Cognitive Impairment, Metastatic Malignant Neoplasm in the Brain, Solid Neoplasm
Conditions
Brief summary
This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiotherapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.
Detailed description
PRIMARY OBJECTIVES: I. Determine whether the addition of whole-brain radiotherapy with hippocampal avoidance (HA-WBRT) increases time to neurocognitive failure at months 2, 4, 6, and 12 as measured by neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B. SECONDARY OBJECTIVES: I. Determine whether the addition of HA-WBRT preserves neurocognitive function at months 2, 4, 6, and 12 as separately measured by each test, the HVLT-R for Total Recall, Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B. II. Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT). III. Assessment of quality adjusted survival and cost analysis using the five-level version of the EuroQol five-dimensional (EQ-5D-5L). IV. Compare cumulative incidence of progression and overall survival after WBRT versus HA-WBRT. V. Compare adverse events between the treatment arms according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 criteria. TERTIARY OBJECTIVES: I. Collect serum, plasma, and imaging studies for future translational research analyses. II. Evaluate magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry at baseline and 6 months as potential predictors of neurocognitive decline and differential benefit from HA-WBRT as compared to WBRT. III. Association of symptom burden and anxiety/depression with neurocognitive function. IV. Evaluate the potential correlation between the prognostic scoring systems Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive function at baseline and overtime. After completion of study treatment, patients are followed up at 12 months.
Interventions
RADIATIONWhole brain radiation therapy with hippocampal avoidance
Intensity modulated radiation therapy (IMRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately two week; starting within 21 calendar days after randomization.
DRUGMemantine
Given PO daily during and after radiation therapy for a total of 24 weeks. Week 1: 5 mg in the AM, none in the PM; Week 2: 5 mg in the AM, 5 mg in the PM; Week 3: 10 mg in the AM, 5 mg in the PM; Weeks 4-24: 10 mg in the AM, 10 mg in the PM. Should start the same day as radiation therapy, at latest before the fourth radiation treatment.
RADIATIONWhole brain radiation therapy
Whole brain radiation therapy (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRIOR TO STEP 1 REGISTRATION: * Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =\< 21 days prior to Step 1 registration; an allowed exception, regarding ability to image brain metastases, would be that patients who had undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not have to have visible disease but do need a pre-surgery MRI or computed tomography (CT) scan demonstrating brain metastases; however, the brain metastases could not have been within 5 mm of either hippocampus * Patients must have a gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) axial MRI scan with standard axial and coronal gadolinium contrast-enhanced T1-weighted sequence and axial T2/FLAIR sequence acquisitions; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal and sagittal contrast-enhanced T1 sequences can be up to 2.5 mm in slice thickness; this MRI must be obtained =\< 21 days prior to step 1 registration; the vendor specific MRI protocols are available for download from the Alzheimer's Disease Neuroimaging Initiative (ADNI) * Patients must provide study-specific informed consent prior to registration * PRIOR TO STEP 2 REGISTRATION: * The following baseline neurocognitive assessments must be completed prior to Step 2 registration: HVLT-R, TMT, and COWA; * Pathologically (histologically or cytologically) proven diagnosis of solid tumor malignancy within 5 years prior to Step 2 registration * History and physical examination within 28 days prior to Step 2 registration * Karnofsky performance status of \>= 70 within 28 days prior to Step 2 registration * Serum creatinine =\< 3 mg/dL (265 umol/L) and creatinine clearance \>= 30 ml/min * Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. \< 20 mg/dL) * Total bilirubin =\< 2.5 mg/dL (43 umol/L) * Patients may have had prior therapy for brain metastasis, including radiosurgery and surgical resection; patients must have completed prior therapy by at least 14 days prior to Step 2 for surgical resection and 7 days for radiosurgery * Negative serum pregnancy test (in women of childbearing potential) =\< 14 days prior to Step 2; women of childbearing potential and men who are sexually active must practice adequate contraception while on study * Patients who are primary English or French speakers are eligible
Exclusion criteria
* Prior external beam radiation therapy to the brain or whole brain radiation therapy * Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior chemotherapy * Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt * 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 * Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration * 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 cluster of differentiation (CD)4 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 registration; 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 * Prior allergic reaction to memantine (memantine hydrochloride) * Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine) * Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per month for the past 2 months * Patients with definitive leptomeningeal metastases * Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma * Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies * Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function * Current use of (other N-methyl D-aspartate \[NMDA\] antagonists) amantadine, ketamine, or dextromethorphan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Neurocognitive Failure | From randomization to last follow-up. Maximum follow-up was 15.6 months. | Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline using the reliable change index (RCI) on at least one of the following assessments or parts of : Hopkins Verbal Learning Test - Revised (HVLT-R), Trail Making Test (TMT), or Controlled Oral Word Association (COWA). The HVLT-R has 3 parts that were analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition. The TMT has 2 parts that were analyzed separately: Part A and Part B. Neurocognitive failure rate is estimated using the cumulative incidence method. Analysis was planned to occur after 233 events were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.Analysis was planned to occur after 233 events were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | Baseline, 2, 4, 6, and 12 months | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Cognitive Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed. |
| Change in EQ-5D-5L VAS Score at 12 Months | Baseline and 12 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here. |
| Intracranial Progression-Free Survival | From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months. | Intracranial progression-free survival time is defined as time from registration/randomization to the date of progression in the brain or death from any cause. Intracranial progression-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided. |
| Overall Survival | From randomization to last follow-up. Maximum follow-up was 15.6 months. | Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided. |
| Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment | From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months. | . Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. |
| Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Scores are standardized, adjusting for age, education, gender as needed, so that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). A lower score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | Baseline, 2, 4, 6, and 12 months | The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score. |
| Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | Baseline, 2, 4, 6, and 12 months | Clinical Trial Battery Composite score is the arithmetic mean of the HVLT-R (Free Recall, Delayed Recall, Delayed Recognition), TMTA, TMTB, and COWA scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.Change is calculated as baseline score subtracted from post-baseline score. |
| Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | Baseline, 2, 4, 6, and 12 months | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items, given that a specified minimum numbers of items were completed. |
| Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | Baseline, 2, 4, 6, and 12 months | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Interference) is the average of the subscale items, given that a specified minimum numbers of items were completed. |
| Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | Baseline, 2, 4, 6, and 12 months | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Neurologic Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed. |
| Change in EQ-5D-5L Index Score at 2 Months | Baseline and 2 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here. |
| Change in EQ-5D-5L Index Score at 4 Months | Baseline and 4 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here. |
| Change in EQ-5D-5L Index Score at 6 Months | Baseline and 6 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here. |
| Change in EQ-5D-5L Index Score at 12 Months | Baseline and 12 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here. |
| Change in EQ-5D-5L VAS Score at 2 Months | Baseline and 2 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here. |
| Change in EQ-5D-5L VAS Score at 4 Months | Baseline and 4 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here. |
| Change in EQ-5D-5L VAS Score at 6 Months | Baseline and 6 months | The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effect of White Matter Injury and Hippocampal Volume on Neurocognitive Function | Up to 12 months | Evaluated through MRI scans using physician-contoured and auto-contoured scores. Concordance rates will be assessed using Kappa statistics. The auto-contoured scores will be used for the remaining analyses due to the number of physicians reviewing the scans. White matter injury is measured by FLAIR volume change and is a continuous variable. Hippocampal volume is measured as a continuous variable also and both will be covariates considered in the Cox proportional hazards model to assess the impact on time to neurocognitive failure and the longitudinal modeling of neurocognitive function. |
| MDASI-BT Mood Variables | Up to 12 months | The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed. |
| Effect of Radiation Therapy Oncology Group (RTOG) RPA and the Diagnosis-specific Graded Prognostic Assessment (DSGPA) on Neurocognitive Function | Up to 12 months | Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be correlated with both the RTOG RPA and the DS-GPA classification systems. Baseline neurocognitive function for each test will be compared between both RPA classes using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data. |
