Stereotactic radiosurgery (SRS Financials) is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor control rates are superior to whole brain radiotherapy (WBRT) alone. As a result, WBRT plus SRS was widely adopted for patients with a limited number of brain metastases (“limited number” customarily means 1-4). Subsequent trials focused on answering whether WBRT upfront was necessary at all. Based on current randomized controlled trials (RCTs) and meta-analyses comparing SRS alone to SRS plus WBRT, adjuvant WBRT results in better intracranial control; however, at the expense of neurocognitive functioning and quality of life. These adverse effects of WBRT may also negatively impact on survival in younger patients. Based on the results of these studies, treatment has shifted to SRS alone in patients with a limited number of metastases. Additionally, RCTs are evaluating the role of SRS alone in patients with >4 brain metastases. New developments in SRS include fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood brain barrier and/or stimulate an immune response. We present in this review the current high level evidence and rationale supporting SRS as the standard of care for patients with limited brain metastases, and emerging applications of SRS.

Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.

As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.

Although the role of neurosurgery had been established in the 1990s as a means to achieve local control and prolong survival, it was reserved for the minority of patients presenting with a single metastasis and no other disease beyond the brain [4-7]. Still lacking was a focal ablative non-invasive treatment that could be applied efficiently to a much broader population of patients with brain metastases. This set the stage for the development of stereotactic radiosurgery (SRS). SRS is a focused ablative radiation treatment delivered with sub-millimeter precision to the tumor localized in three-dimensions in 1-5 fractions.

The focus of this review is to summarize the current high level evidence to clarify the role of SRS as optimal management for patients presenting with limited brain metastases. Furthermore, we provide an overview of the emerging applications of SRS as it continues to evolve into a treatment alternative to WBRT, with the intent to maximize neurcognitive function and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from a primary tumor mass to form distant colonies through implantation at an ectopic site, such as the brain [8-10]. To do so requires CTCs to arrest within the circulation, extravasate from the bloodstream or lymphatics into the brain, and survive and proliferate [11-13]. The process of metastatic colonization involves a direct interaction of CTCs with endothelial cells and astrocytes in the brain microenvironment. For example, CTCs that have arrested within the capillary bed direct local endothelial cells to remodel the adjacent environment to promote tumour cell growth and invasion [14-16]. Further, metastatic tumour cells recruit systemic stromal cells, such as fibroblasts, to assist with early colonization , and co-opt local stromal cells, such as reactive astrocytes and microglia, to promote tissue invasion [15, 18, 19]. Astrocytes within the tumour microenvironment may also play a role in protecting tumour cells from chemotherapy-induced cytotoxicity, through a yet to be defined mechanism requiring cell-cell contact [20, 21]. Tumour cells, through release of migration inhibitory factor, interleukin-8, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to enhance tumor-cell proliferation in vitro [22-24]. These molecular processes represent novel and understudied possible therapeutic targets for the treatment of intracranial metastatic disease.

SRS was initially a very resource intensive therapy offered only at specialized centers and indicated only for metastatic patients with a good life expectancy. The challenge lay in prognosticating patients effectively and as a result the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) [28, 29] was developed. Based on the patient's Karnofsky Performance Status (KPS), age, status of the primary tumor and presence of extracranial disease, patients were grouped into class 1, 2 or 3 with corresponding median survivals of 7.1, 4.2 and 2.3 months, respectively. Although a major development at the time, the RPA is now considered overly simplistic as current oncologic decision making is far more complex incorporating molecular, histological, clinical and radiographic disease characteristics. There are now more sophisticated classification tools, such as the diagnosis-specific graded prognostic assessment (DS-GPA). This system provides histology-specific estimates of survival and can separate, for example, the most favorable breast cancer patients with an expected survival of 25 months (excellent KPS and luminal B type breast cancer) from the least favorable patients with an expected survival of 3 months (poor KPS and basal-like breast cancer) . Despite advances in prognostication of patients with brain metastases, physicians are still largely unable to accurately predict long-term survivors. A study asking expert physicians to estimate survival of a 150 patients with information about cancer type, number of brain metastases, neurological presentation, extra-cranial disease status, KPS, RPA class, prior whole-brain radiotherapy, and synchronous or metachronous presentation, showed that more than 45% of predictions were off by more than 6 months and 18% were off by more than 12 months . Further advances in prognostic tests such as the “liquid biopsy” (a non-invasive blood test that can detect tumor DNA or RNA fragments or CTCs) are needed and in development . These combine advanced patient and tumor specific genomic information into the equation, in order to achieve personalized survival predictions.

Surgery continues to be an important treatment option for patients with limited brain metastases. It is indicated when metastases are large (>3-4 cm), or when a pathologic diagnosis is needed. In addition, surgery is preferred in the presence of significant edema requiring prolonged high dose dexamethasone, or to potentially reverse neurological deficits. Otherwise, the current evidence suggests that the efficacy of SRS is sufficient to achieve durable local control that is comparable to surgery. Although there are n