Outcome in Patients With 4 or More Brain Metastases Treated With Single-Isocenter, Multi-Target (SIMT) Stereotactic Radiosurgery: A Prospective Single-arm Study in Adults With Brain Metastases
Phase: NA
Conditions: Brain Metastases, Adult
Sponsor: Duke University

A Radiation Therapy Study  
Outcome in patients with 4 or more Brain Metastases Treated with Single-Isocenter, Multi-
Target (SIMT) Stereotactic Radiosurgery:  
A prospective single-arm study in adults with brain metastases  
Principal Investigator       
Grace J Kim, MD, PhD 
Department of Radiation Oncology 
Duke University Medical Center 
Co-Principal Investigator 
John Kirkpatrick, MD, PhD 
Department of Radiation Oncology 
Duke University Medical Center 
Co-Investigator(s) 
Justus Adamson, PhD  
Peter E. Fecci, MD, PhD 
Scott R. Floyd, MD, PhD 
John H. Sampson, MD, PhD 
Zhiheng Wang, PhD 
Statistician 
James E. Herndon, II, PhD 
Amended version: 21 December 2017 
Original version:  
September 8th 2016 
Sponsor:  
 
 
PI – Duke Cancer Institute 
Funding Source: 
 
Varian Medical Systems  
 
 
 
 
The Department of Radiation Oncology 
Duke IRB#: 
 
 
Pro00075429
ClinicalTrials.gov 
 
NCT02886572

 
 
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1 Table of Contents 
2 
LIST OF ABBREVIATIONS ......................................................................................................................... 6 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ................................................................................. 7 
3.1 
Purpose ......................................................................................................................................... 7 
3.2 
Background and Significance ........................................................................................................ 7 
3.3 
Design and Procedure ................................................................................................................... 8 
3.4 
Selection of Subjects ..................................................................................................................... 9 
3.5 
Duration of study .......................................................................................................................... 9 
3.6 
Data Analysis and Statistical Considerations ................................................................................ 9 
4 
INTRODUCTION .................................................................................................................................... 10 
4.1 
Study Disease .............................................................................................................................. 10 
4.2 
Radiation Therapy ....................................................................................................................... 10 
4.3 
Study Purpose/Rationale ............................................................................................................ 10 
5 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 11 
6 
STUDY SCHEMA .................................................................................................................................... 12 
7 
SUBJECT ELIGIBILITY ............................................................................................................................. 13 
7.1 
Inclusion Criteria ......................................................................................................................... 13 
7.2 
Exclusion Criteria ......................................................................................................................... 13 
8 
INVESTIGATIONAL PLAN ....................................................................................................................... 13 
8.1 
Study Design................................................................................................................................ 13 
8.1.1 
Dose Modification ............................................................................................................... 13 
8.1.2 
Safety Considerations ......................................................................................................... 13 
8.1.3 
Treatment Interruptions during RT ..................................................................................... 14 
8.1.4 
Concomitant Medications/Therapies ................................................................................. 14 
8.1.5 
Randomization .................................................................................................................... 14 
8.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration ......................................... 14 
8.3 
Rationale for Correlative Studies ................................................................................................ 14 
8.4 
Definition of Evaluable Subjects, On Study, and End of Study ................................................... 14 
8.5 
Early Study Termination .............................................................................................................. 14 
9 
RADIATION THERAPY ............................................................................................................................ 15 

 
 
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9.1 
Type, Classification, Location, and Short Description ................................................................. 15 
9.2 
Equipment ................................................................................................................................... 15 
9.3 
Dose Specifications ..................................................................................................................... 15 
9.4 
Localization, Simulation, and Immobilization ............................................................................. 16 
9.5 
Imaging ........................................................................................................................................ 16 
9.6 
Treatment Planning/Target Volumes ......................................................................................... 17 
9.7 
Dose Limitations for Normal Tissue ............................................................................................ 17 
9.8 
Treatment Verification ................................................................................................................ 17 
9.9 
Quality Assurance of Dose Distribution ...................................................................................... 17 
10 PATIENT ASSESSMENTS ....................................................................................................................... 18 
10.1 
Pretreatment Evaluations/Management .................................................................................... 19 
10.2 
Screening Examination ................................................................................................................ 19 
10.3 
Treatment Period ........................................................................................................................ 20 
10.4 
End of Treatment ........................................................................................................................ 20 
10.5 
Follow-up Period ......................................................................................................................... 20 
10.6 
End of Study ................................................................................................................................ 20 
10.7 
Early Withdrawal of Subject(s) .................................................................................................... 20 
10.7.1 
Criteria for Early Withdrawal .............................................................................................. 20 
10.7.2 
Follow-up Requirements for Early Withdrawal .................................................................. 21 
10.7.3 
Replacement of Early Withdrawal(s) .................................................................................. 21 
10.8 
Study Assessments ...................................................................................................................... 21 
10.8.1 
Medical History ................................................................................................................... 21 
10.8.2 
Physical Exam ...................................................................................................................... 21 
10.8.3 
Correlative Assessment ....................................................................................................... 21 
11 SAFETY MONITORING AND REPORTING ............................................................................................. 21 
11.1 
Adverse Events ............................................................................................................................ 21 
11.1.1 
AEs of Special Interest ......................................................................................................... 22 
11.1.2 
Reporting of AEs .................................................................................................................. 23 
11.2 
Serious Adverse Events ............................................................................................................... 23 
11.3 
Safety Oversight Committee (SOC) ............................................................................................. 23 
11.4 
External Data and Safety Monitoring Board (DSMB) .................................................................. 23 
12 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................. 24 

 
 
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12.1 
Monitoring .................................................................................................................................. 24 
12.2 
Audits .......................................................................................................................................... 24 
12.3 
Data Management and Processing ............................................................................................. 24 
12.3.1 
Case Report Forms (CRFs) ................................................................................................... 24 
12.3.2 
Data Management Procedures and Data Verification ........................................................ 25 
12.3.3 
Study Closure ...................................................................................................................... 25 
13 STATISTICAL METHODS AND DATA ANALYSIS .................................................................................... 25 
13.1 
Analysis Sets ................................................................................................................................ 25 
13.2 
Patient Demographics and Other Baseline Characteristics ........................................................ 25 
13.3 
Treatments .................................................................................................................................. 25 
13.4 
Primary Objective........................................................................................................................ 26 
13.4.1 
Variable ............................................................................................................................... 26 
13.4.2 
Statistical Hypothesis, Model, and Method of Analysis ...................................................... 26 
13.4.3 
Inferences............................................................................................................................ 26 
13.5 
Secondary Objectives .................................................................................................................. 27 
13.5.1 
Key Secondary Objective ..................................................................................................... 27 
13.5.2 
Other Secondary Objectives ............................................................................................... 27 
13.6 
Exploratory Objectives ................................................................................................................ 28 
13.6.1 
Key Exploratory Objectives ................................................................................................. 28 
13.6.2 
Other Exploratory Objectives .............................................................................................. 28 
13.7 
Interim Analysis ........................................................................................................................... 28 
13.8 
Sample Size Calculation .............................................................................................................. 28 
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ............................................................................. 28 
14.1 
Regulatory and Ethical Compliance ............................................................................................ 28 
14.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee .................................... 29 
14.3 
Informed Consent ....................................................................................................................... 29 
14.4 
Study Documentation ................................................................................................................. 29 
14.5 
Privacy, Confidentiality, and Data Storage ................................................................................. 30 
14.6 
Data and Safety Monitoring ........................................................................................................ 30 
14.7 
Protocol Amendments ................................................................................................................ 31 
14.8 
Records Retention ....................................................................................................................... 31 
15 REFERENCES ......................................................................................................................................... 32 

 
 
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16 Appendix A: GPA Criteria for NSCLC, Melanoma, Breast, Renal Cell & GI Cancers .............................. 34 
17 Appendix B: GPA Criteria for Other Cancer Histology .......................................................................... 35 
18 Appendix C: Stereotactic Radiotherapy QA Guidelines........................................................................ 35 
20 Appendix E: 
The Mini-Mental State Exam Instructions and Exam .................................................. 37 
21   Appendix F  
TRAIL MAKING TEST .................................................................................................... 41 
Trail Making (continued) ............................................................................................................................. 43 
           Trail Making (continued)………………………………………………………………………………………………………………43 
22  Appendix G:  FACT-BR ..……………………………………………………………………………………………………………………45 
23  Appendix H:  Hopkins Verbal Learning Test …………….……….....……………..…..………..……….……………………48 
 
 

 
 
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2 LIST OF ABBREVIATIONS 
 
 
3D                  3 Dimensional 
AE                 Adverse events 
BED               Biologically Equivalent Dose 
CBCT            Cone Beam Computed Tomography 
CPC               Cancer Protocol Committee 
CT                Computed Tomography 
CTCAE        
Common Terminology Criteria for Adverse Events 
CTV             
Clinical Tumor Volume 
DCI              
Duke Cancer Institute 
DLT             
Dose Limiting Toxicity 
Dmax            Maximum dose to any voxel within a volume 
DUHS           Duke University Health System 
G3 or G4      Grade 3 or Grade 4 toxicity 
GCP              Good Clinical Practice 
GTV             Gross Tumor Volume 
GY               
Gray 
HDR            
High Dose Rate 
HVLT            Hopkins Verbal Learning Test 
ICRU            International Commission on Radiation Units and Measurement 
ID                 Identification  
IMRT           Intensity Modulated Radiation Therapy (including Volumetric Modulated Arc Therapy) 
IRB              
Institutional Review Board 
KPS             
Karnofsky Performance Scale 
LINAC         
Linear Accelerator 
LRC             
Loco-regional control 
MMSE            Mini-Mental Status Examination 
MRI             
Magnetic Resonance Imaging. 
MTD            Maximum Tolerated Dose 
MV              
Megavoltage 
NCI             
National Cancer Institute 
OS               
Overall Survival 
PET             
Positron Emission Tomography 
PI                
Primary Investigator 
PTV            
Planning Target Volume 
RTOG         
Radiation Therapy Oncology Group 
SIMT               Single Isocenter Multi-Target 
SOC           
Safety Oversight Committee 
SRS                  Stereotactic Radiosurgery 
TD5/5         
Toxic dose of 5% at 5 years 
V12            
Volume of normal brain receiving 12 Gy 
VMAT             Volumetric modulated arc therapy 
WBRT  
Whole Brain Radiation Therapy 
 
 
 
 

 
 
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3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
3.1 
Purpose 
To examine the effectiveness and efficiency of Single Isocenter Multi-Target Stereotactic 
Radiosurgery (SIMT SRS) in patients with four or more brain metastases. 
 
