Clinical Perspectives in Brain Metastasis

Abstract

Brain metastases (BMs) are responsible for decline in neurological function, reduction in overall quality of life, and mortality from recurrent or untreatable lesions. Advances in diagnostics and imaging have led to increased detection of central nervous system (CNS) metastases in patients with progressive cancers. Improved control of extracranial systemic disease, and the limited ability of current therapeutics to cross the blood-brain barrier (BBB) also contribute to the increase in incidence of brain metastases, as tumor cells seek refuge in the brain. Surgery, chemotherapy, and/or radiation (whole-brain radiation therapy and stereotactic radiation surgery [WBRT/SRS]) are a clinically established treatment paradigm for patients with brain metastases. With the advent of genetic and molecular characterization of tumors and their immune microenvironment, clinical trials seek to include targeted drugs into the therapeutic regimen for eligible patients. Several challenges, like treatment of multiple CNS lesions, superior uptake of chemotherapy into the brain, and trials with multidisciplinary approaches, are now being clinically addressed.

Figure 1.

Barriers to entry. The blood–brain barrier, the blood–cerebrospinal fluid barrier, and the blood–spinal cord barrier: (1) A primary tumor originating in the body enters the blood stream in the beginning phases of metastasis. (2–4) Circulating tumors cells in the blood stream arrive at three different locations in the central nervous system (CNS): (2) the blood–brain barrier (BBB), (3) the blood–cerebrospinal fluid barrier (BCSFB), and (4) the blood–spinal cord barrier (BSCB). Each of these barriers comprise of different molecules designed to shield the CNS from external influence. (2) The BBB is composed of tight junctions (zonulae occludens) between endothelial cells, which create a mostly impenetrable barrier. Tight junctions include transmembrane and cytoplasmic proteins consisting of occludin, claudins, and junctional adhesion molecules (JAMs). These are further associated with regulatory proteins including ZO-1, ZO-2, ZO-3, and cingulin. (3) The BCSFB is a structure, which has increased permeability compared with the BBB. BCSFB endothelial cells lack tight junctions and are thus have a leaky choroid plexus tight junction for membrane integrity. (4) The overall framework for the BSCB is similar to the BBB with main difference being in the architecture of the endothelial cells.