A Phase II Pilot Trial of Preoperative SRS/SRT Versus Postoperative SRS/SRT for Brain Metastases
Phase: NA
Conditions: Brain Metastases
Sponsor: University of Arkansas

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Study Title: 
A Phase II Pilot Trial of Preoperative SRS/SRT versus 
Postoperative SRS/SRT for Brain Metastases 
(NCT04422639) 
 
Principal Investigator:  
Analiz Rodriguez MD, PhD 
 
Director of Neurosurgical Oncology 
 
Assistant Professor  
 
Department of Neurosurgery 
 
University of Arkansas for Medical Sciences 
 
 
Co-Investigator (s): 
Fen Xia, MD, PhD 
 
Professor and Chair 
 
Department of Radiation Oncology 
 
University Arkansas College of Medicine 
 
 
Gary D. Lewis, MD 
 
Assistant Professor 
 
Department of Radiation Oncology 
 
University Arkansas College of Medicine 
 
 
Manoj Kumar, MD 
Associate Professor 
Department of Radiology, Neuroradiology 
 
 
Mausam Patel, MD 
 
Resident Physician 
 
Department of Radiation Oncology 
 
University Arkansas College of Medicine 
 
Sub-Investigator (s): 
Leslie Harrell, DO 
 
Professor 
 
Department of Radiation Oncology 
 
University Arkansas College of Medicine 
 
 
 
J.D. Day, MD 
 
Professor and Chair 
 
Department of Neurosurgery 
 
University of Arkansas for Medical Sciences 
 
 
T.W. Morris, III, MD 
 
Assistant Professor  
 
Department of Neurosurgery 
 
University of Arkansas for Medical Sciences 

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Viktoras Palys, MD 
 
Assistant Professor  
 
Department of Neurosurgery 
 
University of Arkansas for Medical Sciences 
 
 
 
Study Statistician: 
Eric R. Siegel, MS 
 
Biostatistics Project Manager 
 
Department of Biostatistics 
 
University of Arkansas for Medical Sciences 
 
 
 
Study location: 
University of Arkansas for Medical Sciences 
 
 

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Background and Rationale 
The incidence of brain metastases has been rising in recent years.1 As a result, the 
optimal management of patients with brain metastases is a topic of important concern. 
For a patient with a single or solitary brain metastasis, surgical resection has been 
associated with improved survival.2 Surgical resection is also an important option for 
patients with large brain metastases causing mass effect or symptoms. However, surgical 
resection alone, even with a gross total resection, is associated with high rates of local 
recurrence (on the order of 50%), likely due to tumor spill.3 As a result, post-operative 
adjuvant radiotherapy has been used to reduce the rate of local recurrence. 
Work by Patchell et al. demonstrated that whole brain radiotherapy (WBRT) after surgical 
resection of a single brain metastasis reduced the rate of recurrence at the site of the 
original metastasis and at other sites of the brain.3 It also decreased the likelihood of 
death from neurologic causes. However, WBRT is not without side effects; there is 
particular concern with the long-term neurocognitive effects of treatment.  
As a result, postoperative stereotactic radiosurgery (SRS) and less than 5 fractions of 
stereotactic radiation therapy (SRT) has become increasingly popular. SRS/SRT delivers 
high doses of radiotherapy via multiple beam angles and highly conformal planning 
techniques to the target, sparing normal brain tissue. A randomized trial by Brown et al. 
found that postoperative SRS had similar overall survival (OS) when compared to 
postoperative WBRT (median OS of 12.2 months vs. 11.6 months, respectively [p = 0.70]) 
but had lower rates of cognitive deterioration (52% vs 85% [p<0.001]).4 When compared 
to observation after surgery, a separate trial demonstrated improved local control with 
postoperative SRS.5 
There is growing interest in whether SRS/SRT delivery for brain metastases can be 
transitioned to the preoperative (or neoadjuvant) setting. Radiotherapy has been used 
neoadjuvantly for many disease sites, including rectal, pancreatic, esophageal and 
sarcomatous cancers. Neoadjuvant timing for brain metastases offers several potential 
benefits. First, target delineation is much simpler preoperatively compared to 
postoperatively (where the tumor bed is large and can change over time). This smaller 
treatment volume may also decrease the risk of toxicity or radiation necrosis.  
Neoadjuvant radiotherapy may also help with disease control. Local recurrence remain 
somewhat high (~44%) for tumors greater than 3cm in diameter,5 likely related to tumor 
spill at the time of surgery. In addition, there is concern for leptomeningeal spread after 
surgery due to surgical tract seeding into the meningeal space. Preoperative SRS or SRT 
to the tumor may serve as a way to, in effect, “sterilize” the tumor site and reduce the risk 
of local recurrence and leptomeningeal spread. Series have suggested that neoadjuvant 
SRS or SRT results in lower rates of leptomeningeal disease when compared to 
postoperative SRS or SRT.6,7 
The purpose of this study is to prospectively compare preoperative (neoadjuvant) 
SRS/SRT to postoperative (adjuvant) SRS/SRT in patients undergoing surgical resection 
for brain metastases. 

