UCSD Image-Guided Cognitive-Sparing Radiosurgery for Brain Metastases: Avoidance of Eloquent White Matter and Hippocampal Regions
Phase: PHASE2
Conditions: Brain Metastases, Adult, Neurocognitive Function, Cancer
Sponsor: Jona Hattangadi-Gluth

 
1 
Image-Guided Cognitive-Sparing Radiosurgery for Brain Metastases: Avoidance of Eloquent White 
Matter and Hippocampal Regions 
 
 
 
Version Date:    7/8/2019 
 
UC San Diego/Moores Cancer Center Human Protections/IRB Approval Number:  170848 
*This is a newly designed clinical protocol that has been IRB approved* 
 
 
Principal Investigator: 
 
Jona Hattangadi-Gluth, MD 
 
 
 
 
 
University of California San Diego Health Sciences 
 
 
 
 
 
Assistant Professor 
 
 
 
 
 
Department of Radiation Medicine and Applied Sciences 
 
 
 
 
 
jhattangadi@ucsd.edu 
 
Co-Investigators: 
 
 
Carrie McDonald, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Professor 
 
 
 
 
 
Department of Psychiatry 
 
 
 
 
 
camcdonald@ucsd.edu 
 
Roshan Karunamuni, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Project Scientist 
 
 
 
 
 
Department of Radiation Medicine and Applied Sciences 
 
 
 
 
 
rakarunamuni@ucsd.edu 
 
Kevin Moore, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Associate Professor/Physicist 
 
 
 
 
 
Department of Radiation Medicine and Applied Sciences  
 
 
 
 
 
k3moore@ucsd.edu 
 
Armin Schwartzman, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Associate Professor/Bio-statistician 
 
 
 
 
 
Department of Medicine  
 
 
 
 
 
a7schwartzman@ucsd.edu 
 
 
 
Collaborators: 
 
 
Nikdokht Farid, MD 
 
 
 
 
 
University of California San Diego Health Sciences 
Association Professor/Neuroradiologist 
 
 
 
 
 
Department of Radiology 
 
 
 
 
 
nfarid@ucsd.edu 
 
Vitali Moiseenko, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Professor/Physicist 
 
 
 
 
 
Department of Radiation Medicine and Applied Sciences 
 
 
 
 
 
vmoiseenko@ucsd.edu 
 

 
2 
Jeremy Rich, MD 
 
 
 
 
 
University of California San Diego Health Sciences 
Professor, Neuro-Oncology/ Director of Brain Tumor Institute 
 
 
 
 
 
Moores Cancer Center  
 
 
 
 
 
jrich@ucsd.edu 
 
Anders Dale, PhD 
 
 
 
 
 
University of California San Diego Health Sciences 
Professor/ Director of Center for Translational Imaging & Precision 
Imaging 
 
 
 
 
 
Department of Radiology  
 
 
 
 
 
adale@ucsd.edu 
 
 
 
 

 
3 
CLINICAL TRIAL PROTOCOL: TABLE OF CONTENTS 
 
 
1. Statement of Purpose ………………………………………………………………………………...4 
 
2. Background and Significance ………………………………………………………………………..4 
 
3. Research Plan …………………………………………………………………………………………6 
 
 
Recruitment ………………………………………………………………………………………6 
 
 
 
Inclusion Criteria ………………………………………………………………………………...7 
 
 
Exclusion Criteria ………………………………………………………………………………..7 
 
 
Screening Evaluation …………………………………………………………………………...7 
 
   
Informed Consent 
 ……………………………………………………………………….....7 
 
 
Standard of Care Treatment Procedures …………………………………………………….8 
 
 
Study Procedures ……………………………………………………………………………….8 
 
 
Payment ………………………………………………………………………………………...11 
 
Statistical Considerations……………………………………………………………………...11 
 
4. Risks …………………………………………………………………………………………………..13 
 
 
 
5. Privacy and Confidentiality....………………………………………………………………………..13 
 
6. Data Safety and Monitoring …………………………………………………………………….…...14 
 
7. References ………………………………………………………………………………………….…16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4 
1. Statement of Purpose 
       Brain metastases affect one third of all adult cancer patients1. Stereotactic radiosurgery (SRS), a highly 
precise modality for focal ablative radiotherapy, is standard of care for patients with limited brain metastases1-2. 
However, many patients will experience decline in neurocognitive function after brain SRS3,4,5,6, given the 
potential for high doses to eloquent brain tissue. Neurocognition has emerged as a critical endpoint along with 
survival and tumor control in brain tumor clinical trials7,5,8. Radiation-induced cognitive impairment after SRS can 
manifest as a range of cognitive problems, particularly deficiencies in memory, language, attention and executive 
functioning, depending on tumor location and dose delivered to critical brain tissue.  
 Any focal intervention in the brain should occur with a detailed understanding of the brain’s functional and 
anatomic relationships relative to the target9-10. With the aid of modern magnetic resonance imaging (MRI) 
techniques, eloquent brain regions can be well demarcated in imaging studies and projected into three-
dimensional (3D) space. In particular, diffusion tensor imaging (DTI) tractography with automated white matter 
segmentation can be used to identify critical white-matter pathways (tracts) of the brain11,12,13. 3-D volumetric 
MRI and automated brain parcellation software can be used to segment discrete areas of the brain including the 
hippocampus, a structure critical for memory14,15. In radiation planning, particularly in brain SRS planning, these 
new technologies have not yet been prospectively tested for sparing healthy and sensitive parts of the brain 
from high doses of radiation. 
These novel imaging techniques also allow us to directly and non-invasively measure microstructural 
changes after radiotherapy to critical brain structures in vivo. Using diffusion imaging biomarkers, we have shown 
that radiation therapy results in dose dependent damage to uninvolved white matter16 with greater susceptibility 
to injury among white matter tracts critical for neurocognition17. Our studies with 3-D volumetric MRI and 
automated parcellation of the hippocampus have shown dose-dependent hippocampal atrophy after fractionated 
brain radiotherapy15,18. These imaging biomarkers hold promise to help elucidate the mechanisms behind 
radiation-induced cognitive decline.  
In this study, we propose a novel approach to cognitive-sparing brain SRS. Specifically, we will incorporate 
eloquent white matter tracts and hippocampal volumes obtained from DTI and volumetric MRI, respectively, into 
brain SRS planning in a cohort of patients with brain metastases. We will use innovative, advanced image 
acquisition and robust, automated image processing techniques. Cognitive outcomes, specifically language, 
memory, attention, and executive functioning, along with imaging tests to measure microstructural changes in 
these eloquent areas will be prospectively assessed, along with tumor control.  
 
