Testing if High Dose Radiation Only to the Sites of Brain Cancer Compared to Whole Brain Radiation That Avoids the Hippocampus is Better at Preventing Loss of Memory and Thinking Ability

Stage IV Lung Cancer AJCC v8 Clinical Trial

Official title:

Phase III Trial of Stereotactic Radiosurgery (SRS) Versus Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for 10 or Fewer Brain Metastases From Small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04804644
• Other study ID #: NRG-CC009
• Secondary ID: NCI-2020-11651NR
• Status: Recruiting
• Phase: Phase 3
• Start date: March 24, 2021
• Est. completion date: July 1, 2030

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial compares the effect of stereotactic radiosurgery to standard of care memantine and whole brain radiation therapy that avoids the hippocampus (the memory zone of the brain) for the treatment of small cell lung cancer that has spread to the brain. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Whole brain radiation therapy delivers a low dose of radiation to the entire brain including the normal brain tissue. Hippocampal avoidance during whole-brain radiation therapy (HA-WBRT) decreases the amount of radiation that is delivered to the hippocampus which is a brain structure that is important for memory. The drug, memantine, is also often given with whole brain radiotherapy because it may decrease the risk of side effects related to thinking and memory. Stereotactic radiosurgery may decrease side effects related to memory and thinking compared to standard of care HA-WBRT plus memantine.

Description:

PRIMARY OBJECTIVE: I. Determine whether stereotactic radiosurgery (SRS) relative to whole brain radiotherapy with hippocampal avoidance (HA-WBRT) plus memantine hydrochloride (memantine) for brain metastases from small cell lung cancer (SCLC) prevents cognitive function failure as measured by cognitive decline on a battery of tests: the Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, and the Trail Making Test (TMT). SECONDARY OBJECTIVES: I. Determine whether SRS relative to HA-WBRT plus memantine for brain metastases from SCLC preserves cognitive function as separately measured by the HVLT-R, COWA, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP). II. Assess perceived difficulties in cognitive abilities using Patient Reported Outcomes Measurement Information System (PROMIS) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. III. Assess symptom burden using the MD Anderson Symptom Inventory for brain tumor (MDASI-BT) after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. IV. Compare cumulative incidence of intracranial disease progression after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. V. Compare overall survival after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VI. Compare cumulative incidence of neurologic death after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VII. Compare the number of salvage procedures used to manage recurrent intracranial disease following SRS relative to HA-WBRT plus memantine for SCLC brain metastases. VIII. Compare adverse events between the treatment arms according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria. IX. Compare the risk of developing cerebral necrosis between SRS and HA-WBRT plus memantine in patients receiving concurrent immunotherapy. EXPLORATORY OBJECTIVES: I. Compare cumulative incidence of local brain recurrence, distant brain relapse, and leptomeningeal dissemination after SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. II. Compare the cost of brain-related therapies and quality-adjusted life years in patients who receive SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. III. Evaluate the time delay to salvage WBRT or HA-WBRT in patients enrolled on the SRS arm. IV. Evaluate whether a time delay for chemotherapy in patients receiving HA-WBRT plus memantine relative to SRS for brain metastases from SCLC has an effect on overall survival. V. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from SRS relative to HA-WBRT plus memantine for brain metastases from SCLC. VI. Evaluate the correlation between neurocognitive functioning and patient-reported outcomes. VII. Collect serum, plasma and imaging studies for future translational research analyses. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo SRS over 1 day (in some cases several days). ARM II: Patients undergo HA-WBRT once daily (QD) for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive memantine orally (PO) QD or twice daily (BID) for up to 24 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2-3 months for 1 year, and then every 6 months thereafter.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: July 1, 2030
• Est. primary completion date: July 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);
• Patients with de novo or recurrent small cell lung cancer are permitted.
• Ten or fewer brain metastases = 3 cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed = 21 days prior to study entry.
• Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.
• The total tumor volume must be 30 cm^3 or less. Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
• Brain metastases must be diagnosed on MRI, which will include the following

elements:

• REQUIRED MRI ELEMENTS
• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (Brain Volume Imaging) or 3D Fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm.
• Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged).
• A minimum of one axial T2 FLAIR (preferred) or T2 sequence is required. This can be acquired as a two dimensional (2D) or 3D image. If 2D, the images should be obtained in the axial plane.
• ADDITIONAL RECOMMENDATIONS
• Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence.
• Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1.
• Recommendation is that imaging be performed on a 3 Tesla (3T) MRI.
• Recommendation is that the study participants be scanned on the same MRI instrument at each time point.
• Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020.
• If additional sequences are obtained, total imaging time should not exceed 60 minutes.
• History/physical examination
• Age = 18
• Karnofsky performance status of = 70
• Creatinine clearance = 30 ml/min
• Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.
• Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.
• Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.
• Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.
• Patients may have had prior intracranial surgical resection. Patients must have completed prior intracranial surgical resection at least 14 days prior to registration.
• Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
• The patient must provide study-specific informed consent prior to study entry.
• Patients with impaired decision-making capacity are not permitted on study.
• ELIGIBILITY CRITERIA PRIOR TO STEP 2 REGISTRATION
• The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.
• NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.

Exclusion Criteria:

• Planned infusion of cytotoxic chemotherapy on the same day as SRS or HA-WBRT treatment. Patients may have had prior chemotherapy. Concurrent immunotherapy is permitted.
• Prior allergic reaction to memantine.
• Intractable seizures while on adequate anticonvulsant therapy; more than 1 seizure per month for the past 2 months.
• Patients with definitive leptomeningeal metastases.
• Known history of demyelinating disease such as multiple sclerosis.
• Contraindication to MR imaging such as implanted metal devices that are MRI-incompatible, allergy to MRI contrast that cannot be adequately addressed with pre-contrast medications, or foreign bodies that preclude MRI imaging. (Questions regarding MRI compatibility of implanted objects should be reviewed with the Radiology Department performing the MRI).
• Current use of (other N-methyl-D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan.
• Radiographic evidence of hydrocephalus or other architectural change of the ventricular system resulting in significant anatomic distortion of the hippocampus, including placement of external ventricular drain or ventriculoperitoneal shunt.
• Mild cases of hydrocephalus not resulting in significant anatomic distortion of the hippocampus are permitted.
• Prior radiotherapy to the brain, including SRS, WBRT, or prophylactic cranial irradiation (PCI).
• 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
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Small Cell
• Lung Neoplasms
• Metastatic Lung Small Cell Carcinoma
• Metastatic Malignant Neoplasm in the Brain
• Neoplasms
• Recurrent Lung Small Cell Carcinoma
• Small Cell Lung Carcinoma
• Stage IV Lung Cancer AJCC v8
• Stage IVA Lung Cancer AJCC v8
• Stage IVB Lung Cancer AJCC v8

Intervention

Drug:
• Memantine Hydrochloride
Given PO

Other:
• Neurocognitive Assessment
Ancillary studies

Radiation:
• Stereotactic Radiosurgery
Undergo SRS
• Whole-Brain Radiotherapy
Undergo HA-WBRT

