Cognitive/Functional Effects, Metastatic Cancer, Neurotoxicity, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
cognitive/functional effects, neurotoxicity, tumors metastatic to brain, unspecified adult solid tumor, protocol specific
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.
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.
Interventions
DRUGMemantine
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.
OTHERPlacebo
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.
RADIATIONWhole 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
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| WBRT+Memantine Whole brain radiation therapy (WBRT) and memantine | 256 |
| WBRT+Placebo Whole brain radiation therapy (WBRT) and placebo | 252 |
| Total | 508 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 95 | 78 |
| Overall Study | Missing reason not reported | 16 | 20 |
| Overall Study | Missing reason not specified | 1 | 2 |
| Overall Study | Not tested due to disability | 6 | 12 |
| Overall Study | Patient refusal | 37 | 37 |
| Overall Study | Protocol Violation | 22 | 24 |
| Overall Study | Withdrawal by Subject | 30 | 25 |
Baseline characteristics
| Characteristic | WBRT+Memantine | WBRT+Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60 years | 59 years | 59 years |
| Sex: Female, Male Female | 141 Participants | 145 Participants | 286 Participants |
| Sex: Female, Male Male | 115 Participants | 107 Participants | 222 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 160 / 251 | 166 / 246 |
| serious Total, serious adverse events | 80 / 251 | 67 / 246 |
Outcome results
Primary
Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks
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
Population: All eligible patients with Hopkins Verbal Learning Test-Revised for delayed recall (HVLT-R delayed recall) at baseline and 24 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT+Memantine | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks | 0 units on a scale |
| WBRT+Placebo | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 24 Weeks | -0.9 units on a scale |
Comparison: 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.p-value: 0.059Wilcoxon (Mann-Whitney)
Secondary
Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks
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
Population: Eligible patients with FACT-Br score at baseline and 24 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT+Memantine | Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks | 0 units on a scale |
| WBRT+Placebo | Change in Functional Assessment of Cancer Therapy With Brain Subscale (FACT-Br) at 24 Weeks | 1 units on a scale |
Comparison: 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.p-value: 0.77Wilcoxon (Mann-Whitney)
Secondary
Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks
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
Population: Eligible patients with baseline and respective post-baseline measurements
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| WBRT+Memantine | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 8-weeks | -0.36 units on a scale |
| WBRT+Memantine | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 16-weeks | 0 units on a scale |
| WBRT+Memantine | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 52-weeks | 0 units on a scale |
| WBRT+Placebo | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 8-weeks | -0.72 units on a scale |
| WBRT+Placebo | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 16-weeks | 0 units on a scale |
| WBRT+Placebo | Change in the Hopkins Verbal Learning Test - Revised for Delayed Recall (HVLT-R-delayed Recall) at 8, 16, and 52 Weeks | 52-weeks | 0 units on a scale |
Comparison: 8 weeksp-value: 0.0692Wilcoxon (Mann-Whitney)
Comparison: 16 weeksp-value: 0.4541Wilcoxon (Mann-Whitney)
Comparison: 52 weeksp-value: 0.397Wilcoxon (Mann-Whitney)
Secondary
Median Progression-free Survival Time
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.
Population: All eligible patients
| Arm | Measure | Value (MEAN) |
|---|---|---|
| WBRT+Memantine | Median Progression-free Survival Time | 4.7 months |
| WBRT+Placebo | Median Progression-free Survival Time | 5.5 months |
Comparison: 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.p-value: 0.2795% CI: [0.87, 1.3]Log Rank
Secondary
Median Time to Neurocognitive Failure
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
Population: All randomized eligible patients with neurocognitive scores from baseline to 12 months from start of drug treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT+Memantine | Median Time to Neurocognitive Failure | 2.6 years |
| WBRT+Placebo | Median Time to Neurocognitive Failure | 2.3 years |
Comparison: 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.p-value: 0.0195% CI: [0.62, 0.99]Gray's test
Secondary
Overall Survival
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.
Population: All eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT+Memantine | Overall Survival | 6.7 months |
| WBRT+Placebo | Overall Survival | 7.8 months |
Comparison: 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.p-value: 0.02595% CI: [0.86, 1.31]Log Rank