Cerebrospinal Fluid-Administered Therapies for Leptomeningeal Metastases from Solid Tumors

Abstract

Aims/purpose: Leptomeningeal metastases (LM) are associated with substantial morbidity and mortality. Several approaches are used to treat LM, including intrathecally administered therapies. We consolidated current studies exploring intrathecal therapies for LM treatment. Patients & methods: A review of clinical trials using intrathecal agents was conducted with outcomes tabulated and trends described. 48 trials met the inclusion criteria. Initial investigations began with cytotoxic agents; following this were formulations with longer cerebrospinal fluid half-lives, targeted antibodies and radionucleotides. Results & conclusion: Outcomes were not reported consistently. Survival, when reported, remained poor. Intrathecal therapies for LM remain a viable option. Their use can be informed by an understanding of efficacy, safety and toxicity. They may be an important component of future LM treatments.

Plain language summary

This paper summarizes the findings from 48 clinical trials conducted since the 1970s about the treatment of leptomeningeal metastases through an intrathecal approach (administering drugs directly into the cerebrospinal fluid – a fluid that surrounds the brain and spinal cord). The results of these studies suggest that although these therapies show promise for the future, they currently do not clearly and consistently report a benefit. Further work is needed to explore the possible use of these treatments.

Keywords::

• chemotherapy
• CSF
• intrathecal
• leptomeningeal metastases

Supplementary data

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Financial & competing interests disclosure

R Lukas: speakers’ bureau for Merck, speakers’ bureau for Novocure, scientific advisory board for Merck, research support (drug only) from BMS. P Kumthekar reports consulting fees from Biocept, Affinia, Enclear, Angiochem, Bioclinica; payment or honoraria from Novocure, Sintetica; patents: European Patent 3307327, 12 August 2020; US Patent Pending 15/737, 188; participation on a Data Safety Monitoring Board or Advisory Board for Berg, Janssen, Mirati, Orbus Therapeutics, Celularity, SDP Oncology; and stock or stock options for Enclear. A Boire reports the following patents: Boire A and J Massagué, inventors, Sloan Kettering Institute, assignee – Modulating Permeability of The Blood Cerebrospinal Fluid Barrier, United States Provisional Application No.: 62/258,044, 20 November 2015; Boire A, Chen Q and J Massagué, inventors, Sloan Kettering Institute, assignee – Methods for Treating Brain Metastasis, United States Patent number 10413522, 17 September 2019; Boire A and Y Chi, inventors, Sloan Kettering Institute, assignee – Methods for Treating Leptomeningeal Metastasis, United States Provisional Application No.: 63/052,139, 15 July 2020. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

R Lukas: speakers’ bureau for Merck, speakers’ bureau for Novocure, scientific advisory board for Merck, research support (drug only) from BMS. P Kumthekar reports consulting fees from Biocept, Affinia, Enclear, Angiochem, Bioclinica; payment or honoraria from Novocure, Sintetica; patents: European Patent 3307327, 12 August 2020; US Patent Pending 15/737, 188; participation on a Data Safety Monitoring Board or Advisory Board for Berg, Janssen, Mirati, Orbus Therapeutics, Celularity, SDP Oncology; and stock or stock options for Enclear. A Boire reports the following patents: Boire A and J Massagué, inventors, Sloan Kettering Institute, assignee – Modulating Permeability of The Blood Cerebrospinal Fluid Barrier, United States Provisional Application No.: 62/258,044, 20 November 2015; Boire A, Chen Q and J Massagué, inventors, Sloan Kettering Institute, assignee – Methods for Treating Brain Metastasis, United States Patent number 10413522, 17 September 2019; Boire A and Y Chi, inventors, Sloan Kettering Institute, assignee – Methods for Treating Leptomeningeal Metastasis, United States Provisional Application No.: 63/052,139, 15 July 2020. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.