Phase II Study Determining the Efficacy of Pre-operative Stereotactic Radiosurgery Followed by Resection for Brain Metastases
Phase: NA
Conditions: Malignant Neoplasm Brain
Sponsor: Christopher Wilke

Page 1 of 21 
 
14-150 
Pre-operative Stereotactic Radiosurgery Followed by Resection for   
Brain Metastases 
Phase II Study Determining the Efficacy of Pre-operative Stereotactic 
Radiosurgery Followed by Resection for Brain Metastases (HCC 14-150) 
(Version dated 04-07-2021) 
 
NCT02514915 
 
Principal Investigator: 
 
 
Christopher T. Wilke, MD, PhD 
 
 
 
 
 
Mary Hillman Jennings Radiation Oncology Center 
 
 
 
 
 
   at UPMC Shadyside 
 
 
 
 
 
5230 Centre Avenue 
 
 
 
 
 
Pittsburgh, PA  15232 
 
 
 
 
 
siddiquza@upmc.edu  
 
 
 
 
 
Ph: (412) 623-7070 
 
 
 
 
 
 
 
Version Date: 
 
 
 
11/28/2022 
 
 
 

Page 2 of 21 
 
14-150 
TABLE OF CONTENTS 
 
PROTOCOL SUMMARY …………………………………………………………………… 5 
 
1.0  
BACKGROUND ………………………….…………………………………...………6 
 
2.0  
OBJECTIVES …………………………………………………………………………8 
 
3.0  
INVESTIGATIONAL PLAN………………………………………………………… 9 
 
4.0  
SUBJECT SELECTION AND ELIGIBILITY.……………………………………..12 
 
5.0  
TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION…15 
 
6.0  
STUDY EVALUATIONS ……………..………………………………………..……..17 
 
7.0  
STATISTICAL CONSIDERATIONS………………………………………..……….19 
 
8.0  
DATA SAFETY AND MONITORING………...……...……………….…..…………20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 3 of 21 
 
14-150 
List of Abbreviations 
 
3D CRT 
 
3 Dimension Conformal External Beam Radiation Therapy 
5-FU  
 
5-fluorouracil 
AE                               Adverse Event 
BSA  
 
Body Surface Area 
CAPEOX 
 
Capecitabine plus Oxaliplatin 
CMR  
 
Complete Metabolic Response 
CR 
 
 
Complete Response 
CS 
 
 
Clinical Stage  
CT Scan 
 
Computed Tomography Scan 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTV  
 
Clinical Treatment Volume 
CXR  
 
Chest X-Ray 
DSMC  
 
Data Safety Monitoring Committee 
DVH  
 
Dose Volume Histogram 
EB 
 
 
External Beam 
EBRT  
 
External Beam Radiation Therapy 
ECOG  
 
Eastern Cooperative Oncology Group 
EGD  
 
Esophagogastroduodenoscopy  
EQD  
 
Equivalent Dose 
EUS 
Endoscopic Ultrasound 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FDG-PET/CT 
[18F]-flourodeoxyglucose Positron Emissions Tomography / Computed 
Tomography 
FHSI  
 
