of the target is used instead of a mechanical isocenter. For non-IMRT or dose painting 
techniques, the conformal field aperture size and shape should correspond nearly identically to 
the projection of the PTV along a beam’s eye view (i.e., no additional “margin” for dose buildup at 
the edges of the blocks or MLC jaws beyond the PTV). The only exception will be when observing 
the minimum field dimension of 3 cm when treating small lesions (see above). As such, 
prescription lines covering the PTV will typically be the 60-90% line (rather than 95-100% as is 
common with conventional radiotherapy).  Higher isodoses (hotspots) must be manipulated to 
occur within the target and not in adjacent normal tissue. The stereotactic reference point 
(corresponding to the mechanical isocenter for gantry mounted treatment units) will be 
determined from system fiducials (or directly from the tumor) and translated to the treatment 
record.  
In contrast to conventional radiotherapy planning, there is no inherent desire or intent for 
achieving dose homogeneity within a target for an SABR treatment plan.  Rather than prioritizing 
target dose homogeneity, SABR treatment planning prioritizes adequate minimum target 
coverage and rapid dose fall-off gradients outside of the target.  Hot spots within targets 
(inhomogeneity) are generally accepted without consequence since targets are mostly tumor.  In 
the case, however, of a PTV intersection with an adjacent serially functioning named normal 
structure (e.g., the esophagus), measures will be taken to avoid hot spots specifically in the 
intersecting normal structures as will be described in later sections. 
4.5.3.1 
Normalization 
The treatment dose plan for each lesion treated will be made up of multiple static beams 
or arcs as described above. For both IMRT and CyberKnife treatments, the apertures are 
determined by inverse treatment planning. The plan should be normalized to a defined point 
corresponding closely to the center-of-mass of the PTV (COMPTV). This normalization is used to 

___________________________122013-030_______________________________________ 
Page 19 of 59 
select the isodose surface surrounding the target (see below where the exact coverage is stated 
as 95% of the PTV). Typically, in the case of the gantry mounted treatment units, this point will be 
the isocenter of the beam rotation; however, it is not a protocol requirement for this point to be the 
isocenter. For treatment units that do not have a mechanical isocenter, the center-of-mass of the 
PTV should be used.  
Regardless of the treatment unit type, the point identified as COMPTV must have defined 
stereotactic coordinates and must receive 100% of the normalized dose. Because the beam 
apertures for the 3D-CRT approach coincide nearly directly with the edge of the PTV (little or no 
added margin), the external border of the PTV will be covered by a lower isodose surface than 
usually used in conventional radiotherapy planning, typically around 80% but ranging from 60-
90%. For the treatment techniques that use inverse planning algorithms, this same isodose 
coverage must be achieved. The prescription dose will be delivered to the margin of the PTV (as 
defined below) and fulfill the requirements below. As such, a “hotspot” will exist within the PTV 
centrally at the COMPTV with a magnitude of the prescription dose times the reciprocal of the 
chosen prescription isodose line (i.e., 60-90%). 
4.5.3.2 
Tissue Density Correction (Tissue Heterogeneity) 
 
For purposes of dose planning and calculation of monitor units for actual 
treatment, approved corrections for tissue heterogeneity must be used. Examples of appropriate 
tissue density heterogeneity correction algorithms include properly commissioned 
superposition/convolution (collapsed cone), AAA, and Monte Carlo. Simple pencil beam and 
Clarkson algorithms that account for attenuation but not scatter will not be allowed. 
4.5.3.3 
Composite Planning Dosimetry 
 
While a successful strategy of iterative treatment planning on a per lesion basis is 
typically carried out in practice when optimizing dosimetry, overall treatment appropriateness and 
compliance will be judged based on the composite treatment plan summarizing the effects of all 
beams to all lesions treated simultaneously in absolute (not percentage) dose.  This is required 
even if different lesions are treated on different days.  Only composite plans will be submitted for 
quality assurance.  An exemption will be if large (more than 40 cm) cranio-caudal distances 
separate two adjacent lesions where scanning a common dataset for planning might be 
problematic (e.g., tube over-heating).  In this case, two separate planning data sets will be 
submitted without a composite plan. 
 
4.5.3.4 
Successful Treatment Planning 
Successful treatment planning for each lesion treated will require accomplishment of all 7 of the 
following criteria:  
1. Normalization  
The treatment plan should be normalized such that 100% corresponds to the center of mass of 
the PTV (COMPTV) receiving the highest dose on protocol.  
2. Prescription Isodose Surface Coverage  
The prescription isodose surface will be chosen such that 95% of the target volume (PTV) is 
conformally covered by the prescription isodose surface selected for that lesion and 99% of the 
target volume (PTV) receives a minimum of 90% of the prescription dose selected for that lesion.  
3. Target Dose Heterogeneity  
The prescription isodose surface selected in number 2 (above) must be ≥ 60% of the dose at the 
center of mass of the PTV (COMPTV) and ≤ 90% of the dose at the center of mass of the PTV 
(COMPTV). The COMPTV corresponds to the normalization point (100%) of the plan as noted in 
number 1 above.  
4. High Dose Spillage  
a) Location: Any dose > 105% of the prescription dose selected for that lesion should occur 
primarily within the PTV itself and not within the normal tissues outside the PTV. In addition for 
the PTV receiving the highest dose in the plan, the cumulative volume of all tissue outside the 
PTV receiving a dose > 105% of the highest prescription dose should be no more than 15% of 

___________________________122013-030_______________________________________ 
Page 20 of 59 
the size of the PTV volume receiving the highest dose.  
b) Volume: Conformality of PTV coverage will be judged such that the ratio of the volume of the 
prescription isodose meeting criteria 1 through 4 to the volume of the PTV is ideally < 1.2. These 
criteria will not be required to be met in treating very small tumors (< 2.0 cm axial GTV dimension 
or < 1.0 cm craniocaudal GTV dimension) in which the required minimum field size of 3.0 cm 
results in the inability to meet a conformality ratio of 1.2.  
5. Intermediate Dose Spillage  
The falloff gradient beyond the each PTV extending into normal tissue structures must be rapid in 
all directions and meet the following criteria:  
a) Location: The maximum total dose over all 3 fractions in Gray (Gy) to any point 2 cm or greater 
away from the PTV in any direction must be no greater than D2cm where D2cm is given by the 
tables below.  
b) Volume: The ratio of the volume of the 50% isodose volume (50% of the prescription dose for 
the treated lesion) to the volume of the PTV must be no greater than R50% where R50% is given 
by the table below.  
Ratio of 50%   
Isodose Volume  
to the PTV, R50%  
Maximum Dose at 
2 cm from PTV 
in any direction as % of 
prescribed dose (PxD). 
D2cm (Gy) = % x PxD 
PTV 
Volum
e 
(cc) 
Deviation 
Deviation 
non
e 
acceptabl
e 
none 
acceptabl
e 
<5.9 
<7.5 
<50.
0 
<57.0 
1.8 
<5.5 
<6.5 
<50.
0 
<57.0 
3.8 
<5.1 
<6.0 
<50.
0 
<58.0 
7.4 
<4.7 
<5.8 
<50.
0 
<58.0 
13.2 
<4.5 
<5.5 
<54.
0 
<63.0 
22.0 
<4.3 
<5.3 
<58.
0 
<68.0 
34.0 
<4.0 
<5.0 
<62.
0 
<77.0 
50.0 
<3.5 
<4.8 
<66.
0 
<86.0 
70.0 
<3.3 
<4.4 
<70.
0 
<89.0 
95.0 
<3.1 
<4.0 
<73.
0 
<91.0 
126.0 
<2.9 
<3.7 
<77.
0 
<94.0 
163.0 
Note 1: For values of PTV dimension or volume not specified, linear interpolation between table 
entries is required.  
Note 2: Institutions are encouraged to stay within the values listed as “none” in the table above so 
that the treatment plan is considered to be per protocol. It is recognized that some treatment 
planning situations might be more challenging and fall outside these limits, so staying within the 
values listed as “acceptable” is also permitted. Protocol deviations greater than listed here as 
“acceptable” will be classified as “unacceptable” for protocol compliance. 
Note 3:  For tumors within 2 cm of the skin, it may be difficult to meet the values for D2cm and 
R50.  In these cases, these criteria will not be used. 
 

___________________________122013-030_______________________________________ 
Page 21 of 59 
6. Adherence to Critical Organ Dose-Volume Limits  
Attempts should be made to meet or be better than the normal tissue constraints listed below 
while observing the treatment planning priorities listed in Section 5.7. 
7. Conducting planning with respect to the planning priorities (Section 5.7)   
 
4.6 
Planning Priorities 
4.6.1 
Overall Strategies 
Successful treatment planning criteria are listed in the previous section. In general, 
attempts should be made to successfully satisfy all of the criteria without deviation. In some 
circumstances, improvements can be made to the dosimetry plan beyond simply meeting the 
specified goals. In other circumstances, clinicians are faced with the prospect of not ideally 
meeting one or more of the criteria (i.e., accepting an acceptable deviation). In this section, we 
provide priorities in which a most ideal plan for protocol purposes is realized. Suggested priority 
of planning goals in order of importance is:  
1. Respect spinal cord, cauda equine and sacral plexus dose constraints.  
2. Meet dose “compactness” constraints including the prescription isodose surface 
coverage, high dose spillage (location and volume), and intermediate dose spillage (D2cm, and 
R50) as these define the “essence” of SABR.  
3. Meet critical structure constraints other than those listed in 1.  
The organ constraints are last in priority (except for nervous system tolerance), because 
they are the least validated. The “essence” of a stereotactic plan is captured mostly in the dose 
compactness justifying their higher priority. As an example in a case where not all goals can be 
met, it would be suggested to meet dose compactness goals without deviation even at the 
expense of a non-spinal cord normal tissue having acceptable deviation. Unacceptable deviations 
should be avoided in all cases. Again, these are suggested planning priorities and clinicians must 
use their judgment and experience in actual treatment given the variability of patient presentation 
and tolerance.  
As an example, in some cases a target abuts a normal tissue structure with an assigned 
constraint. Obviously, it would be impossible to utilize the required expansions, treat to 54 Gy 
PTV dose, and also meet the normal tissues maximum dose constraint. With the exception of the 
spinal cord, the protocol allows an “acceptable” deviation such that the abutting normal tissue is 
allowed a maximum point dose of 105% of the prescription dose; however, the volume constraint 
must still be respected. As such, the dosimetry might be manipulated by falloff dose polarization 
so that the compactness criteria are met with an “acceptable” deviation of normal tissue 
constraints. 
4.6.2 
Specific Strategies 
Tumors very near or abutting serially functioning normal structures (e.g., esophagus, 
great vessels, etc.) make it difficult to meet normal tissue constraints while giving compliant target 
dose coverage.  PTV expansions may cross into adjacent normal tissues confounding the ability 
to respect the constraint.  The planning priorities listed in the previous section must be respected.  
In cases where a higher priority takes precedence over a normal tissue constraint, attempts 
should non-the-less be made to spare as much high and intermediate dose to the normal tissue 
as possible.  Specifically, since the prescription dose in each arms is only required to cover 95% 
of the PTV volume, the 5% not fully covered by the prescription dose can be purposefully 
manipulate to anatomically occur in the vicinity of a critical normal structure or in the portion of a 
PTV/normal tissue overlap.  While 90% of the prescription dose must still cover the target, this 
allows the planner to at least lower the maximum dose to the adjacent structure to around 90% of 
the prescription dose with corresponding lowering of dose fall-off as well.  This strategy potentially 
used for non-spinal cord serial tissues is depicted in the following figure (note:  respecting the 
spinal cord constraints takes precedence over all priorities). 
 

