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Page 2 of 20 Pellerino et al. J Cancer Metastasis Treat 2020;6:41 I http://dx.doi.org/10.20517/2394-4722.2020.80

INTRODUCTION
Leptomeningeal metastases (LM) represent an end-stage complication of advanced systemic cancer
in approximately 5% of patients. Autopsy series have revealed a high prevalence of undiagnosed or
[1]
asymptomatic LM in 19% of patients with solid tumors , representing the third most common metastatic
complication of the nervous system after brain metastases (BM) and epidural metastases. The incidence of
LM in patients with cancer is increasing due to better tools for diagnosis and monitoring and more effective
[2]
targeted therapies that lead to prolonged survival . However, overall survival remains in the order of weeks
to months regardless of treatment type.

A recent cohort study of 163 patients with LM has shown a median age of 57 years, and LM was the initial
presentation of cancer in 19 patients (11.7%), while in 28 patients (19%) LM was diagnosed during the
initial treatment course of primary tumor, and in the remaining 116 patients (81%) LM was diagnosed at
recurrence. The most common primary solid tumors in this cohort are non-small cell lung adenocarcinoma
[3]
(NSCLC - 52%), followed by small cell lung carcinoma (SCLC - 18%), and breast cancer (16%) .
[4]
NSCLC has a significant risk LM (20% of patients) with a median development time of 12 months (range
2-18 months) from diagnosis of the primary tumor . Epidermal growth factor receptor (EGFR) mutated
[3]
[5,6]
and anaplastic lymphoma kinase (ALK) gene rearranged NSCLC are more prone to recur with LM .
Thus, there is need to improve diagnostic tools, validate biomarkers to monitor disease progression, and
search for new treatment regimens for LM patients.

Here, we review the clinical and diagnostic challenges of LM from NSCLC, the role of magnetic resonance
imaging (MRI), cerebrospinal fluid (CSF) cytology and liquid biopsy, as well as the most recent clinical
trials on targeted therapies.

THE ROLE OF CNS BARRIERS IN DRUG DELIVERY
The CNS is considered as a sanctuary site which is protected by different barriers from neurotoxic agents.
The blood-brain barrier (BBB) consists of tight junctions (TJs) linked to the endothelial cells of the brain,
[7]
creating a physical barrier that limits the passage of molecules . The specialized endothelial cells maintain
a continuous, non-fenestrated basal lamina and interact with other perivascular cells, such as astrocytes,
[8]
pericytes, and perivascular macrophages, which contribute to the integrity of the BBB . Molecules may
cross the BBB by two mechanisms. The paracellular transport consists of a diffuse and passive flow between
the endothelial cells, and is regulated by physicochemical properties, including molecular weight, electrical
charge, and lipophilicity. In general, the TJs reduce the paracellular transport of molecules when the
BBB is intact; thus, the paracellular transport is limited to small, lipophilic molecules that are less than
[9]
500 Daltons . The transcellular transport consists of a flow of molecules across the luminal side of the
endothelial cell, through the cytoplasm, and then to the abluminal side into the brain interstitium. Some
active transport mechanisms are typical of transcellular transport for larger and less lipophilic molecules,
[10]
such as glucose, insulin, albumin, blood cells, infectious agents, and potential neurotoxins .
Similarly, the BBB impacts the ability of therapeutic agents to penetrate the CNS. In fact, more than 90%
of all small-molecules, and nearly 100% of large compounds, have poor penetration through the BBB ,
[11]
leading to a decreased efficacy on CNS disease control from chemotherapy and targeted agents. Notably,
the BBB is normal in pre-metastatic niche and micrometastases (< 1 mm), and protects them from most of
anticancer agents that are employed in the adjuvant treatment of NSCLC [12,13] . The most recent generations
of anaplastic lymphoma kinase (ALK) inhibitors and EGFR tyrosine kinase inhibitors (TKIs) display
an increased ability to cross the BBB, reaching significant CSF concentrations [Table 1], but these drugs
may be actively transported back into the cerebral blood flow by efflux pumps. The most important is the