Primary Objective 
1. Assess the impact of using linear-accelerator-based, single-isocenter, image-guided stereotactic 
radiosurgery on the survival of patients with four or more brain metastases.  
 
Secondary Objectives 
1. Describe the time to local brain recurrence 
2. Describe the time to distant brain recurrence 
3. Describe the time to death due to neurologic causes 
4. Describe the prevalence of significant adverse events 
 
Exploratory Objectives 
1. Describe changes over time in neurocognition 
2. Describe changes over time in quality of life 
3. Quantify treatment set-up and dosimetric data for this treatment technique 
4. Describe the rate of salvage therapy 
5. Describe prevalence of radionecrosis at the SRS site 
6. Describe length and intensity of steroid usage post-SRS 
 
Hypotheses 
1. This protocol will test the hypothesis that SIMT SRS in patients with four or more brain metastases 
is efficacious and can be delivered efficiently with minimal toxicity and no significant effect on quality 
of life and neurocognition. 
 
3.2 
Background and Significance 
Brain metastases (BM) occur in 10 - 40% of cancer patients1,2  with variable incidences according to 
the primary disease. Despite advances in diagnosis and treatment, the development of brain 
metastases is typically associated with short life expectancy. For patients with a limited number of 
BM, surgery and whole brain radiotherapy (WBRT) may improve local control and survival.3,4  
However, WBRT is associated with neurocognitive deficits without offering a survival advantage over 
a more focal radiotherapy approach such as stereotactic radiosurgery (SRS).5-8  The use of SRS alone 
provides a very high response rate and local control.6,9,10 
 
SRS treatment is usually recommended for a limited number of BMs, mostly for 1-3 lesions.8,11 
However, with evolving radiotherapy technology and brain imaging and recognition of the WBRT long-
term side effects, there is a growing interest in using SRS treatments for patients with more than a 
limited number of BM. A prospective trial looking into SRS, without WBRT, for patients with up to 10 
brain metastases found no survival or local recurrence difference between patients treated for 2-4 
BMs and those with 5-10 BMs.12 In fact, cumulative tumor volume and largest treated tumor size were 
more significant predictors of outcome than the number of treated lesions.  
 

 
 
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Another obstacle in using SRS for the treatment of a larger number of BMs is the lengthy treatment 
time required when each lesion was treated with a separate stereotactic radiotherapy plan. SIMT 
volumetric modulated arc therapy (VMAT) for SRS planning and delivery enables the treatment of 
many lesions simultaneously. This technique was shown to substantially reduce treatment time with 
the potential for small improvements in conformity indexes and normal brain dose compared with 
multiple isocenter plans.13,14 Data on clinical outcomes with the use of this technique is sparse with 
one study showing high local control and a survival rate of 60% after 6 months.15    
 
The 2016 NCCN guidelines for treating patients with >3 brain metastases recommends WBRT or SRS 
based on the treating physicians’ clinical assessment and judgment. Choosing the most appropriate 
patients with multiple BMs for SRS treatment rather than WBRT remains an unresolved issue. The 
goal of this study is to evaluate the efficacy and safety of SIMT SRS as well as the impact of this 
technology on neurocognition and quality of life. 
 
 
3.3 
Design and Procedure 
Forty patients with four or more brain metastases will be enrolled prior to radiosurgery. A planning 
MRI brain scan will be performed with GD-DPTA within one week prior to radiosurgery, per the 
standard of care. Patients who have completed a diagnostic MRI with contrast within 14 days of 
radiosurgery do not need to  have  a planning MRI. At that time, Neurocognitive (Mini-Mental Status 
Examination (MMSE), Trail-making test A&B, Hopkins Learning Verbal (HVLT)) and functional 
assessment of cancer therapy-brain (FACT– Br) will also be obtained. Dose will be prescribed to the 
maximum isodose line encompassing the resulting PTV using the dose guidelines as described below.  
The primary endpoint will be the proportion of patients who live longer than predicted based on the 
diagnosis-specific GPA score.  The Kaplan-Meier estimator will be used to describe the survival of all 
patients treated with SIMT SRS. Secondary endpoints will be the rate of recurrence at the treated 
metastases sites, the rate of new brain metastases at a site different from the SRS-treated metastases 
sites, the rate of death due to neurological causes, and the prevalence of significant adverse events.  
Exploratory endpoints include change over time in neurocognition and quality of life, quantification 
of dosimetric measures, the rate of salvage therapy, the rate of radionecrosis at the SRS treatment 
sites, and the rate and intensity of steroid-usage post-SRS.  Dosimetric endpoints to be collected 
include: maximum and minimum dose to GTV, and conformity index. These endpoints will be 
compared to historical data calculated by Sperduto et al. from the literature on radiosurgery alone, 
radiosurgery plus WBRT or WBRT alone, where appropriate.16 All patients will be evaluated for 
neurocognitive function via MMSE, HVLT, and Trail-making tests A & B, quality of life via FACT-Br, and 
for local recurrence via MRI every 3 months over the course of the study. These evaluations will be 
done at regular follow-up evaluations or when local recurrence is suspected on the basis of symptoms. 
Distant recurrence is defined as the appearance of new brain metastases at a site different from that 
of the original metastases. Recurrence will further be defined as a new area of enhancement that 
measures greater than 5 millimeters in the axial plane on MRI. The length of time to recurrence of the 
original brain metastases will be calculated from the date of the brain metastases radiosurgery to the 
date that a recurrence was detected by MRI. Patients with suspected recurrent tumor and/or who are 
symptomatic may undergo a stereotactic biopsy to evaluate for radionecrosis versus recurrent brain 
metastases, as is standard of care. 
There may or may not be a direct medical benefit to participants. The hope is that but the 
information gained from this study will help in treating patients with brain metastases in the future.   

 
 
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3.4 
Selection of Subjects 
Inclusion criteria: 
1. A contrast-enhanced MRI scan showing ≥ 4 treatable brain metastases.  
2. Age >18 years of age. 
3. KPS > 70 
4. Patient must have a GPA score 0.5 or greater (See Appendix A)  
5. Life expectancy of at least 3 months 
6. Postoperative patients with resected brain metastases are eligible. 
7. Largest lesion < 4cm diameter 
8. Must be a candidate for MRI imaging 
9. Previous cranial SRS/WBRT is allowed if > 3 months prior to SIMT 
10. Must be capable of providing informed consent. 
11. Women of childbearing age must have a negative serum pregnancy test to meet eligibility per 
Duke Policy. Adequate birth control must be used if childbearing potential as outlined in the 
protocol. 
 
Exclusion  
1. Primary lesion with the following histologies: small cell carcinoma, germ-cell tumors, lymphoma, 
leukemia, and multiple myeloma. 
2. Metastases within 2 mm of the optic apparatus  
3. Patients unable to obtain MRI. 
4. Evidence of leptomeningeal disease 
5. Greater than 10 brain metastases; excluding previously treated and stable brain metastases. 
6. Pregnant women are excluded. 
 
3.5 
Duration of study 
The study will last three years. We aim to accrue 40 patients. Overall survival, local control, distant 
failure, neurocognition, and quality of life will be collected on the 3, 6, 9, and 12-month time points.  
3.6 
Data Analysis and Statistical Considerations 
Though local control is of primary interest in this study, there is concern about the ability to 
differentiate between swelling due to radiation and disease progression without conducting a biopsy.  
The use of a biopsy to determine recurrence is not feasible given the number of brain metastases.  
Hence we focus on the survival of patients newly diagnosed with brain metastases who are treated 
with SIMT SRS.  The goal of the study is to confirm that use of SIMT SRS does not reduce the prognosis 
of patients. 
 
The population of patients newly diagnosed with brain metastases is a heterogeneous population 
with expected survival ranging between 3 and 25 months.  We will use the expected survival defined 
by the diagnosis-specific GPA (Graded Prognostic Assessment) index to assess the efficacy of SIMT 
SRS.16 Specifically, for each patient we will determine whether the patient lives longer than expected 
based upon the GPA index.  If the survival of patients treated with SIMT SRS is truly comparable to the 
survival of patients treated with currently available treatment regimens, then we would expect that 
approximately half of the patients would live longer than expected.  A test of non-inferiority will be 
conducted to assess whether the survival of patients treated with SIMT SRS is similar or better than 
that seen among Sperduto’s cohort.16   Factors such as the technical feasibility of administering SIMT 

 
 
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SRS and clinical factors such as neurologic control and local control will be considered in determining 
whether further usage of SIMT SRS is reasonable.   
 
