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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
81
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.
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.
Gamma Knife Center Tilburg, Elisabeth-TweeSteden Hospital
Tilburg, North Brabant, Netherlands
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.
Time frame: 3 months
Verbal memory
Verbal memory is measured with the Hopkins Verbal Learning Test-Revised (HVLT-R)
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT
Motor dexterity
Motor dexterity is measured with the Grooved Pegboard (GP)
Time frame: 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.
Time frame: Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT
Fatigue
Fatigue is measured with the Multidimensional Fatigue Inventory (MFI).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 12 months after GKRS/WBRT
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