Article Test

Introduction
Leptomeningeal Carcinomatosis (LC) was first described in the late 19th century 1,2, however its pathogenesis details were only elucidated recently. Like the pathophysiology of brain metastases, a multistep biological process also leads to LC, in which tumor cells must leave the primary tumor, travel through the vasculature and then reach a location where they can traverse into the CSF, widely known as seed and soil hypothesis3. Within the Cerebral Spinal Fluid (CSF), tumor cells upregulate the production of complement system (mainly c3), leading to disruption of the Blood Brain Barrier (BBB) and entry of plasma growth factors into CSF, promoting uncontrolled cell growth4. Leptomeningeal carcinomatosis is occasionally a terminal event for several solid tumors, with no efficacy treatment so far. According last EANO/ESMO  guidelines,  patients  with  metastatic solid tumors have a lifetime risk of developing leptomeningeal metastasis (LM) around 10% and contrastingly, CNS metastases reflects a median overall survival (mOS) of approximately 12 months while patients having LC are limited to 3 months5.

Lung cancer is generally accepted as the most frequent cause of metastatic brain tumors (followed by breast and melanoma). It accounts for 30% to 60% of all brain metastases and occurs in 17% to 65% of patients with primary lung cancer6,7. Up to 5% of lung cancer patients might have LC, particularly in those with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements8. Small cell lung cancer and adenocarcinoma are the most identified sources of brain metastases9,10. Current management of LC requires an individualized multidisciplinary approach including surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, more recently, immunotherapy10. The literature suggests better outcomes for patients with driver gene alterations such as EGFR mutations and ALK translocation when treated with target therapy.

Intrathecal chemotherapy is broadly prescribed in this scenario in attempt to reach symptoms control. To date, only weak evidence is available, diverging in terms of clinical outcomes11,12. In an attempt to elucidate this dilemma, real world data acquired from multicentric institutions could shed light on this issue. Our data were compiled into TriNetX13 database by its software to describe the current patterns of treatment among lung cancer patients with leptomeningeal carcinomatosis and its respective impact on overall survival.

Methods
All data analytics procedures were done using TriNetX13, a global federated health research network providing access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) across large healthcare organizations (HCOs). This study was done under a set of HCOs grouped into a network called Global Collaborative Network. This network included 101 HCO(s). The analysis process includes two main steps: 1) Defining the cohort through query criteria; 2) Setting up and running the analysis. Setting up the analysis requires definitions for the index event, outcomes criteria, and time frame.

Cohort selection
Two cohorts were selected to evaluate the effect of IC over patients harboring leptomeningeal carcinomatosis originated from lung cancer. Cohort 1 enrolled patients submitted to IC while Cohort 2 enrolled patients not receiving IC during their treatment pathway. Cohort 1 query criteria was run on the Global Collaborative Network with 101 HCOs queried, 31 of them provided patient data. The final cohort included 172 patients who matched the query criteria listed in the table 1. Cohort 2 query criteria was also run on the same Global Collaborative Network with 101 HCOs queried and 89 of them provided patient data. Query criteria were listed in the table 2. Flow diagram of patient and data selection were depicted in Consort 1.

Index Event & Time Window Definitions
Our analysis included outcomes that occurred in the time window that started 1 day after the first occurrence of the index event (described at table 1 and 2). The index event only included events that occurred up to 20 years ago. Patients whose index event occurred 20 years or more ago were excluded. In this analysis, 16 patients in Cohort 1 and 3,186 patients in Cohort 2 were excluded because they met the index event more than 20 years ago.

Survival Analysis
The Kaplan-Meier Analysis estimated probability of the outcome at a respective time interval. In order to account for the patients who exited the cohort during the analysis period, and therefore should not be included in the analysis, censoring was applied. In this analysis, patients were removed from the analysis (censored) after the last fact in their record. The output summary included: Patients in each Cohort (count of patients meeting query criteria); Patients with Outcome (of the patients in the cohort, count of patients that had the outcome in the time window); Median Survival (the number of days when the survival drops below 50%); and Survival Probability at End of Time Window (the % survival at the end of the time window). In addition, Log-Rank test, Hazard Ratio and test for proportionality were performed. Outcome definition and settings for the performed analyses are outlined in table 3.