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Hypothesis, Objectives, and Outcomes 
We hypothesize that neoadjuvant SRS/SRT prior to surgical resection of brain 
metastases will result in improved freedom from Central Nervous System (CNS) events 
when compared to adjuvant SRS/SRT after surgical resection. 
Primary Objectives 
• Our primary objectives are: (1) to determine the Time to a Central Nervous System 
(CNS) Composite Event (CE) in subjects who receive either neoadjuvant (pre-
operative) SRS/SRT or adjuvant (post-operative) SRS/SRT for their brain 
metastases, and (2) to compare the two treatment arms for evidence of improved 
Time to a CNS CE among subjects who received neoadjuvant SRS/SRT. 
o A CNS CE will consist of one of the following three events: Local 
Recurrence (LR) of the treated lesions, symptomatic radiation necrosis 
(SRN) to the treated lesions, or development of leptomeningeal disease 
(LMD). See below for detailed definitions of LR, SRN, and LMD. 
o Time to a CNS CE, the primary outcome, will be measured as the time from 
the date of randomization to the date of a documented LR, SRN, or LMD, 
whichever occurs first. 
o Death before occurrence of a CNS CE will be treated as a competing risk. 
Study participants who are alive and have yet to experience a CNS CE at 
their last evaluation will be right-censored for Time to CNS CE on the date 
of their last evaluation. 
Secondary Objectives related to the Primary Objective. Some of our secondary objectives 
include (a) determining in each study subject the secondary outcomes listed below, and 
(b) comparing the treatment arms for evidence of improvements in these secondary 
outcomes.  
• Index lesion local recurrence (ILLR), a component of CNS CE, will be defined as 
the development of new nodular contrast enhancement in the surgical bed 
compared with the immediate postoperative MRI.  
• Non-index lesion LR, also a component of CNS CE, will be defined as an increase 
of more than 25% in the size of any treated non-resected brain lesion.  
o Time to LR, a secondary outcome, will be measured as the time from the 
date of randomization to the date of documented occurrence of the LR. 
Death before occurrence of LR will be treated as a competing risk. Study 
subjects who are alive and free of LR at their last evaluation will be right-
censored for Time to LR on the date of their last evaluation.  
• 
Leptomeningeal disease (LMD), a component of CNS CE, will be diagnosed by 
imaging results consistent with this condition (either local or diffuse leptomeningeal 
disease) or by examination of spinal fluid positive for malignant cells. 

