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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
19
Undergo blood sample collection
Undergo CT
Undergo MRI
Given PO
Ancillary studies
Ancillary studies
Undergo SRS/fSRS
Undergo HA-WBRT
Banner University Medical Center - Tucson
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
City of Hope Corona
Corona, California, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
City of Hope at Irvine Lennar
Irvine, California, United States
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.
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.
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.
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.
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
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.
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.
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Roseville, California, United States
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Sacramento, California, United States
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