FACT-Hepatobiliary Symptom Index 
FNA  
 
Fine Needle Aspirate 
Fx 
 
 
Fraction 
GEMCAP 
 
Gemcitabine and Capecitabine 
GEMOX 
 
Gemcitabine and Oxaliplatin 
GERCOR 
 
European Groupe Cooperateur Multidisciplinaire en Oncologie 
GGT  
 
Gamma Glutamyl Transferase 
GI 
 
 
Gastrointestinal 
GITSG 
 
Gastrointestinal Tumor Study Group 
GTVc  
 
Gross Tumor Volume on CT 
GTVp  
 
Gross Tumor Volume on PET 
GU 
 
 
Genitourinary 
Gy 
 
 
Gray 
HCC  
 
Hepatocellular Carcinoma 
HDR  
 
High-Dose Rate 
IMRT  
 
Intensity Modulated Radiotherapy 
INR 
 
 
International Normalized Ratio 
IORT  
 
Intraoperative Radiation Therapy 
IR  
 
 
Intermediate Risk 
IV 
 
 
Intravenous 
 
LDR  
 
Low-Dose Rate 

Page 4 of 21 
 
14-150 
LFT 
 
 
Liver Function Test 
LINAC 
 
Linear Accelerator 
LPFS  
 
Local Progression-Free Survival 
MD 
 
 
Maximum Dose 
MLC  
 
Multi-Leaf Collimation 
MRI 
 
 
Magnetic Resonance Imaging 
MV 
 
 
Mega Voltage 
NCI   
 
National Cancer Institute 
NCR  
 
Near Complete Response 
OESM  
 
Ordered Subset Expectation Maximization 
OS 
 
 
Overall Survival 
PD 
 
 
Prescription Dose 
PD 
 
 
Progressive Disease 
PE 
 
 
Physical Exam 
PET/CT 
 
Positron Emissions Tomography / Computed Tomography 
PIV 
 
 
Prescription Isodose Volume 
PIV/TV 
 
Prescription Isodose Volume/Tumor Volume 
PMD  
 
Progressive Metabolic Disease 
PMR  
 
Partial Metabolic Response 
PO 
 
 
By mouth 
PR 
 
 
Partial Response 
PTV 
 
 
Planning Target Volume 
QOL  
 
Quality of Life 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RPM  
 
Real-time Position Management 
RT 
 
 
Radiation Therapy 
RTOG  
 
Radiation Therapy Oncology Group 
SD 
 
 
Stable Disease 
SBRT  
 
Stereotactic Body Radiotherapy 
SMA  
 
Superior Mesenteric Artery 
SMD  
 
Stable Metabolic Disease 
SMS  
 
Short Metal Stent 
SMV/PV 
 
Superior Mesenteric Vein  / Portal Vein 
SUV   
 
Standard Uptake Value 
TTP 
 
 
Time to Progression 
TV 
 
 
Tumor Volume 
WOOCBP 
 
Women of Child-Bearing Potential 
 
 
 
 
 
 
 
 
 

Page 5 of 21 
 
14-150 
PROTOCOL SUMMARY 
 
Title 
Pre-operative Stereotactic Radiosurgery Followed by Resection for Brain Metastases 
Phase II Study Determining the Efficacy of Pre-operative Stereotactic Radiosurgery 
Followed by Resection for Brain Metastases 
 
Objectives 
The primary objective of this study is to determine the efficacy of giving pre-operative 
radiosurgery to patients pending resection of a brain metastasis.  
 
The secondary objectives of this study are: 
1. To evaluate overall survival (OS) 
2. To evaluate distant intracranial failure associated with this therapy. 
3. To evaluate the Health Related Quality of Life (HRQL) associated with this therapy. 
 
The exploratory objectives of this study are: 
1. To collect and store the resected body tissue(s) and blood samples for potential 
correlation to clinical outcome. 
 
 
Patient population 
In order to be eligible for this study, patients must have an extra-cranial primary tumor diagnosis 
and no more than 4 distinct lesions within the brain. Patients mut be at least 18 years of age and 
able to give informed consent. They must have a Karnofsky Performance Status ≥ 50 and a life 
expectancy of at least 12 weeks. 
 
Number of patients 
24 
 
Study design and methodology 
This is a prospective single-arm phase II study. The treatment schema detail is in Section 6.3. 
 
Treatment administered 
Patients will receive a single fraction pre-operative stereotactic radiosurgery radiation dose. The 
dose will be determined by the diameter of the tumor. 
 
Efficacy data collected 
The following evaluations will be performed to assess the efficacy of preoperative stereotactic 
radiation therapy: 
• Objective local control rate measuring tumor volume 
• Health Related Quality of Life assessment using the Functional Assessment of Cancer 
Therapy – Brain (FACT-Br) tool. 
 
Safety data collected 
The following evaluations will be conducted to assess the safety of radiosurgery: 

Page 6 of 21 
 
14-150 
• Recording of all toxicity data per NCI CTCAE version 4.0 
 
 
1.0 BACKGROUND 
 
1.1 Brain metastases and whole brain radiation therapy 
Brain metastases are a frequent cause of morbidity and mortality representing the most 
common intracranial tumor in adults, affecting upwards of 30-40% of all cancer patients 
[1-3]. There exist multiple treatment options for patients with brain metastases including: 
whole brain radiation therapy (WBRT), surgical resection, and stereotactic radiosurgery 
(SRS) [4-9]. Without treatment the prognosis is often poor, with survival limited to only a 
few months [10]. 
 
The mainstay of treatment for brain metastases has been WBRT, which has been used for 
decades and is thus well studied. The use of WBRT for patients with brain metastases from 
various primary cancers has been shown to improve both existing neurologic symptoms 
and overall survival compared to corticosteroids and supportive care (median survival = 4- 
5 months) [11]. Unfortunately, the use of WBRT is associated with neurotoxicity and 
neurocognitive decline, especially in long-term survivors [12]. 
 
Surgical resection has been typically reserved for patients with good performance status, 
limited intracranial disease, isolated symptomatic lesions, and lesions resistant to WBRT 
[13, 14]. For patients with a solitary accessible lesion, surgical resection has been shown 
to be an effective primary treatment approach that is able to relieve mass effect and 
improve survival [14]. However, the limitation of surgical resection alone as a treatment 
modality is associated with high rates of local failure [8]. Interestingly, the benefit of WBRT 
as an adjuvant treatment post-surgical resection has been established. WBRT alone has 
been compared to surgery followed by WBRT and several studies have shown both 
improved local control (LC) and reduced neurological death with the latter approach [15- 
17]. 
 
