Integration of Systemic Therapy and Stereotactic Radiosurgery for Brain Metastases

SIMPLE SUMMARY: In the multi-modal treatment of brain metastasis (BM), the role of systemic therapy has undergone a recent revolution. Due to the development of multiple agents with modest central nervous system penetration of the blood-brain barrier, targeted therapies and immune checkpoint inhibitors are increasingly being utilized alone or in combination with radiation therapy. However, the adoption of sequential or concurrent strategies varies considerably, and treatment strategies employed in clinical practice have rapidly outpaced evidence development. Therefore, this review critically analyzes the data regarding combinatorial approaches for a variety of systemic therapeutics with stereotactic radiosurgery and provides an overview of ongoing clinical trials. ABSTRACT: Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and resection. However, the increased availability of molecular-based therapies with central nervous system (CNS) penetration now permits the individualized selection of tailored systemic therapies to be used alongside local treatments. Moreover, the introduction of immune checkpoint inhibitors (ICIs), with demonstrated CNS activity has further revolutionized the management of BM patients. The rapid introduction of these cancer therapeutics into clinical practice, however, has led to a significant dearth in the published literature about the optimal timing, sequencing, and combination of these systemic therapies along with SRS. This manuscript reviews the impact of tumor biology and molecular profiles on the management paradigm for BM patients and critically analyzes the current landscape of SRS, with a specific focus on integration with systemic therapy. We also discuss emerging treatment strategies combining SRS and ICIs, the impact of timing and the sequencing of these therapies around SRS, the effect of corticosteroids, and review post-treatment imaging findings, including pseudo-progression and radiation necrosis.