Stereotactic Radiation Therapy With or Without Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT00377156
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 213
• Locations: 64
• Arms: 2
• Actual Duration (Months): 161.5
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Stereotactic radiation therapy can 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 radiation therapy is more effective with or without whole-brain radiation therapy in treating patients with brain metastases.

PURPOSE: This randomized phase III trial is studying stereotactic radiation therapy and whole-brain radiation therapy to see how well they work compared with stereotactic radiation therapy alone in treating patients with brain metastases.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Cognitive/Functional Effects; Lung Cancer; Metastatic Cancer; Prostate Cancer	Radiation: radiation therapy; Radiation: stereotactic radiosurgery	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare the overall survival of patients with 1 to 3 cerebral metastases treated with stereotactic radiosurgery with vs without whole-brain radiotherapy.

Secondary

• Compare time to CNS (brain) failure in patients treated with these regimens.

• Compare quality of life, duration of functional independence, and long-term neurocognitive status of patients treated with these regimens.

• Compare post-treatment toxicity in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (18 to 59 vs 60 and over), extracranial disease (controlled for ≤ 3 months vs controlled for

3 months), and number of brain metastases (1 vs 2 vs 3). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo stereotactic radiosurgery (SRS).

• Arm II: Patients undergo SRS as in arm I. Within 14 days, patients then undergo whole-brain radiotherapy 5 days a week for 2.5 weeks.

Quality of life, functional independence, and neurocognitive status are assessed at baseline, at the beginning of each treatment, at weeks 6 and 12, and then at 6, 9, 12, 16, 24 , 36, 48, and 60 months.

PROJECTED ACCRUAL: A total of 238 patients will be accrued for this protocol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 213 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Randomized Trial of the Role of Whole Brain Radiation Therapy in Addition to Radiosurgery in Patients With One to Three Cerebral Metastases
• Actual Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Dec 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I Patients undergo stereotactic radiosurgery (SRS)	Radiation: stereotactic radiosurgery
Experimental: Arm II Patients undergo SRS as in arm I. Within 14 days, patients then undergo whole-brain radiotherapy 5 days a week for 2.5 weeks.	Radiation: radiation therapy; Patients undergo radiation therapy 5 days a week for 2.5 weeks; Radiation: stereotactic radiosurgery

Outcome Measures

Primary Outcome Measures

1. Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months [3 months post radiosurgery]

   The primary endpoint was cognitive deterioration (progression), defined as a decline of greater than 1 SD from baseline on at least 1 of 7 cognitive tests (all tests are standardized based on published norms and transformed so that higher values represent improved cognition) at the 3-month post-SRS evaluation. The number of participants who experienced cognitive deterioration by 3 months is reported for each arm below. For primary analysis of the 3-month cognitive deterioration endpoint, the Fisher exact 2-group binomial test was used to compare the proportion of evaluable patients with 3-month cognitive deterioration between the 2 groups.

Secondary Outcome Measures

1. Number of Participants With Local and Distant Tumor Control up to 3 Months [Up to 3 months]

   Number of Participants with Local and Distant Tumor Control up to 3 months is defined as....

2. Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month] [From Baseline to 3-Month Evaluation]

   Quality of Life was assessed using the Functional Assessment of Cancer Therapy-Brain, for which the range is from 0 to 200 and higher scores indicate better QOL. The Quality of Life (QOL) scores were transformed to a 0- to 100-point scale (with 100 being most favorable), in which a 10-point change was considered clinically significant. Intergroup changes in QOL scores were compared using a 2-sample t test.

3. Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months [From baseline to 12 months]

   Long-Term Neurocognitive Status > To ascertain in patients with one to three brain metastases whether there is better long-term neurocognitive status in patients who receive SRS alone (Arm A) compared to patients who receive SRS combined with WBRT (Arm B). Long-term survival status is defined as evaluable patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days.

