Medical Research: What is the background for this study?
Response: Brain metastases are a serious complication of advanced malignancy and for most patients the objective is to maximise quality of survival. As treatment decisions become increasingly tailored to the individual, patient-focussed measures of efficacy such as neurocognitive function (NCF) are an important consideration. This is illustrated by the NCCTG N0574 randomised study reported last month at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. 208 patients with 1-3 brain metastases each <3cm were randomised to stereotactic radiosurgery (SRS) or SRS with whole brain radiotherapy (WBRT). The addition of WBRT improved intracranial disease control but did not translate into a survival benefit and was associated with a decline in neurocognitive function at 3 months.
The objective of our study was to describe the types of changes in neurocognitive function that can occur, summarise how they are assessed and review approaches used to mitigate their effects. We wanted to provide busy physicians with a clear and comprehensive overview of the topic that could be used to inform clinical decisions.
Medical Research: What are the main findings?
Response: Using sensitive tests, most patients with brain metastases have deficits in neurocognitive function at diagnosis. Evaluating and understanding changes after treatment is complex because neurocognitive function is a dynamic process that is influenced by a long list of inter-related factors.
For patients treated using whole brain radiotherapy alone, worsening neurocognitive function is observed in about two-thirds within 2-6 months. Deficits in verbal memory and fine motor control are most common. It is unclear what proportion relates to treatment toxicity as opposed to disease progression or pre-terminal decline because both are unfortunately also common events during this interval. By contrast, in other patients, NCF improves after WBRT due to treatment response.
For patients with 1-4 brain metastases treated using SRS, the addition of WBRT improves intracranial disease control at the expense of deficits in verbal memory at 4 months but the impact of recurrence and salvage therapy on neurocognitive function later than this is uncertain. Scant data suggests that some deficits in neurocognitive function after WBRT may improve with time in long term survivors. For patients with ≥5 brain metastases, SRS and/or systemic therapies may be considered in select patients instead of upfront whole brain radiotherapy but high quality evidence is lacking.
Advanced radiotherapy technologies, such as hippocampal-sparing WBRT and post-operative cavity SRS, can limit the dose delivered to unaffected areas of the brain in the hope of reducing toxicity. Randomised studies assessing their efficacy and cost-effectiveness in various clinical situations are underway prior to routine use. Small but statistically significant improvements in certain neurocognitive domains can also be achieved using medications such as memantine and donepezil. Preclinical data suggests that some commonly available drugs (such as ramipril, lithium and indomethacin) may have neuroprotective properties following WBRT; further evaluation is warranted.
Medical Research: What should clinicians and patients take away from your report?
Response: The key points are:
- Disease progression and treatment toxicity can both adversely affect neurocognitive function.
- In appropriately-selected patients, omitting whole brain radiotherapy after SRS may preserve neurocognitive function at 4 months but data beyond this time point are lacking.
- Whole brain radiotherapy-associated deficits in memory may partially recover with time.
- Hippocampal-sparing WBRT and cavity SRS are investigational alternatives to WBRT.
- Drugs that can mask or potentially reverse radiotherapy-induced neurotoxicity are emerging.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: Neurocognitive endpoints are necessary in all modern brain metastases trials to evaluate new treatments because benefits beyond overall survival and radiological measures of intracranial disease control are required.
Individual patients may attribute differing importance to certain neurocognitive domains and time point measures, depending on their individual circumstances and prognosis. Decision-making tools to aid patients evaluating such pros and cons may be of value. Progress in functional imaging and biomarkers to predict those at greatest risk of intracranial progression and/or neurotoxicity could also inform treatment decisions.
MB. Pinkham (2015). Cognitive Function Decline Common After Whole Brain Radiotherapy For Brain Metastases