Memantine in Preventing Side Effects in Patients Undergoing Whole-Brain Radiation Therapy for Brain Metastases From Solid Tumors

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00566852
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 554
• Locations: 235
• Arms: 2
• Duration (Months): 105
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Memantine may be able to decrease side effects caused by whole-brain radiation therapy. It is not yet known if memantine is effective in preventing side effects caused by whole-brain radiation therapy.

PURPOSE: This randomized phase III trial is studying memantine to see how well it works compared to a placebo in preventing side effects caused by whole-brain radiation therapy in patients with brain metastases from solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Cognitive/Functional Effects; Metastatic Cancer; Neurotoxicity; Unspecified Adult Solid Tumor, Protocol Specific	Drug: Memantine; Other: Placebo; Radiation: Whole brain radiation therapy	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Determine whether the addition of memantine hydrochloride to whole-brain radiotherapy (WBRT) preserves cognitive function, specifically memory, as measured by the Hopkins Verbal Learning Test for delayed recall (HVLT-delayed recall), over that of placebo and WBRT in patients with brain metastases at 24 weeks from the start of drug treatment.

Secondary

• Determine whether the addition of memantine hydrochloride preserves cognitive function, specifically memory, as measured by the HVLT-delayed recall at 8 weeks, 16 weeks, and 12 months from the start of drug treatment.

• Determine whether the addition of memantine hydrochloride increases time to neurocognitive failure as measured by cognitive decline on a battery of tests including the HVLT for free recall, delayed recall, and delayed recognition; the Controlled Word Association Test (COWAT); the Trail Making Test Parts A and B (TMT); the Medical Outcomes Scale-Cognitive Functioning Subscale (MOS); and the Mini-Mental Status Examination (MMSE).

• Evaluate the potential benefit of memantine hydrochloride in change and overall quality of life, as measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) subscale.

• Determine whether the addition of memantine hydrochloride increases progression-free survival.

• Determine whether the addition of memantine hydrochloride increases overall survival.

• Compare adverse events between the treatment arms according to the CTCAE v3.0 criteria.

• Collect serum, plasma, buffy coat cells, urine, and cerebrospinal fluid (CSF) for future translational research analyses.

OUTLINE: This is a multicenter study. Patients are stratified according to recursive partitioning analysis (RPA) prognostic class (class I vs class II with controlled systemic disease) and prior surgical therapy (none vs radiosurgery or surgical resection). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) 5 days a week for 3 weeks (15 fractions). Patients also receive oral memantine hydrochloride once daily beginning on day 1 of WBRT and continuing for 24 weeks.

• Arm II: Patients undergo WBRT as in arm I. Patients also receive oral placebo once daily beginning on day 1 of WBRT and continuing for 24 weeks.

After completion of study treatment, patients are followed at 6 months, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 554 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Randomized, Phase III, Double-Blind, Placebo-Controlled Trial of Memantine for Prevention of Cognitive Dysfunction in Patients Receiving Whole-Brain Radiotherapy
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: WBRT+Memantine Whole brain radiation therapy (WBRT) and memantine	Drug: Memantine; Patients began taking memantine(by mouth) while receiving radiation therapy. Patients continued taking memantine for 24 weeks or until doctor thinks it is in their best interest to stop. They started with 5 mg once a day. After a week dose increased to 5 mg twice a day. At week 3, dose increased to 10 mg in the morning and 5 mg in the evening. Weeks 4-24, dose was 10 mg twice a day.; Radiation: Whole brain radiation therapy; Whole brain radiation therapy (WBRT) once a day (2.5Gy), five days a week (Monday to Friday) for three weeks, for total fifteen treatments and 37.5 Gy
Active Comparator: WBRT+Placebo Whole brain radiation therapy (WBRT) and placebo	Other: Placebo; Patients began taking placebo(by mouth) while receiving radiation therapy. Patients continued taking placebo for 24 weeks or until doctor thinks it is in their best interest to stop. They started with 5 mg once a day. After a week dose increased to 5 mg twice a day. At week 3, dose increased to 10 mg in the morning and 5 mg in the evening. Weeks 4-24, dose was 10 mg twice a day.; Radiation: Whole brain radiation therapy; Whole brain radiation therapy (WBRT) once a day (2.5Gy), five days a week (Monday to Friday) for three weeks, for total fifteen treatments and 37.5 Gy

Outcome Measures

Primary Outcome Measures

1. Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks [Baseline and 24 weeks from the start of drug treatment]

   The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from 24-week value. Imputation methods were used to determine values for all alive patients missing the 24 week assessment. This tool is being used to measure cognitive function, specifically memory.

Secondary Outcome Measures

1. Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks [Baseline, 8, 16, and 52 weeks from the start of drug treatment]

   The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from the respective later time point value. Imputation methods were used to determine values for all alive patients missing the post-baseline assessments. This tool is being used to measure cognitive function, specifically memory.

2. Median Time to Neurocognitive Failure [Baseline to 12 months from the start of drug treatment]

   Neurocognitive failure is defined as the first cognitive failure on any of the neurocognitive tests: the HVLT-R for immediate recall, delayed recognition, and delayed recall; the Controlled Oral Word Association Test (COWAT); the Trail-Making Test (TMT) Parts A and B. Cognitive failure for each test is defined as a post-treatment score that meets one of the following criteria: follow-up score is at least 2 standard deviations worse than the patient's personal baseline score or the patient's raw score change is greater than the reliable change index. The cumulative incidence approach was used to estimate the median time to neurocognitive failure to account for the competing risks of disease progression and death.

3. Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks [Baseline and 24 weeks from start of treatment]

   The FACT-Br is a 50-question self-report questionnaire contains the following domains (scales): Physical well-being (7 questions), social/family well-being (7 questions), emotional well-being (6 questions), functional well-being (7 questions) and brain cancer subscale which contains concerns relevant to patients with brain tumors (23 questions). Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 times the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. The FACT-Br total is obtained by adding all domains together if the overall question response rate is greater than 80%. Total scores on the FACT-Br range from 0 to 184 with lower scores indicating declining quality of life. Change is calculated as baseline score subtracted from 24-week score.

4. Median Progression-free Survival Time [From randomization to date of progression, death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used.]

   Disease progression is defined as the first of the following events: an increase of at least 50% for lesions less than or equal to 1cm, an increase of least 25% for lesions greater than 1cm, appearance of any new brain metastases. Failure for progression-free survival is disease progression or death. Median progression-free survival was estimated using the Kaplan-Meier method.

5. Overall Survival [From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used.]

   Failure for overall survival is death from any cause. Median survival was estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of a solid tumor malignancy within the past 5 years

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

• Brain metastases must be visible on contrast-enhanced MRI or a contrast enhanced CT scan (for patients unable to undergo MRI within the past 28 days)

• Patients unable to undergo MRI imaging because of non-compatible devices are eligible, provided the contrast-enhanced CT scans are obtained and are of sufficient quality

• Patients who had undergone radiosurgery or surgical resection and are planning adjuvant whole-brain radiotherapy do not have to have visible disease but do need a baseline MRI

• Must have stable systemic disease (i.e. no evidence of systemic disease progression within the past 3 months)

• Patients with brain metastases at initial presentation are eligible and do not need to demonstrate 3 months of stable scans

PATIENT CHARACTERISTICS:

Inclusion

• Karnofsky performance status 70-100%

• Serum creatinine ≤ 3 mg/dL and creatinine clearance ≥ 30 mL/min

• Total bilirubin ≤ 2.5 mg/dL

• Blood urea nitrogen (BUN) < 20 mg/dL

• Mini-mental status exam score ≥ 18

• Negative serum pregnancy test

• Fertile patients must practice adequate contraception

Exclusion

• Severe, active co-morbidity, defined as follows:

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

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

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

• Pregnant or lactating women

• Prior allergic reaction to memantine hydrochloride

• Current alcohol or drug abuse

• Intractable seizures while on adequate anticonvulsant therapy (i.e., more than one seizure per month for the past 2 months)

PRIOR CONCURRENT THERAPY:

Inclusion

• At least 14 days but no more than 56 days since prior therapy for brain metastasis, including radiosurgery and surgical resection

• No systemic chemotherapy for 14 days prior, during, or for 14 days after completion of whole-brain radiotherapy (WBRT)

Exclusion

• Prior cranial radiotherapy

• Patients may have received up to 3 prior WBRT treatments and still be registered and randomized on the protocol provided WBRT parameters meet protocol requirements