4. Overall Survival [Up to 5 years]

   Overall survival, defined as the time from randomization until death due to any cause, was compared between the groups using stratified log-rank tests.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Diagnosis of cerebral metastases meeting the following criteria:

• One to three presumed brain metastases

• Metastases must be from a histologically confirmed extracerebral site (e.g., lung, breast, prostate)

• Histologic confirmation may have been from the primary tumor site, from another metastatic site (e.g., osseous metastasis, adrenal metastasis), or from the metastatic brain lesion(s)

• Each lesion must measure less than 3.0 cm by contrast MRI of the brain performed within the past 21 days

• Lesions must not be within 5 mm of the optic chiasm or within the brainstem

• Eligibility for treatment with gamma knife or linear accelerator-based radiosurgery confirmed by a radiation oncologist

• No primary germ cell tumor, small cell carcinoma, or lymphoma

• No leptomeningeal metastases

• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Male or female

• Menopausal status not specified

• ECOG performance status 0-2

• Not pregnant

• Negative pregnancy test

• Fertile patients must use effective contraception

• Male patients must continue to use contraception for 3 months after the completion of radiotherapy

• No pacemaker or other MRI-incompatible metal in the body

• No known allergy to gadolinium

PRIOR CONCURRENT THERAPY:

• More than 7 days since prior and no concurrent chemotherapy

• No prior cranial radiotherapy

• No prior resection of cerebral metastases

• Concurrent hormonal agents, steroids, and/or anticonvulsants allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology-Deer Valley Center	Phoenix	Arizona	United States	85027
2	Arizona Oncology Services Foundation	Scottsdale	Arizona	United States	85260
3	Memorial Medical Center	Modesto	California	United States	95355
4	Kaiser Permanente - Division of Research - Oakland	Oakland	California	United States	94611
5	St. Joseph Hospital Regional Cancer Center - Orange	Orange	California	United States	92868
6	Rohnert Park Cancer Center	Rohnert Park	California	United States	94928
7	Kaiser Permanente Medical Center - Santa Clara Kiely Campus	Santa Clara	California	United States	95051
8	Kaiser Permanente Medical Center - Santa Rosa	Santa Rosa	California	United States	95403
9	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
10	Veterans Affairs Medical Center - Denver	Denver	Colorado	United States	80220
11	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
12	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
13	Northside Hospital Cancer Center	Atlanta	Georgia	United States	30342-1611
14	Saint Joseph's Hospital of Atlanta	Atlanta	Georgia	United States	30342-1701
15	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
16	Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler	Savannah	Georgia	United States	31405
17	Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center	Boise	Idaho	United States	83706
18	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
19	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
20	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
21	Owensboro Mercy Medical Center	Owensboro	Kentucky	United States	42303
22	Ochsner Cancer Institute at Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
23	Lowell General Hospital	Lowell	Massachusetts	United States	01854
24	Saint Vincent Hospital at Worcester Medical Center	Worcester	Massachusetts	United States	01608
25	Henry Ford Hospital	Detroit	Michigan	United States	48202
26	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
27	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
28	CCOP - Duluth	Duluth	Minnesota	United States	55805
29	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
30	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
31	Cancer Institute of Cape Girardeau, LLC	Cape Girardeau	Missouri	United States	63703
32	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri	United States	64111
33	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
34	Immanuel Medical Center	Omaha	Nebraska	United States	68122
35	Seacoast Cancer Center at Wentworth - Douglass Hospital	Dover	New Hampshire	United States	03820
36	Elliot Regional Cancer Center at Elliot Hospital	Manchester	New Hampshire	United States	03103
37	Somerset Medical Center	Somerville	New Jersey	United States	08876
38	J. Phillip Citta Regional Cancer Center at Community Medical Center	Toms River	New Jersey	United States	08755
39	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
40	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
41	Cape Fear Valley Medical Center Cancer Center	Fayetteville	North Carolina	United States	28302-2000
42	Coastal Carolina Radiation Oncology Center	Wilmington	North Carolina	United States	28401
43	Forsyth Regional Cancer Center at Forsyth Medical Center	Winston-Salem	North Carolina	United States	27103
44	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
45	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
46	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
47	Cancer Care Center, Incorporated	Salem	Ohio	United States	44460
48	Cancer Treatment Center	Wooster	Ohio	United States	44691
49	Legacy Mount Hood Medical Center	Gresham	Oregon	United States	97030
50	Legacy Good Samaritan Hospital & Comprehensive Cancer Center	Portland	Oregon	United States	97210
51	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
52	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
53	Frankford Hospital Cancer Center - Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
54	Cancer Centers of the Carolinas - Faris Road	Greenville	South Carolina	United States	29605
55	CCOP - Greenville	Greenville	South Carolina	United States	29615
56	Greenville Cancer Center of the Carolinas (CCOP)	Greenville	South Carolina	United States	29615
57	University of Texas Medical Branch	Galveston	Texas	United States	77555
58	Legacy Salmon Creek Medical Center	Vancouver	Washington	United States	98686
59	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
60	All Saints Cancer Center at Wheaton Franciscan Healthcare	Racine	Wisconsin	United States	53405
61	Tom Baker Cancer Centre - Calgary	Calgary	Alberta	Canada	T2N 4N2
62	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
63	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
64	CHUS-Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4

