A Phase I Dose Escalation Trial of Five Fraction Stereotactic Radiation Therapy for Brain
Phase: NA
Conditions: Brain Metastases
Sponsor: University of Alabama at Birmingham

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RAD 1705/UAB 1796: A Phase I Dose Escalation Trial of  
Five Fraction Stereotactic Radiation Therapy for Brain Metastases  
 
TABLE OF CONTENTS 
 
1.0 OBJECTIVES 
2.0 BACKGROUND AND RATIONALE 
3.0 SCHEMA 
4.0 PATIENT SELCTION CRITERIA 
5.0 DRUG INFORMATION 
6.0 TREATMENT PLAN 
7.0 THERAPY MODIFICATIONS 
8.0 STUDY PARAMETERS 
9.0 EVALUATION CRITERIA 
10.0 PATIENT REGISTRATION 
11.0 STUDY ENDPOINTS 
12.0 REFERENCES 
 
APPENDICES 
 
A. KARNOFSKY PERFORMANCE STATUS CHART 
B. RANO CRITERIA 
C. QUALITY OF LIFE QUESTIONNAIRE (FACT-Br) 
 
 

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PRINCIPAL INVESTIGATOR:  
 John Fiveash, MD 
 
 
CO-INVESTIGATORS: 
Samuel Marcrom, MD 
Andrew McDonald, MD 
Richard Popple, PhD 
James Markert, MD 
Barton Guthrie, MD 
Kristen Riley, MD 
Markus Bredel, MD, PhD 
Sharon Spencer, MD 
Christopher Willey, MD, PhD 
Drexell Hunter Boggs, MD  
Michael C. Dobelbower, MD, PhD 
 
 
Biostatistician: 
 
 
Sejong Bae, PhD 
 
 
Research Nurse Coordinator: 
Laronica Conway 
 
 
Data Coordinator: 
 
 
Laronica Conway 
 
 
Regulatory: 
 
 
 
Kristin Webb, CCRP 
Tiffany Williams 
 
 
Document History Table 
 
Version/Update Date 
Amendment # 1 
March 5, 2020 
Activation 
May 10, 2018 
Original 
January 4, 2018 
 
 
 

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Summary of Changes 
 
Protocol Amendment #1 
 
Protocol: RAD 1705/UAB 1796 
 
Date: March 5, 2020 
 
# 
Section 
Comments 
1 
Title Page 
The current investigator list has been updated. 
2 
Title Page 
The current regulatory staff has been updated. 
3 
Title Page 
The UAB 1796 trial name has been added to the protocol title. 
4 
Footer 
The protocol version and amendment number has been updated. 
5 
8.2 
Table 8.1 updated to include 2 week post-treatment phone call. 
6 
11.5.1 
Added paragraph highlighting the more conservative enrollment schema. 
 
 

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1.0 OBJECTIVES 
 
1.1 Primary:  
 
1.1.1 
To determine the maximum tolerated dose of five fraction stereotactic 
radiotherapy for patients with either tumors 2.1-4.0 cm in diameter or 4.1-6.0 
cm in diameter 
 
1.2 Secondary:  
 
1.2.1 
To assess the acute toxicity of five fraction stereotactic radiotherapy for 
tumors 2.1-6.0 cm in diameter 
 
1.2.2 
To assess the late toxicity of five fraction stereotactic radiotherapy for tumors 
2.1-6.0 cm in diameter 
 
1.2.3 
To determine the rate of local tumor control with five fraction stereotactic 
radiotherapy for tumors 2.1-6.0 cm in diameter 
 
1.2.4 
To obtain preliminary estimates of changes in QOL after five fraction 
stereotactic radiotherapy for tumors 2.1-6.0 cm in diameter (FACT-BR) 
 
1.3 Exploratory:  
 
1.3.1 
To assess the feasibility of capturing patient reported outcomes (FACT-Br) 
electronically in the Radiation Oncology clinic 
 
2.0 BACKGROUD AND RATIONALE 
 
2.1 Brain Metastases Overview 
 
Brain metastases are one of the most commonly encountered complications of 
cancer, and they represent the most common intracranial neoplasm in adults. Brain 
metastases are a well-established cause of morbidity and mortality, affecting 
approximately 20%-40% of patients with cancer.1-3 Due to the significance of brain 
metastases, there has been a great deal of focus on the appropriate treatment for 
these lesions. 
Treatment options for brain metastases are broadly divided into three categories of 
systemic therapy, surgical resection and radiation therapy. The selection of the 
appropriate management option involves a complex decision-making process that 
considers patient performance status, extent of intracranial and extracranial disease, 
degree of symptoms secondary to tumor mass effect, systemic therapy options, and 

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patient preferences. As treatment decisions are guided by several important nuances, 
additional prospective data is needed to better inform decision making. 
2.2 Role of Radiation Therapy in Brain Metastases Treatment 
 
The rationale for the management of brain metastases with radiation therapy is based 
on several factors regarding systemic therapy, surgery, and radiation. These include 
the presence of the blood-brain barrier that reduces the efficacy of many systemic 
therapies in the central nervous system and the invasiveness of surgical resection with 
a prohibitively high risk of permanent neurologic deficits associated with resections of 
tumors in certain locations. Additionally, radiation therapy is a relatively non-invasive 
treatment strategy that has the potential of targeting any location within the brain. 
 
The use of whole brain radiation therapy (WBRT) to target brain metastases dates 
back to the mid-twentieth century.4 In the 1970s, whole brain radiation to treat brain 
metastases was shown to improve survival compared to corticosteroids alone.5 
Several randomized trials have since evaluated the role of surgery, whole brain 
radiation, and stereotactic radiosurgery (SRS). WBRT alone renders a 6-12-month local 
tumor control rate of approximately 50%-70%, and the addition of surgery or SRS 
improves local control rates to 80%-90%. Although WBRT decreases the rate of distant 
brain failures, the addition of WBRT to either surgery or SRS has not been shown to 
improve survival.6-9 Furthermore, WBRT has the potential to negatively impact 
cognitive function; therefore, appropriately selected patients may be treated with 
focal therapy while omitting WBRT.10 
 