Additionally, the Kaplan-Meier estimator will be used to describe the survival of all patients treated 
with SIMT SRS.  The survival of patients within diagnosis-specific subgroups will also be similarly 
described.  Within the context of the Kaplan-Meier estimator, median survival, 6-month survival, and 
12-month survival will be estimated.  Survival is defined as the time between initiation of SIMT SRS 
and death, and will be censored at last follow-up if the patient remains alive. 
4 INTRODUCTION 
4.1 
Study Disease 
While systemic therapy has improved for many cancers including melanoma, breast, NSCLC, GI, and 
renal cell carcinoma, the blood brain barrier prevents many of these agents from being effective in 
the brain. Thus as systemic therapies have increased survival, brain metastases have become more 
prevalent. The consequences of brain disease are devastating with complications ranging from 
headache and seizures to paralysis, so maximizing control while minimizing side effects is crucial. The 
historical standard of care has been whole brain radiation therapy, which can be effective in 
controlling some tumors but patients will inevitably experience neurocognitive decline as a side effect 
of this therapy.  
4.2 
Radiation Therapy 
Stereotactic radiosurgery (SRS) has emerged as standard of care treatment for those patients with 1-
3 brain metastases.  This treatment has surpassed whole brain radiation therapy with regard to 
superior local control of brain metastases as well as preservation of neurocognition and quality of 
life.8 Now that new systemic therapies are increasing life expectancy, in patients who have brain 
metastases it is imperative to preserve neurocognition while managing local control.  
With advances in radiosurgery technology, it has become possible to stereotactically treat multiple 
targets at once in an efficient and accurate manner rather than treating each metastasis with SRS 
individually which would be time consuming and difficult for the immobilized patient. There have 
been at least three single institutional studies that examine the feasibility of SIMT SRS but do not 
report clinical outcome.13,14,17  There has been one small study of 26 patients with a range of 2-13 
metastases which reported clinical outcome but did not study quality of life and cognitive endpoints. 
One year local control was reported to be 83%, but median follow up for all patients was only 3.3 
months.15  
4.3 
Study Purpose/Rationale 
There has not been a prospective trial investigating efficacy, survival and quality of life endpoints. The 
purpose of this study is to demonstrate the efficacy and efficiency of SIMT technology for the 
simultaneous treatment of multiple brain metastases, as well as to evaluate quality of life and 
cognition endpoints. We are already using SIMT technology in our clinic as our current departmental 
standard of care for patients with multiple (>4) brain metastases and have seen excellent results in 
terms of local control and quality of life. We are currently working on publishing our retrospective 
results and there is a need for a prospective trial demonstrating the efficacy of this technology. 

 
 
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5 OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Analysis 
Primary 
Assess the impact of using 
SIMT SRS for the treatment 
of brain metastases on 
survival 
Proportion of patients who live 
longer than predicted according to 
the Graded Prognostic Assessment 
(GPA) score 
See Section 13.4 
Key Secondary 
Describe the time to local 
brain recurrence 
Proportion of patients that 
experience local brain recurrence 
within 1 year of SIMT SRS treatment. 
See Section 
13.5.1 
Other Secondary 
Describe the time to distant 
brain recurrence 
Proportion of patients that 
experience a new brain metastasis at 
a site different from the original 
brain metastasis site 1 year after 
SIMT SRS treatment 
See Section 
13.5.2 
Other Secondary 
Describe the time to death 
due to neurological causes  
 
Proportion of patients who are dead 
within 1 year of SIMT SRS treatment 
due to neurologic reasons 
See Section 
13.5.2 
Other Secondary 
Describe the prevalence of 
significant adverse events 
Proportion of patients who 
experience grade 3, 4, or 5 
neurologic adverse events 
attributable to SIMT SRS 
See Section 
13.5.2 
Key Exploratory 
Describe changes over time 
in neurocognition 
Mean changes from baseline in 
subscales of the Trailmaking 
instruments and the HLVT 
See Section 
13.6.1 
Key Exploratory 
Describe changes over time 
in quality of life 
Mean changes from baseline in 
subscales of the FACT-Brain 
instrument 
See Section 
13.6.1 
Other Exploratory 
Quantify treatment set up 
and dosimetric data for this 
treatment technique 
Mean length of time to set-up and 
treat patient, Volume of brain 
exposed to 12Gy, Mean PTV dose,   
Total volume of all brain metastases, 
conformity index, maximum dose 
See Section 
13.6.2 
Other Exploratory 
Describe the rate of salvage 
therapy 
The proportion of patients who 
receive salvage treatment after 
failing SIMT SRS 
See Section 
13.6.2 
Other Exploratory 
Describe prevalence of 
radionecrosis at the SRS site 
Proportion of patients with 
radionecrosis at the SRS site; the 
proportion of lesions showing 
radionecrosis 
See Section 
13.6.2 
Other Exploratory 
Describe length and 
intensity of steroid usage 
post-SRS 
Descriptive statistics 
See Section 
13.6.2 
 
 
 
 
 

 
 
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6 STUDY SCHEMA 
 
 
 
40 patients enrolled with
≥4 brain metastases evaluated by 
brain MRI 
 
SRS treatment 
 
SRS QA
collect data on treatment 
time and position deviation 
 
Follow-up Visits
≈ 4 wks. post SRS 
Year 1 – Every 3 mos. (± 2 wks.), post SRS 
Year 2 – Every 6 mos. (± 2 wks.), post SRS 
 with brain MRI as clinically indicated, 
neurocognitive assessment and QOL 
questionnaire 
 

 
 
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7 SUBJECT ELIGIBILITY 
All patients seeking treatment for cancer metastatic to the brain from an extracranial primary site 
with a contrast-enhanced MRI scan showing 4 or more brain metastases at the Duke Comprehensive 
Cancer Center will be considered.  
 
7.1 
Inclusion Criteria 
 
1. A contrast-enhanced MRI scan showing ≥ 4 treatable brain metastases.  
 
2. Age >18 years of age. 
3. KPS > 70 
4. Patient must be GPA score 0.5 or greater (See Appendix A)  
5. Life expectancy of at least 3 months 
6. Postoperative patients with resected brain metastases are eligible. 
7. Largest lesion < 4cm diameter 
8. Must be a candidate for MRI imaging 
9. Previous cranial SRS/WBRT is allowed if > 3 months prior to SIMT 
10. Must be capable of providing informed consent. 
11. Women of childbearing age must have a negative serum pregnancy test to meet eligibility  
per Duke policy. 
7.2 Exclusion Criteria 
1. Primary lesions with the following histologies: small cell carcinoma, germ-cell tumors, 
lymphoma, leukemia, and multiple myeloma. 
2. Metastases within 2 mm of the optic apparatus  
3. Patients who are unable to obtain MRI 
4. Evidence of leptomeningeal disease. 
5. Greater than 10 brain metastases; excluding previously treated and stable brain metastases. 
6. Pregnant women are excluded. 
8 INVESTIGATIONAL PLAN 
8.1 
Study Design 
This prospective study of 40 patients will assess the efficacy of SIMT SRS for multiple brain 
metastases. Dosimetric data, treatment delivery endpoints, clinical outcomes including local 
control, distant failure and quality of life will be assessed through this trial.   
8.1.1 
Dose Modification 
       Radiation doses will be adjusted as described below in Section 9 
8.1.2 
Safety Considerations 
Patients will be evaluated throughout the study for toxicity. Patients will be assessed for all 
adverse events during treatment and post completion of SRS.  Adverse events will be 
considered to be any grade 3, 4, or 5 event that is deemed by the PI to be probably, possibly, 
or definitely related to the SRS treatment. Acute adverse events will be collected at the first 
post-SRS visit. This visit will occur approximately 4 weeks after the last fraction of SRS is 

 
 
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delivered. These will be collected and reported. In our experience, SRS treatment side effects 
are rare and are solely neurologic. 
In light of previous observations, it may be that increasing the treatment volume may also 
come with a potential cost of increased morbidity.   
8.1.3 
Treatment Interruptions during RT 
There will be no need for treatment interruptions as most treatments will be a single 
treatment. Some patients will require five treatments on business days (refer to section 9.3) 
and in our experience, patients are able to complete all five treatments without 
interruption.  Patients can start their treatment any day of the week and weekend breaks 
are permitted as long as patients have their treatments on consecutive business days. They 
will be evaluated daily by radiation therapists and if a treatment interruption occurs, as long 
as medically stable as deemed by the treating physician, patients will continue treatment 
until completion. If a treatment interruption occurs but the patient completes all five 
treatments within 10 business days, then this would not be considered a protocol deviation. 
8.1.4 
Concomitant Medications/Therapies  
Symptomatic patients should be placed on dexamethasone at the time of brain metastasis 
diagnosis at the discretion of the treating radiation oncologist. The drug may be 
administered orally or intravenously and the dose adjusted throughout the course of 
treatment. In patients who cannot tolerate taper and/or cessation of steroids, the steroid 
dose will be maintained at the lowest dose consistent with good medical practice. 
8.1.5 
Randomization 
There will be no randomization. 
8.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
Doses for radiosurgery are derived from the RTOG 90-05 study, which calculated the 
maximum tolerated dose for brain metastases as a function of size.18 We also found that for 
large lesions in our study of SRS for GBM that this fractionation was well tolerated19 as it 
would certainly reduce the biologically effective dose likely leading to RN. 
8.3 
Rationale for Correlative Studies 
Not applicable. 
8.4 
Definition of Evaluable Subjects, On Study, and End of Study 
All patients who receive SIMT SRS will be included in analyses. 
8.5 
Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all 
subjects on study should be notified as soon as possible.  Additional procedures and/or 
follow up should occur in accordance with Section 10.7, which describes procedures and 
process for prematurely withdrawn patients. 
 