Sponsors and Collaborators

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

Investigators

• Study Chair: Paul D. Brown, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00377156
• Other Study ID Numbers: N0574; NCCTG-N0574; ACOSOG-N0574; CDR0000499633; NCI-2009-00653
• First Posted: Sep 15, 2006
• Last Update Posted: Feb 12, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Alliance for Clinical Trials in Oncology: cognitive/functional effects; tumors metastatic to brain; stage IV breast cancer; stage IV prostate cancer; stage IV non-small cell lung cancer; male breast cancer; recurrent breast cancer; recurrent prostate cancer; recurrent non-small cell lung cancer
• Additional relevant MeSH terms: Breast Neoplasms; Lung Neoplasms; Prostatic Neoplasms

Study Results

Participant Flow

Recruitment Details	At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. 70 patients accrued by ACOSOG Z0300 were included in the power calculation and also included for this study.

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> > Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Period Title: Overall Study
STARTED	111	102
COMPLETED	63	48
NOT COMPLETED	48	54

Baseline Characteristics

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)	Total
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> > Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.	Total of all reporting groups
Overall Participants	111	102	213
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (10.4)	61.4 (10.6)	60.6 (10.5)
Age, Customized (Count of Participants)
18 to 59	53 47.7%	44 43.1%	97 45.5%
>= 60	58 52.3%	58 56.9%	116 54.5%
Sex: Female, Male (Count of Participants)
Female	57 51.4%	47 46.1%	104 48.8%
Male	54 48.6%	55 53.9%	109 51.2%
Region of Enrollment (participants) [Number]
Canada	23 20.7%	22 21.6%	45 21.1%
United States	88 79.3%	80 78.4%	168 78.9%

Outcome Measures

1. Primary Outcome

Title	Neurocognitive Progression as Measured by the Number of Participants With Cognitive Deterioration by 3 Months
Description	The primary endpoint was cognitive deterioration (progression), defined as a decline of greater than 1 SD from baseline on at least 1 of 7 cognitive tests (all tests are standardized based on published norms and transformed so that higher values represent improved cognition) at the 3-month post-SRS evaluation. The number of participants who experienced cognitive deterioration by 3 months is reported for each arm below. For primary analysis of the 3-month cognitive deterioration endpoint, the Fisher exact 2-group binomial test was used to compare the proportion of evaluable patients with 3-month cognitive deterioration between the 2 groups.
Time Frame	3 months post radiosurgery

Outcome Measure Data

Analysis Population Description

Patients who died prior to the 3-month evaluation, who did not return for the 3-month evaluation or a subsequent evaluation, or who did not complete the required baseline tests were excluded from the analysis population for the primary end point.

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> > Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Measure Participants	63	48
Count of Participants [Participants]	40 36%	44 43.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (SRS), Arm II (SRS+WBRT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-28.2
	Confidence Interval	(2-Sided) 90%; -41.9 to -14.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cognitive deterioration, the primary end point in evaluable patients at 3 months, was less frequent after Arm I than Arm II (40/63 [63.5%] vs 44/48 [91.7%],> respectively. The percent difference was -28.2%; 90% CI, -41.9% to -14.4%; P < .001).

