Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Breast Neoplasm, Metastatic Malignant Digestive System Neoplasm, Metastatic Malignant Neoplasm in the Brain, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Renal Cell Carcinoma, Recurrent Brain Neoplasm, Stage IV Lung Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Conditions
Brief summary
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.
Detailed description
PRIMARY OBJECTIVE: I. To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS). SECONDARY OBJECTIVES: I. To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs overall survival as compared to SRS. II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS. III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS. IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year. V. To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year. VI. To tabulate and descriptively compare the adverse events associated with the interventions. VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions. EXPLORATORY OBJECTIVES: I. To collect serum, plasma, and whole blood for translational research analyses. II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis. III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months. IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity. V. To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS. VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity \>= 4 new brain metastases/year. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial. ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial. Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
DRUGMemantine
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
RADIATIONStereotactic Radiosurgery
Undergo SRS/fSRS
RADIATIONWhole-Brain Radiotherapy
Undergo HA-WBRT
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have developed their distant brain relapse(s) at least 8 weeks after last SRS and within 21 days prior to randomization * Distant brain relapse lesions to be treated must measure =\< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure \< 30 mL on the contrast-enhanced diagnostic MRI brain scan obtained within 21 days prior to randomization * last SRS refers to the most recent SRS procedure that the patient received prior to enrollment on this study * Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements: * REQUIRED MRI ELEMENTS * Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm * Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged) * A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane * ADDITIONAL RECOMMENDATIONS * Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence * Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1 * Recommendation is that imaging be performed on a 3 Tesla (3T) MRI * Recommendation is that the study participants be scanned on the same MRI instrument at each time point * Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020 * If additional sequences are obtained, total imaging time should not exceed 60 minutes * Brain metastasis velocity (BMV) since last SRS must be \>= 4 brain metastases/year * The patient or a legally authorized representative must provide study-specific informed consent prior to study entry * Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis) * Other histologies are not permitted * History and physical examination within 28 days prior to randomization * Age \>= 18 * Karnofsky performance status of \>= 70 within 28 days prior to randomization * Calculated creatinine clearance (CrCl) \>= 30 ml/min (within 28 days prior to randomization) * Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization) * Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
Exclusion criteria
* BMV \>= 4 brain metastases/year at time of any SRS prior to enrollment. * Patients are permitted to have undergone multiple SRS treatments to different brain metastases so long as prior BMV has been less than 4 brain metastases/year * Prior WBRT or prophylactic cranial irradiation * Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed) * Brain metastases from primary germ cell tumor or lymphoma * Definitive leptomeningeal metastasis * Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted * Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt * Known history of demyelinating disease such as multiple sclerosis * Inability to swallow pills * Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury * Contraindications to memantine, including: * Allergy, including prior allergic reaction to memantine * Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months * Current use of N-methyl-D-asparatate (NMDA) agonist * Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine * 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 randomization * Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization * Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease * Renal tubular acidosis or metabolic acidosis * Human immunodeficiency virus (HIV) positive with CD4 count \< 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count \>= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol * Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Neurologic Death | From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months. | Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Progression-Free Survival (IPFS) | Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months. | IPFS rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients with alive without intracranial progression is reported, and no statistical testing was done. Per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, intracranial progression is defined as local progression of lesions treated with prior radiation or distant progression/development of a new brain lesion. Given the small number of participants due to early study closure, only the number of patients alive without intracranial progression is reported and no statistical testing was done. |
| Brain Metastasis Velocity at Subsequent Relapse (BMVs) | Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months. | BMVs = \[total number of new brain metastases since on-study SRS/HA-WBRT\] / (years since on-study SRS/HA-WBRT). BMVs is calculated at the time of distant brain relapse. Higher BMVs is associated with lower rates of survival and higher rates of neurologic death. |
| Overall Survival | Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months. | Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients alive at time of study termination is reported, and no statistical testing was done. |
