Avoiding the Hippocampus During Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01227954
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 113
• Locations: 63
• Arm: 1
• Duration (Months): 69.1
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells.

PURPOSE: This phase II trial is studying how well avoiding the hippocampus during whole-brain radiation therapy works in treating patients with brain metastases.

Condition or Disease	Intervention/Treatment	Phase
Cognitive/Functional Effects; Metastatic Cancer; Unspecified Adult Solid Tumor, Protocol Specific	Radiation: intensity-modulated radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate delayed recall as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R) at 4 months after hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) in patients with brain metastasis.

Secondary

• Evaluate auditory and visual learning and memory, as assessed by two CogState tests (International Shopping List Test and One Card Learning Test), after HA-WBRT in these patients.

• Compare psychometric properties of the 2 CogState tests to the HVLT-R for the assessment of memory decline after HA-WBRT in these patients.

• Evaluate health-related quality of life [as assessed by the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR) and the Barthel Index of Activities of Daily Living (ADLs)] after HA-WBRT in these patients.

• Evaluate time to radiographic progression after HA-WBRT in these patients.

• Evaluate overall survival of these patients after HA-WBR.

• Evaluate the adverse events of HA-WBR.

• Evaluate predictive biomarkers of cognitive function.

OUTLINE: This is a multicenter study.

Patients undergo 10 fractions of intensity-modulated whole-brain radiotherapy (WBRT), avoiding hippocampal (HA) regions, once daily, 5 days a week, for 2-2½ weeks.

Patients neurocognitive functions (delayed recall, auditory and visual learning, and memory) are evaluated by the Hopkins Verbal Learning Test-Revised (HVTL-R), The One Card Learning Test (OCLT), and the International Shopping List Test (ISLT) at baseline and periodically during study.

Patients may undergo serum, plasma, or whole blood collection at baseline and at 4 months after completion of HA-WBRT for correlative studies.

Patients may complete the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR), and the Barthel Index of Activities of Daily Living (ADLs) quality-of-life questionnaires at baseline and periodically during study and follow up.

After completion of study therapy, patients are followed up periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 113 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Hippocampal Avoidance During Whole Brain Radiotherapy for Brain Metastases
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Other: WBRT with Hippocampal Avoidance Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)

Radiation: intensity-modulated radiation therapy; 30 Gy in 10 fractions to the whole brain using intensity-modulated radiation therapy excluding the hippocampal avoidance area. Bilateral hippocampal contours manually generated on the fused planning MRI CT image set by the treating physician according to protocol-specified contouring instructions. Hippocampal avoidance regions generated by three-dimensionally expanding the hippocampal contours by 5 mm.; Other Names: IMRT

Outcome Measures

Primary Outcome Measures

1. Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) [Baseline and 4 months from start of treatment]

   Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100*[(baseline score - 4 month score)/ baseline score]

Secondary Outcome Measures

1. Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT) [Baseline and 4 months from start of treatment]

   The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].

2. Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT) [Baseline and 4 months from start of treatment]

   The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].

3. Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) [Baseline and 4 months from start of treatment]

   The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires >= 50% of items to be completed while the overall response rate must be > 80%. If items are missing, the subscale scores can be prorated.

4. Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) [Baseline and 4 months from start of treatment]

   The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.

5. Overall Survival [Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)]

   Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.

6. Progression-free Survival [Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)]

   Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions < 1cm, at least 25% for lesions >=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).

7. The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment [From start of treatment to 12 months from start of treatment]

   For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE

8. ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function [Baseline and 4 months from start of treatment]

   Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Histologically or cytologically confirmed non-hematopoietic malignancy within the past 5 years

• If histologic proof of malignancy is from > 5 years ago, then a more recent pathological confirmation is required (e.g., from systemic metastatic or brain metastasis)

• Patients with metastasis of unknown primary tumor are permitted

• Measurable brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast-enhanced MRI obtained within the past 30 days

• Have not been or will not be treated with stereotactic radiosurgery (SRS) or surgical resection

• These treatment options are allowed only at relapse

• Patients who have brain metastases at initial presentation allowed and do not need to demonstrate 3 months of stable scans

• At least 1 week since open biopsy

• Karnofsky performance status 70-100%

• Fertile patients must use effective contraception

• Negative pregnancy test 2 weeks or less prior to study entry

• Patients must be English proficient, with patients who speak English as a second language eligible

