A Phase I/II Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases
Phase: NA
Conditions: Brain Cancer, Neoplasm Metastasis, Cancer of Brain and Nervous System, Metastatic Malignant Neoplasm to Brain
Sponsor: Stanford University

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A PHASE I/II STUDY OF FRACTIONATED STEREOTACTIC RADIOSURGERY TO 
TREAT LARGE BRAIN METASTASES 
 
NCT00928226 
 
 
Coordinating Center: 
Stanford Cancer Center 
 
875 Blake Wilbur Drive  
 
Stanford, CA 94305 
 
*Principal Investigator: 
Scott G. Soltys, M.D. 
 
 
 
 
Stanford Cancer Center 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305 
 
 
 
 
 
 
 
 
 
Co-Investigators: 
 
Clara Y. Choi, M.D., Ph.D. 
 
 
 
 
300 Pasteur Drive 
 
 
 
 
Stanford, CA 94035-5327 
 
 
 
 
 
 
 
 
 
 
Iris C. Gibbs, M.D. 
 
 
 
 
Stanford Cancer Center 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305 
 
 
 
 
 
 
 
 
 
 
Steven D. Chang, M.D. 
 
 
 
 
300 Pasteur Drive  
 
 
 
 
Stanford, CA 94305-5327 
 
 
 
 
 
 
 
 
 
 
Griffith Harsh, M.D. 
 
 
 
 
300 Pasteur Drive 
 
 
 
 
Stanford, CA 94035-5327 
 
 
 
 
 
 
 

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Biostatistician: 
 
Alex McMillan, Ph.D. 
Health Research & Policy  
259 Campus Drive 
Stanford, CA 94305-5327 
 
Study Coordinator: 
Jacob Wynne 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305 
 
  
 
 
 
 
 
Protocol Type / Version # / Version Date: 
Revision / 1.6 / 18Nov2013 
 

 
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TABLE OF CONTENTS 
 
 
 
Page 
PROTOCOL SYNOPSIS ..............................................................................................................5 
SCHEMA ........................................................................................................................................8 
LIST OF ABBREVIATIONS .......................................................................................................9 
 
1. OBJECTIVES ........................................................................................................................10 
1.1.Primary Objectives.............................................................................................................10 
1.2.Secondary Objectives.........................................................................................................10 
2. BACKGROUND ....................................................................................................................10 
2.1.Brain Metastasis .................................................................................................................10 
2.2.Surgery ...............................................................................................................................10 
2.3.Neurocognitive Effects of Whole Brain Radiotherapy ......................................................11 
2.4.Stereotactic Radiosurgery ..................................................................................................11  
2.5.Large Brain Metastases ......................................................................................................11 
2.6.Fractionated Radiosurgery .................................................................................................12 
3. PARTICIPANT SELECTION AND ENROLLMENT 
PROCEDURES ......................................................................................................................12
...................................................................................................................................................... 
3.1.Inclusion Criteria ...............................................................................................................12 
3.2.Exclusion Criteria ..............................................................................................................13 
3.3.Informed Consent Process .................................................................................................13 
3.4.Randomization Procedures ................................................................................................13 
4. TREATMENT PLAN ............................................................................................................14 
4.1.Investigational Agent or Device Administration ...............................................................14 
4.2.General Concomitant Medication and Supportive Care Guidelines ..................................15 
4.3.Duration of Therapy ...........................................................................................................16 
4.4.Duration of Follow Up .......................................................................................................16 
4.5.Criteria for Removal from Study .......................................................................................16 
4.6.Alternatives ........................................................................................................................17 
4.7.Compensation ....................................................................................................................17 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ..................17 
5.1.Investigational Agent/Device/Procedure ...........................................................................17 
5.2.Availability ........................................................................................................................17 
5.3.Agent Ordering ..................................................................................................................18 
5.4.Agent Accountability .........................................................................................................18 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................18 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ..............................................18 
7.1.Potential Adverse Events ...................................................................................................18 
7.2.Adverse Event Reporting ...................................................................................................18 
8. CORRELATIVE/SPECIAL STUDIES ...............................................................................20 
9. STUDY CALENDAR ............................................................................................................21 
10. MEASUREMENT OF EFFECT ..........................................................................................21 
10.1.Anti-tumor Effect .............................................................................................................21 

 
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10.2.Other Response Parameters .............................................................................................22 
11. DATA REPORTING/REGULATORY CONSIDERATIONS ..........................................23 
11.1.Monitoring Plan ...............................................................................................................23 
11.2.Stopping Rules .................................................................................................................23 
11.3.Data Management ............................................................................................................24 
11.4.Confidentiality .................................................................................................................24 
12. STATISTICAL CONSIDERATIONS .................................................................................24 
12.1.Endpoints .........................................................................................................................24 
12.2.Analysis Populations ........................................................................................................25 
12.3.Sample Size ......................................................................................................................25 
12.4.Interim analyses ...............................................................................................................25 
 
REFERENCES .............................................................................................................................25 
 
APPENDICES 
 
A. Informed Consent Form 
 
B. Participant Eligibility Checklist 
 
C. RTOG CNS Acute Radiation Morbidity Scoring Criteria 
 
D. RTOG CNS Late Radiation Morbidity Scoring Criteria 
 
E. NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0  
 
F. EORTC QLQ - BN20 
 
G. EORTC QLQ – C30 
 
 

 
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PROTOCOL SYNOPSIS 
 
TITLE 
A PHASE I/II STUDY OF 
FRACTIONATED STEREOTACTIC 
RADIOSURGERY TO TREAT LARGE 
BRAIN METASTASES 
STUDY PHASE 
I/II 
INDICATION 
Histologically or pathologically proven solid 
tumor malignancy and 1 to 4 total brain 
metastases, one of which is 4.2-33.5 cm3, 
with no previous whole brain irradiation.   
PRIMARY OBJECTVES 
Determine the maximum tolerated dose 
(MTD) of SRS given in 3 fractions for brain 
metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
SECONDARY OBJECTIVES 
1. Determine the local control rate as 
assessed on MRI and clinical exam.    
2. Determine short- and long-term adverse 
effects. 
3. Determine the distant intra-cranial control 
rate. 
4. Determine the overall survival rate. 
5.  Assess the patient’s health related quality 
of life. 
HYPOTHESES 
Fractionated SRS treatment of large brain 
metastases will improve local control and 
toxicity profile compared to single fraction 
SRS. 
STUDY DESIGN 
The MTD of SRS given in 3 fractions for 
brain metastases 4.2 - 14.1 cm3 and 14.2 - 
33.5 cm3 will be determined using the 6+6 
study design. 
PRIMARY ENDPOINTS AND 
SECONDARY ENDPOINTS 
Primary Endpoint: 
Determine the maximum tolerated dose 
(MTD) of SRS given in 3 fractions for brain 
metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
 