• Chronic short-acting benzodiazepine use

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MBCCOP - Gulf Coast	Mobile	Alabama	United States	36604
2	Providence Cancer Center at Providence Hospital	Mobile	Alabama	United States	36608
3	Arizona Oncology Services Foundation	Phoenix	Arizona	United States	85013
4	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
5	Arizona Oncology - Tucson	Tucson	Arizona	United States	85704
6	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724-5024
7	Auburn Radiation Oncology	Auburn	California	United States	95603
8	Providence Saint Joseph Medical Center - Burbank	Burbank	California	United States	91505
9	Radiation Oncology Centers - Cameron Park	Cameron Park	California	United States	95682
10	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
11	Enloe Cancer Center at Enloe Medical Center	Chico	California	United States	95926
12	Cancer Care Center at John Muir Health - Concord Campus	Concord	California	United States	94524-4110
13	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
14	Glendale Adventist Medical Center	Glendale	California	United States	91206
15	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
16	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
17	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
18	St. Joseph Hospital Regional Cancer Center - Orange	Orange	California	United States	92868
19	Radiation Oncology Center - Roseville	Roseville	California	United States	95661
20	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
21	University of California Davis Cancer Center	Sacramento	California	United States	95817
22	Mercy General Hospital	Sacramento	California	United States	95819
23	Stanford Cancer Center	Stanford	California	United States	94305-5824
24	Emanuel Regional Cancer Services at Emanuel Medical Center	Turlock	California	United States	95382
25	Solano Radiation Oncology Center	Vacaville	California	United States	95687
26	John Muir/Mt. Diablo Comprehensive Cancer Center	Walnut Creek	California	United States	94598
27	Rocky Mountain Cancer Centers - Aurora	Aurora	Colorado	United States	80012
28	Rocky Mountain Cancer Centers - Colorado Springs	Colorado Springs	Colorado	United States	80909
29	Poudre Valley Radiation Oncology	Fort Collins	Colorado	United States	80528
30	Yale Cancer Center	New Haven	Connecticut	United States	06520-8028
31	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
32	Washington Cancer Institute at Washington Hospital Center	Washington, D.C.	District of Columbia	United States	20010
33	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
34	Integrated Community Oncology Network	Jacksonville Beach	Florida	United States	32250
35	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
36	Integrated Community Oncology Network at Southside Cancer Center	Jacksonville	Florida	United States	32207
37	Baptist Medical Center South	Jacksonville	Florida	United States	32258
38	Integrated Community Oncology Network - Orange Park	Orange Park	Florida	United States	32073
39	Florida Institute of Research, Medicine and Surgery Cancer Center	Orlando	Florida	United States	32806
40	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
41	Flagler Cancer Center	Saint Augustine	Florida	United States	32086
42	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
43	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
44	Veterans Affairs Medical Center - Atlanta (Decatur)	Decatur	Georgia	United States	30033
45	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
46	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
47	John H. Stroger, Jr. Hospital of Cook County	Chicago	Illinois	United States	60612-3785
48	Cancer Institute at St. John's Hospital	Springfield	Illinois	United States	62702
49	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
50	Saint John's Cancer Center at Saint John's Medical Center	Anderson	Indiana	United States	46016
51	Bloomington Hospital Regional Cancer Institute	Bloomington	Indiana	United States	47403
52	Radiation Oncology Associates Southwest	Fort Wayne	Indiana	United States	46804
53	Parkview Regional Cancer Center at Parkview Health	Fort Wayne	Indiana	United States	46805
54	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana	United States	46526
55	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
56	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana	United States	46202
57	Central Indiana Cancer Centers - East	Indianapolis	Indiana	United States	46219
58	Community Regional Cancer Care at Community Hospital East	Indianapolis	Indiana	United States	46219
59	Community Regional Cancer Care at Community Hospital North	Indianapolis	Indiana	United States	46256
60	Cancer Center at Ball Memorial Hospital	Muncie	Indiana	United States	47303-3499
61	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
62	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
63	Kansas City Cancer Centers - Southwest	Overland Park	Kansas	United States	66210
64	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
65	Norton Suburban Hospital	Louisville	Kentucky	United States	40207
66	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
67	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
68	Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center	Baltimore	Maryland	United States	21237
69	Good Samaritan Hospital of Maryland	Baltimore	Maryland	United States	21239
70	Central Maryland Oncology Center	Columbia	Maryland	United States	21044
71	Tate Cancer Center at Baltimore Washington Medical Center	Glen Burnie	Maryland	United States	21061
72	Cancer Institute at St. Joseph Medical Center	Towson	Maryland	United States	21204
73	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
74	Charach Cancer Center at Huron Valley - Sinai Hospital	Commerce	Michigan	United States	48382
75	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
76	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
77	Great Lakes Cancer Institute at McLaren Regional Medical Center	Flint	Michigan	United States	48532
78	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
79	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
80	William Beaumont Hospital - Royal Oak Campus	Royal Oak	Michigan	United States	48073
81	Albert Lea Cancer Center at Albert Lea Medical Center	Albert Lea	Minnesota	United States	56007
82	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
83	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
84	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
85	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
86	Immanuel St. Joseph's	Mankato	Minnesota	United States	56002
87	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
88	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
89	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
90	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
91	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
92	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
93	United Hospital	Saint Paul	Minnesota	United States	55102
94	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
95	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi	United States	39581
96	Kansas City Cancer Centers - South	Kansas City	Missouri	United States	64131
97	Kansas City Cancer Centers - North	Kansas City	Missouri	United States	64154
98	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri	United States	63141
99	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
100	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
101	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
102	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
103	Methodist Estabrook Cancer Center	Omaha	Nebraska	United States	68114
104	Nebraska Medical Center	Omaha	Nebraska	United States	68198
105	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
106	Renown Institute for Cancer at Renown Regional Medical Center	Reno	Nevada	United States	89502
107	Payson Center for Cancer Care at Concord Hospital	Concord	New Hampshire	United States	03301
108	Elliot Regional Cancer Center at Elliot Hospital	Manchester	New Hampshire	United States	03103
109	Ocean Medical Center at Meridian Health	Bricktown	New Jersey	United States	08724
110	Cancer Institute of New Jersey at Cooper University Hospital - Camden	Camden	New Jersey	United States	08103
111	Trinitas Comprehensive Cancer Center at Trinitas Hospital	Elizabeth	New Jersey	United States	07207
112	Princeton Radiation Oncology Center	Jamesburg	New Jersey	United States	08831
113	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
114	University Medical Center at Princeton	Princeton	New Jersey	United States	08540-3298
115	J. Phillip Citta Regional Cancer Center at Community Medical Center	Toms River	New Jersey	United States	08755
116	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
117	Lovelace Medical Center - Downtown	Albuquerque	New Mexico	United States	87102