1.2 Sterotatic radiation surgery (SRS) 
In more recent years, SRS has been shown to be an effective alternative therapy for 
patients with brain metastases. It is especially useful in patients with progression of 
disease following WBRT, for whom treatment-related neurotoxicity is a major concern. SRS 
enables the delivery of a highly focused radiation dose to a small target with rapid fall-off, 
thereby limiting radiation to the surrounding normal brain tissue. This feature should 
potentially reduce the likelihood of developing late neurocognitive deficits, an issue that 
becomes an increasing concern in long-term survivors. SRS has even emerged as a 
treatment strategy to limit WBRT and has been studied in the setting of brain metastasis. 
SRS has been investigated in postoperative management of solitary brain metastases. At 
least a dozen retrospective reports have been published describing the results of adjuvant 
SRS. The reported 1-year local control rates is variable and has been found to be as low as 
35% and as high as 100% [18, 19]. Review of UPMC’s institutional experience showed 6- 
month and 1-year LC of 76% and 76% respectively, which is consistent with most other 
reports [20]. 

Page 7 of 21 
 
14-150 
 
However, delivery of postoperative SRS is particularly challenging due to the nebulous 
appearance of the tumor bed after resection. This difficulty of delineating the margins of 
the resection cavity may be responsible for the rate of local failure (LF) despite the 
utilization of adjuvant therapy and lead to additional symptomatic brain necrosis. A 
commonly employed strategy to improve LC with adjuvant SRS is the addition of a margin 
to account for target uncertainty and microscopic extension of disease. The Stanford 
University group reported a significant improvement in (LF) rates with the addition of a 2- 
mm margin (1-year LF: 3% vs. 16%) without an associated increase in toxicity [21]. In 
contrast, a French group has reported an experience of delivering SRS with a 2-mm margin 
and reported no improvement in 1-year LC (69% vs. 72%) and an increased rate of severe 
parenchymal complications [22]. 
 
In addition to localizing the tumor bed, another potential negative consequence to the 
sequence of postoperative SRS is the time course between resection and radiation 
treatment. Typically SRS is performed several weeks after surgical removal of brain 
metastases. During this interval, the tumor bed is given additional time and may have a 
detrimental impact on LC. 
 
For these reasons, once a patient has been deemed a candidate for surgical resection of a 
brain metastasis, it is generally accepted that radiation of some form must be given to 
facilitate local control. For patients with a symptomatic or sizable brain metastasis that 
requires surgical resection, one option is to perform radiosurgery up front, followed by 
surgical removal of the tumor. 
 
1.3 Pre-operative SRS 
For patients who require surgical removal of a brain metastasis, we hypothesize a more 
sensible strategy to improve LC may be the delivery of pre-operative SRS followed by 
immediate tumor resection. Pre-operative target delineation is likely to be more accurate 
and result in fewer marginal misses. Furthermore, this treatment package could be 
completed more expeditiously by eliminating the prolonged interval from surgery to SRS. 
In our experience, this interval was approximately 5 weeks. In addition, the same MRI 
scan could be used for SRS and surgical resection; resulting in cost savings for patients 
who otherwise would receive two separate MRI scans for treatment. Finally, pre-operative 
SRS may facilitate better resection margins by the delivery of dose in the radiation 
penumbra surrounding the tumor. An early study of pre-operative SRS on brain 
metastases by Stuart Burri et al., 2010 demonstrated actuarial LC of 97.7%, 84.6%, and 
64.0% at six, twelve, and twenty four months, respectively [23]. More recently according 
to the interim analysis from a phase 1 study of pre-operative SRS for brain metastases by 
the University of Alabama, pre-operative SRS appears safe with low rates of wound 
complications or acute grade toxicity along with target volume reduction of 39% [24]. We 
therefore propose a phase II clinical trial to further investigate the efficacy of this novel 
approach. 
 
 
 

Page 8 of 21 
 
14-150 
 
 
 
2.0 OBJECTIVES 
 
 
Primary 
 
2.1 To determine the efficacy of giving pre-operative radiosurgery to patients pending resection  
of a brain metastasis. The primary outcome will be measured by local control rate; that is, the 
tumor volume as measured at a later date and compared to the tumor volume at the start of 
radiotherapy (time frame: up to 3 years). 
 
 
Secondary 
 
The secondary objectives of this study are: 
 
2.2 To determine the overall survival (OS) as measured by the length of time after the beginning 
of treatment that diagnosed patient remains alive. 
 
2.3 To evaluate distant intracranial failure associated with this therapy as measured by the 
presence of new brain metastatses identified via magnetic resonance image. The imaging will 
be conducted every 3 months for 12 months, then every 4 months for up to 3 years. 
 