___________________________122013-030_______________________________________ 
Page 22 of 59 
 
 
 
 
 
4.7 
Critical Structures 
4.7.1 
Critical Structure Dose-Volume Limits 
The following tables list dose limits to a point or volume within several critical 
organs/tissues for a variety of total fractions. For the spinal cord, these are absolute limits, 
and treatment delivery that exceeds these limits will constitute a major protocol violation. 
For the non-spinal cord tissues, acceptable deviation allows a maximum point dose no more than 
105% of the prescription dose for structures within 1 cm of a PTV target while fully respecting the 
defined volume constraint (for serial tissues) OR exceeding the parallel tissue critical volume 
dose maximum by no more than 5%. Unacceptable deviation exceeds the volume constraint for 
serial tissues, exceeds the maximum point dose for serial tissues by more than 105% of the 
prescription dose, or exceeds the parallel tissue critical volume dose maximum by more than 5%.  
The normal tissue constraints listed in the following table list total dose for a specified 
total number of fractions. Participating centers are encouraged to observe prudent treatment 
planning principles in avoiding unnecessary radiation exposure to critical normal structures 
irrespective of these limits. 
 
Three Fractions 
 
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord  
<0.35 cc 
<1.2 cc 
15.9 Gy 
13 Gy 
22.5 Gy 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
neuropathy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
stenosis/fistula 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 

___________________________122013-030_______________________________________ 
Page 23 of 59 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
colitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Renal hilum/vascular 
trunk 
15 cc 
19.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Pneumonitis 
Liver 
700 cc 
17.1 Gy 
 
Basic Liver Function 
Renal cortex (Right & 
Left) 
200 cc 
15 Gy 
 
Basic renal function 
 
 
 
 
 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Four Fractions  
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord  
<0.35 cc 
<1.2 cc 
18 Gy 
14.6 Gy 
25.6 Gy 
myelitis 
Cauda Equina 
<5 cc 
26 Gy 
28.8 Gy 
neuritis 
Sacral Plexus 
<5 cc 
26 Gy 
28 Gy 
neuropathy 
Esophagus* 
<5 cc 
18.8 Gy 
30 Gy 
stenosis/fistula 
Heart/Pericardium 
<15 cc 
28 Gy 
34 Gy 
pericarditis 
Great vessels 
<10 cc 
43 Gy 
49 Gy 
aneurysm 
Rib 
<5 cc 
43 Gy 
54 Gy 
Pain or fracture 
Skin 
<10 cc 
33.6 Gy 
36 Gy 
ulceration 
Stomach 
<5 cc 
25 Gy 
33.2 Gy 
ulceration/fistula 
Bile duct 
 
 
38.4 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
17.2 Gy 
14 Gy 
24.4 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
18.8 Gy 
30 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
26 Gy 
37.2 Gy 
colitis/fistula 
Ureter 
 
 
43 Gy 
stenosis 
Renal hilum/vascular 
trunk 
15 cc 
21.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
11.6 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
12.4 Gy 
V-13Gy<37% 
Pneumonitis 
Liver 
700 cc 
19.2 Gy 
 
Basic Liver Function 

___________________________122013-030_______________________________________ 
Page 24 of 59 
Renal cortex (Right & 
Left) 
200 cc 
17 Gy 
 
Basic renal function 
 
 
 
 
 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Five Fractions  
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord  
<0.35 cc 
<1.2 cc 
22 Gy 
15.6 Gy 
28 Gy 
myelitis 
Cauda Equina 
<5 cc 
30 Gy 
31.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
30 Gy 
32 Gy 
neuropathy 
Esophagus* 
<5 cc 
19.5 Gy 
35 Gy 
stenosis/fistula 
Heart/Pericardium 
<15 cc 
32 Gy 
38 Gy 
pericarditis 
Great vessels 
<10 cc 
47 Gy 
53 Gy 
aneurysm 
Rib 
<5 cc 
45 Gy 
57 Gy 
Pain or fracture 
Skin 
<10 cc 
36.5 Gy 
38.5 Gy 
ulceration 
Stomach 
<5cc 
26.5 Gy 
35 Gy 
ulceration/fistula 
Bile duct 
 
 
41 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
18.5 Gy 
14.5 Gy 
26 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
20 Gy 
32 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
28.5 Gy 
40 Gy 
colitis/fistula 
Ureter 
 
 
45 Gy 
stenosis 
Renal hilum/vascular 
trunk 
15 cc 
23 Gy  
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
12.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
13.5 Gy 
V-13.5Gy<37% 
Pneumonitis 
Liver 
700 cc 
21 Gy 
 
Basic Liver Function 
Renal cortex (Right & 
Left) 
200 cc 
18 Gy 
 
Basic renal function 
 
 
 
 
 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
4.7.2 
Contouring of Critical Structures 
 
Critical structure contours will be drawn in axial planes of the primary planning dataset.  
In general, critical structures should be contoured if they are found within an axial slice within 10 
cm in the craniocaudal direction of any PTV slice treated on protocol.  As such, they may be 
further than 10 cm direct separation and still required to be contoured.  If a named critical 
structure is further than 10 cm from any PTV, then it need not be contoured or submitted. 
 
Spinal Cord  
The spinal cord will be contoured based on the bony limits of the spinal canal. The spinal cord 
should be contoured starting at least 10 cm above the superior extent of any PTV and continuing 
on every CT slice to at least 10 below the inferior extent of any PTV. NOTE: For the spinal cord, 
constraints are absolute limits, and treatment delivery that exceeds defined limits will 
constitute a major protocol violation.  

___________________________122013-030_______________________________________ 
Page 25 of 59 
 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2) include the entire spinal canal 
into the sacrum to the filum. 
Esophagus  
The esophagus will be contoured using mediastinal windowing on CT to correspond to the 
mucosal, submucosa, and all muscular layers out to the fatty adventitia. The esophagus should 
be contoured starting at least 10 cm above the superior extent of any PTV and continuing on 
every CT slice to at least 10 below the inferior extent of any PTV.  
 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing of 
the nerves at the obturator internus muscle. 
 
Heart  
The heart will be contoured along with the pericardial sac. The superior aspect (or base) for 
purposes of contouring will begin at the level of the inferior aspect of the aortic arch (aorto-
pulmonary window) and extend inferiorly to the apex of the heart.  
 
Whole Lung  
Both the right and left lungs should be contoured as one structure. Contouring should be carried 
out using pulmonary windows. All inflated and collapsed lung should be contoured; however, 
gross tumor (GTV) and trachea/ipsilateral bronchus as defined above should not be included in 
this structure.  
 
PTV + 2 cm  
As part of the QA requirements for “low dose spillage” listed above, a maximum dose to any point 
2 cm away in any direction is to be determined (D2cm). To facilitate this QA requirement, an 
artificial structure 2 cm larger in all directions from the PTV is required. Most treatment planning 
systems have automatic contouring features that will generate this structure without prohibitive 
effort at the time of treatment planning. If possible this structure should be constructed as a single 
contour that is 2 cm larger than the PTV.  
 
Skin  
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of uniform 
thickness (0.5 cm) which envelopes the entire body in the axial planes. The cranial and caudal 
surface of the superior and inferior limits of the planning CT should not be contoured as skin 
unless skin is actually present in these locations (e.g., the scalp on the top of the head).  
 
Rib  
Ribs within 5 cm of the PTV should be contoured by outlining the bone and marrow. Typically, 
several portions of adjacent ribs will be contoured as one structure. Adjacent ribs, however, 
should not be contoured in a contiguous fashion (i.e., do not include the inter-costal space as part 
of the ribs).  
 
Stomach 
The entire stomach and its contents should be contoured as a single structure as a continuation 
of the esophagus and ending at the first part of the duodenum. 
 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as one 
structure beginning where the stomach ends and finishing as the superior mesenteric artery 
crosses over the third part of the duodenum. 
 
Jejunum/Ileum 
As a conglomerate of bowel loops within the abdomen distinguished from stomach, duodenum, 

___________________________122013-030_______________________________________ 
Page 26 of 59 
and colorectum. 
 
Colon 
From the ileocecal area to include the ascending, transverse, descending and sigmoid colon as 
one structure. 
 
Renal Hilum 
The collecting system of calyces within the kidney to the pelvis of the kidney and proximal ureters 
 
Renal Cortex (right and left combined as one) 
Specifically, the parallel functioning nephrons of the renal cortices of the kidneys (not the hilum). 
 
Liver 
The entire liver minus the GTV targets. 
 
Bile ducts 
May use the portal vein from its juncture with the splenic vein to it’s right and left birfurcation in 
the liver as a surrogate to identify the bile ducts. 
 
Other Structures  
The constraints tables above contain other structures. These are required if the structure is within 
10 cm of the PTV. 
 
4.8 
SABR Compliance 
4.8.1 
Dosimetry Compliance 
RT treatment plans not meeting the “per protocol” criteria or scored as “variation 
acceptable” will be classified as “deviation unacceptable.” Normal tissue dose constraints are 
listed above. NOTE: For the spinal cord, these are absolute limits, and treatment delivery 
that exceeds these limits will constitute a major protocol violation. For the non-spinal cord 
tissues, acceptable deviation following the planning priorities allows a maximum point dose no 
more than 105% of the prescription dose while fully respecting the defined volume constraint (for 
serial tissues) OR exceeding the parallel tissue critical volume dose maximum by no more than 
5%. Unacceptable deviation exceeds the volume constraint for serial tissues, exceeds the 
maximum point dose for serial tissues by more than 105% of the prescription dose, or exceeds 
the parallel tissue critical volume dose maximum by more than 5%. 
4.8.2 
Contouring Compliance 
Accurate and appropriate contouring is essential for the generation of dose volume statistics. In addition, 
it is the desire of the investigator to compile a comprehensive database of dose volume information 
coupled with outcomes data (control/toxicity) in order to define accurate dose response effects. As such, 
we require that the tumor targets and normal tissues in the vicinity be contoured in all patients. In 
particular, any structure listed with a constraint in Critical Structures and residing within 10 cm in any 
direction from the PTV must be contoured. Appropriateness of contouring will be scored by the study PIs 
as either no deviation, minor deviation, or major deviation. 
4.9 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events table 
(See section 5.4). Toxicity will be assessed according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE), version 4.0 and RTOG/EORTC acute and late toxicity criteria as 
described in http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx and in 
Appendix B and C. Dose adjustments should be made according to the system showing the 
greatest degree of toxicity.  

___________________________122013-030_______________________________________ 
Page 27 of 59 
4.10 
Duration of Therapy 
No more than three SABR fractions will be delivered per week. Therefore the treatment duration will be 
between 2-3 weeks depending on the fractionation scheme chosen. 
4.11 
Duration of Follow Up 
Subjects will be followed for 2-5 years with MRI scans every 6 months for the first year 
and if there is no growth then every six months subsequently; if there is evidence of growth, 
frequency will be determined by physician.  
4.12 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date the 
subject was removed in the Case Report Form. The subject should be followed-up per protocol.   
4.13 
Subject Replacement 
The following are criteria for subject replacement: 1) If the subjects decide to withdraw 
from the study without finishing the course of SABR, 2) if the subjects decide to withdraw from the 
study or lost to follow up (for reasons of death from other causes, moving to other state etc.) or 
refuse follow up scans leading to <3 follow-up scans or <1 year of follow up, 3) if the subjects 
become unable to undergo an MRI or contrast enhanced CT scan with <1 year of follow up. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within two months prior to registration 
unless otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections, history of previous 
cancers, history of previous radiation, family history of cancers. 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry according to ECOG 
performance scale.  