Secondary Endpoints: 
 To determine the local control rate of 
fractionated SRS for brain metastases 
4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 

 
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 To determine the distant brain control 
rate. 
 To determine the overall survival rate. 
 To determine the short- and long-term 
adverse effects of fractionated SRS for 
brain metastases 4.2 - 14.1 cm3 and 
14.2 - 33.5 cm3. 
 Patient health related quality of life 
will be assessed. 
SAMPLE SIZE BY TREATMENT 
GROUP 
If all four dose levels are reached, the 
maximum number of evaluable subjects in 
each arm is 30; therefore, the maximum 
number of subjects for the entire study is 60.  
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
 All patients age 18 years and older with 
pathologically 
proven 
solid 
tumor 
malignancy and 1 to 4 brain metastases, 
one of which is 4.2 – 33.5 cm3.   
 Systemic therapy:  Prior cytoxic systemic 
therapy must be completed ≥ 5 days prior 
to radiosurgery.  No concurrent cytoxic 
systemic therapy along with SRS.  Cytoxic 
systemic therapy to start ≥ 5 days after the 
completion of SRS. 
 Prior surgery or SRS is allowed as long as 
the target metastatic lesion in this study has 
not previously been treated with SRS. 
 Patient must exhibit the ability to 
understand and the willingness to sign a 
written informed consent. 
 Life expectancy of at least 12 weeks. 
 
Exclusion Criteria 
 Patients who have previously been treated 
with whole brain irradiation. 
 Patients whose metastatic lesion in 
question had previously been treated with 
SRS. 
 The patient has greater than 4 total brain 
metastases at the time of initial evaluation. 

 
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 Pediatric patients (age <18), pregnant 
women, and patients who are unable to 
give informed consent will be excluded. 
INVESTIGATIONAL PRODUCTS 
DOSAGE AND ADMINISTRATION 
N/A 
CONTROL GROUP 
N/A 
PROCEDURES 
N/A 
STATISTICAL CONSIDERATIONS 
6+6 design for dose escalation 
 
 
 

 
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SCHEMA 
 
 
 
 
 
 
Arm  Metastasis Size (cm3)  
Surgical Candidate?  
Treatment  
1  
4.2 - 14.1  
Yes 
Surgery → SRS  
2  
14.2 - 33.5  
Yes  
Surgery → SRS  
 
 
 
 
 
 
 
 
 
 
 
Dose Level  
Dose Per Fraction  
Total Dose  
1  
8 Gy  
24 Gy  
2  
9 Gy  
27 Gy  
3  
10 Gy  
30 Gy  
4  
11 Gy  
33 Gy  

 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report/Record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
IRB 
Institutional Review Board 
IV 
Intravenous 
KPS 
Karnofsky Performance Scale 
MR 
Minor response 
OS 
Overall survival  
P 
Progression (disease) 
PD 
Protocol Director 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SRS 
Stereotactic Radiosurgery 
WBRT 
Whole Brain Radiation 
 
 
 

 
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1. OBJECTIVES 
 
1.1. 
Primary Objectives  
 
Determine the maximum tolerated dose (MTD) of SRS given in 3 fractions for 
resection cavities from brain metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
 
1.2. 
Secondary Objectives 
 
 
1.2.1. Determine the local control rate as assessed on MRI and clinical exam.    
1.2.2. Determine short- and long-term adverse effects. 
1.2.3. Determine the distant intra-cranial control rate. 
1.2.4. Determine the overall survival rate. 
1.2.5. Assess the patient’s health related quality of life. 
 
2. BACKGROUND 
 
2.1.Brain Metastases 
Brain metastases are the most common intracranial tumors and occur in approximately 
25% of patients with cancer[1].  In the U.S., approximately 170,000 cancer patients a year 
are diagnosed with brain metastases[2].  Likely as a result of improvements in systemic 
treatments, the incidence of intracranial metastases has increased over the past decade[3].  
The most common malignancies to spread to the brain are lung, breast, kidney, 
colon/rectum, and melanoma.  Clinically, patients with brain metastases can present with 
headache, neurologic deficits, cognitive dysfunction, seizures, or stroke.  Diagnosis is 
made with neuro-imaging.   
 
The prognosis of patients with brain metastases is variable and depends on several factors, 
including performance status, age, control of the primary tumor, and extent of extracranial 
disease[4].  Historically, patients with brain metastases who receive supportive care only 
have median survival of 1 to 2 months.  However, a subgroup of patients with favorable 
prognosis who undergo treatment can enjoy an extended life expectancy with median 
survival of 10 to 16 months[5, 6].  Treatment options for brain metastases include medical 
management, surgery, and radiation.  Surgery and radiation will be discussed further.    
 
2.2.Surgery 
Surgery has an important role in management of brain metastases.  In patients with a large 
tumor causing mass effect, surgical resection can provide rapid relief of symptoms.  
Moreover, surgery followed by conventional whole brain radiation (WBRT) decreases 
local recurrence and improves median survival compared to WBRT alone[7].  In our study, 
patients deemed suitable for surgery will undergo upfront surgical resection followed by 

 
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radiosurgery to the resection cavity.  
 
2.3.Neurocognitive Effects of Whole Brain Radiotherapy 
Radiation therapy can be delivered using 1) conventional fractionated radiation to treat the 
whole brain (WBRT), 2) stereotactic radiosurgery (SRS) to treat individual metastases, or 
3) both.    
 