 
 
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9 RADIATION THERAPY 
9.1 
Type, Classification, Location, and Short Description 
SRS will be performed in the Department of Radiation Oncology, Duke University Medical Center. The 
gross tumor volume will be delineated by Grace Kim MD PhD, John P. Kirkpatrick, MD PhD, or Scott 
Floyd, MD PhD, and radiosurgery planning will be assisted by board-certified Physicists. Patients will 
be treated following the RTOG Stereotactic Radiotherapy Guidelines (Appendix B), available at 
http://dx.doi.org/10.1016/j.prro.2011.06.014 
9.2 
Equipment 
SRS doses will be delivered as described below with a linear accelerator-based Novalis Tx and 
TrueBeam STX system, following established procedures for image guided stereotactic radiosurgery. 
Both systems are high-energy linear accelerators from Varian Medical Systems utilizing the same 
model of a high-definition collimator (2.5mm leaf thickness at isocenter) to precisely shape the 
radiation beam.  Both units use kilovoltage orthogonal x-ray imaging systems and cone-beam CT to 
ensure the patient is set-up in the exact, correct position with each and every treatment.  While the 
system names are different, the Novalis Tx and TrueBeam STx yield equivalent dose distributions.20 
 
9.3 
Dose Specifications 
The total dose is dependent on the maximum diameter of the PTV and total lesion volume as 
described below: 
 
Maximum PTV Diameter  
 Assigned Dose 
< 2.0 cm  
 
        20 Gy x 1 
2.0-3.0 cm  
 
        18 Gy x 1 
≥ 3cm  
          
          5 Gy x 5 
The total prescribed dose is determined by tumor size. These assigned doses may be decreased based 
on clinical judgment. V12 will be recorded for each case. V12 is defined as the volume of normal brain 
receiving 12 Gy. Normal brain is defined as volume of normal brain parenchyma (not including normal 
tissue outside of meninges), minus total PTV volume. 
If V12Gy (Volume receiving 12 Gy) for normal brain parenchyma (i.e., excluding the PTV’s) exceeds 20 
mL, then the dose to all lesions will be 5 x 5 Gy where one treatment will be delivered each day for 
five consecutive business days (i.e. the first treatment may start mid-week and be completed in the 
following week).  If there is a lesion in the brainstem, all lesions will be treated with 5 Gy x 5 because 
the brainstem is particularly sensitive to high doses of radiation given in a single fraction. 
The SRS dose has been selected in order to provide a high rate of local control with minimum risk 
of radionecrosis. These doses are already being used in our clinic as our departmental standard of 
care derived from the RTOG 9005 SRS dose escalation study.18 
The dose will be prescribed to the absolute isodose surface, which encompasses the margin of the 
metastasis, as defined by the contrast-enhanced MRI. The maximum dose, minimum dose to the GTV 
and PTV, and percent volume coverage of the GTV and PTV will be recorded for each patient. The 

 
 
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prescription dose shall be delivered to the absolute isodose surface. The minimum dose shall be 
established by the SRS treatment planning software and/or by the target dose-volume histogram. 
 
Each lesion will be prescribed an SRS dose according to the maximum diameter of the PTV as well as 
the total volume. If any two lesions are within 1 cm of one another, the prescription dose to these 
groups of lesions will be based on the maximum diameter across these two lesions.   At the discretion 
of the PI, the dose to lesions in eloquent areas of the brain (e.g., the motor strip or the speech center) 
may be reduced from 20 to 18 Gy for PTV < 2cm in diameter and from 18 to 16 Gy for PTV 2-3cm 
diameter. 
 
To summarize, lesions will be treated in one fraction unless a lesion is greater than 3cm, located in 
the brainstem, or the V12 of the normal brain exceeds 20 cc.  
 
In the setting of multiple metastases, a lesion(s) may need to be resected because of large size or 
mass effect that causes serious neurologic deficits. The resulting resection cavity/cavities can be 
treated along with the other unresected metastases with the SIMT technique. This has not occurred 
commonly in our practice but surgery does not preclude the use of this technology.   
 
Isodose distributions must be calculated, and the prescription isodose line clearly designated, for each 
target lesion in the transverse, coronal, and sagittal planes. The isodose distributions on the required 
three planes for each target lesion will include isodose lines (in % dose) that represent 20% dose 
increments. Cumulative dose-volume histograms must be calculated for all target lesions, as well as 
the brainstem, optic chiasm, optic nerves, eyes and normal brain parenchyma. 
 
Each lesion will be consistently labeled according to institutional protocol and separately followed 
and documented. With every MRI, any changes in each lesion will be recorded. MRI image registration 
using department radiation planning software (iPlan) will aid in detecting differences in lesion size and 
number.  
9.4 
Localization, Simulation, and Immobilization 
An FDA-approved stereotactic radiosurgery system will be used for all localization and treatment 
planning. All patients must undergo a pretreatment contrast-enhanced planning MRI within one week 
prior to radiosurgery. Patients who have completed a diagnostic MRI with contrast within 14 days of 
radiosurgery  do not need to  have  a planning MRI. All patients will be treated on the Varian/BrainLAB 
linear accelerator-based radiosurgery system (Novalis Tx & TrueBeam STX) following established QA 
procedures for treatment delivery.  
 
Per the standard of care, target volume and isocenter determination will be based on a contrast-
enhanced axial MRI scan. A CT scan will be performed with the patient’s head immobilized in a custom 
thermoplastic mask, and the CT and contrast-enhanced axial 3D MR images fused.  The MRI study 
used to plan the radiosurgical treatment must be the same as used to determine the size of the 
metastatic lesions. The MRI slice thickness may not exceed 1 mm. The target volume will include the 
enhancing portion of the metastatic lesion. Surrounding areas of edema will not be considered part 
of the target volume. 
9.5 
Imaging 
Orthogonal KV and CBCT imaging of patient in the immobilization mask will be done before each 
radiation delivery.  

 
 
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9.6 
Treatment Planning/Target Volumes 
Target Volume Definitions 
The volumes shall be defined by contrast-enhanced MRI with the patient in the treatment position. 
ICRU-50 nomenclature target volumes are defined as follows: GTV: Defined as contrast-enhancing 
tumor seen on pretreatment MRI. PTV: For the purpose of this study, the PTV is defined as the GTV 
uniformly expanded by 1 mm in all dimensions. The PTV must be < 4.0 cm. 
 
Target Dose 
Prescription Specification: The dose should be prescribed to the highest isodose line encompassing 
the PTV. 
 
Dose Definition 
Dose is specified in Gray (Gy). 
9.7 
Dose Limitations for Normal Tissue 
The treatment parameters should be modified to optimize the conformity of the prescription volume 
to the target volume while minimizing dose to critical structures. In patients receiving single fraction 
treatments, the maximum point dose to the optic chiasm and optic nerves should not exceed 10 Gy 
and maximum dose to the brainstem should be less than 12.5 Gy.  In patients receiving 5 Gy per 
fraction for five fractions, the maximum point dose to the optic chiasm and optic nerves should not 
exceed 20 Gy and the maximum dose to 99% of the brainstem should not exceed 26 Gy.   
9.8 
Treatment Verification 
Patients will be monitored by the treating physician (Dr. Grace Kim, Dr. John Kirkpatrick, or Dr. Scott 
Floyd), and the therapists and physicists during the procedure. The departmental policy has been 
standard of care time out prior to delivery of each fraction of radiation therapy and this will be 
meticulously adhered to. 
9.9 
Quality Assurance of Dose Distribution 
Lesion Identification 
Lesions must be uniquely identified by anatomical location, e.g., medial left frontal lobe, inferior/ 
superior right cerebellum, etc, so that these lesions can be readily followed on serial MRI’s.  
 
Isodose QA 
Four isodose lines should be reviewed: The prescription isodose line, 90% of the prescription 
isodose line (not 90% of total dose), 80% of the prescription isodose line, and 50% of the prescription 
isodose line. 
 
Target Coverage QA 
Per protocol: The submitted 100% isodose line (100% of the prescription dose, not maximum dose) 
covers >99% of the target volume. 
Acceptable variation:  100% isodose line covers >95% of the target. 
Unacceptable deviation: 100% isodose line covers >90% of the target. 
 
Dose QA 
Per protocol: If the maximum dimension of the tumor is: 

 
 
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< 2.0 cm: 20 Gy 
> 2.0 cm and < 3.0 cm: 18 Gy 
>3.0 cm: 5 Gy x 5 all lesions, regardless of diameter 
In addition, if any lesion is located in the brainstem or the total V12Gy calculated for single-fraction 
treatment exceeds 20 ml, all lesions will be treated with 5Gy x 5, regardless of diameter. For 
metastases that are close to critical structures, doses will be reduced as stated above in Section 9.3. 
Unacceptable deviation: Anything else 
 
Dose Conformity QA 
The ratio of prescription isodose volume (for maximum planned prescription dose per plan) to the 
total target volume (Conformity Index) is: 
Per protocol if between 1.0 and 2.0 
Acceptable variation if ≥ 0.9 but < 1.0 or >2.0 but ≤ 3.5. 
Unacceptable deviation if > 3.5. 
10 PATIENT ASSESSMENTS 
A clinical research nurse will contact each patient by telephone within 2 weeks after the SRS 
procedure to inquire as to the patient’s health status if the patient does not have an appointment 
with an oncologist at DUMC within that time.  
 
At follow-up visits patients will be evaluated as described in the Table below. Patients will be seen in 
clinic and undergo repeat MRI imaging as standard of care every 3 months for the first 12 months 
following completion of SRS and every 6 months for the following 12 months. During the follow up 
visits, the patient will be examined for new or recurrent neurologic signs/symptoms. On MRI, local 
recurrence is defined as the reappearance of a metastasis in the SRS treated field (within the 50% 
isodose line).  Each treated lesion will be documented separately. Distant recurrence is defined as 
the appearance of a new brain metastasis outside the SRS field (completely outside the 50% isodose 
line).  To be deemed a recurrence or new lesion, the lesion must measure at least 5 mm in the axial 
plane on MRI.  
 
