Cognitive/Functional Effects, Metastatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
cognitive/functional effects, tumors metastatic to brain, unspecified adult solid tumor, protocol specific
Brief summary
RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells. PURPOSE: This phase II trial is studying how well avoiding the hippocampus during whole-brain radiation therapy works in treating patients with brain metastases.
Detailed description
OBJECTIVES: Primary * Evaluate delayed recall as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R) at 4 months after hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) in patients with brain metastasis. Secondary * Evaluate auditory and visual learning and memory, as assessed by two CogState tests (International Shopping List Test and One Card Learning Test), after HA-WBRT in these patients. * Compare psychometric properties of the 2 CogState tests to the HVLT-R for the assessment of memory decline after HA-WBRT in these patients. * Evaluate health-related quality of life \[as assessed by the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR) and the Barthel Index of Activities of Daily Living (ADLs)\] after HA-WBRT in these patients. * Evaluate time to radiographic progression after HA-WBRT in these patients. * Evaluate overall survival of these patients after HA-WBR. * Evaluate the adverse events of HA-WBR. * Evaluate predictive biomarkers of cognitive function. OUTLINE: This is a multicenter study. Patients undergo 10 fractions of intensity-modulated whole-brain radiotherapy (WBRT), avoiding hippocampal (HA) regions, once daily, 5 days a week, for 2-2½ weeks. Patients neurocognitive functions (delayed recall, auditory and visual learning, and memory) are evaluated by the Hopkins Verbal Learning Test-Revised (HVTL-R), The One Card Learning Test (OCLT), and the International Shopping List Test (ISLT) at baseline and periodically during study. Patients may undergo serum, plasma, or whole blood collection at baseline and at 4 months after completion of HA-WBRT for correlative studies. Patients may complete the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR), and the Barthel Index of Activities of Daily Living (ADLs) quality-of-life questionnaires at baseline and periodically during study and follow up. After completion of study therapy, patients are followed up periodically.
Interventions
RADIATIONintensity-modulated radiation therapy
30 Gy in 10 fractions to the whole brain using intensity-modulated radiation therapy excluding the hippocampal avoidance area. Bilateral hippocampal contours manually generated on the fused planning MRI CT image set by the treating physician according to protocol-specified contouring instructions. Hippocampal avoidance regions generated by three-dimensionally expanding the hippocampal contours by 5 mm.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed non-hematopoietic malignancy within the past 5 years * If histologic proof of malignancy is from \> 5 years ago, then a more recent pathological confirmation is required (e.g., from systemic metastatic or brain metastasis) * Patients with metastasis of unknown primary tumor are permitted * Measurable brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast-enhanced MRI obtained within the past 30 days * Have not been or will not be treated with stereotactic radiosurgery (SRS) or surgical resection * These treatment options are allowed only at relapse * Patients who have brain metastases at initial presentation allowed and do not need to demonstrate 3 months of stable scans * At least 1 week since open biopsy * Karnofsky performance status 70-100% * Fertile patients must use effective contraception * Negative pregnancy test 2 weeks or less prior to study entry * Patients must be English proficient, with patients who speak English as a second language eligible
Exclusion criteria
* Small cell lung cancer or germ cell malignancy * Leptomeningeal metastases * Non-small cell lung cancer-associated brain metastases with ≥ 2 organ sites of extracranial metastases * Radiologic evidence of hydrocephalus * Serum creatinine \> 1.4 mg/dL within 30 days prior to study entry * Pregnant or nursing * Contraindication to MRI imaging such as implanted metal devices or foreign bodies or severe claustrophobia * Severe, active co-morbidity including any of the following: * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months * Transmural myocardial infarction within the past 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy * Uncontrolled, clinically significant cardiac arrhythmias * Prior radiotherapy to the brain * Plan for chemotherapy or targeted therapies during WBRT or during the subsequent 7 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) | Baseline and 4 months from start of treatment | Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT\_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100\*\[(baseline score - 4 month score)/ baseline score\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT) | Baseline and 4 months from start of treatment | The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\]. |
| Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) | Baseline and 4 months from start of treatment | The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires \>= 50% of items to be completed while the overall response rate must be \> 80%. If items are missing, the subscale scores can be prorated. |
| Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) | Baseline and 4 months from start of treatment | The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status. |
| Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT) | Baseline and 4 months from start of treatment | The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\]. |
| Progression-free Survival | Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.) | Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions \< 1cm, at least 25% for lesions \>=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals). |
| The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment | From start of treatment to 12 months from start of treatment | For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE |
| ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function | Baseline and 4 months from start of treatment | Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure |
| Overall Survival | Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.) | Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| WBRT With Hippocampal Avoidance Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT) | 100 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | No protocol treatment | 7 |
| Overall Study | Protocol Violation | 6 |
Baseline characteristics
| Characteristic | WBRT With Hippocampal Avoidance |
|---|---|
| Age, Continuous | 61 years |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 96 |
| serious Total, serious adverse events | 13 / 96 |
Outcome results
Primary
Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)
Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT\_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100\*\[(baseline score - 4 month score)/ baseline score\]
Time frame: Baseline and 4 months from start of treatment
Population: Eligible patients who started treatment and had baseline and 4 month data
| Arm | Measure | Value (MEAN) |
|---|---|---|
| WBRT With Hippocampal Avoidance | Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) | 7.0 percent change |
Comparison: To detect a minimum relative 50% improvement leading to an absolute 15% mean relative decline (MRD) in HVLT-R DR, 51 analyzable patients were required to ensure 80% statistical power with 0.05 alpha. Assuming a death rate of 40% before 4 months (based on trial NCT00003563) and a 10% nonevaluable rate, the target sample size was 102. The target MRD was determined from NCT00003563 which demonstrated 30% MRD in HVLT-R DR score from baseline to 4 months, with a standard deviation of 41%.p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function
Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure
Time frame: Baseline and 4 months from start of treatment
Secondary
Overall Survival
Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.