2.3 Increasing Role of Stereotactic Radiosurgery (SRS) 
 
The management of patients with brain metastases is currently evolving. Focal 
techniques are gaining favor as the initial radiotherapy treatment for patients with an 
increased number of brain metastases, and whole brain radiotherapy (WBRT) is 
commonly being deferred citing toxicity concerns and lack of proven survival 
advantage.9-11  
Studies that have compared SRS and WBRT have discovered that SRS alone offers a 
relatively high rate of local tumor control.9,12 WBRT has the benefit of decreasing 
distant brain failure, but the feasibility of salvage SRS after an initial course of 
radiosurgery has been demonstrated.12,13 Additionally, WBRT does not offer a survival 
advantage over SRS alone, and WBRT is more likely to induce cognitive decline in 
treated patients.10,11 
Despite the advantages of treating patients with limited brain metastases with SRS, 
there are many patients that are likely best served with an alternative treatment 
strategy. In fact, increasing tumor size is associated with an increased risk of CNS 
toxicity with the use of single-fraction radiosurgery.13 The desire to utilize an 

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alternative focal therapy that is both safe and effective has created interest in 
fractionated stereotactic radiation therapy (FSRT). 
 
2.4 Rationale for Fractionated Stereotactic Radiation Therapy (FSRT) 
 
As focal radiation techniques are utilized more frequently in the treatment of brain 
metastases, there is increasing need to accurately define the appropriate patient and 
tumor characteristics for focal therapy. Unfortunately, not all patients are good 
candidates for single fraction stereotactic radiosurgery (SRS) since large tumors and 
those in unfavorable locations have been associated with unacceptable rates of 
treatment-related toxicity. Given the limitations of WBRT, extending the paradigm of 
focal therapy to those patients who are not candidates for SRS represents an 
important clinical challenge. 
 
A longstanding principle of radiation biology is that fractionating a course of 
radiotherapy may reduce normal tissue effects while maintaining tumor control. The 
use of multiple smaller fractions of radiation instead of a single large dose of radiation 
to minimize normal tissue toxicity is supported by both preclinical and clinical 
literature.14 Fractionated stereotactic radiotherapy (FSRT) combines the steep dose 
gradients and small treatment margins of SRS with the radiobiologic advantages of 
fractionation. 
 
Radiation dose schedules that utilize more radiation than 2 Gy per fraction are termed 
hypofractionated dose schedules. At dosages as high as those typically administered 
for FSRT, even slight increases in dose per fraction can have a significant impact on 
overall cell kill and calculated biological effective dose (BED). The BED is useful for 
isoeffective dose calculations as it is a measure of true biological dose experienced by 
a respective tissue. It is important to understand that normal tissues and tumor are 
impacted differently by a set dosing schedule. This is represented by the alpha/beta 
ratio (α/β). Alpha represents the component of cell death that occurs via non-
repairable radiation damage, and beta represents the component of cell death 
occurring via potentially repairable damage. A low α/β tissue, as is found in normal 
tissues, experiences a high degree of cell death from potentially repairable damage; 
therefore, fractionating a course of radiation will have a greater relative effect on low 
α/β tissues than on high α/β tissues, such as tumor cells. This phenomenon explains 
the therapeutic advantage of utilizing multiple radiation fractions. This is illustrated in 
Figure 2.1.15 
 
A commonly utilized technique for comparing various radiation fractionation schemes 
relies on calculation of the equivalent dose in 2 Gy per fraction (EQD2). Calculating an 
EQD2 allows comparison of a wide range of prescription doses to their equivalent total 
dose if 2 Gy fractions were used instead of the altered fractionation scheme. Standard 

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conventional fractionation uses 2 Gy per fraction; therefore, this is used as the 
reference standard when comparing various regimens. 
 
 
Figure 2.1 BED isoeffect plots for dose/fraction and number of fractions administered 
for (A) α/β = 2 Gy and (B) α/β = 10 Gy calculated using the linear-quadratic model. 
 
 
 
 
 
 
 
 

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The BED equation is displayed below: 
 
 
 
Where BED = biologically effective dose, D = total dose, d = dose per fraction, and α/β 
= the dose at which cell killing by non-repairable damage is equal to that of repairable 
damage. 
 
  
2.5 FSRT dose schedules are feasible 
 
 
Several authors have reported on the feasibility of FSRT for brain metastases, and it 
appears to be both safe and effective. Previously reported 12-month local control 
estimates of FSRT have ranged from 52%-95%.16-22  Furthermore, FSRT appears to 
have a favorable toxicity profile when compared to SRS for treatment among patients 
with similar tumor characteristics. A summary of previously published reports on FSRT 
is displayed below in Table 2.1. 
 
 
Table 2.1 Summary of dose prescriptions, tumor size, and toxicity in prior FSRT 
studies 
First 
Author 
Sample 
Size 
Tumor Size 
(cm) 
FSRT Schedule 
Presciption 
Point 
Toxicity 
Rejakesari 
60 patients 
70 lesions 
Median diameter: 
1.7 (0.4-6.4) 
5 Gy x 5 fxns 
90-95% IDL 
Symptomatic RN = 4.3% (n=3) 
Seizures = 3% (n=2) 
Minniti 
135 patients 
171 lesions 
Not reported 
9 Gy x 3 fxns (56%) 
12 Gy x 3 fxns (44%) 
80-90% IDL 
Gr ≥3 toxicity = 4% (n=5)
 
Feuvert 
12 patients 
12 lesions 
Median diameter: 
4.4 (3.2-5.95) 
7.7 Gy x 3 fxns 
70% IDL 
Gr 2 toxicity = 25% (n=3) 
No grade ≥3 toxicity 
Aoyoma 
87 patients 
140 lesions 
Not reported 
8.75 Gy x 4 fxns 
80-90% IDL 
Gr ≥3 toxicity = 4.6% (n=4)
 
Kim 
40 patients 
49 lesions 
Not reported 
6 Gy x 6 fxns 
91% IDL 
Gr 1 = 5% (n=2) 
No Gr ≥2 toxicity 
Aoki 
44 patients 
65 lesions 
Not reported 
18-30 Gy in 3-5 fxns 
90% IDL 
Gr 1 = 2% (n=1) 
No Gr ≥2 toxicity 
Kwon 
27 patients 
52 lesions 
Median diameter: 
1.6 (0.17-3.12) 
20-36 Gy in 4-6 fxns 
85% IDL 
Gr ≥3 toxicity = 3.7% (n=1) 
Narayana 
20 patients 
20 lesions 
Not reported 
6 Gy x 5 fxns 
100% IDL 
Irreversible Gr ≥3 toxicity = 
15% (n=3) 
Saitoh 
49 patients 
78 lesions 
Median diameter: 
1.2 (0.4-3.8) 
39-42 Gy in 3 fxns 
90% IDL 
Gr ≥3 toxicity = 12% (n=6) 
Fokas 
107 patients 
 
