Leptomeningeal Metastases: New Opportunities in the Modern Era

Abstract

Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.

Breast to Brain: A Case Report and Literature Review of Leptomeningeal Carcinomatosis

“…One unique and novel treatment modality that is currently undergoing research is the depletion of one specific nutrient in the CSF, iron. Given that LC is anatomically devoid of a blood-tumor capillary network, it is found that free iron in the CSF is one of the main nutrients that LC survives off [ 18 ]. An iron-binding transporter that is possessed by cancer cells is lipocalin-2, along with its receptor, SLC22A17 [ 18 ].…”

“…Given that LC is anatomically devoid of a blood-tumor capillary network, it is found that free iron in the CSF is one of the main nutrients that LC survives off [ 18 ]. An iron-binding transporter that is possessed by cancer cells is lipocalin-2, along with its receptor, SLC22A17 [ 18 ]. Current pre-clinical studies in mice show that by restricting the cancer cells from iron by intrathecal administration of an iron chelator, deferoxamine, there is an observed reduction in tumor burden correlated with prolonged survival.…”

“…Current pre-clinical studies in mice show that by restricting the cancer cells from iron by intrathecal administration of an iron chelator, deferoxamine, there is an observed reduction in tumor burden correlated with prolonged survival. Other novel therapies that exist are targeted radioimmunotherapy, commonly used in the pediatric population, and brachytherapy using liposomally encapsulated radionucleotides, used in solid tumor LC [ 18 ].…”

Cerebrospinal fluid‐dissemination of a ovarian clear cell carcinoma: A leptomeningial carcinomatosis with diagnostic challenges

“…In our patient, the last test showed a serum value of 492.There are currently several treatment modalities for LM. Intrathecal chemotherapy, whole‐brain radiation therapy (WBRT), radiation therapy for spinal cord disease (RT), and CNS‐sensitive chemotherapy regimens can be selected 23 . LM represents an advanced disease with a short survival time and an aggressive clinical presentation.…”

Development of a Triple-Negative Breast Cancer Leptomeningeal Disease Model in Zebrafish

“…Leptomeningeal disease (LMD) occurs when cancer cells metastasize from an original tumor site into the cerebrospinal fluid (CSF) that occupies the subarachnoid space between the pia and arachnoid mater layers of the meninges that surround the central nervous system [ 1 , 2 , 3 , 4 ]. LMD comprises up to 8% of solid and 15% of hematological malignancies, with over 100,000 new cases annually in the United States, and has a very poor prognosis with a median survival of 3–16 weeks despite treatment [ 5 , 6 ].…”