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o Time to LMD, a secondary outcome, will be measured as the time from the 
date of randomization to the date of documented first occurrence of the 
LMD. Death before occurrence of LMD will be treated as a competing risk. 
Study subjects who are alive and free of LMD at their last evaluation will be 
right-censored for Time to LMD on the date of their last evaluation. 
• 
Radiation Necrosis (RN) of the treated lesions. If radiation necrosis is suspected 
based on imaging criteria (progression of contrast-enhancing mass that is 
associated with reduced perfusion on dynamic MRI, increased T2 flair/T2 
hyperintensive signals within previous radiation treatment fields for the index 
lesion), then follow-up MRI imaging (with MRS, PET/SPECT as optional) will be 
obtained 4-6 weeks later to confirm the diagnosis of RN. The Time to RN will be 
back-dated to the initial imaging-findings date if the diagnosis of RN is confirmed 
by the follow-up imaging. 
o Stratified by surgical site versus non-surgical sites and the use of targeted 
therapy, cytotoxic chemotherapy, or immunotherapy 
• 
Symptomatic Radiation Necrosis (SRN), a component of CNS CE, will be 
documented radiation necrosis of the treated lesions (see above) that is 
accompanied by symptoms (headaches, nausea, vomiting, or other neurologic 
symptoms). 
o Time to SRN, a secondary outcome, will be measured as the time from the 
date of randomization to the date of documented occurrence of the SRN. 
Death before occurrence of the SRN will be treated as a competing risk. 
Study subjects who are alive and free of SRN at their last evaluation will be 
right-censored for Time to SRN on the date of their last evaluation. 
Other Secondary Objectives include determining the other secondary outcomes 
described below, and comparing treatment arms for improvements with neoadjuvant 
SRS/SRT in (a) the rates of secondary yes/no outcomes such as Local Control, or (b) the 
6-month, 12-month, 18-month, month rates of secondary time-to-event outcomes such 
as Duration of Local Control: 
• 
Local Control.  
o Local Control will be defined as Complete Response [CR], Partial Response 
[PR], or Stable Disease [SD] of the index lesion resulting from the assigned 
treatment. It will be determined at the first evaluation following successful 
completion of either neoadjuvant or adjuvant SRS/SRT of all metastatic 
lesions and surgical resection of the index lesion. 
 
Stratified by GTR or STR, piecemeal vs en bloc resection 

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o Treatment Failure will be defined either as Progressive Disease [PD] during 
the assigned treatment, or as the absence of Local Control at the first 
evaluation following successful completion of the assigned treatment. 
o Duration of Local Control (DLC) will be measured as the time from the date 
when Local Control is first documented to the date when: 
 
the treated lesions show documented evidence of LR or PD, or  
 
the patient undergoes whole-brain radiotherapy, repeat SRS, repeat 
surgical intervention 
• 
Time to distant in-brain failure.  
o Distant in-brain failure (DiBF) will be defined as the occurrence of any new 
parenchymal lesion outside of the planning target volume. 
o Time to DiBF will be measured as the time from the date of randomization 
to the date of occurrence of the DiBF. Death before occurrence of DiBF will 
be treated as a competing risk. Study subjects who are alive and free of 
DiBF at their last evaluation will be right-censored for Time to DiBF on the 
date of their last evaluation.   
• 
Overall survival. 
o Overall survival (OS) will be measured as the time from the randomization 
date to the date of death for any reason. Study participants who are still 
alive at last follow-up will be right-censored for OS on the date of their last 
follow-up. 
• 
Time to systemic therapy. 
o Time to initiation or re-initiation of systemic therapy will be measured as the 
time from the date when the assigned treatment (neoadjuvant versus 
adjuvant SRS/SRT) is successfully completed to the date when the 
systemic therapy is initiated or re-initiated. 
• 
Time to subsequent brain treatment, including whole-brain radiotherapy (WBRT), 
will be measured as the time from the date when the assigned treatment is 
successfully completed to the date when the WBRT or other subsequent treatment 
is initiated. 
• 
Radiation/Surgery toxicity 
o The rate of symptomatic (≥grade 2) radiation/surgery toxicity 

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o Incidence of adverse events as graded by the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0  
Study Design and Procedures 
Design: This pilot study is a randomized, open-label, 2-arm active-controlled phase II 
clinical trial conducted at a single study site (UAMS) located in central Arkansas. 
Prospective enrollees will be screened based on the inclusion/exclusion criteria listed 
below in the Study Population section. Study-eligible candidates who agree to participate 
will be assigned by randomization to one of the 2 treatment arms shown in the table 
below: 
Treatment Arm  
Intervention/treatment  
Experimental: Arm I (pre-operative 
SRS/SRT) 
 
