Treatment Of Leptomeningeal Metastases Research Articles

Efficacy and safety of osimertinib for leptomeningeal metastases from EGFR-mutant non-small cell lung cancer: a pooled analysis

BackgroundThe aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).MethodsWe conducted a systematic review and meta-analysis to aggregate the clinical outcomes of patients with LM from EGFR-mutant NSCLC treated with osimertinib. A comprehensive literature search for published and unpublished studies was implemented in April 2021 of PubMed, EMBASE, the Cochrane Library, and several international conference databases, in accordance with the PRISMA guidelines. Meta-analysis of proportions was conducted to calculate the pooled rate of overall response rate (ORR), disease control rate (DCR), one-year overall survival (OS), and adverse events (AEs).ResultsA total of eleven studies (five prospective and six retrospective) including 353 patients were included. The majority of patients (346/353, 98.0%) received osimertinib as ≥ 2nd-line treatment for LM, either at a dosage of 80 mg (161/353, 45.6%) or 160 mg (191/353, 54.1%). The pooled rates of ORR and DCR were 42% (95% CI 24% to 59%) and 93% (95% CI 88% to 97%), respectively. The pooled one-year OS rate was 59% (95% CI 53% to 65%) in 233 patients from five studies. The highest incidence of AEs of all grades was rash (53%), followed by diarrhea (45%), paronychia (35%), decreased appetite (35%), and dry skin (27%), based on data from four studies.ConclusionsOur study highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM from EGFR-mutant advanced NSCLC.

The Riddle of the Sphinx: Progress in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer.

Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC), and the incidence of LM has been increasing yearly in recent times. There is no consensus on the best treatment modality for LM, which underscores a difficult problem in the management of advanced NSCLC patients. The existing treatments include molecular targeted therapy, systemic chemotherapy, local radiotherapy, antivascular tumor therapy, intrathecal chemotherapy, and immunotherapy, but their efficacy is not satisfactory. In this article, we briefly describe the clinical manifestations, diagnosis, and treatment of NSCLC-LM and discuss progress regarding evaluation of the efficacy of LM treatment to better provide a necessary reference for clinical practice and clinical trial evaluation.

Investigation of Methods and Influencing Factors to Increase the Positive Rate of Cytological Pathology of Cerebrospinal Fluid from Lung Cancer Leptomeningeal Metastases

In advanced non-small cell lung cancer (NSCLC), leptomeningeal metastases (LM) is a common consequence with rapid progression and a poor prognosis. LM affects roughly 3% to 5% of NSCLC patients, and it affects as many as 9.4% of individuals with epidermal growth factor receptor (EGFR) mutations. Cerebrospinal fluid cytology is the gold standard for diagnosing LM, while conventional cytopathology has a positive detection rate of less than 50%, resulting in a delay in diagnosis and treatment of LM. The fixation treatment of cerebrospinal fluid samples has a significant impact on the positive cytology detection rate, and how to improve the positive cytopathology detection rate of cerebrospinal fluid is a hot topic in clinical research. From June 2019 to November 2021, 105 cases diagnosed with LM based on clinical symptoms and positive imaging were collected and retrospectively evaluated in the second ward of the Department of Oncology of The Second Affiliated Hospital of Harbin Medical University. The effect of different fixation methods on the positive rate of cerebrospinal fluid cytopathology was investigated, and specimens of cerebrospinal fluid were collected and sent for examination using different delivery methods, including the application of the TIB cell preservation solution kit (experimental group) and the routine application of sterile plastic tubes in lumbar puncture bags (control group). Biochemical assays (glucose and total protein) were performed on the cerebrospinal fluid fluid, and Logistic regression analysis and receiver operating characteristic (ROC) curve were used to evaluate the supplementary diagnostic value for LM patients with lung cancer. The relevance of chemical indexes in the assessment of therapeutic efficacy was examined, and biochemical (glucose, total protein) indices and cytological changes in cerebrospinal fluid fluid after pemetrexed intrathecal injection therapy were dynamically monitored. In the control group, 24 (45.28%) patients were positive for the first time, while 42 (80.77%) patients were positive for the first time and 10 (19.23%) patients were negative for the first time in the experimental group. Significant differences existed between the two groups (P<0.001). The results of Logistic regression analysis of patients with the first cerebrospinal fluid biochemical test showed that the risk of positive cerebrospinal fluid biochemical pathology with less than 2.5 mmol/L was 2.456 times greater than 2.5 mmol/L of cerebrospinal fluid glucose (OR=2.456, P<0.05), and total cerebrospinal fluid biochemical protein greater than 430 mg/L was 2.647 times less than 430 mg/L (OR=2.647, P>0.05). The ROC curve showed glucose sensitivity of 76.9% in cerebrospinal fluid, the specificity of 54.5%, Youden index of 0.315 and area under the curve (AUC) of 0.620, total protein sensitivity in cerebrospinal fluid of 44.4%, 90.6%, Youden index of 0.350 and AUC of 0.671. After 2 cycles of pemetrexed intrathecal treatment with complete cerebrospinal fluid cytology and cerebrospinal fluid biochemical (glucose, total protein) tests in 73 and 50 patients, respectively, the rate of cerebrospinal fluid cytology turning negative was gradually increased. Cerebrospinal fluid glucose levels increased after 2 cycles of treatment compared with the first time, with a statistically significant difference (P<0.001). The use of a cell preservation solution kit to immediately fix cerebrospinal fluid samples following isolation in patients with clinical symptoms and positive imaging greatly enhances the rate of positive cerebrospinal fluid cytology detection. The effect of treatment can be assessed and predicted by continuous dynamic monitoring of cerebrospinal fluid biochemistry and cytology.

The Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA can Predict Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastasis

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is a devastating disease with poor survival. Proton craniospinal irradiation (pCSI) is a promising treatment for LM, and there is a need for biomarkers for patient selection. Understanding the genetic variation of LM pre- and post-pCSI can elucidate differences in response to radiotherapy. We analyzed the observed mutations in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) of LM patients treated with pCSI and explored whether the variant allele fraction (VAF) can predict survival. <h3>Materials/Methods</h3> We examined 14 patients from a phase I trial pCSI for solid tumor LM (NCT03281889) with pre- and post-pCSI ctDNA assessment. Mutations were identified using an institutional targeted-sequencing panel, MSK-IMPACT, and allele specific copy number variation was used to determine mutation clonality. Primary tumors or solid tumor metastases, and ctDNA in the plasma was also analyzed. VAF and cancer cell fraction (CCF) were calculated. An independent clinical sequencing cohort of 50 LM patients who did not receive pCSI was used for comparison. Kaplan Meier analysis was used to associate mutation measures and survival outcomes. <h3>Results</h3> The median overall survival for the cohort was 9 months (IQR: 5-21 months). The median number of mutations observed in the CSF ctDNA pre- pCSI was 10 (range:0-25) and post-pCSI was 9 (range:0-42). We observed the clonal evolution between solid tissue and ctDNA of the CSF and plasma, and we identified mutations that are unique by compartment, with more mutations seen in the CSF compared to plasma. A higher VAF pre-pCSI (VAF_pre) was associated with worse OS (8 months for VAF_pre≥0.32 [median] vs 21 months for VAF_pre<0.32, p=0.05). Patients with increased VAF after pCSI had significantly worse survival (6 months vs 18 months, p=0.008). The CCF of novel subclonal mutations after pCSI showed that higher values were associated with worse OS (8 months vs 17 months, p=0.05). In the comparison cohort, VAF≥0.37 [median] was associated with worse OS after CNS-directed RT (8 months vs 9 months, p=0.05). <h3>Conclusion</h3> In LM patients undergoing pCSI, there are unique baseline mutation profiles and distinct responses to pCSI that may be able to predict survival after radiotherapy. Analysis of the ctDNA of LM patients before and after pCSI shows that improved outcomes are associated with lower frequency of mutations. The quantification of these mutations has important implications for patient stratification in CNS-directed radiotherapy and escalation of therapy after pCSI.