Propensity Score Matching
Propensity score matching was performed on 34 characteristics. In the Demographics category patients were matched on Current Age, Age at Index, Female, Male, Not Hispanic or Latino, Hispanic or Latino, Unknown Ethnicity, Unknown Race, White, American Indian or Alaska Native, Asian, Black or African American characteristics. In the Medication category patients were matched on data of therapy administered during treatment pathway: carboplatin, paclitaxel, etoposide, bevacizumab, pembrolizumab, nivolumab, osimertinib, cisplatin, docetaxel, erlotinib, afatinib, alectinib, gefitinib, methotrexate, pemetrexed, cytarabine, cytarabine liposome and thiotepa. In the Genomic category patients were matched on EGFR, ALK, MET, TP53 and KRAS genetic profile. Characteristics of the cohorts before and after matching are summarized in the table 4.

Treatment pattern analysis
We performed an analysis for treatment pattern across those who received intrathecal chemotherapy. A line of treatment included any treatment taken within 1 days of the index event. The line of treatment finished after any of the following events: (1) When a new treatment appears in the patient record after the first day, (2) When a patient dies, (3) When a patient’s medical record ends and (4) When the analysis time window ends.

Results
Trinetx13 database comprises a total of 127,437,189 patients that were queried with aforementioned terms. Our analysis initiated with Cohort 1 represented by 172 patients and cohort 2 represented by 77,882 patients. After propensity score matching our cohort was reduced to Cohort 1

(N = 139) and cohort 2 (N = 139) with balanced characteristics (consort 1). The most relevant discrepancy that were not able to be balanced was MET mutation, cohort 1 (n= 10, 7,2%), cohort 2 (n=0, 0%) with p value of 0.001 standard difference of 0.394. Graphic 1 and Table 4

Risk analysis for the outcome of death were performed on the cohorts after propensity score matching, revealing a statistically significant increased risk among those receiving intrathecal chemotherapy during clinical pathway. Cohort 1 risk of  73.4%  and  cohort 2 risk  of  59.0%  (95% CI=0.034, 0.254; z= 2.536 p<0.011). Graphic 2 Kaplan - Meier survival analysis revealed a mOS of 109 vs 280 days between cohort 1 and 2, respectively (Survival probability at end of time window was 16.78% vs 22.43%). Log-Rank Test (x2=21.443, p 0.004, with a hazard ratio of 1.538, 95% CI = 1.148 – 2.060) Graphic 3.

Treatment pattern analysis revealed that among those receiving intrathecal chemotherapy (cohort 1), 62 patients or 38.2% of the cohort, a clinical pathway were not available on medical record. The most common treatment received by patients, irrespective of the sequence, were Methotrexate (42%), Cytarabine or Cytarabine liposomal (32%), combination of Methotrexate + Cytarabine (9%) and others (17%). Graphic 4 and 5. According to the sunburst diagram, graphic 6 supplement, the most common sequence of treatment received by patients were: first line methotrexate followed by second line cytarabine. Due to the reduced number of patients, we couldn’t compare the outcome of overall survival between treatments.

Discussion
Intrathecal chemotherapy has been historically adopted in patients harboring LC from lung cancers, however literature review highlights the controversial role of IC and currently it is not possible to describe a certain survival benefit or improvement in quality of life when IC is administered14. Our real word data analysis revealed that lung cancer patients receiving IC during their clinical pathway had inferior outcome regarding overall survival than those who were not submitted to this treatment modality, median overall survival was 109 days in intrathecal chemotherapy (cohort 1) and 280 days in those who did not received intrathecal chemotherapy (cohort 2), with a Hazard Ratio of 1.538 (95% CI 1.148 - 2.060) and log rank test providing a x2 of 8.462 with p=
0.004. This fact comes in consonance with some authors15,16 suggesting that addition of IC does not lead to survival benefit and is associated with an increased risk of neurotoxicity, confronting currently adopted protocols of IC for LC. It is noteworthy that our data were extracted from medical records in a retrospectively method and in despite of our efforts for cohort balancing with PSM with carefully selected terms of query, the results described in our study should be evaluated with caution and, treatment decision of indicating intrathecal chemotherapy must consider individual characteristics.