The primary objectives of this study are: 1). To evaluate whether the relative sparing of eloquent white matter 
tracts (those critical for memory, language, attention, and executive functioning) and hippocampal volumes from 
high doses during brain SRS results in improved 3-month post-SRS cognitive performance relative to historical 
controls among patients with 1 to 3 brain metastases and 2.) To measure longitudinal trends in white matter 
damage (using diffusion imaging) and hippocampal atrophy (using volumetric change) among patients receiving 
cognitive-sparing brain SRS and correlate these imaging biomarkers with domain-specific cognitive outcomes. 
 
2. Background and Significance 
 
The incidence of brain metastases is rising, and they currently affect up to one-third of all adult cancer 
patients, most commonly among lung, melanoma, renal cell, and breast cancer primaries1. As novel systemic 
therapies improve survival rates and systemic disease control in cancer patients, brain metastases become a 
greater burden: these therapeutic agents poorly cross the blood-brain-barrier, creating a sanctuary site in the 
brain to harbor metastatic disease. At the same time, targeted therapeutics have changed the prognoses 
associated with brain metastases patients from the historically dismal few months19 to several years for certain 
groups who receive targeted agents and radiotherapy20. This has transformed the paradigm of management for 
brain metastases patients from rapid palliation to treatments with durable local control and few long-term side 
effects. 
Radiotherapy (RT) is the mainstay of treatment for patients with brain metastases1, with a shift over the past 
two decades from whole brain radiotherapy (WBRT), which treats the entire brain, to focal stereotactic 
radiosurgery (SRS) for patients with a limited number or volume of tumors2,21,22. Randomized trials have shown 
that WBRT provides no survival benefit over SRS for these patients1. SRS targets the metastases alone with 
high, ablative doses of radiotherapy, most commonly in a single treatment, with minimal interruptions to systemic 
therapy schedules.  

 
5 
The challenge of radiation-induced cognitive decline. While radiotherapy is indispensable for the 
management of intracranial tumors, it is associated with an inevitable decline in neurocognitive function in up to 
90% of patients who survive more than 6 months after treatment23. This manifests with changes in verbal and 
nonverbal memory, language and semantic processing, attention and processing speed, and/or executive 
functioning, and can be devastating for patients and their quality of life. Neurocognitive outcome is increasingly 
being recognized as a primary endpoint in brain tumor clinical trials, next to tumor control and patient 
survival7,24,25. WBRT is notorious for significant post-treatment cognitive decline, and cognitive-sparing therapies 
that have been explored on WBRT trials include hippocampal-avoidance7,25-27 and the addition of medications 
like memantine (N-methyl-D-aspartate receptor blocker)28  or donepezil29.  
A recent landmark phase III randomized controlled trial, Alliance study N0574, compared SRS alone vs. SRS 
+ WBRT for patients with limited (1 to 3) brain metastases, with neurocognitive decline as the primary outcome5. 
The rate of cognitive deterioration at 3 months after treatment was significantly higher in the SRS + WBRT arm 
(91.7% vs. 63.5%), establishing SRS alone as the less toxic option and reflecting a general consensus in 
treatment strategy for limited brain disease1,2,22. Yet the most striking result from this trial was the high rate of 
cognitive deterioration (nearly 64% at 3 months) with SRS alone.  Another Alliance trial, N107C, which 
randomized patients with a resected brain metastasis to SRS vs. WBRT showed 52% cognitive deterioration at 
6 months after SRS alone8. Clearly SRS is an improvement over WBRT for neurocognition, but the post-
treatment cognitive outcomes are still dismal with standard SRS.  
Mechanisms of radiation brain injury: the case for safer SRS. The pathogenesis of radiation-induced brain 
injury is complex4,30,31.  With higher, ablative single doses like those delivered in SRS, damage is driven by 
oligodendrocyte depletion and vascular injury with downstream white matter demyelination and necrosis32. 
Radiotherapy also causes inhibition of neurogenesis and depletion of neurogenic progenitor cells33, which reside 
in the hippocampal dentate gyrus and subventricular zone, especially at higher doses. These effects, along with 
neuroinflammation, mediate radiation-induced cognitive impairment. Thus, efforts to avoid cognitive decline in 
SRS must be aimed at sparing critical brain regions from high doses of radiation, and white matter tracts and 
the hippocampus are clear choices for avoidance.  
Imaging Tools for Cognitive Sparing.  Within standard SRS planning, the division of the brain into eloquent 
structures to avoid remains crude; beyond the optic nerves, optic chiasm and brainstem, there is little attention 
paid to the anatomic and functional importance of eloquent regions. Diffusion tensor imaging (DTI) tractography 
can be used to non-invasively and accurately demarcate the brain’s white matter pathways, and these imaging 
techniques have been implemented in modern neurosurgical navigation systems9,10. In RT planning, such 
techniques have only sparsely been applied for white matter tract sparing.  One previous study utilizing DTI of 
the corticospinal tract (white matter bundle critical for motor functioning) in RT planning showed reduced motor 
complications in a retrospective cohort34, and another similar study found that relative sparing of the corticospinal 
tract was feasible using DTI35. A retrospective DTI study correlated high RT doses to the arcuate fasciculus with 
symptomatic aphasia in 12 patients with brain lesions36. Despite these initial studies, there are no prospective 
data on the use of DTI for increasing precision and white matter avoidance in SRS. 
Hippocampal avoidance has been an area of great interest for cognitive sparing in the setting of WBRT25,26, 
but has not yet been examined prospectively for cognitive sparing SRS. A recent retrospective planning study 
showed that sparing the hippocampi was feasible with SRS37. We contend that brain SRS should be safer and 
more precise, and that by sparing eloquent white matter tracts and the hippocampi, this could help mitigate the 
cognitive effects of radiation injury. 
Imaging as a biomarker of injury: Radiation-induced cognitive impairment can be observed before gross 
structural and histologic damage takes place, requiring highly sensitive means to detect these changes. Novel 
magnetic resonance imaging (MRI) techniques allow us to directly and non-invasively measure microstructural 
radiation-induced changes to brain tissue in vivo, and correlate with radiation dose effects and downstream 
cognitive outcomes. Diffusion tensor imaging (DTI), a highly sensitive technique to identify changes in white 
matter, measures the diffusion of water on a microscopic scale using directional gradients12. Animal studies have 
shown that changes in diffusion imaging biomarkers correlate with pathologic white matter demyelination and 
axonal injury after radiation38,39. In humans, DTI has been used to study dose-dependent white matter changes 
after RT16,40  and correlate these with cognitive functioning41,42.  
Measuring hippocampal volumetric changes with high-resolution 3D volumetric MR imaging has proven 
clinical utility in a variety of diseases, including Alzheimer’s disease43,44, temporal lobe epilepsy45, and traumatic 
brain injury46. In the setting of partial brain irradiation, there is evidence that higher RT dose to the hippocampus 
may be associated with worse memory impairment47,48. Given the sensitivity of the hippocampal area to radiation 