EP08.02-050 A Retrospective Study of Aumolertinib in Combination with Bevacizumab for EGFR-mutated NSCLC with the Presence of Leptomeningeal Metastasis

Patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal metastasis (LM) have a poor prognosis. There is no standard treatment for LM with EGFRm NSCLC. Recently, EGFR tyrosine kinase inhibitors (TKIs) has been shown to be a potential therapeutic option for patients with EGFRm NSCLC and LM. Preclinical evidence shows that third-generation EGFR-TKIs, being investigated as a therapy for LM, have greater penetration of the blood-brain barrier compared with first- and second-generation treatment.

Advances in Diagnosis and Treatment of Leptomeningeal Metastasis of Lung Cancer

脑膜转移癌（leptomeningeal metastases, LM）是晚期肺癌中进展迅速、预后差的常见并发症。脑膜转移癌临床诊断率低，治疗手段有限，疗效差，自然生存时间短。脑脊液细胞学作为诊断脑膜转移癌的金标准，但是目前临床症状及影像学阳性的患者脑脊液首次细胞病理学阳性诊断率一般不超过50%，导致脑膜转移癌患者的诊断延迟、治疗延误。随着驱动基因阳性肺癌靶向治疗、驱动基因阴性肺癌免疫治疗的进展，肺癌患者生存期延长，但是脑膜转移癌发病率逐年增加，如何提高诊断率、寻找有效的治疗手段是目前临床研究的热点。本文就肺癌脑膜转移癌诊断及治疗研究进展予以综述。

Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review

Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.

Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis.

Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80-90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9months in Switch-TKI patients and 4.9months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Treatment Options for Leptomeningeal Metastases of Solid Cancers: Literature Review and Personal Experience.

Leptomeningeal metastases (LM) may complicate the clinical course of any solid cancer or hematological malignancy. Diagnosis of such cases requires a multifaceted approach, including careful evaluation of the clinical history, detailed neurological examination, advanced imaging studies, and related laboratory data analysis. Therapeutic options for management of LM have not been standardized yet. Conventional intrathecal chemotherapy with or without involved-field fractionated radiotherapy has only modest efficacy, and the prognosis of most patients remains grim. Therefore, development of new, more aggressive multimodal treatment strategies is definitely needed. Immune checkpoint inhibitors-in particular, molecular targeted therapy-have demonstrated promising results in selected groups of patients. There may be an important role for stereotactic radiosurgery as well. Because organization of prospective randomized multi-institutional trials on treatment of LM of solid cancers may be problematic, practical guidelines for optimal therapeutic strategies in such cases should be established on the basis of integrated results of small-scale prospective and retrospective studies.

NCMP-03. INTRATHECAL TRASTUZUMAB TREATMENT OF HER-2 POSITIVE LEPTOMENINGEAL BREAST CANCER: THE UNIVERSITY OF MICHIGAN EXPERIENCE

Abstract PURPOSE Breast cancer is the most common solid tumor to metastasize to the leptomeninges, affecting up to 5% of breast cancer patients. Overall survival for patients with leptomeningeal metastases (LM) is poor, with median survival of 4–6 months following diagnosis. There is limited data available on the efficacy of intrathecal (IT) trastuzumab in the treatment of Her-2 positive LM. METHODS A total of 30 patients with Her-2 positive breast cancer with LM treated at the University of Michigan from 2008–2020 were identified retrospectively. Of these, 13 patients were treated with IT trastuzumab beginning in June 2010 and followed through April 2020. Initial dose was 50–80 mg twice weekly for a minimum of 4 weeks, followed by slow taper. The 17 patients with Her-2 positive breast cancer with LM who did not receive IT trastuzumab served as control. RESULTS The median age of patients in the treatment group was 42 and 52 in the control group. Whole brain radiation therapy was received by 92% of patients in the treatment group and 76% in the control group. The median overall survival from diagnosis of LM to death was 20 months (interquartile range [IQR] 13–60 months) in the treatment group and 6 months (IQR 2–17 months) in the control group. Survival at 3 years and 5 years was 40% and 13%, respectively for the treatment group and 8% and 0% (no data available at 60 months), for the control group. Hazard ratio for death with IT trastuzumab 0.38 (95% CI 0.16–0.91, p=0.024). IT trastuzumab was overall well-tolerated (one patient developed meningitis, while another had shunt malfunction necessitating removal of the reservoir). CONCLUSIONS Patients with HER2+ LM who received IT trastuzumab demonstrated significantly improved OS compared to control with minimal toxicity.

