Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies

Abstract

BACKGROUND: Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed. METHODS: In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and timedependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS. RESULTS: Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months (95% CI, 7.9-11.3 months). Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months [95% CI, 10.47-17.06 months] vs 7.0 months [95% CI, 6.1-8.3 months]; P = .0003). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination (P < .0001), increasing numbers of brain metastases at diagnosis (P < .0001), earlier MBM diagnosis year (P = .0008), higher serum levels of lactate dehydrogenase (P < .0001), receipt of immunotherapy before MBM diagnosis (P = .003), and the presence of extracranial disease (P = .02). The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy (P = .01). CONCLUSIONS: The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM.

Cerebrospinal fluid diversion for leptomeningeal metastasis: palliative, procedural and oncologic outcomes

“…The survival of 3.63 months identified in even highly-symptomatic shunt-dependent patients with KPS > 60 compares favorably to that described in previously published all-comer LM cohorts [3,[5][6][7]10]. That year of LM diagnosis did not associate with differences in overall survival suggests that improving cancer outcomes generally [2,11,[23][24][25] have not yet translated into progress in LM survival, at least for the subpopulation requiring shunt placement. Procedures performed in this population must therefore have clear and defined outcomes that ethically qualify their potential harms and can be reviewed in goals of care discussions [22].…”

“…Metastatic spread to the leptomeningeal compartment and subarachnoid spaces of the brain, known as leptomeningeal metastasis (LM; also known as leptomeningeal disease or carcinomatous meningitis), occurs in 3-5% of patients with solid tumor malignancies [1]. LM incidence roughly mirrors that of the commonest central nervous system (CNS) parenchymal sources including non-small cell lung cancer (NSCLC), breast cancer, and melanoma, and its development is associated with poor prognosis and shortened survival on the scale of months [2][3][4][5][6][7][8][9][10][11]. Treatments are limited for these patients, in part due to clinical trial exclusion.…”

Decoding molecular programs in melanoma brain metastases

“…BMCs and conventional melanoma cell lines were kept at 37°C/ 5% CO 2 and 95% humidity in cell culture medium (DMEM, 4.5 g/L glucose, stabilized glutamine/GlutaMax, pyruvate, Gibo/ThermoFisher) supplemented with 10% fetal bovine (FBS, Gibco) serum and 1% penicillin/streptomycin (P/S) (Gibo/ThermoFisher). BMCs were kept at low passages (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and split according to their proliferative capacity (1:2-1:10) at a confluence of ~80 %. Cells were seeded onto glass 8-chamber slides to a density of 5,000-10,000 cells per chamber.…”

“…The time from initial diagnosis of primary tumors to the detection of BM ranges from 1-10 years, supporting the assumption of a slow evolutionary process of BM in 20 – 40% of melanoma patients 3, 14 . The median overall survival of melanoma patients after diagnosis of a BM (MBM) is 8.9 months 15 and is determined by the speed of intracranial progression that in turn depends on the efficacy of development of macrometastases and the response to therapeutic interventions.…”

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

“… 4 Historically, brain metastases have been regarded as a terminal disease stage harboring a poor prognosis with a median overall survival (OS) of 3 months with best supportive care or up to 6 months with whole brain radiation therapy and up to 8 months in selected patients undergoing surgical metastasis removal combined with adjuvant treatment. 1 , 4 , 5 In a subset of patients with good functional status and surgically accessible or symptomatic brain metastases, aggressive treatment—including craniotomy with neurosurgical resection followed by local irradiation and systemic treatment—is common practice. 4 , 5 , 6 However, there is a lack of specific and prospective randomized studies in the context of neurosurgically treated patients comparing different treatment options, including local therapy and systemic treatment using chemotherapy or immune checkpoint inhibitors (ICIs).…”