 
6 
injury, our group has applied this quantitative biomarker to measure hippocampal volume changes in brain tumor 
patients receiving fractionated brain RT15,18,49. 
In this proposal, we introduce advanced diffusion and volumetric imaging techniques along with innovative, 
automated image parcellation methods to identify critical brain regions, incorporate into cognitive-sparing SRS, 
and analyze biomarkers of radiation response. This work will advance our understanding of neurocognitive 
changes after brain SRS and help create interventions that preserve cognitive-function in brain metastases 
patients. 
 
3. Research Plan 
 
We will prospectively enroll 60 adult patients with 1-3 brain metastases who are eligible for treatment with 
intracranial stereotactic radiosurgery (SRS) at UC San Diego(UCSD)/Moores Cancer Center.  
Inclusion criteria include: age ≥18; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 
(score of 0, no symptoms; 1, mild symptoms; 2, symptomatic, <50% in bed during the day); pathologic 
confirmation of extra-cerebral tumor site (i.e. breast, lung, melanoma); ability to answer questions and follow 
commands via neurocognitive testing; estimated life expectancy > 6 months. 
Exclusion criteria include: inability to undergo MRI with contrast, prior WBRT, ineligibility for brain SRS (i.e. 
leptomeningeal metastases; metastases from lung small cell carcinoma or primary CNS lymphoma), ineligibility 
for cognitive-sparing (tumor infiltrating hippocampus or critical white matter (WM) tracts). Concurrent 
chemotherapy with brain SRS is not allowed on study. These criteria closely follow the Alliance Trial N05745, 
given that the cognitive deterioration rate from their standard SRS arm will be used as historical controls to power 
the current trial. Patient and tumor-specific variables including age, sex, race/ethnicity, educational status, 
occupation, primary tumor histology, systemic therapy, use of steroids and anti-epileptic drugs, tumor number, 
tumor size and tumor location, will be prospectively recorded.  
The study protocol and timeline for each patient is shown in Figure 1 below. Patients will undergo MR 
imaging with DTI and 3D volumetric imaging at baseline (pre-SRS), and 1 month, 3 months, and 6 months 
afterwards. This regimen of post-SRS MR imaging is clinical standard of care2. Segmentation of critical white 
matter and hippocampal volumes will be performed pre-SRS for use in brain SRS planning. Formal 
neurocognitive assessments will be performed at baseline and 3 months post-SRS5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Timeline of consent, MRIs, Neurocognitive (NC) assessments, SRS planning and Delivery, and 
Follow-ups. WM=White matter; HC=Hippocampus. 
 
 
Recruitment 
Subjects will include those patients seen at UC San Diego/Moores Cancer Center. A study coordinator will screen 
for eligible adult patients with brain metastases. They will review the patient’s medical record and determine if 
they would be a candidate for the study. The principal investigator will be notified of subject eligibility and consult 

 
7 
with the treating radiation oncologist as to whether the patient is eligible. Study investigator(s) will approach the 
subject and offer participation in the trial. Subjects willing to participate will sign informed consent, approved by 
the UC San Diego Institutional Review Board.  Approximately 150 patients are treated at UCSD yearly that meet 
our eligibility criteria. 
 
Inclusion Criteria 
1. Patients 18 years or older 
2. One to three brain metastases targets, all smaller than 3 cm in diameter (intact or resected tumor 
bed) 
3. Eastern cooperative Oncology Group (ECOG) performance status 0-2 (score of 0, no symptoms; 1, 
mild symptoms; 2, symptomatic, <50% in bed during the day) 
4. Ability to answer questions and follow commands via neurocognitive testing 
5. Estimated life expectancy greater than 6 months 
6. Pathologic confirmation of extracerebral tumor site (eg, lung, breast, prostate) from either the 
primary site or a metastatic lesion 
7. Willingness/Ability to undergo brain MRI scans 
8. Able to give informed consent 
 
Exclusion Criteria 
1. Pregnant or nursing women 
2. Women of childbearing potential unwilling to use adequate contraception 
3. Inability to complete a magnetic resonance imaging scan with contrast 
4. Tumor directly invading the critical area to be spared (for example a patient with tumor invading a 
critical white matter tract; ineligible for cognitive-sparing) 
5. Planned chemotherapy during SRS (on the day of SRS) 
6. Previous whole brain radiation therapy 
7. Leptomeningeal metastases (ineligible for SRS) 
8.   Metastases from primary germ cell tumor, small cell carcinoma, or primary CNS lymphoma 
(ineligible for SRS) 
 
Screening Evaluation 
Evaluation includes standard studies for brain metastases which may include but are not limited to: appropriate 
blood work including CBC and a complete metabolic panel and brain MRI. Previous biopsy results and medical 
history are necessary to evaluate disease status. There are no study-related screening procedures other than 
the informed consent process. 
 
