Stereotactic Radiosurgery or Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases That Have Been Removed By Surgery

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT01372774
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 194
• Locations: 37
• Arms: 2
• Actual Duration (Months): 101.5
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Stereotactic radiosurgery may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Radiation therapy uses high-energy x rays to kill tumor cells. It is not yet known whether stereotactic radiosurgery is more effective than whole-brain radiation therapy in treating patients with brain metastases that have been removed by surgery.

PURPOSE: This randomized phase III trial studies how well stereotactic radiosurgery works compared to whole-brain radiation therapy in treating patients with brain metastases that have been removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Cognitive/Functional Effects; Metastatic Cancer; Neurotoxicity; Radiation Toxicity; Unspecified Adult Solid Tumor, Protocol Specific	Radiation: stereotactic radiosurgery; Radiation: whole-brain radiation therapy	Phase 3

Detailed Description

Primary Goals

1. Overall Survival - To determine in patients with one to four brain metastases whether there is improved overall survival in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

2. Neurocognitive Progression - To determine in patients with one to four brain metastases whether there is less neurocognitive progression post-randomization in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

Secondary Goals

1. Quality of Life (QOL) - To determine in patients with resected brain metastases whether there is improved QOL in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

2. Central Nervous System Failure - To determine in patients with one to four brain metastases whether there is equal or longer time to central nervous system (CNS) failure (brain) in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

3. Functional Independence - To determine in patients with one to four brain metastases whether there is longer duration of functional independence in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

4. Long-Term Neurocognitive Status - To determine in patients with one to four brain metastases whether there is better long-term neurocognitive status in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

5. Adverse Events - To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.

6. Local Tumor Bed Recurrence - To evaluate local tumor bed recurrence at 6 months with post-surgical SRS to the surgical bed in comparison to WBRT.

7. Local Recurrence - To evaluate time to local recurrence with post-surgical SRS to the surgical bed in comparison to WBRT.

8. CNS Failure Patterns - To evaluate if there is any difference in CNS failure patterns (local, distant, leptomeningeal) in patients who receive SRS to the surgical bed compared to patients who receive WBRT.

OUTLINE: This is a multicenter study. Patients are stratified according to age in years (< 60 vs ≥ 60), extracranial disease controlled (≤ 3 months vs > 3 months), number of pre-operative brain metastases (1 vs 2-4), histology (lung vs radioresistant [brain metastases from a sarcoma, melanoma, or renal cell carcinoma histology] vs other), and resection cavity maximal diameter (≤ 3 cm vs > 3 cm). Patient must complete baseline QOL and neurocognitive tests prior to registration/randomization. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks.

• Arm II: Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure.

Event monitoring occurs up to 5 years post registration/randomization.

Study Design

• Study Type: Interventional
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared With Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease
• Actual Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Dec 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I - WBRT Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Radiation: whole-brain radiation therapy; Undergo radiotherapy (RT)
Experimental: Arm II - SRS Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Radiation: stereotactic radiosurgery; Undergo RT

Outcome Measures

Primary Outcome Measures

1. Cognitive Deterioration Free Survival Post-radiation in Patients Who Received SRS Compared to Patients Who Received WBRT [from baseline up to 5 years post radiation]

   To determine in patients with one to four brain metastases whether there is less nuerocognitive progression post-randomization in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Neurocognitive progression is defined as a drop of at least one stanard deviation from baseline in one of the six neurocognitive tests at post-randomization evaluation.

2. Overall Survival [from baseline up to 5 years post radiation]

   To determine in patients with one to four brain metastases whether there is improved overall survival in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Overall survival is defined as the time from randomization to death from any cause.

Secondary Outcome Measures

1. Local Control of the Surgical Bed [Up to 6 months post radiation]

   Local control of the surgical bed means that tumor did not recur at the unresected metastases treated with stereotactic radiosurgery, SRS, or whole brain radiotherapy, WBRT. Intercranial Brain Control Rates estimated via 1-Cumulatice Incidence Rate from Competing Risk survival analysis of time to the specific recurrence type. Deaths without recurrence are censored at time of death.

