Brain metastases remain a challenging and feared complication for patients with cancer and research in this area has lagged behind research into metastases to other organs. Due to their location and the risks associated with neurosurgical biopsies, the biology underpinning brain metastases response to treatment and evolution over time remains poorly understood. Liquid biopsies are proposed to overcome many of the limitations present with tissue biopsies, providing a better representation of tumor heterogeneity, facilitating repeated sampling, and providing a noninvasive assessment of tumor biology. Several different liquid biopsy approaches have been investigated including circulating tumor cells, circulating tumor DNA, extracellular vesicles, and tumor-educated platelets; however, these have generally been less effective in assessing brain metastases compared to metastases to other organs requiring improved techniques to investigate these approaches, studies combining different liquid biopsy approaches and/or novel liquid biopsy approaches. Through this review, we highlight the current state of the art and define key unanswered questions related to brain metastases liquid biopsies.

Purpose of review: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has resulted in plethora of publications. We review the existing evidence for individual treatments and new evidence for the integration of systemic and combination of local treatments. Recent findings: Encouraging efficacy of systemic therapies supports combination of systemic and local treatment albeit with little randomized trial data. Efficacy particularly of targeted agents provides an opportunity to delay local treatments including radiosurgery and whole brain radiotherapy. Randomized trials testing the integration of surgery, radiotherapy and radiosurgery are reviewed with emphasis on patient relevant endpoints to guide the clinician in the choice and sequence of treatments and integrating systemic and local therapies. Summary: There is increasing tendency to use focused radiation for single and oligometastases with or without surgery and decline in whole brain radiotherapy which is limited to multiple metastases in tumours without effective systemic options. Systemic therapies have promising intracranial efficacy and the sequence and combination with localized radiation is awaiting trials. Changes in practice with a move to primary systemic treatment for brain metastases without radiation, should be undertaken with caution and close monitoring.

Predicting survival is essential to tailoring treatment for patients diagnosed with brain metastases. We have evaluated the performance of widely used, validated prognostic scoring systems (Graded Prognostic Assessment and diagnosis-specific Graded Prognostic Assessment) in over 1000 'real-world' patients treated with stereotactic radiosurgery to the brain, selected according to National Health Service commissioning criteria. Survival outcomes from our dataset were consistent with those predicted by the prognostic systems, but with certain cancer subtypes showing a significantly better survival than predicted. Although performance status remains the simplest tool for prediction, total brain tumour volume emerges as an independent prognostic factor, and a new, improved, prognostic scoring system incorporating this has been developed.

Randomised control trial data support the use of stereotactic radiosurgery (SRS) in up to 4 brain metastases (BMs), with non-randomised prospective data complementing this for up to 10 BMs. There is debate in the neuro-oncology community as to the appropriateness of SRS in patients with >10 BMs. We present data from a large single-centre cohort, reporting survival in those with >10 BMs and in a >20 BMs subgroup. A total of 1181 patients receiving SRS for BMs were included. Data were collected prospectively from the time of SRS referral. Kaplan–Meier graphs and logrank tests were used to compare survival between groups. Multivariate analysis was performed using the Cox proportional hazards model to account for differences in group characteristics. Median survival with 1 BM (n = 379), 2–4 BMs (n = 438), 5–10 BMs (n = 236), and >10 BMs (n = 128) was 12.49, 10.22, 10.68, and 10.09 months, respectively. Using 2–4 BMs as the reference group, survival was not significantly different in those with >10 BMs in either our univariable (p = 0.6882) or multivariable analysis (p = 0.0564). In our subgroup analyses, median survival for those with >20 BMs was comparable to those with 2–4 BMs (10.09 vs. 10.22 months, p = 0.3558). This study contributes a large dataset to the existing literature on SRS for those with multi-metastases and supports growing evidence that those with >10 BMs should be considered for SRS.