118	Radiation Oncology Associates, PA	Albuquerque	New Mexico	United States	87109
119	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131-5636
120	New York Oncology Hematology, PC at Albany Regional Cancer Care	Albany	New York	United States	12206
121	Veterans Affairs Medical Center - Albany	Albany	New York	United States	12208
122	New York Methodist Hospital	Brooklyn	New York	United States	11215
123	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
124	Sands Cancer Center	Canandaigua	New York	United States	14424
125	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
126	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
127	Highland Hospital of Rochester	Rochester	New York	United States	14620
128	Lipson Cancer and Blood Center at Rochester General Hospital	Rochester	New York	United States	14621
129	University Radiation Oncology at Parkridge Hospital	Rochester	New York	United States	14626
130	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
131	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
132	New Hanover Radiation Oncology, PA	Wilmington	North Carolina	United States	28401
133	Trinity CancerCare Center	Minot	North Dakota	United States	58701
134	McDowell Cancer Center at Akron General Medical Center	Akron	Ohio	United States	44307
135	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
136	Barberton Citizens Hospital	Barberton	Ohio	United States	44203
137	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
138	Cleveland Clinic Cancer Center at Fairview Hospital	Cleveland	Ohio	United States	44111
139	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
140	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
141	Cleveland Clinic Cancer Center	Independence	Ohio	United States	44131
142	Northwest Ohio Oncology Center	Maumee	Ohio	United States	43537-1839
143	Hillcrest Cancer Center at Hillcrest Hospital	Mayfield Heights	Ohio	United States	44124
144	St. Charles Mercy Hospital	Oregon	Ohio	United States	43616
145	Cancer Care Center, Incorporated	Salem	Ohio	United States	44460
146	North Coast Cancer Care, Incorporated	Sandusky	Ohio	United States	44870
147	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
148	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
149	CCOP - Toledo Community Hospital	Toledo	Ohio	United States	43617
150	St. Anne Mercy Hospital	Toledo	Ohio	United States	43623
151	Precision Radiotherapy at University Pointe	West Chester	Ohio	United States	45069
152	Cancer Treatment Center	Wooster	Ohio	United States	44691
153	Cleveland Clinic - Wooster	Wooster	Ohio	United States	44691
154	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
155	Willamette Valley Cancer Center - Eugene	Eugene	Oregon	United States	97401
156	Three Rivers Community Hospital	Grants Pass	Oregon	United States	97527
157	Dubs Cancer Center at Rogue Valley Medical Center	Medford	Oregon	United States	97504
158	Providence Cancer Center at PMCC	Medford	Oregon	United States	97504
159	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
160	UPMC Cancer Center at Beaver Medical Center	Beaver	Pennsylvania	United States	15009
161	St. Luke's Cancer Network at St. Luke's Hospital	Bethlehem	Pennsylvania	United States	18015
162	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
163	UPMC Cancer Center at Jefferson Regional Medical Center	Clairton	Pennsylvania	United States	15025
164	Cancer Center at Clarion Hospital	Clarion	Pennsylvania	United States	16214
165	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
166	Delaware County Regional Cancer Center at Delaware County Memorial Hospital	Drexel Hill	Pennsylvania	United States	19026
167	Northeast Radiation Oncology Center	Dunmore	Pennsylvania	United States	18512
168	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
169	UPMC Cancer Center - Arnold Palmer Pavilion	Greensburg	Pennsylvania	United States	15601
170	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
171	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
172	UPMC Cancer Center at the John P. Murtha Pavilion	Johnstown	Pennsylvania	United States	15901
173	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania	United States	15132
174	UPMC - Moon	Moon	Pennsylvania	United States	15108
175	UPMC Cancer Center - Natrona Heights	Natrona Heights	Pennsylvania	United States	15065
176	Jameson Memorial Hospital - North Campus	New Castle	Pennsylvania	United States	16105
177	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
178	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
179	Albert Einstein Cancer Center	Philadelphia	Pennsylvania	United States	19141
180	UPMC - Shadyside	Pittsburgh	Pennsylvania	United States	15213-2582
181	UPMC Cancer Center at Magee-Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
182	UPMC Cancer Center at UPMC St. Margaret	Pittsburgh	Pennsylvania	United States	15215
183	UPMC Cancer Center at UPMC Passavant	Pittsburgh	Pennsylvania	United States	15237
184	UPMC Cancer Center - Upper St. Clair	Pittsburgh	Pennsylvania	United States	15243
185	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania	United States	16346
186	UPMC Cancer Center - Uniontown	Uniontown	Pennsylvania	United States	15401
187	Washington Hospital Cancer Center	Washington	Pennsylvania	United States	15301
188	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
189	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
190	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
191	CCOP - Upstate Carolina	Spartanburg	South Carolina	United States	29303
192	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
193	Texas Oncology, PA at Texas Cancer Center - Arlington South	Arlington	Texas	United States	76014
194	Texas Oncology, PA at Harris Center HEB	Bedford	Texas	United States	76022
195	Medical City Dallas Hospital	Dallas	Texas	United States	75230
196	Texas Oncology, PA at Texas Cancer Center Dallas Southwest	Dallas	Texas	United States	75237
197	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
198	Texas Oncology, PA at Texas Cancer Center - Denton South	Denton	Texas	United States	76210
199	Klabzuba Cancer Center at Harris Methodist Fort Worth Hospital	Fort Worth	Texas	United States	76104
200	Longview Cancer Center	Longview	Texas	United States	75601
201	West Texas Cancer Center	Odessa	Texas	United States	79761
202	Cancer Care Centers of South Texas - Northeast	San Antonio	Texas	United States	78217
203	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
204	Texas Oncology, PA at Texas Cancer Center - Sherman	Sherman	Texas	United States	75090
205	Texas Oncology, PA at Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas	United States	77479
206	Tyler Cancer Center	Tyler	Texas	United States	75702
207	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
208	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah	United States	84403
209	Dixie Regional Medical Center - East Campus	Saint George	Utah	United States	84770
210	Utah Cancer Specialists at UCS Cancer Center	Salt Lake City	Utah	United States	84106
211	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah	United States	84112
212	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont	United States	05401
213	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
214	Sentara Cancer Institute at Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
215	CCOP - Virginia Mason Research Center	Seattle	Washington	United States	98101
216	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
217	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
218	Schiffler Cancer Center at Wheeling Hospital	Wheeling	West Virginia	United States	26003
219	Theda Care Cancer Institute	Appleton	Wisconsin	United States	54911
220	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
221	Franciscan Skemp Healthcare - La Crosse Campus	La Crosse	Wisconsin	United States	54601
222	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
223	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
224	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin	United States	53051
225	Vince Lombardi Cancer Clinic at Aurora St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
226	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
227	All Saints Cancer Center at Wheaton Franciscan Healthcare	Racine	Wisconsin	United States	53405
228	University of Wisconcin Cancer Center at Aspirus Wausau Hospital	Wausau	Wisconsin	United States	54401
229	West Allis Memorial Hospital	West Allis	Wisconsin	United States	53227
230	Nova Scotia Cancer Centre	Halifax	Nova Scotia	Canada	B3H 1V8
231	London Regional Cancer Program at London Health Sciences Centre	London	Ontario	Canada	N6A 4L6
232	Maisonneuve-Rosemont Hospital	Montreal	Quebec	Canada	H1T 2M4
233	Hopital Notre-Dame du CHUM	Montreal	Quebec	Canada	H2L 4M1
234	McGill Cancer Centre at McGill University	Montreal	Quebec	Canada	H2W 1S6
235	Centre Hospitalier Universitaire de Quebec	Quebec City	Quebec	Canada	G1R 2J6