2. Time to CNS Failure in These Patients [Up to 5 years post radiation]

3. Change in Quality-of-life at 6 Months [Up to 6 months post randomization]

   Clinically significant change in quality of life is defined as ten-point change on QOL scores (transformed to a 0 to 100 scale). As measured by the overall score from the FACT-Br. An improvement is defined as a change greater than or equal ten points.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Pre-registration Inclusion Criteria:

1. Number of Brain Metastases - Four or fewer brain metastases (as defined on the pre-operative MRI or CT brain scan) and status post resection of one of the lesions.

2. Non-CNS Primary Site - Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Note: Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.

3. Size of Metastases - Any unresected lesions must measure < 3.0 cm in maximal extent on the contrasted MRI or CT brain scan obtained ≤ 35 days prior to pre-registration. The unresected lesions will be treated with SRS as outlined in the treatment section of the protocol. Note: The metastases size restriction does not apply to the resected brain metastasis; with resected brain metastases only surgical cavity size determines eligibility.

4. Size of Resection Cavity - Resection cavity must measure <5.0 cm in maximal extent on the post-operative MRI or CT brain scan obtained ≤35 days prior to pre-registration.

Note: It is permissible for the resection of a dominant brain metastasis to include a smaller "satellite" metastasis as long as the single resection cavity is less than the maximum size requirements.

1. Tumor Staging Procedures - All standard tumor-staging procedures necessary to define baseline extra cranial disease status completed ≤42 days prior to pre-registration.

2. Treatment with Gamma Knife or Radiosurgery - Able to be treated with either a gamma knife or a linear accelerator-based radiosurgery system.

3. Age ≥ 18 years

4. Neurocognitive Testing - Willing and able to complete neurocognitive testing without assistance from family and companions. Note: Because neurocognitive testing is one of the primary goals of this study, patients must be able to utilize English language booklets (and/or French booklets if enrolled in Canada).

5. Quality of Life (QOL) Questionnaires - Willing and able to complete QOL by themselves or with assistance

6. ECOG Performance Status - ECOG Performance Status (PS) 0, 1, or 2.

7. SRS Credentialed by IROC Houston Quality Assurance - The site's SRS facility is IROC Houston Quality Assurance approved.

8. Neurocognitive Testing Credentialing - The site study team member performing neurocognitive testing of patients must have credentialing confirming completion of the neurocognitive testing training of the protocol.

9. Written Informed Consent - Provide written informed consent

10. Mandatory Samples for Correlative Tests - Willing to provide mandatory blood and urine samples for correlative research purposes.

Pre-registration Exclusion Criteria:

1. Pregnancy, Nursing and Contraception - pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment.

2. Prior Cranial Radiation Therapy

3. MRI or CT Scans - Inability to complete a MRI or CT scan with contrast of the head.

4. Gadolinium Allergy - Known allergy to gadolinium.

5. Cytotoxic Chemotherapy - Planned cytotoxic chemotherapy during the SRS or WBRT.

6. Other Tumor Types - Primary germ cell tumor, small cell carcinoma, or lymphoma

7. Leptomeningeal Metastasis - Widespread definitive leptomeningeal metastasis

8. Location of Brain Metastasis - A brain metastasis that is located ≤ 5 mm of the optic chiasm or within the brainstem.

Randomization Inclusion Criteria:

1. Number of Unresected Lesions - Post-operative MRI or CT scan confirmed zero, one, two or three unresected lesions.

1.1 Each unresected lesion must measure ≤ 3.0 cm in maximal extent on the contrasted post-operative MRI or CT brain scan.

1.2 Note: The pre-registration, post-operative, brain scan may be used for the randomization scan if obtained ≤ 28 days prior to randomization.

1.3 Note: If there are no unresected brain metastases (i.e., all brain metastases have been resected), a post-operative CT brain scan may be used if obtained ≤ 28 days prior to randomization.

1. Size of Resection Cavity - Post-operative MRI or CT scan confirms resection cavity measures < 5.0 cm in maximal extent.

2.1 Note: The pre-registration, post-operative brain scan may be used for the randomization scan if obtained ≤ 28 days prior to randomization.

2.2 Note: If there are no unresected brain metastases (i.e., all brain metastases have been resected), a post-operative CT brain scan may be used if obtained ≤28 days prior to randomization.