Patients undergo SRS or SRT within 
15 days of randomization followed by 
surgery within 15 days of radiation 
completion. Patients may undergo 
additional SRS or SRT if disease 
returns after treatment. 
Radiation: Stereotactic Radiosurgery 
Undergo SRS/SRT 
Other Names: 
• 
Stereotactic External Beam Irradiation 
• 
stereotactic external-beam radiation 
therapy 
• 
stereotactic radiation therapy 
• 
Stereotactic Radiotherapy 
• 
stereotaxic radiation therapy 
• 
stereotaxic radiosurgery 
 
Active Comparator: Arm II (post-
operative SRS/SRT) 
 
Patients undergo surgery within 15 
days of randomization followed by 
standard-of-care SRS or SRT within 30 
days of surgery. Patients may undergo 
additional SRS or SRT if disease 
returns after treatment. 
Undergo SRS/SRT 
Other Names: 
• 
Stereotactic External Beam Irradiation 
• 
stereotactic external-beam radiation 
therapy 
• 
stereotactic radiation therapy 
• 
Stereotactic Radiotherapy 
• 
stereotaxic radiation therapy 
• 
stereotaxic radiosurgery 

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The dose, volume and fractionation of radiotherapy will be at the discretion of the radiation 
oncologist at the time of SRS/SRT depending on the size, location, and proximity to critical 
structures. Before treatment commences, each study participant will be stratified 
according to two stratification factors: 
• Size of Index Lesion (<3 cm versus ≥3 cm) 
• Number of Brain Metastases (4 or fewer versus 5 or more) 
These stratification factors will be used during the randomization procedure to assure that 
the treatment arms will be well-balanced with respect to index-lesion size and brain-
metastasis number.  
On-study Plan: After first signing the IRB-approved Informed Consent form, and after 
then being stratified according to size of index lesion and number of brain metastases, 
study participants will be registered and assigned a study number by a clinical research 
associate (CRA) or Study Coordinator.  
Randomization and Treatment Allocation: After the study participant’s eligibility has 
been confirmed, and after the participant has been stratified (see above) and registered 
in the Research Participant Registration System (RPRS), the study coordinator will do 
two things. First, the study coordinator will use the RPRS to assign the participant to one 
of the four possible strata defined by the stratification factors. Then the study coordinator 
will use the RPRS to randomize the participant in a 1:1 allocation ratio to either Arm I 
(pre-operative SRS/SRT) or Arm II (post-operative SRS/SRT). The randomizations will 
be balanced 1:1 on treatment arms within each stratum by using a permuted-blocks 
approach. Study participants will receive either pre-operative or post-operative SRS/SRT 
depending on the study arm to which they are randomized. Accordingly the two study 
arms will follow the treatment schedules shown in the table.  
Sample Collection: The extent (gross total or subtotal resection) and technique for 
surgery (en bloc or piecemeal) will be determined by the neurosurgeon. The pathological 
specimen will be analyzed and stored by the Department Pathology per standard 
operating procedure for resected brain tumor specimens. 
Follow-up: After completion of radiotherapy and surgery, study subjects will be followed 
by Brain MRI every 2-3 months for the first year and then every 4-6 months indefinitely 
(in accordance with National Comprehensive Cancer Network [NCCN] guidelines). 
Imaging and follow-up can be done sooner than these specified times if clinically 
indicated. MRI’s will be included in study results up to 18 months. 
Study Population 
Ages Eligible for Study:   
18 Years and older   (Adult, Older Adult) 
Sexes Eligible for Study:   
All 
Accepts Healthy Volunteers:  
No 
Estimated Enrollment 
104 (we anticipate consenting 120 in order to 
reach this goal) 
 
 

