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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02360215
Other study ID # NRG-CC001
Secondary ID NCI-2015-00030NR
Status Completed
Phase Phase 3
First received
Last updated
Start date July 2015
Est. completion date August 26, 2019

Study information

Verified date February 2020
Source NRG Oncology
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 518
Est. completion date August 26, 2019
Est. primary completion date April 30, 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Radiation:
Whole 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.
Drug:
Memantine
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.
Radiation:
Whole brain radiation therapy
Whole brain radiation therapy (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks

Locations

Country Name City State
Canada CHUM - Centre Hospitalier de l'Universite de Montreal Montreal Quebec
Canada CHUM - Hopital Notre-Dame Montreal Quebec
Canada McGill University Department of Oncology Montreal Quebec
Canada The Research Institute of the McGill University Health Centre (MUHC) Montreal Quebec
Canada CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ) Quebec City Quebec
Canada Allan Blair Cancer Centre Regina Saskatchewan
Canada Saskatoon Cancer Centre Saskatoon Saskatchewan
Canada Centre Hospitalier Universitaire de Sherbrooke-Fleurimont Sherbrooke Quebec
United States Abington Memorial Hospital Abington Pennsylvania
United States Cleveland Clinic Akron General Akron Ohio
United States Summa Akron City Hospital/Cooper Cancer Center Akron Ohio
United States Mayo Clinic Health System in Albert Lea Albert Lea Minnesota
United States Saint Joseph Mercy Hospital Ann Arbor Michigan
United States Langlade Hospital and Cancer Center Antigo Wisconsin
United States Emory Saint Joseph's Hospital Atlanta Georgia
United States Emory University Hospital Midtown Atlanta Georgia
United States Emory University Hospital/Winship Cancer Institute Atlanta Georgia
United States Grady Health System Atlanta Georgia
United States Piedmont Hospital Atlanta Georgia
United States MedStar Union Memorial Hospital Baltimore Maryland
United States University of Maryland/Greenebaum Cancer Center Baltimore Maryland
United States McLaren Cancer Institute-Bay City Bay City Michigan
United States UM Upper Chesapeake Medical Center Bel Air Maryland
United States Billings Clinic Cancer Center Billings Montana
United States Sanford Bismarck Medical Center Bismarck North Dakota
United States Boca Raton Regional Hospital Boca Raton Florida
United States Saint Alphonsus Cancer Care Center-Boise Boise Idaho
United States Saint Luke's Mountain States Tumor Institute Boise Idaho
United States Tufts Medical Center Boston Massachusetts
United States Rocky Mountain Cancer Centers-Boulder Boulder Colorado
United States Saint Vincent's Medical Center Bridgeport Connecticut
United States Montefiore Medical Center - Moses Campus Bronx New York
United States New York-Presbyterian/Brooklyn Methodist Hospital Brooklyn New York
United States Crozer-Keystone Regional Cancer Center at Broomall Broomall Pennsylvania
United States Henry Ford Cancer Institute-Downriver Brownstown Michigan
United States Bryn Mawr Hospital Bryn Mawr Pennsylvania
United States Providence Saint Joseph Medical Center/Disney Family Cancer Center Burbank California
United States Lahey Hospital and Medical Center Burlington Massachusetts
United States Saint Francis Medical Center Cape Girardeau Missouri
United States Mercy San Juan Medical Center Carmichael California
United States SIH Cancer Institute Carterville Illinois
United States Saint Luke's Hospital Cedar Rapids Iowa
United States Christiana Care Health System-Concord Health Center Chadds Ford Pennsylvania
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Saint Joseph Mercy Chelsea Chelsea Michigan
United States John H Stroger Jr Hospital of Cook County Chicago Illinois
United States Northwestern University Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States 21st Century Oncology MHP - Clarkston Clarkston Michigan
United States McLaren Cancer Institute-Clarkston Clarkston Michigan
United States Case Western Reserve University Cleveland Ohio
United States Cleveland Clinic Cancer Center/Fairview Hospital Cleveland Ohio
United States Cleveland Clinic Foundation Cleveland Ohio
United States Henry Ford Macomb Hospital-Clinton Township Clinton Township Michigan
United States Penrose-Saint Francis Healthcare Colorado Springs Colorado