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Paul D. Brown, MD, Mayo Clinic
• Study Chair: Christina A. Meyers, PhD, M.D. Anderson Cancer Center
• Study Chair: Sherry Fox, RN, PhD, Bon Secours Cancer Institute at St. Mary's Hospital
• Study Chair: Deepak Khuntia, MD, University of Wisconsin, Madison

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Manuscript for primary analysis results

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00566852
• Other Study ID Numbers: RTOG-0614; CDR0000577872; NCI-2009-00735
• First Posted: Dec 4, 2007
• Last Update Posted: Aug 21, 2017
• Last Verified: Jul 1, 2017

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

Study Results

Participant Flow

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Period Title: Overall Study
STARTED	278	276
COMPLETED	71	78
NOT COMPLETED	207	198

Baseline Characteristics

Arm/Group Title	WBRT+Memantine	WBRT+Placebo	Total
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo	Total of all reporting groups
Overall Participants	256	252	508
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	59	59
Sex: Female, Male (Count of Participants)
Female	141 55.1%	145 57.5%	286 56.3%
Male	115 44.9%	107 42.5%	222 43.7%

Outcome Measures

1. Primary Outcome

Title	Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks
Description	The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from 24-week value. Imputation methods were used to determine values for all alive patients missing the 24 week assessment. This tool is being used to measure cognitive function, specifically memory.
Time Frame	Baseline and 24 weeks from the start of drug treatment

Outcome Measure Data

Analysis Population Description

All eligible patients with Hopkins Verbal Learning Test-Revised for delayed recall (HVLT-R delayed recall) at baseline and 24 weeks.

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	71	78
Median (Inter-Quartile Range) [units on a scale]	0	-0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	Null hypothesis: patients on memantine will experience less decline than patients receiving placebo. Based on a one-sided Wilcoxon rank sum test with alpha=0.025, 221 patients per arm would be required to have 80% statistical power to detect a mean difference of 0.87 in the HVLT-R change scores between the two treatment arms. Assuming that 20% of patients may be ineligible, or die prior to the 24 week assessment, the target sample size for randomization was set to 536.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	Significance level was 0.025.
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks
Description	The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. Standardized scores are used by calculating an average standardized z score for each part of the HVLT-R. Change is calculated by subtracting baseline value from the respective later time point value. Imputation methods were used to determine values for all alive patients missing the post-baseline assessments. This tool is being used to measure cognitive function, specifically memory.
Time Frame	Baseline, 8, 16, and 52 weeks from the start of drug treatment

Outcome Measure Data

Analysis Population Description

Eligible patients with baseline and respective post-baseline measurements

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	128	128
8-weeks	-0.36	-0.72
16-weeks	0	0
52-weeks	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	8 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0692
	Comments	One-sided significance level of 0.025
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	16 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4541
	Comments	One-sided significance level of 0.025
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	52 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3970
	Comments	One-sided significance level of 0.025
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Median Time to Neurocognitive Failure
Description	Neurocognitive failure is defined as the first cognitive failure on any of the neurocognitive tests: the HVLT-R for immediate recall, delayed recognition, and delayed recall; the Controlled Oral Word Association Test (COWAT); the Trail-Making Test (TMT) Parts A and B. Cognitive failure for each test is defined as a post-treatment score that meets one of the following criteria: follow-up score is at least 2 standard deviations worse than the patient's personal baseline score or the patient's raw score change is greater than the reliable change index. The cumulative incidence approach was used to estimate the median time to neurocognitive failure to account for the competing risks of disease progression and death.
Time Frame	Baseline to 12 months from the start of drug treatment

Outcome Measure Data

Analysis Population Description

All randomized eligible patients with neurocognitive scores from baseline to 12 months from start of drug treatment.