Management of Drug Therapy for Leptomeningeal Metastasis of Sensitive Driver Gene Positive Non-small Cell Lung Cancer

脑膜转移（leptomeningeal metastasis, LM）是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）严重并发症之一，虽然发生率不高，但临床症状表现严重，预后差。驱动基因阳性NSCLC较驱动基因阴性患者更容易发生LM。目前，LM的治疗方法主要包括分子靶向治疗、系统化疗、全脑放疗、鞘内化疗及免疫治疗等。尽管治疗手段很多，但LM的疗效仍不令人满意。本文就敏感驱动基因阳性NSCLC LM的药物治疗方面作一综述。

Leptomeningeal Metastases in Non-small Cell Lung Cancer: Optimal Systemic Management in NSCLC With and Without Driver Mutations

As a devastating complication of non-small cell lung cancer (NSCLC), the incidence of leptomeningeal metastasis (LM) is rising, largely due to overall longer survival of NSCLC, especially in patients with targetable molecular driver mutations. There is no clear consensus on the optimal management of LM. This review will cover recent advances in diagnosis, monitoring, and treatment of LM in NSCLC. In LM without oncogene drivers, systemic chemotherapy, intrathecal therapy, and radiation have modestly improved the clinical outcomes. Emerging data have also suggested encouraging activity of immunotherapy. At the same time, in LM with sensitizing EGFR mutations, osimertinib should be considered regardless of T790M status. Pulse erlotinib, afatinib, and newer agents with improved CNS penetration have also shown benefits. Moreover, accumulating evidences support potential benefits of molecularly targeted therapy in ALK-rearranged and other oncogene-driven NSCLC with LM. Future studies are warranted to better define the underlying mechanism, to optimize the clinical management, and to improve patient outcomes.

Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer

PurposeThe CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration.MethodsCSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response.ResultsFifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0–200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2–3 months prior to changes seen on MRI, and while CSF cytology remained negative.ConclusionOur study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology.Trial Registration: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

Classification of Leptomeningeal Metastases from Solid Organ Malignancies and Clinical Outcomes: Series from a Cancer Research Centre.

Leptomeningeal metastases (LMs) are a critical neurological manifestation of solid organ malignancies. Early diagnosis and prompt treatment is necessary to improve outcomes. We classified LM on the basis of cytological or histological and imaging studies. A total of 14 patients of LM from solid organ malignancies diagnosed between July 2016 and December 2018 were included in the series. LM was classified based on cerebrospinal fluid (CSF) cytology and magnetic resonance imaging (MRI) findings. Survival outcomes were noted. LM from carcinoma of breast and lung accounted for most of the cases. Type I LM was seen in 12 patients while 2 accounted for type II LM. Median overall survival (OS) was 40.5days. Newer-generation tyrosine kinase inhibitor (TKI) therapy seems promising in the treatment of LM. Classification of LM based on cytology/histology and imaging findings allows early diagnosis and treatment. Newer-generation TKIs should be used for the treatment of LM if indicated.

Abstract OT2-01-02: TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in

Abstract Background: Treatment options for patients with leptomeningeal disease (LMD) from HER2-positive breast cancer (HER2+ BC) are limited, and the prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and notable early combinatory anti-tumor activity, including partial responses in heavily treated patients and those with parenchymal brain metastases (BM). Trial Design: This is a phase 2 single arm study to evaluate the efficacy of the combination of tucatinib plus trastuzumab (T) and capecitabine(C) in patients with HER2+ BC and newly diagnosed LMD. CNS disease will be evaluated at screening and every six weeks by MRI, CSF cytology, and neurological assessments according to RANO-LMD (adapted) and RANO-BM criteria. CT scans/PET-CT will evaluate extracranial disease according to RECIST criteria at screening and every 12 weeks. All patients will be followed for survival from the date of the last dose until death, lost to follow-up, or consent withdrawal. Symptom burden and quality of life assessments are conducted throughout the study. Blood and CSF sample collections occur at each cycle for the planned correlative analyses. Eligibility Criteria: Eligible patients are adults (&amp;gt;18 years old) with HER2+ BC, ECOG status&amp;lt;3/KPS&amp;gt;50, and newly diagnosed untreated LMD (defined as positive CSF cytology and/or radiographic evidence of LMD, plus clinical signs/symptoms. Patients with a history of treated BM or concurrent/new BM are allowed. Patients previously treated with tucatinib or capecitabine (within the last 12 months) are excluded. Specific Aims: The primary endpoint is OS. Secondary endpoints include safety, CNS PFS at 12 weeks, RR and CBR in CNS and extra-CNS disease, and symptom burden/quality of life. Statistical methods: This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, we define success to be CNS PFS for 12 weeks. An event will be considered to be either CNS progression or death from any cause before 12 weeks.We will stop enrollment if there are fewer than two successes in the first 15 patients. If the trial continues to completion, the regimen will be considered worthy of future study if the median overall survival is &amp;gt; 4.4 months. Study Accrual: The target accrual is 30 patients. The study is currently active at UAB and MDACC. Other TBCRC sites throughout the country are to be activated this year. Citation Format: Rashmi K Murthy, Barbara J O'Brien, Ken R Hess, Nick Navin, Jason Johnson, Maria Gule-Monroe, Jose P Leone, Jennifer Specht, Michelle Melisko, Aki Morikawa, Anna M Storniolo, Adam Brufsky, Paula R Pohlmann, Deric M Park, Ben H Park, Ian Krop, Nancy U Lin, Antonio Wolff, Andres Forerro-Torres, Erica Stringer-Reasor. TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-02.

Leptomeningeal metastasis from extracranial solid tumors

Background: Leptomeningeal metastasis (LM) is a dreaded complication associated with solid tumors which is increasing due to the advances in cancer-directed therapy. Proper diagnostic and treatment criteria are still not established for the handling of LM. This article aims to help outline a management plan for LM. Methods: A systematic review of the articles on LM and solid tumors was done in PubMed for the past 15 years and eligible articles were eligible articles were considered. The articles related to hematological malignancies and brain tumors were excluded. Results and Discussion: LM usually requires a strong suspicion based on the natural history of the disease and symptoms for diagnosis. Symptomatology, cerebrospinal fluid (CSF) examination, and magnetic resonance imaging aid in the diagnosis. The treatment involves a multimodal institution of intra-CSF therapy, systemic chemotherapy, craniospinal irradiation, and surgical interventions for relief of symptoms. The prognosis is usually poor despite treatment and expected survival is between 4 and 6 months. Conclusion: The different options for the treatment of LM should be discussed in a multidisciplinary clinic. The treatment must be decided based on the neurological and general health condition of the patient, previous lines of treatment, and the presence of other metastatic sites. The improvement of levels of evidence for the various therapeutic procedures for patients with LM requires dedicated trials.

Application of cerebrospinal fluid circulating cell-free DNA in the diagnosis and treatment of leptomeningeal metastases from non-small-cell lung cancer