1. Urine or Serum Pregnancy Test - Negative urine or serum pregnancy test done ≤ 7 days prior to randomization, for women of child bearing potential only.

Randomization Exclusion Criteria: none

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mills - Peninsula Hospitals	Burlingame	California	United States	94010
2	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
3	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
5	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
6	John B Amos Cancer Center	Columbus	Georgia	United States	31904
7	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
8	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
9	Lowell General Hospital	Lowell	Massachusetts	United States	01854
10	Saint Vincent Hospital/Reliant Medical Group	Worcester	Massachusetts	United States	01608
11	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
12	Sanford Clinic North-Bemidji	Bemidji	Minnesota	United States	56601
13	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
14	Regions Hospital	Saint Paul	Minnesota	United States	55101
15	United Hospital	Saint Paul	Minnesota	United States	55102
16	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
17	Wentworth-Douglass Hospital	Dover	New Hampshire	United States	03820
18	Somerset Medical Center	Somerville	New Jersey	United States	08876
19	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
20	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
21	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28233-3549
22	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
23	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58102
24	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
25	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
26	Case Western Reserve University	Cleveland	Ohio	United States	44106
27	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
28	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
29	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
30	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
31	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
32	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
33	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117
34	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
35	University of Texas Medical Branch	Galveston	Texas	United States	77555
36	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
37	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)

Investigators

• Study Chair: Paul D. Brown, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT01372774
• Other Study ID Numbers: N107C; NCCTG-N107C; CDR0000701474; NCI-2011-02676
• First Posted: Jun 14, 2011
• Last Update Posted: Feb 13, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Alliance for Clinical Trials in Oncology: neurotoxicity; radiation toxicity; cognitive/functional effects; tumors metastatic to brain; unspecified adult solid tumor, protocol specific
• Additional relevant MeSH terms: Neurotoxicity Syndromes

Study Results

Participant Flow

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. whole-brain radiation therapy: Undergo radiotherapy (RT)	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. stereotactic radiosurgery: Undergo RT
Period Title: Overall Study
STARTED	96	98
COMPLETED	92	93
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Arm I - WBRT	Arm II - SRS	Total
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. whole-brain radiation therapy: Undergo radiotherapy (RT)	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. stereotactic radiosurgery: Undergo RT	Total of all reporting groups
Overall Participants	96	98	194
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	62	61	61
Sex: Female, Male (Count of Participants)
Female	46 47.9%	52 53.1%	98 50.5%
Male	50 52.1%	46 46.9%	96 49.5%
Region of Enrollment (participants) [Number]
North America	96 100%	98 100%	194 100%

Outcome Measures

1. Primary Outcome

Title	Cognitive Deterioration Free Survival Post-radiation in Patients Who Received SRS Compared to Patients Who Received WBRT
Description	To determine in patients with one to four brain metastases whether there is less nuerocognitive progression post-randomization in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Neurocognitive progression is defined as a drop of at least one stanard deviation from baseline in one of the six neurocognitive tests at post-randomization evaluation.
Time Frame	from baseline up to 5 years post radiation

Outcome Measure Data

Analysis Population Description

All enrolled patients were included in the analysis of this outcome. This includes the 9 patients that did not receive treatment.

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. whole-brain radiation therapy: Undergo radiotherapy (RT)	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. stereotactic radiosurgery: Undergo RT
Measure Participants	96	98
Median (95% Confidence Interval) [Months]	3.0	3.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - WBRT, Arm II - SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Overall Survival
Description	To determine in patients with one to four brain metastases whether there is improved overall survival in patients who receive SRS to the surgical bed compared to patients who receive WBRT. Overall survival is defined as the time from randomization to death from any cause.
Time Frame	from baseline up to 5 years post radiation

Outcome Measure Data

Analysis Population Description

All enrolled patients were included in the analysis of this outcome. This includes the 9 patients that did not receive treatment.

