Whole Brain Radiation Therapy With Simultaneous Boost to Gross Metastatic Tumor Volume Using Volumetric Modulated Arc Therapy (RapidArc)
Phase: NA
Conditions: Neoplasm Metastasis
Sponsor: Emory University

Version: 9/9/2013 
 
RapidArc Brain Met - 1 
WHOLE BRAIN RADIATION THERAPY WITH SIMULTANEOUS BOOST TO  
GROSS METASTATIC TUMOR VOLUME USING VOLUMETRIC MODULATED 
ARC THERAPY (RAPIDARC) 
 
Principal Investigator 
 
 
Hui-Kuo Shu, M.D., PhD. 
 
Co-investigators 
Ian Crocker, M.D. 
Walter Curran, M.D. 
Liza Stapleford, M.D. 
Shravan Kandula, M.D. 
William Hall, M.D. 
 
Department of Radiation Oncology 
Winship Cancer Institute of Emory University 
 
 
1.0 
INTRODUCTION/BACKGROUND 
 
Brain metastases are the most common adult intracranial tumor, occurring in 
approximately 10% to 30% of adult cancer patients, and represent an important cause of 
morbidity and mortality in this population.1 The risk of developing brain metastases differs 
with different primary tumor histologies, with lung cancer accounting for approximately 
one half of all brain metastases.2 The prognosis of patients with brain metastases is poor.  
The median survival time of untreated patients is approximately 1 month.3  With treatment, 
the overall median survival time after diagnosis is approximately 4 months.4  The RTOG 
recursive partitioning analysis (RPA) describes three prognostic classes, defined by age, 
Karnofsky Performance Score (KPS), and disease status.5  The most widely used treatment 
for patients with multiple brain metastases is WBRT.  The appropriate use of WBRT can 
provide rapid attenuation of many neurological symptoms, improve quality of life, extend 
median survival, and be especially beneficial in patients whose brain metastases are 
surgically inaccessible or when other medical considerations preclude surgery.6,7  The use 
of adjuvant WBRT after resection or sterotactic radiosurgery (SRS) has been proven to be 
effective in terms of improving local control of brain metastases, and thus, the likelihood 
of neurological death is decreased.8   
 
The majority of patients who achieve local tumor control die from progression of 
extracranial disease, whereas the cause of death is most often due to CNS disease in patients 
with recurrent brain metastases.7,8  Currently, no consensus on the optimal radiation 
schedule for patients with brain metastases is established.  Standard treatment regimens 
include dose fractionation schemes evaluated in the early RTOG studies and range from 
20 Gy in 5 fractions to 40 Gy in 20 fractions.  The exact regimen used is generally at the 
discretion of the treating physician and often depends upon issues such as the severity of 
CNS symptoms, the extent of systemic disease, and physician preference.   
 

Version: 3/22/2013 
 
RapidArc Brain Met - 2 
More recently, a phase III randomized study (RTOG 9508) found that the combination of 
WBRT and SRS boost was superior to WBRT alone in selected patients.9  On this study, 
patients with a solitary brain metastases had an overall survival benefit when SRS was 
given.  Furthermore, patients in the SRS group were more likely to have a stable or 
improved Karnofsky Performance Status (KPS) score at 6 months follow-up than were 
patients allocated WBRT alone.  Intracranial disease control and use of steroids were also 
improved with SRS in patients with multiple brain metastasis.9  While the benefits of 
improved local control gained by adding SRS to WBRT are clear, many factors continue 
to limit the use of SRS.  This procedure is generally contraindicated in lesions larger than 
3-4 cm in size.  In addition, while multiple lesions can be treated with SRS, the procedure 
can quickly become unwieldy as the number of lesions increases and dosimetric 
considerations may also start to increase the risk of toxicity.   
 