___________________________122013-030_______________________________________ 
Page 28 of 59 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed prior to the beginning of treatment See 
section 7.0 for Adverse Event monitoring and reporting. 
5.1.9 Hematology 
CBC with differential 
5.1.10 Blood draw for correlative studies 
See Section 8.0 for details. 
5.1.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, BUN, creatinine, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, 
phosphate and calcium. 
5.1.12 
Urine analysis 
Urine analysis including RBC, WBC, protein, creatinine, protein to creatinine 
ratio. 
5.1.13 
Pregnancy test (for females of child bearing potential)  
Standard urine pregnancy test will be used to rule out pregnancy  
5.1.14 
Biopsy of Renal lesion 
5.1.14.1 Pre-treatment biopsy: 
A CT-guided biopsy of a tumor lesion will be performed prior to study 
registration, unless previous biopsy of the same lesion is performed within 
the last one year exists and a review of slides shows it to be adequate, in 
which case a pretreatment biopsy is optional.  
5.1.14.2 Post-treatment biopsy: 
A post-treatment biopsy will be performed at one year post treatment 
regardless of whether clinical indication (tumor growth >4mm, 
enhancement, etc.) is present or not.  
5.1.15 
Tumor assessment 
Tumor assessment will be performed using MRI with (preferred) or without 
contrast, or contrast enhanced CT. A growth of >2mm of tumor size within one 
year period must be demonstrated to meet be eligible for this study.  
5.1.16 
Kidney function assessment: 
Kidney perfusion assed by Renal scinctigraphy scan performed at baseline and 
at one year post treatment.  
5.2 
Procedures during Treatment 
SABR treatment will be delivered either in three, four or five fractions.  For a given lesion 
(target), a minimum of 40 hours and a maximum of 8 days should separate consecutive 
treatments.   All treatment must be completed within 21 days. 
 
5.2.1 
Prior to starting first SABR treatment: Baseline assessment is sufficient 
and need not be repeated if done within the past two months  
 Physical exam, vital signs 

___________________________122013-030_______________________________________ 
Page 29 of 59 
5.2.2 
Day 1 
 First fraction of SABR 
 Correlative Blood draw 1-2 hours after first SABR fraction only (see section 8). 
5.2.3 
4 weeks (+/-1 week) after treatment termination 
 Physical Exam: including: medical history and vital signs 
 Hematology 
 Serum chemistries 
 Lab corollary blood draw 
 Urine Analysis 
 Performance status 
 Toxicity evaluation 
5.3 
Follow-up Procedures 
Subject will be followed at every six months (+/- 2 weeks) thereafter for five years after 
their first follow up at 1 month (+/- 1 week).  
With every visit, patients will have: 
 
Physical exam including: vital signs, weight, height and BMI 
 
MRI with or without contrast or CT with contrast 
 
Renal scinctgraphy scan at 1 year 
 
Hematology 
 
Serum Chemistries 
 
Urine Analysis 
 
Lab corollary blood draw at 1 month and six month 
 
Performance status 
 
Toxicity evaluation 
 
Tumor measurements 
*Note: Subjects who show progressive disease or develop a new primary will be followed 
for survival only and will no longer strictly adhere to study calendar.   
5.4 
Time and Events Table  
 
 
 
 
Pre-study 
Within 2 
months 
prior to  
registration 
Day 1 
First 
SABR 
At One 
month (+/- 
1 week) 
q6 Months 
(+/- 2 
weeks)  
At one 
year (+/- 
2 weeks)  
Assessment 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Diagnostic/ 
Pre-
treatment 
Renal 
Bx 
X 
 
 
 
 
Post-treatment 
Renal Bx 
 
 
 
 
X 
Physical Exam 
X 
X 
X 
X 
 
Performance 
Status 
X 
 
X 
X 
 
Toxicity 
Evaluations 
 
 
X 
X 
 
Tumor 
Measurements 
X 
 
 
X 
 

___________________________122013-030_______________________________________ 
Page 30 of 59 
Chemistry 
X 
 
X 
X 
 
CBC 
X 
 
X 
X 
 
Correlative Labs 
X 
X* 
X* 
X* 
 
Urine Analysis 
X 
 
X 
X 
 
MRI or CT 
X 
 
 
X 
 
Renal Scan 
X 
 
 
 
X 
*Correlative labs will be drawn at baseline, on first day of SABR (see section 8), at one month and 
at 6 month after SABR. 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (follow-up permitted) 
 
5.5.4.1 Tumor size >4cm 
 
5.5.4.2 Loco-regional progression as defined in AJCC 7; stage >T1a. 
5.5.5 
Subject experiences toxicity that makes continuation with the remaining SABR 
fractions unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event) prior to the completion of SABR treatments; 
5.5.8  
Subject becomes unable to undergo imaging studies after enrollment, subject will 
be either replaced or withdrawn from study based on investigator’s assessment; 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires systemic treatment which 
could interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 

___________________________122013-030_______________________________________ 
Page 31 of 59 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with SABR. 
 
Evaluable for objective response.  Only those subjects who have measurable or 
non-measurable disease present at baseline, have received ALL fractions of 
SABR and have had their disease re-evaluated with a minimum of one year of 
follow up will be considered evaluable for response. These subjects will have 
their response classified according to the definitions stated below.  
6.1.2 
Disease Parameters 
Measurable Disease: Tumor lesions: Must be accurately measured in at least 
one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of: 
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
2. 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable) 
3. 20 mm by chest x-ray. 
 
Non-measurable disease.  
All other lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
Target lesions. 
All measurable lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions. 
 
All measurable lesions should be recorded and measured at baseline.  A sum of 
the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the five target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 28 days before the beginning 
of the treatment planning session. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 

___________________________122013-030_______________________________________ 
Page 32 of 59 
 
Conventional CT with contrast:  These techniques should be performed with cuts 
of 1 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  
 
MRI: Will be performed with gadolinium if possible. These techniques should be 
performed with cuts of 1 mm or less in slice thickness contiguously.  
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Lesions 
Complete Response (CR): Disappearance of all target lesions.   
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm (the sum may not be “0” if there are target nodes).  Determined by 
two separate observations conducted not less than 4 weeks apart. There 
can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): > 20% increase in the SLD taking as 
reference the smallest SLD recorded since the treatment started (nadir) 
and minimum 5 mm increase over the nadir.   
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. There can be no unequivocal new 
lesions. 
 
Tumor Growth (TG):  At least a 4mm increase in the LD of treated lesion 
in a single scan when compared to baseline scan (or an increase of 
>2.0mm in two consecutive scans). 
 
Local Control: No TG AND a complete radiographic or pathologic 
absence of tumor viability.  
 
Local Failure: Any TG OR any radiographic or pathologic evidence of 
tumor viability. 
 
Indeterminate Disease Response: (IDR): 1) Presence of radiographic 
evidence of viable disease without any increase in the LD (<4mm) 
sufficient enough to qualify for TG; 2) complete absence of radiographic 
evidence of viable disease regardless of any change in tumor diameter. 
 
A biopsy is recommended in the case of tumors with ≥4mm increase in 
size with no radiographic evidence of viable tumor, OR any tumors with 
radiographic evidence of viable tissue. 
 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 

___________________________122013-030_______________________________________ 
Page 33 of 59 
 
Incomplete Response/Stable Disease (Non-CR/Non-PD): Persistence of 
one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The subject’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Time point response: patients with target (+/– non-target) disease. 
Target lesions 
Non-target lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease, PR = 
partial response, SD = stable disease. 
 
Time point response: patients with non-target disease only. 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive 
disease 
A ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can 
be measured is not advised. 
 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 

___________________________122013-030_______________________________________ 
Page 34 of 59 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
6.2 
Pathologic Response: 
The pathologic response is evaluated by a required 1-year post-treatment biopsy where the tumor 
viability must be confirmed on FFPE tissue with appropriate staining (Ki67, PHH3, mitotic index 
etc.) showing continued tumor proliferation as compared to pre-treatment biopsy tissue.  
6.3 
Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one fraction of 
radiation of study intervention. The study will use the CTCAE version 4.0 for reporting of 
non-hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified 
criteria for hematologic adverse events (Appendix #/letter). 
7.0 
ADVERSE EVENTS 
7.1 
SABR 
The contraindications and adverse events for SABR are mostly related to the location of 
the SRM in relation to renal pelvis and its distance from loops of small bowel which is the 
most radio-sensitive organ nearby. The allowed radiation dose constraints of the kidney, 
small bowel and all the other nearby organs are discussed in detail in section 4.1 
7.1.1 
Contraindications: None  
7.1.2 
Special Warnings and Precautions for Use: N/A 
7.1.3 
Interaction with other medications: None 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject  
safety and care. 
 
All subjects experiencing an adverse event, regardless of its relationship to study 
intervention, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 

___________________________122013-030_______________________________________ 
Page 35 of 59 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study intervention for the 
changes observed; or 
 death. 
 
7.2.1 
Definition 
An adverse event is defined as any untoward or unfavorable medical occurrence 
in a human research study participant, including any abnormal sign (for example, 
abnormal physical exam, imaging finding or clinically significant laboratory 
finding), symptom, clinical event, or disease, temporarily associated with the 
subject’s participation in the research, whether or not it is considered related to 
the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they can occur in the 
context of social and behavioral research. Adverse events may be expected or unexpected. Acute Adverse 
Events 
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. Adverse events occurring through 
the time period of the start of treatment through the first follow up occurring 12 weeks 
post treatment will be considered acute adverse events.  All acute adverse events will be 
assessed and reported as per below. 
 
Late Adverse Events  
Adverse effects occurring in the time period from the end of acute monitoring, to 3 years 
post treatment for progression or death (whichever comes first), will be defined as late 
adverse events. These events will include all adverse events reported directly to a 
member of the study team and will be captured, assessed, graded and reported as 
appropriate.  
In addition, the study team will review encounters in a select specialty category relevant to 
study endpoints. These select specialties include hospitalizations, medical oncology, and 
radiation oncology records and will be limited in scope based on categorization of events 
(GU/GI) and also the type of records that will be queried (hospitalizations, medical 
oncology, and radiation oncology).  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
 

___________________________122013-030_______________________________________ 
Page 36 of 59 
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is 
available at http://ctep.cancer.gov/reporting/ctc.html 
Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse 
Event log according to the general guidelines provided by the NCI CTCAE and as 
outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
7.2.2 
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient 
hospital stay equal to or greater than 24 hours. Hospitalization is used as an 
indicator of the seriousness of the adverse event and should only be used for 
situations where the AE truly fits this definition and NOT for hospitalizations 
associated with less serious events. For example: a hospital visit where a patient 
is admitted for observation or minor treatment (e.g. hydration) and released in less 
than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is not an 
AE and therefore is not to be reported either as a routine AE or in an expedited 
report.Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 

___________________________122013-030_______________________________________ 
Page 37 of 59 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
AND 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
AND 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 

___________________________122013-030_______________________________________ 
Page 38 of 59 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
 
the radiation therapy known toxicities section of this protocol 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE/UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized when a sponsor form is unavailable and SAE 
submission to the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the DOT Manager or lead coordinator ensures that all 
participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon 
receipt from the DSMC Coordinator.  The DSMC Chairperson determines whether action 
is required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
The following instructions section may be modified as needed to ensure clear guidance 
for institutions participating in the trial who will not report directly to the UTSW Institutional 
Review Board. If needed, this reporting may be facilitated by the UTSW study team for 
example.  
Telephone reports to: 
(Investigator/study team: Insert names and phone numbers for required notifications) 
 
 
Written reports to: 
(Investigator/study team: Insert names, fax numbers, an addresses for required 
notifications)  
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 

___________________________122013-030_______________________________________ 
Page 39 of 59 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to 
their relying IRB according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
7.4 
Stopping Rules 
Interim analysis will be performed after enrollment of 6 patients. The stopping rules for 
study includes grade 3 acute toxicity in >30% of enrolled patients, and tumor 
progression/growth in >50% of enrolled patients.  
 