| Anxiety/Depression Measured Using the EQ-5D-5L | Up to 12 months | An exploratory analysis, beginning with correlation coefficients, will be used to assess the association of symptom burden and anxiety/depression with neurocognitive function at each time point. The symptom burden items of interest are the distressed (upset), sad, and mood items. From the EQ-5D-5L, the depression/anxiety item will be of interest. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Registered patients who completed required baseline neurocognitive assessments were randomized. Of 561 registered patients, 518 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| WBRT + Memantine Whole brain radiation therapy (WBRT) and memantine | 257 |
| HA-WBRT + Memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine | 261 |
| Total | 518 |
Baseline characteristics
| Characteristic | HA-WBRT + Memantine | WBRT + Memantine | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 61 years | 61.5 years |
| Education Bachelor's Degree | 38 Participants | 43 Participants | 81 Participants |
| Education Doctoral degree or professional degree | 8 Participants | 5 Participants | 13 Participants |
| Education Grade school | 5 Participants | 9 Participants | 14 Participants |
| Education High school graduate (including equivalency) | 85 Participants | 86 Participants | 171 Participants |
| Education Master's Degree | 22 Participants | 17 Participants | 39 Participants |
| Education No formal education | 1 Participants | 1 Participants | 2 Participants |
| Education Not high education graduate | 22 Participants | 15 Participants | 37 Participants |
| Education Not reported | 9 Participants | 13 Participants | 22 Participants |
| Education Some college or associate degree | 71 Participants | 68 Participants | 139 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 229 Participants | 231 Participants | 460 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 21 Participants | 44 Participants |
| Karnofsky Performance Status 100 | 47 Participants | 34 Participants | 81 Participants |
| Karnofsky Performance Status 70 | 48 Participants | 53 Participants | 101 Participants |
| Karnofsky Performance Status 80 | 81 Participants | 75 Participants | 156 Participants |
| Karnofsky Performance Status 90 | 85 Participants | 95 Participants | 180 Participants |
| Metastases Brain | 98 Participants | 98 Participants | 196 Participants |
| Metastases Brain and Other Sites | 163 Participants | 159 Participants | 322 Participants |
| Neurologic Function Status Minor neurologic symptoms, FA without assistance | 92 Participants | 86 Participants | 178 Participants |
| Neurologic Function Status Moderate NS, FA but requires assistance | 24 Participants | 27 Participants | 51 Participants |
| Neurologic Function Status Moderate NS, less than FA and requires assistance | 18 Participants | 15 Participants | 33 Participants |
| Neurologic Function Status No neurologic symptoms, FA without assistance | 113 Participants | 119 Participants | 232 Participants |
| Neurologic Function Status Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Neurologic Function Status Unknown | 13 Participants | 9 Participants | 22 Participants |
| Primary tumor Analcanal | 1 Participants | 2 Participants | 3 Participants |
| Primary tumor Bone | 1 Participants | 1 Participants | 2 Participants |
| Primary tumor Breast | 51 Participants | 45 Participants | 96 Participants |
| Primary tumor Colon | 4 Participants | 6 Participants | 10 Participants |
| Primary tumor Esophagus | 6 Participants | 7 Participants | 13 Participants |
| Primary tumor Gastroesophageal Junction | 1 Participants | 1 Participants | 2 Participants |
| Primary tumor Kidney | 5 Participants | 8 Participants | 13 Participants |
| Primary tumor Lung | 156 Participants | 151 Participants | 307 Participants |
| Primary tumor Other | 17 Participants | 25 Participants | 42 Participants |
| Primary tumor Ovary | 3 Participants | 3 Participants | 6 Participants |
| Primary tumor Pancreas | 1 Participants | 1 Participants | 2 Participants |
| Primary tumor Skin | 15 Participants | 7 Participants | 22 Participants |
| Prior Radiosurgery No | 200 Participants | 197 Participants | 397 Participants |
| Prior Radiosurgery Yes | 61 Participants | 60 Participants | 121 Participants |
| Prior Surgical Resection No | 198 Participants | 189 Participants | 387 Participants |
| Prior Surgical Resection Yes | 63 Participants | 68 Participants | 131 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 23 Participants | 52 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 | 22 Participants | 23 Participants | 45 Participants |
| Race (NIH/OMB) White | 205 Participants | 206 Participants | 411 Participants |
| Recursive Partitioning Analysis (RPA) Class Class I | 33 Participants | 38 Participants | 71 Participants |
| Recursive Partitioning Analysis (RPA) Class Class II | 228 Participants | 219 Participants | 447 Participants |
| Sex: Female, Male Female | 150 Participants | 149 Participants | 299 Participants |
| Sex: Female, Male Male | 111 Participants | 108 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 138 / 232 | 135 / 223 |
| other Total, other adverse events | 214 / 232 | 201 / 223 |
| serious Total, serious adverse events | 98 / 232 | 106 / 223 |
Outcome results
Primary
Time to Neurocognitive Failure
Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline using the reliable change index (RCI) on at least one of the following assessments or parts of : Hopkins Verbal Learning Test - Revised (HVLT-R), Trail Making Test (TMT), or Controlled Oral Word Association (COWA). The HVLT-R has 3 parts that were analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition. The TMT has 2 parts that were analyzed separately: Part A and Part B. Neurocognitive failure rate is estimated using the cumulative incidence method. Analysis was planned to occur after 233 events were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.Analysis was planned to occur after 233 events were reported.