Time frame: Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: Eligible patients who started study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT With Hippocampal Avoidance | Overall Survival | 6.8 months |
Secondary
Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT)
The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
Time frame: Baseline and 4 months from start of treatment
Population: Eligible patients who started treatment and had baseline and 4 month data
| Arm | Measure | Value (MEAN) |
|---|---|---|
| WBRT With Hippocampal Avoidance | Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT) | 18.0 percent change |
Secondary
Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT)
The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100\*\[(baseline score - 4 month score)/ baseline score\].
Time frame: Baseline and 4 months from start of treatment
Population: Eligible patients who started treatment and had baseline and 4 month data
| Arm | Measure | Value (MEAN) |
|---|---|---|
| WBRT With Hippocampal Avoidance | Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT) | -8 percent change |
Secondary
Progression-free Survival
Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions \< 1cm, at least 25% for lesions \>=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).
Time frame: Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: Eligible patients who started study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WBRT With Hippocampal Avoidance | Progression-free Survival | 5.9 months |
Secondary
Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL)
The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.
Time frame: Baseline and 4 months from start of treatment
Population: Eligible patients who started treatment and completed at least one ADL assessment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) | Baseline | 20 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) | 2 month | 20 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) | 4 month | 20 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL) | 6 month | 20 units on a scale |
Comparison: A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Intercept is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Time is reported here.p-value: 0.1579Mixed Models Analysis
Comparison: A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Neurologic function status (some symptoms) is reported here.p-value: 0.0559Mixed Models Analysis
Comparison: A general linear fixed effects model was run with ADL (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Age (\>= 60) is reported here.p-value: 0.0749Mixed Models Analysis
Secondary
Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br)
The FACT-Br is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires \>= 50% of items to be completed while the overall response rate must be \> 80%. If items are missing, the subscale scores can be prorated.
Time frame: Baseline and 4 months from start of treatment
Population: Eligible patients who started treatment and completed at least one FACT-Br assessment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) | 4 month | 115 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) | 6 month | 126.22 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) | Baseline | 121.25 units on a scale |
| WBRT With Hippocampal Avoidance | Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) | 2 month | 111.94 units on a scale |
Comparison: A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and recursive partitioning analysis class (RPA) (I vs. II). Explanatory variables are reported separately and only if in the final model (p\< 0.10, except time forced in the model.). Intercept is reported here.p-value: <0.0001Mixed Models Analysis
Comparison: A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Time is reported here.p-value: 0.1961Mixed Models Analysis
Comparison: A general linear fixed effects model was run with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Primary site (lung) is reported here.p-value: 0.0715Mixed Models Analysis
Comparison: A general linear fixed effects model with FACT-Br total score (baseline, 2, 4, 6 mo. from end of treatment) as outcome of interest. Explanatory variables in the model: Age (\>= 60 vs. \<60), primary site (lung,breast,colon each vs. other), neurologic function status (no vs. some symptoms), and RPA class(I vs. II). Explanatory variables are reported separately and only if they are in the final model (p\< 0.10, except time forced in the model.). Neurologic status (no symptoms) is reported here.p-value: 0.0554Mixed Models Analysis
Secondary
The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment
For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
Time frame: From start of treatment to 12 months from start of treatment
Population: Eligible patients who started study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| WBRT With Hippocampal Avoidance | The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment | 2 Participants |