RapidArc (RA) (Varian Medical Systems, Palo Alto, CA) is a volumetric modulated arc 
technique that uses a single 358 degree rotation of the linear accelerator to deliver highly 
conformal intensity modulated three dimensional dose distributions.  The combination of 
accurate and reproducible patient setup prior to treatment with a RA plan provides an 
alternative to conventional SRS by allowing for integration of the WBRT with fractionated 
SRS-like boost.  A recent publication generated composite RA plans consisting of WBRT 
with an integrated boost to gross brain metastases.  These RA plans were then measured in 
a solid water phantom.  It was also clinically delivered in 3 patients.  The generated plans 
demonstrated excellent PTV coverage with a steeper dose gradient outside of brain 
metastasis as well as higher conformity index than WBRT followed by SRS.10  A similar 
experience was recently published describing WBRT with simultaneous infield boost using 
helical tomotherapy.  Generated plans demonstrated similar target coverage with improved 
critical tissue sparing in patients with one to three metastatic brain metastases.11  RapidArc 
delivery allows for giving differential, highly conformal, radiation doses to different 
portions of the brain. With conventional WBRT, the entire brain is treated to the 
“macroscopic disease dose” due to the inability with conventional fields to selectively 
deliver dose to specific areas of the brain. The conventional “macroscopic disease” dose is 
typically 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. Several studies have indicated 
that patients at high risk of brain involvement, but without gross brain metastases, achieve 
high levels of intracranial control with lower “prophylactic disease” doses. The typical 
prophylactic cranial irradiation (PCI) dose for lung cancer is 25 Gy in 10 fractions. RTOG 
0214 randomized patients with locally advanced non-small cell lung cancer status post 
definitive therapy to PCI or not.12 These patients are known to be at high risk of brain 
metastases, up to 25% at 2 years. PCI reduced the 1 year incidence of brain metastases 
significantly from 18% to 8%. With RapidArc technology, the whole brain at risk could be 
given a reduced PCI dose, while the gross disease seen on MRI can be boosted with higher 
doses known to lead to better local control. We feel that the reduced whole brain dose 
allowed by this technique would lead to similar rates of distant brain control as 
conventional dosing, but with the possibility of reduced neurcognitive toxicity, as critical 
structures such as the white matter tracts and hippocampi will receive lower radiation 
doses.    
 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 3 
Varian Medical Systems has notified and received clearance from the Food and Drug 
Administration (FDA) to use RapidArc in patient care. This technology is not considered 
an experimental device. The standard of care for patients with 1 – 4 brain metastases is 
currently WBRT with or without SRS boost. Patients with more than 4 brain metastases 
are typically eligible for WBRT only. With an integrated boost method, we believe that we 
can deliver increased dose to the gross disease, in a more convenient and time efficient 
manner, include patients who would not otherwise be SRS candidates, and spare more 
normal brain tissue, which may translate into improved local control and median survival. 
We believe that the risk:benefit ratio is favorable for patients who would be enrolled on 
this study due for several reasons: the current very poor prognosis of the condition, the use 
of an existing FDA approved technology, and the integration of a proven treatment into a 
more efficient regimen.   
 
Given the limitations of the SRS boost technique, the purpose of our investigation is to 
evaluate an alternative strategy for giving WBRT with highly focal boost to gross visible 
lesions in patients with brain metastasis.  In this study, we plan to assess the tolerability of 
using volumetric modulated arc therapy (RapidArc) on patients with brain metastasis to 
simultaneously treat the entire brain with a concomitant focal boost to grossly identified 
lesions on MRI scan to try to improve local control and reduce neurocognitive toxicities.   
 