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Inclusion Criteria 
• Patients with prior histopathological diagnosis of cancer other than small cell lung 
cancer, lymphoma, and germ cell histologies. 
• MR imaging of the brain with findings strongly suggestive of metastatic tumor(s) 
as assessed by the radiologist. 
• Seen by a neurosurgeon or radiation oncologist and judged to be appropriate for 
participation in this study, including the ability to tolerate both surgery and 
SRS/SRT, e.g., the ability to lie flat in a stereotactic soft head frame. 
• ECOG ≤ 2 
• 1-2 index lesion(s) appropriate for resection, not previously treated with SRS/SRT. 
Index lesion(s) should be ≥ 1.5 cm and < 5 cm in largest dimension, and require 
resection. Alternatively, patients with a diagnosis of melanoma and a lesion < 
1.5cm in largest dimension may also be included.  
o All other brain lesions must be appropriate for SRS/SRT alone and treated 
according to physician preference. Prior neurosurgery and/or prior 
SRS/SRT at a non-overlapping location are permitted at the discretion of 
the treating physician. 
• MRI confirmed 1-10 lesions, 1-2 of which are the index lesions undergoing surgery. 
Each non-index lesion (up to 10) must measure ≤ 3.0 cm in maximal extent on 
contrasted MRI scan, and not otherwise require resection. 
• Clinical indication and plan for stereotactic radiosurgery to all known brain lesions 
requiring treatment (≤ 10 metastases). 
• Surgical resection able to be performed within 15 days of radiotherapy completion. 
• Written informed consent obtained from subject, or a legally designated power of 
attorney and ability for subject to comply with the requirements of the study. 
• Negative pregnancy test in women of childbearing potential (WOCBP) within 30 
days of radiation. WOCBP is a female patient less than 50 years of age or who 
has menstruated within the last 12 months. 
• Platelet count > 80 k/cumm, Hgb > 7.5 gm/dL, INR < 1.3, ANC > 1.5 k/cumm 
Exclusion Criteria 
• Not a surgical candidate per neurosurgeon's discretion. 
• Contraindication to general anesthesia. 
• Not a radiosurgical candidate per radiation oncologist's discretion. 
• Metastatic germ cell tumor, small cell carcinoma, leukemia, multiple myeloma or 
lymphoma or any primary brain tumor 
• ECOG > 2 
• < 3 months expected survival 
• Radiologic documentation of hydrocephalus in addition to symptoms of 
hydrocephalus 
• Radiographic or cytologic evidence of leptomeningeal disease. 
• Imaging Findings: 

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o Midline shift > 6mm 
o >10 lesions, one of which is the index lesion 
o Largest lesion > 5cm 
• Pregnancy 
• Known allergy to gadolinium, pacemaker, or other contraindication such as metal 
implant that is not safe for MRI. Patients with MRI-compatible implants are eligible. 
• Patients who have local recurrence of previously treated brain metastasis. 
• Patients who have received prior WBRT. 
• Inherited radiation hypersensitivity syndromes 
o Ataxia Telangiectasia, Nijmegen Breakage Syndrome, Fanconi Anemia, 
DNA Ligase IV, Mre 11 deficiency, SCID, Bloom’s syndrome 
• Collagen vascular diseases 
o Active systemic lupus erythematous (SLE), scleroderma, mixed connective 
tissue disorder, polymyositis or dermatomyositis, CREST Syndrome 
• Cytotoxic Chemotherapy within 7 days prior to SRS/SRT.  
o Molecularly targeted therapies, including immune-modulatory drugs, can be 
given within 7 days of SRS/SRT at the discretion of the treating physician. 
• Patients who received anti-VEGF therapy within 6 weeks prior to enrollment, as 
there is increased risk of fatal brain hemorrhage with surgical resection. 
• Treatment plan respecting normal tissue tolerances using dose fractionation 
specified within the protocol cannot be achieved. 
 
Risks and Benefits 
Potential risks 
A risk to study participants is the potential for loss of confidentiality of study data.  
Measures to protect the confidentiality of study data will be implemented as described in 
the Data Handling and Recordkeeping section below. 
A risk to study participants is that pathologic confirmation of target lesion is not available. 
There is a possibility that a lesion (that is radiologically/clinically consistent with a brain 
metastasis) may represent an infectious/inflammatory process or a separate malignancy. 
In that case, neoadjuvant SRS/SRT may not represent the optimal treatment option. This 
risk is being minimized by only including patients with biopsy proven malignancies (where 
the biopsy was performed at the primary cancer site or another metastatic site) but there 
is still a small risk that the target lesion may represent an infectious/inflammatory process 
or a separate malignancy. However, this risk is not greater than the standard of care for 
brain metastases diagnosed by radiographic imaging or clinical findings, as these patients 
may receive surgery and/or radiation of the target lesion without pathologic confirmation. 
A risk to study participants is the increased risk of delayed wound healing with 
neoadjuvant SRS/SRT compared to adjuvant SRS/SRT. 
Potential benefits  

