A Prospective Randomized Study to Compare Neurocognitive Outcome after Stereotactic Radiosurgery or Whole Brain Radiation Therapy for the Treatment of Multiple Brain Metastases

Background 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, 15, and 21 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, 15 and 21 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, 15, and 21 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 Study design Prospective randomized study with follow-up (cognitive testing) at 3, 6, 9, 15, and 21 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, systemic disease status, KPS, age, histology, and baseline cognitive functioning. Study population Adult patients with 11-20 non-melanoma BM on planning-MRI scan with controlled primary cancer, no prior treatment for BM, and KPS >/=70. Intervention 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® Perfexion, Elekta Instruments, AB (GKRS). Depending upon the volume, a dose of 18-25 Gy will be prescribed with 99-100% coverage of the target. Outcome measures • Cognitive functioning as assessed with a battery of neuropsychological tests: The revised Hopkins Verbal Learning Test (HVLT-R), WAIS Digit Span and Digit Symbol, TMT A and B, COWA, and Grooved Pegboard • Fatigue (MFI) • Health related QOL (FACT-BR) • Depression and anxiety (HADS) • Overall Survival • Local and distant tumor control Sample size 80 patients (40 in both groups), based both on power calculations and availability of patients (number of treatments in 2013). Data analyses • Repeated measures analysis of variance comparing subsequent follow-ups to baseline to assess cognitive change over time • Reliable Change Index (RCI) adjusted for practice effects: A standardized score representing the change in a patient’s score (personalized statistics) • Univariate and multivariate Cox proportional hazards analyses • Kaplan-Meier survival analysis • Type and duration of systemic therapy and medication use will be taken into account Time schedule Total duration of the trial will be four years. Accrual will start in May 2014 until May 2016. Patient will be followed up until February 2018. End of study will be in May 2018.