Cognitive Outcome After SRS or WBRT in Patients With Multiple Brain Metastases (CAR-Study B)

Study Overview
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Brief Summary
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Whole Brain Radiation Therapy (WBRT) has long been the mainstay of treatment for patients with multiple brain metastases (BM). Meanwhile, Gamma Knife radiosurgery (GKRS) has been increasingly employed in the management of multiple BM to spare healthy tissue. Hence, GKRS is expected to cause fewer cognitive side effects than WBRT. Treatment of multiple BM without cognitive side effects is becoming more important, as more patients live longer due to better systemic treatment options. There are no published randomized trials yet directly comparing GKRS to WBRT in patients with multiple BM, including objective neuropsychological testing. CAR-Study B is a prospective randomized trial comparing cognitive outcome after GKRS or WBRT in eligible patients with 11-20 BM.

Detailed Description
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CAR-Study B is a prospective randomized trial comparing cognitive outcome after GKRS or WBRT in eligible patients with 11-20 BM on a triple dose gadolinium-enhanced MRI-scan. Neuropsychological assessment will be performed at baseline and at 3, 6, 9, 12 and 15 months after treatment. Follow-up assessments will be combined with 3-monthly MRI-scans. Patients will be randomized to either GKRS or WBRT. Groups will be balanced at baseline (prior to radiotherapy), taking into account several (stratification) factors that may influence cognitive functioning over time, such as: total tumor volume in the brain, systemic treatment, KPS, age, histology, and baseline HVLT-R total recall score.

Official Title
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A Prospective Randomized Study to Compare Cognitive Outcome After Stereotactic Radiosurgery or Whole Brain Radiation Therapy in Patients With 11-20 Brain Metastases

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Radiation: Gamma Knife radiosurgery
* Radiation: Whole Brain Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven malignant cancer 11-20 newly diagnosed brain metastases on a triple dose gadolinium-enhanced MRI-scan Maximum total tumor volume ≤ 30 cm3 Lesion ≥ 3 mm from the optic apparatus Age ≥ 18 years Karnofsky Performance Status (KPS) ≥ 70 Anticipated survival > 3 months Exclusion Criteria: No prior histologic confirmation of malignancy Primary brain tumor A second active primary tumor Small cell lung cancer (SCLC) Lymphoma Leukemia Meningeal disease Progressive, symptomatic systemic disease without further treatment options Prior brain radiation Prior surgical resection of BM Cardiovascular accident (CVA) < 2 years ago Additional history of a significant neurological or psychiatric disorder Contra indications to MRI or gadolinium contrast Underlying medical condition precluding adequate follow-up Participation in a concurrent study in which neuropsychological testing and/or health-related QOL assessments are involved Lack of basic proficiency in Dutch IQ below 85 Severe aphasia Paralysis grade 0-3 according to MRC scale (Medical Research Council)

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stereotactic radiosurgery (SRS)<br>Gamma Knife radiosurgery | Radiation: Gamma Knife radiosurgery<br>* GKRS is performed with a Leksell Gamma Knife® Icon, Elekta Instruments, AB. Depending upon the volume, a dose of 18-25 Gy will be prescribed with 99-100% coverage of the target.<br>|
| Active Comparator: Whole Brain Radiation Therapy (WBRT)<br>Whole Brain Radiation Therapy | Radiation: Whole Brain Radiation Therapy<br>* Patients in the WBRT group will receive 4 Gy x 5 fractions (total of 20 Gy) in one week, which is a commonly utilized treatment schedule according to Dutch guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive decline at 3 months | Cognitive decline is defined as a significant decline (5 point decrease from baseline based on the Reliable Change Index (RCI) with correction for practice effects) in HVLT-R Total Recall score (verbal learning and memory test) after treatment with either GKRS or WBRT in patients with 11-20 brain metastases at time of treatment initiation. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verbal memory | Verbal memory is measured with the Hopkins Verbal Learning Test-Revised (HVLT-R) | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Cognitive flexibility | Cognitive flexibility is measured with the Controlled Oral Word Association (COWA) | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Word Fluency | Word Fluency is measured with the Controlled Oral Word Association (COWA) | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Working memory | Working memory is measured with the Wechsler Adult Intelligence Scale - Digit Span | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Processing speed | Processing speed is measured with the Wechsler Adult Intelligence Scale - Digit Symbol | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Motor dexterity | Motor dexterity is measured with the Grooved Pegboard (GP) | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Health Related Quality Of Life (HRQOL) | The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure HRQOL. | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Fatigue | Fatigue is measured with the Multidimensional Fatigue Inventory (MFI). | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Depression and anxiety | Depression and anxiety are measured with the Hospital Anxiety and Depression Scale (HADS). | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | 
| Median Overall Survival | Overall survival is defined as the time in months from the start of treatment to the date of death or last contact if alive. Kaplan-Meier methods are used to estimate overall survival. | 12 months after GKRS/WBRT | 
| Local tumor control | Local brain tumor control of the initial treated lesions is defined as a complete, partial, or stable response, or less than a 25% increase in diameter on contrast-enhanced MRI follow-up and not requiring resection. Any initial treated lesions increased by more than 25% in diameter on contrast-enhanced MRI or required resection will be considered a local failure. | 12 months after GKRS/WBRT | 
| Distant tumor control | Distant brain tumor control is defined as the absence of any new brain metastases, distinct from the initial treated lesion(s), on follow-up MRI. The appearance of one or more new lesions in the brain by contrast-enhanced follow-up MRI is considered distant failure. | 12 months after GKRS/WBRT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain metastases, Cognition, Radiosurgery, Gamma Knife Radiosurgery, Stereotactic radiosurgery, Whole Brain Radiation Therapy, Quality of Life, Fatigue, Anxiety, Depression