United States UCHealth Memorial Hospital Central Colorado Springs Colorado
United States Central Maryland Radiation Oncology in Howard County Columbia Maryland
United States Ohio State University Comprehensive Cancer Center Columbus Ohio
United States UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida
United States Siteman Cancer Center at West County Hospital Creve Coeur Missouri
United States Geisinger Medical Center Danville Pennsylvania
United States Decatur Memorial Hospital Decatur Illinois
United States UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida
United States Henry Ford Hospital Detroit Michigan
United States Wayne State University/Karmanos Cancer Institute Detroit Michigan
United States Wentworth-Douglass Hospital Dover New Hampshire
United States City of Hope Comprehensive Cancer Center Duarte California
United States Northeast Radiation Oncology Center Dunmore Pennsylvania
United States Mayo Clinic Health System-Eau Claire Clinic Eau Claire Wisconsin
United States Crossroads Cancer Center Effingham Illinois
United States Swedish Medical Center Englewood Colorado
United States Sanford Roger Maris Cancer Center Fargo North Dakota
United States 21st Century Oncology MHP - Farmington Farmington Hills Michigan
United States Genesys Hurley Cancer Institute Flint Michigan
United States McLaren Cancer Institute-Flint Flint Michigan
United States Parkview Hospital Randallia Fort Wayne Indiana
United States Unity Hospital Fridley Minnesota
United States University of Texas Medical Branch Galveston Texas
United States Northwestern Medicine Cancer Center Delnor Geneva Illinois
United States Banner MD Anderson Cancer Center Gilbert Arizona
United States UM Baltimore Washington Medical Center/Tate Cancer Center Glen Burnie Maryland
United States Crozer Regional Cancer Center at Brinton Lake Glen Mills Pennsylvania
United States Aurora Cancer Care-Grafton Grafton Wisconsin
United States Spectrum Health at Butterworth Campus Grand Rapids Michigan
United States Benefis Healthcare- Sletten Cancer Institute Great Falls Montana
United States Aurora BayCare Medical Center Green Bay Wisconsin
United States Greenville Health System Cancer Institute-Eastside Greenville South Carolina
United States Greenville Health System Cancer Institute-Faris Greenville South Carolina
United States Self Regional Healthcare Greenwood South Carolina
United States Legacy Mount Hood Medical Center Gresham Oregon
United States The Radiation Oncology Center-Hilton Head/Bluffton Hilton Head Island South Carolina
United States Edward Hines Jr VA Hospital Hines Illinois
United States M D Anderson Cancer Center Houston Texas
United States Cleveland Clinic Cancer Center Independence Independence Ohio
United States Community Cancer Center East Indianapolis Indiana
United States Community Cancer Center North Indianapolis Indiana
United States Community Cancer Center South Indianapolis Indiana
United States UW Cancer Center Johnson Creek Johnson Creek Wisconsin
United States West Michigan Cancer Center Kalamazoo Michigan
United States North Kansas City Hospital Kansas City Missouri
United States University of Kansas Cancer Center Kansas City Kansas
United States Aurora Cancer Care-Kenosha South Kenosha Wisconsin
United States Gundersen Lutheran Medical Center La Crosse Wisconsin
United States Mayo Clinic Health System-Franciscan Healthcare La Crosse Wisconsin
United States UC San Diego Moores Cancer Center La Jolla California
United States McLaren Cancer Institute-Lapeer Region Lapeer Michigan
United States Lawrence Memorial Hospital Lawrence Kansas
United States UTMB Cancer Center at Victory Lakes League City Texas
United States Dartmouth Hitchcock Medical Center Lebanon New Hampshire
United States University of Kentucky/Markey Cancer Center Lexington Kentucky
United States Condell Memorial Hospital Libertyville Illinois
United States Saint Mary Mercy Hospital Livonia Michigan
United States Kaiser Permanente Los Angeles Medical Center Los Angeles California
United States Los Angeles County-USC Medical Center Los Angeles California
United States USC / Norris Comprehensive Cancer Center Los Angeles California
United States Lowell General Hospital Lowell Massachusetts
United States University of Wisconsin Hospital and Clinics Madison Wisconsin
United States Mayo Clinic Health Systems-Mankato Mankato Minnesota
United States Loyola University Medical Center Maywood Illinois