Informed Consent 
Subjects will be asked to provide written consent, using the IRB-approved consent form. The consent process 
will take place prior to performing any study related procedures and in a private location. The Investigator or 
study coordinator will describe the study, including detailed information about risks and benefits, to potential 
subjects. The investigator or study coordinator will provide potential subjects with an IRB-approved consent form. 
Subjects will be given ample time to read this consent form at the same visit or may take it with them to read at 
another time. Potential study subjects will be given the opportunity to ask and receive answers to all questions 
they may have about the study, its risks and benefits, or the consent form itself before signing the consent form.  
As this research is subject to HIPAA privacy rule provisions, participants will also be requested to sign a separate 
authorization for the use of protected health information (i.e., HIPAA form specific to the research study).  The 
investigator or study coordinator will obtain informed consent in a language understood by the prospective using 
certified translations of study documents and qualified translators, where applicable. 
Subjects who fulfill the eligibility criteria will be offered further participation in this study.  Only subjects who have 
consented and provided HIPAA authorization will have identifiers or linked information (e.g., subjects initials, 
study numbers, etc.) recorded on the Screening/Enrollment Log.   
A copy of the signed informed consent and assent (when applicable) forms and HIPAA authorization will be 
placed in the research subject’s medical record. The original consent form and HIPAA authorization will be 
retained in the master research file.  

 
8 
 
Standard of Care Treatment Procedures 
Intracranial SRS will be performed identically to standard of care, except for implementing additional imaging 
techniques and software for additional regional avoidance for cognitive sparing, as outlined below.  In cases 
where sparing of these structures cannot be performed without significantly sacrificing treatment of the tumor 
or another critical structure, this will be recorded and the default will be the standard clinical plan.  While clinical 
benchmarks of SRS quality will not be sacrificed on this study, there is a possibility that changing the SRS plan 
to achieve cognitive sparing may change the dose distribution to other structures in the brain.  It is unclear 
whether this would change any clinical outcomes since SRS plans must adhere to the same rigorous 
standards as the current standard of care. 
 
Study Procedures 
 
Neuroimaging:  
 
MRI acquisition and pre-processing: All MR imaging will be performed on a 3T Signa Excite HDx scanner (GE 
Healthcare, Milwaukee, Wisconsin) equipped with an 8-channel head coil, at the UCSD Center for Translational 
Imaging and Precision Medicine (CTIPM). The imaging protocol includes pre- and post-contrast 3D volumetric 
T1-weighted inversion recovery spoiled gradient-echo sequence, and a 3D T2-weighted FLAIR sequence. 
Diffusion-weighted data will be acquired using a single-shot pulsed field gradient spin-echo EPI sequence with 
diffusion weightings (b-values) of 0, 500, 1500, and 4000 s/mm2, with 6, 6, and 15 unique gradient directions for 
each non-zero b-value, respectively. T1- and T2-weighted imaging data will be corrected for distortions attributed 
to gradient nonlinearities74 and imaging non-uniformities arising from bias fields75. Diffusion-weighted data will 
be corrected for spatial distortions arising from eddy currents76, and B0 field inhomogeneities64 using methods 
described in the literature and developed at our institution. Imaging series at each time point will be co-registered 
to each other using a rigid-body registration algorithm and mutual information-based cost function.  
 
MRI study acquisition: The image acquisition parameters, including the echo time (TE), repetition time (TR), 
inversion time (TI), diffusion time (TD), and field-of-view for the T1-weighted, FLAIR, and diffusion-weighted 
sequences are included below:  
 
TE (ms) 
TR (ms) 
TI (ms) 
TD (ms) 
Field-of-View (mm) 
T1 
2.8 
6.5 
450 
- 
240 x 240 x 200  
FLAIR 
126 
6000 
1863 
- 
240 x 240 x 204 
Diffusion 
97 
1700 
- 
90 
240 x 240 x 120 
 
RSI-modeling of DWI: As a summary, the diffusion-weighted signal in each voxel is modeled as a linear 
combination of the response functions of different diffusion components with pre-specified diffusion properties 
(primary and secondary apparent diffusion components) and geometries (spherical or cylindrical). The 
contribution of each component to the overall signal is then estimated using a Tikhonov-regularized linear 
regression. The signal contribution from any one or combination of these components can then be isolated and 
used for further analysis. In brain tumors, the RSI framework consists of four components: spherically-restricted, 
cylindrically-restricted, cylindrically-hindered and spherically-free. The signal contribution of the cylindrically 
restricted component can be thought to arise from pools of water whose motion is impeded (trapped) by the 
white matter axons, and can then therefore be used in its segmentation while minimizing the influences of other 
populations of water (such as edema) within the same voxel. 
Estimation of tensor and RSI-derived biomarkers: Diffusion data acquired using b-values of 0, 500, and 1500 
s/mm2 will be fit to a single tensor using a linear least-squares optimization of the log-transformed signal at each 
voxel. The diffusion tensors will then be used to estimate 3D volumes of the mean, axial, and radial diffusivity as 
well as the FA. Second, the entire diffusion data set will be fit using the RSI framework described previously to 
generate signal contributions of the 4 diffusion components (spherically restricted, cylindrically-restricted, 

