Experimental Treatments for Leptomeningeal Metastases From Solid Malignancies

Solmaz Sahebjam, MD; Peter A. Forsyth, MD; Keiran S. Smalley, PhD; Nam D. Tran, MD, PhD


Cancer Control. 2017;24(1):42-46. 

In This Article

Abstract and Introduction


Background. Leptomeningeal metastasis is a consequence of advanced solid malignancies and has limited treatment options. It is possible that it is becoming more common as the leptomeninges act as a sanctuary site for recurrence from systemic cancer.

Methods. Potential targeted and immunotherapy agents for the most common types of solid-tumor leptomeningeal metastasis are reviewed, as are their dosing/delivery strategies and novel, immunological approaches.

Results. Historically, patients with leptomeningeal metastasis have been excluded from clinical trials, and data on the management of leptomeningeal metastasis come from single case reports and retrospective analyses.

Conclusion. For the first time ever, published reports suggest the tide may be turning in this challenging disease.


Leptomeningeal metastasis occurs in more than 5% of patients with advanced solid tumors.[1] The most common solid malignancies leading to leptomeningeal metastasis are adenocarcinomas of the breast (12%–35%), adenocarcinomas of the lung (10%–26%), and melanoma (5%–25%).[1] Prognosis is poor for leptomeningeal metastasis: The median overall survival rate after diagnosis is approximately 2 to 3 months.[1,2] Improved imaging techniques have resulted in an increased number of diagnosed cases of leptomeningeal metastasis. The advent of targeted drugs and immunotherapies — often with limited penetration into the central nervous system (CNS) — have improved the survival of patients with advanced solid malignancies.

However, these advancements have led to an increased prevalence of CNS metastases and leptomeningeal metastases over time. The leptomeningeal compartment has unique features that may allow it to function as a "sanctuary site" for recurrence from systemic cancer.

Drugs with poor blood–cerebrospinal fluid (CSF) permeability undertreat the tumoral cells in the subarachnoid space, which can subsequently escape the antitumoral effect and proliferate on the meninges.[1]

Treatment options for patients with leptomeningeal metastasis remain limited: Neither whole-brain radiotherapy nor systemic or intrathecal chemotherapy significantly improves outcomes.[1] In general, patients with leptomeningeal metastasis are excluded from clinical trials because of their poor prognosis and to minimize results that are not reproducible. Thus, treatment data for leptomeningeal metastasis are limited to small case series, thereby limiting our ability to draw conclusions that will apply to patients with leptomeningeal metastasis.

Investigational treatment options (targeted and immunotherapies) that may be beneficial in patients with the most common types of leptomeningeal metastasis are discussed below and also appear in the Table.[3–18]