Current Approaches and Future Directions for the Treatment of Solid Tumour Brain Metastases

Abstract

Brain metastases (BrM) are most common among patients with metastatic lung cancer, breast cancer, and melanoma. Historically, management of BrM consisted of local treatments with surgical resection and/or radiation therapy, with either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Current guidelines recommend SRS as the initial therapy for patients who have up to four BrM, but several studies have demonstrated that upfront SRS may be considered for some patients who have more than four BrM given additional clinical benefits of improved memory function and quality of life compared to WBRT.

Systemic therapies are increasingly understood to cross the blood-brain barrier (BBB) following disruption of its integrity upon BrM development. Disseminated tumour cells intravasate into the circulation and spread hematogenously with a “seed and soil” tropism for the brain that provides a suitable tumour microenvironment. Tumour cells extravasate and increase the permeability of the BBB by decreasing tight junction protein expression, decreasing astrocyte pedicles, reducing pericyte coverage, and increasing neoangiogenesis. The altered integrity of the BBB allows penetration of large drug molecules, such as antibody-drug conjugates (ADCs), which exert their therapeutic effects on BrM by binding to tumour cell-specific epitopes and releasing a cytotoxic payload, even in the absence of radiation. Other therapeutic mechanisms of action include molecular (passive or receptor-mediated transport), physical (radiation or focused ultrasound), direct delivery to the brain (intrathecal or intratumoral), and cell‑mediated (immune cell extravasation) (Figure 1).