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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial of Hippocampal Avoidance During Whole Brain Radiotherapy for Brain Metastases

Conditions
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Cognitive/Functional Effects, Metastatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Radiation: intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: WBRT with Hippocampal Avoidance<br>Whole brain radiotherapy (WBRT) with hippocampal avoidance using intensity-modulated radiation therapy (IMRT) | Radiation: intensity-modulated radiation therapy<br>* 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.<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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] | Baseline and 4 months from start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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]. | Baseline and 4 months from start of treatment | 
| 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]. | Baseline and 4 months from start of treatment | 
| 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. | Baseline and 4 months from start of treatment | 
| 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. | Baseline and 4 months from start of treatment | 
| 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. | 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-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). | 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.) | 
| 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 | From start of treatment to 12 months from start of treatment | 
| 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 | Baseline and 4 months from start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive/functional effects, tumors metastatic to brain, unspecified adult solid tumor, protocol specific