Not reported 
5 Gy x 7 fxns (50%) 
4 Gy x 10 fxns (50%) 
Not reported 
Gr ≥3 toxicity = 3% (n=3) 
 

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2.5.1 
UAB Experience with FSRT 
 
The University of Alabama at Birmingham Department of Radiation Oncology 
began utilizing FSRT for the management of brain metastases in 2008. Since 
that time, the number of patients receiving this treatment as well as treating 
physician comfort with FSRT has steadily increased. We retrospectively 
evaluated our experience and identified 72 patients with 182 brain 
metastases that were treated with definitive FSRT. The Kaplan-Meier estimate 
of overall 12-month local control was 86%; however, local tumor control in 
larger tumors was significantly lower than smaller tumors. The 12-month local 
control estimate of tumors <2 cm in diameter was 100% compared to 74% for 
the tumors ≥2 cm in diameter.  A dose response was observed with greater 
12-month local tumor control observed in patients receiving 30 Gy in 5 
fractions as compared to 25 Gy in 5 fractions (91% vs. 75%) (p<0.001). Serious 
toxicity occurred in only 4 patients (6%) in which subsequent surgical 
resection was required; however, we observed that increasing tumor 
diameter was associated with increased toxicity risk {HR 2.45 (1.04-5.742) 
(p=0.04)}.23 
 
This experience highlights the problem that clinicians face. Overall, the rate of 
local tumor control as well as the toxicity profile of FSRT is quite favorable. 
However, increasing tumor diameter results in lower tumor control and 
higher toxicity rates. Additionally, dose escalation appears to improve local 
tumor control, but it could also lead to an increase in toxicity. The purpose of 
this study is meant to identify the appropriate radiation prescription to 
balance tumor control with adverse events. 
 
 
2.6 Rationale for Radiation Dose Escalation 
 
 
Multiple reports suggest that local tumor control with single-fraction SRS improves in 
a dose dependent fashion.24,25 Among studies looking at FSRT there has been a 
suggestion of improved tumor control with dose escalation, particularly in tumors 
receiving an EQD2 >35 Gy (alpha/beta = 10) or BED12 >40 Gy (linear quadratic cubic 
model).25-27 Furthermore, a recent review of available FSRT literature found a dose 
dependent local tumor control associated with increasing BED.28 Unfortunately, none 
of these dose studies were prospective and did not systematically evaluate the 
relationship between prescription dose and tumor volume in determining the risk of 
toxicity. 
 
 
 
 

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2.7 Rationale for Dose Selection in Current Trial 
 
As previously discussed, there are reports of improved tumor control with dose 
escalation. Additionally, multiple authors have found that increasing tumor size is 
associated with decreased local tumor control.24,29 Furthermore, increasing tumor size 
is also associated with increased risk of CNS toxicity.13 As tumor size increases, 
identifying the balance between dose escalation to improve tumor control and 
avoiding excessive risk of CNS toxicity remains an important clinical challenge.  
 
Small tumors (i.e. ≤ 2 cm in diameter) appear to have excellent tumor control with SRS 
along with minimal CNS toxicity from the treatment. As per RTOG 9005, tumors 2.1-4 
cm in diameter were 7.3-16 times more likely than tumors ≤ 2 cm in diameter to 
experience CNS toxicity from SRS.13 The elevated toxicity risk in tumors > 2 cm in 
diameter has created interest in the utilization of FSRT in this patient population. The 
proposed dosing schedule (Table 2.2) stratifies patients by tumor size (2.1-4 cm vs. 
4.1-6cm) to account for the increased risk of CNS toxicity in the larger tumor group. 
 
As demonstrated in Table 2.1, institutions have utilized a variety of dosages, ranging 
from 5 Gy x 5 fractions to 14 Gy x 3 fractions in their retrospective studies with 
excellent safety. Also, the previously mentioned review article included patients 
treated with BEDs ranging from 29-100. The authors of this review found that at BEDs 
of 40, 50, and 60, the 1-year local tumor control was 73%, 78%, and 84% 
respectively.28 The proposed doses fall well within the range of that previously 
reported. In this trial, we expect that larger diameter tumors will have a lower 
maximum tolerated dose (MTD); therefore, we are starting at a lower dose level in 
larger tumors. Table 2.3 displays the BED and equivalent 2 Gy per fraction dose 
schedules proposed in this study. 
 
Table 2.2 Dose Escalation Schedule 
 
 
 
 
 
 
 
Table 2.3 BED and EQD2 of FSRT Dose Schedules 
FSRT Dose Schedule 
Biologically Effective Dose 
(BED) 
2 Gy per fraction dose 
equivalent (EQD2) 
6 Gy x 5 fractions 
48.0 Gy 
40.0 Gy 
7 Gy x 5 fractions 
59.5 Gy 
49.6 Gy 
8 Gy x 5 fractions 
72.0 Gy 
60.0 Gy 
9 Gy x 5 fractions 
85.5 Gy 
71.3 Gy 
Dose Level 
2.1-4.0 cm diameter 
4.1-6.0 cm diameter 
1 
7 Gy 
6 Gy 
2 
8 Gy 
7 Gy 
3 
9 Gy 
8 Gy 

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2.8 Rationale for Inclusion of Patients with More Than One Tumor 
 
In this trial, dose escalation will only occur to the single largest tumor with other 
tumors receiving a standard of care dose of five fraction radiosurgery. The possibility 
exists that more than one tumor could be large and therefore patients with more than 
one tumor over 3 cm in diameter are excluded. Otherwise, up to 10 tumors total could 
be treated. 
 