 
9 
cylindrically-hindered, and spherically free). The fraction of the total 
signal described by the cylindrically-restricted component will be 
estimated at each voxel location, and used as an RSI-derived feature 
of white matter structure. 
White matter and hippocampal segmentation: Detailed descriptions 
of the RSI framework for modeling the diffusion-weighted signal as a 
function of the b-value and gradient direction has been previously 
published by our group53. The cylindrically-restricted signal, assumed 
to arise from water trapped within white matter axons, is fit to a 
diffusion tensor, from which the per-voxel direction of the primary 
eigenvector (V0) and the fractional anisotropy (FA) are estimated. 
Population-based atlases of FA and V0 with ground-truth per-voxel 
white matter labels will then be non-linearly registered and resampled 
to the patient diffusion space62. This will be performed in AtlasTrack. 
The white matter atlas will be used to estimate the probability that a 
given patient voxel belongs to a particular white matter label. The 
voxel will be assigned the white matter label with the largest probability.  
Pre-contrast high resolution volumetric T1-weighted images will be used as the input for the automated 
hippocampal segmentation software, FreeSurfer65,66 (https://surfer.nmr.mgh.harvard.edu/). Per-voxel 
segmentations of the hippocampi, with unique labels for each hemisphere, will then be extracted. White matter 
and hippocampal segmentations will be visually inspected for accuracy and manually corrected, if needed, by 
Dr. Hattangadi-Gluth (PI) and Dr. Farid (neuro-radiologist).  
 
Critical Structures for Sparing: Brain structures to be included for cognitive-sparing (white matter tracts and 
hippocampi) are shown in Table 1. The rationale for hippocampal avoidance has been discussed previously77. 
The cingulum, including the cingulate and parahippocampal portions, corpus callosum, and fornix were chosen 
based on their radiation sensitivity17 and critical importance to memory and attention/processing speed78. The 
arcuate fasciculus is critical for language79 and preliminary evidence has shown that selective avoidance during 
SRS may prevent radiation-induced language disorders38. Microstructural changes to the inferior frontostriatal 
tracts results in poorer executive functioning80, necessitating its inclusion. The uncinate fasciculus is implicated 
in both executive functioning and memory formation/retrieval, and the inferior  longitudinal fasciculus in language 
and memory78.  
 
SRS Planning with Knowledge-based Planning (KBP): Radiation treatment plans are manually planned by 
medical dosimetrists and physicists using commercial treatment planning software. Brain SRS planning is 
especially complicated given the higher doses, small margins, and critical structures involved. This planning 
process is time-consuming and inefficient, requiring multiple iterations over several days, with a wide variation 
in plan quality66,67. Automated knowledge-based SRS planning, which was developed by Dr. Moore and his team, 
is an innovative approach which eliminates the variability and inefficiency of standard planning, allows the 
addition of new critical structures and optimization objectives into complex treatment plans, and delivers high 
quality, deliverable brain SRS plans68,69. This automated SRS planning system is ideal for use in this trial where 
new clinical objectives for critical structures (eloquent white matter tracts, hippocampus) will need to be optimized 
and accounted for in planning each brain SRS case, with targets in different areas around the brain. This system 
is already integrated into our clinical workflow with a fast planning turn-around time of 20-35 minutes.  
 
 
 
 
 
 
 
Table 1: White Matter and 
Hippocampal Structures for 
Cognitive-Sparing 
Eloquent Cognitive Structures 
Cingulum 
Uncinate Fasciculus 
Inferior longitudinal fasciculus 
Corpus Callosum 
Arcuate fasciculus 
Inferior frontostriatal tracts 
Fornix 
Hippocampus 
*all bilateral except Corpus Callosum 

 
10
Neuropsychological data: A well-established, well-validated, battery of neurocognitive tests will be performed 
prior to SRS and 3-months following SRS to 
evaluate different neurocognitive domains 
including 
verbal 
memory, 
executive 
functioning, attention/processing speed, and 
language. These are shown in Table 2. This 
cognitive battery takes 30 minutes to 
perform. This core battery is frequently 
employed in large-scale clinical trials, 
including Alliance Trial N05745, because the 
tests are brief, repeatable, have good 
psychometric properties, and have been 
shown to be sensitive to cognitive decline in 
patients with metastatic brain tumors70. Most 
tests have several alternate forms, making 
them ideal for repeat measurements. Health-
related quality of life will also be assessed. 
Since depression may also influence test 
scores71,72, we will administer the Beck 
Depression 
Inventory 
(BDI)73 
at 
each 
evaluation to screen for depression and 
include the BDI score as an additional 
covariate. All cognitive testing will be performed by a trained, certified neuropsychologist.  
 
Radiation Planning Dose Constraints: As of yet, there are no evidence-based dose constraints for cognitive-
sparing in brain SRS. Rational dose tolerances in clinical trials (a dose which predicts a particular likelihood of 
dysfunction) must be calculated based on normal tissue complication probability (NTCP) analyses78. 
Hippocampal dose constraints used in WBRT trials25 are not relevant to SRS (where high ablative doses are 
delivered) given that the prescription dose is so low in WBRT (30Gy in 10 fractions). In another IRB-approved 
longitudinal, prospective, observational study of primary brain tumor patients receiving definitive fractionated 
radiotherapy, we have been prospectively tracking domain-specific cognitive decline with all the standard 
cognitive measures in Table 1. Based on preliminary NTCP analyses from 28 patients, we found that maximum 
dose to the left hippocampus >28Gy (in 30 fractions) predicted for a >10% risk of significant decline (reliable 
change index <90% confidence interval) in HVLT total and HVLT delayed memory scores (p=0.01). 
Conversion of this maximum dose to a single fraction SRS dose constraint based on the linear quadratic 
formalism with α/β=2.5 Gy for normal brain tissue yields a hippocampal maximum dose of 8.4Gy. This 
conversion was performed by solving for isoeffective dose by equating biologically effective doses from SRS 
single-fraction treatment, DSRS, and reference fractionation, dose Dref, delivered in Nref fractions (set to 30):  
 