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. whole-brain radiation therapy: Undergo radiotherapy (RT)	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization. stereotactic radiosurgery: Undergo RT
Measure Participants	96	98
Median (95% Confidence Interval) [months]	11.6	12.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - WBRT, Arm II - SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Local Control of the Surgical Bed
Description	Local control of the surgical bed means that tumor did not recur at the unresected metastases treated with stereotactic radiosurgery, SRS, or whole brain radiotherapy, WBRT. Intercranial Brain Control Rates estimated via 1-Cumulatice Incidence Rate from Competing Risk survival analysis of time to the specific recurrence type. Deaths without recurrence are censored at time of death.
Time Frame	Up to 6 months post radiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.
Measure Participants	96	98
Number (95% Confidence Interval) [percentage of patients]	87.1	80.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - WBRT, Arm II - SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.00068
	Comments	Intracranial Brain Control Rates estimated via 1-Cumulative Incidence Rate from Competing Risk survival analysis of time to the specific recurrence type. Deaths without recurrence are censored at time of death.
	Method	Gray's K-sample
	Comments

4. Secondary Outcome

Title	Time to CNS Failure in These Patients
Time Frame	Up to 5 years post radiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.
Measure Participants	96	98
Median (95% Confidence Interval) [Months]	27.5	6.4

5. Secondary Outcome

Title	Change in Quality-of-life at 6 Months
Description	Clinically significant change in quality of life is defined as ten-point change on QOL scores (transformed to a 0 to 100 scale). As measured by the overall score from the FACT-Br. An improvement is defined as a change greater than or equal ten points.
Time Frame	Up to 6 months post randomization

Outcome Measure Data

Analysis Population Description

Only patients with baseline and 6 month QOL assessment scores were included in this analysis.

