A Single Arm Study of Neurocognitive Outcomes in Patients With Brain Metastases Managed With Stereotactic Radiosurgery (SRS)

This will be a prospective, multi-institution, non-randomized trial of neurocognitive
outcomes in patients with multiple, newly-diagnosed brain metastases managed primarily with
stereotactic radiosurgery (SRS), specifically the Gamma Knife (GK) system. The goal of the
study is to enroll 45 patients with 1-10 newly-diagnosed brain metastases from varied primary
cancers with the largest intracranial tumor volume ≤10 cc, ≤15 cc total tumor volume, absence
of leptomeningeal disease on MRI, and Karnofsky performance status (KPS) score ≥70 (unless
due to intracranial disease), and KPS expected to improve to ≥70 with treatment. The enrolled
patients are expected to have fairly good pre-treatment cognitive function, defined as online
neurocognitive function (oNCF) assessment scores ≥70 (within 2 standard deviations of mean,
100).

All study participants will undergo standard, pre-treatment clinical evaluations that
include: complete clinical/neurologic exam, performance status assessment, systemic staging,
and diagnostic MRI of the brain. Upon enrollment, the patients will further undergo
high-resolution MRI, including track density imaging (TDI). The baseline neurocognitive
function (NCF) will be assessed by a short (20-30 minute) online test battery that can be
completed by patients at home, CogState assessment (22 minutes), as well as by a
comprehensive neuropsychological evaluation (2-3 hours). The eligible patients will
subsequently go on to receive a radiosurgical treatment for their brain metastases.

All patients will have treatment response assessments every 10-12 weeks consisting of a
clinical/neurologic exam, performance status evaluation, disease re-staging (if indicated),
and diagnostic MRI of the brain. If progressive disease is identified (radiographic
progression of treated lesions or new brain lesions), the patients will be considered for
"salvage" therapy which will include repeat SRS, whole-brain radiation therapy (WBRT),
surgery with or without brachytherapy or best supportive care (e.g. steroids only). The
preferred salvage therapy will be SRS provided that the re-treatment criteria are met. Along
with regular clinical MRIs, TDI will be obtained.

Mandatory comprehensive follow-up testing by a neuropsychologist (1-2 hours) will occur every
10-12 weeks, starting 4 weeks after completion of SRS, and will continue at these intervals
even if salvage therapy is administered for intracranial recurrence. Online NCF testing (oNCF
and CogState) will take place in the office setting on the same day as a comprehensive
cognitive assessment. Patients will also have the option to do web-based oNCF assessments
from home but not more frequently than every 2 weeks. These optional assessments will not be
included in the data analysis. All study participants will be followed until death or
withdrawal from the study.

The primary aim of the study is to validate the oNCF battery and to demonstrate the
feasibility of its use in patients with metastatic brain disease. The former will be
accomplished by correlating the findings of the oNCF testing with those of a comprehensive
neurocognitive function (cNCF) assessment of a neuropsychologist. Every attempt will be made
to identify imaging correlates of neurocognitive function derived from high-resolution MRI,
and TDI. The aggregate data in combination with lesion location information (and the
corresponding treatment) should provide unique insights into mechanisms that underlie
radiation therapy (RT)-related brain injury. Because salvage therapy with WBRT is also
permitted and will likely be necessary in a subset of patients, some insights may also be
gained on the relative extent, specificity, and temporal evolution of post-treatment NCF
dysfunction of each treatment modality.

The data gained from this pilot study could form the basis of future trials of NCF outcomes
in cancer patients, especially if oNCF test battery is validated as this may provide a
cost-effective method for including NCF outcomes in clinical trials.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of a
non-hematopoietic malignancy other than small cell lung cancer and germ cell
malignancy within 5 years of registration. If the original histologic proof of
malignancy is greater than 5 years, then pathological confirmation is required (e.g.
from extra- or intracranial disease).

- Patients with 1-10 measurable brain metastases on a diagnostic-quality
contrast-enhanced magnetic resonance imaging (MRI) scan obtained within 30 days prior
to registration.

- Patients with ≤10 cc largest tumor volume, and ≤15 cc total tumor volume.

- History/physical examination within 30 days prior to registration.

- If an open biopsy is performed, the patient must be at least one week post biopsy.
This requirement does not apply to patients who undergo stereotactic biopsies.

- Age ≥18 years.

- Karnofsky performance status ≥70 (RTOG recursive partitioning analysis (RPA) Class I &
II).

- Minimum pre-treatment oNCF score ≥70.

- Patients must provide study-specific informed consent prior to study entry.

- Women of child-bearing age must have a negative, quantitative serum pregnancy test ≤14
days prior to study entry, or have a documented reason why such a test is not
necessary (e.g. history of tubal ligation).

- Patients must be able to speak and read English fluently (required for the use of
online NCF testing).

Exclusion Criteria:

- Clinical (e.g. multiple cranial nerve deficits in the absence of obvious radiographic
disease to explain symptoms) or radiographic evidence of leptomeningeal disease.

- Patients with measurable brain metastasis(es) resulting from small cell lung cancer
and/or germ cell malignancy

- No documentation of prior cytotoxic or other therapy for malignancy if such therapy
was previously received. Note: This does not apply to patients with synchronous
metastases at initial diagnosis.

- Contraindication to MR imaging, such as implanted metal devices or foreign bodies,
severe claustrophobia, or contraindications to contrast agent administration.

- Estimated glomerular filtration rate (eGFR) <60 within 6 weeks prior to registration.

- Prior radiation therapy to the brain.

- Severe, active co-morbidity, defined as follows:

- Unstable angina, and/or congestive heart failure requiring hospitalization within
the last 6 months.

- Transmural myocardial infarction within the last 6 months.

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration.

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization, or precluding study therapy at the time of
registration.

- Uncontrolled, clinically significant cardiac arrhythmias.

- Radiologic or clinical evidence of hydrocephalus, or history of previously
treated hydrocephalus.

- Women of childbearing potential and male participants who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the radiation treatment involved in this study is potentially
teratogenic.