This previous version of this study was a phase I dose escalation trial giving 25 Gy in 10 
fractions to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 
fractions to gross brain metastatic disease. Prior to this, patients were enrolled onto one of 
two cohorts with whole brain dose of 30 Gy in 10 fractions with SIB to total of 45 Gy in 
10 fractions to gross brain metastatic disease or whole brain dose of 37.5 Gy in 15 fractions 
with SIB to total of 52.5 Gy in 15 fractions to gross brain metastatic disease. A total of 12 
patients have been previously enrolled on this trial. No patients have experienced a dose 
limiting toxicity (grade 3 or above) at least possibly due to study therapy. Also, no patients 
experienced local brain failure/progression at a site of treated metastatic brain disease. 
Based on this, we no longer feel that dose escalation to the gross brain disease is warranted 
and would proceed with a single arm pilot study treating patients with 25 Gy in 10 fractions 
to the whole brain with simultaneous infield boost (SIB) to a total of 45 Gy in 10 fractions 
to gross brain metastatic disease. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
2.1.1 To determine the feasibility of treating brain metastasis patients with whole brain 
radiation and simultaneous focal boost using an RA technique.  (see Section 11.4) 
2.1.2 To determine the locoregional control [at visible lesion(s) and new site(s)] in the 
brain of patients treated with a concomitant boost RA plan.   
 
2.2 
Secondary Objectives  
2.2.1 To determine the overall survival of brain metastasis patients treated with such an 
RA plan.   
 

Version: 3/22/2013 
 
RapidArc Brain Met - 4 
2.2.2 To determine the progression-free survival of brain metastasis patients treated with 
such an RA plan.   
2.2.3 To assess the long-term neurocognitive effects of this treatment using the Hopkins 
Verbal Learning Test–Revised (HVLT-R), Mini Mental Status Exam (MMSE) and 
Cognitive Functioning Subscale of the Medical Outcomes Scale (MOS).   
2.2.4 To assess quality of life (QOL) outcomes after this treatment using the quality of 
life questionnaire for the Functional Assessment of Cancer Therapy-Brain (FACT-
Br).   
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
3.1.1 Pathologic proven diagnosis of solid tumor malignancy.   
3.1.2 Age ≥ 18.   
3.1.3 KPS ≥ 70.   
  
3.1.4 Mini Mental Status Exam (MMSE) ≥ 18 prior to study entry.   
3.1.5 RPA class I (KPS≥70, primary cancer controlled, age<65, metastases in brain only) 
or class II (lack of one or more of class I criteria) (see Appendix A for definitions).   
3.1.6 One to ten brain metastatic lesions.   
 
3.2 
Exclusion Criteria 
3.2.1 Previous whole brain radiation therapy 
3.2.2 Previous radiosurgery to any currently progressive gross metastatic disease 
3.2.3 Previous radiosurgery to any intracranial site within the prior 6 weeks   
3.2.4 RPA class III (KPS<70, see Appendix A).   
3.2.5 Radiosensitive (eg. small cell lung carcinomas, germ cell tumors, leukemias, or 
lymphomas) or unknown tumor histologies.   
3.2.6 Concurrent chemotherapy (no chemotherapy starting 14 days before start of 
radiation 
3.2.7 Evidence of leptomeningeal disease by MRI and/or CSF cytology.  
3.2.8 Current pregnancy  
3.2.9 No metastases to brain stem, midbrain, pons, or medulla or within 7 mm of the optic 
apparatus (optic nerves and chiasm). 
 
4.0 
PRE-TREATMENT EVALUATION 
4.1 
MRI scan with and without contrast (at least 5mm resolution on T1 post-contrast 
imaging).   
4.2 
History and physical including a detailed neurologic exam.   
4.3 
Steroid and anti-convulsant doses must be documented.   
4.4 
Baseline MMSE.   
4.5 
Baseline neurocognitive function using the HVLT-R (memory).   
4.6 
Baseline neurocognitive function using MOS (self-report).   
4.7 
Baseline QOL assessment using FACT-Br.   
4.8 
Documentation of extent of systemic disease. 
4.9  
Pregnancy test in women of child bearing potential when there is clinical suspicion 
of pregnancy 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 5 
 
5.0  
REGISTRATION 
This will be a single cohort pilot study. Safety of the chosen dose level has been shown 
based on the previous phase I dose escalation iteration of this study. 
 
18 patients will be enrolled consecutively into this single arm pilot study.   
 