WBRT is associated with a short-term decline in quality of life and long-term deficits in 
neurocognitive function[8, 9].  In conventionally fractionated WBRT, radiation to the 
whole cranium is delivered in 10 to 20 daily treatments.  Late toxicity of WBRT, such as 
memory impairment and dementia, is usually irreversible and is likely due to 
demyelination, vascular damage, and necrosis.   Following WBRT, the actuarial rate of 
neurocognitive toxicity at 2 years can be up to 49%[10].  Meyers reported that 59% of the 
patients after WBRT demonstrated a greater than 2 standard deviation decline in their 
performance at 6 months[11].  Results from a recently presented phase III randomized trial 
reported WBRT to be linked to a marked decline in learning and memory function at 4 
months compared to SRS alone (49% vs. 23%, respectively).    
2.4.Stereotactic Radiosurgery 
Unlike WBRT, stereotactic radiosurgery has the advantage of sparing normal brain.  In 
SRS, high energy radiation is precisely directed at the target lesion.  Due to the steep fall–
off of the radiation dose away from the target, relative sparing of the normal brain is 
possible.  To minimize the potential late effects of WBRT, investigators have explored the 
use of SRS alone, deferring the use of WBRT for salvage treatment if needed.  Both 
retrospective analyses[12-15] and a prospective randomized trial[16] reported no apparent 
survival benefit to combining WBRT with SRS compared to SRS alone.   
We have recently published a retrospective review of patients with brain metastases treated 
with surgical resection followed by adjuvant SRS to the resection cavity while deferring 
WBRT for salvage.  Actuarial local control rates at 6 and 12 months were 88% and 79%, 
respectively.  This value compares favorably with historic results with observation alone 
(54%) and postoperative WBI (80-90%)[17].  Given its negative neurocognitive effects in 
the absence of survival benefit, it is our current practice to omit WBRT in favor of SRS in 
patients with limited number of brain metastases.   
2.5.Large Brain Metastases 
Neither WBRT nor SRS has been shown to adequately control large brain metastases.  
WBRT has been shown to have less than 5% complete response rate with brain metastases 
larger than 2 cm[18].  Radiation Therapy Oncology Group (RTOG) 90-05 study 
determined maximum tolerated dose (MTD) and subsequent dose selection guidelines for 
single fraction radiosurgery in patients with recurrent brain metastases who had received 
prior partial or whole brain irradiation[19].  The MTD for metastases < 2cm, 2-3 cm and 

 
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3-4 cm were not reached, 24, and 18 Gy, respectively.  Based on these results, the 
recommended single fraction radiosurgery dose for brain metastases of <2 cm, 2-3 cm, and 
3-4 cm are 24 Gy, 18 Gy, and 15 Gy, respectively.  However, subsequent reports on the 
usage of these dosing guidelines show a local control of only 49% and 45% for metastases 
2-3 cm and 3-4 cm in diameter, respectively[20].   Similarly, a series from Pittsburgh 
showed only a 49% local control rate for tumors >4 cc (approximately >2 cm 
diameter)[21].  The importance of controlling brain metastases is demonstrated by the 
significant decline in neurocognitive function in those patients with disease progression 
compared to those with controlled disease[11].  Given the negative impact of recurrent 
intracranial disease on the quality of life and neurocognitive ability of patients, a great need 
exists for the improvement of local control in patients with large brain metastases.   
 
2.6.Fractionated Radiosurgery 
One technique which may improve local control and toxicity profile is fractionation of SRS 
treatments.  Fractionation has been demonstrated to increase tumor kill by allowing inter-
fraction re-oxygenation and cell reassortment to minimize radioresistance due to hypoxia 
and cell cycle[22].  In addition, fractionation reduces the late effects of radiotherapy. 
 
Despite the widespread use of fractionated radiosurgery, no prospective data exist to 1) 
provide dose guidelines, 2) determine whether fractionation of SRS improves local control, 
and 3) examine the effects of fractionation on acute and late side effects.    
The protocol outline here proposes SRS to be delivered in 3 fractions with initial dose of 
24 Gy in 3 fractions (i.e., 8 Gy x 3 fractions) for brain metastases 4.2 - 14.1 cm3 (2 – 3 cm 
diameter) and for metastases 14.2 - 33.5 cm3 (3 - 4 cm diameter).  This dose is 
radiobiologically equivalent to 16 Gy in a single fraction.  This conservative dose of 24 Gy 
in 3 fractions is below or similar to the MTD for single fraction SRS determined in the 
RTOG 90-05 in patients who had already received previous brain irradiation.    
 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
Refer to the Participant Eligibility Checklist in Appendix B.  
 
3.1 Inclusion Criteria 
 
3.1.1. All patients age 18 years and older with pathologically proven solid tumor 
malignancy and 1 to 4 brain metastases, one of which is 4.2 – 33.5 cm3.   
3.1.2. Systemic therapy:  Prior cytoxic systemic therapy must be completed ≥ 5 days prior 
to radiosurgery.  No concurrent cytoxic systemic therapy along with SRS.  Cytoxic 
systemic therapy to start ≥ 5 days after the completion of SRS. 
3.1.3. Prior surgery or SRS is allowed as long as the target metastatic lesion in this study 
has not previously been treated with SRS. 

 
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3.1.4. Patient must exhibit the ability to understand and the willingness to sign a written 
informed consent. 
3.1.5. Life expectancy of at least 12 weeks. 
3.2 Exclusion Criteria 
 
3.2.1.  Patients who have previously been treated with whole brain irradiation. 
3.2.2. Patients whose metastatic lesion in question had previously been treated with SRS. 
3.2.3. The patient has greater than 4 total brain metastases at the time of initial evaluation. 
3.2.4. Pediatric patients (age <18), pregnant women, and patients who are unable to give 
informed consent will be excluded. 
 
3.3       Informed Consent Process 
 
3.3.1 Informed consent may be obtained by the PI or a designee who is a member of the 
research team. 
3.3.2 The PI is ultimately responsible for determining whether a subject has the 
capacity to consent, although informed consent may be obtained by either the PI 
or designee. If the subject is lacking such capacity, whether due to cognitive 
impairment, the subject’s age, or other causes, the PI/designee may obtain consent 
from a legally authorized representative. 
3.3.3 As part of the consent process, the subject’s or his/her representative’s questions 
must be answered prior to consent being given and throughout the study. The 
subject or his/her representative should be asked if there are any questions prior to 
consent being obtained and at all subsequent visits or contacts. These elements of 
the informed consent process must be documented in the patient’s medical record. 
3.3.4 When giving the consent, the subject or a duly authorized legal representative 
needs to read each page and sign and date the last page of the form along with the 
investigator or designee obtaining consent. 
3.3.5 The signed Informed Consent Form should be filed in the following location. 
3.3.5.1 The signed consent will be filed in the patient’s research study record. 
3.3.5.2 One copy of the signed consent will be sent to Stanford Medical Records 
where it will be scanned into the patient’s electronic medical record. 
3.3.5.3 An additional copy of the consent form will be filed in the study Regulatory 
Binder. 
 