 
8.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to measure the induced immune 
response to patient’s pre-treatment tumor tissue antigens (see section 1.5 for detail).  In addition, 

___________________________122013-030_______________________________________ 
Page 40 of 59 
the correlative studies will evaluate the immune response generated by the regiment. The 
submission of collected whole blood before, during and post treatment as indicated in Section 5 is 
mandatory and will be performed at baseline, during RT (1-2 hours after first SABR fraction), at 4 
weeks and at 24 weeks. A CT-guided biopsy of a tumor lesion will be performed prior to study 
registration, unless previous biopsy of the primary lesion is performed within the last one year 
exists and a review of slides shows it to be adequate, in which case a pretreatment biopsy is 
optional. The one year post-treatment biopsy will be processed the same way as the pre-
treatment biopsy.   
8.1 
Sample Collection Guidelines 
Samples will be labeled with the subject’s de-identified study number and collection date 
and delivered for analysis during regular business hours to: NC7: 208; Attn Dr. Raquibul 
Hannan. 
8.1.1 
Whole blood sample: Patient’s whole blood will be collected in EDTA (Lavender 
top) tubes for ~ 100 ml at baseline, at 4 weeks (+/- 1 week) and at six months 
starting from the first day of study registration for immunologic assays. In 
addition, 10 ml will be collected in anti-coagulant-free tubes (Red top) for the 
collection of sera.  The only exception is the blood collection one hour post first 
SABR fraction which will be for 20ml in EDTA and 20 ml in anti-coagulant-free 
tubes. The blood will immediately be processed (within 2 hours) by centrifugation 
(1000g, 15min, 4 oC), collecting the supernatant and freezing at -80 oC in 5 
aliquots for future experiments. The pellet will be re-suspended in PBS and 
PBMC will be isolated using standard protocol. Briefly, the cell suspension will be 
carefully placed on 10ml polystyrene tube containing 1ml ficoll and centrifuged 
(400g, 30min, RT).  Collect the PBMC region from the ficoll and washed 3x with 
PBS. Count and freeze cells in 5 aliquots with 10%DMSO 90%FBS in -80oC.  
8.1.2 
Renal mass biopsy sample:  An image-guided biopsy of tumor lesion consisting 
of 4-5 18G needle cores is recommended at the time of registration of the 
patients to the study.  A second biopsy at one year after the SABR treatments is 
required.  
8.1.2.1 
Initial required biopsy: 3-4 core biopsies will be processed as routine 
diagnostic specimens by Pathology for the purpose of diagnosis and 
Immumo-histochemistry (IHC). After on site adequacy check using touch 
imprint slides, the cores will be fixed in 10% buffered formalin for up to 8 
hours and processed routinely to obtain formalin fixed paraffin embedded 
blocks. Eight, 3-micron thick sections will be cut. The first and last 
sections will be stained with hematoxylin and eosin (H&E) stain to 
evaluate the presence, extent, and grade of renal carcinoma. The 
remaining sections will be used to perform immunohistochemical staining 
if needed. (see section 8.2.6 for IHC detail).  Two additional cores will 
be placed in normal saline on wet ice and brought to NC9.208 (Dr. 
Raquibul Hannan) for generation of tumor lysates to be used as a source 
of antigen in the immunoassays. The biopsy cores will be chopped into 
minute pieces. Small volume of normal saline is added and the mixture is 
passed through a 19G needle, attached to a 5 ml syringe, several times, 
until the passage of the mixture occurred without difficulty. The process 
is repeated with 21G, 23G, and if possible 25G needle. The entire 
mixture is placed in liquid nitrogen until frozen, and then thawed in a 
water bath at 42°C. The freezing and thawing is repeated for a total of 
five times. The sample is passed through another 23G or 25G needle to 
disperse any clumps. The sample is then centrifuged at high speed, the 

___________________________122013-030_______________________________________ 
Page 41 of 59 
supernatant collected, protein concentration measured using 
NanoDrop2000 and frozen at -80 oC in 5 aliquots. 
8.1.2.2 
One-year Biopsy: Processed same as initial biopsy.   
8.2 
Assay Methodology 
8.2.1 
Elispot: IFN-  ELISpot assays will be performed according to manufacturer’s 
protocol using a commercial ELISpot kit (MabTECH). Brieﬂy, 96 well plates are 
coated overnight with 0.015 mg/ml of an anti-human IFN-g monoclonal antibody.  
PBMC from patients will be incubated in triplicates wells and stimulated in the 
presence of either protein lysate from patient biopsy (50µg/ml) or 5 ng/ml PMA 
and 0.5 ng/ml ionomycin as positive control and albumin as negative control.  For 
ELISPOT assays, plates are incubated for 48 hours, washed, probed with 
biotinylated anti-IFNg, further washed, and then incubated with streptavidin 
alkaline phosphatase. Spot development is achieved with 5-bromo-4-chloro-3-
indolyl phosphate/nitroblue tetrazolium (BCIP/NBT; Invitrogen) and spots are 
enumerated by an automatic ELISpot reader. 
8.2.2 
ELISA: In this procedure, patient tumor tissue lysate is first adsorbed to an EIA 96 
well microplate (Fischer).  Patient plasma is then added to each well as a source 
of primary antibody and serially diluted.  After extensive washes, detection 
enzyme (HRP)-linked anti-human mAb is then added to each well and allowed to 
bind.  Appropriate substrate is then added to each well and color development 
occurs within 5-60 min.  UV Microplate Reader will be used to read the plates 
8.2.3 
3H-thymidine Proliferation Assay: PBMC from patients will be incubated in a 
similar manner as above for five days at 37 oC then overnight with 0.5 mCi tritiated 
3H-thymidine, harvested onto a glass-fiber filter using a 96-well FilterMate cell 
harvester. The radioactivity of the 3H-thymidine is detected by a direct betaplate 
counter. The degree of antigen-specific clonal T cell expansion will be expressed 
as a stimulation index (SI) of the ratio of 3H-thymidine incorporation by cells 
incubated with patient tumor lysate compared with media controls. An alternate 
method utilizing FACS analysis with carboxy fluorescein diacetate succinimidyl 
ester (CFSE) is also available [95]. 
8.2.4 
Chromium Release Cytotoxicity Assays: For cell-mediated cytotoxicity 
analysis, A 50 µl sample of 51Cr-labeled target cells (Caki-2 and ACHIN human 
renal cancer cells) is mixed with 100µl of effector cells (patient PBMC) at various 
target to effector ratio (E:T ratios). After centrifugation at 100 X G, the cells are 
incubated for 2 hr at 37°C. The radioactivity of culture supernatant is measured 
using a gamma counter and percentage of cytotoxicity is calculated. For antibody-
dependent cytotoxicity analysis this procedure will be performed with patient’s 
plasma instead of PBMC and the percentage of cytotoxicity is calculated in similar 
manner. An alternate and non-radioactive labeling method utilizes GAPDH 
enzyme release from lysed cells called Bioluminescence Non Radioactive 
Cytotoxicity Assay (aCella-TOX, T Cell Technology, INC) [96, 97]. 
8.2.5 
Flow cytometric analysis (FACS):  For FACS analysis of cell-surface molecules, 
the cell samples are stained with fluorescent dye – conjugated monoclonal 
antibodies against the selected markers on ice followed by fixation with 4% 
paraformaldahyde. Data are acquired on a LSRII (BD Biosciences) and analyzed 
using FACSDiva software (BD Biosciences). The PBMC of each patient before 
and after treatment will be analyzed to identify the relative sub-population of CTLs, 

___________________________122013-030_______________________________________ 
Page 42 of 59 
regulatory T-Cells, effector memory T cells, MDSCs, neutrophils and NK cells 
utilizing appropriate cell surface markers (see section 1.5).   
8.2.6 
Immunohistochemical staining (IHC): Standard immunohistochemistry staining 
procedure will be performed using the Benchmark XT automated stainer 
(Ventana) for both antibodies. Briefly, formalin-fixed, paraffin-embedded tissue 
sections will be cut at 3-4 micron and air-dried overnight. The sections will be 
deparaffinized, rehydrated, and subjected to heat-induced epitope retrieval. 
Sections will then be incubated with appropriate primary antibody. For signal 
detection, ultraView universal detection system (Ventana) will be used. The slides 
will be developed using 3-3’-diaminobenzidine chromogen and counterstained 
with hematoxylin. Appropriate positive and negative controls will be utilized for 
each run of immunostains.  The evaluation of the immunostaining will be carried 
out by a genitourinary pathologist without knowledge of any clinicopathologic data. 
Only nuclear reactivity will be considered positive. An H score will be assigned as 
the product of average intensity of staining (0 for negative, 1 for weakly positive, 2 
for moderately positive, and 3 for strongly positive) and extent of 
immunoexpression (0-100% percentage of cells staining). In addition,  Dual-
antibody ISH will be performed to identify and analyze TILs, CTL (CD3+,CD8+), 
Tregs (CD4+FoxP3), DC (CD11c) , NK/T (CD3+, CD1d), neutrophils (CD11b, 
Ly6G} and MDSC (CD14+,CD11b) in the tumor tissue before and after treatment, 
when available (see section 1.5). 
8.2.7 
Serum Cytokine Analysis: Multiplex cytokine analysis in patient’s plasma will be 
performed in precoated 96 well plates (Human TH1/TH2 10 plex ultrasensitive 
assay, Meso Scale Discovery – MSD, Maryland, USA) according to 
manufacturer’s instructions. 25 µL of diluent 2 is dispersed into each well. The 
plate is sealed and incubated by vigorous horizontal shaking for 30 minutes at RT. 
25 µL of the patient plasma is added per well and all samples measured in 
triplicates. Plates are sealed and incubated by vigorous horizontal shaking for two 
hours at RT. Plates are washed three times with 0.05% Tween 20 in PBS . 25 µL 
of 1× detection antibody solution is placed per well and sealed plates are 
incubated by vigorous horizontal shaking for two hours at RT. Plates are washed 
three times with 0.05% Tween 20 in PBS. 150 µL of 2× Read Buffer T is added to 
each well. Plates are analysed using the MSD SECTOR Imager 2400 and 
Discovery Workbench 3.0 software (both from Meso Scale Discovery, USA). The 
mean value of two wells is taken as the recorded reading, provided that the 
coefficient of variation (CV) was less than 10%. Concentrations recorded lower 
than the standard curve are kept as absolute values. For purposes of logarithmic 
analysis, readings of 0 are adjusted to 0.01 pg/ml.  The following cytokines will be 
measured before and after treatment for each patients: Th1/Th2/Th17 cytokines, 
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; pro-
inflammatory cytokines: GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, 
TNF-α; Chemokines: Eotaxin, MIP-1β, TARC, IP-10, IL-8, MCP-1, MCP-4 and 
others including IL-6, TGF-β and HMGB1 (see section 1.5). 
8.2.8 
Western-blot/Immuno-blot: Caki-2 and ACHIN human renal cancer cells lysate 
will be used to perform immune-blott using plasma collected from patients before 
and after treatment.  The Caki-2 and ACHIN cell 106 cells/mL will be lysed in 
immunoprecipitation assay buffer on ice for 30 min. Standard western blott 
methodology will be utilized. Briefly, 400 µg of protein will be separated using pre-
made gradient 4% to 12% Bis-Tris gels (Invitrogen, Burlington, ON, Canada) and 
transferred to nitrocellulose. Patient sera/plasma will be diluted 1/500 in Blotto 
(5% dry milk powder; 0.1% Tween 20; 50 mmol/L Tris; 150 mmol/L NaCl) and 
incubated with nitrocellulose membranes for 1 h at room temperature using a 
multichannel immuoblotting device (Mini Protean II Multiscreen, Bio-Rad, 