 
2.4 To measure Health Related Quality of Life (HRQL) in patients with primary brain tumors 
treated with stereotactic radiosurgery using the Functional Assessment of Cancer Therapy-
Brain assessment tool for up to 3 years. 
 
 
 
The exploratory objective of this study is: 
 
To collect and store the resected body tissue(s) and blood samples for potential correlation to 
clinical outcome. 
 
 
 
 
 
 
 
 
 
 
 

Page 9 of 21 
 
14-150 
3.0 INVESTIGATIONAL PLAN 
 
3.1 Overall design and plan of the study 
Detailed visit-by-visit study procedures and a study flow chart are provided in Section 6.3.  Prior 
to enrollment, all subjects will be evaluated with physical examination, histologic confirmation 
and baseline imaging to establish the size and location of the brain metastatic lesions.  Patients 
will receive a single SRS radiation dose and then followed periodically for up until 3 years. 
 
3.2 Screening procedures 
• Complete physical evaluation with a performance status, vital signs, height, and weight, 
   and a complete medical history. 
• CT (computed tomography) Scan of the brain 
• MRI (Magnetic Resonance Imaging) Scan of the brain 
• For women of childbearing potential, i.e., females who are not at least 1 year postmenopausal 
  or who have not undergone a surgical sterilization procedure, a urine pregnancy 
  test will be done. If this comes back positive or questionable, a serum pregnancy test will 
  be completed by taking a small sample (about 1 teaspoonful) of blood. Pregnant women, or 
  women who are currently breast-feeding an infant, will not be allowed to take part in this 
  study. 
 
3.3 Personnel performing the procedures 
All procedures will be performed by appropriate certified medical personnel, including but 
not limited to physicians, nurses, technologists and research staff. Potential candidates for 
the study will be identified by Dr. Amankulor based on his clinical judgment of a need for 
resection of a presumed brain metastasis. Potential research subjects will be sent to radiation 
oncology co-investigators for possible enrollment, and pre-operative SRS. 
 
3.4 Location and duration of procedures 
All study visits will take place on an outpatient basis in the UPMC Shadyside Radiation 
Oncology Department. However, it is possible that a subject may be an inpatient at the 
time of diagnosis. The duration of study visits will vary dependent on the procedures to be 
completed during that study time-point. We expect for visits to last between 1-4 hours. 
 
3.5 Timeline of study procedures 
Once eligible by screening, stereotactic radiosurgery will take place, 1-7 days later, there 
will be a surgical removal of the tumor. Monitoring will take place 10-14 days after 
surgery, every 3 months for the first year and every 4 months thereafter. 
 
3.6 Research Activities 
 
3.6.1 Pretreatment Evaluation 
The following tests/procedures will be performed in order to ascertain subject eligibility 
within 28 days prior to registration unless otherwise specified. 
• Complete physical evaluation with a performance status, vital signs, height, and weight, 
             and a complete medical history. 
• CT (computed tomography) scan of the brain 

Page 10 of 21 
 
14-150 
• MRI (Magnetic Resonance Imaging) Scan of the brain 
• For women of child bearing potential, a urine pregnancy test will be done. If this come 
back positive or questionable, a serum pregnancy test will be completed by taking a smal 
sample (about 1 teaspoonful) of blood. Pregnant women, or women who are currently 
breast-feeding an infant, will not be allowed to take part in this study. 
• Pretreatment blood sample for research bank if patient agrees. 
 
In addition to the procedures listed above, the following Quality of Life questionnaire will be 
done for research purposes: 
• FACT – BR (FACT – BRAIN) - This assessment will take approximately 5 (five) 
minutes to complete. 
 
3.6.2 Evaluation during treatment 
Administration of stereotactic radio surgery: 
 
Patients will receive a single fraction pre-operative SRS radiation dose. The dose will be 
determined depending on diameter of the tumor as follows: 24 Gy, 18 Gy, and 15 Gy for 
tumors < 21 mm, 21-30 mm, and 31-40 mm in maximum diameter respectively. 
 
Dose 
Diameter 
15 Gy 
31-40 mm 
18 Gy 
21-30 mm 
24 Gy 
< 21mm 
 
Tumor tissue collection only if participant agrees and there is leftover from clinical collection. 
 
Blood sample collection pre and post SRS treatment (within 24 hours) 
 
Complete physical evaluation with a performance status, vital signs, height, and weight, and a 
complete medical history 
 
3.7 Surgical removal 
One to seven days after the single SRS, patient will then be prepared for surgical removal of the 
tumor that was designated by surgeon as part of normal standard of care for dominant brain 
metastasis. Only the symptomatic tumor will be removed surgically. Surgery will be performed 
at Shadyside Hospital.  
 