Time frame: From randomization to last follow-up. Maximum follow-up was 15.6 months.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WBRT + Memantine | Time to Neurocognitive Failure | 68.2 percentage of participants |
| HA-WBRT + Memantine | Time to Neurocognitive Failure | 59.3 percentage of participants |
Comparison: Null hypothesis: the addition of HA-WBRT as compared to WBRT will increase time to neurocognitive failure from 53.8% in the WBRT arm to 42.8% in the HA-WBRT arm at 6 months. Treating death as a competing risk and using a Gray's test with two-sided α=0.05 to test for statistically significant difference in the distribution of neurocognitive failure times, it was calculated that 230 events over both arms would provide 90% statistical power.p-value: 0.02995% CI: [0.59, 0.96]Gray's test
Secondary
Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline]
Clinical Trial Battery Composite score is the arithmetic mean of the HVLT-R (Free Recall, Delayed Recall, Delayed Recognition), TMTA, TMTB, and COWA scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with standardized score at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 2 months | -1.09 units on a scale | Standard Deviation 3.45 |
| WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 4 months | -0.81 units on a scale | Standard Deviation 3.22 |
| WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 6 months | -0.44 units on a scale | Standard Deviation 1.71 |
| WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 12 months | -0.98 units on a scale | Standard Deviation 2.51 |
| HA-WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 12 months | -0.61 units on a scale | Standard Deviation 2 |
| HA-WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 2 months | -0.87 units on a scale | Standard Deviation 2.35 |
| HA-WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 6 months | -0.21 units on a scale | Standard Deviation 1.65 |
| HA-WBRT + Memantine | Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] | 4 months | -0.27 units on a scale | Standard Deviation 1.66 |
Comparison: A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.2552Mixed Models Analysis
Comparison: A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline composite score is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline)
The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with standardized score at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 2 months | -0.28 units on a scale | Standard Deviation 0.96 |
| WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 4 months | -0.06 units on a scale | Standard Deviation 0.98 |
| WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 6 months | -0.15 units on a scale | Standard Deviation 0.87 |
| WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 12 months | -0.44 units on a scale | Standard Deviation 1.71 |
| HA-WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 12 months | -0.21 units on a scale | Standard Deviation 1.65 |
| HA-WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 2 months | -0.29 units on a scale | Standard Deviation 1.04 |
| HA-WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 6 months | -0.11 units on a scale | Standard Deviation 1.04 |
| HA-WBRT + Memantine | Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) | 4 months | -0.08 units on a scale | Standard Deviation 0.99 |
Comparison: A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline COWA is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.9749Mixed Models Analysis
Comparison: A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here. is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline)
The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with standardized score at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 4 months | -0.88 units on a scale | Standard Deviation 1.61 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 12 months | -0.89 units on a scale | Standard Deviation 1.65 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 6 months | -0.54 units on a scale | Standard Deviation 1.55 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 2 months | -0.75 units on a scale | Standard Deviation 1.51 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 12 months | -0.87 units on a scale | Standard Deviation 1.71 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 2 months | -0.73 units on a scale | Standard Deviation 1.53 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 4 months | -0.68 units on a scale | Standard Deviation 1.44 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) | 6 months | -0.30 units on a scale | Standard Deviation 1.31 |
Comparison: A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.2656Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: 0.0067Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Delayed Recall is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline)
The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 4 months | -0.11 units on a scale | Standard Deviation 1.98 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 12 months | -0.48 units on a scale | Standard Deviation 2.12 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 6 months | -0.55 units on a scale | Standard Deviation 1.83 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 2 months | -0.69 units on a scale | Standard Deviation 1.9 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 12 months | -0.30 units on a scale | Standard Deviation 1.65 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 4 months | -0.12 units on a scale | Standard Deviation 1.41 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 6 months | -0.06 units on a scale | Standard Deviation 1.4 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) | 2 months | -0.70 units on a scale | Standard Deviation 1.88 |
Comparison: A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.0993Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Delayed Recognition is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline)