Although tumor volume is a well-recognized risk factor for radiosurgery toxicity, tumor 
number by itself is not.  In a retrospective study of over 1800 patients with multiple 
tumors undergoing single fraction radiosurgery, the treatment of 2-9 tumors vs 10 or 
more tumors did not predict radiosurgery toxicity.30  In the largest prospective trial of 
radiosurgery ever performed, Yamamoto et al treated 1194 brain metastases patients 
with radiosurgery alone for up to ten tumors.  The number of tumors was not 
predictive of toxicity.31 
 
For patients treated with single fraction radiosurgery to a single target, the total 
volume of brain receiving 12Gy (V12) is an established factor predictive of radiation 
toxicity.  In an effort to understand predictors of the 12Gy volume treated with either 
Gamma Knife radiosurgery or single isocenter volumetric modulated arc therapy 
(VMAT) radiosurgery, investigators at UAB performed a regression analysis of patients 
treated with multiple metastases. V12 was independent of the number of tumors and 
is a simple function of tumor volume. This relationship is demonstrated in Figure 2.2.32  
Others have reported large volume computer simulations of radiosurgery for 1-25 
tumors of varying tumor volume and can predict V12 as a linear function of tumor 
volume independent of tumor number.33 
 
In the retrospective UAB experience of FSRT, increasing tumor diameter, evaluated as 
a continuous variable, was significantly associated with increased risk of CNS toxicity 
{HR 2.45 (1.04-5.742) (p=0.04)}. Additionally, 3 out of the 4 (75%) grade ≥3 grade 3 
CNS toxicities occurred in patients with tumor diameter ≥3 cm.23 By limiting the 
inclusion criteria to not having a second tumor over 3 cm, we will ensure that the main 
risk of toxicity to the patient is the index lesion undergoing dose escalation.  
 
 
 
 
 
 
 
 
 
 

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Figure 2.2 The Volume of Brain Receiving 12 Gy is Directly Related to Tumor Volume 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.0 SCHEMA 
 
 
 
 
3.1 Patients will be enrolled if they have a pathologic diagnosis of cancer along with 
imaging consistent with one or more brain metastases. All patients must meet all 
enrollment criteria. 
 
3.2 Only 1 target per patient, termed the index lesion, will be enrolled and receive the 
investigational dose prescription. The enrolled index lesion will be the largest brain 
metastasis by definition. Any additional treated non-index lesion will receive a 
standard of care dose prescription that has previously been demonstrated to be safe. 
 
3.2.1 
Therefore, each enrolled patient will be included in either the cohort of 
patients with an index lesion measuring 2.1-4 cm in maximum diameter or the 
cohort of patients with an index lesion measuring 4.1-6 cm in maximum 
diameter. An individual patient can only be included in 1 of the 2 cohorts as 
Identification of Appropriate Study Participants: Patients with 
Brain Metastases that are 2.1-6 cm in size 
Identify index lesion based on MRI and CT-simulation imaging 
Treatment planning – VMAT approach 
Treatment delivery – Prescription based on tumor diameter 
Dose escalation utilizing the mTPI method 
Safety, efficacy, and quality of life evaluations with follow-up 
clinical exams and imaging 

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determined by the index lesion diameter. The index lesion maximum diameter 
will determine the cohort and subsequent dose escalation schedule. 
 
3.3 Enrolled patients will undergo appropriate MRI brain imaging that will be fused with 
the treatment planning CT-simulation scan for target identification. 
 
3.4 Utilizing available clinical data (pathology, physical exam, MRI, and CT-simulation) 
physicians, medical dosimetrists, and physicists will create and approve a treatment 
plan if all dosimetric and quality assurance requirements are met. 
 
3.5 FSRT will be delivered over 5-14 calendar days. The exact treatment schedule will be 
at the discretion of the treating physician. 
 
3.6 Following completion of treatment, patients will be evaluated with clinical exams, 
imaging, and quality of life questionnaires at regular intervals. 
 
4.0 PATIENT SELECTION CRITERIA 
 
4.1 Inclusion Criteria 
 
4.1.1 
All patients must have histologically confirmed malignancy. 
 
4.1.2 
All patients must have imaging suggestive of one or more brain metastases. 
 
4.1.3 
Karnofsky performance status (KPS) ≥ 60 
 
4.1.4 
Age > 18 years 
 
4.1.5 
Patients must provide written informed consent to participate in the study. 
 
4.1.6 
Patients must have less than or equal to 10 brain metastases as identified on 
brain MRI. 
 
 
4.2 Exclusion Criteria 
 
4.2.1 
History of surgical resection to the tumor of interest 
 
4.2.2 
History of radiation to the tumor of interest 
 
4.2.3 
History of previous whole brain irradiation 
 
4.2.4 
Receipt of systemic therapy within one week of planned radiation treatment 
except for hormonal agents 

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4.2.5 
Patient is unable to have MRI or MRI contrast 
 
4.2.6 
Inability to meet the appropriate normal tissue dose constraints secondary to 
tumor location should result in exclusion of the patient / tumor 
 
4.2.7 
Patients with a non-index tumor (second tumor) greater than 3 cm in 
diameter will be excluded 
 
4.2.8 
Patient is currently pregnant 
 
4.2.9 
Patients with histologies that are considered exquisitely radiosensitive, 
including germ cell tumors, small cell carcinoma, and lymphomas 
 
 
5.0 DRUG INFORMATION 
 
5.1 No experimental medications are utilized in this study. 
 
5.2 Oral or intravenous corticosteroids are considered standard of care and will be utilized 
at the discretion of the treating physician. 
 
6.0 TREATMENT PLAN 
 
6.1 Treatment planning CT-simulation and contour/volume delineation 
 
6.1.1 
Patients will undergo a pre-treatment CT-simulation scan in the supine 
position. The CT scan will be obtained with thin slices (1 mm) to improve 
target delineation. Intravenous contrast will be administered at the time of 
CT-simulation. A personalized thermoplastic facemask will be utilized for 
immobilization. 
 
6.1.2 
CT-simulation images will be electronically fused with MRI images within the 
treatment planning software. The fused images will be used for contours and 
treatment planning. 
 
6.1.2.1 The treating physician will define the gross target volume (GTV) and 
adjacent organs at risk. 
 
6.1.2.2 The GTV is defined as the enhancing tumor on post-contrast imaging 
as well as any additional component as determined by the treating 
physician. 
 

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6.1.2.3 Adjacent organs at risk to be contoured include the brain, brainstem, 
spinal cord, optic nerves, optic chiasm, cochlea and eyes. 
 