Comparisons among the efficacy of different IC protocols were not feasible due to insufficient number of patients in the cohorts, however methotrexate seems to be the most adopted drug. In fact, few trials that compared head-to-head IC agents revealed that, in mixed tumor types, response to Methotrexate (MTX) was superior  to  combined  MTX/Ara-C,  but  not statistically significant (61% v 45%; p > 0.10)17. However, combination of MTX and liposomal cytarabine was feasible in a small retrospective cohort18. Grossman and colleagues19 evaluated IC in 52 patients with mixed primary tumors, assigned to receive IC MTX or thiotepa, revealing a non- statistically difference in mOS (15.9 weeks vs 14.1 weeks; p = 0.36). Additionally, the benefits of IC (MTX or ARA-C) compared to physician-chosen systemic therapy has also been evaluated, revealing that IC can be omitted safely as it did not improve patient outcomes and increased treatment- related toxicity14. In contrast to systemic chemotherapy, the effectiveness of IC may be limited, with no effect on survival compared with other treatment modalities and even associated with an increased rate of therapy-associated complications20,21.

Our trial has not performed a cohort analysis with dual therapy (systemic and intrathecal) because our intent was to focus only in IC. Literature available revealed that patients who received IC liposomal cytarabine + conventional systemic therapy vs systemic therapy alone, the achieved mOS was 4.0 months in the control arm versus 7.3 months in the experimental arm (HR 0.85, 95% CI: 0.53–1.36; p=0.05), after adjusted, the differences were significant. However, the control arm was more heavily pretreated and systemic therapy was not standardized22. Additionally, IC thiotepa23 and IC MTX24 treatment combination was also tested, and some patients clearly had a long survival and authors suggests a clinical benefit. New drugs like pemetrexed were recently evaluated in a Chinese phase I/II trial, for EGFR mutated patients with LC who had failed targeted therapy; the clinical response was 84% (22 of 26 patients) although clinical promising, this approach needs to be confirmed in phase III trial25. Recently published phase I trial demonstrates that concurrent Intrathecal and intravenous administration of nivolumab was safe with preliminary evidence of clinical benefit in a subset of patients26. Controversies on immunotherapy approach of LC exists since CSF penetrability of immune checkpoint inhibitors are relatively low, associated with a dysfunctionaland paucicellular immune repertoire in the leptomeninges. These factors highlight the need for innovative strategies to amplify immunotherapeutic responses in the spinal fluid.

Several other therapeutically active strategies are under investigation in patients with brain and leptomeningeal metastases27, such as: Kirsten rat sarcoma viral oncogene homologue (KRAS) inhibitor adagrasib (NCT03785249); Lazertinib (third-generation EGFR-TKIs) in combination with amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity (NCT04965090); Tucatinib, a third- generation reversible and highly selective HER2 inhibitor (NCT03501979); HER2 antibody-drug conjugates, trastuzumab deruxtecan (T-DXd) (NCT04420598) and HER2 chimeric antigen receptor (CAR) T cells (NCT03696030). In our cohort only few patients has been treated with any target therapy and once this therapy were not delivered intrathecal, this analysis was not formally tested, however this group of patients might have better outcomes. Particulary targeting EGFR, the phase I BLOOM trial28, in patients with LC pre- treated with a first or a second-generation tyrosine kinase inhibitor, meaningful outcomes were achived with 160mg of Osimertinib. LC response rate and duration of response by neuroradiologic BICR were 62% and 15.2 months, respectively. Median overall survival was 11.0 months.

