Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions

Abstract

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.

Keywords: consensus guideline; intrathecal therapy; leptomeningeal disease; leptomeningeal metastases; radiation therapy; systemic therapy.

Figure 1.

Biology of leptomeningeal metastases (LM). (A)In a healthy individual, CSF is produced by choroid plexi (red structures) located within the ventricles. CSF circulates from the ventricles through the subarachnoid spaces of the brain and spinal cord, and is reabsorbed into blood circulation via arachnoid granulations in a pressure-dependent manner. (B) LM grows as adherent cells on the surface of the brain and spinal cord, appearing on magnetic resonance imaging as contrast-enhancing plaques, and/or freely floating cells in the CSF, which may be detected by CSF cytopathologic examination. These 2 states are highly plastic and maintained by unknown factors. (C) LM produces a range of factors that perturbs the function of the blood-CSF barrier at the choroid plexus, allowing entry of nutrients and mitogens from plasma into the CSF. Created with BioRender.com.

Figure 2.

Classic magnetic resonance imaging (MRI) features in patients with leptomeningeal metastases. (A) Thick sulcal enhancement involving the right frontoparietal sulci (arrowhead) on MRI brain axial T1-MPRAGE post-contrast images. (B) Linear ill-defined enhancement and nodules studding the cerebellar folia (arrowhead) on MRI brain axial T1-MPRAGE post-contrast images. Smooth leptomeningeal enhancement may also be seen coating the cranial nerves in the posterior fossa. (C) Smooth widespread enhancement of the conus medullaris and cauda equina (arrowhead) on MRI lumbar spine sagittal T1 post-contrast images. (D) Enhancement and clumping of the cauda equina nerve roots (arrowhead) on MRI lumbar spine axial T1 post-contrast images.

Figure 3.

Cytospin of CSF from a patient harboring leptomeningeal metastases secondary to breast cancer. (A) Low-power image illustrating abundant cellular material and proteinaceous deposits. (B) High-power image demonstrating major cell types present: Lymph, Lymphocyte; Gran, Granulocyte; Cancer, Cancer Cell. Scale Bar = 50 mm.