6.0 
RADIATION THERAPY 
 
6.1 
Localization, Simulation, and Immobilization 
6.1.1 Patient immobilization 
The patient shall be treated in the supine or other appropriate position for the 
location of the lesion.  A standard head-holding device involving a thermoplastic 
mask that is transparent to x-rays will be used to ensure adequate immobilization 
during therapy and daily reproducibility.   
6.1.2 Simulation CT scan  
At simulation, a non-contrasted CT scan with at least 1.25mm resolution will be 
obtained.   
6.1.3 MRI scan 
A post-contrast T1 MRI series with at least 5 mm resolution will be required for 
study entry.  This image series will be fused/registered with the simulation CT scan 
using appropriate software.   
6.1.4 Target definition 
Target/tumor volumes will be contoured.  Target volumes shall include the whole 
brain parenchyma inferiorly bordered by the foramen magnum with boost to gross 
metastatic tumor(s) as defined by the post-contrast T1 weighted MRI. The whole 
brain CTV will be expanded by 3 mm to create the whole brain PTV. Each 
metastatic tumor GTV will be expanded by 2 mm to obtain the planning target 
volumes (PTVs) for the boost targets.   
6.1.5 Daily patient setup 
Patients will be setup with daily on-board imaging guidance.  This will involve 
obtaining orthogonal kV images prior to each treatment fraction and making 
appropriate adjustments to ensure treatment setup accuracy.   
 
6.2 
Technical Factors 
6.2.1 X-ray energy 
Treatment shall be delivered with megavoltage machines of energy ranging from 
6MV up to and including 18 MV photons.  Selection of the appropriate photon 
energy should be based on optimizing the RT dose distribution within the target 
volume and minimizing dose to non-target normal tissues.   
6.2.2 Hardware configuration 
Treatment will be delivered via volumetric modulated arc therapy (Rapid Arc) with 
1-3 arcs with rotations up to 358o.  Collimator will be turned at 45o for the planning. 
 
6.3 
Dose specifications 
6.3.1 Planning goals 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 6 
Goal is to obtain 95% PTV coverage with the prescription dose with a Dmin to 
PTVs of 90% of the prescribed dose.  Whole brain PTV will be prescribed 25 Gy.  
The boost PTV(s) will be prescribed according to the dose escalation scheme 
described below.  In the optimization process, dose to the brain outside of the boost 
PTV should be minimized as much as possible while maintaining the dose 
prescription goals listed above.   
 
6.3.2 Dose 
This cohort is based on giving 25 Gy in 10 fractions to the whole brain** (see 
below).  The efficacy and tolerability of this fractionation has also been established.   
 
Group  
Dose (to lesions) 
SIB dose/fx 
BED10 
BED3 
Patients    . 
Brain dose 
2.5 Gy x 10 fx 
 
31.25 
45.83 
 
 
** resection cavity 3 Gy x 10 fx 
0.5 Gy SIB 
Cohort group  
4.5 Gy x 10 fx 
2 Gy SIB 
65.25 
112.5 
 
18 
Gy, Gray; fx, fraction; SIB, simultaneous in-field boost; BED10, biologically equivalent dose for α/β of 10 
(response of tumor, or early-reacting tissue); BED3, biologically equivalent dose for α/β of 3 (response of 
late-reacting tissue).   
 
** If a patient has had brain metastases resected that is part of the whole brain volume, 
then that resection cavity with a 2mm PTV expansion will be boosted to a total of 
30 Gy in 10 fx with a 0.5 Gy SIB / fx over the whole brain 25 Gy in 10 fx baseline.   
 
6.4 
Critical Structures  
Dose specification to be used in the treatment planning process to limit dose to 
critical structures are as follows: 1) the lens (<10 Gy), 2) globes (<30 Gy), 3) optic 
chiasm/nerves (<37 Gy), 4) brainstem (90% < 37 Gy), and 5) cervical spinal cord 
(<36 Gy) 
 
6.5 
Radiation Adverse Events  
6.5.1 Acute (≤ 90 days from treatment start) 
Expected adverse events include sore throat, hair loss, erythema of the scalp, 
headache, nausea and vomiting, lethargy, and transient worsening of neurological 
deficits.  Reactions in the ear canals and on the ear should be observed and treated 
symptomatically.   
6.5.2 Late (> 90 days from treatment start) 
Possible adverse events include radiation necrosis, cognitive dysfunction, visual 
difficulties, accelerated atherosclerosis, and radiation-induced neoplasms.   
 