𝐷𝐷𝑟𝑟𝑟𝑟𝑟𝑟(1 +
𝐷𝐷𝑟𝑟𝑟𝑟𝑟𝑟
𝑁𝑁𝑟𝑟𝑟𝑟𝑟𝑟
൘
𝛼𝛼𝛽𝛽
ൗ
) = 𝐷𝐷𝑆𝑆𝑆𝑆𝑆𝑆(1 + 𝐷𝐷𝑆𝑆𝑆𝑆𝑆𝑆
𝛼𝛼𝛽𝛽
ൗ
) 
 
For white matter tracts, within the left parahippocampal cingulum, V45Gy at 20.6% was predictive of 
significant decline on HVLT total and HVLT delayed memory scores (p=0.001). Conversion of this to a single 
fraction SRS dose constraint with α/β=2.5 Gy for normal brain tissue (same method as above) yields a white 
matter maximum dose of 12Gy. Furthermore, a recently published analysis of SRS dose tolerances for the 
optic pathway (another critical white matter tract) established 12Gy in 1 fraction maximum dose as resulting in 
<1% risk of radiation-induced optic nerve neuropathy, supporting this white matter constraint. Dose constraints 
for single fraction SRS are summarized in Table 3. For lesions receiving 3 fractions, isoeffective dose 
constraints from Table 3 will be calculated based on α/β=2.5 Gy. 
 
 
 
 
Table 2. Neurocognitive Domains and Tests 
Cognitive Domain 
Neuropsychological Test 
Verbal Memory 
• Hopkins Verbal Learning Test–
Revised (HVLT-R); Immediate, 
Delayed Recall 
Executive 
Functioning 
• Controlled Oral Word Association 
Test (COWA): letter fluency 
• Trail Making Test Part B (TMT-B) 
Attention/Processing 
Speed
• Trail Making Test Part A (TMT-A) 
Language 
• Boston Naming Test (BNT) 
• Controlled Oral Word Association 
Test (COWA): category fluency 
Mood 
• Beck Depression Inventory (BDI) 
Quality of Life 
• Functional Assessment of Cancer 
Therapy-Brain (FACT-BR) 

 
11
Table 3: Dose Constraints 
 
Eloquent Cognitive 
Structures 
Max Dose 
(Gy) 
Cingulum 
12 
Uncinate Fasciculus 
12 
Inferior longitudinal fasciculus 
12 
Corpus Callosum 
12 
Arcuate fasciculus 
12 
Inferior frontostriatal tracts 
12 
Fornix 
12 
Hippocampus 
8.4 
*all bilateral except Corpus Callosum 
 
 
SRS planning, plan optimization, and treatment: Patients will undergo setup, immobilization and simulation for 
frameless linear accelerator-based intracranial SRS with non-coplanar volumetric modulated arc radiosurgery 
(VMAR) as previously described79. White matter and hippocampal 3D segmentations will be imported into the 
Eclipse treatment planning software (Varian Medical Systems, Palo Alto, California) for each patient. High-
resolution, distortion-corrected stereotactic-protocol contrast-enhanced T1-weighted images will be co-
registered with CT. Target volumes (enhancing tumor + 1mm margin for planning target volume, PTV) and 
standard organs at risk (OARs), such as the brainstem, optic nerves, and optic chiasm, will be manually 
contoured by the treating radiation oncologist. Tolerance doses for SRS planning include the white matter and 
hippocampal doses above, and standard single fraction dose constraints for other OARs as previously 
published80. Prescription doses to each target lesion will be based on volume: 24 Gy in a single fraction if the 
target is less than 1 cc, 22Gy for 1.1-4cc target, and 20Gy for those between 4.1-10cc. For larger lesions or 
tumor beds, fractionated SRS with 24Gy in 3 fractions will be used respecting the constraints above. These 
doses closely follow a large Japanese SRS study22 with modern target volume-based doses, and are also similar 
to the Alliance N0574 trial5.   
 
Automated knowledge-based brain SRS plans will be generated as previously described69, with dose 
optimized within standard clinical guidelines (98% of the PTV receiving 100% of the prescription dose34,36) and 
tolerance OAR doses above. Dose volume histograms will be assessed and re-optimized if necessary, without 
compromising coverage of tumor or sparing of standard critical structures (i.e. brainstem, optic structures.). All 
plans will be reviewed by the PI and the UCSD CNS Radiosurgery team for approval. Treatment delivery will 
follow the UCSD standard frameless brain SRS protocol79. 
 
Patients will be seen by the treating physician on the day of SRS, and on subsequent follow-up visits. They 
will be followed closely with clinical and imaging exams for safety and tumor recurrence (i.e.,1 month, 3 months, 
6 months post-SRS). All treatment-related toxic effects and adverse events will be recorded according to NCI 
Common Terminology Criteria for Adverse Events, version 4.0. Local tumor control rates for each treated lesion 
will be assessed according to the revised Response Assessment in Neuro-oncology (RANO) criteria81,82. 
 
Payment 
Parking for study patients related to study visits will be complementary. Subjects will be compensated $100 for 
participation in this study to help compensate for time and travel costs. 
 
Statistical Considerations 
 
Primary Objective Analysis: 
Cognitive test results (pre- and post-SRS) will be scored based on standardized published norms72,87. Cognitive 
deterioration will be defined as a decline of greater than 1 SD on at least 1 of the 7 cognitive tests (Table 2, not 
including BDI or FACT-BR). Fisher’s exact 2-group binomial test will be used to compare the proportion of 
patients with 3-month post-SRS cognitive deterioration between the current cognitive-sparing SRS study and 
previously reported with standard SRS.5 Further analyses of pre- to post-SRS cognitive change for each test will 

 
12
utilize a reliable change index (RCI)87. This index is derived from the standard error of measurement of each 
test, and it represents the 90% confidence interval (CI) for the difference in raw scores from baseline to follow-
up that is expected if no real change has occurred. RCI values below the 90% CI are indicative of significant 
decline. RCIs also account for practice effects, which is ideal for this study where evaluations are 3 months apart. 
One-sample t-tests (H0=0) will be used to determine significant group decline in RCIs by test and cognitive 
domain. Pearson correlation coefficients will be used to assess associations between RCIs and depression 
scores. Bonferroni corrections will be applied to control for Type I errors due to multiple comparisons. 
 