2. Secondary Outcome

Title	Number of Participants With Local and Distant Tumor Control up to 3 Months
Description	Number of Participants with Local and Distant Tumor Control up to 3 months is defined as....
Time Frame	Up to 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> > Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Measure Participants	105	95
Count of Participants [Participants]	79 71.2%	89 87.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (SRS), Arm II (SRS+WBRT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-18.4
	Confidence Interval	(2-Sided) 95%; -29.0 to -7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Quality of Life, as Measured by Mean Change From Baseline [3 Month]
Description	Quality of Life was assessed using the Functional Assessment of Cancer Therapy-Brain, for which the range is from 0 to 200 and higher scores indicate better QOL. The Quality of Life (QOL) scores were transformed to a 0- to 100-point scale (with 100 being most favorable), in which a 10-point change was considered clinically significant. Intergroup changes in QOL scores were compared using a 2-sample t test.
Time Frame	From Baseline to 3-Month Evaluation

Outcome Measure Data

Analysis Population Description

All patients in the SRS and SRS+WBRT groups that had a baseline and 3-month QOL score were used in this analysis.

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> >> > >> Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Measure Participants	65	50
Mean (95% Confidence Interval) [QOL score change from baseline points]	-0.1	-12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (SRS), Arm II (SRS+WBRT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.9
	Confidence Interval	(2-Sided) 95%; 4.8 to 19.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Long-Term Neurocognitive Status (Long-Term Cognitive Status), as Measured by Percentage of Long-term Survivors With Cognitive Deterioration at 12 Months
Description	Long-Term Neurocognitive Status > To ascertain in patients with one to three brain metastases whether there is better long-term neurocognitive status in patients who receive SRS alone (Arm A) compared to patients who receive SRS combined with WBRT (Arm B). Long-term survival status is defined as evaluable patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days.
Time Frame	From baseline to 12 months

Outcome Measure Data

Analysis Population Description

Patients who survived for at least 12 months and had at least one cognitive assessment on or after 365 days were included in this analysis.

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.> > Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Measure Participants	10	18
Number [percentage of participants]	60 54.1%	94.44 92.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (SRS), Arm II (SRS+WBRT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-34.4
	Confidence Interval	(2-Sided) 95%; -74.4 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	The incidence of cognitive deterioration was less in Arm I than Arm II at 12 months (6/10 [60%] vs 17/18 [94.4%]. The percent difference was -34.4% (95% CI: -74.4% to 5.5%; P = .04)

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival, defined as the time from randomization until death due to any cause, was compared between the groups using stratified log-rank tests.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

A survival comparison was performed on an intention-to-treat basis using the entire study population.