7.0 
DRUG THERAPY 
 
Corticosteroid and anti-convulsant use will be documented.   
 
8.0 
SURGERY 
 
Not applicable to this protocol.   
 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 7 
9.0 
OTHER THERAPIES 
 
Not applicable to this protocol.   
 
10.0 
PATHOLOGY 
 
All patients will have a pathologically documented malignancy prior to initiating therapy.   
 
11.0 
PATIENT ASSESSMENTS 
 
11.1 
Neurocognitive Assessments 
11.1.1 Tests to be administered 
 
Cognitive Domain  
Assessment  
Memory  
Hopkins Verbal Learning Test-Revised  
Global Function  
Mini-Mental Status Examination  
Cognitive Function (self-report)  
Medical Outcomes Cognitive Scale  
 
11.1.2 Hopkins Verbal Learning Test- Revised (HVLT-R) 
The patient learns 12 words read to them 3 times; free recall is tested after each 
learning trial.  Delayed recall is evaluated after 20 minutes.  Following the delayed 
recall trial, the patient completes a delayed recognition test to determine if an 
impairment of delayed recall is due to a retrieval deficit or to a consolidation deficit.  
Entire test requires about 5 minutes to complete.   
11.1.3 Mini-Mental Status Examination (MMSE) 
This is a brief, standardized tool to grade patients’ global cognitive function.  The 
MMSE begins with an assessment of orientation to place and time.  Next is a test 
of memory (immediate recall) by having the subject immediately repeat the names 
of 3 objects presented orally.  Following this, the patient subtracts sevens serially 
from 100.  The subject is then asked to recall the three items previously repeated 
(delayed recall).  The final section evaluates aphasia and apraxia by testing naming, 
repetition, compliance with a 3-step command, comprehension of written words, 
writing, and copying a drawing.  The maximum score that can be obtained for the 
entire MMSE is 30 points.   
11.1.4 Cognitive Functioning Subscale of the Medical Outcomes Scale (MOS)(Self-
report) 
This 6-item, self-report measure is designed to measure day-to-day cognitive 
functioning of which the patient would be aware, including difficulty with problem-
solving, slowed reaction times, forgetfulness, and concentration.  Reliability and 
validity have been reported for patients with cancer.  Scale is based on multiple 
choice questions asking about cognitive function where the item is present 1= all 
of the time to 6=none of the time.  Scored in five steps (data cleaning, changing out 
of range values to missing, item re-calibration and skip pattern recording, reverse 
scoring of items so that the highest score reflects the best health state, transforming 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 8 
scores linearly to a common metric with a range of 0-100, averaging across items 
in the same scale).  Completion time is estimated to be less than 5 minutes.   
11.1.5 Frequency of neurocognitive assessments 
 
All tests will be given at baseline and at every follow-up for the first 6 months, then 
every 6 months thereafter (at 1, 3, 6, 12, 18, and 24 months).  A window period of 
+/- 6 weeks will be allowed to correlate with each study time-point visit. 
 
11.2 
Quality of Life Evaluation 
11.2.1 Functional Assessment of Cancer Therapy-Brain (FACT-Br) 
This assessment is a commonly used instrument measuring general quality of life 
(QOL) reflecting symptoms or problems associated with brain malignancies across 
5 scales: physical well-being (7 items); social/family well-being (7 items); 
emotional well-being (6 items); functional well-being (7 items); and concerns 
relevant to patients with brain tumors (23 items).  Patients rate all items using a 
five-point rating scale ranging from "not at all" to "very much."  The measure yields 
information about total QOL, as well as information about the dimensions of 
physical well-being, social/family well-being, emotional well-being, functional 
well-being, and disease-specific concerns.  Six additional experimental items 
request information regarding how much each dimension affects QOL, using a "0" 
(not at all) to "10" (very much so) rating scale.   
11.2.2 Frequency of QOL assessment 
 
The FACT-Br will be given at baseline and at every follow-up for the first 6 months, 
then every 6 months thereafter (at 1, 3, 6, 12, 18, and 24 months).  A window period 
of +/- 6 weeks will be allowed to correlate with each study time-point visit. 
 