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	256	252
Median (95% Confidence Interval) [years]	2.6	2.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	A one-sided log-rank test with alpha 0.025 accruing 221 patients/arm with 12 months of follow-up would ensure 98% statistical power to detect a 33% relative reduction in the monthly hazard rate with the use of memantine. Gray's test was used to test for a statistically significant difference in the distribution of neurocognitive failure times and Cox proportional hazards regression model was used to determine hazard ratios and 95% confidence intervals for the treatment difference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Gray's test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks
Description	The FACT-Br is a 50-question self-report questionnaire contains the following domains (scales): Physical well-being (7 questions), social/family well-being (7 questions), emotional well-being (6 questions), functional well-being (7 questions) and brain cancer subscale which contains concerns relevant to patients with brain tumors (23 questions). Each question has a value 0-4. For some questions a higher indicates better outcome and others are the opposite. The former are summed as is, the latter are reversed in value before adding, such that each domain ranges from 0 to 4 times the number of questions in the domain, with 0 indicating worst and the highest possible value indicating best outcome. The FACT-Br total is obtained by adding all domains together if the overall question response rate is greater than 80%. Total scores on the FACT-Br range from 0 to 184 with lower scores indicating declining quality of life. Change is calculated as baseline score subtracted from 24-week score.
Time Frame	Baseline and 24 weeks from start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients with FACT-Br score at baseline and 24 weeks.

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	71	66
Median (Inter-Quartile Range) [units on a scale]	0	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	Assuming normally distributions, the two sample t-test assuming equal variances would be used to compare the arms at the 0.025 significance level. If normality assumptions were not met, the Wilcoxon rank sum would be used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Median Progression-free Survival Time
Description	Disease progression is defined as the first of the following events: an increase of at least 50% for lesions less than or equal to 1cm, an increase of least 25% for lesions greater than 1cm, appearance of any new brain metastases. Failure for progression-free survival is disease progression or death. Median progression-free survival was estimated using the Kaplan-Meier method.
Time Frame	From randomization to date of progression, death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used.

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	256	252
Mean (Inter-Quartile Range) [months]	4.7	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	The stratified log-rank test was used to test for a statistically significant difference in survival distributions with a one-sided alpha of 0.025 . In addition, the Cox proportional hazards regression model was used to determine hazard ratios and 95% confidence intervals for the treatment difference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Overall Survival
Description	Failure for overall survival is death from any cause. Median survival was estimated using the Kaplan-Meier method.
Time Frame	From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome. Patients are followed until death and all follow-up collected at time of analysis is used.