3.8 Follow-up procedures 
Standard care procedures will be performed and assessed 10-14 days post-surgery. These 
include: 

Page 11 of 21 
 
14-150 
• Complete physical evaluation with a performance status (a measure of how well 
you carry on daily activities), vital signs (blood pressure, temperature, heart rate, 
respiration rate), height, and weight, and a complete medical history. 
MRI (magnetic resonance imaging). 
• Scan of the brain will be performed every 3 months after your surgical procedure. If 
additional brain metastases are detected on one of your follow up scans, then they will be 
treated as per standard of care, likely using either additional SRS or whole brain 
radiation. 
 
In addition, patient will be asked to complete a health-related quality of life assessment at each 
visit. The assessment is for research purposes and will take approximately 5 (five) minutes to 
complete. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 12 of 21 
 
14-150 
2.5 
SUBJECT SELECTION AND ELIGIBILITY 
 
4.1 Selection of subjects 
Enrollment is defined as the first day of protocol therapy. 
 
Patients enrolled in this study must have a measurable brain metastasis which is defined as 
lesions that can be accurately measured in at least one dimension: [longest diameter to be 
recorded] on the MRI scan. Patients will have no more than 4 distinct lesions within the brain. 
The target lesion must measure at least 15mm in at least one dimension and no more than 40mm 
in any dimension. 
 
4.2. Screening and sample size 
50 patients will be screened with an expectation that 24 patients will proceed to study protocol. 
Patients will not be excluded based upon gender nor ethnicity. This study will be limited to 
adults, in whom stereotactic radiosurgery is a common treatment modality used in the 
management of brain metastases. Brain metastases are less frequent in children and when they do 
occur are often represented by histologies with an increased sensitivity to radiotherapy and 
would have drastic differences in clinical outcome. Research with children under the age of 18 is 
conducted at Children's Hospital of UPMC. 
 
4.2.2  Justification of sample size/accrual rate 
No more than 24 evaluable patients will be treated in the trial. This study of 24 patients will 
have 80% power to detect a difference in postulated local tumor control of 85% to a known 
inference local tumor control set at 60% to be excluded, using a 1-sided test with Type I error 
rate of 0.05 for 6, 12, and 24 months. The sample size was estimated using a non-inferior power 
analysis for inference of a single proportion compared to a known proportion. Also, an attrition 
rate of 20% was included into the estimated sample size. Based on previous efforts in recruiting 
patients at the University of Pittsburgh Cancer Institute, it is anticipated that at least 5 patients 
per year will be enrolled in the protocol and the accrual will be completed within 5 years. An 
evaluable patient is defined as one who completes a single fractions of preoperative SRS 
followed by surgical resection of appropriate brain metastases. Patients who are not evaluable 
will be replaced. 
 
4.3 Identification and initiation of contact with study participants 
Potential research subjects are first identified by their neurosurgeon (Dr. Amankulor). These 
patients will be deemed as candidates for surgical resection of their brain metastasis, either 
because of regional mass effect (i.e. pressure on other brain structures) or neurologic 
symptoms/signs related to the tumor (e.g. weakness, visual disturbance, gait dysfunction, 
seizures, speech disorder). Once a potential subject has been set up for surgical resection of a 
brain metastasis by Dr. Engh or Dr. Amankulor, they will then be referred to radiation oncology 
for discussion of the clinical trial and potential up front SRS. "Cold-calling" will not be used to 
recruit subjects. "Finder's fees" for referring a potential subject for participation in a research 
study are prohibited. 
 
Physicians and other health care professionals in the area are aware of active studies at the 
Department of Radiation Oncology at UPMC by means of various publications including the 

Page 13 of 21 
 
14-150 
World Wide Web. Such publication and Web listings are not advertisements for specific 
studies. Rather, they are public listings of trials available. 
 
Once a subject is identified as a potential participant in a research study as indicated 
above, he/she is screened for eligibility. No identifiable information (e.g. name, diagnosis, 
treatment, etc.) will be released until the subject has given written authorization. No 
research-related procedures (including review of the subject's medical records) will be 
performed until the subject has provided written informed consent. The consent process 
will be carried out as a joint effort among the subject's physicians, the study coordinators, 
and a physician who is listed as an investigator on the study. 
 