Arm/Group Title	Arm I (SRS)	Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.	Patients undergo stereotactic radiosurgery (SRS) plus whole-brain radiotherapy (WBRT) received 22 Gy in a single fraction if lesions were less than 2.0cm or 18 Gy if lesions were 2 to 2.9 cm in maximum diameter.>> >> Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
Measure Participants	111	102
Median (Full Range) [months]	10.4	7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (SRS), Arm II (SRS+WBRT)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 60 months from the start of treatment
Adverse Event Reporting Description	All patients that began treatment and were assessed at least once for adverse events are included in this analysis. Adverse Events were collected at weeks 6 and 12 after radiation treatment, and at months 6, 9, 12, 16, 24, 36, 48, and 60 after radiation treatment.
Arm/Group Title	Arm I (SRS)		Arm II (SRS+WBRT)
Arm/Group Description	Patients undergo stereotactic radiosurgery (SRS) received 24 Gy in a single fraction if lesions were less than 2.0cm or 20 Gy if lesions were 2 to 2.9 cm in maximum diameter.		Patients randomly assigned to SRS plus WBRT received 30 GY in 12 fractions of 2.5-Gy WBRT delivered 5 days a week. Whole brain radiotherapy began within 14 days of SRS.
All Cause Mortality
	Arm I (SRS)		Arm II (SRS+WBRT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/68 (7.4%)		7/64 (10.9%)
Serious Adverse Events
	Arm I (SRS)		Arm II (SRS+WBRT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/68 (11.8%)		11/64 (17.2%)
Ear and labyrinth disorders
Hearing loss	0/68 (0%)	0	1/64 (1.6%)	2
Gastrointestinal disorders
Nausea	1/68 (1.5%)	2	0/64 (0%)	0
Vomiting	1/68 (1.5%)	2	0/64 (0%)	0
General disorders
Death	0/68 (0%)	0	3/64 (4.7%)	6
Disease progression	3/68 (4.4%)	6	2/64 (3.1%)	3
Fatigue	1/68 (1.5%)	2	0/64 (0%)	0
Infections and infestations
Bladder infection	1/68 (1.5%)	1	0/64 (0%)	0
Bronchitis	0/68 (0%)	0	1/64 (1.6%)	2
Encephalitis infection	0/68 (0%)	0	1/64 (1.6%)	1
Investigations
Alanine aminotransferase increased	0/68 (0%)	0	1/64 (1.6%)	2
Alkaline phosphatase increased	0/68 (0%)	0	1/64 (1.6%)	2
Aspartate aminotransferase increased	0/68 (0%)	0	1/64 (1.6%)	2
Bilirubin increased	0/68 (0%)	0	1/64 (1.6%)	2
Leukocyte count decreased	0/68 (0%)	0	1/64 (1.6%)	2
Neutrophil count decreased	0/68 (0%)	0	1/64 (1.6%)	2
Platelet count decreased	0/68 (0%)	0	1/64 (1.6%)	2
Metabolism and nutrition disorders
Hyperglycemia	0/68 (0%)	0	1/64 (1.6%)	2
Hyponatremia	0/68 (0%)	0	1/64 (1.6%)	2
Nervous system disorders
Central nervous system necrosis	1/68 (1.5%)	2	0/64 (0%)	0
Cognitive disturbance	0/68 (0%)	0	1/64 (1.6%)	2
Encephalopathy	0/68 (0%)	0	1/64 (1.6%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/68 (0%)	0	1/64 (1.6%)	2
Pleural effusion	1/68 (1.5%)	2	0/64 (0%)	0
Pneumonitis	1/68 (1.5%)	2	1/64 (1.6%)	2