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	WBRT+Memantine	WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine	Whole brain radiation therapy (WBRT) and placebo
Measure Participants	256	252
Median (95% Confidence Interval) [months]	6.7	7.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	WBRT+Memantine, WBRT+Placebo
	Comments	The stratified log-rank test was used to test for a statistically significant difference in survival distributions with a one-sided alpha of 0.025 . In addition, the Cox proportional hazards regression model was used to determine hazard ratios and 95% confidence intervals for the treatment difference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	Adverse events are reported for all eligible randomized patients with adverse event data. Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-serious adverse events.
Arm/Group Title	WBRT+Memantine		WBRT+Placebo
Arm/Group Description	Whole brain radiation therapy (WBRT) and memantine		Whole brain radiation therapy (WBRT) and placebo
All Cause Mortality
	WBRT+Memantine		WBRT+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	WBRT+Memantine		WBRT+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/251 (31.9%)		67/246 (27.2%)
Blood and lymphatic system disorders
Blood disorder	1/251 (0.4%)		1/246 (0.4%)
Febrile neutropenia	1/251 (0.4%)		0/246 (0%)
Hemoglobin decreased	4/251 (1.6%)		7/246 (2.8%)
Cardiac disorders
Arrhythmia supraventricular	2/251 (0.8%)		1/246 (0.4%)
Atrial fibrillation	1/251 (0.4%)		0/246 (0%)
Atrial flutter	1/251 (0.4%)		0/246 (0%)
Cardiac disorder	1/251 (0.4%)		0/246 (0%)
Cardiac pain	0/251 (0%)		1/246 (0.4%)
Left ventricular failure	1/251 (0.4%)		0/246 (0%)
Myocardial ischemia	0/251 (0%)		2/246 (0.8%)
Pericardial effusion	1/251 (0.4%)		0/246 (0%)
Sinus tachycardia	1/251 (0.4%)		0/246 (0%)
Ear and labyrinth disorders
Ear pain	1/251 (0.4%)		0/246 (0%)
External ear inflammation	1/251 (0.4%)		0/246 (0%)
Hearing loss	0/251 (0%)		1/246 (0.4%)
Eye disorders
Eye disorder	1/251 (0.4%)		1/246 (0.4%)
Vision blurred	1/251 (0.4%)		0/246 (0%)
Gastrointestinal disorders
Abdominal pain	5/251 (2%)		4/246 (1.6%)
Colonic hemorrhage	1/251 (0.4%)		0/246 (0%)
Constipation	1/251 (0.4%)		2/246 (0.8%)
Diarrhea	2/251 (0.8%)		1/246 (0.4%)
Dysphagia	2/251 (0.8%)		1/246 (0.4%)
Ileal perforation	1/251 (0.4%)		0/246 (0%)
Ileus	1/251 (0.4%)		0/246 (0%)
Mucositis oral	0/251 (0%)		1/246 (0.4%)
Nausea	9/251 (3.6%)		6/246 (2.4%)
Pancreatitis	1/251 (0.4%)		0/246 (0%)
Small intestinal obstruction	0/251 (0%)		1/246 (0.4%)
Vomiting	10/251 (4%)		9/246 (3.7%)
General disorders
Chest pain	1/251 (0.4%)		1/246 (0.4%)
Death	10/251 (4%)		12/246 (4.9%)
Disease progression	12/251 (4.8%)		10/246 (4.1%)
Edema limbs	1/251 (0.4%)		2/246 (0.8%)
Fatigue	9/251 (3.6%)		9/246 (3.7%)
Fever	1/251 (0.4%)		1/246 (0.4%)
General symptom	2/251 (0.8%)		0/246 (0%)
Pain [NOS]	1/251 (0.4%)		0/246 (0%)
Pain [other]	1/251 (0.4%)		0/246 (0%)
Sudden death	3/251 (1.2%)		0/246 (0%)
Infections and infestations
Colitis, infectious (e.g., Clostridium difficile)	1/251 (0.4%)		0/246 (0%)
Eye infection [with normal or Grade 1-2 ANC]	1/251 (0.4%)		0/246 (0%)
Infection [neck, with normal or Grade 1-2 ANC]	1/251 (0.4%)		0/246 (0%)
Infection [other]	1/251 (0.4%)		2/246 (0.8%)
Infectious colitis [with unknown ANC]	1/251 (0.4%)		0/246 (0%)
Infectious meningitis [with unknown ANC]	0/251 (0%)		1/246 (0.4%)
Peritoneal infection [with unknown ANC]	1/251 (0.4%)		0/246 (0%)
Pleural infection [with normal or Grade 1-2 ANC]	1/251 (0.4%)		0/246 (0%)
Pneumonia [with Grade 3-4 ANC]	0/251 (0%)		1/246 (0.4%)
Pneumonia [with normal or Grade 1-2 ANC]	2/251 (0.8%)		3/246 (1.2%)
Pneumonia [with unknown ANC]	0/251 (0%)		3/246 (1.2%)
Urinary tract infection [with normal or Grade 1-2 ANC]	1/251 (0.4%)		1/246 (0.4%)
Wound infection [with unknown ANC]	0/251 (0%)		1/246 (0.4%)
Injury, poisoning and procedural complications
Arterial injury - Extremity-upper	1/251 (0.4%)		0/246 (0%)
Fracture	1/251 (0.4%)		0/246 (0%)
Investigations
Alanine aminotransferase increased	1/251 (0.4%)		2/246 (0.8%)
Alkaline phosphatase increased	1/251 (0.4%)		1/246 (0.4%)
Aspartate aminotransferase increased	2/251 (0.8%)		1/246 (0.4%)
Cardiac troponin I increased	2/251 (0.8%)		1/246 (0.4%)
Creatinine increased	0/251 (0%)		1/246 (0.4%)
INR increased	2/251 (0.8%)		0/246 (0%)
Laboratory test abnormal	1/251 (0.4%)		1/246 (0.4%)
Leukopenia	3/251 (1.2%)		2/246 (0.8%)
Lymphopenia	1/251 (0.4%)		0/246 (0%)
Neutrophil count decreased	3/251 (1.2%)		1/246 (0.4%)
Platelet count decreased	1/251 (0.4%)		3/246 (1.2%)
Weight loss	1/251 (0.4%)		4/246 (1.6%)
Metabolism and nutrition disorders
Acidosis	0/251 (0%)		1/246 (0.4%)
Anorexia	3/251 (1.2%)		1/246 (0.4%)
Dehydration	8/251 (3.2%)		8/246 (3.3%)
Hyperglycemia	3/251 (1.2%)		5/246 (2%)
Hypoalbuminemia	1/251 (0.4%)		1/246 (0.4%)
Hypocalcemia	0/251 (0%)		1/246 (0.4%)