| Number of Participants With a Grade 3 or Higher Adverse Event | Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months. | Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Adverse events reported as possibly, probably, or definitely related to treatment are considered to be treatment-related adverse events. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Number of Participants Who Received Salvage Procedures | Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months. | Salvage procedures are defined as procedures for the purpose of managing recurrent intracranial disease following protocol treatment. |
| Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score | Baseline and 4 months from treatment start | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the presence and severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (not present) to 10 (as bad as you can imagine) and is rated as the worst occurrence in the last 24 hours. The Symptom Severity subscale score is the average of the symptom severity items, ranging from 0 (best) to 10 (worst). Change from baseline is calculated as score at 4 months minus score at baseline. A negative change value indicates improvement in symptom severity, while a positive change value indicates worsening. |
Countries
Canada, Hong Kong, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Memantine, HA-WBRT) Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity. | 10 |
| Arm II (SRS/fSRS) Patients undergo salvage SRS or fSRS. | 9 |
| Total | 19 |
Baseline characteristics
| Characteristic | Total | Arm I (Memantine, HA-WBRT) | Arm II (SRS/fSRS) |
|---|---|---|---|
| Age, Continuous | 63 years | 63.5 years | 60 years |
| Brain Metastasis Velocity (BMV) >13 | 13 Participants | 8 Participants | 5 Participants |
| Brain Metastasis Velocity (BMV) 4 - 13 | 6 Participants | 2 Participants | 4 Participants |
| Diagnosis-specific graded prognostic assessment (DS-GPA) 0-2 | 15 Participants | 9 Participants | 6 Participants |
| Diagnosis-specific graded prognostic assessment (DS-GPA) 3-4 | 4 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Is participant receiving immunotherapy? No | 16 Participants | 8 Participants | 8 Participants |
| Is participant receiving immunotherapy? Yes | 3 Participants | 2 Participants | 1 Participants |
| Karnofsky performance status 70 | 5 Participants | 3 Participants | 2 Participants |
| Karnofsky performance status 80 | 7 Participants | 3 Participants | 4 Participants |
| Karnofsky performance status 90 | 7 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 10 | 4 / 9 |
| other Total, other adverse events | 6 / 8 | 6 / 8 |
| serious Total, serious adverse events | 4 / 8 | 1 / 8 |
Outcome results
Primary
Percentage of Participants With Neurologic Death
Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done.
Time frame: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Memantine, HA-WBRT) | Percentage of Participants With Neurologic Death | 3 Participants |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Percentage of Participants With Neurologic Death | 3 Participants |
Secondary
Brain Metastasis Velocity at Subsequent Relapse (BMVs)
BMVs = \[total number of new brain metastases since on-study SRS/HA-WBRT\] / (years since on-study SRS/HA-WBRT). BMVs is calculated at the time of distant brain relapse. Higher BMVs is associated with lower rates of survival and higher rates of neurologic death.
Time frame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants who subsequently relapsed with new brain metastases
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Brain Metastasis Velocity at Subsequent Relapse (BMVs) | 33.18 brain metastases/year |
Secondary
Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the presence and severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (not present) to 10 (as bad as you can imagine) and is rated as the worst occurrence in the last 24 hours. The Symptom Severity subscale score is the average of the symptom severity items, ranging from 0 (best) to 10 (worst). Change from baseline is calculated as score at 4 months minus score at baseline. A negative change value indicates improvement in symptom severity, while a positive change value indicates worsening.
Time frame: Baseline and 4 months from treatment start
Population: Randomized participants with data at baseline and 4 months from start of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Memantine, HA-WBRT) | Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score | -0.82 score on a scale | Standard Deviation 1.29 |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score | 0.53 score on a scale | Standard Deviation 1.61 |
Secondary
Intracranial Progression-Free Survival (IPFS)
IPFS rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients with alive without intracranial progression is reported, and no statistical testing was done. Per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, intracranial progression is defined as local progression of lesions treated with prior radiation or distant progression/development of a new brain lesion. Given the small number of participants due to early study closure, only the number of patients alive without intracranial progression is reported and no statistical testing was done.
Time frame: Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Memantine, HA-WBRT) | Intracranial Progression-Free Survival (IPFS) | 5 Participants |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Intracranial Progression-Free Survival (IPFS) | 2 Participants |
Secondary
Number of Participants Who Received Salvage Procedures
Salvage procedures are defined as procedures for the purpose of managing recurrent intracranial disease following protocol treatment.
Time frame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants who started treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Memantine, HA-WBRT) | Number of Participants Who Received Salvage Procedures | 2 Participants |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Number of Participants Who Received Salvage Procedures | 1 Participants |
Secondary
Number of Participants With a Grade 3 or Higher Adverse Event
Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Adverse events reported as possibly, probably, or definitely related to treatment are considered to be treatment-related adverse events. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants who started treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Memantine, HA-WBRT) | Number of Participants With a Grade 3 or Higher Adverse Event | 4 Participants |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Number of Participants With a Grade 3 or Higher Adverse Event | 3 Participants |
Secondary
Overall Survival
Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients alive at time of study termination is reported, and no statistical testing was done.
Time frame: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Memantine, HA-WBRT) | Overall Survival | 5 Participants |
| Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) | Overall Survival | 5 Participants |