6.2 FSRT Dose Specifications 
 
6.2.1 
The radiation prescription dose is normalized to cover 99-100% of the index 
target volume.  If a patient has more than one tumor being treated, the 
largest tumor is considered the index lesion. Smaller tumors will receive a 
previously demonstrated safe dose prescription. 
 
6.3 Critical Structures 
 
6.3.1 
All radiation plans will follow the standard of care normal tissue constraints as 
outlined by the UAB Department of Radiation Oncology treatment planning 
guidelines. The following table lists the 5 fraction constraints: 
 
Table 6.1 Normal tissue constraints for CNS structures 
Central Nervous System Constraints (5 Fraction Treatment) 
Organ 
Constraint (Max Dose) 
Priority 
Brain-GTV 
30 Gy 
II 
Brainstem 
31 Gy, V26 Gy < 1 cc 
I 
Optic Nerve / Chiasm 
25 Gy, V20 Gy < 0.2 cc 
I 
Cochlea 
27.5 Gy 
II 
Lens 
7 Gy 
II 
Retina 
15 Gy 
II 
Spinal Cord 
30 Gy, V22.5 < 0.25 cc 
I 
 
I = Do not violate. Achieving constraint is more important than target coverage. 
II = Planning goal, but less important than target coverage. 
 
 
6.4 Treatment plan physics quality assurance 
 
6.4.1 
All treatment plan dose distributions will be verified by UAB staff physicists 
and must meet the standard of care quality assurance procedures set forth by 
the Department of Radiation Oncology prior to radiation treatment 
administration. 
 
6.4.2 
Dose will be validated by either an ion chamber/film combination in a solid 
water phantom or a dose calibrated diode array. In either case, the phantom 
will be irradiated with the same plan as the patient including all couch angles 
and beam projections. A dose plane will be calculated and exported from the 

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treatment planning system and will be compared with the measured dose 
plane from the one of the above techniques. 
 
 
6.5 Technical Factors 
 
6.5.1 
All treatment plans will be devised utilizing intensity modulated radiotherapy 
(IMRT) or volumetric modulated arc therapy (VMAT). 
 
6.5.2 
Treatments will be delivered on an appropriately selected linear accelerator, 
equipped with image guided radiation therapy (IGRT) capability and a six 
degree of freedom couch. 
 
6.6 Treatment Delivery 
 
6.6.1 
Image-guidance with kilovoltage orthogonal x-rays and cone-beam CT scans 
are to be utilized immediately prior to administration of each radiation 
fraction. At the treating physician’s discretion, Optical Surface Monitoring 
System (OSMS) may be utilized during treatment to monitor intra-fraction 
motion. A physician is to approve appropriate patient positioning based upon 
set-up imaging for each radiotherapy fraction. 
 
6.7 Treatment Delivery Schedule 
 
6.7.1 
Radiation treatments will be delivered in accordance with the standard 
radiation oncology clinic procedures. Treatment must be completed within 
the time frame of 5 to 14 calendar days, in which the first day of treatment 
will be considered day 1. The exact treatment schedule is left to the discretion 
of the treating physician. 
 
6.7 
Treatment Dose Schedule 
 
 
 
 
 
 
 
7.0 THERAPY MODIFICATIONS 
 
7.1 Dose Modifications 
 
All prescription doses are determined in accordance with the previously described 
dosing schema. The index lesion will receive the current investigational dose, and all 
Dose Level 
2.1-4.0 cm diameter 
4.1-6.0 cm diameter 
1 
7 Gy 
6 Gy 
2 
8 Gy 
7 Gy 
3 
9 Gy 
8 Gy 

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other treated tumors will receive a previously demonstrated safe, standard of care 
dose prescription. No dose modifications are to be made outside of the selected dose 
prescriptions utilized in the study.  
 
7.2 Concomitant Medication 
 
7.2.1 
All medications administered since protocol enrollment will be recorded in 
the medical record 
 
7.2.2 
No cytotoxic chemotherapies are to be administered during the 
administration of FSRT 
 
7.2.3 
Administration of pre-treatment or post-treatment corticosteroids (for 
example, dexamethasone 4-10 mg within 1 hour of radiation) is at the 
discretion of the treating physician. 
 
7.3  Adverse Events (AE’s) and Serious Adverse Events (SAE’s) 
 
7.3.1 
Definition of Adverse Event (AE): Any untoward medical occurrence, which 
does not necessarily have a causal relationship with the study treatment. This 
includes any physical or clinical change experienced by the subject, whether 
or not considered related to the study treatment. An AE can therefore be any 
unfavorable or unintended sign, symptom, or disease temporally associated 
with the study treatment. Progression of the patient’s cancer, including 
intracranial progression, is not considered to be an AE. AE’s will be recorded 
in the medical record. 
 
7.3.2 
Definition of Serious Adverse Event (SAE): Any event occurring during the 
study evaluation period that results in any of the following outcomes: 
 
Death attributed to treatment 
 
Inpatient hospitalization 
 
Any irreversible grade ≥ 3 CNS toxicity per the Common Terminology 
Criteria for Adverse Events (CTCAE) CNS toxicity criteria 
 
All SAE’s must be recorded in the medical record. The onset and end dates, 
severity, duration, effect on study administration 
(discontinuation/cancellation, for example), relationship to study treatment, 
and administration of any drugs or therapies to treat the SAE’s will be 
recorded in the medical record. 
 
 
 
 
 

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7.4 Guidelines for adverse event recording 
 
7.4.1 
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0, 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf) will be used for grading adverse events. 
 
7.4.2 
The investigator must assess the relationship of any AE or SAE to the use of 
the study treatment using the following guidelines outlined in the table 
below: 
 
Table 7.1 Attribution of Adverse Events 
Code 
Descriptor 
Definition 
5 
Definite 
The adverse event is clearly related to the 
investigational treatment 
4 
Probable 
The adverse event is likely related to the 
investigational treatment 
3 
Possible 
The adverse event may be related to the 
investigational treatment 
2 
Unlikely 
The adverse event is doubtfully related to the 
investigational treatment 
1 
Unrelated 
The adverse event is clearly not related to the 
investigational treatment 
 
 
7.5 Monitoring of adverse events 
 
Subjects having AE’s or SAE’s will be monitored with relevant clinical assessments and 
laboratory tests as determined by the subject’s treating physician. All adverse events 
must be followed to satisfactory resolution or stabilization of the event(s). Any actions 
taken and follow-up results must be recorded in the subject’s medical record. For all 
AE’s or SAE’s which require the subject to be discontinued from the study, relevant 
clinical assessments and laboratory tests will be repeated as clinically indicated, until 
final resolution or stabilization of the event(s). 
 