Vascular disorders
Thrombosis	1/68 (1.5%)	2	0/64 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (SRS)		Arm II (SRS+WBRT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/68 (66.2%)		53/64 (82.8%)
Blood and lymphatic system disorders
Hemoglobin decreased	5/68 (7.4%)	12	3/64 (4.7%)	8
Cardiac disorders
Arrhythmia supraventricular	1/68 (1.5%)	2	0/64 (0%)	0
Cardiopulmonary arrest	1/68 (1.5%)	2	1/64 (1.6%)	2
Left ventricular dysfunction	1/68 (1.5%)	2	0/64 (0%)	0
Pericardial effusion	1/68 (1.5%)	2	0/64 (0%)	0
Sinus tachycardia	1/68 (1.5%)	2	1/64 (1.6%)	2
Ear and labyrinth disorders
External ear inflammation	2/68 (2.9%)	4	4/64 (6.3%)	8
Hearing loss	1/68 (1.5%)	2	11/64 (17.2%)	28
Tinnitus	1/68 (1.5%)	2	0/64 (0%)	0
Eye disorders
Diplopia	0/68 (0%)	0	1/64 (1.6%)	2
Eye disorder	0/68 (0%)	0	1/64 (1.6%)	2
Optic nerve disorder	1/68 (1.5%)	2	0/64 (0%)	0
Retinopathy	1/68 (1.5%)	2	2/64 (3.1%)	4
Gastrointestinal disorders
Abdominal distension	0/68 (0%)	0	1/64 (1.6%)	2
Abdominal pain	2/68 (2.9%)	6	1/64 (1.6%)	2
Colonic perforation	0/68 (0%)	0	1/64 (1.6%)	2
Diarrhea	2/68 (2.9%)	4	0/64 (0%)	0
Duodenal obstruction	1/68 (1.5%)	2	0/64 (0%)	0
Dysphagia	0/68 (0%)	0	2/64 (3.1%)	4
Esophageal ulcer	0/68 (0%)	0	1/64 (1.6%)	2
Esophagitis	1/68 (1.5%)	2	1/64 (1.6%)	2
Mucositis oral	1/68 (1.5%)	2	0/64 (0%)	0
Nausea	21/68 (30.9%)	62	26/64 (40.6%)	108
Small intestinal obstruction	0/68 (0%)	0	1/64 (1.6%)	2
Vomiting	11/68 (16.2%)	28	14/64 (21.9%)	52
General disorders
Chest pain	2/68 (2.9%)	4	0/64 (0%)	0
Edema limbs	4/68 (5.9%)	10	0/64 (0%)	0
Fatigue	8/68 (11.8%)	22	9/64 (14.1%)	30
Gait abnormal	0/68 (0%)	0	1/64 (1.6%)	2
Localized edema	1/68 (1.5%)	2	0/64 (0%)	0
Pain	0/68 (0%)	0	4/64 (6.3%)	10
Hepatobiliary disorders
Hepatic failure	0/68 (0%)	0	1/64 (1.6%)	2
Immune system disorders
Hypersensitivity	0/68 (0%)	0	1/64 (1.6%)	2
Infections and infestations
Gingival infection	0/68 (0%)	0	1/64 (1.6%)	2
Infection	1/68 (1.5%)	2	1/64 (1.6%)	2
Pancreas infection	1/68 (1.5%)	4	0/64 (0%)	0
Pneumonia	3/68 (4.4%)	6	1/64 (1.6%)	4
Skin infection	2/68 (2.9%)	4	0/64 (0%)	0
Injury, poisoning and procedural complications
Dermatitis radiation	5/68 (7.4%)	12	11/64 (17.2%)	26
Vascular access complication	0/68 (0%)	0	1/64 (1.6%)	2
Investigations
Alanine aminotransferase increased	0/68 (0%)	0	2/64 (3.1%)	4
Alkaline phosphatase increased	1/68 (1.5%)	2	0/64 (0%)	0
Amylase increased	1/68 (1.5%)	2	0/64 (0%)	0
Aspartate aminotransferase increased	2/68 (2.9%)	4	2/64 (3.1%)	4
Bilirubin increased	1/68 (1.5%)	2	1/64 (1.6%)	2
Coagulopathy	1/68 (1.5%)	2	0/64 (0%)	0
Creatinine increased	0/68 (0%)	0	1/64 (1.6%)	2
INR increased	0/68 (0%)	0	1/64 (1.6%)	2
Leukocyte count decreased	0/68 (0%)	0	2/64 (3.1%)	8
Lipase increased	1/68 (1.5%)	2	0/64 (0%)	0
Lymphocyte count decreased	2/68 (2.9%)	8	2/64 (3.1%)	8
Neutrophil count decreased	1/68 (1.5%)	2	2/64 (3.1%)	8