Arm/Group Title	Arm I - WBRT	Arm II - SRS
Arm/Group Description	Patients undergo whole brain radiotherapy (WBRT) once a day, 5 days a week, for approximately 3 weeks. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.	Patients undergo stereotactic radiosurgery (SRS) using a gamma knife or a linear accelerator procedure. Patient observation/follow up occurs at week 12 and months 6, 9, 12, 16 and 24 post registration/randomization. Event monitoring occurs every 6 months until 5 years post registration/randomization.
Measure Participants	64	65
Improvement	4 4.2%	6 6.1%
Stable	24 25%	33 33.7%
Decline	17 17.7%	12 12.2%
Missing	19 19.8%	14 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I - WBRT, Arm II - SRS
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
Arm/Group Title	Arm I - WBRT		Arm II - SRS
Arm/Group Description	whole-brain radiation therapy: Undergo radiotherapy (RT)		stereotactic radiosurgery: Undergo RT
All Cause Mortality
	Arm I - WBRT		Arm II - SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I - WBRT		Arm II - SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/92 (15.2%)		19/93 (20.4%)
Blood and lymphatic system disorders
Anemia	1/92 (1.1%)	2	0/93 (0%)	0
Leukocytosis	1/92 (1.1%)	1	0/93 (0%)	0
Eye disorders
Optic nerve disorder	0/92 (0%)	0	1/93 (1.1%)	1
Gastrointestinal disorders
Nausea	3/92 (3.3%)	4	0/93 (0%)	0
Vomiting	2/92 (2.2%)	4	0/93 (0%)	0
General disorders
Death NOS	1/92 (1.1%)	1	1/93 (1.1%)	1
Fatigue	2/92 (2.2%)	2	0/93 (0%)	0
Localized edema	1/92 (1.1%)	1	0/93 (0%)	0
Multi-organ failure	1/92 (1.1%)	1	0/93 (0%)	0
Sudden death NOS	1/92 (1.1%)	1	0/93 (0%)	0
Infections and infestations
Esophageal infection	1/92 (1.1%)	1	0/93 (0%)	0
Meningitis	1/92 (1.1%)	1	0/93 (0%)	0
Otitis media	0/92 (0%)	0	1/93 (1.1%)	1
Pancreas infection	1/92 (1.1%)	1	0/93 (0%)	0
Sepsis	1/92 (1.1%)	1	0/93 (0%)	0
Wound infection	1/92 (1.1%)	1	1/93 (1.1%)	1
Injury, poisoning and procedural complications
Wound dehiscence	1/92 (1.1%)	2	0/93 (0%)	0
Investigations
Alanine aminotransferase increased	1/92 (1.1%)	1	0/93 (0%)	0
Alkaline phosphatase increased	1/92 (1.1%)	1	0/93 (0%)	0
Aspartate aminotransferase increased	1/92 (1.1%)	1	0/93 (0%)	0
Blood bilirubin increased	1/92 (1.1%)	1	0/93 (0%)	0
Creatinine increased	1/92 (1.1%)	1	0/93 (0%)	0
Hemoglobin increased	1/92 (1.1%)	1	0/93 (0%)	0
Lipase increased	1/92 (1.1%)	1	0/93 (0%)	0
Lymphocyte count decreased	1/92 (1.1%)	1	0/93 (0%)	0
Serum amylase increased	1/92 (1.1%)	1	0/93 (0%)	0
Metabolism and nutrition disorders
Anorexia	2/92 (2.2%)	2	0/93 (0%)	0
Dehydration	4/92 (4.3%)	4	0/93 (0%)	0
Hyperglycemia	2/92 (2.2%)	4	0/93 (0%)	0
Hypoalbuminemia	2/92 (2.2%)	4	0/93 (0%)	0
Hypocalcemia	1/92 (1.1%)	2	0/93 (0%)	0
Hypokalemia	2/92 (2.2%)	2	0/93 (0%)	0
Hyponatremia	1/92 (1.1%)	1	0/93 (0%)	0
Hypophosphatemia	2/92 (2.2%)	3	0/93 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/92 (0%)	0	1/93 (1.1%)	1
Generalized muscle weakness	1/92 (1.1%)	1	0/93 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/92 (2.2%)	2	1/93 (1.1%)	1
Nervous system disorders
Central nervous system necrosis	0/92 (0%)	0	1/93 (1.1%)	1
Cognitive disturbance	1/92 (1.1%)	1	1/93 (1.1%)	1
Depressed level of consciousness	2/92 (2.2%)	2	0/93 (0%)	0
Intracranial hemorrhage	0/92 (0%)	0	1/93 (1.1%)	1