 
11.3 
Toxicity and Outcome Assessments 
11.3.1 Imaging followup 
Patients will undergo brain MRI prior to study entry and at 1 month, 3 months and 
every 3 months thereafter or when otherwise indicated (eg. at onset of clinical 
deterioration).  A window period of +/- 6 weeks will be allowed to correlate with 
each study time-point MRI.   
11.3.2 Brain metastasis size evaluation 
The treating radiation oncologist will measure and calculate the volume for each 
brain metastasis identified as a contrast enhancing mass on MRI at baseline using 
radiation oncology treatment planning software. This value will be recorded on the 
baseline form and every subsequent follow-up form.  The appearance (yes/no) of 
any new brain metastases will be recorded on all follow-up forms.   
11.3.3 Lesion response evaluation 
Each treated lesion will have a volumetric measurement made at each study 
imaging follow-up using the visit high resolution MRI scan and radiation oncology 
treatment planning software. Percentage change in volume from the original 
baseline volume will be calculated using the formula: [original volume – current 
volume] / original volume. Lesions with complete resolution will be noted as 
complete response (CR). 
11.3.4 Definition of CNS progression 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 9 
CNS progression will be defined as a > 25% increase in volume for any tracked 
brain metastasis, or the appearance of any new brain metastasis on a follow-up 
MRI.  For lesions smaller than 1 cm in maximum diameter, a maximum increase 
of 50% in volume will be necessary to score as progression.  This caveat is included 
to account for potential variability in measurement, which will be most susceptible 
to proportionate errors at smaller sizes.  For greater than 1 cm lesions, the definition 
will use a 25% rule for change.   
11.3.5 RTOG CNS toxicity determination 
Neurologic/brain toxicity assessment will be made during treatment and at each 
follow up (1 month, 3 months, and every 3 months thereafter) (See Appendix B for 
definitions). 
11.3.6 Adverse Events (AEs) 
 
Any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a medical treatment or procedure regardless of whether it is 
considered related to the medical treatment or procedure (attribution of unrelated, 
unlikely, possible, probable, or definite).  These events will be recorded for each 
subject and is subject to review by the investigators and data safety monitoring 
committee (DSMC).   
11.3.7 Serious Adverse Events (SAEs) 
Any adverse event that results with any of the following outcomes:  
• Death;  
• A life-threatening experience;  
• Inpatient hospitalization or prolongation of existing hospitalization;  
• A persistent or significant disability/incapacity;  
• A congenital anomaly/birth defect; or 
• Other medically important events.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition.  These events will also be 
recorded for each subject and is subject to review by the investigators and data 
safety monitoring committee (DSMC).  In addition, these events will be reported 
to the Emory University Institutional Review Board (IRB).   
 
11.4 
Feasibility Assessment 
11.4.1 Criteria of feasibility 
Treatment plans using the RapidArc treatment planning software to deliver 
simultaneous in-field boosts to gross metastatic lesions have been successfully 
generated in our department.  Therefore, the main question of feasibility is 
regarding whether the treatment setup and delivery can be accomplished in a 
“reasonable” period of time.  A typical treatment slot for conventional radiation 
therapy in our department is 15 minutes.  We will define 2 treatment slots, or 30 
minutes as a “reasonable” time for this treatment.  Therefore, this treatment will 
considered feasible if the treatment setup/delivery time is <30 minutes in >90% of 
treatment fractions.   
 