3.4       Randomization Procedures 
 
This is not a randomized trial.  There will be no randomization. 
 
 
 

 
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4. TREATMENT PLAN 
 
4.1 Investigational Agent or Device Administration 
4.1.1. PRETREATMENT EVALUATIONS 
Patients will be evaluated by a multi-disciplinary team composed of radiation 
oncologists and neurosurgeons to assess for their eligibility.  Patient’s oncologic 
history, presenting symptoms, physical examination, pathology, and imaging studies 
will be reviewed.  Patients will be evaluated for surgical candidacy and resectability.   
 
 
4.1.2. SURGICAL TREATMENT 
Patients who are good surgical candidates, as determined by neurosurgical evaluation, 
will undergo a surgical resection prior to radiotherapy.  All others will receive primary 
SRS. 
 
4.1.3. RADIATION THERAPY 
4.1.3.1.Dose specifications/escalation 
SRS will be delivered in 3 fractions.  Provided that the MTD has not been reached, 
the total dose will be increased in 3 Gy increments:   
 
Dose Level Dose Per Fraction Total Dose 
1 
8 Gy 
24 Gy 
2 
9 Gy 
27 Gy 
3 
10 Gy 
30 Gy 
4 
11 Gy 
33 Gy 
 
A minimum of six patients will be enrolled per arm:   
 
Arm  
1 
4.2 - 14.1 cm3 brain metastasis following surgical resection 
2 
14.2 - 33.5 cm3 brain metastasis following surgical resection 
 
 
 
 
 
Similar to RTOG 90-05, the dose limiting toxicity (DLT) is defined as grade 3, 4, 
or 5 RTOG central nervous system (CNS) acute radiation morbidity scoring criteria 
(Appendix C) observed within 30 days of radiosurgery.  The MTD is defined as 
one dose level below the highest toxic dose (i.e., the DLT dose). 
 
The occurrence of late toxicities will be continuously monitored. If a late DLT occurs in 3 
or more out of 6 (or 4 or more out of 12) patients at a certain dose level after the radiation 
dose had already been escalated to the next level, the MTD will be backtracked to the level 

 
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below the one at which the DLTs occurred. 
 
 
Does escalation will proceed as follows, with minimum waiting period of 30 days 
before proceeding with the next higher dose level: 
 
Number of Patients at a Given 
Dose Level with a DLT 
Escalation Decision Rule 
0-1 out of 6 
Enter 6 patients at the next higher dose level 
2 out of 6 
 
 
 
 
Enter at least 6 more patients at the current dose level. 
 If 0-1 of these 6 experience a DLT (i.e., 2-3 
out of 12), then proceed to next dose level. 
 If 2 or more of these 6 experience a DLT (4 or 
more out of 12), then dose escalation will be 
stopped.  Six additional patients will be 
entered at the next lower dose level if only 6 
patients were previously entered. 
3 or more out of 6 
Dose escalation will be stopped. Six additional 
patients will be entered at the next lower dose level if 
only 6 patients were previously entered. 
 
Should a patient not be evaluable at 30 days (due to death or loss to follow-up or 
discontinuation of the protocol follow-up per patient preference), then additional patients 
may be enrolled on each arm such that at least 5 of 6 are evaluable and experience no DLT.  
For example, should one patient be lost to follow up, but the remaining 5 patients have no 
DLT, then dose escalation may proceed. 
 
4.1.3.2.Technical factors 
Treatment shall be delivered using the Trilogy™ Linear Accelerator (Varian Medical 
Systems, Palo Alto, CA) or the CyberKnife™ Robotic Radiosurgery System (Accuray, 
Sunnyvale, CA). 
 
4.1.3.3.Localization, simulation, and immobilization 
The patient shall be treated in the supine position.  An aquaplast head mask will be used 
to ensure adequate immobilization during therapy.  The target volume shall be either the 
resection cavity or the unresectable lesion.  When the resection cavity is targeted, a 
uniform isotropic 2 mm expansion of the cavity will be the target volume[17]. 
 
4.1.3.4.Critical structures 

 
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Critical normal structures (e.g., optic apparatus, brain stem) will be contoured and their 
doses minimized.  The patient will be excluded from the protocol if the tumor’s proximity 
to critical structures is such that a dosimetrically acceptable plan is not achievable to 
conform to these constraints. 
 
 
4.2  
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive treatment may include anti-emetics, anti-diarrheal medications, anti-
pyretics, anti-histamines, analgesics, antibiotics, and others, such as blood products.  
Patients will be permitted to receive appropriate supportive care measures as deemed 
necessary by the treating physician. 
Steroids may be given after each SRS treatment to decrease the risk of CNS symptoms 
due to cerebral edema.  In addition, steroids may be used as required to control CNS 
symptoms due to tumor-associated or RT-associated cerebral edema, but wherever 
possible, should be tapered and stopped.  
 
Nausea/vomiting:  Nausea and vomiting should be treated aggressively. In particular, 
the use of antiemetics including 5HT3 antagonists and/or dexamethasone is 
encouraged. Patients should be strongly encouraged to maintain liberal oral fluid 
intake during therapy. 
 
4.3  
Duration of Therapy 
 
SRS will be given in 3 fractions, each approximately 24 hours apart. 
 
4.4  
Duration of Follow Up 
 
Follow-up schedule is summarized in section 9. Study Calendar. 
Patients will be seen in follow-up at 1st, 3rd, 6th, 9th, and 12th months following radiation.  
The following will be obtained at pre-treatment evaluation and at each follow-up time 
point:  Neurologic history and physical examination, KPS, steroid use assessment, and 
toxicity evaluation.  MRI with gadolinium will be obtained at pre-treatment and at 3, 
6, 9, and 12 months following treatment until progression is documented and 
continuing every 3 months for those without evidence of intracranial progression.   
After the first 12 months, patients will be followed every 3-6 months at the discretion 
of the patient’s physician.  At each visit, interval history, physical exam, KPS, toxicity 
evaluation, and brain MRI scans will be obtained. 
For those subjects who are unable to come for clinic visits, clinical follow-up 
information will be obtained via 1) a phone call to the patient and/or 2) clinic source 
document from his/her local physician.  For subjects unable to appear in person for 
clinic visits, HRQOL questionnaires will be completed via a telephone interview or 
mail. 
 

 
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For patients unable to return for imaging studies, source documents from outside 
institutions will be used to document imaging follow-up.   
 
