Abstract
Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.
Highlights
Leptomeningeal metastases (LM) result from metastatic infiltration of the leptomeninges by malignant cells originating from an extrameningeal primary tumor site that may be extraneural or intraneural
The use of newer targeted therapies with poor central nervous system (CNS) penetration such as trastuzumab (Herceptin used for her2/neu positive cancers) and rituximab (Rituxan used for B‐cell malignancies) is another factor that contributes to an increased incidence of LM.[9,131,168,212]
The majority of clinical trials in LM have utilized a combination of Cerebrospinal fluid (CSF) cytology and clinical response to determine success of LM‐directed treatment
Summary
Leptomeningeal metastases (LM) result from metastatic infiltration of the leptomeninges by malignant cells originating from an extrameningeal primary tumor site that may be extraneural (most common) or intraneural (less common). Surgical resection of parenchymal cerebellar metastases has purportedly resulted in subsequent development of LM.[82,205,245] Resection of a supratentorial brain metastasis that violates the ventricular system appears to increase the risks of developing LM.[3,82,96,285] The presumed mechanism in both instances likely is spillage of cancer cells directly into CSF and subsequent dissemination Another important factor contributing to an increased incidence of LM is more effective systemic therapy, both adjuvant and salvage, leading to a prolongation of survival and late metastatic spread to the CNS. Tumor cells in the subarachnoid space are not adequately treated by systemic cytotoxic therapy and may escape cytotoxic effects of systemic therapy and proliferate as previously observed in acute leukemia prior to the introduction of CNS‐directed therapy
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