Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy

Abstract

Melanoma frequently metastasizes to the brain, with CNS involvement being clinically evident in ∼30% of patients (as high as 75% at autopsy). In ∼5% cases melanoma cells also metastasize to the leptomeninges, the sub-arachnoid space and cerebrospinal fluid (CSF). Patients with leptomeningeal melanoma metastases (LMM) have the worst prognosis and are characterized by rapid disease progression (mean survival 8-10 weeks) and a death from neurological causes. The recent years have seen tremendous progress in the development of targeted and immune therapies for melanoma that has translated into an increased survival benefit. Despite these gains, the majority of patients fail therapy and there is a suspicion that the brain and the leptomeninges are a "sanctuary" sites for melanoma cells that escape both targeted therapy and immunologic therapies. Emerging evidence suggests that (1) Cancer cells migrating to the CNS may have unique molecular properties and (2) the CNS/leptomeningeal microenvironment represents a pro-survival niche that influences therapeutic response. In this Mini-Review, we will outline the clinical course of LMM development and will describe how the intracranial immune and cellular microenvironments offer both opportunities and challenges for the successful management of this disease. We will further discuss the latest data demonstrating the potential use of BRAF inhibitors and immune therapy in the management of LMM, and will review future potential therapeutic strategies for the management of this most devastating complication of advanced melanoma.

Keywords: BRAF; brain; immunotherapy; leptomeninges; melanoma.

Figure 1. The anatomy of the CNS and leptomeninges

A). Representative figure of the head and neck showing the brain, meninges and the placement of the Ommaya reservoir into the ventricles. B). High powered representation of the leptomeninges showing the relationship of the arachnoid mater, pia mater and brain parenchyma. Note the CSF is found between the two layers of the dura and within the sub-arachnoid space.

Figure 2. MRI imaging of leptomeningeal disease

A). MRI image of a 46-year-old man with metastatic melanoma (BRAF V600E mutant) on his left upper back that was resected in 2011. In 12/2014 after developing fatigue, fevers, abdominal pain and syncope, he was found to have multiple masses in his liver and subcutaneous masses. He was started on dabrafenib/trametinib and shortly thereafter, he presented with headaches. An MRI brain demonstrated extensive supratentorial and infratentorial leptomeningeal carcinomatosis with involvement of the cranial nerves and mild hydrocephalus. Enhancement is seen on the surface of the brain on the surface of the gyri (blue arrow) and deep within the sulci (red arrows). He had an Ommaya reservoir placed and was treated with IT Thiotepa followed by whole brain radiation therapy. Cytology was diagnostic for malignancy. B). MRI image of the spine of a 44 year old man who was successfully treated for metastatic melanoma in his lungs with Ipilimumab. Four years later he had a small brain metastasis and had SRS. Six months later he had back pain and a MRI showed characteristic findings of LMM. There is a small nodule in the cauda equina (orange arrow), an accumulation of enhancing tumor in the thecal sac (red arrow), and fine linear enhancement on the ventral and dorsal surfaces of the spinal cord (blue arrow). His cytology was positive for malignant cells. He was treated with intrathecal thiotepa and local RT to his LS spine.