Lung Cancer with Leptomeningeal Carcinomatosis – Does intrathecal chemotherapy has a role? A Real Word Data approach using Trinetx
Main Article Content
Abstract
Background: Lung cancer is one of the neoplasms that most frequently spreads to the meninges and currently there is no consensus or standard management of this condition. Intrathecal chemotherapy (IC) has been adopted as an attempt to reach disease control, however real-world data regarding the efficacy of this therapeutic approach is yet to be described in literature.
Aim: To evaluate the impact of intrathecal chemotherapy on overall survival (OS) of patients with lung cancer and leptomeningeal carcinomatosis in a contemporary and real-world setting.
Methods: Our study was performed by using TriNetX, a global health network dataset of electronic medical records of patients from 101 healthcare organizations around the world. We queried for patients with specific terms between January 2003 and March 2023 and performed a propensity score matching (PSM) analysis for cohort balancing. Cohort 1 enrolled patients submitted to IC while cohort 2 enrolled patients not receiving IC during their treatment pathway. OS was estimated by Kaplan–Meier and log-rank test was applied.
Results: After initial query and propensity score matching, 139 patients were selected in each cohort. Methotrexate (42%) and Cytarabine (32%) were the most frequent treatment received by patients and the most common sequence of treatment that patients followed during their treatment pathway. Median overall survival was 109 days in intrathecal chemotherapy (cohort 1) and 280 days in those who did not receive 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.
Conclusions: In despite of the limitations inherent of a real-world data analysis, our study revealed that intrathecal chemotherapy had a detrimental effect on overall survival with increased risk of death among lung cancer patients having leptomeningeal carcinomatosis.
Article Details
How to Cite
CHA, Teixeira; JC, Betiol.
Lung Cancer with Leptomeningeal Carcinomatosis – Does intrathecal chemotherapy has a role? A Real Word Data approach using Trinetx.
Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4041>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i7.1.4041.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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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
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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
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