Patients with a recurrent or new lesion, who are symptomatic, may undergo a biopsy to determine 
if the lesion is secondary to radionecrosis or metastasis.  Appropriate salvage therapy will be 
performed at the discretion of the treating radiation oncologist. 
 
If on evaluation the treating physician decides not to pursue an MRI because of clinical decline, this 
will not be a protocol violation.  The most current brain MRI will be used in the determination of local 
control. Conversely, if a brain MRI needs to be done at an earlier time point due to medical necessity, 
an MRI at that time point will also not be a protocol deviation and can be included in the data 
collection. Brain MRI’s may be done at 3 month intervals with a one month before or after allowance. 
 
In addition, included in the category of updated medical history is pertinent interim oncologic and 
medication history. A medical oncologist overseeing patient’s standard of care will have been 
responsible for chemotherapy management as well as systemic staging scans. We will record the 
type and duration of systemic therapies with each visit as well as the latest information on staging 
scans (stable or regression vs. progression of disease).  
 

 
 
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Study Calendar 
 
 
Pre-
study 
During 
SRS 
First visit 
post SRS 
(≈ 4 wks.) 
Follow-up
Yr.1: every 3-mos. 
Yr. 2: every 6-mos. 
(±2 wks.) 
Informed Consent
X
 
 
 
PE including Neurological 
exam, updated Med 
History. 
X1
 
X
X
Neurocognitive 
Assessments  
X
 
X4
X4
Performance Status
X
 
X
X
FACT-Br
X
 
X
X
Adverse Event Assessment
X
X
X3
X2 
MRI
X
 
 
X2
Tumor Measurements
X
 
 
X2
1. No more than 15 days prior to SRS.    
2. As clinically indicated  
3. Acute toxicity will be collected at this visit which will occur approximately 4 weeks’ after 
the last fraction of SRS. If patients are unable to attend follow up due to clinical decline this 
would not be considered a protocol deviation. 
4. It will not be considered a protocol deviation if a patient declines to complete 
neurocognitive testing at any follow up visit. 
 
10.1 Pretreatment Evaluations/Management 
 
Complete history and physical examination with a detailed neurological examination 
within 15 days of study registration. 
 
Quality of Life form FACT-Br completion (see Appendix F) 
 
Neurocognitive assessment: HVLT, TMT, MMSE (see Appendices D and E) 
10.2 Screening Examination 
Patients will be registered only after eligibility criteria are met. Once research staff and PI have 
verified that the patient is eligible per Departmental policy and that the study ongoing regulatory 
requirements have been met, a patient-specific case number will be assigned. An informed 
consent must be signed by the patient before any screening procedure takes place. If, however, 

 
 
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standard of care evaluation procedures have been obtained and are within the screening 
evaluation time points, the SOC procedures do not need to be repeated and may be included in 
the screening examination. All of the eligibility inclusion and exclusion criteria should be satisfied 
during each screening process. 
10.3 Treatment Period 
Treatment will range from 1 to 5 consecutive business days and those patients that get multiple 
treatments will be observed every day by radiation therapists.  
 
Those patients that will be treated in 5 days are the following: 
1) at least 1 metastasis > 3cm 
2) V12 > 20 cc for normal brain parenchyma, all lesions will receive 5 Gy x 5 
3) If there is a brainstem lesion 
 
If a treatment interruption occurs but the patient completes all five treatments within 10 business 
days, then this would not be considered a protocol deviation. 
 
Sexually active, subjects must agree to use appropriate contraceptive measures for the duration of 
the study treatment (i.e. from SRS CT simulation to the completion of SRS treatment, which is 
approximately 1-2 weeks). 
10.4 End of Treatment 
They will be seen by either an NP or MD to be given discharge instructions. Any acute side effects of 
treatment will be assessed via CTCAE v.4 and documented.  
10.5 Follow-up Period 
Follow-up period will be two years. The first visit is approximately 4 weeks post SRS, every 3 months 
in the 1st year post SRS, and then every 6 months in the 2nd year within ± 2-weeks. Each visit will 
include an updated medical history and physical exam, neurological exam, performance status, 
adverse events and toxicity assessment, quality of life, and neurocognitive testing. During the follow 
up period a standard of care contrasted MRI and/or tumor measurements will be performed as 
clinically indicated by the treating investigator.    
10.6 End of Study 
End of study will be completion of data analysis.   
10.7 Early Withdrawal of Subject(s) 
10.7.1 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject 
from the study at any time based on his/her discretion.  Reasons for PI-initiated withdrawal may 
include, but is not limited to the following: 
 
- 
Protocol deviation 
- 
Administrative issues 
- 
Local or distant recurrence evident on Brain MRI imaging 
 

 
 
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Patients who demonstrate local or distant progression in the brain after study treatment will 
be followed for overall survival only but will not have neurocognitive testing performed. 
10.7.2 Follow-up Requirements for Early Withdrawal 
Patients will continue to be assessed every three months with an MRI and history and physical 
exam which is our standard of care.  
10.7.3 Replacement of Early Withdrawal(s) 
We will accrue 40 patients and will not replace patients once the accrual process is through. We 
treat over 300 SRS patients a year and we estimate that we should be able to accrue to the study 
readily. 
10.8 Study Assessments 
10.8.1 Medical History 
A thorough medical history and review of systems will be obtained by the NP/MD. Oncologic 
information will be updated each visit, such as: type and duration of systemic therapies and 
performance status. The HVLT, MMSE, and FACT-BR will also be administered with each  visit.  
10.8.2 Physical Exam 
Standard Physical exam including extensive neurology exam will be performed with each follow 
up visit.  
10.8.3 Correlative Assessment 
Not applicable 
11 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse 
events, as defined below.  At each study visit, the PI or designee must assess, through non-
suggestive inquiries of the subject or evaluation of study assessments, whether an AE or SAE has 
occurred. 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and 
which does not necessarily have a causal relationship with this treatment.  For this protocol, the 
definition of AE also includes worsening of any pre-existing medical condition.  An AE can therefore 
be any unfavorable and unintended or worsening sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of radiation therapy, whether or not 
related to use of the radiation therapy.  Abnormal laboratory findings with or without clinical 
significance will be attributed to systemic therapy and should not be recorded as AEs.  
 
From the time the subject signs the informed consent form through the End of Study visit (as 
defined in Section 10.4), all AEs judged by the treating physician or study investigators to be 
possibly, probably, or definitely related to the SIMT treatment must be recorded in the subject 
medical record and adverse events case report form. AEs related to systemic therapies will be 
managed by the treating MD or study investigators and will not be collected.  

 
 
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AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, 
the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or 
fatal (5). 
 
Attribution of AEs will be indicated as follows: 
 
Definite:  The AE is clearly related to the study therapy 
 
Probably:  The AE is likely related to the study therapy 
 
Possible:  The AE may be related to the study therapy 
 
Unlikely:  The AE is doubtfully related to the study therapy 
 
Unrelated:  The AE is clearly NOT related to the study therapy 
11.1.1 
AEs of Special Interest 
Patients will be evaluated throughout the study for toxicity. Patients will be assessed for all 
adverse events during treatment and post completion of RT. Adverse Events (AEs) that are 
deemed by the PI to be related to the SIMT SRS treatment will be collected and reported. Acute 
adverse events will be collected at the first post-SRS visit. This visit will occur approximately 4 
weeks after the last fraction of SRS is delivered. While not all-inclusive, the list below indicates 
side effects that may be related to the treatment. In the largest trial examining SRS treatment to 
5-10 multiple targets (n = 1194), grade I & 2 toxicity was seen in 5% and Grades 3-4 were seen in 
3%, and grade 5 toxicity <1%. 12 
SRS Possible Side Effects 
Likely: 
Mild erythema in the treatment field 
Nausea / vomiting 
Headaches 
Fatigue 
 
Less likely: 
Hair loss in the treatment field 
Decreased mental abilities 
Extremity weakness 
Parathesias 
Speech difficulties 
Hydrocephalus 
Radionecrosis 
Seizures 
Vision loss 
Death 
 
 
 
 

 
 
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11.1.2 
Reporting of AEs 
For all adverse events deemed by the PI to be related to the SIMT SRS treatment, the information 
should be recorded in the patient’s medical record and the Case Report Form or AE database for 
that patient.  This should include a description of the event, its severity or toxicity grade, the 
relationship to the study treatment, and the intervention, outcome and sequelae of the event. 
11.2 Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
 
Fatal 
 
Life-threatening 
 
Constitutes a congenital anomaly or birth defect 
 
A medically significant condition (defined as an event that compromises subject safety or 
may require medical or surgical intervention to prevent one of the three outcomes above) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption to conduct normal life 
functions 
Any serious or unexpected event, which occurs to any patient in the course of their treatment on 
this study or within 30 days following cessation of treatment, is reported immediately to the Study 
Coordinator by telephone 668-3726, within 24 hours of the clinician learning of its occurrence.   
11.3 Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data 
Safety Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and 
new information that may affect subject safety or efficacy. Annual safety reviews include but may not 
be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, 
reference literature, and interim analyses as provided by the sponsor-investigator.  The SOC in concert 
with the DCI Monitoring Team (see Section 12.1 for Monitoring Team description) oversees the 
conduct of DUHS cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies 
that do not have an external monitoring plan, ensuring subject safety and that the protocol is 
conducted, recorded and reported in accordance with the protocol, standing operating procedures 
(SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements. The DCI Safety Oversight 
Committee (SOC) will perform annual reviews on findings from the DCI Monitoring Team visit and 
additional safety and toxicity data submitted by the Principal Investigator. 
11.4 External Data and Safety Monitoring Board (DSMB) 
We do not have a potential conflict of interest. 