United States Riddle Memorial Hospital Media Pennsylvania
United States Community Memorial Hospital Menomonee Falls Wisconsin
United States Saint Luke's Mountain States Tumor Institute - Meridian Meridian Idaho
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States UH Seidman Cancer Center at Southwest General Hospital Middleburg Heights Ohio
United States Ascension Columbia Saint Mary's Water Tower Medical Commons Milwaukee Wisconsin
United States Aurora Saint Luke's Medical Center Milwaukee Wisconsin
United States Aurora Sinai Medical Center Milwaukee Wisconsin
United States Medical College of Wisconsin Milwaukee Wisconsin
United States Zablocki Veterans Administration Medical Center Milwaukee Wisconsin
United States Abbott-Northwestern Hospital Minneapolis Minnesota
United States Community Medical Hospital Missoula Montana
United States West Virginia University Healthcare Morgantown West Virginia
United States McLaren Cancer Institute-Macomb Mount Clemens Michigan
United States McLaren Cancer Institute-Central Michigan Mount Pleasant Michigan
United States Mercy Health Mercy Campus Muskegon Michigan
United States Saint Luke's Mountain States Tumor Institute - Nampa Nampa Idaho
United States Vanderbilt University/Ingram Cancer Center Nashville Tennessee
United States Tulane University Health Sciences Center New Orleans Louisiana
United States NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York
United States Christiana Care Health System-Christiana Hospital Newark Delaware
United States Helen F Graham Cancer Center Newark Delaware
United States Mayo Clinic Radiation Therapy-Northfield Northfield Minnesota
United States Kaiser Permanente Oakland-Broadway Oakland California
United States Ogden Regional Medical Center Ogden Utah
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States University of Nebraska Medical Center Omaha Nebraska
United States UF Cancer Center at Orlando Health Orlando Florida
United States Vince Lombardi Cancer Clinic - Oshkosh Oshkosh Wisconsin
United States University of Kansas Cancer Center-Overland Park Overland Park Kansas
United States McLaren Cancer Institute-Owosso Owosso Michigan
United States Stanford Cancer Institute Palo Alto Palo Alto California
United States University Hospitals Parma Medical Center Parma Ohio
United States Methodist Medical Center of Illinois Peoria Illinois
United States OSF Saint Francis Medical Center Peoria Illinois
United States McLaren Cancer Institute-Northern Michigan Petoskey Michigan
United States Aria Health-Torresdale Campus Philadelphia Pennsylvania
United States Fox Chase Cancer Center Philadelphia Pennsylvania
United States Temple University Hospital Philadelphia Pennsylvania
United States Thomas Jefferson University Hospital Philadelphia Pennsylvania
United States Saint Joseph Mercy Oakland Pontiac Michigan
United States McLaren-Port Huron Port Huron Michigan
United States Legacy Good Samaritan Hospital and Medical Center Portland Oregon
United States Kaiser Permanente-Rancho Cordova Cancer Center Rancho Cordova California
United States Renown Regional Medical Center Reno Nevada
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Mayo Clinic Rochester Minnesota
United States University of Rochester Rochester New York
United States Rohnert Park Cancer Center Rohnert Park California
United States Sutter Cancer Centers Radiation Oncology Services-Roseville Roseville California
United States The Permanente Medical Group-Roseville Radiation Oncology Roseville California
United States Mercy Cancer Center - Sacramento Sacramento California
United States Sutter Medical Center Sacramento Sacramento California
United States Norris Cotton Cancer Center-North Saint Johnsbury Vermont
United States Lakeland Medical Center Saint Joseph Saint Joseph Michigan
United States Mercy Hospital Saint Louis Saint Louis Missouri
United States Missouri Baptist Medical Center Saint Louis Missouri
United States Siteman Cancer Center-South County Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Park Nicollet Clinic - Saint Louis Park Saint Louis Park Minnesota
United States Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri
United States Huntsman Cancer Institute/University of Utah Salt Lake City Utah
United States University of California San Diego San Diego California
United States California Pacific Medical Center-Pacific Campus San Francisco California
United States Stanford Cancer Center South Bay San Jose California