With RCI at 3-months post-SRS as the outcome variable, linear regression modeling will be used to analyze 
patient-specific (e.g. age, sex), tumor-specific (e.g. histology, number of lesions, imaging progression), and 
treatment-specific (e.g. previous chemotherapy, anti-epileptic drugs) predictors of neurocognitive change after 
cognitive-sparing SRS.  Model selection will be based on Akaike Information Criterion (AIC)88,89. Given the small 
sample size and multiple variables of interest, this will be an exploratory analysis. Given that cognitive-sparing 
on this study will not be performed at the sacrifice of tumor coverage, we expect the overall local control and 
survival rates in the cohort to be comparable to those in other studies of SRS alone for patients with 1-3 brain 
metastases1,5,6,22. Treated tumor local control rates will be assessed at 3- and 6-months post-SRS. Local tumor 
control of each treated lesion will be assessed with modified RANO criteria84 where tumor progression is defined 
as >25% increase in the size of a treated lesion. Tumor progression of treated metastases will be evaluated 
independently of the development of new lesions5.  Local tumor control rate at 6 months and overall survival rate 
(death from any cause) at 12 months will be compared to historical values5 using a 1-sample t-test.   
 
Secondary Objective Analyses 
The imaging biomarker of each structure (mean white matter diffusivity metrics and hippocampal volume) 
will be modeled as a function of time using linear mixed effect models13,16. These models are well-suited for 
longitudinal analysis since they account for within-subject correlation between repeated measures, and allow for 
incomplete outcome data. Individual structures will be classified based on whether they received greater or less 
than the median dose for that structure across all patients. The interaction of dose and time will be tested within 
the model to assess whether dose mediates longitudinal trends. In addition, potential fixed-effect covariates will 
be selected from a list of patient and tumor-specific variables, such as age, sex, tumor size and location. Model 
selection will be based on AIC. To account for correlated observations within subjects, patient-specific random 
intercepts and time-associated slopes will be tested.  
Associations between average changes in imaging biomarkers at the 3-month time point and RCI of domain-
specific neurocognitive tests will be estimated using linear models with model selection based on AIC. As an 
exploratory analysis, associations between early changes in imaging biomarkers, measured at the 1-month time 
point, with RCIs of domain-specific neurocognitive tests will also be estimated using the same methodology. This 
may help to identify those metrics that can serve as early indications of 3-month neurocognitive deterioration.  
TractCrawler imaging software will be used to generate slices perpendicular to the medial axis for each white 
matter structure. We will then generate slice-averaged values of diffusion imaging metrics as a function of length 
along the medial axis of the tract, defined in a common coordinate system across patients at each time point. 
Sensitivity metrics will be generated per- patient and per-slice to quantify the degree to which changes in diffusion 
metrics in that slice differ from the mean change across the entire structure for each of the post-RT time points 
compared to baseline. T-tests can then be used to identify regions (slices or groups of slices) along the length 
of the white matter tract where changes are significantly greater or smaller than the rest of the tract. 
Feasibility: Accrual of 60 patients over 3 years is feasible given that over 100 brain metastases patients are 
treated yearly at our institution that would meet eligibility criteria. Patients will be compensated $100 for study 
participation to offset transportation costs and time. We will enroll approximately 3-4 patients per month, allowing 
full enrollment to be completed by around 15-20 months.  This will allow all testing and analyses to be completed 
within the four-year grant period. The imaging methods, processing techniques and automated KBP capabilities 
are already integrated into our brain tumor imaging and brain SRS workflow, making the study execution highly 
feasible. The team of investigators and collaborators have already established a successful research and clinical 
collaboration for this and other research projects and grants. 
 
Sample Size Determination: This study is powered based on the endpoint of cognitive deterioration at 3 
months post-SRS, defined as decline of greater than 1 standard deviation (SD) from baseline on at least 1 of 
the neurocognitive tests. This was the primary endpoint of the Alliance N0574 study. With 60 accrued patients 

 
13
and assuming a 20% drop-out rate, we will have sample size n=48.  We have 85% power to detect a change in 
the cognitive deterioration rate from 64% in standard SRS to 42.5% in the current cognitive-sparing study with 
n=48 (Fisher’s exact 2-group binomial test, 2-tailed α=0.05).  
 
 
4. Risks 
 
The anticipated risk to patients in this study is minimal.   
 
The MRI scans to be obtained at baseline would be added on to the same scan performed for routine SRS 
planning for patients.  Follow up MRI would be standard of care imaging and would be obtained regardless of 
whether the patient is on or off study. These scans do not involve any radiation exposure. There are no additional 
risks associated with the research scans aside from discomfort due to the additional 8-10 minutes of scan time 
required.  However, these scans are frequently performed as part of standard of care during presurgical planning 
without adverse effects.   Some patients may experience claustrophobia in the MR scanner and may require the 
use of medications for this, as is prescribed routinely for brain MRIs when indicated.   
 
Intracranial SRS would be performed identically to standard of care, except for adding additional regional 
avoidance for cognitive sparing. In cases where sparing of these structures cannot be performed without 
sacrificing treatment of the tumor or another critical structure, this will be recorded and the default will be the 
standard clinical plan. While clinical benchmarks of SRS quality will not be sacrificed on this study, there is a 
possibility that changing the SRS plan to achieve cognitive sparing may change the dose distribution to other 
structures in the brain. It is unclear whether this would change any clinical outcomes since SRS plans must 
adhere to the same rigorous standards as the current standard of care.   
 