The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with standardized score at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 2 months | -0.63 units on a scale | Standard Deviation 1.25 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 6 months | -0.34 units on a scale | Standard Deviation 1.33 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 12 months | -0.55 units on a scale | Standard Deviation 1.52 |
| WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 4 months | -0.68 units on a scale | Standard Deviation 1.29 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 6 months | -0.06 units on a scale | Standard Deviation 1.14 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 2 months | -0.47 units on a scale | Standard Deviation 1.21 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 4 months | -0.36 units on a scale | Standard Deviation 1.16 |
| HA-WBRT + Memantine | Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) | 12 months | -0.34 units on a scale | Standard Deviation 1.34 |
Comparison: A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.0586Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\>61 year vs. \<= 61 years) is reported here.p-value: 0.0048Mixed Models Analysis
Comparison: A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Total Recall is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline)
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Scores are standardized, adjusting for age, education, gender as needed, so that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with standardized score at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 2 months | -1.42 units on a scale | Standard Deviation 6.27 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 6 months | -2.09 units on a scale | Standard Deviation 13.02 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 12 months | -1.28 units on a scale | Standard Deviation 5.1 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 4 months | -0.28 units on a scale | Standard Deviation 2.42 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 6 months | 0.17 units on a scale | Standard Deviation 2.19 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 2 months | -1.31 units on a scale | Standard Deviation 5.47 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 4 months | 0.03 units on a scale | Standard Deviation 2.8 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) | 12 months | -0.70 units on a scale | Standard Deviation 3.1 |
Comparison: A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.5988Mixed Models Analysis
Comparison: A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: 0.0005Mixed Models Analysis
Comparison: A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline TMT Part A is reported here.p-value: <0.0001McNemar
Secondary
Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline)
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). A lower score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 2 months | -2.86 units on a scale | Standard Deviation 16.6 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 4 months | -3.38 units on a scale | Standard Deviation 17.88 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 6 months | -0.47 units on a scale | Standard Deviation 7.78 |
| WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 12 months | -2.49 units on a scale | Standard Deviation 8.18 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 12 months | -1.44 units on a scale | Standard Deviation 6.59 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 2 months | -2.27 units on a scale | Standard Deviation 9.91 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 6 months | -1.06 units on a scale | Standard Deviation 6.55 |
| HA-WBRT + Memantine | Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) | 4 months | -0.89 units on a scale | Standard Deviation 6.14 |
Comparison: A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.9226Mixed Models Analysis
Comparison: A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: <0.0024Mixed Models Analysis
Comparison: A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline TMT Part B is reported here.p-value: <0.0001Regression, Cox
Secondary
Change in EQ-5D-5L Index Score at 12 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
Time frame: Baseline and 12 months
Population: Participants with baseline and 12-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L Index Score at 12 Months | -0.03 score on a scale | Standard Deviation 0.17 |
| HA-WBRT + Memantine | Change in EQ-5D-5L Index Score at 12 Months | -0.01 score on a scale | Standard Deviation 0.14 |
p-value: 0.66t-test, 2 sided
Secondary
Change in EQ-5D-5L Index Score at 2 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
Time frame: Baseline and 2 months
Population: Participants with baseline and 2-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L Index Score at 2 Months | -0.04 score on a scale | Standard Deviation 0.17 |
| HA-WBRT + Memantine | Change in EQ-5D-5L Index Score at 2 Months | -0.05 score on a scale | Standard Deviation 0.16 |
p-value: 0.86t-test, 2 sided
Secondary
Change in EQ-5D-5L Index Score at 4 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
Time frame: Baseline and 4 months
Population: Participants with baseline and 4-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L Index Score at 4 Months | -0.03 score on a scale | Standard Deviation 0.17 |
| HA-WBRT + Memantine | Change in EQ-5D-5L Index Score at 4 Months | -0.03 score on a scale | Standard Deviation 0.16 |
Secondary
Change in EQ-5D-5L Index Score at 6 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
Time frame: Baseline and 6 months
Population: Participants with baseline and 4-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L Index Score at 6 Months | -0.03 score on a scale | Standard Deviation 0.14 |
| HA-WBRT + Memantine | Change in EQ-5D-5L Index Score at 6 Months | -0.03 score on a scale | Standard Deviation 0.17 |
p-value: 0.95t-test, 2 sided
Secondary
Change in EQ-5D-5L VAS Score at 12 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
Time frame: Baseline and 12 months