CSF Tumor cell clearance in CSF was achieved 28% of the patients (11 of 40 patients). Exposure to osimertinib-containing regimens (a known drug of higher CFS penetration), prior to development of LC, probably influence the natural history of LC disease with longer mOS independent of the systemic therapy administered after LC diagnosis29, although more studies are required to clarify the Osimertinib high-dose usefulness in more advanced lines. Moreover, the combination of trametinib (MEKi, mitogen-activated protein kinase/ extracellular-signal-regulated kinase inhibitor) and osimertinib, to resensitize cells that become resistant to osimertinib are currently under evaluation30. Anaplastic lymphoma kinase gene rearrangement inhibitors (ALKi – Ceritinib; Brigatinib), has shown encouraging results in terms of disease control and survival31,32. Currently limited data are available regarding the use of immunotherapy in LC, however some case reports revealed promising results and phase I trial results were published26 with a mOS of 4.9 months. Cancer Immunotherapy combinatorial strategies are under investigation for patients with LC, such as combination with Whole Brain Radiotherapy (NCT03719768), the multi-kinase VEGFR inhibitor lenvatinib (NCT04729348), encorafenib and binimetinib (NCT04511013), and EGFR inhibition (NCT04833205).

Two systematic reviews33,34  highlighted the scarcity of high-quality data regarding the benefit of IC, and it is consensus that more accurate predictive and prognostic tools are required to improve treatment and to wisely choose those who benefit from IC approach. In 2017, the EANO- ESMO Clinical Practice Guidelines proposed a classification of LC in solid tumors. Type I (confirmed LC), verified cytologically or histologically and type II (probable or possible LC), based on the presence of clinical signs and neuroimaging6. The prognostic value of this classification was assessed in a retrospective study with better results for patients with type II LC compared to type I LC (median OS 4.5    months versus 2.4 months, respectively).

Currently, the only response predictors in routine clinical practice during intrathecal therapy are: (i) CSF cytology clearance by 8 weeks35, and (ii) serial MRI imaging, generally assessed 2 to 3 months following initiation of treatment5. Additionally, the administration of intrathecal, but also of systemic pharmacotherapy was associated with significantly increased survival only in type I LC, although the number of patients with type II were lower and there was a trend towards better survival with systemic pharmacotherapy36. One limitation of our study was the software analytical methodology not being able to provide clinical data for classification and stratification of LC according EANO-ESMO guideline. Various diagnostic tools and therapeutic efforts are currently under development aiming to improve survival as well as quality of life for patients with LC37. Cell-free tumor DNA (ctDNA) in the CSF for the diagnosis and characterization of actionable genomic alterations and monitor responses to therapy in patients with LC seems to be a valuable one38.

Conclusion
According to our data and due to conflicting evidence from literature review, intrathecal chemotherapy seems to add relevant toxicity without evident clinical benefit and should be cautiously indicated considering individual clinical, radiological and pathological characteristics. The therapeutic strategy cannot ignore a prognostic evaluation and multidisciplinary discussion and IC must not be adopted as a general protocol for every patient with lung cancer that evolves with leptomeningeal carcinomatosis. Tailored treatment according with genetic alterations might enhance efficacy in this scenario, especially for adenocarcinomas with LC. There is an urgent need of clinical practice implementation and validation of prognostic scores, such as EANO- ESMO, to properly select a subgroup of patients that could benefit. Prospective randomized controlled trials could pave the way for a definitive treatment guideline over this tragic disease evolution that carries one of the worst prognoses in oncology literature.

Conflicts of Interests Statement
The authors declare no conflicts of interests.
Funding Statement
The authors declare no funding sources for this study.
Acknowledgements
The authors are thankful to Gema Hernández Ibarburu, PhD - TriNetX Senior Data Expert and Healthcare Partnership Manager EMEA, TriNetX, LLC for supporting our research and to William Soares dos Santos - TriNetX Regional Director, LATAM region.

