Integration of Systemic Therapy and Stereotactic Radiosurgery for Brain Metastases

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.

Keywords: brain metastases; chemotherapy; immunotherapy; stereotactic radiosurgery; targeted therapy.

Figure 1

Categorization of various chemotherapeutic drugs or regimens based on CNS response (defined as proportion of patients with stable disease, partial response, or complete response) into low (<25%), medium (25–50%), and high (>50%).

Figure 2

Illustration of the immune stimulatory effects of SRS leading to a localized breakdown and permeability of the BBB, causing the release of tumor associated neoantigens, ultimately leading to T-cell activation by antigen presenting cells (modest local tumor response and a weak abscopal effect); in contrast, the addition of immune checkpoint inhibitors (anti-CTLA4, anti-PD1 and anti-PDL1) to SRS leads to strong local tumor response and a strong abscopal effect (abscopal effect is defined as tumor shrinkage or elimination in sections of the body not directly targeted by local therapy).