 
 
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12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject 
safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the 
protocol, standard operating procedures, good clinical practice, and applicable regulatory 
requirements.  As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will 
conduct routine monitoring after the third subject is enrolled, followed by annual monitoring of 1 – 3 
subjects until the study is closed to enrollment and subjects are no longer receiving study 
interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS 
and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the 
sponsor, the Principal Investigator, or the IRB.  All study documents must be made available upon 
request to the DCI Monitoring Team and other authorized regulatory authorities, including but not 
limited to the National Institute of Health, National Cancer Institute, and the FDA.  Every reasonable 
effort will be made to maintain confidentiality during study monitoring. 
12.2 Audits 
The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) may conduct confidential 
audits to evaluate compliance with the protocol and the principles of GCP.  The PI agrees to allow the 
OARC auditor(s) direct access to all relevant documents and to allocate his/her time and the time of 
the study team to the OARC auditor(s) in order to discuss findings and any relevant issues. 
 
OARC audits are designed to protect the rights and well-being of human research subjects. OARC 
audits may be routine or directed (for cause). Routine audits are selected based upon risk metrics 
generally geared towards high subject enrollment, studies with limited oversight or monitoring, 
Investigator initiated Investigational Drugs or Devices, federally-funded studies, high degree of risk 
(based upon adverse events, type of study, or vulnerable populations), Phase I studies, or studies that 
involve Medicare populations. Directed audits occur at the directive of the IRB or an authorized 
Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess 
whether the research is conducted according to the protocol approved by the DUHS IRB. The primary 
purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials 
and the quality of data produced by the clinical trial research are met. The audit/review will serve as 
a quality assurance measure, internal to the institution. Additional goals of such audits are to detect 
both random and systemic errors occurring during the conduct of clinical research and to emphasize 
“best practices” in the research/clinical trials environment. 
12.3 Data Management and Processing 
12.3.1 Case Report Forms (CRFs) 
The REDCap Database CRF (electronic) will be the primary data collection document for the study.  
The CRF will be updated in a timely manner following acquisition of new source data.  Only 
approved study staff are permitted to make entries, changes, or corrections in the CRF. 

 
 
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An audit trail will be maintained automatically by the REDCap electronic CRF management system. 
Designated personnel will complete user training, as required or appropriate per regulations. 
12.3.2 Data Management Procedures and Data Verification 
Clinical research nurses, all investigators, and statisticians involved in the project will have access 
to REDCAP based on their specific roles in the protocol.  The designated data manager will be 
managing the REDCAP database.  
 
Completeness of entered data will be checked automatically by the eCRF system, and users will 
be alerted to the presence of data inconsistencies.  Additionally, the data manager will cross-
reference the data to verify accuracy.  Missing or implausible data will be highlighted for the PI 
requiring appropriate responses (i.e. confirmation of data, correction of data, completion or 
confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only 
after resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to 
the data. 
12.3.3 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following 
 
activities: 
- 
Data clarification and/or resolution 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories. 
13 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key personnel.  
Any data analysis carried out independently by the investigator must be approved by the statistician 
before publication or presentation. 
13.1 Analysis Sets 
All patients who undergo SIMT SRS treatment will be included in both safety and efficacy analyses. 
13.2 Patient Demographics and Other Baseline Characteristics 
Socio-demographic and clinical characteristics of patients enrolled and treated on this study will be 
summarized.  For categorical variables, frequencies and percentages will be provided.  Means with 
standard deviations and medians/percentiles will summarize non-categorical variables.  Included 
among the clinical variables that will be summarized will be diagnosis (i.e. site of primary disease), 
and size and location of brain metastases. 
13.3 Treatments 
A frequency distribution for the number and volume of brain metastases, as well as the total brain 
volume receiving 12 Gy or more (V12Gy), will be generated.  Details about concomitant treatment of 
the primary disease will also be summarized. 

 
 
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13.4 Primary Objective 
The primary objective of this study is to assess the impact of using SIMT SRS for the treatment of 
patients with ≥4 brain metastases. 
13.4.1 Variable 
Though local control is of primary interest in this study, there is concern about the ability to 
differentiate between swelling due to radiation and disease progression without conducting a 
biopsy.  The use of a biopsy to determine recurrence is not feasible given the number of brain 
metastases.  Hence we focus on the survival of patients with brain metastases who are treated 
with SIMT SRS.  The goal of the study is to confirm that use of SIMT SRS does not reduce the 
prognosis of patients. 
 
The population of patients with brain metastases is a heterogeneous population with expected 
survival ranging between 3 and 25 months.  We will use the expected survival defined by the 
diagnosis-specific GPA (Graded Prognostic Assessment) index to assess the efficacy of SIMT SRS.16  
Specifically, for each patient we will determine whether the patient lives longer than expected 
based upon the GPA index.  If the survival of patients treated with SIMT SRS is truly comparable 
to the survival of patients treated with currently available treatment regimens, then we would 
expect that approximately half of the patients would live longer than expected.   
 
Hence, the primary endpoint of the study will be the proportion of patients who live longer than 
expected according to the diagnosis-specific GPA index. 
13.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The goal of the study is to confirm that the use of SIMT SRS does not significantly reduce or 
compromise the prognosis of patients.  Within each of 5 diagnosis groups (non-small cell lung 
cancer, melanoma, breast cancer, renal cell carcinoma, and GI cancer), various prognostic groups 
have been defined by Sperduto.16  Within each of these diagnosis-prognosis groups, an expected 
survival has been determined.  It is hoped that the survival of patients treated with SIMT SRS is 
similar to or better than that seen among Sperduto’s cohort.  In other words, it is hoped that the 
survival with SIMT SRS is not inferior to that reported in the Sperduto paper. 
 
With the expected proportion of patients living longer than expected to be 50%, a test of non-
inferiority will be conducted.  Details are provided in the section concerning sample size 
justification. 
 
Additionally, the Kaplan-Meier estimator will be used to describe the survival of all patients 
treated with SIMT SRS.  The survival of patients within diagnosis-specific subgroups will also be 
similarly described.  Within the context of the Kaplan-Meier estimator, median survival, 6-month 
survival, and 12-month survival will be estimated.  Survival is defined as the time between 
initiation of SIMT SRS and death, and will be censored at last follow-up if the patient remains alive. 
13.4.3 Inferences 
This study has been designed with the best historical data currently available to assess the efficacy 
of SIMT SRS in a single-arm study.  However, this benchmark is imperfect, and does not reflect 
the possible impact of rapidly emerging novel therapeutics, including immunotherapies, that 
target the primary disease of these patients. In addition, this benchmark does not reflect the few 

 
 
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patients we may have with recurrent brain metastases as the GPA scoring was developed from a 
database that included patients who completed brain treatment within 2 months of the diagnosis 
of brain metastases. If a better benchmark data becomes available during the conduct of this 
study, the design of this single-arm study may be modified. 
 
Though a decision-rule is provided in section 13.8 to test the non-inferiority of SIMT SRS treatment 
relative to the Sperduto GPA-based benchmark, other factors will be considered in determining 
whether further usage of SIMT SRS is reasonable.  Two important issues that will factor into this 
decision-making include:  technical feasibility of administering SIMT SRS, and clinical factors such 
as neurologic control and local control. 
13.5 Secondary Objectives 
The key secondary objective is to describe the time to local recurrence.  Other secondary 
objectives focus on the time to distant recurrence, time to neurologic death, and the prevalence 
of significant adverse events. 
13.5.1 Key Secondary Objective 
The time until local brain recurrence will be calculated as the time between initiation of SIMT SRS 
and local recurrence of brain metastases.  The time to local brain recurrence will be censored at 
the time of last follow-up if the patient remains alive without local recurrence, or will be censored 
at death if the patient dies without local recurrence of brain metastases.  A Kaplan-Meier 
estimator will be used to describe the time until local recurrence.  Within the context of Kaplan-
Meier curve, an estimate of the proportion of patients without local brain recurrence one year 
after SIMT SRS treatment will be generated.  The time until local brain recurrence will also be 
described within diagnosis-specific subgroups. 
13.5.2 Other Secondary Objectives 
The time until distant brain recurrence will be calculated as the time between initiation of SIMT 
SRS and distant recurrence of brain metastases.  The time to distant brain recurrence will be 
censored at the time of last follow-up if the patient remains alive without distant recurrence, or 
will be censored at death if the patient dies without distant recurrence of brain metastases.  A 
Kaplan-Meier estimator will be used to describe the time until distant recurrence.  An estimate of 
the proportion of patients without distance recurrence one year after SIMT SRS treatment will be 
generated.  The time until distant brain recurrence will also be described within diagnosis-specific 
subgroups. 
 
Time to neurologic death is defined as the time between initiation of SIMT SRS and death due to 
neurologic causes.  If a patient remains alive or dies for reasons unrelated to neurologic disease, 
the time to neurologic death will be censored at the time of last follow-up or death not due to 
neurologic causes.  Analyses similar to other “time to an event” outcomes will be conducted 
including the generation of Kaplan-Meier curves.  
 
The proportion of patients who experience grade 3 or worse neurologic toxicity attributable to 
SIMT SRS will be summarized.  In addition, adverse events experienced by protocol subjects will 
also be summarized in several other forms to satisfy scientific and monitoring needs, as well as 
various regulatory reporting needs (e.g. DCI SOC, and ClinicalTrials.gov). The frequency of adverse 
events that are possibly, probably, or definitely related to protocol treatment will be tabulated by 
the maximum grade for each type of adverse event.   