References
1.    Eberth CJ. Zur Entwickelung des Epithelioms (Cholesteatoms) der Pia und der Lunge. Arch für Pathol Anat und Physiol und für Klin Med. 1869;49(1):51–63. doi: 10.1007/BF02214196.
2.    Palma JA, Fernandez-Torron R, Esteve-Belloch P, et al. Leptomeningeal carcinomatosis: prognostic value    of    clinical,    cerebrospinal    fluid,    and neuroimaging features. Clin Neurol Neurosurg. 2013;115(1):19-25. doi:10.1016/j.clineuro.2012.03.048
3.    Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol. 2002;3(1):53- 57. doi:10.1016/s1470-2045(01)00622-2
4.    Boire A, Zou Y, Shieh J, Macalinao DG, Pentsova E, Massagué J. Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell. 2017;168(6):1101-1113.e13. doi:10.1016/j.cell.2017.02.025
5.    Le Rhun E, Weller M, Brandsma D, et al. EANO- ESMO Clinical Practice Guidelines for diagnosis, treatment    and    follow-up    of    patients    with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017;28(suppl_4):iv84-iv99. doi:10.1093/annonc/mdx221
67. Franchino F, Rudà R, Soffietti R. Mechanisms and Therapy for Cancer Metastasis to the Brain. Front Oncol. 2018;8:161. Published 2018 May 24. doi:10.3389/fonc.2018.00161
7.    Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865-2872. doi:10.1200/JCO.2004.12.149
8.    Wang Y, Yang X, Li NJ, Xue JX. Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment. Lung Cancer. 2022;174:1-13. doi:10.1016/j.lungcan.2022.09.013
9.    Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am. 2011;22(1):1-v. doi:10.1016/j.nec.2010.08.007
10.    Wang N, Bertalan MS, Brastianos PK. Leptomeningeal metastasis from systemic cancer: Review and update on management. Cancer. 2018;124(1):21-35. doi:10.1002/cncr.30911
11.    Ozcan    G,    Singh    M,    Vredenburgh    JJ. Leptomeningeal Metastasis from Non-Small Cell Lung Cancer and Current Landscape of Treatments. Clin Cancer Res. 2023;29(1):11-29. doi:10.1158/1078-0432.CCR-22-1585
12.    Ferguson SD, Bindal S, Bassett RL Jr, et al. Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD). J Neurooncol. 2019;142(3):499-509. doi:10.1007/s11060-019-03121-2t
13.    ©2023 TriNetX, LLC All Rights Reserved. The data used in this study was collected on April, 06th, 2023, from the TriNetX Global Collaborative Network, which provided access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) from approximately 127 million patients from 101 healthcare organizations. Acessed April 06, 2023. https://live.trinetx.com/
14.    Glitza IC, Haymaker C, Bernatchez C, et al. Intrathecal Administration of Tumor-Infiltrating Lymphocytes Is Well Tolerated in a Patient with Leptomeningeal Disease from Metastatic Melanoma: A Case Report. Cancer Immunol Res. 2015;3(11):1201-1206. doi:10.1158/2326- 6066.CIR-15-0071
15.    Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer. 2004;40(18):2726-2733. doi:10.1016/j.ejca.2004.08.012
16.    Niwińska A, Rudnicka H, Murawska M. Breast cancer leptomeningeal metastasis: the results of combined    treatment    and  the    comparison    of methotrexate and liposomal cytarabine as intra- cerebrospinal fluid chemotherapy. Clin Breast Cancer. 2015;15(1):66-72. doi:10.1016/j.clbc.2014.07.004
17.    Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol. 1987;5(10):1655- 1662. doi:10.1200/JCO.1987.5.10.1655
18.    Scott BJ, van Vugt VA, Rush T, et al. Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study. J Neuroonco l. 2014;119(2):361-368.    doi:10.1007/s11060- 014-1486-2
19.    Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective    comparison    of        intraventricular methotrexate        and    thiotepa    in        patients    with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol. 1993;11(3):561-569. doi:10.1200/JCO.1993.11.3.561
20.    Orlando L, Curigliano G, Colleoni M, et al. Intrathecal chemotherapy in carcinomatous meningitis from breast cancer. Anticancer Res. 2002;22(5):3057-3059.