Version: 3/22/2013 
 
RapidArc Brain Met - 10 
11.4.2 Feasibility data to be collected 
Our departmental record-and-verify system will document the time when setup OBI 
images are first obtained and when the radiation treatment delivery is turned off for 
each treatment fraction.  This time will be recorded for each treatment fraction.  An 
additional 5 minutes will be added to this time to estimate the time required to setup 
a patient prior to the acquisition of the first OBI image plus the time from when the 
machine is turned off to when the patient is released from the treatment couch.  This 
total time will need to be <30minutes for the treatment to be considered 
“reasonable.”   
 
12.0 
DATA COLLECTION 
 
12.1 
Data Fields 
The following data will be collected on each patient: name, date of birth, medical 
record number, tumor characteristics by pathology of surgical specimen, radiologic 
results, performance status, radiation and chemotherapy treatment parameters, 
clinical outcome including local and regional control, overall survival, treatment 
complications, neurocognitive assessments, and QOL assessments.   
 
12.2 
Criteria for patient to be considered off study 
12.1.1 Local CNS disease progression.   
12.1.2 Patient death.   
12.1.3 Patient request to come off study. 
12.1.4 Patient is discharged to hospice 
 
12.3 
Data Safety Monitoring 
12.3.1 Data Safety Monitoring Committee (DSMC) 
We will use the Winship Cancer Institute data safety monitoring committee chaired 
by Dr. Suresh Ramalingam as an independent review. As per WCI policy, the 
DSMC monitors all investigator initiated studies and cooperative group studies at 
Winship. Each qualifying study is reviewed at least once a year. Two of the first 5 
patients enrolled to investigator-initiated studies and 10% of total accrual is 
reviewed.  
 
Once a chart is monitored, the PI and the study coordinator are presented with the 
findings. They have a 2 week period to respond to the findings. A summary report 
is submitted to the DSMC for committee review. Any serious unanticipated 
problem is reported to the IRB with due notice to the PI. 
 
Included in the review: 
• Regulatory documents 
• Patient eligibility 
• Informed consent process 
• Accuracy and timeliness of data 
• Verification of source documents 
• Toxicity assessment process 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 11 
• Submission of SAEs 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study endpoints 
13.1.1 Primary endpoints 
• Feasibility – Measurement of the amount of time required for daily treatment 
• Rates of toxicities 
• Local brain control 
• Regional brain control 
 
13.1.2 Secondary Endpoints (to be compared with standard historical controls) 
• Progression-free survival 
• Overall Survival 
• Neurocognitive effects 
• QOL outcomes 
 
13.2 
Sample size 
This will be a single cohort pilot study. Safety of the chosen dose level has been shown 
based on the previous phase I dose escalation iteration of this study. 
 
18 patients will be enrolled consecutively into this single arm pilot study.   
 
If a patient is not able to complete follow up to the toxicity assessment point of 4 months 
due to a toxicity judged not to be at least possibly related to therapy, then that patient will 
be replaced by the next patient enrolled. 
 
 
13.3 
Statistical Analysis 
Descriptive statistics will be performed on the clinical and treatment factors on 
subjects on this study.  Categorical data will be presented on frequency tables while 
continuous data will be presented as mean, standard deviation, median and range.  
Local control, regional brain control, progression-free survival and overall survival 
will be assessed using the Kaplan-Meier method with censoring as appropriate.  
Univariate and multivariate analysis will be performed with these endpoints to 
determine patient factors that may influence outcome.  These curves will also be 
compared to previously published results as historical controls.  The results of the 
neurocognitive and quality of life surveys/tests will be plotted for each patient to 
assess for a general trend over time.  The trend over time can also analyzed by linear 
regression analysis.  Each point in time can be compared with historical controls 
using a student’s t-test to determine whether there is a significant difference in the 
survey/test scores in patients on our study versus historical results.   
 