7.6 Adverse event reporting 
 
7.6.1 
Notification of all SAE’s must be reported to the Principal Investigator or his 
designee. A written report should be submitted to the appropriate 
Institutional Review Board (IRB) and UAB Clinical Trials Monitoring Committee 
per institutional policy.    
 
7.6.2 
Adverse events will be reported to the Clinical Trials Monitoring Committee.    
 

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7.7 Data and safety monitoring plan 
 
7.7.1 
This protocol will follow the UAB Data and Safety Monitoring Plan maintained 
by the UAB Comprehensive Cancer Center. 
 
7.7.2 
Serious adverse events will be reviewed in the UAB radiation oncology 
treatment planning or new patient conference, and the SAE’s will also be 
reviewed by the Department of Radiation Oncology Quality Assurance 
committees. 
 
7.8 Early Termination 
 
Patients may be discontinued from the study prior to completion of study 
requirements for any of the following reasons: 
 
7.8.1  
The patient has a clinically significant adverse event as determined 
by the principal investigator. 
 
7.8.2  
The patient requests to be withdrawn from the study. 
 
7.8.3  
The patient fails to comply with the requirement for study evaluation/visits. 
 
7.8.4  
Other conditions for which, in the investigator’s opinion, it is in the patient’s 
best interest to be withdrawn from the study. 
 
7.8.5  
The patient did not meet eligibility requirements. 
 
8.0 STUDY PARAMETERS 
 
8.1 For the purposes of this study, acute toxicity will be defined as event(s) 
that occur within 90 days of the completion of radiotherapy. Acute 
 
toxicity will be determined by both intra-treatment examinations and by 
scheduled follow-up evaluations after the treatment has completed. Late 
toxicity will be defined as any toxicity occurring > 90 days after the 
completion of treatment. 
 
8.2 Baseline evaluations of enrolled patients must occur within four weeks of study 
enrollment. 
 
 
 
 
 
 

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Table 8.1 Required study evaluations 
 
Baseline 
2 wk. 
post- 
FSRT 
1 month
3 
months 
6 
months 
12 
months 
History and physical exam 
x 
 
x 
x 
x 
x 
Toxicity / AE evaluation 
 
X1
x 
x 
x 
x 
Performance status (KPS) 
x 
 
x 
x 
x 
x 
MRI brain (Local & CNS 
control per protocol/RANO-
BM) 
x 
 
x 
x 
x 
x 
FACT-Br (QOL evaluation) 
x 
 
x 
x 
x 
x 
1 A 2 week post-treatment phone call will be made to the patient to see how they are feeling 
and evaluate if the patient is experiencing any toxicities.  
 
9.0 EVALUATION CRITERIA 
 
 
9.1 Pretreatment evaluations (baseline) will include the following: 
 
 
Complete medical history 
 
Physical examination including neurologic examination 
 
Vital Signs including weight 
 
Karnofsky performance status 
 
MRI of the brain 
 
Completion of FACT-Br questionnaire 
 
To be eligible for enrollment, the patient must meet all inclusion criteria. Results of all 
baseline or screening evaluations, which assure that all inclusion and exclusion criteria 
have been addressed, must be reviewed by the investigator prior to enrollment of 
each patient. In addition, the patient must be thoroughly informed about all aspects of 
the study, including the study visit schedule, required evaluations, and all regulatory 
requirements for informed consent. Written informed consent must be obtained from 
the patient prior to enrollment. 
 
 
 9.2 Treatment delivery 
 
9.2.1 
All treatment plan dose distributions will be verified by UAB staff physicists 
and must meet the quality assurance standards set forth by the Department 
of Radiation Oncology prior to patient FSRT administration. Pre-treatment 
tissue phantom quality assurance checks will be completed. The phantom will 
be irradiated with the same plan as the patient including all couch angles and 
beam projections. 
 

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Once plans have met physics quality assurance parameters, treatment 
delivery will commence. Clinical treatment delivery feasibility will be 
determined by the ability of the patient to be set up accurately with 
confirmation of appropriate geometry on kilovoltage orthogonal imaging and 
cone beam CT imaging. Treatment delivery will be considered feasible if each 
set of pre-treatment set up images is approved by the treating physician(s) 
prior to administration of radiotherapy. 
 
 
 
9.3 Treatment phase 
 
 
 
9.3.1 
The patient will be evaluated at least once by the treating physician during the 
time that he or she is undergoing radiation treatment. 
 
 
 
9.4 Follow-up 
 
Enrolled patients will participate in a follow-up schedule as outlined in Table 8.1. Two 
weeks post- FSRT, the study coordinator will call the patient to assess how they are 
feeling and/or experiencing any toxicities. This will include a history and physical 
examination, performance status evaluation, MRI of the brain, and completion of the 
FACT-Br questionnaire at 1 month, 3 months, 6 months, and 12 months after 
completion of radiation treatment.  
 
10.0 PATIENT REGISTRATION 
 
10.1 Patients can be registered by contacting the study coordinator, Laronica Conway, at 
205-975-2879. 
 
11.0 STUDY ENDPOINTS 
 
 
11.1 The primary endpoint of this study is to clinically assess early toxicity, specifically, to 
evaluate for the presence of a dose-limiting toxicity within 90 days of the initial 
treatment. We are interested in a risk of 20% or less. 
 
 
 
11.1.1 The definition of a dose-limiting toxicity event will be the same as that used in 
RTOG 9005. It will be defined as an irreversible grade 3, any grade 4, or any 
grade 5 neurologic toxicity related to treatment that occurs within 90 days of 
the start of treatment. Since a patient may have more than one tumor treated 
the toxicity should be assigned to the tumor and not the patient if at all 
possible. Only 1 target per patient will receive the investigational dose 
prescription, and this target will be considered the index lesion. Any 
additional treated non-index lesion will receive a standard of care dose 
prescription that has previously been demonstrated to be safe.  
 
 

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11.2 Secondary endpoints include toxicity and efficacy assessments. 
 