EXCLUSION CRITERIA:

• Small cell lung cancer or germ cell malignancy

• Leptomeningeal metastases

• Non-small cell lung cancer-associated brain metastases with ≥ 2 organ sites of extracranial metastases

• Radiologic evidence of hydrocephalus

• Serum creatinine > 1.4 mg/dL within 30 days prior to study entry

• Pregnant or nursing

• Contraindication to MRI imaging such as implanted metal devices or foreign bodies or severe claustrophobia

• Severe, active co-morbidity including any of the following:

• Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months

• Transmural myocardial infarction within the past 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy

• Uncontrolled, clinically significant cardiac arrhythmias

• Prior radiotherapy to the brain

• Plan for chemotherapy or targeted therapies during WBRT or during the subsequent 7 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Arizona Center for Cancer Care - Peoria	Peoria	Arizona	United States	85381
3	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
4	Arizona Oncology - Tucson	Tucson	Arizona	United States	85704
5	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724-5024
6	Veterans Affairs Medical Center - Long Beach	Long Beach	California	United States	90822
7	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
8	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
9	University of California Davis Cancer Center	Sacramento	California	United States	95817
10	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
11	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
12	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
13	Baptist-South Miami Regional Cancer Program	Miami	Florida	United States	33176
14	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
15	Piedmont Hospital	Atlanta	Georgia	United States	30309
16	Rush University Medical Center	Chicago	Illinois	United States	60612
17	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
18	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana	United States	46526
19	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
20	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana	United States	46202
21	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
22	NSMC Cancer Center - Peabody	Danvers	Massachusetts	United States	01923
23	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
24	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
25	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
26	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
27	Nebraska Medical Center	Omaha	Nebraska	United States	68198
28	St. Barnabas Medical Center Cancer Center	Livingston	New Jersey	United States	07039
29	New York Oncology Hematology, PC at Albany Regional Cancer Care	Albany	New York	United States	12206
30	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
31	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
32	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
33	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
34	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
35	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
36	Southwest General Health Center	Middleburg Heights	Ohio	United States	44130
37	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
38	Willamette Valley Cancer Center - Eugene	Eugene	Oregon	United States	97401
39	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon	United States	97213-2967
40	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
41	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
42	Regional Cancer Center - Erie	Erie	Pennsylvania	United States	16505
43	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
44	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
45	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
46	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
47	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
48	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
49	Texas Oncology, PA at Harris Center HEB	Bedford	Texas	United States	76022
50	Klabzuba Cancer Center at Harris Methodist Fort Worth Hospital	Fort Worth	Texas	United States	76104
51	Memorial Hermann Hospital - Memorial City	Houston	Texas	United States	77024
52	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
53	Texas Oncology, PA at Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas	United States	77479
54	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
55	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah	United States	84403
56	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah	United States	84112
57	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
58	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
59	CCOP - Virginia Mason Research Center	Seattle	Washington	United States	98101
60	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
61	London Regional Cancer Program at London Health Sciences Centre	London	Ontario	Canada	N6A 4L6
62	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
63	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Minesh P. Mehta, MD, University of Maryland Medical Systems

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01227954
• Other Study ID Numbers: RTOG-0933; CDR0000687490; NCT01366755
• First Posted: Oct 25, 2010
• Last Update Posted: Sep 27, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Radiation Therapy Oncology Group: cognitive/functional effects; tumors metastatic to brain; unspecified adult solid tumor, protocol specific
• Additional relevant MeSH terms: Brain Neoplasms

Study Results

Participant Flow

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Period Title: Overall Study
STARTED	113
COMPLETED	100
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Overall Participants	100
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	52 52%
Male	48 48%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)
Description	Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100*[(baseline score - 4 month score)/ baseline score]
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment and had baseline and 4 month data

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	42
Mean (95% Confidence Interval) [percent change]	7.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	To detect a minimum relative 50% improvement leading to an absolute 15% mean relative decline (MRD) in HVLT-R DR, 51 analyzable patients were required to ensure 80% statistical power with 0.05 alpha. Assuming a death rate of 40% before 4 months (based on trial NCT00003563) and a 10% nonevaluable rate, the target sample size was 102. The target MRD was determined from NCT00003563 which demonstrated 30% MRD in HVLT-R DR score from baseline to 4 months, with a standard deviation of 41%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT)
Description	The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment and had baseline and 4 month data