4.4 Inclusion criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
a. Male or female patients ≥ 18 years of age 
b. A life expectancy of at least 12 weeks with a Karnofsky performance status of at least     
    50 (Appendix I) 
c. Patient has no contraindications to MRI scanning with intravenous contrast. 
d. MRI scan consistent with brain metastasis as per radiology report. 
e. The target lesion must measure at least 15 mm in at least one dimension, and no more 
    than 4 cm in any dimension. 
f. Patients must have an extra-cranial primary tumor diagnosis. 
g. Patients will have no more than 4 distinct lesions within the brain. At least 1 lesion has 
    been recommended for surgical removal based on size, symptomology, or regional  
    mass effect on the brain. 
h. The additional lesions will each be treated with stereotactic radiosurgery. 
i. Patients with a documented symptomatic lesion size smaller than 3cm requiring clinical 
    surgical resection 
j. Must be aware of the neoplastic nature of his/her disease and willingly provide written, 
informed consent after being informed of the procedure to be followed, the         
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks   
and discomforts. 
 
 
k. Signed consent 
 
 
 
4.5.1 Exclusion criteria 
Subjects meeting any one of the following exclusion criteria are not to be enrolled in the study: 
a. Primary tumor histology of lymphoma, leukemia, multiple myeloma or germ cell  
tumor. 
b.   Moribund status or status epilepticus. 
c.   Supratentorial mass effect with greater than 5 mm of midline shift or hydrocephalus. 
d.   Infratentorial mass effect with fourth ventricle effacement or hydrocephalus. 
e.   More than four additional diagnosed brain metastases. 
f.   Contraindication to general anesthesia. 
g.   Adjacent tumor location to optic apparatus or brainstem, precluding achievement of 
      meaningful dose with SRS. 
h.   Primary brain tumor. 
i.   Contraindication to MRI scans or intravenous contrast. 

Page 14 of 21 
 
14-150 
j.   Pregnant and breast-feeding females. 
 
 
4.5.2 Specific criteria to exclude pregnant females and feta/neonatal exposure 
For all females who are not at least one year post-menopausal or who have not undergone 
a surgical sterilization procedure, a urine pregnancy test will be done. If this is positive or 
questionable a serum pregnancy test will be done. The results of the pregnancy test must 
be negative in order for the patient to participate in this study. 
 
Women who are pregnant or breastfeeding are excluded from participation in this study. All 
females of childbearing potential must have a serum pregnancy test within 14 days of the 
radiation. The results of the pregnancy test must be negative for the patient to participate 
in this study. 
 
Subjects will be informed by the study staff that is extremely important that they not 
become pregnant or father a baby while participating in this study, and that avoiding sexual 
activity is the only certain method of preventing pregnancy. However, if a subject chooses 
to be sexually active, he or she must agree to use an appropriate "double barrier" method 
of birth control starting from the subject's participation in the screening process and 
continuing until two weeks following the subject's participation in the study. Birth control 
methods can include intrauterine device (IUD), contraceptive sponge and spermicide, in 
addition to male use of a condom, or the female should be using prescribed birth control 
implant. Subjects will be instructed to notify the study doctor of their birth control method 
prior to the start of the study, and also if they plan to change their birth control method. 
 
Subjects that choose to be sexually active must be made aware that even with the use of 
birth control measures, pregnancy could still result. Subjects will be informed that if they 
become pregnant or impregnate a woman while taking part in this study, they must 
immediately notify one of the doctors listed on the consent form. 
 
The information listed above will be relayed to applicable subjects by the study staff. If will 
also be listed in the consent form, a copy of which will be provided to the patients for them 
to take home. 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 15 of 21 
 
14-150 
5.0 TREATMENT EVALUATION, ADMINISTRATION, AND MODIFICATION 
 
5.1 Tissue constraints 
Treatment shall be delivered via linear accelerator (LINAC) commissioned and equipped to 
deliver stereotactic radiosurgery. Normal tissues and sensitive critical structures (e.g. 
spinal cord, brainstem, optic nerves, optic chiasm, and pituitary) shall be contoured and the 
dose to these organs limited. Normal tissue constraints are outlined below. 
 
Normal Tissue Constraints: 
Organ Maximum Dose in 1 Fractions 
Brain V12 <5-10 cc Dose/Volume 
Spinal Cord <13 Gy 
Brainstem <12.5 Gy 
Optic Nerves <12 Gy 
Optic Chiasm <12 Gy 
Pituitary <20 Gy 
Cochlea <14 Gy Dose/Volume 
 
Normal Tissue Constraints 
Organ 
Maximum Dose 
in 1 Fraction 
Brain V12 
<5-10 cc Dose / Volume 
Spinal Cord 
< 13 Gy 
Brainstem 
<12.5 Gy 
Optic Nerves 
<12 Gy 
Optic Chiasm 
<12 Gy 
Pituitary 
<20 Gy 
Cochlea 
<14 Gy Dose / Volume 
 
 
5.2 Dose Specification, Homogeneity Considerations & Plan Evaluation 
The treatment plan used shall be based on the assessment of the dose-volume histogram 
(DVH) with attention to coverage of the planning tumor volume (PTV) and critical normal 
structures. 
 
The prescription dose is the isodose cloud that encompasses at least 80% of the PTV. 
No more than 20% of any PTV shall receive doses >110% of its prescribed dose. 
No more than 2% of any PTV shall receive <93% of its prescribed dose. 
No more than 5% of any normal tissue shall receive doses in excess of 110% of the 
primary PTV dose. 