 
 
11.2.1 Determine the frequency and severity of acute neurologic toxicity. 
 
 
 
11.2.2 Determine the frequency and severity of late neurologic toxicity. 
 
 
 
11.2.3 Determine the rate of local tumor control with FSRT. 
 
11.2.3.1 
The index lesion’s treatment response will be assessed according 
to the RANO-BM criteria where a 20% increase in maximal 
diameter from nadir represents local tumor progression.34 
Additionally, the presence of more than scant tumor cells present 
at the time of salvage surgery will be considered a local tumor 
failure. An apparent increase in tumor diameter that is observed 
and found to subsequently decrease in size upon further imaging 
will be considered an effect of therapy rather than a local failure. 
 
11.2.4 Determine the extent of central nervous system disease control in accordance 
with the Response Assessment in Neuro-Oncology (RANO) criteria for brain 
metastases.34 
 
11.2.5 Determine quality of life over time as assessed by the FACT-Br questionnaire. 
 
 
11.3 Exploratory endpoint 
 
 
 
11.3.1 The feasibility of capturing patient reported outcomes (FACT-Br) electronically 
in the Radiation Oncology clinic will be assessed. Feasibility will be defined as 
75% or greater compliance with electronic completion of the questionnaire at 
the specified time points. 
 
 
11.4 Toxicity evaluation 
 
 
11.4.1  Acute and late toxicity will be graded per the CTCAE version 4.0.  
 
 
11.4.2  Definition of acute toxicity: any possible, probable, or definite 
 
treatment-related AE or SAE occurring within 90 days of the 
 
completion of radiotherapy. 
 
11.4.3  Definition of late toxicity: any possible, probable, or definite 
treatment-related AE or SAE occurring later than 90 days from the 
completion of radiotherapy. 
 
 
 

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11.5 Dose Escalation and statistical considerations  
 
11.5.1 The modified toxicity probability interval (mTPI) method with adjustment 
based on observed dose limiting toxicity (DLT) rate will be employed in 
decision making concerning dose escalation within each cohort investigated.35 
The assumptions to be applied in establishing the mTPI methodology are:  
 
•  
Each specific tumor size cohort exploration may include up to 30 patients 
for a total enrollment of up to 60 patients. 
•  
The MTD is defined to have 0.20 probability of toxicity. 
•  
The acceptable variance around the MTD is ± 0.05 (i.e., the region of the 
MTD is 15% to 25% incidence of dose limiting toxicity). 
 
The dose assignment recommendations for cumulative number of patients 
are presented in Table 11.1. The size of each patient cohort during the dose 
escalation phase of the study will be at least 3 patients. Once the initial three 
evaluable patients have cleared the DLT evaluation period then an mTPI 
design will be used to determine whether to escalate or de-escalate the dose. 
Up to 10 evaluable patients may be enrolled at a specific dose prior to making 
a final dose escalation/de-escalation decision. If the DLT rate of the current 
dose does not exceed the maximum permitted toxicity rate as defined by the 
mTPI, then we will evaluate the next dose level.  Patients not evaluable for 
assessment of DLT may be replaced. For any subsequent cohort of patients, 
the recommended dose assignment action will be based on the total number 
of patients with DLTs in the current and prior cohorts treated at the same 
dose level. For example, if a cohort of 3 patients are treated at dose level 1 for 
the first time and one of them experiences a DLT, then the recommended 
action for the next cohort of patients will be to stay at the current dose level 
(S); if this recommendation is accepted, then the selected dose level for the 
next cohort of patients will be 1; if a total of 6 additional patients are treated 
at dose level 1 and there are no more DLTs observed, then the cumulative 
number of patients treated at dose level 1 is 9, and the cumulative number of 
patients with DLTs at dose level 1 is 1 out of 9, thus the recommendation 
would be to escalate the dose for the subsequent cohort (E).  
 
The dose escalation plan will allow enrollment of a three-patient cohort prior 
to the mTPI rule taking effect at the beginning of each dose level. Up to three 
patients can be enrolled at the beginning of each dose escalation level.  Those 
three patients must be followed throughout the dose evaluation period (90 
days).  If one of those three patients develop a DLT, then cohorts of up to 
three additional patients may be treated at that dose level and be within the 
90-day evaluation period at any given time. For example, if 1 out of the 3 
patients develops a DLT, then patients 4-6 may then be enrolled.   Patient 7 

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may be enrolled after patient 4 has been followed without toxicity for 90 
days.   
  
Dose-finding for a cohort may be stopped when one of the following criteria is 
met: 
 
 The lowest dose level appears too toxic after at least 3 patients are dosed 
at that dose level. 
 The maximum sample size in dose finding of 30 evaluable patients per 
cohort has been reached. 
 A minimum of 10 evaluable patients have been treated at the estimated 
MTD. 
 
Analysis will be descriptive and exploratory. Data will be summarized and 
listed by dose level. Toxicity, local tumor control local, central nervous system 
disease control in accordance with the Response Assessment in Neuro-
Oncology (RANO) criteria for brain metastases, and QOL, will be presented in 
the form of patient data listings that include, but are not limited to, age, 
gender, dose, and tumor response at each visit. If the data permits, local 
tumor control rate, central nervous system disease control rate and 
corresponding exact confidence interval will be calculated. Additional 
exploratory data analysis will be performed as data permits. 
 
Interim review of enrolled patients demonstrated that the first three patients 
were not evaluable at the timepoint for the primary endpoint due to systemic 
disease progression and/or other medical illnesses that were deemed to be 
unrelated to their radiation treatment. This was presented to the clinical trials 
monitoring committee, and it was decided that study continuation was 
appropriate; however, it was agreed upon that there should be enrollment of 
6 patients at dose level 1 in the cohort of patients with tumors 2.1–4 cm in 
diameter prior to consideration of dose escalation in order to ensure safety. 
After this, dosing decisions will return to the originally proposed chart as 
displayed below. 
 
 
 
 
 
 
 
 
 
 
 

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Table 11.1 Dose Escalation rule of the modified toxicity probability interval method 
 
 
 
 
11.5 Toxicity rates 
 
 
 
11.6.1 The primary endpoint of the study is to assess the rate of dose limiting toxicity 
experienced within 90 days of the completion of treatment. The maximum 
tolerated dose is defined to have a dose limiting toxicity rate of 20% or less. 
This will be assessed according to the mTPI method as described above. 
 