Population: Participants with baseline and 6-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L VAS Score at 12 Months | 2.86 score on a scale | Standard Deviation 19.6 |
| HA-WBRT + Memantine | Change in EQ-5D-5L VAS Score at 12 Months | 2.42 score on a scale | Standard Deviation 23.37 |
p-value: 0.92t-test, 2 sided
Secondary
Change in EQ-5D-5L VAS Score at 2 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
Time frame: Baseline and 2 months
Population: Participants with baseline and 2-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L VAS Score at 2 Months | -5.64 score on a scale | Standard Deviation 24.67 |
| HA-WBRT + Memantine | Change in EQ-5D-5L VAS Score at 2 Months | -1.41 score on a scale | Standard Deviation 25.79 |
p-value: 0.18t-test, 2 sided
Secondary
Change in EQ-5D-5L VAS Score at 4 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
Time frame: Baseline and 4 months
Population: Participants with baseline and 4-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L VAS Score at 4 Months | -1.35 score on a scale | Standard Deviation 23.14 |
| HA-WBRT + Memantine | Change in EQ-5D-5L VAS Score at 4 Months | -2.98 score on a scale | Standard Deviation 25.71 |
p-value: 0.64t-test, 2 sided
Secondary
Change in EQ-5D-5L VAS Score at 6 Months
The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
Time frame: Baseline and 6 months
Population: Participants with baseline and 6-month scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| WBRT + Memantine | Change in EQ-5D-5L VAS Score at 6 Months | 3.97 score on a scale | Standard Deviation 25.33 |
| HA-WBRT + Memantine | Change in EQ-5D-5L VAS Score at 6 Months | 3.49 score on a scale | Standard Deviation 22.9 |
p-value: 0.91t-test, 2 sided
Secondary
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Cognitive Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 12 months | 1.04 score on a scale | Standard Deviation 2.33 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 2 months | 0.45 score on a scale | Standard Deviation 1.81 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 4 months | 0.52 score on a scale | Standard Deviation 1.64 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 6 months | 0.57 score on a scale | Standard Deviation 2.61 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 6 months | 0.01 score on a scale | Standard Deviation 2.72 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 12 months | 0.50 score on a scale | Standard Deviation 1.69 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 4 months | 0.32 score on a scale | Standard Deviation 1.78 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score | 2 months | 0.50 score on a scale | Standard Deviation 1.95 |
Comparison: A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.1964Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline cognitive factor score is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Prior radiotherapy (yes vs. no) is reported here.p-value: 0.0032Mixed Models Analysis
Secondary
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Interference) is the average of the subscale items, given that a specified minimum numbers of items were completed.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 4 months | 0.35 score on a scale | Standard Deviation 2.57 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 6 months | 0.57 score on a scale | Standard Deviation 2.61 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 2 months | 0.84 score on a scale | Standard Deviation 2.45 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 12 months | 0.64 score on a scale | Standard Deviation 2.86 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 12 months | 0.14 score on a scale | Standard Deviation 3 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 4 months | 0.51 score on a scale | Standard Deviation 2.6 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 2 months | 1.09 score on a scale | Standard Deviation 2.79 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score | 6 months | 0.01 score on a scale | Standard Deviation 2.72 |
Comparison: A mixed effects model was run with MDASI-BT Interference Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.9118Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Interference Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline interference score is reported here.p-value: <0.0001Mixed Models Analysis
Secondary
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the 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 (best condition) to 10 (worst condition). A subscale score (Neurologic Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 2 months | 0.17 score on a scale | Standard Deviation 1.91 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 4 months | 0.13 score on a scale | Standard Deviation 2.06 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 6 months | 0.23 score on a scale | Standard Deviation 1.89 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 12 months | 0.60 score on a scale | Standard Deviation 2.2 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 12 months | 0.40 score on a scale | Standard Deviation 2.53 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 2 months | 0.28 score on a scale | Standard Deviation 2.31 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 6 months | 0.15 score on a scale | Standard Deviation 2.11 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score | 4 months | 0.24 score on a scale | Standard Deviation 1.97 |
Comparison: A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.8877Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline neurologic factor is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Age (\> 61 years vs. \<= 61 years) is reported here.p-value: 0.0078Mixed Models Analysis
Secondary
Change in M. D. Anderson Symptom Inventory Brain Tumor (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 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 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items, given that a specified minimum numbers of items were completed.