 
 
4.5 
Criteria for Removal from Study 
 
 Disease progression or death 
 Intercurrent illness that prevents further administration of treatment:  a condition, 
injury, or disease unrelated to cancer, that renders continuing of radiation 
treatment unsafe or regular study visits impossible.  
 Unacceptable adverse event(s) (see adverse events) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition that render the patient 
ineligible for the study 
 Non-compliance with protocol-required evaluations and study visits 
 Inability of subject to comply with study requirements 
 Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 Patients who inadvertently become pregnant   
 At the discretion of the treating investigators 
 
Subjects who are discontinued from the study will still be followed for disease 
progression and survival. 
 
Subjects who discontinue should, if possible, be seen and assessed by an 
investigator(s). The reason for withdrawal and the date of withdrawal must be 
documented.   
 
If the reason for withdrawal from the trial is the death of the subject, the two options 
for categorizing withdrawal are either progressive disease or an adverse event (AE; 
more than one AE may be documented as a reason for withdrawal).  Only one event 
will be captured as the cause of death.  Note that death is an outcome and not an AE.  
 
All trial treatment-related toxicities and serious adverse events (SAEs) must be 
followed up until resolution. 
 
At withdrawal, all on-going study-related toxicities and SAEs must be followed until 
resolution, unless in the investigator’s opinion, the condition is unlikely to resolve due 
to the subject’s underlying disease.   
 
Subjects/patients who discontinue from the study for reasons unrelated to the study 
(e.g., personal reasons, or adverse events after registration but prior to receiving study 
therapy) may be replaced as required for the study to meet its objectives.  The decision 

 
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to remove a subject/patient and to replace dropouts will be made by the treating 
investigator.  The replacement will generally receive the same treatment or treatment 
sequence (as appropriate) as the allocation number replaced. 
4.6 
 Alternatives 
 
Alternative treatments include conventional fractionated whole brain radiotherapy, 
stereotactic radiosurgery alone, systemic therapy, or no therapy. 
 
4.7 
 Compensation 
 
Subjects will not be paid for their participation in the study.  
 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
 
5.1 
 Investigational Agent/Device/Procedure   
 
N/A 
 
5.2 
 Availability 
 
N/A 
 
5.3 
 Agent Ordering 
 
N/A 
 
5.4 
 Agent Accountability 
 
N/A 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
N/A 
 
7. ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1 
Potential Adverse Events 
 
7.1.1. Early, < 30 days from treatment:  Expected adverse events include fatigue, 
headache, neck pain, nausea and vomiting, and lethargy.   
7.1.2. Late, > 30 days from treatment:  Possible adverse events include focal neurologic 
deficits, memory difficulties, dementia, radiation necrosis, and radiation induced 
neoplasm.   

 
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7.2 
Adverse Event Reporting 
 
In the event of an adverse event the first concern will be for the safety of the subject.  
Appropriate medical, psychological and/or supportive intervention should be initiated 
as soon as possible.  All subjects/patients with serious adverse experiences must be 
followed up for outcome. 
 
7.2.1. Definition: 
7.2.1.1.Definition of adverse event:  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).   
7.2.1.2.Definition of serious adverse event:  any adverse experience that results in 
any of the following outcome: death, a life-threatening experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse event when, based 
upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
7.2.1.3.Definition of unanticipated problems involving risks to participants or 
others (UPs):   events (including internal or external events, death, life-
threatening experiences, injuries, breaches of confidentiality, or other 
problems) that occur any time during or after the research study, which in the 
opinion of the PD are:  
7.2.1.4.Unexpected - not in the consent form, protocol, package insert, or label; or 
unexpected in its frequency, severity, or specificity, AND 
7.2.1.5.Related to the research procedures – caused by, or probably caused by research 
activity, or, if a device is involved, probably caused by , or associated with the 
device, AND 
7.2.1.6.Harmful – caused harm to participants or others, or placed them at increased 
risk of harm (including physical, psychological, economic, or social harm. 

 
20 of 34 
 
7.2.1.7.Definition of reportable information:  New information that indicates a 
change to the risks or potential benefits of the research, in terms of severity or 
frequency. 
7.2.1.7.1. Protocol deviation or violation, only if: 
7.2.1.7.1.1.Intended to eliminate apparent immediate hazard to a research 
participant, or 
7.2.1.7.1.2.Harmful (caused harm to participants or to others, or placed them at 
increased risk of harm – including physical, psychological, 
economic, or social harm), or 
7.2.1.7.1.3.Possible serious or continued noncompliance 
7.2.1.7.2. Complaint that is unresolved by the research team, or that indicates 
increased or unexpected risks. 
7.2.1.7.3. Incarceration when in the opinion of the PD it is in the best interest of 
the participant to remain on the study. 
7.2.1.8.Unanticipated adverse device effect.  New information about the effect on 
health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence, or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or 
welfare or subjects. 
Changes resulting from normal growth and development which do not vary 
significantly in frequency or severity from expected levels are not to be considered 
adverse experiences. Examples of this may include, but are not limited to, teething, 
typical crying in infants and children, and onset of menses or menopause occurring 
at a physiologically appropriate time. 
If disease progression is noted during a protocol-specified reevaluation of the status 
of a patient’s cancer, and the progression is manifested solely by results of tumor 
markers and/or radiologic imaging, that occurrence of progressive disease will 
NOT be recorded as an adverse experience.    
 
7.2.2. Adverse Event Reporting 
 
7.2.2.1.PIs or designees should report AEs, whether considered treatment related or 
not, to the CCTO Safety Coordinator per protocol and regulatory timeframes. 

 
21 of 34 
 
Events should be reported within 10 working days of becoming aware of the 
event (5 days if the event is life-threatening or resulted in death). 
 
7.2.2.2.Unanticipated adverse device effects should be reported to FDA, CCTO and 
participating investigators within 10 working days of becoming aware of the 
event (5 days if the event is life threatening or resulted in death).  
 
7.2.2.3. RTOG central nervous system (CNS) acute radiation morbidity scoring 
criteria (Appendix C) will be used to grade acute CNS toxicity. 
 