14.0 
REFERENCES 
 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 12 
1. Wen PY, Black PM, Loeffler JS: Cancer: Principles and Practice of Oncology (ed 6). 
In Metastatic Brain Cancer Edited by: DeVita V, Hellman S, Rosenberg SA. 
Philadelphia, PA, Lippincott, WIlliams, & Wilkins; 2001:2655-2670. 
2. Zimm S, Wampler GL, Stablein D, et al.: Intracerebral metastases in solid-tumor 
patients: Natural history and results of treatment. Cancer 1981, 48:384-394. 
3. Sundstrom JT, Minn H, Lertola KK, et al.: Prognosis of patients treated for intracranial 
metastase with whole-brain irradiation. Ann Med 1998, 30:296-299. 
4. Chao JH, Phillips R, Nickson JJ: Roentgenraytherapy of cerebral metastases. Cancer 
1954, 7:682-689. 
5. Gaspar L, Scott C, Rotman M, et al.: Recursive partitioning analysis (RPA) of 
prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain 
metastases trials. Int J Radiat Oncol Biol Phys 1997, 37:745-754. 
6. Patchell RA, Regine WF: The rationale for adjuvant whole brain radiation therapy with 
radiosurgery in the treatment of single brain metastases. Technol Cancer Res Treat 
2003, 2:111-115. 
7. Arbit E, Wronski M, Burt M, Galicich JH: The treatment of patients with recurrent 
brain metastases:A retrospective analysis of 109 patients with nonsmall cell lung 
cancer. Cancer 1995, 76:765-773. 
8. Wen PY, Loeffler JS: Management of brain metastases. Oncology (Huntingt) 1999, 
13:941    
9. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or 
without stereotactic radiosurgery boost for patients with one to three brain metastases: 
Phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665–1672. 
10. Lagerwaard F, Van der Hoorn E, Verbakel W, Senan S, et al. Whole-Brain 
Radiotherapy With Simultaneous Integrated Boost to Multiple Brain Metastases Using 
Volumetric Modulated Arc Therapy. Int J Radiat Oncol Biol Phys 2009, 75: 253-259. 
11. Bauman G, Yartsev S, Fisher B, Kron T, Laperriere N, Heydarian M, VanDyk J. 
Simultaneous infield boost with helical tomotherapy for patients with 1 to 3 brain 
metastases. Am J Clin Oncol. 2007 30:38-44. 
12. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial 
irradiation versus observation in patients with locally advanced non-small-cell lung 
cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin 
Oncol. 2011 Jan 20;29(3):272-8. Epub 2010 Dec 6. 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 13 
APPENDIX A  
 
RTOG RPA Classification System 
 
RPA Class I 
All of the following criteria: 
 
KPS ≥ 70%  
 
Age < 65 years  
 
Absence of extracranial metastases  
 
Controlled primary cancer  
 
RPA Class II 
KPS ≥ 70% and  
 
One or more of the following criteria:  
 
Age > 65 years  
 
Presence of extracranial metastases  
 
Uncontrolled primary cancer  
 
RPA Class III 
KPS < 70%  
 
 

Version: 3/22/2013 
 
RapidArc Brain Met - 14 
APPENDIX B 
 
CTCAE (Common Terminology Criteria for Adverse Events), version 4.02 
 
The exact full criteria for toxicity assessment can be obtained at the NCI CTEP website at the 
following link:  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf.   
 
 
APPENDIX C – Evaluation Timeline 
SEE BELOW 
 
 

Version: 9/9/2013 
 
RapidArc Brain Met - 15 
APPENDIX C - Timeline 
 
Note: ).  A window period of +/- 6 weeks will be allowed to correlate with each study time-point 
and MRI visit. 
 
 
Baselin
e 
1 
mont
h 
4 
mont
hs 
7 
mont
hs 
10 
mont
hs 
13 
mont
hs 
16 
mont
hs 
19 
mont
hs 
22 
mont
hs 
25 
mont
hs 
H&P 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessme
nt 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HVLT-R 
X 
X 
X 
X 
 
X 
 
X 
 
X 
MMSE 
X 
X 
X 
X 
 
X 
 
X 
 
X 
MOS 
X 
X 
X 
X 
 
X 
 
X 
 
X 
FACT-Br 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Imaging 
Respons
e 
Evaluatio
n 
 
X 
X 
X 
X 
X 
X 
X 
X 
X