A prospective randomized study to compare neurocognitive outcome after Stereotactic Radiosurgery or Whole Brain Radiation Therapy for the treatment of multiple brain metastases

There is a trend to treat multiple brain metastases (BM) with stereotactic
radiosurgery (SRS). This is supported by prospective data and the recently
published American guideline on BM. In The Netherlands, the standard of care
for patients with multiple metastases (>4) remains whole brain radiotherapy
(WBRT). Nonetheless, in our hospital, SRS has been successfully applied in
patients with up to 10 BM and occasionally up to 20. SRS is expected to cause
fewer cognitive side effects than WBRT. There are no published trials yet
directly comparing SRS to WBRT, including objective neuropsychological testing.

Primary Objective
Our primary aim is to compare cognitive decline at 3 months, defined as a
significant decline (5 point decrease from baseline based on the reliable
change index with correction for practice effects) in HVLT-R Total Recall score
(verbal learning and memory test) after treatment with either SRS or WBRT in
patients with 11-20 non-melanoma BM at time of treatment initiation.

Secondary Objectives
• To determine the magnitude of the cognitive effects at 6, 9, 12, and 15
months follow-up in both treatment arms: improvements and/or declines
in memory, executive function, attention, processing speed, and upper extremity
fine motor dexterity
• To determine overall survival in both treatment arms
• To determine local and distant tumor control in the brain at 3, 6, 9, 12 and
15 months post treatment
• To assess psychological functioning (fatigue, depression and anxiety) and
health related Quality of Life (QOL) in both treatment arms
at 3, 6, 9, 12, and 15 months post treatment
• To identify possible predictors of cognitive functioning (age, sex, number
and cumulative volume of BM, extracranial disease status, type and duration of
systemic and salvage therapies, local and distant control, psychological
functioning) after each type of treatment

Prospective randomized multicenter study with follow-up (cognitive testing) at
3, 6, 9, 12, and 15 months and 3-monthly MRI scans after treatment with either
WBRT or SRS.
Groups will be balanced at baseline (prior to radiotherapy), taking into
account several (stratification) factors that may influence cognitive
functioning over time, such as: cumulative tumor volume in the brain, systemic
treatment, KPS, age, histology, and baseline cognitive functioning.

Patients in the WBRT group will receive 4 Gy x 5 fractions in one week, which
is a commonly utilized treatment schedule according to Dutch guidelines.
SRS will be performed with a Leksell Gamma Knife® Icon, Elekta Instruments, AB
(GKRS). Depending upon the volume, a dose of 18-25 Gy will be prescribed with
99-100% coverage of the target.

After randomisation (the minimisation method) patients will receive either WBRT
(the standard treatment in the Netherlands for patients with >10 BM) or SRS.

Although SRS has been proven effective as the initial treatment option in
patients with more than 10 BM, according to the Dutch guidelines, this is not a
standard treatment.
WBRT consist of a series of treatments, usually 5 sessions in one week, unlike
SRS, which is a one-day treatment. Patients randomised to WBRT will be treated
at a radiation treatment center nearby their home address. While the MRI scan
used for treatment planning is made at the Gamma Knife Center in Tilburg. A
possible disadvantage might be that patients will be treated elsewhere.
According to study protocol MRI scans will occur every three months at the
Gamma Knife Center.
Neuropsychological assessments (existing of six tests and three questionnaires)
will take mental effort. To reduce this effort as much as possible, a shortened
neuropsychological test battery was chosen (1,5 hour). Moreover, assessments
will be combined with patients' hospital visits.

Ultimately, the purpose of this line of research is to assist both doctors and
patients in individual decision-making with regard to the cognitive effects of
treatment with either WBRT or SRS.