___________________________122013-030_______________________________________ 
Page 43 of 59 
Missassauga, ON, Canada). The membrane will then incubated for 1 h at room 
temperature with horseradish peroxidase–conjugated goat anti-human IgG (H+L; 
Jackson ImmunoResearch, West Grove, PA) diluted 1/10,000 in Blotto and 
visualized by enhanced chemiluminescence. 
8.2.9 
Gene expression analyses: The current Illumina whole genome DASL platform 
allows for the interrogation of over 29,000 genes based upon the RefSeq (Build 
36.2, release 38) database. This assay requires 50-200 ng of total RNA from 
archival FFPE samples or 10-100 ng total RNA from fresh frozen tissue. RNA will 
be isolated using the one column protocol from the Roche High Pure miRNA 
Paraffin Kit, which isolates total RNA, including miRNA. A 3mm x 10um section is 
sufficient to generate 200 ng total RNA from archival specimens. A cDNA pool is 
created using oligodT and random primers. The cDNA pool is interrogated using a 
paired 5’ and 3’ gene-specific 50-mer probes (annealing and selection) that also 
contain universal primer sequence. Probe extensions are ligated and then PCR 
amplified using the universal primer pairs. The PCR product is captured using 
standard Illumina bead technology and hybridized to the Illumina HT12 V4 chip 
and scanned. Expression values are highly reproducible (r2 > 0.97) and are similar 
to results by qPCR (r2 > 0.85). mRNA expression of specific genes by qRT-PCR 
will serve to validate DASL results as needed.Caki-2  
 
8.3 
BOLD/TOLD MRI  
The BOLD/TOLD MRI sequences will be added to the routine MRI sequences (T1, T2 
etc.) performed at baseline and at follow-up,  which may require additional time on the 
MRI table (~30minues), but will not require any additional infusions or intravenous 
contrast as described in literature previously [98, 99]. These additional sequences will be 
optional.  
8.4 
Tumor respiratory motion modeling 
 
Real-time optical surface monitoring data will be acquired from human patients with primary or 
metastatic kidney lesions during and after their 4DCT scan (standard-of-care at our institution). A 
patient-specific 4D model will be developed using the raw 4DCT projections time-correlated with 
real-time surface monitoring. In addition, before delivering each dose fraction, we will acquire 
three 15s kV fluoroscopic image acquisitions, time-correlated with optical surface monitoring. The 
acquisitions will be distributed over three well-spaced beam angles, e.g., every 4th angle for a 12-
field plan.  
 
The kV fluoro data will be used offline to update and validate the model as follows. The data 
acquired from the three beam angles will be used in a "missing-view" fashion, i.e., two of the 
three fluoro sequences will be used to update the model and the third will be used to validate the 
model. The ground truth will be the in-plane X-Y trajectories of features-of-interest obtained from 
kV fluoro. The model will be used to create 2D+t digitally reconstructed fluoroscopic series 
(DRFs) from the beam's eye view of each kV beam. The model will be validated by calculating 
the geometric error between the trajectories from the kV fluoro (ground truth) and those obtained 
from the corresponding DRFs.  
 
Surface monitoring procedure ―The procedure is expected to last approximately 15 minutes 
after the end of the 4DCT scan, which is the standard-of-care at our institution. The procedure will 
consist of real-time surface tracking using the VisionRT system of the thoracic and/or abdominal 
region. Continuous audiovisual contact will be maintained with the subject during scanning. Each 
individual will be informed that they can stop the procedure at any point. 
 

___________________________122013-030_______________________________________ 
Page 44 of 59 
Fluoroscopic imaging procedure ─ Fluoroscopic imaging will be performed in the treatment room 
with the patient lying in treatment position. Three 15s acquisitions will be performed under free 
breathing conditions, each from a different beam angle, using the on-board kV imager. Audiovisual 
contact will be maintained at all times with the patient.  
 
All surface monitoring will be performed using a surface photogrammetry system (VisionRT, 
London, UK) which uses visible light to monitor the motion of the surface. There are no known 
significant risks with this procedure at this time. This device and procedure is low-risk.  
 
For the fluoroscopic acquisition, we estimate that for three 15 s acquisitions, each at 10 
frames/s, 120 kVp, 40 mA, 10 ms, with 0.1 mGy/mAs, the total skin dose will be ~24 mGy ─ 
comparable to that from a kV cone-beam CT (CBCT) scan [100, 101]. Daily CBCT is standard-of-
care for patient localization for SBRT at UT Southwestern. No additional ionizing radiation, other 
than the kV fluoro and standard-of-care, will be administered to the patient as a result of this aspect 
of the study. 
 
8.5 
Specimen Banking 
Subject samples collected for this study will be retained at the department of pathology 
and at the lab of Dr. Hannan (NC7. 208). Specimens will be stored indefinitely or until 
they are used up. If future use is denied or withdrawn by the subject, best efforts will be 
made to stop any additional studies and to destroy the specimens. 
 
Raquibul Hannan will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of UTSW. Collaborators will be 
required to complete an agreement (a Material Transfer Agreement or recharge 
agreement) that states specimens will only be released for use in disclosed research. 
Any data obtained from the use of clinical specimen will be the property of UTSW for 
publication and any licensing agreement will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or 
commercial value. The Informed Consent form contains this information and informs the 
subject that there is the potential for financial gain by UTSW, the investigator or a 
collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided, 
among other, to research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is an open label single-arm phase II non-randomized prospective single arm study 
that treats a single SRM with SABR. The primary objective is local control of the SRMs. 
Local control is defined as less than 4mm increase in the longest diameter of tumor 
measured using either MRI or contrast enhanced CT scan and with no radiographic or 
pathologic evidence of viable tumor. The endpoint will be measured at a minimum follow 
up of one year. Secondary objections and endpoints explore the safety, toxicity, growth, 
growth rate, local failure, IDR, immune response and progression of the SRMs after 
SABR. 
 

___________________________122013-030_______________________________________ 
Page 45 of 59 
The stopping rules for this study include any treatment-related >grade 3 toxicity.  If there 
are any treatment related grade 3 acute toxicity in >30% of enrolled patients after 
enrollment of at least 6 patients, the study will be suspended until permitted by a safety 
review. 
9.2 
Sample Size and Accrual 
There is no reliable historic information on local control rate of SABR for primary RCC 
since the retrospective studies have used a wide range of SABR dose fractions and 
varying definitions of local failure. From the retrospective studies and one phase I trial, 
we found three local failures out of 34 patients (section 1.3). Thus, it is expected that the 
local control rate will be at least 90% in this trial. With a sample size of 16 patients, the 
standard error of local control rate will be at most 7.5% with a 95% confidence interval of 
15%, since the local control rate is expected to be at least 90%.  
 
A sample size of 16 patients in this single-arm phase II trial will have more than 90% 
power to detect the difference between 100% pre-treatment tumor growth and 50% post-
treatment tumor growth using a two-sided binomial test with a 0.05 significance level. 
With the sample size of 16 patients in this single-arm phase II trial, a single group t-test 
with a two-sided 0.10 significance level will have 80% power to detect the difference 
between a pre-treatment tumor growth rate of 0.4 cm/year and a post-treatment tumor 
growth rate of 0.16 cm/year (a 60% reduction), assuming that the standard deviation is 
0.36 cm/year. The power calculations were conducted using the software PASS 12.  
9.3 
Data Analyses Plans 
The local control rate and the proportion of patients whose tumors did not grow will be 
estimated along with the corresponding 95% confidence interval using the exact binomial 
method. The frequency of the adverse events associated with the administration of SABR 
to SRMs will be computed. Descriptive statistics such as mean, range, and 95% 
confidence interval will be computed for the growth rate of SRMs after SABR treatment, 
and the changes in kidney function, creatinine levels, renal perfusion and GFR after 
SABR treatment. Descriptive statistics will be also computed for radiographic changes of 
the SRM after SABR treatment, including tumor viability, %enhancement, necrosis, T2 
signal, and tumor cellularity with diffusion-weighted imaging.  
 
Kaplan-Meier method will be used to estimate the time to progression (TTP) of disease 
from the first SABR treatment, progression free survival (PFS), and overall survival (OS). 
Exploratory data analysis will be conducted to assess the cytokine changes brought on 
by SABR to SRM and to evaluate generation of any immune response specific to tumor 
cells.  
 
We will compute the following characteristics of CT and MRI acquired prior to the 
treatment and follow-up scan: intensity features such as minimum, maximum, mean, 
standard deviation, median, skewness, kurtosis; texture features such as energy, 
entropy, correlation, inertia, cluster shade; geometry features such as volume, major axis 
length, minor axis length, eccentricity, elongation, roundness. The ability of each feature 
to predict treatment response will be quantified by the area under the receiver operating 
characteristic curve (AUC). An AUC of<0.7 will be considered to have low accuracy, 0.7-
0.9 to have moderate accuracy, and >0.9 to have high accuracy.   
 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
 

___________________________122013-030_______________________________________ 
Page 46 of 59 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
10.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office, Department of Radiation Oncology, UTSW. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federal wide Assurance letter 
 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if institution} holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
10.4 
Registration Procedures 
All subjects must be registered with the Clinical Research Office, Department of 
Radiation Oncology, UTSW, before enrollment to study. Prior to registration, eligibility 
criteria must be confirmed with the Clinical research office Study Coordinator.  
10.5 
Data Management and Monitoring/Auditing 
The monitoring activities are designed to provide safety monitoring, data quality 
assurance, and oversight of protocols for study progress. The Radiation Oncology 
Clinical Research Office (CRO) reports serious adverse events (SAEs) to Radiation 
Oncology Safety Assurance Committee (ROSAC) monthly. These SAEs are also 
reported to the University of Texas Southwestern Medical Center (UTSW) IRB and 

___________________________122013-030_______________________________________ 
Page 47 of 59 
Simmons Comprehensive Cancer Center DSMC. SCCC-DSMC will audit in accordance 
with the DSMC plan guidelines. 
  
The purpose of the Radiation Oncology Safety Assurance Committee (ROSAC) is to 
ensure that clinical trial data is accurate and valid and to ensure the safety of trial 
participants. The plan complies with the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Plan and the University of Texas Southwestern Medical 
Center (UTSW) IRB guidelines.  
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
 
 
ROSAC is charged with developing, implementing, and maintaining the Data and Safety 
Monitoring Plan. The membership consists of a Medical Director of Clinical Research as 
well as representation from the following groups: clinical research, nursing, regulatory, 
pharmacy, physicists, radiation therapists, and faculty. Additional members are contacted 
to participate as needed.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT and/or the CRO 
Multi-Center IIT Monitor. This review includes but is not limited to accuracy of case report 
forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
 
 
Clinical trials are assessed for safety on a continual basis throughout the life of the trial. 
All SAE’s and any AEs that are unexpected and definitely or probably related to study 
participation are reported to UTSW IRB through an electronic research system per UTSW 
IRB guidelines. SAEs are reported to the sponsor per specific sponsor requirements. 
These SAEs are reported to the SCCC DSMC on a real time basis. All local SAEs will be 

___________________________122013-030_______________________________________ 
Page 48 of 59 
reported to the SCCC DSMC. SAE reports can be either scanned/emailed to the 
coordinator of SCCC DSMC or sent through interoffice mail. 
10.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
10.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
 
intentional on part of the investigator; or 
 
in the investigator’s control; or 
 
not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require 
prospective IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major deviation. 
10.6.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
 
avoid immediate apparent harm, or 
 
protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 
10.6.3 Major Deviations (also called violations): include any departure from IRB-
approved research that: 
 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or others), or 
 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of the 
data) or the science of the research (e.g., the primary outcome/endpoint of the study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
10.6.4 Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did not 
have the potential to negatively affect the safety, rights, or welfare of subjects or others), 
or 
 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or validity 
of the data) or the science of the research (e.g., the primary outcome/endpoint of the 
study) 
 Reporting requirement: Minor deviations should be tracked and summarized in the 
progress report at the next IRB continuing review. 
 
10.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 

___________________________122013-030_______________________________________ 
Page 49 of 59 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
10.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
11.0 
REFERENCES 
 
1. 
AmericanCancerSociety, Cancer Facts and Figures 2012. 2012  
2. 
Jayson, M. and H. Sanders, Increased incidence of serendipitously discovered renal cell 
carcinoma. Urology, 1998. 51(2): p. 203-5. 
3. 
Smith, S.J., et al., Renal cell carcinoma: earlier discovery and increased detection. Radiology, 
1989. 170(3 Pt 1): p. 699-703. 
4. 
Belldegrun, A., et al., Efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based 
on the new 1997 tumor-node-metastasis staging system. J Clin Oncol, 1999. 17(9): p. 2868-75. 
5. 
Fergany, A.F., K.S. Hafez, and A.C. Novick, Long-term results of nephron sparing surgery for 
localized renal cell carcinoma: 10-year followup. J Urol, 2000. 163(2): p. 442-5. 
6. 
Herr, H.W., Partial nephrectomy for unilateral renal carcinoma and a normal contralateral kidney: 
10-year followup. J Urol, 1999. 161(1): p. 33-4; discussion 34-5. 

___________________________122013-030_______________________________________ 
Page 50 of 59 
7. 
Morgan, W.R. and H. Zincke, Progression and survival after renal-conserving surgery for renal 
cell carcinoma: experience in 104 patients and extended followup. J Urol, 1990. 144(4): p. 852-7; 
discussion 857-8. 
8. 
Lee, C.T., et al., Surgical management of renal tumors 4 cm. or less in a contemporary cohort. J 
Urol, 2000. 163(3): p. 730-6. 
9. 
Lee, D.I., et al., Retroperitoneal laparoscopic cryoablation of small renal tumors: intermediate 
results. Urology, 2003. 61(1): p. 83-8. 
10. 
Lerner, S.E., et al., Disease outcome in patients with low stage renal cell carcinoma treated with 
nephron sparing or radical surgery. J Urol, 1996. 155(6): p. 1868-73. 
11. 
Lerner, S.E., et al., Disease outcome in patients with low stage renal cell carcinoma treated with 
nephron sparing or radical surgery. 1996. J Urol, 2002. 167(2 Pt 2): p. 884-9; discussion 889-90. 
12. 
Gill, I.S., et al., Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical 
techniques. J Urol, 2002. 167(2 Pt 1): p. 469-7; discussion 475-6. 
13. 
Wolf, J.S., Jr., B.D. Seifman, and J.E. Montie, Nephron sparing surgery for suspected 
malignancy: open surgery compared to laparoscopy with selective use of hand assistance. J Urol, 
2000. 163(6): p. 1659-64. 
14. 
Gervais, D.A., et al., Renal cell carcinoma: clinical experience and technical success with radio-
frequency ablation of 42 tumors. Radiology, 2003. 226(2): p. 417-24. 
15. 
Gill, I.S., et al., Laparoscopic renal cryoablation in 32 patients. Urology, 2000. 56(5): p. 748-53. 
16. 
Gill, I.S., et al., Renal cryoablation: outcome at 3 years. J Urol, 2005. 173(6): p. 1903-7. 
17. 
Jacomides, L., et al., Laparoscopic application of radio frequency energy enables in situ renal 
tumor ablation and partial nephrectomy. J Urol, 2003. 169(1): p. 49-53; discussion 53. 
18. 
Ogan, K., et al., Percutaneous radiofrequency ablation of renal tumors: technique, limitations, and 
morbidity. Urology, 2002. 60(6): p. 954-8. 
19. 
Pavlovich, C.P., et al., Percutaneous radio frequency ablation of small renal tumors: initial results. 
J Urol, 2002. 167(1): p. 10-5. 
20. 
Shingleton, W.B. and P.E. Sewell, Jr., Percutaneous renal tumor cryoablation with magnetic 
resonance imaging guidance. J Urol, 2001. 165(3): p. 773-6. 
21. 
Hara, R., et al., Stereotactic single high dose irradiation of lung tumors under respiratory gating. 
Radiother Oncol, 2002. 63(2): p. 159-63. 
22. 
Herfarth, K.K., et al., Stereotactic single-dose radiation therapy of liver tumors: results of a phase 
I/II trial. J Clin Oncol, 2001. 19(1): p. 164-70. 
23. 
Hof, H., et al., Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer 
(NSCLC). Int J Radiat Oncol Biol Phys, 2003. 56(2): p. 335-41. 
24. 
Potters, L., et al., American Society for Therapeutic Radiology and Oncology (ASTRO) and 
American College of Radiology (ACR) practice guideline for the performance of stereotactic body 
radiation therapy. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 326-32. 
25. 
Kavanagh, B.D., R.C. McGarry, and R.D. Timmerman, Extracranial radiosurgery (stereotactic 
body radiation therapy) for oligometastases. Semin Radiat Oncol, 2006. 16(2): p. 77-84. 
26. 
Milano, M.T., et al., Oligometastases treated with stereotactic body radiotherapy: long-term 
follow-up of prospective study. Int J Radiat Oncol Biol Phys, 2012. 83(3): p. 878-86. 
27. 
Salama, J.K., et al., Stereotactic body radiotherapy for multisite extracranial oligometastases: 
Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer, 
2012. 118(11): p. 2962-70. 
28. 
Timmerman, R., et al., Stereotactic body radiation therapy for inoperable early stage lung cancer. 
JAMA, 2010. 303(11): p. 1070-6. 
29. 
Boike, T.P., et al., Phase I dose-escalation study of stereotactic body radiation therapy for low- 
and intermediate-risk prostate cancer. J Clin Oncol, 2011. 29(15): p. 2020-6. 
30. 
King, C.R., et al., Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis 
from a multi-institutional consortium of prospective phase II trials. Radiother Oncol, 2013. 
31. 
Katz, A.J., et al., Stereotactic body radiotherapy for localized prostate cancer: disease control and 
quality of life at 6 years. Radiat Oncol, 2013. 8(1): p. 118. 
32. 
Timmerman, R.D., et al., Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol, 
2007. 25(8): p. 947-52. 
33. 
Berber, B., et al., Emerging role of stereotactic body radiotherapy in the treatment of pancreatic 
cancer. Expert Rev Anticancer Ther, 2013. 13(4): p. 481-7. 

___________________________122013-030_______________________________________ 
Page 51 of 59 
34. 
Tao, C. and L.X. Yang, Improved radiotherapy for primary and secondary liver cancer: 
stereotactic body radiation therapy. Anticancer Res, 2012. 32(2): p. 649-55. 
35. 
Kwon, J.H., et al., Long-term effect of stereotactic body radiation therapy for primary 
hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic 
radiotherapy for liver cancer. BMC Cancer, 2010. 10: p. 475. 
36. 
Bondiau, P.Y., et al., Phase 1 clinical trial of stereotactic body radiation therapy concomitant with 
neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol Phys, 2013. 85(5): p. 1193-
9. 
37. 
Chang, B.K. and R.D. Timmerman, Stereotactic body radiation therapy: a comprehensive review. 
Am J Clin Oncol, 2007. 30(6): p. 637-44. 
38. 
Lo, S.S., et al., Stereotactic body radiation therapy for oligometastases. Expert Rev Anticancer 
Ther, 2009. 9(5): p. 621-35. 
39. 
Lo, S.S., et al., Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin 
Oncol, 2010. 7(1): p. 44-54. 
40. 
Shuto, T., et al., Treatment strategy for metastatic brain tumors from renal cell carcinoma: 
selection of gamma knife surgery or craniotomy for control of growth and peritumoral edema. J 
Neurooncol, 2010. 98(2): p. 169-75. 
41. 
Gerszten, P.C., et al., Radiosurgery for spinal metastases: clinical experience in 500 cases from 
a single institution. Spine (Phila Pa 1976), 2007. 32(2): p. 193-9. 
42. 
Gerszten, P.C., et al., Stereotactic radiosurgery for spinal metastases from renal cell carcinoma. J 
Neurosurg Spine, 2005. 3(4): p. 288-95. 
43. 
Yamada, Y., et al., High-dose, single-fraction image-guided intensity-modulated radiotherapy for 
metastatic spinal lesions. Int J Radiat Oncol Biol Phys, 2008. 71(2): p. 484-90. 
44. 
Nguyen, Q.N., et al., Management of spinal metastases from renal cell carcinoma using 
stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys, 2010. 76(4): p. 1185-92. 
45. 
Beitler, J.J., et al., Definitive, high-dose-per-fraction, conformal, stereotactic external radiation for 
renal cell carcinoma. Am J Clin Oncol, 2004. 27(6): p. 646-8. 
46. 
Wersall, P.J., et al., Extracranial stereotactic radiotherapy for primary and metastatic renal cell 
carcinoma. Radiother Oncol, 2005. 77(1): p. 88-95. 
47. 
Svedman, C., et al., A prospective Phase II trial of using extracranial stereotactic radiotherapy in 
primary and metastatic renal cell carcinoma. Acta Oncol, 2006. 45(7): p. 870-5. 
48. 
Ponsky, L.E., et al., Initial evaluation of Cyberknife technology for extracorporeal renal tissue 
ablation. Urology, 2003. 61(3): p. 498-501. 
49. 
Dawson, L.A., et al., Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys, 2010. 76(3 
Suppl): p. S108-15. 
50. 
Svedman, C., et al., Stereotactic body radiotherapy of primary and metastatic renal lesions for 
patients with only one functioning kidney. Acta Oncol, 2008. 47(8): p. 1578-83. 
51. 
Chawla, S.N., et al., The natural history of observed enhancing renal masses: meta-analysis and 
review of the world literature. J Urol, 2006. 175(2): p. 425-31. 
52. 
Volpe, A. and M.A. Jewett, The natural history of small renal masses. Nat Clin Pract Urol, 2005. 
2(8): p. 384-90. 
53. 
Oda, T., et al., Growth rates of primary and metastatic lesions of renal cell carcinoma. Int J Urol, 
2001. 8(9): p. 473-7. 
54. 
Rendon, R.A., et al., The natural history of small renal masses. J Urol, 2000. 164(4): p. 1143-7. 
55. 
Wehle, M.J., et al., Conservative management of incidental contrast-enhancing renal masses as 
safe alternative to invasive therapy. Urology, 2004. 64(1): p. 49-52. 
56. 
Punnen, S., et al., Variability in size measurement of renal masses smaller than 4 cm on 
computerized tomography. J Urol, 2006. 176(6 Pt 1): p. 2386-90; discussion 2390. 
57. 
Finkelstein, S.E., et al., The confluence of stereotactic ablative radiotherapy and tumor 
immunology. Clin Dev Immunol, 2011. 2011: p. 439752. 
58. 
Corso, C.D., A.N. Ali, and R. Diaz, Radiation-induced tumor neoantigens: imaging and 
therapeutic implications. Am J Cancer Res, 2011. 1(3): p. 390-412. 
59. 
Rubner, Y., et al., How does ionizing irradiation contribute to the induction of anti-tumor 
immunity? Front Oncol, 2012. 2: p. 75. 
60. 
Ma, Y., et al., Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol, 
2010. 22(3): p. 113-24. 