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	34
Mean (95% Confidence Interval) [percent change]	18.0

3. Secondary Outcome

Title	Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT)
Description	The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment and had baseline and 4 month data

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	34
Mean (95% Confidence Interval) [percent change]	-8

4. Secondary Outcome

Title	Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br)
Description	The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires >= 50% of items to be completed while the overall response rate must be > 80%. If items are missing, the subscale scores can be prorated.
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment and completed at least one FACT-Br assessment

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	80
Baseline	121.25
2 month	111.94
4 month	115
6 month	126.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and recursive partitioning analysis class (RPA) (I vs. II). Explanatory variables are reported separately and only if in the final model (p< 0.10, except time forced in the model.). Intercept is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1961
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Primary site (lung) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0715
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Neurologic status (no symptoms) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0554
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

5. Secondary Outcome

Title	Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL)
Description	The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment and completed at least one ADL assessment

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	81
Baseline	20
2 month	20
4 month	20
6 month	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Intercept is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1579
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Neurologic function status (some symptoms) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0559
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	WBRT With Hippocampal Avoidance
	Comments	A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (>= 60 vs. <60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p< 0.10, except time forced in the model.). Age (>= 60) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0749
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable in the final model is reported separately.

6. Secondary Outcome

Title	Overall Survival
Description	Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.
Time Frame	Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	96
Median (95% Confidence Interval) [months]	6.8

7. Secondary Outcome

Title	Progression-free Survival
Description	Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions < 1cm, at least 25% for lesions >=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).
Time Frame	Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	96
Median (95% Confidence Interval) [months]	5.9

8. Secondary Outcome

Title	The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment
Description	For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
Time Frame	From start of treatment to 12 months from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	96
Count of Participants [Participants]	2 2%

9. Secondary Outcome

Title	ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function
Description	Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure
Time Frame	Baseline and 4 months from start of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
Measure Participants	0

Adverse Events

Adverse Event Reporting Description	Eligible patients with adverse event data are included. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	WBRT With Hippocampal Avoidance
Arm/Group Description	Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT)
All Cause Mortality
	WBRT With Hippocampal Avoidance
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	WBRT With Hippocampal Avoidance
	Affected / at Risk (%)	# Events
Total	13/96 (13.5%)
Blood and lymphatic system disorders
Anemia	1/96 (1%)
Cardiac disorders
Chest pain - cardiac	1/96 (1%)
Pericardial effusion	1/96 (1%)
Sinus tachycardia	1/96 (1%)
Gastrointestinal disorders
Colonic perforation	2/96 (2.1%)
Nausea	1/96 (1%)
Vomiting	1/96 (1%)
General disorders
Death NOS	2/96 (2.1%)
Infections and infestations
Lung infection	1/96 (1%)
Sepsis	1/96 (1%)
Metabolism and nutrition disorders
Anorexia	1/96 (1%)
Dehydration	2/96 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1/96 (1%)
Nervous system disorders
Cognitive disturbance	2/96 (2.1%)
Dizziness	1/96 (1%)
Headache	1/96 (1%)
Nervous system disorders - Other	1/96 (1%)
Seizure	2/96 (2.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/96 (1%)
Pleural effusion	1/96 (1%)
Vascular disorders
Thromboembolic event	2/96 (2.1%)
Other (Not Including Serious) Adverse Events
	WBRT With Hippocampal Avoidance
	Affected / at Risk (%)	# Events
Total	46/96 (47.9%)
Eye disorders
Blurred vision	8/96 (8.3%)
Gastrointestinal disorders
Constipation	5/96 (5.2%)
Nausea	13/96 (13.5%)
Vomiting	6/96 (6.3%)
General disorders
Fatigue	34/96 (35.4%)
Gait disturbance	7/96 (7.3%)
Investigations
Weight loss	7/96 (7.3%)
Metabolism and nutrition disorders
Anorexia	13/96 (13.5%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	5/96 (5.2%)
Nervous system disorders
Dizziness	6/96 (6.3%)
Dysgeusia	6/96 (6.3%)
Headache	17/96 (17.7%)
Memory impairment	10/96 (10.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/96 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	21/96 (21.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.