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

Sponsor

Elisabeth-TweeSteden Ziekenhuis (Other)

Overall Status

Recruiting

CT.gov ID

NCT02953717

Collaborator

Tilburg University (Other), ZonMw: The Netherlands Organisation for Health Research and Development (Other)

Enrollment

Location

Arms

84.9

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neoplasm Metastasis	Radiation: Gamma Knife radiosurgery Radiation: Whole Brain Radiation Therapy	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

46 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2016

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Stereotactic radiosurgery (SRS) Gamma Knife radiosurgery	Radiation: Gamma 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.
Active Comparator: Whole Brain Radiation Therapy (WBRT) Whole Brain Radiation Therapy	Radiation: Whole 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.

Arm

Intervention/Treatment

Active Comparator: Stereotactic radiosurgery (SRS)

Gamma Knife radiosurgery

Radiation: Gamma 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.

Active Comparator: Whole Brain Radiation Therapy (WBRT)

Whole Brain Radiation Therapy

Radiation: Whole 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.

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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)
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)
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)