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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neoplasm Metastasis
• Intervention / Treatment: Radiation: Gamma Knife radiosurgery; Radiation: Whole Brain Radiation Therapy

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 Type: Interventional
• Enrollment (Actual): 81
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wietske CM Schimmel, MSc.; Phone Number: +31 135391333; Email: w.schimmel@etz.nl
• Study Contact Backup: Name: Eline Verhaak, MSc.; Phone Number: +31 135391333; Email: e.verhaak@etz.nl

Study Locations

• Netherlands
  • Noord-Brabant
    • Tilburg, Noord-Brabant, Netherlands, 5022 GC
      • Gamma Knife Center Tilburg, Elisabeth-TweeSteden Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Elisabeth-TweeSteden Ziekenhuis
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Tilburg University
• Investigators: Principal Investigator: Patrick EJ Hanssens, MD, Gamma Knife Center Tilburg, Elisabeth-TweeSteden Hospital, The Netherlands

Publications and helpful links

General Publications

• Schimmel WCM, Verhaak E, Hanssens PEJ, Gehring K, Sitskoorn MM. A randomised trial to compare cognitive outcome after gamma knife radiosurgery versus whole brain radiation therapy in patients with multiple brain metastases: research protocol CAR-study B. BMC Cancer. 2018 Feb 21;18(1):218. doi: 10.1186/s12885-018-4106-2.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): July 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: November 1, 2016
• First Posted (Estimated): November 3, 2016

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Depression; Quality of Life; Anxiety; Fatigue; Cognition; Stereotactic radiosurgery; Radiosurgery; Brain metastases; Gamma Knife Radiosurgery; Whole Brain Radiation Therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: 842003006; NTR5463 (Registry Identifier: Netherlands Trail Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO