- •Around 20% of the patients with leptomeningeal disease (LMD) received no treatment.
- •The presence of a BRAF mutation seems to be higher in patients with LMD.
- •At diagnosis of LMD, most of the patients had concomitant brain metastases.
- •The prognosis of LMD remains poor with a median overall survival of 2.9 months.
The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients.
We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019.
In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0–91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7–4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4–4.9).
Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.
Abbreviations:CI (confidence interval), CR (complete response), CSF (cerebrospinal fluid), ctDNA (circulating tumor DNA), DCR (disease control rate), ECOG (Eastern Cooperative Oncology Group), HR (hazard ratio), ICB (immune checkpoint blockade), LDH (lactate dehydrogenase), LMD (leptomeningeal disease), MRI (magnetic resonance imaging), ORR (overall response rate), OS (overall survival), PD (progressive disease), PD-1 (anti-programmed cell death 1), PFS (progression-free survival), PR (partial response), RANO (Response Assessment in Neuro-Oncology), SD (stable disease), TT (targeted therapy)
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- Carcinomatous meningitis: leptomeningeal metastases in solid tumors.Surg Neurol Int. 2013; 4: S265-S288
- Neoplastic meningitis due to lung, breast, and melanoma metastases.Cancer Control. 2017; 24: 22-32
- Therapy of leptomeningeal metastasis in solid tumors.Canc Treat Rev. 2016; 43: 83-91
- Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features.Neuro Oncol. 2008; 10: 199-207
- Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD).J Neuro Oncol. 2019; 142: 499-509
- Leptomeningeal metastasis in melanoma: a prospective clinical study of nine patients.In Vivo. 2012; 26: 1079-1086
- Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2.ESMO open. 2018; 3 (e000283)
- Leptomeningeal disease in melanoma patients: an update to treatment, challenges, and future directions.Pig Cell Melanoma Res. 2020; 33: 527-541
- Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516
- Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.Lancet Oncol. 2014; 15: 323-332
- Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723
- Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526
- Pooled analysis of llong-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.J Clin Oncol. 2015; 33: 1889-1894
- Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34
- Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356
- Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study.Lancet Oncol. 2018; 19: 672-681
- Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma.Ann Oncol. 2016; 27: 1138-1142
- Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study.Ann Oncol. 2017; 28: 634-641
- A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.J Chron Dis. 1987; 40: 373-383
- New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.J Natl Cancer Inst. 2000; 92: 205-216
- The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal.Neuro Oncol. 2019; 21: 648-658
- Leptomeningeal metastases: a RANO proposal for response criteria.Neuro Oncol. 2017; 19: 484-492
- Neoplastic meningitis: how MRI and CSF cytology are influenced by CSF cell count and tumor type.TheScientificWorldJOURNAL. 2013; 2013: 248072
- Prognostic validation and clinical implications of the EANO ESMO classification of leptomeningeal metastasis from solid tumors.Neuro Oncol. 2020; https://doi.org/10.1093/neuonc/noaa298http://www.ncbi.nlm.nih.gov/pubmed/33367859Date: 2020Date accessed: December 23, 2020
- Long-term stabilization of leptomeningeal disease with whole-brain radiation therapy in a patient with metastatic melanoma treated with vemurafenib: a case report.Melanoma Res. 2013; 23: 175-178
- Vemurafenib in leptomeningeal carcinomatosis from melanoma: a case report of near-complete response and prolonged survival.Melanoma Res. 2016; 26: 312-315
- Vemurafenib for leptomeningeal melanomatosis.J Clin Oncol. 2013; 31: e173-e174
- Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab.J Neurol. 2012; 259: 1976-1978
- Rapid resolution of leptomeningeal disease with targeted therapy in a metastatic melanoma patient.J Neuro Oncol. 2017; 133: 663-665
- Combined nivolumab and ipilimumab in melanoma metastatic to the brain.N Engl J Med. 2018; 379: 722-730
- Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 863-873
- J Clin Oncol. 2020; 38 (suppl; abstr 10008)https://doi.org/10.1200/JCO.2020.38.15_suppl.10008
- Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery.J Neurosurg. 2013; 119: 457-462
- Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.Lancet Oncol. 2014; 15: 387-395
- Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade.Eur J Canc. 2018; 99: 58-65
- Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup.J Natl Cancer Inst. 2007; 99: 112-128
- Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials.Lancet Oncol. 2003; 4: 748-759
- Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.Eur J Canc (Oxford, England: 1990). 2019; 110: 11-20
- Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma.Br J Canc. 2014; 111: 292-299
- Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases.Canc Discov. 2019; 9: 628-645
- Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target.Clin Canc Res. 2014; 20: 5537-5546
- Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.Canc Med. 2013; 2: 76-85
- Evaluating circulating tumor DNA from the cerebrospinal fluid of patients with melanoma and leptomeningeal disease.J Neuropathol Exp Neurol. 2018; 77: 628-635
- Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma.Nat Commun. 2015; 6: 8839
- Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases.J Neuro-oncol. 2016; 128: 93-100
Published online: March 28, 2021
Accepted: February 3, 2021
Received in revised form: February 1, 2021
Received: November 13, 2020
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