Leptomeningeal metastatic disease: new frontiers and future directions

The pathogenesis of leptomeningeal metastatic disease (LMD) is distinct from that of brain metastases. Cancer cell dissemination and attachment to the leptomeninges involves remodelling of the blood–choroid plexus barrier and the pia mater. Unique mechanisms for cancer cell survival within the resource-scarce cerebrospinal fluid (CSF) include outcompeting tumour-associated macrophages, elevated levels of branched-chain keto-acids, and exploitation of the complement system. Advances in the development of tools for diagnostic confirmation, disease surveillance and standardized criteria for response assessment will enable the comprehensive longitudinal work-up of LMD, with potential for integration of CSF liquid biopsy. Trials testing the efficacy of novel therapeutic approaches in patients with LMD, such as systemic antibody–drug conjugates, intrathecal targeted therapies and immunotherapies (including dendritic cell-based vaccines), are warranted, whereas promising data are emerging for strategies such as proton-based craniospinal irradiation. Learning from prior failures in neuro-oncology through better-optimized trials and international prospective registries remains essential for the success of future studies, a focus of which should be longitudinal CSF profiling. The implementation of an LMD-specific core outcome set, meticulous pharmacokinetic and pharmacodynamic evaluations prior to late-phase trials, use of CSF flow studies in trials of intrathecal therapies, integration with multi-omics analyses, and use of adaptive designs will help to optimize future trials.