Leptomeningeal metastatic disease: new frontiers and future directions.

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.
Competing Interests: Competing interests: S.A.G. has been a paid consultant for Plus Therapeutics. A.S. has been a paid consultant for Abbvie, BrainLAB, Elekta AB, Merck, Roche and Varian; has received honoraria for past educational seminars from Accuray, AstraZeneca, BrainLAB, Elekta AB, Seagen and Varian; has received research grants from BrainLAB, Elekta AB and Seagen; has received support for travel accommodation/expenses from BrainLAB, Elekta AB and Varian; belongs to the Elekta MR Linac Research Consortium; and is a Clinical Steering Committee Member and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. E.L.R. has received research grants from Bristol Myers Squibb and honoraria for lectures or as an advisory board member from Bayer, Janssen, Leo Pharma, Pierre Fabre, Seattle Genetics and Servier. M.W. has received research grants from Quercis and Versameb and honoraria for lectures, advisory board membership and/or a paid consultancy for Bayer, Curevac, Medac, Merck, Novartis, Novocure, Orbus, Philogen, Roche and Sandoz. T.W. has received research grants from Philogen and honoraria for lectures, advisory board membership and consultancy from Philogen. T.T.B. has received grants from ONO pharmaceuticals through their institution and receives royalties from Oxford University Press and UpToDate, Inc. P.Y.W. has received research grants from AstraZeneca, Black Diamond, Bristol Myers Squibb, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines and has been a paid consultant/advisory board member for AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Boston Pharmaceuticals, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Karyopharm, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics and VBI Vaccines. D.A.H.-K. has had leadership roles in EmpNia, Graegis Pharmaceuticals and TeleRad Oncology; received honoraria from Cincinnati Children’s Hospital DSMC, Defense Finance Service Agent DHHS, General Dynamic Information Tech, and Inc Reviewer; has had consulting or advisory roles at Gerson Lehrman Group and Guidepoint Global; received research funding from Artios; and provided expert testimony to Bendin, Bowman and Brooke, Sumrall and Ladner, and The EMMES Company. M.K. reports grants or contracts from AbbVie, BioNTech, BMS, CNS Pharmaceuticals, Daiichi Sankyo, Immorna Therapeutics, Immvira Therapeutics, JAX lab for genomic research, and Personalis; received consulting fees from AnHeart Therapeutics, Berg Pharma, George Clinical, Menarini Stemline and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPG Bio. R.R. has been an advisory board member and/or received research grants from Bayer, Curevac, Novocure and Servier. C.B. has been a paid consultant for Bionaut Labs, Depuy-Synthes, Haystack Oncology, and Privo Technologies and is a co-founder of Belay Diagnostics and OrisDx. G.F.W. has received grants from Focused Ultrasound Foundation and clinical trial support from Insightec. R.S. has been an advisory board member and/or received research grants from Medacc, Seagen and Servier. P.V. has been a paid consultant for and owns stock in Need Inc.; has received honoraria for lectures from Bayer; and has been an advisory board member for Cercare Medical. V.S. reports grants and/or contracts from AbbVie, AgenSys, Alfa‐Sigma, Altulm, Amgen, Bayer HealthCare Pharmaceuticals, Berghealth, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, Celgene Corporation, Dragonfly Therapeutics, Exelixis, F. Hoffmann‐La Roche AG, FUJIFILM Medical Systems USA, Genentech USA, GlaxoSmithKline, Idera Pharma, Incyte Corporation, Inhibrx, LOXO Oncology, MedImmune, Multivir, Nanocarrier, the National Cancer Institute, the National Comprehensive Cancer Network, Novartis Pharma, OncLive, Oncusp, PERS, Pfizer, PharmaMar, Relay Therapeutics and Takeda Oncology; personal and/or consulting fees from AbbVie, Bayer HealthCare, Pharmaceuticals, F. Hoffmann‐La Roche AG, Illumina, Incyte Corporation, Jazz Pharmaceuticals, LabCorp, Regeneron Pharmaceuticals and Relay Therapeutics; support for other professional activities from Aadi Biosciences, Clinical Care Communications, Illumina, Jazz Pharmaceuticals, Med Learning Group, Medscape, and Phenon Therapeutics; and travel support from ASCO, ESMO, Helsinn Healthcare, and Incyte Corporation outside the submitted work. M.S.A. has received grants from AstraZeneca, Bayer, Bristol Myers Squibb, Incyte, Pharmacyclics, Merck, MimiVax and Novocure; has been a paid consultant for Anheart Therapeutics, Apollomics, Bayer, Cairn Therapeutics, Caris Lifesciences, Cellularity, GSK, Insightec, Janssen, Kiyatec, Novocure, Nuvation, Prelude, Pyramid Biosciences, SDP Oncology, Theraguix, Tocagen, Varian Medical Systems, Viewray, Voyager Therapeutics and Xoft; is a scientific advisory board member for Cairn Therapeutics, Modifi Biosciences and Pyramid Biosciences; and is a stock shareholder in Cytodyn, MedInnovate Advisors and MimiVax. A.O., H.W., D.B., N.M., M.G., L.C.P. and A.M. declare no competing interests.
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