Leptomeningeal Metastases: New Opportunities in the Modern Era

Abstract

Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.

Keywords: Brain metastases; Central nervous system metastases; Cerebrospinal fluid; Craniospinal radiation; Intrathecal therapy; Leptomeningeal disease; Leptomeningeal metastases.

Fig. 1

Anatomic considerations and conventional therapeutic strategies for leptomeningeal metastases. This illustration outlines the two phenotypic states of leptomeningeal metastases (LM), existing as both free-floating disseminated cells and adherent plaques to the brain and spinal cord. The three pillars of conventional therapies are shown, including intrathecal therapy (blue dots) through an Ommaya reservoir, systemic therapy (yellow dots) entering the cerebrospinal fluid (CSF) via the blood-CSF barrier of the choroid plexus, and involved-field radiation therapy (yellow beam) directed here against the adherent cells of the conus medullaris and cauda equina