Leptomeningeal metastasis (LM) occurs when malignant cells spread to the leptomeninges (the pia, arachnoid, and the cerebrospinal fluid (CSF) in subarachnoid space) overlying the brain parenchyma and spinal cord. Though LM is a common metastatic complication of central nervous system (CNS) tumors, it can also result from non-CNS cancers including hematologic malignancies, and solid tumors such as breast cancer, lung cancer, and melanoma. The incidence of LM is also significantly increased following metastasis of these cancers to the brain. Brain metastasis and LM are a significant cause of high morbidity and mortality rates for patients with advanced malignancies. Paradoxically, current cancer treatment strategies may lead to increased incidence of CNS metastasis. Better management of cancer patients, improved survival and exposure to radiation therapy and chemotherapy may select for expansion of resistant clones, making brain metastasis and LM more aggressive. Many anti-neoplastic agents have limited CNS and CSF distribution due to blood brain and blood CSF barriers, potentially making brain and leptomeningeal space protected sites for cancer cells that have escaped therapies. Treatment of metastatic diseases in the CNS is complicated and involves maintaining a balance of treating systemic, metastatic cancers, and improvement of neurological symptoms.

However, despite current treatment approaches, the aggressive growth of metastatic cancers in the CNS still remains a devastating and frequently lethal late complication in cancer patients. Therefore, brain metastasis and LM represent a significant barrier to improvement in the prognosis of patient population which has achieved better diseases control and longer survival. The daunting challenge of CNS metastasis requires a multi-faceted approach to improve the clinical outcomes for cancer patients. Though CSF cytology is currently used for diagnosis of LM and assessment of treatment response, its sensitivity is relatively low. Specific and sensitive biomarkers of LM are needed to allow for earlier diagnosis and treatment. Therapies that effectively address both the systemic cancers and CNS metastasis are necessary. The cascade of molecular and cellular events underlying the development of brain metastasis and LM is gradually being unraveled. Targeted therapeutic reagents are being pursued that sufficiently reach the brain and CSF. The development and validation of accurate animal models that recapitulate metastasis in the CNS is a vital part of our efforts to test newer diagnostic and therapeutic approaches. Nevertheless, there is much work to be accomplished to address the dismal consequences for patients with brain metastasis and LM.

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