Page 16 of 21 
 
14-150 
5.3 Follow-up procedures 
Patients will be seen in follow-up 10-14 days post treatment then every 3 months for 12 
months, then every 4 months up until 3 years, with the following evaluations: 
 
- Complete physical evaluation with a performance status, vital signs, height, and weight, 
  and a complete medical history 
- MRI scans at 3 months post-treatment and every 3 months for 12 months, then every 4 
  months up until 3 years for assessment of response to therapy and 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 17 of 21 
 
14-150 
 
6.0 STUDY EVALUATION 
 
6.1 Pre-research screening 
After signing consent form, participant will undergo the following screening tests and/or 
procedures (some may not have to be repeated if they were recently performed as part of 
standard of care): 
 
• Complete physical evaluation with a performance status (a measure of how well 
you carry on daily activities), vital signs (blood pressure, temperature, heart rate, 
respiration rate), height, and weight, and a complete medical history. 
• CT (computed tomography) Scan of the brain (an imaging test that takes many xrays 
from different angles to form images of the brain). 
• MRI (Magnetic Resonance Imaging) Scan of the brain (an imaging test that uses 
no radiation, but rather a magnetic field to create high detailed images of the 
brain) 
• For women of who are not at least one year post-menopausal or who have not 
undergone a surgical sterilization procedure, a urine pregnancy test will be done. 
If this comes back positive or questionable, a serum pregnancy test will be 
completed by taking a small sample (about 1 teaspoonful) of blood from a vein in 
the arm for a pregnancy test. Pregnant women, or women who are currently 
breast-feeding an infant, will not be allowed to take part in this study. 
• A health-related quality of life assessment for research purposes. This assessment will 
take approximately 5 (five) minutes to complete. 
 
6.2 Ending subject’s participation in the study 
A subject’s participation in the study will be halted if any one of the following would occur: 
 
• Pregnancy test proves to be positive. 
• Disease status becomes worse. 
• Develop side effects from treatment. 
• Physician feels that this preoperative SRS is no longer in your best interest. 
• Patient is not compliant with the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 18 of 21 
 
14-150 
6.3 Treatment schema 
 
 
6.4. Tumor response on CT (RECIST) 
Measurable Disease Response: CTEP’s RECIST guidelines will be followed. A quick reference 
to the RECIST guidelines can be downloaded at the following URL:  
http://ctep.info.nih.gov/Policies/WordDocs/RCSTF.PH2TEMPF.doc.   
 
 
6.5 Post-surgery procedures 
Patients will be seen in follow-up 10-14 days post treatment then every 3 months for 12 
months, then every 4 months up until 3 years, with the following evaluations: 
 
• Complete physical evaluation with a performance status, vital signs, height, and weight, 
and a complete medical history 
• MRI scans at 3 months post-treatment and every 3 months for 12 months, then every 4 
months up until 3 years for assessment of response to therapy and monitoring. 
• Administration of Fact-Brain questionnaire at each follow-up visit/scan. 
 
 
 
 
Parameter 
Pre-Study 
SRS 
  
Within 24 
hrs post 
SRS 
  
Surgical 
resection 1-7 
days post SRS 
  
10-14 days 
post surgery 
Q3 months for 
12 months, then 
q4 months to 3 
years 
  
History  
X 
X 
  
X 
X 
X 
Physical exam 
X 
X 
  
X 
X 
X 
Vital Signs 
X 
 X 
  
  
X 
X 
Performance Status 
X 
 X 
  
  
X 
X 
MRI 
X 
  
  
  
  
X 
CT Scan for treatment 
planning 
X 
  
  
  
  
  
Serum or Urine Pregnancy 
Test for WOCBP 
X 
  
  
  
  
  
FACT - Brain assessment 
X 
  
  
  
X 
X 
Blood sample for research * 
  
X 
X 
  
  
  

Page 19 of 21 
 
14-150 
7.0 STATISTICAL CONSIDERATIONS 
 
7.1 Study objectives and design 
The primary objective of this study is to determine the efficacy of giving pre-operative 
radiosurgery to patients pending resection of a brain metastasis.  
 
The secondary objectives of this study include: 
1. To evaluate overall survival (OS) 
2. To evaluate distant intracranial failure associated with this therapy. 
3. To evaluate the Health Related Quality of Life (HRQL) associated with this therapy. 
 
This clinical trial is planned as a prospective single-arm phase II study. 
 