Objective To investigate the application value of cerebrospinal fluid circulating cell-free DNA (cfDNA) in the diagnosis and treatment of leptomeningeal metastases in non-small-cell lung cancer (NSCLC). Methods Twenty-five patients with leptomeningeal metastases of NCSLC from Fudan University Huashan Hospital North during the period from September 2017 to November 2018 were enrolled. All 25 patients were confirmed leptomeningeal metastases by cerebrospinal fluid cytology and immunocytochemical staining of cytokeratin(CK7), carcinoembryonic antigen(CEA), thyroid transcription factor-1(TTF-1) and Ki67. The cerebrospinal fluid cfDNA was extracted and genetic variation of 12 genes including epidermal growth factor receptor(EGFR), TP53 and anaplastic lymphoma kinase(ALK) was detected by next-generation sequencing [PlasAim TM gene non-invasive detection of lung cancer (12 gene) kit, Singlera Genomics].The application value of cerebrospinal fluid cfDNA in the diagnosis and treatment of leptomeningeal metastases of NSCLC was analyzed with the cfDNA mutation data and the clinical follow-ups. Results Morphologically typical lung cancer tumor cells with tumor immunochemistry markerCK, CK7 and CEA were found in the cerebrospinal fluid of all 25 patients. Next generation sequencing of cerebrospinal fluid showed that 96% (24/25) patients had at least one single nucleotide variation (SNV) or copy number variation (CNV). The EGFR and TP53 mutations were identified in 80% (20/25) and 48%(12/25) of the patients, respectively. In addition, patients with bone metastases had a higher rate of EGFR mutations than those without bone metastases (100% vs 64%, P<0.05). Changes in the mutant allele frequency of EGFR and TP53 in cerebrospinal fluid were consistent with patients′ disease progression parameters including neurological symptoms, imaging, and tumor biomarkers. The results indicate that genetic alteration of EGFR in cerebrospinal fluid cfDNA is an actionable biomarker for targeted therapy of leptomeningeal metastases of lung cancer. Conclusion Cerebrospinal fluid cfDNA accurately reveals the unique genetic background of leptomeningeal metastasis in NSCLC, showing great application value in the diagnosis and treatment of the leptomeningeal metastasis of NSCLC. Key words: Carcinoma, non-small-cell lung; Neoplasm metastasis; Meningeal neoplasms; Cell-free nucleic acids; Cerebrospinal fluid; High-throughput nucleotide sequencing

Characteristics and prognosis of leptomeningeal metastasis in patients with breast cancer

Abstract Background The incidence of leptomeningeal metastasis (LM) in breast cancer is reported to be approximately 5% and prognosis of breast cancer patients with LM is poor. Characteristics and treatment for breast cancer with LM remain unclear. The objective of this study is to observe outcome of breast cancer patients with LM in the current background. Patients and methods: We retrospectively reviewed 84 breast cancer patients who were diagnosed with LM and received treatment for LM between 2005 and 2018 in our institution. LM was diagnosed by brain imaging and/or lumbar puncture with the presence of malignant cells in cerebrospinal fluid. Results: Median age at diagnosis of LM was 56.5 years (33-76). Thirty-nine (46%), 7 (8%), 12 (14%), and 24 (29%) were HR+/HER2-, HR+/HER2+, HR-/HER2+ and triple negative, respectively. Median time to LM from the diagnosis of distant metastasis was 66.6 months, and significantly longer in HR+/HER2+ compared with other subtypes (p

Use of Ommaya Reservoirs to Deliver Pemetrexed in Leptomeningeal Metastasis from Non-small Cell Lung Cancer: A Case Report and Review of the Literature

软脑膜转移（leptomeningeal metastasis, LM）是非小细胞肺癌（non-small cell lung cancer, NSCLC）最严重的并发症之一。随着靶向药物的发展，LM发病率逐年上升，目前缺乏标准有效的治疗方案。鞘内化疗是治疗LM的一种重要方法，但对于NSCLC伴LM，现有的经鞘内途径给化疗药物治疗效果有限，最佳的药物、给药途径、给药模式和剂量仍不清楚。本文报道1例NSCLC伴LM患者，经奥希替尼治疗病情进展后，予培美曲塞经Ommaya囊脑室内化疗，颅内病灶得到较好控制，脑脊液（cerebrospinal fluid, CSF）细胞学转为阴性，同时患者耐受良好，生活质量明显改善，病情长时间内维持稳定，从确诊LM后随访至今已17个月。本文报道了国内外第一例关于经Ommaya囊鞘内注射培美曲塞治疗NSCLC患者LM的临床案例，并结合相关文献总结了鞘内化疗的安全性及有效性，为临床提供了一种LM局部治疗的新策略。

LPTO-07. CARCINOEMBRYONIC ANTIGEN OF CEREBROSPINAL FLUID PREDICT PROGNOSIS OF LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

BACKGROUND: Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS: Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS: Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION: Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.