Abstract
Leptomeningeal metastatic disease (LMD), encompassing entities of ‘meningeal carcinomatosis’, neoplastic meningitis’ and ‘leukaemic/lymphomatous meningitis’, arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients. Underdiagnosis and misdiagnosis are common, response assessment remains challenging, and the prognosis associated with this disease of whole neuroaxis remains extremely poor. The dearth of effective therapies is further challenged by the difficulties in studying this dynamic disease state. In this Review, a multidisciplinary group of experts describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Drawing upon paradigm-changing advances in mechanistic science, computational approaches, and trial design, the authors discuss domain-specific and cross-disciplinary strategies for optimizing the clinical and translational research landscape for LMD. Advances in diagnostics, multi-agent intrathecal therapies, cell-based therapies, immunotherapies, proton craniospinal irradiation and ongoing clinical trials offer hope for improving outcomes for patients with LMD.
Key points
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.