 
 
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13.6 Exploratory Objectives 
This protocol includes several exploratory objectives: (1) To describe changes in neurocognition 
over time, (2) To describe changes in quality of life over time, (3) To quantify treatment set-up 
and dosimetric data for the SIMT SRS treatment technique, (4) To describe the rate of salvage 
therapy, (5) To describe the prevalence of radionecrosis at the SRS site, and (6) To describe the 
length and intensity of steroid usage post-SRS. 
13.6.1 Key Exploratory Objectives 
The mean changes from baseline in neurocognition as measured by Trailmaking A and B, the 
MMSE and the HVLT will be summarized.  Similarly, the mean changes from baseline in quality of 
life as measured by the FACT-Brain, will be summarized. 
13.6.2 Other Exploratory Objectives 
Descriptive statistics (e.g. mean, median, quantiles) will be used to describe the treatment set-up 
and dosimetric data associated with the SIMT SRS treatment technique.  Specifically, the mean 
and median time to set-up of the patient’s SIMT treatment will be generated.  Means and medians 
will also describe the mean volume of brain exposed to 12Gy, the PTV dose, and the total volume 
of all brain metastases. 
 
The proportion of patients who receive salvage treatment after failing SIMT SRS will be estimated, 
and the type of treatment received will be summarized.   
 
Data concerning radionecrosis will be summarized at the level of a lesion, as well as the patient 
level.  The proportion of lesions who exhibit radionecrosis after SIMT SRS treatment will be 
summarized.  With each patient having multiple lesions, the percentage of lesions within a patient 
that show radionecrosis will also be summarized with medians and quantiles. 
 
The length and dose of steroid usage post-SRS will be summarized using descriptive statistics. 
13.7 Interim Analysis 
Adverse events experienced by patients will be reviewed in an aggregate manner at least annually. 
13.8 Sample Size Calculation 
Forty (40) patients will be accrued to this study and treated with SIMT SRS.  If 17 or more of these 
patients live longer than expected according to the GPA score, then SIMT SRS will be considered non-
inferior to historical data pertaining to survival of patients with brain metastases.  With this decision 
rule and 40 patients, there is 90% power to detect a non-inferiority difference of -0.2 using a one-
sided exact test with a target significance level of 0.10 (PASS 14, 2015).  The actual significant level 
achieved is 0.0633.   
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 

 
 
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14.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related 
documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol 
Committee (CPC) for review.  The study may be initiated only after the Principal Investigator has 
received written and dated approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any 
protocol amendments that potentially affect research design or data analysis (i.e. amendments 
affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, 
etc.).  
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most 
recent IRB approval.  The Principal Investigator must also obtain protocol re-approval from the CPC 
within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject 
enrollment. 
14.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other study-
related matters.  This discussion will occur in a location that ensures subject privacy and in a manner 
that minimizes the possibility of coercion.  Appropriate accommodations will be made available for 
potential subjects who cannot read or understand English or are visually impaired.  Potential subjects 
will have the opportunity to contact the Principal investigator or authorized key personnel with 
questions, and will be given as much time as needed to make an informed decision about participation 
in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must obtain written 
informed consent from the subject or a legally acceptable representative.  The original informed 
consent form will be stored with the subject’s study records, and a copy of the informed consent form 
will be provided to the subject.  The Principal Investigator is responsible for asking the subject whether 
the subject wishes to notify his/her primary care physician about participation in the study.  If the 
subject agrees to such notification, the Principal Investigator will inform the subject’s primary care 
physician about the subject’s participation in the clinical study. 
14.4 Study Documentation 
Study documentation includes but is not limited to source documents, case report forms (CRFs), 
monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 

 
 
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Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical trial.  When possible, the 
original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
 
A REDCap case report form (CRF) will be the primary data collection document for the study.  The 
CRFs will be updated within two weeks of acquisition of new source data.  Only investigators and 
research nurse staff are permitted to make entries, changes, or corrections in the CRF.  For paper 
CRFs, errors will be crossed out with a single line, and this line will not obscure the original entry.  
Changes or corrections will be dated, initialed, and explained (if necessary).  The investigators or 
authorized key personnel will maintain a record of the changes and corrections.  For electronic CRFs, 
an audit trail will be maintained by the REDCap CRF management system. 
14.5 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will 
be maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional 
Site Based Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study.  Prospective participants will be consented in an exam room where it is just 
the research staff, the patient and his family, if desired. For all future visits, interactions with research 
staff (study doctors and study coordinators) regarding research activities will take place in a private 
exam room. All research related interactions with the participant will be conducted by qualified 
research staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff. Subjects will be identified only by a unique study number 
and subject initials.  Electronic records of subject data will be maintained using a dedicated database 
(REDCap), which is housed in an encrypted and password-protected drive.  Access to electronic 
databases will be limited to the research study team in the Department of Radiation oncology.  
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
 
14.6 Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring 
Plan.  For a more detailed description of the DSMP for this protocol, refer to Section 11 (Sections 11.3 
and 11.4 in particular) along with section 12. 

 
 
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14.7 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior 
to implementation.  IRB approval is not required for protocol changes that occur to protect the safety 
of a subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and 
all other applicable regulatory agencies of such action immediately. 
14.8 Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of:  
 
at least six years after study completion  
 
 
 

 
 
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15 REFERENCES 
 
1. 
Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of 
patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 
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2. 
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of 
brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer 
Surveillance System. Journal of Clinical Oncology. 2004;22(14):2865-2872. 
3. 
Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single 
metastases to the brain. N Engl J Med. 1990;322(8):494-500. 
doi:10.1056/NEJM199002223220802. 
4. 
Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: 
radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583-590. 
doi:10.1002/ana.410330605. 
5. 
Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy 
vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled 
trial. JAMA. 2006;295(21):2483-2491. doi:10.1001/jama.295.21.2483. 
6. 
Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain 
radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer. 
2012;118(9):2486-2493. doi:10.1002/cncr.26515. 
7. 
Soon YY, Tham IWK, Lim KH, Koh WY, Lu JJ. Surgery or radiosurgery plus whole brain radiotherapy 
versus surgery or radiosurgery alone for brain metastases. Cochrane Database Syst Rev. 
2014;(3):CD009454. doi:10.1002/14651858.CD009454.pub2. 
8. 
Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole 
Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases. JAMA. 
2016;316(4):401-409. doi:10.1001/jama.2016.9839. 
9. 
O'Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O'Fallon JR. A comparison of surgical 
resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat 
Oncol Biol Phys. 2003;55(5):1169-1176. 
10. 
Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: analysis of 
outcome and risk of brain radionecrosis. Radiat Oncol. 2011;6:48. doi:10.1186/1748-717X-6-48. 
11. 
Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly 
diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based 
guideline. Pract Radiat Oncol. 2012;2(3):210-225. doi:10.1016/j.prro.2011.12.004. 
12. 
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple 
brain metastases (JLGK0901): a multi-institutional prospective observational study. The Lancet 

 
 
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Oncology. 2014;15(4):387-395. doi:10.1016/S1470-2045(14)70061-0. 
13. 
Clark GM, Popple RA, Young PE, Fiveash JB. Feasibility of single-isocenter volumetric modulated 
arc radiosurgery for treatment of multiple brain metastases. Int J Radiat Oncol Biol Phys. 
2010;76(1):296-302. doi:10.1016/j.ijrobp.2009.05.029. 
14. 
Huang Y, Chin K, Robbins JR, et al. Radiosurgery of multiple brain metastases with single-
isocenter dynamic conformal arcs (SIDCA). Radiother Oncol. 2014;112(1):128-132. 
doi:10.1016/j.radonc.2014.05.009. 
15. 
Nath SK, Lawson JD, Simpson DR, et al. Single-isocenter frameless intensity-modulated 
stereotactic radiosurgery for simultaneous treatment of multiple brain metastases: clinical 
experience. Int J Radiat Oncol Biol Phys. 2010;78(1):91-97. doi:10.1016/j.ijrobp.2009.07.1726. 
16. 
Sperduto PW, Kased N, Roberge D, et al. Summary Report on the Graded Prognostic Assessment: 
An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain 
Metastases. Journal of Clinical Oncology. 2012;30(4):419-425. doi:10.1200/JCO.2011.38.0527. 
17. 
Sperduto PW1, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other 
indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. 
International Journal of Radiation Oncology Biology Physics. 2008;70(2): 510-514. 
doi:10.1016/j.ijrobp.2007.06.074. 
18.  
Liu H, Andrews DW, Evans JJ, et al. Plan Quality and Treatment Efficiency for Radiosurgery to 
Multiple Brain Metastases: Non-Coplanar RapidArc vs. Gamma Knife. Front Oncol. 2016;6(1):26. 
doi:10.3389/fonc.2016.00026. 
19. 
Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously 
irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J 
Radiat Oncol Biol Phys. 2000;47(2):291-298. 
20. 
Cabrera AR, Cuneo KC, Desjardins A, et al. Concurrent stereotactic radiosurgery and bevacizumab 
in recurrent malignant gliomas: a prospective trial. Int J Radiat Oncol Biol Phys. 2013;86(5):873-
879. doi:10.1016/j.ijrobp.2013.04.029. 
21. 
Kirkpatrick JP, Wang Z, Sampson JH, et al. Defining the optimal planning target volume in image-
guided stereotactic radiosurgery of brain metastases: results of a randomized trial. Int J Radiat 
Oncol Biol Phys. 2015;91(1):100-108. doi:10.1016/j.ijrobp.2014.09.004. 
 