Platelet count decreased	2/68 (2.9%)	4	3/64 (4.7%)	8
Weight gain	1/68 (1.5%)	2	0/64 (0%)	0
Weight loss	2/68 (2.9%)	4	1/64 (1.6%)	2
Metabolism and nutrition disorders
Acidosis	0/68 (0%)	0	1/64 (1.6%)	2
Anorexia	2/68 (2.9%)	4	5/64 (7.8%)	12
Blood bicarbonate decreased	0/68 (0%)	0	1/64 (1.6%)	2
Dehydration	0/68 (0%)	0	5/64 (7.8%)	12
Hyperglycemia	2/68 (2.9%)	6	0/64 (0%)	0
Hypermagnesemia	0/68 (0%)	0	1/64 (1.6%)	2
Hypoalbuminemia	1/68 (1.5%)	2	1/64 (1.6%)	2
Hypocalcemia	1/68 (1.5%)	4	1/64 (1.6%)	2
Hypokalemia	1/68 (1.5%)	2	1/64 (1.6%)	2
Hypomagnesemia	1/68 (1.5%)	2	1/64 (1.6%)	2
Hyponatremia	1/68 (1.5%)	2	1/64 (1.6%)	2
Hypophosphatemia	1/68 (1.5%)	2	1/64 (1.6%)	2
Musculoskeletal and connective tissue disorders
Back pain	3/68 (4.4%)	10	1/64 (1.6%)	2
Bone pain	2/68 (2.9%)	4	0/64 (0%)	0
Chest wall pain	0/68 (0%)	0	1/64 (1.6%)	2
Muscle weakness	0/68 (0%)	0	2/64 (3.1%)	8
Muscle weakness left-sided	0/68 (0%)	0	1/64 (1.6%)	4
Muscle weakness lower limb	3/68 (4.4%)	5	0/64 (0%)	0
Muscle weakness upper limb	0/68 (0%)	0	1/64 (1.6%)	2
Myalgia	0/68 (0%)	0	1/64 (1.6%)	2
Pain in extremity	1/68 (1.5%)	2	1/64 (1.6%)	2
Nervous system disorders
Central nervous system necrosis	4/68 (5.9%)	12	3/64 (4.7%)	10
Cognitive disturbance	14/68 (20.6%)	36	13/64 (20.3%)	42
Depressed level of consciousness	0/68 (0%)	0	1/64 (1.6%)	2
Dizziness	1/68 (1.5%)	2	3/64 (4.7%)	6
Encephalopathy	0/68 (0%)	0	1/64 (1.6%)	2
Headache	5/68 (7.4%)	12	4/64 (6.3%)	12
Neurological disorder NOS	0/68 (0%)	0	1/64 (1.6%)	2
Peripheral motor neuropathy	16/68 (23.5%)	51	13/64 (20.3%)	40
Peripheral sensory neuropathy	1/68 (1.5%)	2	1/64 (1.6%)	2
Seizure	4/68 (5.9%)	10	1/64 (1.6%)	2
Syncope	0/68 (0%)	0	2/64 (3.1%)	4
Tremor	1/68 (1.5%)	2	0/64 (0%)	0
Psychiatric disorders
Agitation	1/68 (1.5%)	2	0/64 (0%)	0
Confusion	1/68 (1.5%)	2	2/64 (3.1%)	4
Insomnia	1/68 (1.5%)	2	0/64 (0%)	0
Renal and urinary disorders
Renal failure	0/68 (0%)	0	1/64 (1.6%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/68 (1.5%)	2	0/64 (0%)	0
Dyspnea	8/68 (11.8%)	17	6/64 (9.4%)	20
Hiccough	1/68 (1.5%)	2	0/64 (0%)	0
Hypoxia	2/68 (2.9%)	4	2/64 (3.1%)	4
Pleural effusion	1/68 (1.5%)	2	0/64 (0%)	0
Pleural hemorrhage	0/68 (0%)	0	1/64 (1.6%)	2
Pneumonitis	0/68 (0%)	0	1/64 (1.6%)	4
Pneumothorax	0/68 (0%)	0	1/64 (1.6%)	2
Respiratory disorder	1/68 (1.5%)	2	0/64 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	23/68 (33.8%)	105	40/64 (62.5%)	162
Hand-and-foot syndrome	0/68 (0%)	0	1/64 (1.6%)	2
Pain of skin	1/68 (1.5%)	2	0/64 (0%)	0
Pruritus	1/68 (1.5%)	2	0/64 (0%)	0
Rash desquamating	1/68 (1.5%)	2	0/64 (0%)	0
Skin disorder	1/68 (1.5%)	2	0/64 (0%)	0
Vascular disorders
Hematoma	1/68 (1.5%)	2	0/64 (0%)	0
Hypertension	1/68 (1.5%)	4	0/64 (0%)	0
Hypotension	0/68 (0%)	0	3/64 (4.7%)	6
Thrombosis	4/68 (5.9%)	8	1/64 (1.6%)	2
Vascular disorder	1/68 (1.5%)	2	0/64 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.