Leukoencephalopathy	1/92 (1.1%)	1	0/93 (0%)	0
Nervous system disorders - Other, specify	1/92 (1.1%)	1	0/93 (0%)	0
Peripheral motor neuropathy	0/92 (0%)	0	1/93 (1.1%)	1
Seizure	2/92 (2.2%)	3	2/93 (2.2%)	4
Stroke	1/92 (1.1%)	1	0/93 (0%)	0
Psychiatric disorders
Agitation	1/92 (1.1%)	1	0/93 (0%)	0
Confusion	1/92 (1.1%)	1	0/93 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/92 (1.1%)	1	0/93 (0%)	0
Proteinuria	1/92 (1.1%)	1	0/93 (0%)	0
Urinary retention	0/92 (0%)	0	1/93 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	2/92 (2.2%)	2	0/93 (0%)	0
Bronchopulmonary hemorrhage	0/92 (0%)	0	1/93 (1.1%)	1
Dyspnea	0/92 (0%)	0	3/93 (3.2%)	3
Hypoxia	0/92 (0%)	0	1/93 (1.1%)	1
Pulmonary edema	0/92 (0%)	0	2/93 (2.2%)	2
Respiratory failure	3/92 (3.3%)	5	1/93 (1.1%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/92 (1.1%)	1	3/93 (3.2%)	3
Vascular disorders
Thromboembolic event	1/92 (1.1%)	2	2/93 (2.2%)	2
Other (Not Including Serious) Adverse Events
	Arm I - WBRT		Arm II - SRS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/92 (80.4%)		64/93 (68.8%)
Blood and lymphatic system disorders
Anemia	2/92 (2.2%)	4	1/93 (1.1%)	2
Blood and lymphatic system disorders - Other, specify	1/92 (1.1%)	3	0/93 (0%)	0
Cardiac disorders
Heart failure	0/92 (0%)	0	1/93 (1.1%)	1
Sinus tachycardia	0/92 (0%)	0	1/93 (1.1%)	1
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	0/92 (0%)	0	1/93 (1.1%)	1
External ear inflammation	6/92 (6.5%)	12	0/93 (0%)	0
Hearing impaired	21/92 (22.8%)	62	15/93 (16.1%)	46
Middle ear inflammation	2/92 (2.2%)	2	0/93 (0%)	0
Tinnitus	1/92 (1.1%)	1	0/93 (0%)	0
Eye disorders
Blurred vision	2/92 (2.2%)	5	0/93 (0%)	0
Eye disorders - Other, specify	0/92 (0%)	0	1/93 (1.1%)	1
Optic nerve disorder	0/92 (0%)	0	1/93 (1.1%)	1
Retinopathy	0/92 (0%)	0	2/93 (2.2%)	2
Gastrointestinal disorders
Colitis	0/92 (0%)	0	1/93 (1.1%)	1
Constipation	1/92 (1.1%)	1	0/93 (0%)	0
Dental caries	1/92 (1.1%)	1	0/93 (0%)	0
Dyspepsia	1/92 (1.1%)	1	0/93 (0%)	0
Dysphagia	1/92 (1.1%)	1	4/93 (4.3%)	7
Fecal incontinence	1/92 (1.1%)	1	0/93 (0%)	0
Gastrointestinal disorders - Other, specify	1/92 (1.1%)	1	0/93 (0%)	0
Mucositis oral	1/92 (1.1%)	1	0/93 (0%)	0
Nausea	36/92 (39.1%)	65	22/93 (23.7%)	31
Oral pain	1/92 (1.1%)	1	1/93 (1.1%)	1
Vomiting	21/92 (22.8%)	24	9/93 (9.7%)	13
General disorders
Death NOS	2/92 (2.2%)	2	0/93 (0%)	0
Fatigue	20/92 (21.7%)	31	10/93 (10.8%)	23
Gait disturbance	1/92 (1.1%)	2	0/93 (0%)	0
General disorders and administration site conditions - Other, specify	1/92 (1.1%)	1	0/93 (0%)	0
Malaise	1/92 (1.1%)	1	0/93 (0%)	0
Multi-organ failure	0/92 (0%)	0	1/93 (1.1%)	1
Non-cardiac chest pain	0/92 (0%)	0	1/93 (1.1%)	1
Pain	2/92 (2.2%)	2	1/93 (1.1%)	1
Infections and infestations
Mucosal infection	1/92 (1.1%)	1	0/93 (0%)	0
Otitis externa	1/92 (1.1%)	1	0/93 (0%)	0
Otitis media	1/92 (1.1%)	1	0/93 (0%)	0
Sepsis	1/92 (1.1%)	1	0/93 (0%)	0
Tooth infection	1/92 (1.1%)	1	0/93 (0%)	0
Upper respiratory infection	1/92 (1.1%)	1	0/93 (0%)	0
Injury, poisoning and procedural complications
Dermatitis radiation	14/92 (15.2%)	19	3/93 (3.2%)	3
Fall	1/92 (1.1%)	1	0/93 (0%)	0
Wound complication	0/92 (0%)	0	1/93 (1.1%)	1
Wound dehiscence	0/92 (0%)	0	1/93 (1.1%)	1
Investigations
Aspartate aminotransferase increased	0/92 (0%)	0	1/93 (1.1%)	1
Creatinine increased	0/92 (0%)	0	1/93 (1.1%)	1