Time frame: Baseline, 2, 4, 6, and 12 months
Population: Participants with baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 2 months | 0.48 score on a scale | Standard Deviation 1.39 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 4 months | 0.29 score on a scale | Standard Deviation 1.5 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 6 months | 0.24 score on a scale | Standard Deviation 1.49 |
| WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 12 months | 0.53 score on a scale | Standard Deviation 1.69 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 12 months | 0.09 score on a scale | Standard Deviation 1.47 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 2 months | 0.61 score on a scale | Standard Deviation 1.62 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 6 months | -0.09 score on a scale | Standard Deviation 1.34 |
| HA-WBRT + Memantine | Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | 4 months | 0.36 score on a scale | Standard Deviation 1.46 |
Comparison: A mixed effects model was run with MDASI-BT Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.p-value: 0.57Mixed Models Analysis
Comparison: A mixed effects model was run with MDASI-BT Symptom Severity score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment\*time, time\*time, time\*time\*time and remained if p\<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline symptom severity is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A two-sample t-test with a 2-sided type I error of 0.05 provides \>90% statistical power to detect a medium effect size of 0.5 for a comparison of the change from baseline to 6 months from the start of treatment. The comparison at six months was tested within a mixed effects model with covariates age, RPA class, prior radiosurgery, prior surgical resection, baseline score, treatment arm, and time was used.p-value: 0.083Mixed Models Analysis
Secondary
Intracranial Progression-Free Survival
Intracranial progression-free survival time is defined as time from registration/randomization to the date of progression in the brain or death from any cause. Intracranial progression-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.
Time frame: From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WBRT + Memantine | Intracranial Progression-Free Survival | 43.9 percentage of participants |
| HA-WBRT + Memantine | Intracranial Progression-Free Survival | 44.8 percentage of participants |
p-value: 0.07695% CI: [0.98, 1.47]Log Rank
Secondary
Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment
. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
Time frame: From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.
Population: Randomized participants who started protocol treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| WBRT + Memantine | Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment | 144 Participants |
| HA-WBRT + Memantine | Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment | 131 Participants |
p-value: 0.47Chi-squared
Secondary
Overall Survival
Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.
Time frame: From randomization to last follow-up. Maximum follow-up was 15.6 months.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WBRT + Memantine | Overall Survival | 54.9 percentage of participants |
| HA-WBRT + Memantine | Overall Survival | 50.6 percentage of participants |
p-value: 0.24295% CI: [0.91, 1.43]Log Rank
Other Pre-specified
Anxiety/Depression Measured Using the EQ-5D-5L
An exploratory analysis, beginning with correlation coefficients, will be used to assess the association of symptom burden and anxiety/depression with neurocognitive function at each time point. The symptom burden items of interest are the distressed (upset), sad, and mood items. From the EQ-5D-5L, the depression/anxiety item will be of interest.
Time frame: Up to 12 months
Other Pre-specified
Effect of Radiation Therapy Oncology Group (RTOG) RPA and the Diagnosis-specific Graded Prognostic Assessment (DSGPA) on Neurocognitive Function
Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be correlated with both the RTOG RPA and the DS-GPA classification systems. Baseline neurocognitive function for each test will be compared between both RPA classes using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
Time frame: Up to 12 months
Other Pre-specified
Effect of White Matter Injury and Hippocampal Volume on Neurocognitive Function
Evaluated through MRI scans using physician-contoured and auto-contoured scores. Concordance rates will be assessed using Kappa statistics. The auto-contoured scores will be used for the remaining analyses due to the number of physicians reviewing the scans. White matter injury is measured by FLAIR volume change and is a continuous variable. Hippocampal volume is measured as a continuous variable also and both will be covariates considered in the Cox proportional hazards model to assess the impact on time to neurocognitive failure and the longitudinal modeling of neurocognitive function.
Time frame: Up to 12 months
Other Pre-specified
MDASI-BT Mood Variables
The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed.
Time frame: Up to 12 months