United States Kaiser Permanente Medical Center - Santa Clara Santa Clara California
United States Lewis Cancer and Research Pavilion at Saint Joseph's/Candler Savannah Georgia
United States Memorial Health University Medical Center Savannah Georgia
United States Virginia Mason Medical Center Seattle Washington
United States Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota
United States Kaiser Permanente Cancer Treatment Center South San Francisco California
United States Greenville Health System Cancer Institute-Spartanburg Spartanburg South Carolina
United States CoxHealth South Hospital Springfield Missouri
United States Memorial Medical Center Springfield Illinois
United States Marshfield Clinic Stevens Point Center Stevens Point Wisconsin
United States Cleveland Clinic Cancer Center Strongsville Strongsville Ohio
United States Aurora Medical Center in Summit Summit Wisconsin
United States UM Saint Joseph Medical Center Towson Maryland
United States 21st Century Oncology MHP - Troy Troy Michigan
United States Banner University Medical Center - Tucson Tucson Arizona
United States Lewis and Faye Manderson Cancer Center Tuscaloosa Alabama
United States Saint Luke's Mountain States Tumor Institute-Twin Falls Twin Falls Idaho
United States Vince Lombardi Cancer Clinic-Two Rivers Two Rivers Wisconsin
United States Carle Cancer Center Urbana Illinois
United States Sutter Solano Medical Center/Cancer Center Vallejo California
United States Northwestern Medicine Cancer Center Warrenville Warrenville Illinois
United States Aspirus Regional Cancer Center Wausau Wisconsin
United States Aurora West Allis Medical Center West Allis Wisconsin
United States Henry Ford West Bloomfield Hospital West Bloomfield Michigan
United States Reading Hospital West Reading Pennsylvania
United States UHHS-Westlake Medical Center Westlake Ohio
United States Cleveland Clinic-Weston Weston Florida
United States Diagnostic and Treatment Center Weston Wisconsin
United States Wheeling Hospital/Schiffler Cancer Center Wheeling West Virginia
United States Ascension Via Christi Hospitals Wichita Wichita Kansas
United States Wesley Medical Center Wichita Kansas
United States Geisinger Wyoming Valley/Henry Cancer Center Wilkes-Barre Pennsylvania
United States NHRMC Radiation Oncology - 16th Street Wilmington North Carolina
United States Aspirus UW Cancer Center Wisconsin Rapids Wisconsin
United States Lankenau Medical Center Wynnewood Pennsylvania
United States North Star Lodge Cancer Center at Yakima Valley Memorial Hospital Yakima Washington

Sponsors (2)

Lead Sponsor Collaborator
NRG Oncology National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, Bovi JA, Robinson C, Konski A, Khuntia D, Grosshans D, Benzinger TLS, Bruner D, Gilbert MR, Roberge D, Kundapur V, Devisetty K, Shah S, Usuki K, Anderson BM, Stea B, Yoon H, Li J, Laack NN, Kruse — View Citation

Outcome

Type Measure Description Time frame Safety issue
Other 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. Up to 12 months
Other 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. Up to 12 months
Other 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. Up to 12 months
Other MDASI-BT Mood Variables The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed. Up to 12 months
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. From randomization to last follow-up. Maximum follow-up was 15.6 months.
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline, 2, 4, 6, and 12 months
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. Baseline and 2 months
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. Baseline and 4 months
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. Baseline and 6 months
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. Baseline and 12 months
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. Baseline and 2 months
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. Baseline and 4 months
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. Baseline and 6 months
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. Baseline and 12 months
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. From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.
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. From randomization to last follow-up. Maximum follow-up was 15.6 months.
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. From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.
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