Locations

Country	Name	City	State
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
United States	Saint Luke's Cancer Center - Allentown	Allentown	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
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	Northside Hospital	Atlanta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Boston Medical Center	Boston	Massachusetts
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Sands Cancer Center	Canandaigua	New York
United States	Northside Hospital-Cherokee	Canton	Georgia
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Caro Cancer Center	Caro	Michigan
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Chambersburg Hospital	Chambersburg	Pennsylvania
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Memorial Hospital North	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	Riverside Methodist Hospital	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	Northside Hospital-Forsyth	Cumming	Georgia
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Saint Luke's Hospital-Anderson Campus	Easton	Pennsylvania
United States	University of Maryland Shore Medical Center at Easton	Easton	Maryland
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Saint Vincent Hospital	Erie	Pennsylvania
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	McLeod Regional Medical Center	Florence	South Carolina
United States	Unity Hospital	Fridley	Minnesota
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Goshen Center for Cancer Care	Goshen	Indiana
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Smilow Cancer Hospital Care Center - Guilford	Guilford	Connecticut
United States	Freeman Health System	Joplin	Missouri
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Sechler Family Cancer Center	Lebanon	Pennsylvania
United States	Beebe Medical Center	Lewes	Delaware
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Northern Westchester Hospital	Mount Kisco	New York
United States	Smilow Cancer Center/Yale-New Haven Hospital	New Haven	Connecticut
United States	Yale University	New Haven	Connecticut
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	TidalHealth Richard A Henson Cancer Institute	Ocean Pines	Maryland
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio
United States	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Saint Luke's Hospital - Upper Bucks Campus	Quakertown	Pennsylvania
United States	Saint Luke's Hospital-Quakertown Campus	Quakertown	Pennsylvania
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	Wilmot Cancer Institute Radiation Oncology at Greece	Rochester	New York
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	TidalHealth Peninsula Regional	Salisbury	Maryland
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Saint Luke's Hospital - Monroe Campus	Stroudsburg	Pennsylvania
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	WellSpan Health-York Cancer Center	York	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time to local brain recurrence (in brain lesions present at trial enrollment and treated with either stereotactic radiosurgery [SRS] or hippocampal-avoidant whole brain radiotherapy [HA-WBRT])		10 years
Other	Time to incidence of distant brain relapses		10 years
Other	Time to leptomeningeal dissemination		10 years
Other	Time delay to salvage WBRT or HA-WBRT in patients on the SRS arm	Gray's test will be used to compare treatment arms (Gray 1988).	Baseline to first salvage treatment, assessed up to 10 years
Primary	Time to Neurocognitive Failure	Neurocognitive failure is the first failure, defined as neurocognitive decline (decline vs. no decline) using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R), Controlled Oral Word Association (COWA) test, or Trail Making Test (TMT) Parts A and B.	1 year
Secondary	Preservation of Neurocognitive Function	A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 year
Secondary	Perceived Difficulties in Cognition	Measured by Patient Reported Outcomes Measurement Information System (PROMIS). For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 year
Secondary	Symptom Burden	Measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT). Four subscales (symptom severity, symptom interference, neurologic factor, and cognitive factor score) as well as certain individual items (fatigue, neurologic factor items, and cognitive factor items) of the MDASI-BT will be analyzed. Mixed effects models will be used to assess changes of the four subscale scores (symptom severity, symptom interference, neurologic factor, and cognitive factor score) across time using all available data while adjusting for stratification variables and other baseline characteristics. For discrete time point analyses, the change from baseline to each follow-up time point, will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.	1 year
Secondary	Overall Survival	Will be estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested using the log rank test (Mantel 1966). The Cox proportional hazard model (Cox 1972) will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient specific risk factors such as number of brain metastases and its interaction with treatment, KPS, and time to salvage chemotherapy as a time varying covariate. A two-sided significance level of 0.05 will be used.	From the date of randomization to the date of death, or otherwise, the last follow-up date on which the patient was reported alive, assessed up to 10 years
Secondary	Time to Neurologic Death	Gray's test will be used to assess between treatment arm comparisons (Gray 1988). Cause-specific Cox proportional hazards models will be used to evaluate the effect of stratification variables (DS-GPA and prior NCF testing exposure) and other baseline characteristics, such as KPS, and number of brain metastases and its interaction with treatment arm. A two-sided significance level of 0.05 will be used.	From the date of randomization to the date of neurologic death, assessed up to 10 years
Secondary	Salvage procedures used to manage recurrent intracranial disease	Will be collected and descriptively compared between arms using Chi-square tests.	10 years
Secondary	Incidence of adverse events	Graded by Common Terminology Criteria for Adverse Events version 5.0. Counts of all adverse events (AEs) by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The rate of grade 3+ AEs related to treatment and the rate of grade 3+ AEs regardless of relationship to treatment will be compared between treatment arms using a Chi-square test at a two-sided significance level of 0.05.	10 years