Ejection fraction decreased	0/92 (0%)	0	1/93 (1.1%)	1
Lymphocyte count decreased	2/92 (2.2%)	3	2/93 (2.2%)	2
Neutrophil count decreased	0/92 (0%)	0	2/93 (2.2%)	2
Platelet count decreased	1/92 (1.1%)	1	1/93 (1.1%)	1
Weight gain	0/92 (0%)	0	1/93 (1.1%)	1
Weight loss	2/92 (2.2%)	5	1/93 (1.1%)	2
White blood cell decreased	1/92 (1.1%)	1	1/93 (1.1%)	1
Metabolism and nutrition disorders
Anorexia	5/92 (5.4%)	8	1/93 (1.1%)	1
Dehydration	2/92 (2.2%)	2	0/93 (0%)	0
Hyperglycemia	3/92 (3.3%)	3	0/93 (0%)	0
Hypoalbuminemia	1/92 (1.1%)	2	1/93 (1.1%)	1
Hyponatremia	1/92 (1.1%)	1	1/93 (1.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/92 (1.1%)	1	0/93 (0%)	0
Back pain	2/92 (2.2%)	4	1/93 (1.1%)	1
Bone pain	0/92 (0%)	0	1/93 (1.1%)	1
Chest wall pain	1/92 (1.1%)	1	0/93 (0%)	0
Generalized muscle weakness	4/92 (4.3%)	7	2/93 (2.2%)	2
Muscle weakness lower limb	0/92 (0%)	0	1/93 (1.1%)	1
Muscle weakness right-sided	0/92 (0%)	0	1/93 (1.1%)	1
Myalgia	1/92 (1.1%)	1	1/93 (1.1%)	1
Pain in extremity	2/92 (2.2%)	2	2/93 (2.2%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/92 (0%)	0	3/93 (3.2%)	3
Nervous system disorders
Ataxia	1/92 (1.1%)	1	0/93 (0%)	0
Central nervous system necrosis	0/92 (0%)	0	6/93 (6.5%)	8
Cognitive disturbance	27/92 (29.3%)	52	17/93 (18.3%)	26
Depressed level of consciousness	0/92 (0%)	0	1/93 (1.1%)	1
Dizziness	1/92 (1.1%)	1	0/93 (0%)	0
Dysarthria	1/92 (1.1%)	1	1/93 (1.1%)	1
Dysgeusia	2/92 (2.2%)	2	0/93 (0%)	0
Facial nerve disorder	0/92 (0%)	0	1/93 (1.1%)	1
Headache	4/92 (4.3%)	4	4/93 (4.3%)	5
Intracranial hemorrhage	1/92 (1.1%)	1	0/93 (0%)	0
Ischemia cerebrovascular	1/92 (1.1%)	1	0/93 (0%)	0
Memory impairment	3/92 (3.3%)	3	0/93 (0%)	0
Meningismus	1/92 (1.1%)	1	0/93 (0%)	0
Nervous system disorders - Other, specify	1/92 (1.1%)	1	0/93 (0%)	0
Peripheral motor neuropathy	10/92 (10.9%)	16	16/93 (17.2%)	23
Peripheral sensory neuropathy	1/92 (1.1%)	1	0/93 (0%)	0
Reversible posterior leukoencephalopathy syndrome	0/92 (0%)	0	1/93 (1.1%)	1
Seizure	3/92 (3.3%)	3	6/93 (6.5%)	6
Tremor	1/92 (1.1%)	1	0/93 (0%)	0
Psychiatric disorders
Confusion	1/92 (1.1%)	1	1/93 (1.1%)	1
Depression	1/92 (1.1%)	2	0/93 (0%)	0
Insomnia	1/92 (1.1%)	2	0/93 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/92 (0%)	0	1/93 (1.1%)	1
Chronic kidney disease	0/92 (0%)	0	1/93 (1.1%)	1
Urinary incontinence	2/92 (2.2%)	2	0/93 (0%)	0
Reproductive system and breast disorders
Uterine hemorrhage	1/92 (1.1%)	1	0/93 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	3/92 (3.3%)	4	1/93 (1.1%)	2
Dyspnea	2/92 (2.2%)	2	4/93 (4.3%)	5
Hoarseness	1/92 (1.1%)	1	1/93 (1.1%)	3
Nasal congestion	1/92 (1.1%)	2	0/93 (0%)	0
Pharyngolaryngeal pain	1/92 (1.1%)	1	0/93 (0%)	0
Pneumonitis	2/92 (2.2%)	2	1/93 (1.1%)	1
Productive cough	1/92 (1.1%)	1	0/93 (0%)	0
Respiratory failure	1/92 (1.1%)	1	0/93 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	1/92 (1.1%)	2	0/93 (0%)	0
Sore throat	1/92 (1.1%)	1	0/93 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	49/92 (53.3%)	119	28/93 (30.1%)	57
Dry skin	1/92 (1.1%)	1	0/93 (0%)	0
Rash acneiform	1/92 (1.1%)	1	0/93 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify	1/92 (1.1%)	1	0/93 (0%)	0
Vascular disorders
Hypotension	1/92 (1.1%)	1	0/93 (0%)	0
Thromboembolic event	4/92 (4.3%)	4	2/93 (2.2%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.