Neoplasm Metastasis
Conditions
Keywords
Brain metastases, Cognition, Radiosurgery, Gamma Knife Radiosurgery, Stereotactic radiosurgery, Whole Brain Radiation Therapy, Quality of Life, Fatigue, Anxiety, Depression
Brief summary
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
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.
Interventions
RADIATIONWhole Brain Radiation Therapy
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.
RADIATIONGamma Knife radiosurgery
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.
Sponsors
Tilburg University
ZonMw: The Netherlands Organisation for Health Research and Development
Elisabeth-TweeSteden Ziekenhuis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive decline at 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive flexibility | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Cognitive flexibility is measured with the Controlled Oral Word Association (COWA) |
| Word Fluency | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Word Fluency is measured with the Controlled Oral Word Association (COWA) |
| Working memory | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Working memory is measured with the Wechsler Adult Intelligence Scale - Digit Span |
| Processing speed | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Processing speed is measured with the Wechsler Adult Intelligence Scale - Digit Symbol |
| Motor dexterity | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Motor dexterity is measured with the Grooved Pegboard (GP) |
| Verbal memory | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Verbal memory is measured with the Hopkins Verbal Learning Test-Revised (HVLT-R) |
| Fatigue | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Fatigue is measured with the Multidimensional Fatigue Inventory (MFI). |
| Depression and anxiety | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | Depression and anxiety are measured with the Hospital Anxiety and Depression Scale (HADS). |
| Median Overall Survival | 12 months after GKRS/WBRT | 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. |
| Local tumor control | 12 months after GKRS/WBRT | 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. |
| Distant tumor control | 12 months after GKRS/WBRT | 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. |
| Health Related Quality Of Life (HRQOL) | Baseline and 3, 6, 9, 12 and 15 months post GKRS/WBRT | The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure HRQOL. |
Countries
Netherlands
Outcome results
None listed