7.2 Sample size and accrual rate 
No more than 24 evaluable patients will be treated in the trial. This study of 24 patients will 
have 80% power to detect a difference in postulated local tumor control of 85% to a known 
inference local tumor control set at 60% to be excluded, using a 1-sided test with Type I error 
rate of 0.05 for 6, 12, and 24 months. The sample size was estimated using a non-inferior power 
analysis for inference of a single proportion compared to a known proportion. Also, an attrition 
rate of 20% was included into the estimated sample size. Based on previous efforts in recruiting 
patients at the University of Pittsburgh Cancer Institute, it is anticipated that at least 5 patients 
per year will be enrolled in the protocol and the accrual will be completed within 5 years. An 
evaluable patient is defined as one who completes a single fractions of preoperative SRS 
followed by surgical resection of appropriate brain metastases. Patients who are not evaluable 
will be replaced. 
 
7.3 Data analysis 
When possible, generalized linear models (subsuming, for example, logistic regression) will 
be used to combine data from different dose levels. Model assumptions will be checked 
graphically prior to analysis. If model assumptions are not met the analysis will be primarily 
descriptive. Baseline description statistics on all evaluable patients will be provided for 
demographic variables (age, sex, race/ethnicity), Karnofsky performance status, disease 
stage and status at the time of enrollment and treatment regimens previously used. 
 
7.4.1 Analysis of the Primary Endpoints 
Local control rates for 6 months, 12 months, and 24 months will be analyzed with Kaplan- 
Meier Survival Curves and the Log-Rank Test. 
 
7.4.2Analysis of Secondary Endpoints 
1. The patient’s overall survival rates for 6 months, 12 months, and 24 months will be 
     analyzed with Kaplan-Meier Survival Curves and the Log-Rank Test. 
2. The probability of distant intracranial failure associated with this therapy will be analyzed 
    with Kaplan-Meier Survival Curves and the Log-Rank Test. 
3. The analysis of HRQL data will be descriptive. The data will be summarized by question at 
    each time point with the frequency and percentage of each quality level. For each patient, 
    the trajectory of the score will be plotted against time. 

Page 20 of 21 
 
14-150 
 
8.0 DATA SAFETY AND MONITORING 
 
8.1 Data monitoring plan 
All patient data will be collected by the Clinical Research Department of Radiation 
Oncology. All data will be secured in a password protected file with observance of all 
applicable HIPAA regulation. A data safety monitoring board will meet monthly to evaluate 
toxicity for this trial. Patients/adverse events will be discussed at these the Radiation 
Oncology Data Safety monthly meetings. Unexpected serious adverse events will be 
reported to the IRB and DSMC and minutes of the monthly disease center meetings will be 
reviewed at the DSMC meetings. 
 
Reports will be submitted annually at the time of the yearly renewal. 
 
All research-related procedures will be conducted by certified medical personnel. The study 
staff will monitor the subjects closely throughout the study for any adverse events, and 
subjects will be strongly encouraged to report all issues to the study staff. All supportive 
measures consistent with optimal patient care will be given throughout the study. 
 
8.2 Stopping criteria 
Research subjects will be withdrawn from the study if any one of the following occur: 
 
1) Documented neurological worsening following SRS. 
2) Inability to tolerate SRS prior to surgical resection. 
3) Multiple seizures following SRS. 
4) Progression of tumor or radiation/treatment effect at the target site sufficient to necessitate     
     repeat surgical resection or repeat SRS. 
 
8.3 Adverse events 
Adverse Events will be graded for intensity according to the National Cancer Institute 
Common Toxicity Criteria, CTCAE Version 4.0. All appropriate treatment areas will have 
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov ). 
 
The dose limiting toxicity (DLT) will be defined as any adverse event that occurs within 60 days 
of treatment initiation of radiotherapy and meets any of the following criteria: 
 
Grade 4 or worse or central nervous system necrosis, or cerebral edema, or encephalopathy, 
or intracranial hemorrhage, or myelitis, or seizure, or stroke, or, 
 
Any other Grade 3 neurologic toxicity which does not improve to grade 2 within 60 days of 
treatment initiation of radiotherapy, or, 
 
Any neurologic patient death within 60 days of treatment initiation of radiotherapy will be 
considered a DLT unless in the opinion of the study radiation oncologist and the 
neurosurgeon, the death is definitely unrelated to treatment or death is definitely related 

Page 21 of 21 
 
14-150 
to disease progression. 
 
There is a theoretical risk that pre-operative SRS could increase the risk of wound healing 
complications, due to exposure of the scalp to radiation before surgical intervention. 
However, the dose of radiation to the scalp in these cases is generally less than 1 Gray, so 
this potential risk is not believed to be a real risk to these patients. 
 
8.4 Assessment of adverse events 
Any clinically significant or unexpected disease or condition that is found during the course 
of this study, will be immediately evaluated by the Principal Investigator and appropriate 
medical staff and then it will be determined how to proceed with the study/ study 
treatment. 
 
The subject would likely be referred to the appropriate specialists for standard follow-up 
medical care.