 
 
 
 
 

 
 
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16 
Appendix A: GPA Criteria for NSCLC, Melanoma, Breast, Renal Cell & GI Cancers 
GPA score: Graded prognostic assessment (GPA), is a prognostic index for patients with brain 
metastases based on histology.  Sperduto et al [16], reported that the diagnosis-specific GPA is the least 
subjective, most quantitative and easiest tool to use based on a multi-institutional database of 3,900 
patients with brain metastases.   
 
 
Abbreviations: Breast Subtype: Basal= Triple Negative (ER/PR/HER2-), LumA: (ER/PR positive, HER2 
negative); LumB = (triple positive); HER2= (ER/PR negative, HER2 positive); brain metastases (BM), 
extracranial metastases (ECM); ER = estrogen receptor; HER = human epidermal growth factor receptor 
2; KPS = Karnofsky performance score; LumA = luminal A; LumB =luminal B; PR = progesterone receptor. 
[16]. 
 
 

 
 
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17 Appendix B: GPA Criteria for Other Cancer Histology 
For histologies that are not listed above and are not excluded , GPA will be calculated using the following 
generalized formula from Sperduto et al [Sperduto PW1, Berkey B, Gaspar LE, Mehta M, Curran W.A 
new prognostic index and comparison to three other indices for patients with brain metastases: an 
analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008 Feb 1;70(2):510-4. ] 
 
 
18 Appendix C: Stereotactic Radiotherapy QA Guidelines  
 
Below is the direct link to the RTOG Stereotactic Radiotherapy Quality Assurance Guidelines: 
http://dx.doi.org/10.1016/j.prro.2011.06.014 
 

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

 
 
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20 Appendix E: 
The Mini-Mental State Exam Instructions and Exam  
 
Instructions for Administration of 
Mini-Mental State Examination (MMSE) 
 
Orientation
 
1. Ask for the Date. Then ask specifically for parts omitted, eg, “Can you also 
tell me what season it is?” Score one point for each correct answer. 
2. Ask in turn, “Can you tell me the name of this hospital?” (town, county, etc.) 
Score one point for each correct answer. 
Registration
 
Ask the patient if you may test his/her memory. Then say the names of 3 
unrelated objects, clearly and slowly, about one second for each. After you have 
said all 3, ask the patient to repeat them. This first repetition determines his/her 
score (0-3) but keep saying them until he/she can repeat all 3, up to 6 trials. If 
all 3 are not eventually learned, recall cannot be meaningfully tested. 
 
Attention and 
Calculation 
 
Ask the patient to spell the word “world” backwards. The score is the numbers 
of letters in correct order (e.g, DLROW=5; DLRW=4; 
DLORW, DLW=3; OW=2; DRLWO=1). 
Recall
Ask the patient if he/she can recall the 3 words you previously asked
him/her to remember. Score 0 – 3. 
Language
Naming: Show the patient a wristwatch and ask him/her what it
is. Repeat for pencil. Score 0 – 2. 
 

 
 
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Repetition: Ask the patient to repeat the sentence after you.
Allow only one trial. Score 0 – 1. 
 
3-stage command: Give the patient a piece of plain blank paper and
repeat the command. Score 1 point for each part correctly executed. 
 
Reading: On a blank piece of paper print the sentence, “Close your eyes,” in 
letters large enough for the patient to see clearly. Ask him/her to read it and 
do what it says. Score 1 point only if he actually closes his eyes.  
 
Writing: Give the patient a blank piece of paper and ask him/her to write a 
sentence for you. Do not Dictate a sentence; it is to be written spontaneously. 
It must contain a subject and verb and be sensible. Correct grammar and 
punctuation are not necessary.  
 
Copying: On a clean piece of paper, draw intersecting pentagons, each side 
about 1 in., and ask him/her to copy it exactly as it is. All 10 angles must be 
present and 2 must intersect to score 1 point. Tremor and rotation are 
ignored.  
 
 

 
 
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MINI MENTAL STATUS EXAMINATION 
 
Patient_______________________________ Examiner ______________________   Date____________ 
 
Maximum  
Score 
Orientation 
5 
 
(      ) 
 
What is the (year) (season) (date) (day) (month)? 
5 
 
(      ) 
 
Where are we (state) (country) (town) (hospital) (floor)? 
 
Registration 
3 
 
(     ) 
 
Name 3 Common objects (eg, “apple,” “table,” “penny”). Take 
1 second to say each. Then ask the patient to repeat all 3 after 
you have said them. Give 1 point for each correct answer. Then 
repeat them until he/she learns all 3. Count trials and record. 
Trials ___________ 
 
Attention and Calculation 
5 
 
(     ) 
 
Serial 7’s. 1 point for each correct answer. Stop after 5 answers. 
Alternatively,  spell “world” backwards. The score is the number of 
letters in correct order (D__L__R__O__W__). 
 
Recall 
3 
 
(     ) 
 
Ask for the 3 objects repeated above. Give 1 point for each correct 
answer. [Note: recall cannot be tested if all 3 objects were not 
remembered during registration] 
 
Language 
2 
 
(     ) 
 
Name a pencil and watch. 
1 
 
(     ) 
 
Repeat the following “No ifs, ands, or buts” 
3 
 
(     ) 
 
Follow a 3-stage command: 
“Take a paper in your hand, fold it in half, and put it on the floor.” 
1 
 
(     ) 
 
Read and obey the following: CLOSE YOUR EYES 
1 
 
(     ) 
 
Write a sentence. 
1 
 
(     ) 
 
Copy the design shown. 

 
 
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_________ 
Total Score 
 
ASSESS level of consciousness along a continuum ____________ 
Alert  Drowsy  Stupor  Coma 
 
"MINI-MENTAL STATE." A PRACTICAL METHOD FOR GRADING THE COGNITIVE STATE OF PATIENTS FOR THE CLINICIAN. Journal 
of Psychiatric Research, 12(3): 189-198, 1975.  
 

 
 
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21   Appendix F  
TRAIL MAKING TEST  
PART A 
Sample Instructions: “On this page (point) are some numbers. Begin at number 1 (point to ‘1’) and draw 
a line from 1 to 2 (point to ‘2’), 2 to 3 (point to ‘3’), 3 to 4 (point to ‘4’), and so on, in order, until you 
reach the end (point to circle marked END). Draw the lines as fast as you can. Ready, begin. (If the 
patient makes a mistake, point out the error and explain it. If the patient completes Sample A correctly, 
say “Good! Let’s try the next one.” Proceed with the test and repeat instructions above. Start timing as 
soon as the instruction is given to “begin.” Watch closely in order to catch any errors as soon as they are 
made. If the patient makes an error during the test, call it to his/her attention immediately and have 
him/her proceed from the point the mistake occurred. DO NOT STOP TIMING. The patient must 
complete the test in 3 minutes or less.)” 
Test Instructions: “On this page are numbers from 1 to 25. Do this the same way. Begin at number one 
(point to ‘1’) and draw a line from one to two (point to ‘2’), two to three (point to ‘3’), three to four 
(point to ‘4’), and so on, in order until you reach the end (point to circle marked ‘End’). Remember, work 
as fast as you can. Ready! Begin!” 
I. Trail Making Test Part A: 
1. Did the patient do Sample A before attempting Part A?  Yes  No 
2. Total amount of time the patient was tested: __ :_ __ (min:sec) 
3. Did the patient reach the “END” of the test? 
 Yes 
 No, tested for 3 minutes OR  No, tested for <3 minutes 
If No, specify the last number reached on the test: __ __ 
Comments: ___________________________________________________________________________ 
PART B 
Sample Instructions: “On this page (point) are some numbers and letters. Begin at number 1 (point to 
‘1’) and draw a line from 1 to A (point to ‘A’), A to 2 (point to ‘2’), 2 to B (point to ‘B’), B to 3 (point to 
‘3’), 3 to C (point to ‘C’) and so on, in order, until you reach the end (point to circle marked ‘End’). 
Remember, you first have a number (point to ‘1’), then a letter (point to ‘A’), then a number (point to 
‘2’), then a letter (point to ’B’), and so on. Draw the lines as fast as you can. Ready, begin. (If the patient 
makes a mistake, point out the error and explain it. If the patient completes Sample B correctly, say 
“Good! Let’s try the next one.” Proceed with the test and repeat instructions above. Start timing as soon 
as the instruction is given to “begin.” Watch closely in order to catch any errors as soon as they are 
made. If the patient makes an error during the test, call it to his/her attention immediately and have 

 
 
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him/her proceed from the point the mistake occurred. DO NOT STOP TIMING. The patient must 
complete the test in 5 minutes or less.)” 
Test Instructions: “On this page are both numbers and letters. Do this the same way. Begin at number 
one (point to ‘1’) and draw a line from one to A (point to ‘A’), A to two (point to ‘2’), two to B (point to 
‘B’), B to three (point to ‘3’), three to C (point to ‘C’), and so on, in order, until the end (point to circle 
marked ‘END’). Remember, first you have a number (point to ‘1’), then a letter (point to ‘A’), and so on. 
Do not skip around, but go from one circle to the next in the proper order. Draw the lines as fast as you 
can. Ready! Begin!” 
II. Trail Making Test Part B: 
1. Did the patient do Sample B before attempting Part B?  Yes  No 
2. Total amount of time the patient was tested: _ :_ _ (min:sec) 
3. Did the patient reach the “END” of the test? 
 Yes 
 No, tested for 5 minutes OR  No, tested for <5 minutes 
If No, specify the last number/letter reached on the test: __ __ 
Comments:___________________________________________________________________________ 

 
 
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Trail Making (continued) 
 
 
 

 
 
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22 Appendix G:   FACT-Br 
 

 
 
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23  Appendix H:  Hopkins Verbal Learning Test 
 
 
 
 
 

 
 
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