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A potential benefit to study participants is the potential improved target delineation with 
neoadjuvant SRS/SRT. Since the tumor bed can change over time, adjuvant SRS/SRT 
involves challenges in delineating the target volume of a dynamically changing target, 
which may lead to geographic miss and increased radiation dose to normal tissues. 
Improved target delineation with neoadjuvant SRS/SRT may potentially improve local 
control and reduce toxicity. 
A potential benefit to study participants is a potential reduction in the rates of radiation 
necrosis. With neoadjuvant SRS/SRT, the tumor and adjacent normal tissue that has 
been irradiated is removed at the time of surgery, reducing the availability of injured tissue 
and inflammatory reaction needed to precipitate radiation necrosis. In contrast, for 
adjuvant SRS/SRT, the irradiated tissue remains. Retrospective data suggests the rate 
of symptomatic radiation necrosis is lower with neoadjuvant SRS/SRT compared to 
adjuvant SRS/SRT.6  
A potential benefit to study participants is a potential reduction in the rates of 
leptomeningeal disease. With neoadjuvant SRS/SRT, the tumor site is “sterilized” and the 
risk of leptomeningeal disease may be minimized even with tumor spill, as tumor cells 
may be replicatively dead. Retrospective data suggests the rate of symptomatic radiation 
necrosis is lower with neoadjuvant SRS/SRT compared to adjuvant SRS/SRT.6  
A potential benefit to study participants is potential immune system activation against 
tumor cells. Radiotherapy to an intact tumor may allow for increased immune activation 
and in situ vaccination, allowing for greater immune response against the tumor cells. 
Animal models have suggested this benefit but it is not well-studied in human subjects.8 
Finally, knowledge gained from the study could potentially benefit patients in the future. 
Data Handling and Recordkeeping 
The Principal Investigators will carefully monitor study procedures to protect the safety of 
research subjects, the quality of the data and the integrity of the study.  
Information will be coded with the key to the code kept separately. Data will be stored 
securely on UAMS-maintained computers and servers. Only investigators listed on this 
protocol will have direct access to patient-identifying data. Research assistants, 
coordinators, and statisticians will only have access to coded data. At the conclusion of 
the study, the coded data will be de-identified. 
Data Safety Monitoring Plan: The study will be monitored by the investigators to ensure 
that the rights and well-being of human subjects are protected, that the data are accurate, 
complete and verifiable from source documents and that the trial is conducted in 
compliance with currently approved protocol/amendments. The PI and sub-Investigators 
will review study conduct on an ongoing basis. The PI will assure that all protocol 
deviations, AEs, and SAEs are reported to the IRB according to the applicable regulatory 
requirements. 
Specimen Handling and Storage  