21.    Jo JC, Kang MJ, Kim JE, et al. Clinical features and outcome of leptomeningeal metastasis in patients with breast cancer: a single center experience.    Cancer    Chemother    Pharmacol. 2013;72(1):201-207.    doi:10.1007/s00280-013-2185-y
22.    Le Rhun E, Wallet J, Mailliez A, et al. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro Oncol. 2020;22(4):524-538. doi:10.1093/neuonc/noz201.
23.    Comte A, Jdid W, Guilhaume MN, et al. Survival of    breast    cancer    patients    with    meningeal carcinomatosis treated by intrathecal thiotepa. J Neurooncol. 2013;115(3):445-452. doi:10.1007/s11060-013-1244-x
24.    Yoshida S, Morii K. Intratechal chemotherapy for patients with meningeal carcinomatosis. Surg Neurol. 2005;63(1):52–55. doi: 10.1016/j.surneu.2004.06.011.
25.    Fan C, Zhao Q, Li L, et al. Efficacy and Safety of    Intrathecal    Pemetrexed    Combined        With Dexamethasone    for    Treating        Tyrosine    Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC-a Prospective, Open-Label, Single-Arm Phase 1/2 Clinical Trial. J Thorac Oncol. 2021 Aug;16(8):1359-1368. doi: 10.1016/j.jtho.2021.04.018. Epub 2021 May 11. PMID: 33989780.
26.    Glitza Oliva IC, Ferguson SD, Bassett R Jr, et al. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Nat Med. 2023;29(4):898-905. doi:10.1038/s41591-022-02170-x
27.    Wilcox JA, Boire AA. Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases. CNS Drugs. 2023;37(1):45-67. doi:10.1007/s40263-022-00975-5
28.    Yang JCH, Kim SW, Kim DW, et al. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin    Oncol.    2020;38(6):538-547. doi:10.1200/JCO.19.00457
29.    Merkhofer CM, Eastman B, Densmore I, Halasz LM, McGranahan T, Baik C. Systemic Treatment Patterns and Outcomes in Patients With EGFR Mutated    Non-small    Cell        Lung        Cancer    and Leptomeningeal    Disease.    Clin    Lung    Cancer. 2022;23(5):446-455. doi:10.1016/j.cllc.2022.03.013
30.    Fukuda K, Otani S, Takeuchi S, et al. Trametinib overcomes    KRAS-G12V-induced    osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer. Cancer Sci. 2021;112(9):3784-3795.
doi:10.1111/cas.15035
31.    Chow LQM, Barlesi F, Bertino EM, et al. ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges. Clin Cancer Res. 2022;28(12):2506-2516. doi:10.1158/1078- 0432.CCR-21-1838
32.    Gaye E, Geier M, Bore P, et al. Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis. Lung Cancer. 2019;133:1-3. doi:10.1016/j.lungcan.2019.04.013
33.    Dudani S, Mazzarello S, Hilton J, et al. Optimal Management of Leptomeningeal Carcinomatosis in Breast Cancer Patients-A Systematic Review. Clin Breast Cancer. 2016;16(6):456-470. doi:10.1016/j.clbc.2016.07.014
34.    Lee YC, Hsieh CC, Chuang JP, Li CY. The necessity of intrathecal chemotherapy for the treatment    of    breast    cancer    patients    with leptomeningeal metastasis: A systematic review and pooled analysis. Curr Probl Cancer. 2017;41(5):355-370. doi:10.1016/j.currproblcancer.2017.07.001
35.    Clatot F, Philippin-Lauridant G, Ouvrier MJ, et al. Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy. J Neurooncol. 2009;95(3):421-426. doi:10.1007/s11060-009-9940-2
36.    Le Rhun E, Devos P, Weller J, et al. Prognostic validation and clinical implications of the EANO ESMO classification of leptomeningeal metastasis from solid tumors [published correction appears in Neuro    Oncol.    2021    Jul    23].    Neuro    Oncol. 2021;23(7):1100-1112. doi:10.1093/neuonc/noaa298
37.    Thakkar JP, Kumthekar P, Dixit KS, Stupp R, Lukas RV. Leptomeningeal metastasis from solid tumors. J Neurol    Sci.    2020;411:116706. doi:10.1016/j.jns.2020.116706
38.    Fitzpatrick A, Iravani M, Mills A, et al. Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis. Clin Cancer Res. 2022;28(6):1180-1191. doi:10.1158/1078- 0432.CCR-21-3017.

SUPPLEMENTARY MATERIAL