The directed neurocognitive evaluations are not standard of care unless a patient requires clinical referral to 
neuropsychology. Neuropsychological testing as described above is done verbally one-on-one with a licensed 
neuropsychologist. This is a 30 minute testing session that is frequently employed in clinical trials. One possible 
risk to neurocognitive testing is a possible increase in psychological strain in susceptible individuals (e.g., to the 
extent that thinking about their cognitive difficulties is stressful, patients might experience stress in being 
evaluated).  However, these neurocognitive evaluations are designed to be non-stressful and to be used for 
patients who may have cognitive difficulties. Patients will be counseled that the testing is merely to assess 
particular functioning (short term memory, attention, etc) and that this would not affect their clinical care. These 
tests are not anticipated to be particularly stressful in any way and patients can stop the testing at any time. 
Patients may find it stressful to know whether they have deficiencies in their neurocognitive functioning. They 
can request to discuss this with the PI or neuropsychologist if they wish. 
 
As mentioned, all imaging and neuropsychological data will be kept in a file that will not contain patient-identifying 
information.  Thus, the risk for a breach of confidentiality is minimal.  Moreover, the data will be stored in 
password-protected files only on the computers of investigators directly involved in the research.   
 
5. Privacy and Confidentiality 
Confidentiality of a subject’s protected health information will be maintained by the following methods:  study-
specific records containing protected health information, and copies of study-related medical records, will be 
kept in locked filing cabinets at the Moores UCSD Cancer Center locked research administrative offices (Clinical 
Trials Office). 
Computers containing access to protected health information will have password-access; and screen-savers will 
be utilized to prevent unauthorized viewers from inadvertently seeing information.  Protected health information 
will be stored on secure servers. The servers supporting these studies are located inside a locked rack within 
the San Diego Supercomputer data center.  The facility features restricted access by means of personal codes 
(PINs) and biometrics, and is monitored 24 hours a day 7 days a week.  The electrical power is backed up by 
battery-powered uninterruptible power supplies, as well as by on-site generators.  Both servers are behind 
firewalls configured to allow access only to credentialed personnel within the UCSD network. Velos, the clinical 

 
14
trials management system, maintains an additional internal access control mechanism via user names and 
passwords.  Data transactions executed over our intranet are encrypted via Secure Sockets Layer.  
Access to a subject’s protected health information will be limited to those study personnel who need to use it to 
accomplish the purpose of the research, and the minimum necessary information to accomplish the purpose of 
the research will be collected, stored, used, and reported.  When protected health information is sent outside the 
University of California, San Diego, it will be disclosed only to those parties listed in the subject’s authorization, 
and an audit trail log will be maintained of what information was sent and to whom it was sent. 
Patients will be assigned a random study identification number for purposes of organizing the data and the data 
for the study will be kept in 2 main files: the “central” file and the “code” file.  After the data is collected, it will be 
stored in the “central” file (that will contain no patient-identifying information such as name, date of birth, MRN, 
etc.).  A separate, password-protected “code” file will contain the mappings of patient name with their random 
study identification number.  This file will be password-protected, with the password known only to CITI-trained 
study personnel, and it will be stored exclusively on the computer of the principal investigator.  These patient 
identifiers will be destroyed following the collection and aggregation of the dataset, and thus the patient data will 
be officially de-identified at this time.   
Subject identifiers will be destroyed by the PI at the earliest opportunity consistent with the conduct of the 
research, unless there is a health or research justification for retaining the identifiers or such retention is required 
by law.  
 
6. Data Safety and Monitoring 
 
Personnel responsible for the safety review and its frequency 
The principal investigator will be responsible for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency which must be conducted at a minimum of every 6 
months (including when re-approval of the protocol is sought). During the review process, the principal 
investigator will evaluate whether the study should continue unchanged, require modification/amendment, 
continue or close to enrollment. The principal investigator has the authority to stop or suspend the study or 
require modifications. This study has been approved by the UCSD Institutional Review Board. 
 
Attribution of Adverse Events 
Adverse events will be monitored for each subject participating in the study and attributed to the study 
procedures by the principal investigator according to the following categories:  
Definite: Adverse event is clearly related to investigational procedures  
Probable: Adverse event is likely related to investigational procedures  
Possible: Adverse event may be related to investigational procedures  
Unlikely: Adverse event is likely not to be related to the investigational procedures Unrelated: Adverse 
event is clearly not related to investigational procedures  
 
Plan for Grading Adverse Events 
 
Adverse events noted during the study will be graded using the NIH Common Toxicity Criteria for Adverse 
Events scale (CTC), version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). Specific conditions and 
symptoms may have values or descriptive comment for each level, but the general guideline is:  
1 - Mild  
2 - Moderate  
3 - Severe  
4 - Life threatening  
5 - Death  
 
Plan for Determining Seriousness of Adverse Events 
In addition to grading the adverse event, the PI will determine whether the adverse event meets the criteria for 
a Serious Adverse Event (SAE). An adverse event is considered serious if it:  
1. Is life-threatening  

 
15
2. Results in in-patient hospitalization or prolongation of existing hospitalization  
3. Results in persistent or significant disability or incapacity  
4. Results in a congenital anomaly or birth defect  
5. Results in death  
6. Based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition  
7. Adversely affects the risk/benefit ratio of the study  
 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse Event. 
Similarly, an adverse event may be graded as moderate but still meet the criteria for an SAE. It is important for 
the PI to consider the grade of the event as well as its “seriousness” when determining whether reporting to the 
HIC or HSC is necessary.  
 
Plan for reporting serious AND unanticipated AND related adverse events, anticipated adverse events 
occurring at a greater frequency than expected, and other unanticipated problems involving risks to 
subjects or others 
The principal investigator will report the following types of adverse events to the HIC, and to any and all co-
investigators:  
a) Serious AND unanticipated AND possibly, probably or definitely related events  
b) Anticipated adverse events occurring with a greater frequency than expected  
c) Other unanticipated problems involving risks to subjects or others.  
These adverse events or unanticipated problems involving risks to subjects or others will be reported to the 
HIC within 48 hours of it becoming known to the investigator, using the appropriate forms found on the website.  
 
The principal investigator will conduct a review of all adverse events upon completion of every study subject. 
The principal investigator will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required.  
 
 

 
16
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