___________________________122013-030_______________________________________ 
Page 52 of 59 
61. 
Apetoh, L., et al., Toll-like receptor 4-dependent contribution of the immune system to anticancer 
chemotherapy and radiotherapy. Nat Med, 2007. 13(9): p. 1050-9. 
62. 
Schmid, T.E. and G. Multhoff, Radiation-induced stress proteins - the role of heat shock proteins 
(HSP) in anti- tumor responses. Curr Med Chem, 2012. 19(12): p. 1765-70. 
63. 
Obeid, M., et al., Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med, 
2007. 13(1): p. 54-61. 
64. 
Lugade, A.A., et al., Local radiation therapy of B16 melanoma tumors increases the generation of 
tumor antigen-specific effector cells that traffic to the tumor. J Immunol, 2005. 174(12): p. 7516-
23. 
65. 
Takeshima, T., et al., Local radiation therapy inhibits tumor growth through the generation of 
tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res, 2010. 
70(7): p. 2697-706. 
66. 
Reits, E.A., et al., Radiation modulates the peptide repertoire, enhances MHC class I expression, 
and induces successful antitumor immunotherapy. J Exp Med, 2006. 203(16636135): p. 1259-
1271. 
67. 
Ogawa, Y., et al., Expression of fas (CD95/APO-1) antigen induced by radiation therapy for 
diffuse B-cell lymphoma: immunohistochemical study. Clin Cancer Res, 1997. 3(12 Pt 1): p. 
2211-6. 
68. 
Sheard, M.A., et al., Up-regulation of Fas (CD95) in human p53wild-type cancer cells treated with 
ionizing radiation. Int J Cancer, 1997. 73(5): p. 757-62. 
69. 
Murphy, K., P. Travers, and M. Walport, T Cell-Mediated Immunity, in Janeway's Immunobiology, 
K. Murphy, P. Travers, and M. Walport, Editors. 2008, Garland Science: New York. p. 323-379. 
70. 
Nemunaitis, J., Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Expert Rev Vaccines, 2005. 
4(3): p. 259-74. 
71. 
Le, D.T., D.M. Pardoll, and E.M. Jaffee, Cellular vaccine approaches. Cancer J, 2010. 16(4): p. 
304-10. 
72. 
Simons, J.W., et al., Induction of immunity to prostate cancer antigens: results of a clinical trial of 
vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-
macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res, 1999. 59(20): p. 
5160-8. 
73. 
Correale, P., et al., In vitro generation of human cytotoxic T lymphocytes specific for peptides 
derived from prostate-specific antigen. J Natl Cancer Inst, 1997. 89(4): p. 293-300. 
74. 
Horoszewicz, J.S., et al., LNCaP model of human prostatic carcinoma. Cancer Res, 1983. 43(4): 
p. 1809-18. 
75. 
Kaighn, M.E., et al., Establishment and characterization of a human prostatic carcinoma cell line 
(PC-3). Invest Urol, 1979. 17(1): p. 16-23. 
76. 
Su, Z.Z., et al., Surface-epitope masking and expression cloning identifies the human prostate 
carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family. Proc Natl Acad Sci 
U S A, 1996. 93(14): p. 7252-7. 
77. 
Berger, A., Th1 and Th2 responses: what are they? BMJ, 2000. 321(7258): p. 424. 
78. 
Kidd, P., Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. 
Altern Med Rev, 2003. 8(3): p. 223-46. 
79. 
Lohr, J., et al., Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J 
Exp Med, 2006. 203(13): p. 2785-91. 
80. 
Finkelstein, S.E., et al., Combination of External Beam Radiotherapy (EBRT) With Intratumoral 
Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma 
Patients. Int J Radiat Oncol Biol Phys, 2012. 82(2): p. 924-32. 
81. 
Sheikh, N.A., et al., Sipuleucel-T immune parameters correlate with survival: an analysis of the 
randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer 
Immunol Immunother, 2012. 
82. 
Rubio, V., et al., Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. Nat Med, 
2003. 9(11): p. 1377-82. 
83. 
Sheikh, N.A. and L.A. Jones, CD54 is a surrogate marker of antigen presenting cell activation. 
Cancer Immunol Immunother, 2008. 57(9): p. 1381-90. 
84. 
Nguyen, X.D., et al., Flow cytometric analysis of T cell proliferation in a mixed lymphocyte 
reaction with dendritic cells. J Immunol Methods, 2003. 275(1-2): p. 57-68. 

___________________________122013-030_______________________________________ 
Page 53 of 59 
85. 
Dong, C., et al., ICOS co-stimulatory receptor is essential for T-cell activation and function. 
Nature, 2001. 409(6816): p. 97-101. 
86. 
Seung, S.K., et al., Phase 1 study of stereotactic body radiotherapy and interleukin-2--tumor and 
immunological responses. Sci Transl Med, 2012. 4(137): p. 137ra74. 
87. 
Huang, K., et al., High-risk CT features for detection of local recurrence after stereotactic ablative 
radiotherapy for lung cancer. Radiother Oncol, 2013. 109(1): p. 51-7. 
88. 
Pucar, D., et al., Prostate cancer: correlation of MR imaging and MR spectroscopy with 
pathologic findings after radiation therapy-initial experience. Radiology, 2005. 236(2): p. 545-53. 
89. 
Mayr, N.A., et al., Pixel analysis of MR perfusion imaging in predicting radiation therapy outcome 
in cervical cancer. J Magn Reson Imaging, 2000. 12(6): p. 1027-33. 
90. 
Overgaard, J. and M.R. Horsman, Modification of Hypoxia-Induced Radioresistance in Tumors by 
the Use of Oxygen and Sensitizers. Semin Radiat Oncol, 1996. 6(1): p. 10-21. 
91. 
Hallac, R.R., et al., Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to 
tumor radiation response. Magn Reson Med, 2014. 71(5): p. 1863-73. 
92. 
Bourke, V.A., et al., Correlation of radiation response with tumor oxygenation in the Dunning 
prostate R3327-AT1 tumor. Int J Radiat Oncol Biol Phys, 2007. 67(4): p. 1179-86. 
93. 
Semenza, G.L., Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell, 2004. 5(5): p. 
405-6. 
94. 
Gray, L.H., et al., The concentration of oxygen dissolved in tissues at the time of irradiation as a 
factor in radiotherapy. Br J Radiol, 1953. 26(312): p. 638-48. 
95. 
Brenchley, J.M. and D.C. Douek, Flow cytometric analysis of human antigen-specific T-cell 
proliferation. Methods Cell Biol, 2004. 75: p. 481-96. 
96. 
Corey, M.J., et al., A very sensitive coupled luminescent assay for cytotoxicity and complement-
mediated lysis. J Immunol Methods, 1997. 207(1): p. 43-51. 
97. 
Schafer, H., et al., A highly sensitive cytotoxicity assay based on the release of reporter enzymes, 
from stably transfected cell lines. J Immunol Methods, 1997. 204(1): p. 89-98. 
98. 
Li, L.P., S. Halter, and P.V. Prasad, Blood oxygen level-dependent MR imaging of the kidneys. 
Magn Reson Imaging Clin N Am, 2008. 16(4): p. 613-25, viii. 
99. 
Muller, A., et al., Intracranial tumor response to respiratory challenges at 3.0 T: impact of different 
methods to quantify changes in the MR relaxation rate R2*. J Magn Reson Imaging, 2010. 32(1): 
p. 17-23. 
100. 
Endo, M., et al., Image characteristics and effective dose estimation of a cone beam CT using a 
video-fluoroscopic system. Ieee Transactions on Nuclear Science, 1999. 46(3): p. 686-690. 
101. 
Islam, M.K., et al., Patient dose from kilovoltage cone beam computed tomography imaging in 
radiation therapy. Medical Physics, 2006. 33(6): p. 1573-1582. 
 
 
 
 

___________________________122013-030_______________________________________ 
Page 54 of 59 
12.0 
APPENDICES 
12.1 
Appendix A: 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. 
 
 

___________________________122013-030_______________________________________ 
Page 55 of 59 
12.2 
Appendix B: RTOG Acute Toxicity Scale: 
As defined in RTOG website: 
http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx 
 
Acute Radiation Morbidity Scoring Criteria  
 
  
[ 0 ] 
[ 1 ] 
[ 2 ] 
[ 3 ] 
[ 4 ] 
SKIN 
No 
change 
over 
baseline 
Follicular, faint or 
dull erythema/ 
epilation/dry 
desquamation/ 
decreased 
sweating 
Tender or bright 
erythema, patchy 
moist 
desquamation/ 
moderate edema 
Confluent, moist 
desquamatiom other 
than skin folds, pitting 
edema 
Ulceration, hemorrhage, 
necrosis 
MUCOUS 
MEMBRANE 
No 
change 
over 
baseline 
Injection/ may 
experience mild 
pain not requiring 
analgesic 
Patchy mucositis 
which may 
produce an 
inflammatory 
serosanguinitis 
discharge/ may 
experience 
moderate pain 
requiring 
analgesia 
Confluent fibrinous 
mucositis/ may include 
severe pain requiring 
narcotic 
Ulceration, hemorrhage 
or necrosis 
EYE 
No 
change 
Mild conjunctivitis 
with or without 
scleral injection/ 
increased tearing 
Moderate 
conjunctivitis with 
or without keratitis 
requiring steroids 
&/or antibiotics/ 
dry eye requiring 
artificial tears/ 
iritis with 
photophobia 
Severe keratitis with 
corneal ulceration/ 
objective decrease in 
visual acuity or in visual 
fields/ acute glaucoma/ 
panopthalmitis 
Loss of vision (unilateral 
or bilateral) 
EAR 
No 
change 
over 
baseline 
Mild external otitis 
with erythema, 
pruritis, secondary 
to dry 
desquamation not 
requiring 
medication. 
Audiogram 
unchanged from 
baseline 
Moderate 
external otitis 
requiring topical 
medication/ 
serious otitis 
medius/ 
hypoacusis on 
testing only 
Severe external otitis 
with dischange or moist 
desquamation/ 
symptomatic 
hypoacusis/tinnitus, not 
drug related 
Deafness 
SALIVARY 
GLAND 
No 
change 
over 
baseline 
Mild mouth 
dryness/ slightly 
thickened saliva/ 
may have slightly 
altered taste such 
as metallic taste/ 
these changes not 
reflected in 
alteration in 
baseline feeding 
behavior, such as 
Moderate to 
complete 
dryness/ thick, 
sticky saliva/ 
markedly altered 
taste 
------- 
Acute salivary gland 
necrosis 

___________________________122013-030_______________________________________ 
Page 56 of 59 
increased use of 
liquids with meals 
PHARYNX & 
ESOPHAGUS 
No 
change 
over 
baseline 
Mild dysphagia or 
odynophagia/ may 
require topical 
anesthetic or non-
narcotic 
analgesics/ may 
require soft diet 
Moderate 
dysphagia or 
odynophagia/ 
may require 
narcotic 
analgesics/ may 
require puree or 
liquid diet 
Severe dysphagia or 
odynophagia with 
dehydration or weight 
loss(>15% from pre-
treatment baseline) 
requiring N-G feeding 
tube, I.V. fluids or 
hyperalimentation 
Complete obstruction, 
ulceration, perforation, 
fistula 
LARYNX 
No 
change 
over 
baseline 
Mild or 
intermittent 
hoarseness/cough 
not requiring 
antitussive/ 
erythema of 
mucosa 
Persistent 
hoarseness but 
able to vocalize/ 
referred ear pain, 
sore throat, 
patchy fibrinous 
exudate or mild 
arytenoid edema 
not requiring 
narcotic/ cough 
requiring 
antitussive 
Whispered speech, 
throat pain or referred 
ear pain requiring 
narcotic/ confluent 
fibrinous exudate, 
marked arytenoid edema 
Marked dyspnea, stridor 
or hemoptysis with 
tracheostomy or 
intubation necessary 
UPPER G.I. 
No 
change 
Anorexia with 
<=5% weight loss 
from pretreatment 
baseline/ nausea 
not requiring 
antiemetics/ 
abdominal 
discomfort not 
requiring 
parasympatholytic 
drugs or 
analgesics 
Anorexia with 
<=15% weight 
loss from 
pretreatment 
baseline/nausea 
&/ or vomiting 
requiring 
antiemetics/ 
abdominal pain 
requiring 
analgesics 
Anorexia with >15% 
weight loss from 
pretreatment baseline or 
requiring N-G tube or 
parenteral support. 
Nausea &/or vomiting 
requiring tube or 
parenteral 
support/abdominal pain, 
severe despite 
medication/hematemesis 
or melena/ abdominal 
distention (flat plate 
radiograph 
demonstrates distended 
bowel loops 
Ileus, subacute or acute 
obstruction, performation, 
GI bleeding requiring 
transfusion/abdominal 
pain requiring tube 
decompression or bowel 
diversion 
LOWER G.I. 
INCLUDING 
PELVIS 
No 
change 
Increased 
frequency or 
change in quality 
of bowel habits 
not requiring 
medication/ rectal 
discomfort not 
requiring 
analgesics 
Diarrhea requiring 
parasympatholytic 
drugs (e.g., 
Lomotil)/ mucous 
discharge not 
necessitating 
sanitary pads/ 
rectal or 
abdominal pain 
requiring 
analgesics 
Diarrhea requiring 
parenteral support/ 
severe mucous or blood 
discharge necessitating 
sanitary pags/abdominal 
distention (flat plate 
radiograph 
demonstrates distended 
bowel loops) 
Acute or subacute 
obstruction, fistula or 
perforation; GI bleeding 
requiring transfusion; 
abdominal pain or 
tenesmus requiring tube 
decompression or bowel 
diversion 
LUNG 
No 
change 
Mild symptoms of 
dry cough or 
dyspnea on 
exertion 
Persistent cough 
requiring narcotic, 
antitussive 
agents/ dyspnea 
Severe cough 
unresponsive to narcotic 
antitussive agent or 
dyspnea at rest/ clinical 
or radiologic evidence of 
Severe respiratory 
insufficiency/ continuous 
oxygen or assisted 
ventilation 