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Tumor specimens will be collected from surgical resection and stored by the Department 
of Pathology and kept as part of standard of care. No samples will be collected specifically 
for use in this study at this time. 
Data Analysis 
Statistical analysis plan 
Patient characteristics will include patient demographics, disease characteristics of the 
primary tumor, and relevant characteristics (number, location, size, etc.) of the brain 
metastases being treated. Patient characteristics will be summarized by treatment arm 
with medians, quartiles, and ranges for numeric characteristics, or with numbers and 
percentages for category characteristics. Each characteristic then will be assessed for 
imbalance between treatment arms with Wilcoxon’s rank-sum test for numeric 
characteristics and the chi-square test for category characteristics. The imbalance 
assessments will consist of 2-sided tests that employ the standard α=0.05 significance 
level.  
Time to a CNS CE, the primary outcome, will be visualized with Cumulative Incidence 
(CI) curves computed using Kaplan-Meier methodology, summarized by treatment group 
as CI proportions at 6, 12, and 18 months, and compared for difference using the Fine 
and Gray model for equality of CI functions when death before a CNS CE is treated as a 
competing risk. Times to each of the individual CNS events (LR, SRN, LMD, DiBF, and 
WBRT) will be analyzed the same way, except that each Fine and Gray model will have 
the competing risk be death before the individual event being analyzed. Overall survival 
will be visualized using standard Kaplan-Meier curves and compared for differences via 
the log-rank test. Because this is a pilot study, all time-to-event outcomes will be 
compared for evidence of improvement on the pre-operative SRS/SRT arm using 1-sided 
tests that employ an α=0.10 significance level.   
Sample size, power, and study duration 
Sample-size calculations are informed by results from Patel et al.’s retrospective study.6 
Based on their results, we expect that the post-operative SRS/SRT arm will have an 
average CNS CE rate of approximately 25% per year, accompanied by an average 
competing-risks rate of approximately 32% per year (where the competing risk is death 
before the CNS CE). Sample-size calculations are also informed by the fact that UAMS 
typically sees approximately 50 patients per year who should meet this study’s eligibility 
requirements.    
To meet its objectives, our randomized Phase II pilot study of pre-operative SRS/SRT 
versus post-operative SRS/SRT needs to have >80% power to detect a 50% decrease in 
the rate of CNS CE on the pre-operative SRS/SRT arm using a 1-sided test at 10% alpha. 
The power of tests under the Fine and Gray competing-risks model is well-approximated 
by the power of log-rank tests calculated with the competing-risk rate represented as non-
zero dropout rates on each study arm. To calculate power of 1-sided log-rank tests at 
10% alpha, we implement the following assumptions in PASS 16 software9: 

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• Accrual duration will be three years while minimum follow-up will be 1.5 years, 
leading to a total study duration of 4.5 years. 
• The post-operative SRS/SRT arm will have a CNS CE rate that averages 25.0% 
per year. 
• The pre-operative SRS/SRT arm will have a CNS CE rate that averages 12.5% 
per year, or half the rate on the post-operative SRS/SRT arm. 
• Both arms will have a dropout rate of 32% per year due to the competing risk. 
• The crossover rate from one arm to the other will be zero on both arms.  
• Sample sizes will be equal on both arms. 
Under these assumptions, a sample size of 52 subjects per treatment arm (a total of 104 
subjects) is calculated to provide the 1-sided log-rank test (and thus the equivalent Fine 
and Gray test) with 80.7% power at 10% alpha to detect a 50% reduction in the CNS CE 
rate with pre-operative SRS/SRT relative to the CNS CE rate with post-operative 
SRS/SRT. Under the same assumptions, the number of CNS CE’s is projected to reach 
expected values of 8.6 with pre-operative SRS/SRT and 17.4 with post-operative 
SRS/SRT for a total expected value of 26.0 by the end of the study.  
Recruiting the required study total of 104 subjects over the 3-year accrual duration leads 
to a recruitment rate of 35 subjects per year. Given that UAMS typically sees 
approximately 50 study-eligible patients per year, a recruitment rate of 35 subjects/year 
represents a recruitment-success rate of 70%. We consider 70% to be a feasible 
recruitment-success rate.  
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and procedures.  This 
protocol and any amendments will be submitted and approved by the UAMS Institutional 
Review Board (IRB) to conduct the study.   
The formal consent of each subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure.  All subjects for this 
study will be provided a consent form describing this study and providing sufficient 
information in language suitable for subjects to make an informed decision about their 
participation in this study.  The person obtaining consent will thoroughly explain each 
element of the document and outline the risks and benefits, alternate treatment(s), and 
requirements of the study.  The consent process will take place in a quiet and private 
room, and subjects may take as much time as needed to make a decision about their 
participation.  Participation privacy will be maintained and questions regarding 
participation will be answered.  No coercion or undue influence will be used in the consent 
process.  This consent form must be signed by the subject or legally authorized 
representative and the person obtaining the consent.  A copy of the signed consent will 
be given to the participant, and the informed consent process will be documented in the 
research record.   

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Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
participant.  The study will be listed on clinicaltrials.gov in accordance with (journal or 
FDA) requirements. 
 
References 
1.  
Routman DM, Yan E, Vora S, et al. Preoperative stereotactic radiosurgery for 
brain metastases. Front Neurol. 2018;9(NOV). doi:10.3389/fneur.2018.00959 
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