 
11.6 Sample size 
 
 
 
11.6.1 The total number of subjects enrolled in the study may vary as the study may 
terminate if the DLT rate exceeds the maximum permitted toxicity rate per 
the mTPI. Each specific tumor size cohort exploration may include up to 30 
patients for a total enrollment of up to 60 patients. 
 
 
 
 

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12.0 REFERENCES 
 
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2. Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic brain tumors. Neurosurg Clin 
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patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 
2002;94(10):2698-705. 
 
4. Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. Cancer. 1954;7(4):682-
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5. Horton J, Baxter DH, Olson KB. The management of metastases to the brain by irradiation and 
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6. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single 
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8. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without 
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9. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after 
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26001 study. J Clin Oncol. 2011;29(2):134-41. 
 
10. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with 
radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet 
Oncol. 2009;10(11):1037-44. 
 
11. 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: A 
Randomized Clinical Trial. JAMA. 2016;316(4):401-9. 
 
12. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without 
whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int 
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13. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously 
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Radiat Oncol Biol Phys. 2000;47(2):291-8. 
 
14. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. Lippincott Williams & Wilkins; 2012. 

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15. Kirkpatrick JP, Soltys SG, Lo SS, Beal K, Shrieve DC, Brown PD. The radiosurgery fractionation 
quandary: single fraction or hypofractionation?. Neuro-oncology. 2017;19(suppl_2):ii38-ii49. 
 
16. Rajakesari S, Arvold N, Jimenez R, et al. Local Control after Fractionated Stereotactic Radiation 
Therapy for Brain Metastases. Journal of Neuro-Oncology. 2014; 120(2): 339-346. 
 
17. Fokas E, Henzel M, Surber G, Kleinert G, Hamm K, Engenhart-Cabillic R. Stereotactic Radiosurgery 
and Fractionated Stereotactic Radiotherapy: Comparison of Efficacy and Toxicity in 260 Patients with 
Brain Metastases. Journal of Neuro-Oncology. 2012; 109(1):91-98. 
 
18. Matsuyama T, Kogo K, Oya N. Clinical Outcomes of Biological Effective Dose-Based Fractionated 
Stereotactic Radiation Therapy for Metastatic Brain Tumors From Non-Small Cell Lung Cancer. 
International Journal of Radiation Oncology, Biology, Physics. 2013; 85(4): 984-990. 
 
19. Fahrig A, Ganslandt O, Lambrecht U, et al. Hypofractionated Stereotactic Radiotherapy for Brain 
Metastases. Strahlentherapie Und Onkologie. 2007; 183(11): 625-630. 
 
20. Minniti G, Angelillo R, Scaringi C, et al. Fractionated Stereotactic Radiosurgery for Patients with Brain 
Metastases. Journal of Neuro-Oncology. 2014; 117(2): 295-301. 
 
21. Märtens B, Janssen S, Werner M, et al. Hypofractionated Stereotactic Radiotherapy of Limited Brain 
Metastases: A Single-centre Individualized Treatment Approach. BMC Cancer. 2012; 12(1): 497-505. 
 
22. Eaton B, Gebhardt B, Prabhu R, Shu H, Curran W, Crocker I. Hypofractionated Radiosurgery for Intact 
or Resected Brain Metastases: Defining the Optimal Dose and Fractionation. Radiation Oncology. 
2013; 8(1): 135-141. 
 
23. Marcrom SR, McDonald AM, Thompson JW, Popple RA, Riley KO, Markert JM, et al. Fractionated 
stereotactic radiation therapy for intact brain metastases. Advances in Radiation Oncology. In press, 
accepted July 2017. http://dx.doi.org/10.1016/j.adro.2017.07.006. 
 
24. Vogelbaum MA, Angelov L, Lee SY, Li L, Barnett GH, Suh JH. Local control of brain metastases by 
stereotactic radiosurgery in relation to dose to the tumor margin. J Neurosurg. 2006;104(6):907-12. 
 
25. Wiggenraad R, Verbeek-de kanter A, Kal HB, Taphoorn M, Vissers T, Struikmans H. Dose-effect 
relation in stereotactic radiotherapy for brain metastases. A systematic review. Radiother Oncol. 
2011;98(3):292-7. 
 
26. Aoyama H, Shirato H, Onimaru R, et al. Hypofractionated stereotactic radiotherapy alone without 
whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive 
fixation of the skull. Int J Radiat Oncol Biol Phys. 2003;56(3):793-800. 
 
27. Märtens B, Janssen S, Werner M, et al. Hypofractionated stereotactic radiotherapy of limited brain 
metastases: a single-centre individualized treatment approach. BMC Cancer. 2012;12:497. 
 
28. Baliga S, Garg MK, Fox J, et al. Fractionated stereotactic radiation therapy for brain metastases: a 
systematic review with tumour control probability modelling. Br J Radiol. 2017;90(1070):20160666. 

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29. De azevedo santos TR, Tundisi CF, Ramos H, et al. Local control after radiosurgery for brain 
metastases: predictive factors and implications for clinical decision. Radiat Oncol. 2015;10:63. 
 
30. Yamamoto M, Kawabe T, Sato Y, et al. Stereotactic radiosurgery for patients with multiple brain 
metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or 
more tumors. J Neurosurg. 2014;121 Suppl:16-25. 
 
31. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain 
metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 
2014;15(4):387-95. 
 
32. Thomas EM, Popple RA, Wu X, et al. Comparison of plan quality and delivery time between 
volumetric arc therapy (RapidArc) and Gamma Knife radiosurgery for multiple cranial metastases. 
Neurosurgery. 2014;75(4):409-17. 
 
33. Hatiboglu MA, Akdur K. Evaluating Critical Brain Radiation Doses in the Treatment of Multiple Brain 
Lesions with Gamma Knife Radiosurgery. Stereotact Funct Neurosurg. 2017;95(4):268-278. 
 
34. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from 
the RANO group. Lancet Oncol. 2015;16(6):e270-8. 
 
35. Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than 
the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-91. 
 
 
 
 
 
 

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APPENDICES 
 
Appendix A: Karnofsky Performance Status (KPS) 
 
 
 
Appendix B: Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) 
 
 
 
 

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