7.2.2.4. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be used for grading of adverse events (Appendix E). 
 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1.Dose heterogeneity and conformality within the target volume will be calculated for each 
lesion to investigate whether these factors have any correlation to local control or toxicity. 
8.2.To identify potential predictors of response, the following pre-treatment tumor 
characteristics will be collected: 
8.2.1. Lesion size 
8.2.2. Histology 
8.2.3. Pattern of enhancement on MRI scan 
8.2.4. Presence or absence of extensive edema  
 
9. STUDY CALENDAR 
 
Parameters 
Pre-
Entry 
1 month a 
3 monthb 6 month b  9 month b  12 month b 
History/ 
Physical Exam 
X 
X 
X 
X 
X 
X 
KPS 
X 
X 
X 
X 
X 
X 
MRI 
X 
 
X 
X 
X 
X 
Steroid use 
Assessment 
X 
X 
X 
X 
X 
X 
Toxicity 
Evaluation 
 
X 
X 
X 
X 
X 
QOL Evaluation X 
X 
X 
X 
X 
X 
 
a time point ± 7 days 

 
22 of 34 
 
b time point ± 14 days 
 
10. MEASUREMENT OF EFFECT 
 
 
10.1 
Anti-tumor Effect 
 
Subjects will be seen in follow-up at 1, 3, 6, 9, and 12 months following SRS.At each 
follow-up, neurologic history and examination will be done.  MRI with gadolinium 
will be obtained at 3, 6, 9, and 12 months.    
 
 
10.1.1 Definitions 
 
Early radiation toxicity is defined as those observed within 30 days of SRS.  Late 
radiation toxicity is defined as those observed after 30 days following SRS.  Tumor 
response will be measured using MRI with gadolinium obtained at 3, 6, 9 and 12 
months following SRS. 
 
10.1.2 Disease Parameters 
 
Target lesion is defined as those treated with radiosurgery.  The size and volume 
of the target lesion will be measured using the treatment planning software.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
MRI with gadolinium will be obtained at 3, 6, 9, and 12 months following SRS. 
 
10.1.4 Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
 
Radiographic response using MRI with gadolinium will be used.  Follow-up MRI 
scans will be obtained at 3, 6, 9, and 12 months following SRS.  Size of the treated 
lesion will be measured and compared to its pre-treatment size.  Local tumor 
progression is defined as the radiographic appearance of a new or increasing 
enhancing lesion within the radiosurgical target volume. Local control is defined as 
lack of progression (P – below). Metabolic imaging may be necessary at times to 
distinguish tumor progression from treatment related radiation necrosis.  
4.1.3.4.1. Complete response (CR):  The tumor is no longer seen on the follow-up 
MRI scan. 
4.1.3.4.2. Partial response (PR):  Decrease of >50% in the product of two 
diameters on the follow-up MRI scan. 

 
23 of 34 
 
4.1.3.4.3. Minor response (MR): Decrease of <50% in the product of two 
diameters on the follow-up MRI scan. 
4.1.3.4.4. Stable disease (SD):  The scan shows no change. 
4.1.3.4.5. Progression (P):  A >25% increase in tumor area (product of two 
diameters). 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
 
The distant control rate will be determined.  Distant brain failure is defined 
as the radiographic appearance of a new or enhancing lesion more than 5 
mm from the radiosurgical target volume[19].  Elsewhere brain failure rate 
will be determined using MRI scanning with gadolinium obtained at 3, 6, 
9, and 12 months following SRS. 
10.1.4.3 
Evaluation of Best Overall Response 
 
N/A 
 
10.1.5 Duration of Response 
 
 
N/A 
 
10.1.6 Progression-Free Survival (or other parameters) 
 
Time to progression will be measured from the time of SRS.  Overall survival will 
be measured from 1) the time of diagnosis, and 2) time of SRS. 
 
10.1.7 Response Review 
 
N/A 
 
10.2 
Other Response Parameters 
 
The primary endpoint of this study is to determine the MTD of tri-fraction SRS.  The MTD 
is defined as one dose level below the highest toxic dose (i.e., the DLT dose).  Similar to 
RTOG 90-05, the dose limiting toxicity (DLT) is defined as grade 3, 4, or 5 RTOG central 
nervous system (CNS) acute radiation morbidity scoring criteria (Appendix C) observed 
within 30 days of radiosurgery.   
The occurrence of late toxicities will be continuously monitored. If a late DLT occurs in 3 
or more out of 6 (or 4 or more out of 12)  patients at a certain dose level after the radiation 
dose had already been escalated to the next level, the MTD will be backtracked to the level 

 
24 of 34 
 
below the one at which the DLTs occurred. 
 
 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 Monitoring plan 
 
Stanford Cancer Center (SCC) Data and Safety Monitoring Committee (DSMC) will be 
responsible for monitoring the research yearly and will operate independently from the 
clinical investigators. The primary responsibility of the DSMC is to review the reported 
study data to confirm it is accurate, complete, and verifiable from source 
documents.  The DSMC will also confirm that the conduct of the trial maintains the 
safety and well being of human subjects, and is in compliance with the currently 
approved protocol, with GCP, and with applicable regulatory requirements.  Study 
safety data will be reviewed by the DSMC in the form of summary reports or data 
listings on a regular basis. 
 
11.2  Stopping rules (for the individual patient and for the study as a whole) 
 
The dose limiting toxicity (DLT) is defined as grade 3, 4, or 5 RTOG central nervous 
system (CNS) acute radiation morbidity scoring criteria (Appendix C) observed within 30 
days of radiosurgery.    
The occurrence of late toxicities will be continuously monitored. If a late DLT occurs in 3 
or more out of 6 (or 4 or more out of 12)  patients at a certain dose level after the radiation 
dose had already been escalated to the next level, the MTD will be backtracked to the level 
below the one at which the DLTs occurred. 
 
 
Does escalation will proceed as follows: 
 
Number of Patients at a Given 
Dose Level with a DLT 
Escalation Decision Rule 
0-1 out of 6 
Enter 6 patients at the next higher dose level 
2 out of 6 
 
 
 
 
Enter at least 6 more patients at the current dose level. 
 If 0-1 of these 6 experience a DLT (i.e., 2-3 
out of 12), then proceed to next dose level. 
 If 2 or more of these 6 experience a DLT (4 or 
more out of 12), then dose escalation will be 
stopped.  Six additional patients will be 
entered at the next lower dose level if only 6 
patients were previously entered. 

 
25 of 34 
 
3 or more out of 6 
Dose escalation will be stopped. Six additional 
patients will be entered at the next lower dose level if 
only 6 patients were previously entered. 
 