Hypokalemia	2/251 (0.8%)		2/246 (0.8%)
Hypomagnesemia	0/251 (0%)		1/246 (0.4%)
Hyponatremia	2/251 (0.8%)		4/246 (1.6%)
Musculoskeletal and connective tissue disorders
Back pain	3/251 (1.2%)		3/246 (1.2%)
Bone pain	2/251 (0.8%)		0/246 (0%)
Joint pain	0/251 (0%)		1/246 (0.4%)
Muscle weakness	6/251 (2.4%)		4/246 (1.6%)
Muscle weakness lower limb	1/251 (0.4%)		1/246 (0.4%)
Musculoskeletal disorder	1/251 (0.4%)		0/246 (0%)
Neck pain	1/251 (0.4%)		0/246 (0%)
Pain in extremity	2/251 (0.8%)		0/246 (0%)
Nervous system disorders
Ataxia	0/251 (0%)		1/246 (0.4%)
Cognitive disturbance	1/251 (0.4%)		4/246 (1.6%)
Depressed level of consciousness	2/251 (0.8%)		4/246 (1.6%)
Dizziness	1/251 (0.4%)		1/246 (0.4%)
Encephalopathy	0/251 (0%)		1/246 (0.4%)
Headache	6/251 (2.4%)		1/246 (0.4%)
Ischemia cerebrovascular	3/251 (1.2%)		0/246 (0%)
Memory impairment	0/251 (0%)		2/246 (0.8%)
Mental status changes	1/251 (0.4%)		0/246 (0%)
Neurological disorder NOS	2/251 (0.8%)		0/246 (0%)
Nystagmus	1/251 (0.4%)		0/246 (0%)
Peripheral motor neuropathy	2/251 (0.8%)		4/246 (1.6%)
Peripheral sensory neuropathy	0/251 (0%)		1/246 (0.4%)
Seizure	2/251 (0.8%)		2/246 (0.8%)
Speech disorder	1/251 (0.4%)		2/246 (0.8%)
Syncope	2/251 (0.8%)		0/246 (0%)
Psychiatric disorders
Agitation	0/251 (0%)		1/246 (0.4%)
Confusion	4/251 (1.6%)		5/246 (2%)
Depression	2/251 (0.8%)		0/246 (0%)
Insomnia	0/251 (0%)		1/246 (0.4%)
Personality change	0/251 (0%)		1/246 (0.4%)
Psychosis	1/251 (0.4%)		0/246 (0%)
Renal and urinary disorders
Bladder hemorrhage	1/251 (0.4%)		1/246 (0.4%)
Renal failure	0/251 (0%)		1/246 (0.4%)
Urinary incontinence	1/251 (0.4%)		0/246 (0%)
Reproductive system and breast disorders
Pelvic pain	1/251 (0.4%)		1/246 (0.4%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	2/251 (0.8%)		1/246 (0.4%)
Cough	3/251 (1.2%)		0/246 (0%)
Dyspnea	11/251 (4.4%)		6/246 (2.4%)
Hemorrhage nasal	1/251 (0.4%)		1/246 (0.4%)
Hypoxia	4/251 (1.6%)		2/246 (0.8%)
Pleural effusion	1/251 (0.4%)		1/246 (0.4%)
Pneumonitis	4/251 (1.6%)		3/246 (1.2%)
Pneumothorax	0/251 (0%)		1/246 (0.4%)
Pulmonary hemorrhage	1/251 (0.4%)		0/246 (0%)
Respiratory disorder	3/251 (1.2%)		1/246 (0.4%)
Skin and subcutaneous tissue disorders
Alopecia	0/251 (0%)		1/246 (0.4%)
Sweating	0/251 (0%)		1/246 (0.4%)
Vascular disorders
Hypertension	1/251 (0.4%)		0/246 (0%)
Hypotension	2/251 (0.8%)		1/246 (0.4%)
Thrombosis	7/251 (2.8%)		9/246 (3.7%)
Other (Not Including Serious) Adverse Events
	WBRT+Memantine		WBRT+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/251 (63.7%)		166/246 (67.5%)
Blood and lymphatic system disorders
Hemoglobin decreased	28/251 (11.2%)		30/246 (12.2%)
Ear and labyrinth disorders
Hearing loss	15/251 (6%)		20/246 (8.1%)
Gastrointestinal disorders
Constipation	34/251 (13.5%)		25/246 (10.2%)
Diarrhea	6/251 (2.4%)		15/246 (6.1%)
Nausea	56/251 (22.3%)		67/246 (27.2%)
Vomiting	15/251 (6%)		34/246 (13.8%)
General disorders
Edema limbs	7/251 (2.8%)		13/246 (5.3%)
Fatigue	117/251 (46.6%)		107/246 (43.5%)
Injury, poisoning and procedural complications
Dermatitis radiation	9/251 (3.6%)		20/246 (8.1%)
Radiation recall reaction (dermatologic)	12/251 (4.8%)		20/246 (8.1%)
Investigations
Alanine aminotransferase increased	11/251 (4.4%)		17/246 (6.9%)
Alkaline phosphatase increased	11/251 (4.4%)		14/246 (5.7%)
Aspartate aminotransferase increased	6/251 (2.4%)		15/246 (6.1%)
Laboratory test abnormal	12/251 (4.8%)		14/246 (5.7%)
Leukopenia	14/251 (5.6%)		13/246 (5.3%)
Lymphopenia	20/251 (8%)		9/246 (3.7%)
Platelet count decreased	18/251 (7.2%)		15/246 (6.1%)
Weight loss	22/251 (8.8%)		27/246 (11%)
Metabolism and nutrition disorders
Anorexia	35/251 (13.9%)		35/246 (14.2%)
Hyperglycemia	28/251 (11.2%)		21/246 (8.5%)
Hypoalbuminemia	18/251 (7.2%)		15/246 (6.1%)
Hyponatremia	19/251 (7.6%)		16/246 (6.5%)
Musculoskeletal and connective tissue disorders
Back pain	12/251 (4.8%)		21/246 (8.5%)
Muscle weakness	7/251 (2.8%)		14/246 (5.7%)
Nervous system disorders
Ataxia	8/251 (3.2%)		14/246 (5.7%)
Dizziness	21/251 (8.4%)		31/246 (12.6%)
Headache	52/251 (20.7%)		48/246 (19.5%)
Memory impairment	15/251 (6%)		23/246 (9.3%)
Peripheral motor neuropathy	14/251 (5.6%)		13/246 (5.3%)
Peripheral sensory neuropathy	24/251 (9.6%)		15/246 (6.1%)
Seizure	6/251 (2.4%)		13/246 (5.3%)
Taste alteration	8/251 (3.2%)		14/246 (5.7%)
Psychiatric disorders
Depression	13/251 (5.2%)		15/246 (6.1%)
Insomnia	21/251 (8.4%)		20/246 (8.1%)
Respiratory, thoracic and mediastinal disorders
Cough	21/251 (8.4%)		21/246 (8.5%)
Dyspnea	32/251 (12.7%)		25/246 (10.2%)
Skin and subcutaneous tissue disorders
Alopecia	68/251 (27.1%)		65/246 (26.4%)

Limitations/Caveats

Given the poor compliance of the HVLT-R at 24 weeks, there was only 35% statistical power to detect the hypothesized effect size. Please see linked manuscript.

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.