___________________________122013-030_______________________________________ 
Page 57 of 59 
with minimal effort 
but not at rest 
acute pneumonitis/ 
intermittent oxygen or 
steroids may be required 
GENITOURINARY No 
change 
Frequency of 
urination or 
nocturia twice 
pretreatment 
habit/ dysuria, 
urgency not 
requiring 
medication 
Frequency of 
urination or 
nocturia which is 
less frequent than 
every hour. 
Dysuria, urgency, 
bladder spasm 
requiring local 
anesthetic (e.g., 
Pyridium) 
Frequency with urgency 
and nocturia hourly or 
more frequently/ dysuria, 
pelvis pain or bladder 
spasm requiring regular, 
frequent narcotic/gross 
hematuria with/ without 
clot passage 
Hematuria requiring 
transfusion/ acute 
bladder obstruction not 
secondary to clot 
passage, ulceration or 
necrosis 
HEART 
No 
change 
over 
baseline 
Asymptomatic but 
objective 
evidence of EKG 
changes or 
pericardial 
abnormalities 
without evidence 
of other heart 
disease 
Symptomatic with 
EKG changes 
and radiologic 
findings of 
congestive heart 
failure or 
pericardial 
disease/ no 
specific treatment 
required 
Congestive heart failure, 
angina pectoris, 
pericardial disease 
responding to therapy 
Congestive heart failure, 
angina pectoris, 
pericardial disease, 
arrhythmias not 
responsive to non-
surgical measures 
CNS 
No 
change 
Fully functional 
status (i.e., able to 
work) with minor 
neurologic 
findings, no 
medication 
needed 
Neurologic 
findings present 
sufficient to 
require home 
case/ nursing 
assistance may 
be required/ 
medications 
including 
steroids/anti-
seizure agents 
may be required 
Neurologic findings 
requiring hospitalization 
for initial management 
Serious neurologic 
impairment which 
includes paralysis, coma 
or seizures>3 per week 
despite 
medication/hospitalization 
required 
HEMATOLOGIC 
WBC (X 1000) 
>=4.0 
3.0 - <4.0 
2.0 - <3.0 
1.0 - <2.0 
<1.0 
PLATELETS (X 
1000) 
>=100 
75 - <100 
50 - <75 
25 - <50 
<25 or spontaneous 
bleeding 
NEUTROPHILS 
>=1.9 
1.5 - <1.9 
1.0 - <1.5 
0.5 - <1.0 
<0.5 or sepsis 
HEMOGLOBIN 
(GM %) 
>11 
11-9.5 
<9.5 - 7.5 
<7.5 - 5.0 
------- 
HEMATOCRIT 
(%) 
>=32 
28 - <32 
<28 
Packed cell transfusion 
required 
------- 
GUIDELINES: The acute morbidity criteria are used to score/grade toxicity from radiation therapy. The critera are 
relevant from day 1, the commencement of therapy, through day 90. Therafter, the EORTC/RTOG Criteria of Late 
Effects are to be utilized. 
 
The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. 
 
An accurate baseline evaluation prior to commencement of therapy is necessary. 
 

___________________________122013-030_______________________________________ 
Page 58 of 59 
All toxicities Grade 3, 4 or 5* must be verified by the Principal Investigator. 
 
*ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. 
 
 
 

___________________________122013-030_______________________________________ 
Page 59 of 59 
12.3 
Appendix C: RTOG/EORTC Late Radiation Morbidity Scoring Schema 
As defined in RTOG website: 
http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx 
 
RTOG/EORTC Late Radiation Morbidity Scoring Schema  
 
ORGAN TISSUE 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
5 
SKIN 
None 
Slight atrophy 
Pigmentation 
change 
Some hair loss 
Patch atrophy; 
Moderate 
telangiectasia; Total 
hair loss 
Marked atrophy; 
Gross telangiectasia Ulceration 
D 
E 
A 
T 
H 
 
D 
I 
R 
E 
C 
T 
L 
Y 
 
R 
E 
L 
A 
T 
E 
D 
 
T 
O 
 
R 
A 
D 
I 
A 
T 
I 
O 
N 
 
L 
A 
T 
E 
 
E 
F 
F 
E 
SUBCUTANEOUS 
TISSUE 
None 
Slight induration 
(fibrosia) and loss 
of subcutaneous fat 
Moderate fibrosis but 
asymptomatic 
Slight field 
contracture 
<10% linear 
reduction 
Severe induration 
and loss of 
subcutaneous tissue 
Field contracture 
>10% linear 
measurement 
Necrosis 
MUCOUS 
MEMBRANE 
None Slight atrophy and 
dryness 
Moderate atrophy 
and telangiectasia 
Little mucous 
Marked atrophy with 
complete dryness 
Severe 
telangiectasia 
Ulceration 
SALIVARY 
GLANDS 
None 
Slight dryness of 
mouth 
Good response on 
stimulation 
Moderate dryness of 
mouth 
Poor response on 
stimulation 
Complete dryness of 
mouth 
No response on 
stimulation 
Fibrosis 
SPINAL CORD 
None Mild L'Hermitte's 
syndrome 
Severe L'Hermitte's 
syndrome 
Objective 
neurological findings 
at or below cord 
level treated 
Mono, para 
quadraplegia 
BRAIN 
None Mild headache 
Slight lethargy 
Moderate headache 
Great lethargy 
Severe headaches 
Severe CNS 
dysfunction (partial 
loss of power or 
dyskinesia) 
Seizures or paralysis 
Coma 
EYE 
None 
Asymptomatic 
cataract 
Minor corneal 
ulceration or 
keratitis 
Symptomatic 
cataract 
Moderate corneal 
ulceration 
Minor retinopathy or 
glaucoma 
Severe keratitis 
Severe retinopathy 
or detachment 
Severe glaucoma 
Panopthalmitis/ 
Blindness 
LARYNX 
None 
Hoarseness 
Slight arytenoid 
edema 
Moderate arytenoid 
edema 
Chondritis 
Severe edema 
Severe chondritis 
Necrosis 
LUNG 
None 
Asymptomatic or 
mild symptoms (dry 
cough) 
Slight radiographic 
appearances 
Moderate 
symptomatic fibrosis 
or pneumonitis 
(severe cough) 
Low grade fever 
Patchy radiographic 
appearances 
Severe symptomatic 
fibrosis or 
pneumonitis 
Dense radiographic 
changes 
Severe respiratory 
insufficiency/ 
Continuous O2/ 
Assisted ventilation 

___________________________122013-030_______________________________________ 
Page 60 of 59 
HEART 
None 
Asymptomatic or 
mild symptoms 
Transient T wave 
inversion & ST 
changes 
Sinus tachycardia 
>110 (at rest) 
Moderate angina on 
effort 
Mild pericarditis 
Normal heart size 
Persistent abnormal 
T wave and ST 
changes 
Low ORS 
Severe angina 
Pericardial effusion 
Constrictive 
pericarditis 
Moderate heart 
failure 
Cardiac 
enlargement 
EKG abnormalities 
Tamponade/ Severe 
heart failure/ Severe 
constrictive pericarditis 
C 
T 
S 
ESOPHAGUS 
None 
Mild fibrosis 
Slight difficulty in 
swallowing solids 
No pain on 
swallowing 
Unable to take solid 
food normally 
Swallowing semi-
solid food 
Dilatation may be 
indicated 
Severe fibrosis 
Able to swallow only 
liquids 
May have pain on 
swallowing 
Dilation required 
Necrosis/ Perforation 
Fistula 
SMALL/LARGE 
INTESTINE 
None 
Mild diarrhea 
Mild cramping 
Bowel movement 5 
times daily 
Slight rectal 
discharge or 
bleeding 
Moderate diarrhea 
and colic 
Bowel movement >5 
times daily 
Excessive rectal 
mucus or intermittent 
bleeding 
Obstruction or 
bleeding 
requiring surgery 
Necrosis/ Perforation 
Fistula 
LIVER 
None 
Mild lassitude 
Nausea, dyspepsia 
Slightly abnormal 
liver function 
Moderate symptoms 
Some abnormal liver 
function tests 
Serum albumin 
normal 
Disabling hepatitic 
insufficiency 
Liver function tests 
grossly abnormal 
Low albumin 
Edema or ascites 
Necrosis/ Hepatic 
coma or 
encephalopathy 
KIDNEY 
None 
Transient 
albuminuria 
No hypertension 
Mild impairment of 
renal function 
Urea 25-35 mg% 
Creatinine 1.5-2.0 
mg% 
Creatinine 
clearance >75% 
Persistent moderate 
albuminuria (2+) 
Mild hypertension 
No related anemia 
Moderate impairment 
of renal function 
Urea>36-60 mg% 
Creatinine clearance 
(50-74%) 
Severe albuminuria 
Severe hypertension 
Persistent anemia 
(<10g%) 
Severe renal failure 
Urea >60 mg% 
Creatinine >4.0 
mg% 
Creatinine clearance 
<50% 
Malignant hypertension 
Uremic coma/Urea 
>100% 
BLADDER 
None 
Slight epithelial 
atrophy 
Minor telangiectasia 
(microscopic 
hematuria) 
Moderate frequency 
Generalized 
telangiectasia 
Intermittent 
macroscopic 
hematuria 
Severe frequency 
and dysuria 
Severe generalized 
telangiectasia (often 
with petechiae) 
Frequent hematuria 
Reduction in bladder 
capacity (<150 cc) 
Necrosis/ Contracted 
bladder (capacity <100 
cc) 
Severe hemorrhagic 
cystitis 
BONE 
None 
Asymptomatic 
No growth 
retardation 
Reduced bone 
density 
Moderate pain or 
tenderness 
Growth retardation 
Irregular bone 
sclerosis 
Severe pain or 
tenderness 
Complete arrest of 
bone growth 
Dense bone 
sclerosis 
Necrosis/ Spontaneous 
fracture 

___________________________122013-030_______________________________________ 
Page 61 of 59 
JOINT 
None 
Mild joint stiffness 
Slight limitation of 
movement 
Moderate stiffness 
Intermittent or 
moderate joint pain 
Moderate limitation 
of movement 
Severe joint stiffness 
Pain with severe 
limitation of 
movement 
Necrosis/ Complete 
fixation