Should a patient not be evaluable at 30 days (due to death or loss to follow-up or 
discontinuation of the protocol follow-up per patient preference), then additional patients 
may be enrolled on each arm such that at least 5 of 6 are evaluable and experience no DLT.  
For example, should one patient be lost to follow up, but the remaining 5 patients have no 
DLT, then dose escalation may proceed.  
 
 
11.3 Data management  
 
All data files (contains patients’ names, medical record numbers, treatment, and 
follow-up information) for this study will be kept in a secure office in the department 
of Neurosurgery and Radiation Oncology.  The electronic data file for this study, 
which contains patients’ names, medical record numbers, treatment, and follow-up 
information, is kept under password protection. 
 
 
11.4 Confidentiality  
 
All signed informed consents and data files (contains patients’ names, medical record 
numbers, treatment, and follow-up information) for this study will be kept in a secure 
office in the department of Neurosurgery and Radiation Oncology.  The electronic 
data file for this study, which contains patients’ names, medical record numbers, 
treatment, and follow-up information, is kept under password protection. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Endpoints 
 
12.1.1 Primary endpoint 
 
Determine the maximum tolerated dose (MTD) of SRS given in 3 fractions for brain 
metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
12.1.2 Secondary endpoints 
 
12.1.2.1.To determine the local control rate of fractionated SRS for brain metastases 
4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
12.1.2.2.To determine the distant brain control rate of fractionated SRS for brain 
metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 
12.1.2.3.To determine the overall survival rate of fractionated SRS for brain metastases 
4.2 - 14.1 cm3 and 14.2 - 33.5 cm3. 

 
26 of 34 
 
12.1.2.4.To determine the short- and long-term adverse effects of fractionated SRS for 
brain metastases 4.2 - 14.1 cm3 and 14.2 - 33.5 cm3.   
12.1.2.5.Patient health related quality of life will be assessed using the EORTC QLQ-
C30 and EORTC Brain Cancer Module QLQ-BN20. 
 
12.2 
Analysis Populations 
 
Each of the four arms will be analyzed separately to determine the MTD for each 
arm. 
 
Arm  
1 
4.2 - 14.1 cm3 brain metastasis following surgical resection 
2 
14.2 - 33.5 cm3 brain metastasis following surgical resection 
 
 
 
 
 
 
There will be no subset analysis.   
 
 
 
 
 
 
 
 
 
 
 
12.3 
Sample Size 
 
12.3.1 Accrual estimates 
 
Six subjects per group will be enrolled at the starting dose for each of the four arms.  
Should a patient not be evaluable at 30 days (due to death or loss to follow-up or 
discontinuation of the protocol follow-up per patient preference), then additional 
patients may be enrolled on each arm such that at least 5 of 6 experience no DLT.   
The maximum number of subjects per arm will depend on the number of dose levels 
reached.  If all four dose levels are reached, the maximum number of evaluable 
subjects in each arm is 30.  If all four dose levels are reached for the all two arms 
of the study, the maximum number of subjects for the entire study is 60.  
 
 
12.3.2 Sample size justification 
 
The sample size will be determined by the number of dose levels reached. 
 
12.3.3 Criteria for future studies 
 
N/A 
 
12.4 
Interim analyses 
 
N/A 

 
27 of 34 
 
 
REFERENCES 
 
1. 
Kaal, E.C., C.G. Niel, and C.J. Vecht, Therapeutic management of brain metastasis. Lancet 
Neurol, 2005. 4(5): p. 289-98. 
2. 
Andrews, D.W., Current neurosurgical management of brain metastases. Semin Oncol, 2008. 
35(2): p. 100-7. 
3. 
Weil, R.J., Does trastuzumab increase the risk of isolated central nervous system metastases in 
patients with breast cancer? Nat Clin Pract Oncol, 2006. 3(5): p. 236-7. 
4. 
Gaspar, L., 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(4): p. 745-51. 
5. 
Wen, P.Y. and J.S. Loeffler, Management of brain metastases. Oncology (Williston Park), 1999. 
13(7): p. 941-54, 957-61; discussion 961-2, 9. 
6. 
Sneed, P.K., D.A. Larson, and W.M. Wara, Radiotherapy for cerebral metastases. Neurosurg 
Clin N Am, 1996. 7(3): p. 505-15. 
7. 
Patchell, R.A., et al., A randomized trial of surgery in the treatment of single metastases to the 
brain. N Engl J Med, 1990. 322(8): p. 494-500. 
8. 
Crossen, J.R., et al., Neurobehavioral sequelae of cranial irradiation in adults: a review of 
radiation-induced encephalopathy. J Clin Oncol, 1994. 12(3): p. 627-42. 
9. 
DeAngelis, L.M., J.Y. Delattre, and J.B. Posner, Radiation-induced dementia in patients cured 
of brain metastases. Neurology, 1989. 39(6): p. 789-96. 
10. 
Nieder, C., et al., Late radiation toxicity after whole brain radiotherapy: the influence of 
antiepileptic drugs. Am J Clin Oncol, 1999. 22(6): p. 573-9. 
11. 
Meyers, C.A., et al., Neurocognitive function and progression in patients with brain 
metastases treated with whole-brain radiation and motexafin gadolinium: results of a 
randomized phase III trial. J Clin Oncol, 2004. 22(1): p. 157-65. 
12. 
Chidel, M.A., et al., Application of recursive partitioning analysis and evaluation of the use of 
whole brain radiation among patients treated with stereotactic radiosurgery for newly 
diagnosed brain metastases. Int J Radiat Oncol Biol Phys, 2000. 47(4): p. 993-9. 
13. 
Sneed, P.K., et al., Radiosurgery for brain metastases: is whole brain radiotherapy necessary? 
Int J Radiat Oncol Biol Phys, 1999. 43(3): p. 549-58. 
14. 
Sneed, P.K., et al., A multi-institutional review of radiosurgery alone vs. radiosurgery with 
whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol 
Biol Phys, 2002. 53(3): p. 519-26. 
15. 
Mehta, M.P., et al., The American Society for Therapeutic Radiology and Oncology (ASTRO) 
evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol 
Phys, 2005. 63(1): p. 37-46. 
16. 
Aoyama, H., 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): p. 2483-91. 
17. 
Soltys, S.G., et al., Stereotactic radiosurgery of the postoperative resection cavity for brain 
metastases. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 187-93. 
18. 
Nieder, C., W. Berberich, and K. Schnabel, Tumor-related prognostic factors for remission of 
brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys, 1997. 39(1): p. 25-30. 

 
28 of 34 
 
19. 
Shaw, E., 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): p. 291-8. 
20. 
Vogelbaum, M.A., et al., Local control of brain metastases by stereotactic radiosurgery in 
relation to dose to the tumor margin. J Neurosurg, 2006. 104(6): p. 907-12. 
21. 
Hasegawa, T., et al., Brain metastases treated with radiosurgery alone: an alternative to 
whole brain radiotherapy? Neurosurgery, 2003. 52(6): p. 1318-26; discussion 1326. 
22. 
Hall, E.J., Radiobiology for the Radiobiologist. 5 ed. 2000, Philadelphia: Lippincott Williams 
and Wilkins. 
 

 
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APPENDICIES  
 
A. Informed Consent Form  
 
Attach a copy of the protocol Informed Consent Form.  A Stanford specific template can 
be found at http://humansubjects.stanford.edu/. The final IRB-approved Informed 
Consent Form and HIPAA Authorization document  for each site must be provided to 
Stanford for approval by the Stanford PI and inclusion in the Regulatory Binder. 
 
 

 
30 of 34 
 
B. Participant Eligibility Checklist 
 
II. Protocol Information: 
 
Protocol Title: 
A Phase I/II Study of Fractionated Stereotactic Radiosurgery 
to Treat Large Brain Metastases 
Protocol Number: 
15107 
Principal Investigator: 
Scott Soltys, MD 
 
III. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
C. Supporting 
Documentation* 
1. Is patient age 18 or older?  (Yes) 
 
 
      
2. Does the patient have a 
pathologically proven solid tumor 
malignancy? (Yes) 
 
 
      
3. Does the patient have 1 to 4 brain 
metastases? (Yes) 
 
 
 
4. Does one of the tumors mentioned in 
(3) have a volume of 4.2 – 33.5 cm3? 
(Yes) 
 
 
      
5. Has the patient completed cytotoxic 
systemic therapy ≥ 5 days prior to 
radiosurgery? (Yes) 
 
 
      
6. Will cytotoxic systemic therapy be 
administered concurrent with SRS? 
(No) 
 
 
      
7. Will the patient receive cytotoxic 
systemic therapy ≤5 days after the 
completion of SRS? (No) 
 
 
      
8. Has the target metastatic lesion 
undergone previous SRS? (No) 
 
 
      

 
31 of 34 
 
9. Patient signed informed consent? 
(Yes) 
 
 
      
10. Life expectancy of at least 12 weeks? 
(Yes) 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Has the patient previously been 
treated with whole brain irradiation? 
(No) 
 
 
      
2. Has the metastatic lesion in question 
previously been treated with SRS? 
(No) 
 
 
      
3. Does the patient have greater than 4 
total brain metastases at the time of 
initial evaluation? (No) 
 
 
      
4. Is the patient a pediatric patient (age 
<18), pregnant woman, or unable to 
give informed consent? (No) 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Study Coordinator Signature: 
Date: 
Printed Name: 
a.  
 
 

 
32 of 34 
 
C.  RTOG CNS ACUTE RADIATION MORBIDITY SCORING CRITERIA 
 
 
0. 
No Change 
1. 
Fully functional status (i.e., able to work) with minor neurologic findings.  No medication 
needed. 
2. 
Neurologic findings present sufficient to require home case; nursing assistance may be 
required; medications including steroids and anti-seizure agents may be required. 
3. 
Neurologic findings requiring hospitalization for initial management. 
4. 
Serious neurologic impairment which includes paralysis, coma, or seizures > 3 per week 
despite medication.  Hospitalization required. 
5. 
Death 

 
33 of 34 
 
D.  RTOG CNS LATE RADIATION MORBIDITY SCORING CRITERIA 
 
 
0. 
None 
1. 
Mild headache; slight lethargy 
2. 
Moderate headache; great lethargy 
3. 
Severe headaches; severe CNS dysfunction (partial loss of power or dyskinesia) 
4. 
Seizures or paralysis; Coma 
5. 
Death 
 
 
 

 
34 of 34 
 
E. NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 
 
See Nervous System Disorders at:  http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
Grade1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
 
 observations only; intervention not indicated. 
 
Grade2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
 
 appropriate instrumental ADL*. 
 
Grade3 Severe or medically significant but not immediately life-threatening; hospitalization or 
  
 prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
 
Grade4 Life-threatening consequences; urgent intervention indicated. 
 
Grade5 Death related to AE. 
 
Activities of Daily Living (ADL): 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.

 
35 of 34 
 
F.  EORTC QLQ - BN20 
 
Patients sometimes report that they have the following symptoms. Please indicate the extent 
to which you have experienced these symptoms or problems during the past week. 
________________________________________________________________________________ 
During the past week:  
Not at 
all 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. Did you feel uncertain about the future?  
1 
2 
3 
4 
32. Did you feel you had setbacks in your condition?  
1 
2 
3 
4 
33. Were you concerned about disruption of family life?  
1 
2 
3 
4 
34. Did you have headaches?  
1 
2 
3 
4 
35. Did your outlook on the future worsen?  
1 
2 
3 
4 
36. Did you have double vision?  
1 
2 
3 
4 
37. Was your vision blurred?  
1 
2 
3 
4 
38. Did you have difficulty reading because of your vision?  
1 
2 
3 
4 
39. Did you have seizures?  
1 
2 
3 
4 
40. Did you have weakness on one side of your body?  
1 
2 
3 
4 
41. Did you have trouble finding the right words to express 
yourself? 
1 
2 
3 
4 
42. Did you have difficulty speaking?  
1 
2 
3 
4 
43. Did you have trouble communicating your thoughts?  
1 
2 
3 
4 
44. Did you feel drowsy during the daytime?  
1 
2 
3 
4 
45. Did you have trouble with your coordination?  
1 
2 
3 
4 
46. Did hair loss bother you?  
1 
2 
3 
4 
47. Did itching of your skin bother you?  
1 
2 
3 
4 
48. Did you have weakness of both legs?  
1 
2 
3 
4 
49. Did you feel unsteady on your feet?  
1 
2 
3 
4 

 
36 of 34 
 
50. Did you have trouble controlling your bladder?  
1 
2 
3 
4 
© Copyright 1994 EORTC Quality of Life Group. (phase IV module) 

 
37 of 34 
 
G.  EORTC QLQ – C30 follows on next page: 

 
38 of 34 
 
 

 
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